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APPLIED FEATURES

OUTSTANDING PEDAGOGY

Resources That Give Instructors and Students an Edge!

To Duejean She walks in beauty, like the night Of cloudless climes and starry skies; And all that’s best of dark and bright Meet in her aspect and her eyes.. .

And on that cheek, and o’er that brow, So soft, so calm, yet eloquent,

The smiles that win, the tints that glow, But tell of days in goodness spent, A mind at peace with all below, A heart whose love is innocent!

—Lord Byron

Copyright © 2015 by SAGE Publications, Inc. All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the publisher. Printed in Canada. Library of Congress Cataloging-in-Publication Data Garrett, Bob. Brain & behavior : an introduction to biological psychology / Bob Garrett ; contributions by Gerald Hough and John Agnew.—Fourth edition. pages cm Includes bibliographical references and index. ISBN 978-1-4522-6095–2 (pbk. : alk. paper) ISBN 978-1-4833-1241-5 (web pdf) 1. Psychobiology—Textbooks. I. Title. II. Title: Brain and behavior. QP360.G375 2014 612.8—dc23 2014007564 14 15 16 17 18 10 9 8 7 6 5 4 3 2 1

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Brief Contents

Preface

About the Author CHAPTER 1. What Is Biopsychology? PART I. Neural Foundations of Behavior: The Basic Equipment CHAPTER 2. Communication Within the Nervous System CHAPTER 3. The Organization and Functions of the Nervous System CHAPTER 4. The Methods and Ethics of Research PART II. Motivation and Emotion: What Makes Us Go CHAPTER 5. Drugs, Addiction, and Reward CHAPTER 6. Motivation and the Regulation of Internal States CHAPTER 7. The Biology of Sex and Gender CHAPTER 8. Emotion and Health PART III. Interacting With the World CHAPTER 9. Hearing and Language CHAPTER 10. Vision and Visual Perception CHAPTER 11. The Body Senses and Movement PART IV. Complex Behavior CHAPTER 12. Learning and Memory CHAPTER 13. Intelligence and Cognitive Functioning CHAPTER 14. Psychological Disorders CHAPTER 15. Sleep and Consciousness Glossary

References

Chapter-Opening Photo Credits

Author Index

Subject Index

Detailed Contents

Preface

About the Author

CHAPTER 1. What Is Biopsychology? The Origins of Biopsychology Prescientific Psychology and the Mind-Brain Problem Descartes and the Physical Model of Behavior Helmholtz and the Electrical Brain The Localization Issue

Nature and Nurture The Genetic Code Application: A Computer Made of DNA Genes and Behavior The Human Genome Project Application: Beyond the Human Genome Project Heredity: Destiny or Predisposition?

PART I. Neural Foundations of Behavior: The Basic Equipment

CHAPTER 2. Communication Within the Nervous System The Cells That Make Us Who We Are Neurons Application: Targeting Ion Channels Glial Cells

How Neurons Communicate With Each Other Chemical Transmission at the Synapse Regulating Synaptic Activity Neurotransmitters Application: Agonists and Antagonists in the Real World Of Neuronal Codes, Neural Networks, and Computers In the News:The Human Brain Project

CHAPTER 3. The Organization and Functions of the Nervous System The Central Nervous System

The Forebrain Application: The Case of Phineas Gage The Midbrain and Hindbrain The Spinal Cord Protecting the Central Nervous System

The Peripheral Nervous System The Cranial Nerves The Autonomic Nervous System

Development and Change in the Nervous System The Stages of Development How Experience Modifies the Nervous System Damage and Recovery in the Central Nervous System In the News:Is the Brain Too Fragile for Sports? In the News:Nuclear Testing Reveals Adult Neurogenesis in Humans Application: Mending the Brain With Computer Chips

CHAPTER 4. The Methods and Ethics of Research Science, Research, and Theory Theory and Tentativeness in Science Experimental Versus Correlational Studies

Research Techniques Staining and Imaging Neurons Light and Electron Microscopy Measuring and Manipulating Brain Activity In the News:Looking Into the Brain Brain Imaging Techniques Application: Scanning King Tut In the News:Growing a Model Brain From Stem Cells Investigating Heredity

Research Ethics Plagiarism and Fabrication Protecting the Welfare of Research Participants In the News:NIH Is Retiring Most of Its Research Chimps Gene Therapy Stem Cell Therapy

PART II. Motivation and Emotion: What Makes Us Go

CHAPTER 5. Drugs, Addiction, and Reward Psychoactive Drugs Opiates Depressants Stimulants Psychedelics Marijuana In the News:Changing Attitudes Toward Marijuana

Addiction The Neural Basis of Addiction and Reward Dopamine and Reward Dopamine, Learning, and Brain Plasticity Treating Drug Addiction Application: Preventing Addiction by Targeting the Immune System

The Role of Genes in Addiction Separating Genetic and Environmental Influences What Is Inherited? Implications of Addiction Research

CHAPTER 6. Motivation and the Regulation of Internal States Motivation and Homeostasis Theoretical Approaches to Motivation Simple Homeostatic Drives

Hunger: A Complex Drive The Role of Taste Application: Predator Control Through Learned Taste Aversion Digestion and the Two Phases of Metabolism Signals That Start a Meal Signals That End a Meal Long-Term Controls Application: How Nicotine and Marijuana Affect Appetite

Obesity The Myths of Obesity The Contributions of Heredity and Environment

In the News:How the FTO Gene Makes Us Obese Application: The Sweet Taste of Obesity Obesity and Reduced Metabolism Treating Obesity

Anorexia, Bulimia, and Binge Eating Disorder Environmental and Genetic Contributions The Role of Serotonin, Dopamine, and Cannabinoids

CHAPTER 7. The Biology of Sex and Gender Sex as a Form of Motivation Arousal and Satiation The Role of Testosterone Brain Structures and Neurotransmitters Odors, Pheromones, and Sexual Attraction Application: Of Love and Bonding

The Biological Determination of Sex Chromosomes and Hormones Prenatal Hormones and the Brain

Gender-Related Behavioral and Cognitive Differences Some Demonstrated Male–Female Differences Origins of Male–Female Differences

Biological Origins of Gender Identity Gender Identity Reversal 46 XY Difference in Sexual Development 46 XX Difference in Sexual Development Cognitive and Behavioral Effects Ablatio Penis: A Natural Experiment Application: Sex, Gender, and Sports In the News:Who Chooses a Child’s Sex?

Sexual Orientation The Social Influence Hypothesis Genetic and Epigenetic Influences Prenatal Influences on Brain Structure and Function Social Implications of the Biological Model

CHAPTER 8. Emotion and Health Emotion and the Nervous System Autonomic and Muscular Involvement in Emotion The Emotional Brain The Prefrontal Cortex Application: Why I Don’t Jump Out of Airplanes The Amygdala Hemispheric Specialization in Emotion

Stress, Immunity, and Health Stress as an Adaptive Response Negative Effects of Stress In the News:Keeping Odd Hours Could Make You Sick Application: One Aftermath of 9/11 Is Stress-Related Brain Damage Social, Personality, and Genetic Factors Pain as an Adaptive Emotion

Biological Origins of Aggression Hormones and Aggression The Brain’s Role in Aggression Neurotransmitters and Aggression Application: Neurocriminology, Responsibility, and the Law Heredity and Environment

PART III. Interacting With the World

CHAPTER 9. Hearing and Language Hearing The Stimulus for Hearing The Auditory Mechanism Frequency Analysis Application: Restoring Hearing Locating Sounds With Binaural Cues Application: I Hear a Tree Over There

Language Broca’s Area Wernicke’s Area The Wernicke-Geschwind Model Reading, Writing, and Their Impairment Mechanisms of Recovery From Aphasia A Language-Generating Mechanism?

In the News:Learning Language Starts Before Birth Language in Nonhumans Neural and Genetic Antecedents In the News:The Link Between Human Language and Birdsong

CHAPTER 10. Vision and Visual Perception Light and the Visual Apparatus The Visible Spectrum The Eye and Its Receptors Pathways to the Brain Application: Restoring Lost Vision

Color Vision Trichromatic Theory Opponent Process Theory A Combined Theory Color Blindness

Form Vision Contrast Enhancement and Edge Detection Hubel and Wiesel’s Theory Spatial Frequency Theory

The Perception of Objects, Color, and Movement The Two Pathways of Visual Analysis Disorders of Visual Perception The Problem of Final Integration Application: When Binding Goes Too Far

CHAPTER 11. The Body Senses and Movement The Body Senses Proprioception The Skin Senses The Vestibular Sense The Somatosensory Cortex and the Posterior Parietal Cortex Pain and Its Disorders Application: Treating Pain in Limbs That Aren’t There

Movement

The Muscles The Spinal Cord The Brain and Movement In the News:Coordinating Artificial Limbs Disorders of Movement In the News:Curing Parkinson’s in a Dish

PART IV. Complex Behavior

CHAPTER 12. Learning and Memory Learning as the Storage of Memories Amnesia: The Failure of Storage and Retrieval Application: The Legacy of HM Mechanisms of Consolidation and Retrieval Where Memories Are Stored Two Kinds of Learning Working Memory

Brain Changes in Learning Long-Term Potentiation How LTP Happens Neural Growth in Learning Consolidation Revisited Changing Our Memories Application: Total Recall In the News:Recalling It Now Helps You Remember It Later

Learning Deficiencies and Disorders Effects of Aging on Memory Alzheimer’s Disease In the News:NIH Teams With Drug Companies Korsakoff’s Syndrome

CHAPTER 13. Intelligence and Cognitive Functioning The Nature of Intelligence What Does “Intelligence” Mean? The Structure of Intelligence

The Biological Origins of Intelligence The Brain and Intelligence Specific Abilities and the Brain Application: We Aren’t the Only Tool Users Heredity and Environment Application: Enhancing Intelligence and Performance

Deficiencies and Disorders of Intelligence Effects of Aging on Intelligence Intellectual Disability Autism Spectrum Disorder Application: Childhood Vaccines and Autism Attention-Deficit/Hyperactivity Disorder In the News:Testing for ADHD

CHAPTER 14. Psychological Disorders Schizophrenia Characteristics of the Disorder Heredity Two Kinds of Schizophrenia The Dopamine Hypothesis Beyond the Dopamine Hypothesis Brain Anomalies in Schizophrenia

Affective Disorders Heredity The Monoamine Hypothesis of Depression Electroconvulsive Therapy Antidepressants, ECT, and Neural Plasticity Application: Electrical Stimulation for Depression Rhythms and Affective Disorders Bipolar Disorder Brain Anomalies in Affective Disorders Suicide

Anxiety Disorders Generalized Anxiety, Panic Disorder, and Phobia Posttraumatic Stress Disorder In the News:Virtual Reality Isn’t Just for Video Games Anomalies in Brain Functioning

Obsessive-Compulsive Disorder

Brain Anomalies in Obsessive-Compulsive Disorder Treating Obsessive-Compulsive Disorder Related Disorders Application: Of Hermits and Hoarders

CHAPTER 15. Sleep and Consciousness Sleep and Dreaming Circadian Rhythms Rhythms During Waking and Sleeping The Functions of REM and Non-REM Sleep Sleep and Memory Brain Structures of Sleep and Waking Sleep Disorders Application: In the Still of the Night Sleep as a Form of Consciousness

The Neural Bases of Consciousness Awareness Attention The Sense of Self Network Explanations of Consciousness In the News:Consciousness and the Dying Brain Application: Determining Consciousness When It Counts

Glossary

References

Chapter-Opening Photo Credits

Author Index

Subject Index

F

Preface A Message From the Author “What one knows in youth is of little moment; they know enough who know how to

learn.” —Henry Brooks Adams

lip through this book and you’ll see that its pages are chock-full of facts—just a sampling gleaned from a vast supply that grows too fast for any of us to keep up. But sifting through those facts and reporting them is neither the most difficult nor

the most important function of a good textbook. A greater challenge is that most students fail to share their instructors’ infatuation with learning; perhaps they lack the genes or the parental role models, or just the revelation that education is life enriching. At any rate, they can find a text like this intimidating, and it is the textbook’s role to change their minds. The colorful illustrations and intriguing case studies may capture students’ interest,

but interest alone is not enough. That’s why I’ve adopted a “big-picture” approach in writing the text, one that marshals facts into explanations and discards the ones left standing around with nothing to do. When you put facts to work that way, you begin to see students look up and say, “That makes sense,” or “I’ve always wondered about that, but I never thought of it that way,” or “Now I understand what was going on with Uncle Edgar.” I believe education has the capacity to make a person healthy, happy, and

productive, and it makes a culture strong. Education realizes that promise when it leads people to inquire and to question, when they learn how to learn. When 45% of the public believes in ghosts, and politics has become a game played by shouting the loudest or telling the most convincing lie, education more than ever needs to teach young people to ask, “Where is the evidence?” and “Is that the only possible interpretation?” To those who would teach and those who would learn, this book is for you.

To the Student Brain & Behavior is my attempt to reach out to students, to beckon them into the fascinating world of biological psychology. These are exceptionally exciting times, comparable in many ways to the renaissance that thrust Europe from the Middle Ages into the modern world. In Chapter 1, I quote Kay Jamison’s comparison of neuroscience, which includes biopsychology, to a “romantic, moon-walk sense of

exploration.” I know of no scientific discipline with greater potential to answer the burning questions about ourselves than neuroscience in general and biopsychology in particular. I hope this textbook will convey that kind of excitement as you read about discoveries that will revolutionize our understanding of what it means to be human. I want you to succeed in this course, but, more than that, I want you to learn more

than you ever imagined you could and to go away with a new appreciation for the promise of biological psychology. So, I have a few tips I want to pass along. First, try to sit near the front of the class, because those students usually get the best grades. That is probably because they stay more engaged and ask more questions; but to ask good questions you should always read the text assignment before you go to class. And so you’ll know where you’re going before you begin to read, take a look at “In this chapter you will learn,” then skim the chapter subheadings, and read the summary at the end of the chapter. Use the questions in the margins as you go through, answer the Concept Check questions, and be sure to test yourself at the end. As you read, pay special attention to the text in blue; these are definitions of the most important terms. Computer icons like the one you see here will tell you which figures have been animated on the text’s website to help sharpen your understanding, and numbered WWW icons in the margins will direct you to a wealth of additional information on the web. Then don’t forget to look up some of the books and articles in For Further Reading. If you do all of these things, you won’t just do better in this course; you will leave saying, “I really got something out of that class!”

I wrote Brain & Behavior with you in mind, so I hope you will let me know where I have done things right and, especially, where I have not ([email protected]). I wish you the satisfaction of discovery and knowledge as you read what I have written for you. To the Instructor When I first wrote Brain & Behavior, I had one goal: to entice students into the adventure of biological psychology. There were other good texts out there, but they read as though they were written for students preparing for their next biopsych course in graduate school. Those students will find this book adequately challenging, but I wrote it so anyone who is interested in behavior, including the newly declared sophomore major or the curious student who has wandered over from the history department, could have the deeper understanding that comes from a biological perspective as they take other courses in psychology. It is not enough to draw students in with lively writing or by piquing their interest

with case studies and telling an occasional story along the way; unless they feel they

are learning something significant, they won’t stay—they’ll look for excitement in more traditional places. As I wrote, I remembered the text I struggled with in my first biopsychology class; it wasn’t very interesting because we knew much less about the biological underpinnings of behavior than we do now. Since that time, we have learned how the brain changes during learning, we have discovered some of the genes and brain deficiencies that cause schizophrenia, and we are beginning to understand how intricate networks of brain cells produce language, make us intelligent, and help us play the piano or find a mate. In other words, biopsychology has become a lot more interesting. So the material is there; now it is my job to communicate the excitement I have felt in discovering the secrets of the brain and to make a convincing case that biopsychology has the power to answer the questions students have about behavior. A good textbook is all about teaching, but there is no teaching if there is no

learning. Over the years, my students taught me a great deal about what they needed to help them learn. For one thing, I realized how important it is for students to build on their knowledge throughout the course, so I made several changes from the organization I saw in other texts. First, the chapter on neuronal physiology precedes the chapter on the nervous system, because I believe that you can’t begin to understand the brain until you know how its neurons work. And I reversed the usual order of the vision and audition chapters, because I came to understand that audition provides a friendlier context for introducing the basic principles of sensation and perception. The chapters on addiction, motivation, emotion, and sex follow the introduction to neurophysiology; this was done to build student motivation before tackling sensation and perception. Perhaps more significantly, some topics have been moved around among chapters so they can be developed in a more behaviorally meaningful context. So language is discussed along with audition, the body senses with the mechanisms of movement, the sense of taste in the context of feeding behavior, and olfaction in conjunction with sexual behavior. Most unique, though, is the inclusion of a chapter on the biology of intelligence and another on consciousness. The latter is a full treatment of recent developments in the field, rather than limited to the usual topics of sleep and split-brain behavior. These two chapters strongly reinforce the theme that biopsychology is personally relevant and capable of addressing important questions. Brain & Behavior has several features that will motivate students to learn and

encourage them to take an active role in their learning. It engages the student with interest-grabbing opening vignettes, illustrative case studies, and In the News items and Application boxes that take an intriguing step beyond the chapter content. Throughout each chapter, questions in the margins keep the student focused on key points, a Concept Check at the end of each section serves as a reminder of the important ideas, and On the Web icons point the way to related information on the Internet. At the end of the chapter, In Perspective emphasizes the importance and

implications of what the student has just read, a summary helps organize that information, and Testing Your Understanding assesses the student’s conceptual understanding as well as factual knowledge. Then, For Further Reading is a guide for students who want to explore the chapter’s topics more fully. I have found over the years that students who use the study aids in a class are also the best performers in the course. New in the Fourth Edition A new edition is largely about updates, and in an effort to maintain the currency lauded by its reviewers, Brain & Behavior, Fourth Edition, has added more than 400 new references, almost 27 per chapter. Several sections have been extensively rewritten, not only to bring them up to date, but also to provide better organization and clarity and to shift focus to the most significant aspects. The discussion of chronic pain, for example, now emphasizes vulnerability factors in the form of brain connectivity, genes, and depression; the section on sexual orientation has been restructured completely, and it has been rewritten to conform to currently accepted terminology; and the discussion of dyslexia now highlights brain anomalies and phonological problems that are detectable before a child begins to learn to read. To support these changes, there are 23 new figures, numerous other figures have been refined to improve clarity and appearance, there are 19 In the News features, and new Applications bring their total up to 39. In addition, the text reflects the current thinking about disorders contained in the newly revised Diagnostic and Statistical Manual of Mental Disorders. Familiar themes from past editions have been preserved and expanded. The

pervasive theme of genetic influence is augmented by recent developments, such as the discovery that the RORA gene, which targets 2,500 other genes and is upregulated by estrogen but downregulated by testosterone, not only contributes to autism but also may help explain its gender difference. On the larger front, genome-wide studies are rapidly adding new genes, including more than 70 that are suspected of playing a role in schizophrenia. Ever mindful of the interplay between genetic and environmental influences, this edition continues to highlight epigenetic contributions, such as the differential expression of large numbers of genes in Alzheimer’s disease and autism. A second recurring theme is the importance of brain connectivity, and this edition includes new evidence of its role in intelligence, autism, schizophrenia, and even chronic pain. The promise of stem cells appears in several chapters, ranging from applications in treating spinal cord injuries, deafness, and blindness to evidence that the rate of neurogenesis in the adult human brain is adequate to support repair. Finally, the text has always emphasized the ways that neuroscience is applied, because real- life application tells students that neuroscience is not just interesting but relevant and useful. In that vein, the text describes the latest treatments for deafness and blindness, documents the trials and tribulations of coming up with effective drugs for obesity and

Alzheimer’s, and tackles issues such as criminal responsibility as viewed from the perspective of the neuroscientist. But the engine of progress is pure science, and unprecedented funding for the brain

sciences is resulting in several ambitious projects in the spirit of the past decade’s Human Genome Project. If successful, the Human Connectome Project will map all the brain’s connections, the Human Brain Project will simulate its activity on a computer, BigBrain and The Brain Observatory will create high-resolution 3-D maps of the brain, and the BRAIN Initiative will map the activity of every neuron. Supplemental Material Student Study Guide This affordable student study guide and workbook to accompany Bob Garrett’s

Brain & Behavior, Fourth Edition, will help students get the added review and practice they need to improve their skills and master their course. Each part of the study guide corresponds to the appropriate chapter in the text and includes the following: chapter outline, chapter summary, study quiz, and a chapter posttest. Student Study Site This free student study site provides additional support to students using Brain &

Behavior, Fourth Edition. The website includes animations of key figures in the text, links to On the Web sites and other Internet resources, e-flashcards, study quizzes (students can receive their score immediately), and relevant SAGE journal articles with critical thinking questions. Visit the study site at edge.sagepub.com/garrett4e. Instructor’s Resources on the Web This set of instructor’s resources provides a number of helpful teaching aids for

professors new to teaching biological psychology and to using Brain & Behavior, Fourth Edition. Included are PowerPoint slides, a computerized test bank to allow for easy creation of exams, lecture outlines, suggested class activities and critical thinking questions, and video and Internet resources for each chapter of the text. Acknowledgments Vicki Knight has been the editor for all four editions of Brain & Behavior. Without her support and vision, the book wouldn’t have reached the second edition, much less the fourth. Her patience and friendship have borne me through all the difficulties a project like this entails. Vicki and I have been nobly aided by production editors Stephanie Palermini and David Felts, photo researcher Eric Schrader, editorial assistants Jessica Miller and Yvonne McDuffee, cover designer Candice Harman, marketing manager Shari Countryman, and market development editor Michelle Rodgerson. Their skill and their good humor have made them a joy to work with. I want to extend special recognition to Gerald Hough at Rowan University and John Agnew at the University of Colorado Boulder. Jerry has produced an exceptional set of ancillaries, particularly the completely revised PowerPoint slides; in addition, he has found my errors, offered criticism, and provided articles that I overlooked. John

wrote most of the new Applications and In the News features, and constantly surprised me with additional research material. Kudos to both for their knowledge, keenness, and inspiring commitment. I have had a number of mentors along the way, to whom I am forever grateful. A

few of those special people are Wayne Kilgore, who taught the joys of science along with high school chemistry and physics; Garvin McCain, who introduced me to the satisfactions of research; Roger Kirk, who taught me that anything worth doing is worth doing over and over until it’s right; and Ellen Roye and Ouilda Piner, who shared their love of language. These dedicated teachers showed me that learning was my responsibility, and they shaped my life with their unique gifts and quiet enthusiasm. But of all my supporters, the most important has been my wife, Duejean; love and

thanks to her for her patient understanding and her appreciation of how important this project is to me. In addition, the following reviewers gave generously of their time and expertise

throughout the development of this text; they contributed immensely to the quality of Brain & Behavior: First Edition: Susan Anderson, University of South Alabama; Patrizia Curran,

University of Massachusetts–Dartmouth; Lloyd Dawe, Cameron University; Tami Eggleston, McKendree College; James Hunsicker, Southwestern Oklahoma State University; Eric Laws, Longwood College; Margaret Letterman, Eastern Connecticut State University; Doug Matthews, University of Memphis; Grant McLaren, Edinboro University of Pennsylvania; Rob Mowrer, Angelo State University; Anna Napoli, University of Redlands; Robert Patterson, Washington State University; Joseph Porter, Virginia Commonwealth University; Jeffrey Stern, University of Michigan– Dearborn; Aurora Torres, University of Alabama in Huntsville; Michael Woodruff, East Tennessee State University; and Phil Zeigler, Hunter College. Second Edition: M. Todd Allen, University of Northern Colorado; Patricia A. Bach,

Illinois Institute of Technology; Wayne Brake, University of California–Santa Barbara; Steven I. Dworkin, University of North Carolina; Sean Laraway, San Jose State University; Mindy J. Miserendino, Sacred Heart University; Brady Phelps, South Dakota State University; Susan A. Todd, Bridgewater State College; and Elizabeth Walter, University of Oregon. Third Edition: John A. Agnew, University of Colorado Boulder; Michael A. Bock,

American International College; Rachel E. Bowman, Sacred Heart University; Jessica Cail, Pepperdine University; Mary Jo Carnot, Chadron State College; Cheryl A. Frye, The University at Albany–State University of New York; Rebecca L. M. Fuller, Catholic University of America; Cindy Gibson, Washington College; Bennet Givens, Department of Psychology, Ohio State University; Robert B. Glassman, Lake Forest College; Gerald E. Hough, Rowan University; Joseph Nuñez, Michigan State

University; and Kimberly L. Thomas, University of Central Oklahoma. Fourth Edition: John A. Agnew, University of Colorado Boulder; Ben Allen,

University of Pittsburgh; Scott L. Decker, University of South Carolina; Carol L. DeVolder; St. Ambrose University; Jeff Dyche, James Madison University; Cindy Gibson, Washington College; Deirdre C. Greer, Columbus State University; William Meil; Indiana University of Pennsylvania; Samar Saade Needham, California State University, Long Beach; M. Foster Olive, Arizona State University; Catherine Powers Ozyurt, Bay Path College; Allen Salo, University of Maine at Presque Isle; Justin P. Smith, University of South Dakota; Gretchen Sprow, University of North Carolina at Chapel Hill; and Sandra Trafalis, San Jose State University.

—Bob Garrett

About the Author Bob Garrett is a Visiting Scholar at California Polytechnic State University, San Luis Obispo. He was Professor of Psychology at DePauw University in Greencastle, Indiana, and held several positions there, including Chairperson of the Department of Psychology, Faculty Development Coordinator, and Interim Dean of Academic Affairs. He received his BA from the University of Texas at Arlington and his MA and PhD from Baylor University. He received further training in the Department of Physiology at

Baylor University College of Medicine and at the Aeromedical Research Primate Laboratory, Holloman Air Force Base. Bob and his wife, Duejean, live on a 3,200- acre ranch they share with 47 other families in the hills outside San Luis Obispo. Their two sons, daughter-in-law, and three beautiful grandchildren all live nearby. About the Contributors

Gerald Hough is an Associate Professor of Biological Sciences and Psychology at Rowan University in Glassboro, New Jersey. He has taught undergraduate courses in both departments on anatomy, animal behavior, research methods, and learning. He has served as the undergraduate advising coordinator for Psychology, the Chair of the IACUC, and curriculum development for the new Cooper Medical School at Rowan University. His research focus is in the neural bases of spatial and

communication behaviors in birds. He received his BS from Purdue University and his MS and PhD from The Ohio State University.

John Agnew is an Instructor in the Department of Psychology and Neuroscience at the University of Colorado Boulder and a Clinical Instructor in the Department of Psychiatry at the University of Colorado Denver Health Science Center. John has taught courses and laboratories in biology, psychology and neuroscience and is an active researcher, studying the efficacy of behavioral interventions for individuals with an Autism Spectrum

Disorder. He earned his BA in Chemistry and Biochemistry from Haverford College and his PhD in Neuroscience from Georgetown University. In his spare time, he enjoys spending time with his family and skiing and exploring Colorado.

N

1 What Is Biopsychology?

In this chapter you will learn • How biological psychology grew out of philosophy and physiology • How brain scientists think about the mind-brain problem • How behavior is inherited and the relationship between heredity and environment

The Origins of Biopsychology Prescientific Psychology and the Mind-Brain Problem Descartes and the Physical Model of Behavior Helmholtz and the Electrical Brain The Localization Issue CONCEPT CHECK

Nature and Nurture The Genetic Code APPLICATION: A COMPUTER MADE OF DNA

Genes and Behavior The Human Genome Project APPLICATION: BEYOND THE HUMAN GENOME PROJECT

Heredity: Destiny or Predisposition? CONCEPT CHECK

In Perspective Summary Study Resources

euroscience is the multidisciplinary study of the nervous system and its role in behavior. An interesting topic, surely, but neuroscience is a romantic moonwalk? To understand why Kay Jamison chose this analogy, you would need to have

watched in astonishment from your backyard on an October night in 1957 as the faint glint of reflected light from Sputnik crossed the North American sky. The American people were stunned and fearful as the Russian space program left them far behind. But as the implications of this technological coup sank in, the United States set about constructing its own space program and revamping education in science and technology. Less than 4 years later, President Kennedy made his startling commitment to put an American astronaut on the moon by the end of the decade. But the real excitement would come on the evening of July 20, 1969, as you sat glued to your television set watching the Eagle lander settle effortlessly on the moon and the first human step onto the surface of another world (Figure 1.1). For Kay Jamison and the

rest of us involved in solving the mysteries of the brain, there is a very meaningful parallel between the excitement of Neil Armstrong’s “giant leap for mankind” and the thrill of exploring the inner space of human thought and emotion. “

There is a wonderful kind of excitement in modern neuroscience, a romantic, moon- walk sense of exploration and setting out for new frontiers. The science is elegant... and the pace of discovery absolutely staggering.

—Kay R. Jamison, An Unquiet Mind

” There is also an inescapable parallel between Kennedy’s commitment of the 1960s

to space exploration and Congress’s declaration 30 years later that the 1990s would be known as the Decade of the Brain. Understanding the brain demands the same incredible level of effort, ingenuity, and technological innovation as landing a human on the moon. There were important differences between those two decades, though. President Kennedy acknowledged that no one knew what benefits would arise from space exploration. But as the Decade of the Brain began, we understood that we would not only expand the horizons of human knowledge but also advance the treatment of neurological diseases, emotional disorders, and addictions that cost the United States an estimated trillion dollars a year in care, lost productivity, and crime (Uhl & Grow, 2004). Another difference was that the moon-landing project was born out of desperation

and a sense of failure, while the Decade of the Brain was a celebration of achievements, both past and current. In the past few years, we have developed new treatments for depression, identified key genes responsible for the devastation of Alzheimer’s disease, discovered agents that block addiction to some drugs, learned ways to hold off the memory impairment associated with old age, and produced a map of the human genes. FIGURE 1.1 The Original Romantic Moonwalk. Space exploration and solving the mysteries of the brain offer similar challenges and excitement. Which do you think will have the greater impact on your life?

SOURCE: Courtesy of NASA. The United States could not have constructed a space program from scratch in the

1960s; the achievement was built on a long history of scientific research and technological experience. In the same way, the accomplishments of the Decade of the Brain had their roots in a 300-year scientific past, and in 22 centuries of thought and inquiry before that. For that reason, we will spend a brief time examining those links to our past. The Origins of Biopsychology The term neuroscience identifies the subject matter of the investigation rather than the scientist’s training. A neuroscientist may be a biologist, a physiologist, an anatomist, a neurologist, a chemist, a psychologist, or a psychiatrist—or even a computer scientist or a philosopher. Psychologists who work in the area of neuroscience specialize in biological psychology, or biopsychology, the branch of psychology that studies the relationships between behavior and the body, particularly the brain. (Sometimes the term psychobiology or physiological psychology is used.) For psychologists, behavior has a very broad meaning, which includes not only overt acts, but also internal events such as learning, thinking, and emotion. Biological psychologists attempt to answer questions like “What changes in the brain when a person learns?” “Why does one person develop depression and another, under similar circumstances, becomes anxious while another seems unaffected?” “What is the physiological explanation for emotions?” “How do we recognize the face of a friend?” “How does the brain’s activity result in consciousness?” Biological psychologists use a variety of research techniques to answer these questions, as you will see in Chapter 4. Whatever their area of study or their strategy for doing research, biological psychologists try to go

beyond the mechanics of how the brain works to focus on the brain’s role in behavior.

What is biopsychology, and how does it relate to neuroscience? To really appreciate the impressive accomplishments of today’s brain researchers, it

is useful, perhaps even necessary, to understand the thinking and the work of their predecessors. Contemporary scientists stand on the shoulders of their intellectual ancestors, who made heroic advances with far less information at their disposal than is available to today’s undergraduate student. Writers have pointed out that psychology has a brief history, but a long past. What

they mean is that thinkers have struggled with the questions of behavior and experience for more than two millennia, but psychology arose as a separate discipline fairly recently; the date most accept is 1879, when Wilhelm Wundt (Figure 1.2) established the first psychology laboratory in Leipzig, Germany. But biological psychology would not emerge as a separate subdiscipline until psychologists offered convincing evidence that the biological approach could answer significant questions about behavior. To do so, they would have to come to terms with an old philosophical question about the nature of the mind. Because the question forms a thread that helps us trace the development of biological psychology, we will orient our discussion around this issue. “

In the sciences, we are now uniquely privileged to sit side by side with the giants on whose shoulders we stand.

—Gerald Holton

” Prescientific Psychology and the Mind-Brain Problem This issue is usually called “the mind-body problem,” but it is phrased differently

here to place the emphasis squarely where it belongs—on the brain. The mind-brain problem deals with what the mind is and what its relationship is to the brain. There can be no doubt that the brain is essential to our behavior, but does the mind control the brain, or is it the other way around? Alternatively, are mind and brain the same thing? How these questions are resolved affects how we ask all the other questions of neuroscience. FIGURE 1.2 Wilhelm Wundt (1832–1920).

SOURCE: © Pictorial Press Ltd/Alamy. At the risk of sounding provocative, I will say that there is no such thing as mind. It

exists only in the sense that, say, weather exists; weather is a concept we use to include rain, wind, humidity, and related phenomena. We talk as if there is a weather when we say things like “The weather is interfering with my travel plans.” But we don’t really think that there is a weather. Most, though not all, neuroscientists believe that we should think of the mind in the same way; it is simply the collection of things that the brain does, such as thinking, sensing, planning, and feeling. But when we think, sense, plan, and feel, we get the compelling impression that there is a mind behind it all, guiding what we do. Most neuroscientists say this is just an illusion, that the sense of mind is nothing more than the awareness of what our brain is doing. Mind, like weather, is just a concept; it is not a something; it does not do anything.

How do monists and dualists disagree on the mind-brain question? This position is known as monism from the Greek monos, meaning “alone” or

“single.” Monism is the idea that the mind and the body consist of the same substance. Idealistic monists believe that everything is nonphysical mind, but most monists take the position that the body and mind and everything else are physical; this view is called materialistic monism. The idea that the mind and the brain are separate is known as dualism. For most dualists, the body is material and the mind is nonmaterial. Most dualists also believe that the mind influences behavior by interacting with the brain. This question did not originate with modern psychology. The Greek philosophers

were debating it in the fifth century BCE (G. Murphy, 1949), when Democritus proposed that everything in the world was made up of atoms (atomos, meaning “indivisible”), his term for the smallest particle possible. Even the soul, which

included the mind, was made up of atoms, so it, too, was material. Plato and Aristotle, considered the two greatest intellectuals among the ancient Greeks, continued the argument into the 4th century BCE. Plato was a dualist, while his student Aristotle joined the body and soul in his attempt to explain memory, emotions, and reasoning. “

The nature of the mind and soul is bodily. —Lucretius, c. 50 BCE

What we call our minds is simply a way of talking about the functions of our brains. —Francis Crick, 1966

”

Defending either position was not easy. The dualists had to explain how a nonphysical mind could influence a physical body, and monists had the task of explaining how the physical brain could account for mental processes such as perception and conscious experience. But the mind was not observable, and even the vaguest understanding of nerve functioning was not achieved until the 1800s, so neither side had much ammunition for the fight.

What is a model in science, and how is it useful? Descartes and the Physical Model of Behavior Scientists often resort to the use of models to understand whatever they are

studying. A model is a proposed mechanism for how something works. Sometimes, a model is in the form of a theory, such as Darwin’s explanation that a species developed new capabilities because the capability enhanced the individual’s survival. Other times, the model is a simpler organism or system that researchers study in an attempt to understand a more complex one. For example, researchers have used the rat to model everything from learning to Alzheimer’s disease in humans, and the computer has often served as a model of cognitive processes. In the 17th century, the French philosopher and physiologist René Descartes

(Figure 1.3a) used a hydraulic model to explain the brain’s activity (Descartes, 1662/1984). Descartes’s choice of a hydraulic model was influenced by his observation of the statues in the royal gardens. When a visitor stepped on certain tiles, the pressure forced water through tubes to the statues and made them move. Using this model, Descartes then reasoned that the nerves were also hollow tubes. The fluid they carried was not water, but what he called “animal spirits”; these flowed from the brain and inflated the muscles to produce movement. Sensations, memories, and other mental functions were produced as animal spirits flowed through “pores” in the brain. The animal spirits were pumped through the brain by the pineal gland (Figure 1.3b). Descartes’s choice of the pineal gland was based on his belief that it was at a perfect

location to serve this function; attached just below the two cerebral hemispheres by its flexible stalk, it appeared capable of bending at different angles to direct the flow of animal spirits into critical areas of the brain. Thus, for Descartes, the pineal gland became the “seat of the soul,” the place where the mind interacted with the body. Although Descartes assigned control to the mind, his unusual emphasis on the physical explanation of behavior foreshadowed the physiological approach that would soon follow. FIGURE 1.3 Descartes (1596–1650) and the Hydraulic Model. Descartes believed that behavior was controlled by animal spirits flowing through the nerves.

SOURCES: (a) Courtesy of the National Library of Medicine. (b) © Bettmann/CORBIS. Descartes lacked an understanding of how the brain and body worked, so he relied

on a small amount of anatomical knowledge and a great deal of speculation. His hydraulic model not only represented an important shift in thinking; it also illustrates the fact that a model or a theory can lead us astray, at least temporarily. Fortunately, this was the age of the Renaissance, a time not only of artistic expansion and world exploration, but of scientific curiosity. Thinkers began to test their ideas through direct observation and experimental manipulation as the Renaissance gave birth to science. In other words, they adopted the method of empiricism, which means that they gathered their information through observation rather than logic, intuition, or other means. Progress was slow, but two critically important principles would emerge as the early scientists ushered in the future. (The WWW icon in the margin indicates that you can find a website on this topic in On the Web at the end of the chapter.

1 Mind and Body: Descartes to James

What two discoveries furthered the early understanding of the brain? Helmholtz and the Electrical Brain In the late 1700s, the Italian physiologist Luigi Galvani showed that he could make

a frog’s leg muscle twitch by stimulating the attached nerve with electricity, even after the nerve and muscle had been removed from the frog’s body. A century later in Germany, Gustav Fritsch and Eduard Hitzig (1870) produced movement in dogs by electrically stimulating their exposed brains. What these scientists showed was that animal spirits were not responsible for movement, but instead, nerves operated by electricity! But the German physicist and physiologist Hermann von Helmholtz (Figure 1.4) demonstrated that nerves do not behave like wires conducting electricity. He was able to measure the speed of conduction in nerves, and his calculation of about 90 feet/second (27.4 meters/second) fell far short of the speed of electricity, which travels through wires at the speed of light (186,000 miles/second or 299,000 kilometers/second). It was obvious that researchers were dealing with a biological phenomenon and that the functioning of nerves and of the brain was open to scientific study. Starting from this understanding, Helmholtz’s studies of vision and hearing gave “psychologists their first clear idea of what a fully mechanistic ‘mind’ might look like” (Fancher, 1979, p. 41). As you will see in later chapters, his ideas were so insightful that even today we refer to his theories of vision and hearing as a starting point before describing the current ones. FIGURE 1.4 Hermann von Helmholtz (1821–1894).

SOURCE: INTERFOTO/Alamy. The Localization Issue The second important principle to come out of this period—localization—emerged

over the first half of the 19th century. Localization is the idea that specific areas of the brain carry out specific functions. Fritsch and Hitzig’s studies with dogs gave objective confirmation to physicians’ more casual observations dating as far back as 17th-century BCE Egypt (Breasted, 1930), but it was two medical case studies that really grabbed the attention of the scientific community. In 1848, Phineas Gage, a railroad construction foreman, was injured when a dynamite blast drove an iron rod through his skull and the frontal lobes of his brain. Amazingly, he survived with no impairment of his intelligence, memory, speech, or movement. But he became irresponsible and profane and was unable to abide by social conventions (H. Damasio, Grabowski, Frank, Galaburda, & Damasio, 1994). Then, in 1861, the French physician Paul Broca (Figure 1.5) performed an autopsy on the brain of a man who had lost the ability to speak after a stroke. The autopsy showed that damage was limited to an area on the left side of his brain now known as Broca’s area (Broca, 1861). FIGURE 1.5 Paul Broca (1824–1880).

SOURCE: Wikimedia Commons. By the mid-1880s, additional observations like these had convinced researchers

about localization (along with some humorists, as the quote from Mark Twain shows!). But a few brain theorists took the principle of localization too far, and we should be on guard lest we make the same mistake. Near the end of the 18th century, when interest in the brain’s role in behavior was really heating up, the German anatomist Franz Gall came up with an extreme and controversial theory of brain localization. According to phrenology, each of 35 different “faculties” of emotion and intellect—such as combativeness, inhabitiveness (love of home), calculation, and order—was located in a precise area of the brain (Spurzheim, 1908). Gall and his student Spurzheim determined this by feeling bumps on people’s skulls and relating any protuberances to the individual’s characteristics (Figure 1.6). Others, such as Karl Lashley (1929), took an equally extreme position at the other end of the spectrum; equipotentiality is the idea that that the brain functions as an undifferentiated whole. According to this view, the extent of damage, not the location, is what determines how much function is lost. We now know that bumps on the skull have nothing to do with the size of the brain

structures beneath and that most of the characteristics Gall and Spurzheim identified have no particular meaning at the physiological level. But we also know that the brain is not equipotential. The truth, as is often the case, lies somewhere between these two extremes. “

I never could keep a promise.... It is likely that such a liberal amount of space was given to the organ which enables me to make promises that the organ which should enable me to keep them was crowded out.

—Mark Twain, in Innocents Abroad

”

FIGURE 1.6 A Phrenologist’S Map of the Brain. Phrenologists believed that the psychological characteristics shown here were controlled by the respective brain areas. SOURCE: © Bettmann/CORBIS. Today’s research tells us that functions are as much distributed as they are

localized; behavior results from the inter action of many widespread areas of the brain. In later chapters, you will see examples of cooperative relationships among brain areas in language, visual perception, emotional behavior, motor control, and learning. In fact, you will learn that neuroscientists these days are less likely to ask where a function is located than to ask how the brain integrates activity from several areas into a single experience or behavior. Nevertheless, the locationists strengthened the monist position by showing that language, emotion, motor control, and so on are controlled by relatively specific locations in the brain (Figure 1.7). This meant that the mind ceased being the explanation and became the phenomenon to be explained. Understand that the nature and role of the mind are still debated in some quarters.

For example, some neuroscientists believe that brain research will be unable to explain how a material brain can generate conscious experience, and that this will spell the final doom of materialism. These nonmaterial neuroscientists interpret the brain changes that occur during behavior therapy as evidence of the mind changing the brain (J. M. Schwartz et al., 1996; see Chapter 14). Of course, what material

Concept Check

neuroscientists see is the brain changing the brain (Gefter, 2008). Neuroscience has been able to explain a great deal of behavior without any reference to a nonmaterial mind, and as you explore the rest of this text you will begin to see why most brain scientists would describe themselves as material monists. FIGURE 1.7 Some of the Brain’s Functional Areas.

What is the danger of mind-as-explanation?

Take a Minute to Check Your Knowledge and Understanding

What change in method separated science from philosophy? What were the important implications of the discoveries that nerve conduction is electrical and that specific parts of the brain have (more or less) specific functions?

Where do scientists stand on the localization issue?

How are characteristics inherited? Nature and Nurture A second extremely important issue in understanding the biological bases of behavior

is the nature versus nurture question, or how important heredity is relative to environmental influences in shaping behavior. Like the mind-brain issue, this is one of the more controversial topics in psychology, at least as far as public opinion is concerned. The arguments are based on emotion and values almost as often as they appeal to evidence and reason. For example, some critics complain that attributing behavior to heredity is just a form of excusing actions for which the person or society should be held accountable. A surprising number of behaviors are turning out to have some degree of hereditary influence, so you will be running into this issue throughout the following chapters. Because there is so much confusion about heredity, we need to be sure you understand what it means to say that a behavior is hereditary before we go any further. FIGURE 1.8 A Set of Human Chromosomes.

SOURCE: U.S. National Library of Medicine. The Genetic Code The gene is the biological unit that directs cellular processes and transmits inherited

characteristics. Most genes are found on the chromosomes, which are located in the nucleus of each cell, but there are also a few genes in structures outside the nucleus, called the mitochondria. Each body cell in a human has 46 chromosomes, arranged in 23 pairs (see Figure 1.8). Each pair is identifiably distinct from every other pair. This is important, because genes for different functions are found on specific chromosomes. The chromosomes are referred to by number, except for the sex chromosomes; in mammals, the female has two X chromosomes, while males typically have an X and a Y chromosome. Notice that the members of a pair of chromosomes are similar, again with the exception that the Y chromosome is much shorter than the X chromosome. Unlike the body cells, the male’s sperm cells and the female’s ova (egg cells) each

have 23 chromosomes. When these sex cells are formed by the division of their parent cells, the pairs of chromosomes separate so each daughter cell receives only one

chromosome from each pair. When the sperm enters the ovum during fertilization, the chromosomes of the two cells merge to restore the number to 46. The fertilized egg, or zygote, then undergoes rapid cell division and development on its way to becoming a functioning organism. For the first 8 weeks (in humans), the new organism is referred to as an embryo and from then until birth as a fetus. FIGURE 1.9 A Strand of DNA.

The mystery of how genes carry their genetic instructions began to yield to researchers in 1953 when James Watson and Francis Crick published a proposed structure for the deoxyribonucleic acid that genes are made of. Deoxyribonucleic acid (DNA) is a double-stranded chain of chemical molecules that looks like a ladder that has been twisted around itself; this is why DNA is often referred to as the double helix (see Figure 1.9). Each rung of the ladder is composed of two of the four nucleotides— adenine, thymine, guanine, and cytosine (A, T, G, C). The order in which these appear on the ladder forms the code that carries all our genetic information. The four-letter alphabet these nucleotides provide is adequate to spell out the instructions for every structure and function in your body. The feature “Application: A Computer Made of DNA” will give you some appreciation of DNA’s complexity and power. We only partially understand how genes control the development of the body and

its activities, as well as how they influence many aspects of behavior. However, we do know that genes exert their influence in a deceptively simple manner: They provide the directions for making proteins. Some of these proteins are used in the construction of the body, and others are enzymes; enzymes act as catalysts, modifying chemical reactions in the body. It is estimated that humans differ among themselves in the sequences of nucleotides that make up our DNA by only about 0.5% (S. Levy et al., 2007); however, you will see throughout this text that this variation leads to enormous differences in development and behavior. Because all but two of the chromosomes are paired, most genes are as well; a gene

on one chromosome is paired with a gene for the same function on the other

chromosome. The exception is that the shorter Y chromosome has only one twenty- fifth as many genes as the X chromosome. Although paired genes have the same type of function, their effects often differ; these different versions of a gene are called alleles. In some cases the effects of the two alleles blend to produce a result; for example, a person with the allele for type A blood on one chromosome and the allele for type B blood on the other will have type AB blood. In other cases, one allele of a gene may be dominant over the other. A dominant

allele will produce its effect regardless of which allele it is paired with on the other chromosome; a recessive allele will have an influence only when it is paired with the same allele. Figure 1.10 illustrates this point. In the example on the left, note that one parent is homozygous for the type A allele, which means that the two alleles are identical; the other parent is heterozygous, with an allele for type A and one for type O. The allele for type A is dominant and, because every child will receive at least one A allele, all of the children will have type A blood. In other words, although the children have different genotypes (combinations of genes), they have the same phenotype (characteristic). In the second example, where both parents are heterozygous, about one out of four children will receive two recessive alleles and, therefore, will have type O blood.

Why do males more often show characteristics that are caused by recessive genes? In the case of unpaired genes on the X chromosome, a recessive gene alone is

adequate to produce an effect because it is not opposed by a dominant gene. A characteristic produced by an unpaired gene on the X chromosome is referred to as X- linked. With such a large discrepancy in the number of genes on the X and Y chromosomes, you can understand the potential for effects from X linkage. One example is that males are eight times more likely than females to have a deficiency in red-green color vision. Some characteristics—such as blood type and the degenerative brain disorder

Huntington’s disease—result from a single pair of genes, but many characteristics are determined by several genes; they are polygenic. Height is polygenic, and most behavioral characteristics such as intelligence and psychological disorders are also controlled by a large number of genes.

APPLICATION

A Computer Made of DNA

The complexity of DNA (left) permits Shapiro to build microscopic computers. Shapiro is holding a large-scale model. SOURCE: (left) National Human Genome Research Institute. (right) Used with permission of Professor Ehud Shapiro of the Computer Science Department at the Weizmann Institute of Science.

When some people look at DNA, they are struck by its similarities with a computer. Ehud Shapiro’s lab at the Weizmann Institute in Israel is taking that similarity to its logical conclusion by building computers out of DNA. They are so small that a single drop of water can hold a trillion of them. Basically, a strand of DNA serves as an “input” molecule, which is operated on by two enzymes and a preprogrammed “software” molecule to produce an “output” molecule. All this happens at the binary level, which means that the computer works by manipulating the equivalent of 1s and 0s. Why would anyone want to make a DNA computer? Shapiro and his

colleagues hope to produce DNA “medical kits” that operate inside the body, detecting a variety of diseases and treating them even before symptoms appear. Already, one of their computers can detect and destroy prostate cancer cells and another can detect a form of lung cancer, though only in a test tube so far (Benenson, Gil, Ben-Dor, Adar, & Shapiro, 2004). These computers are simple and perform a single function, but researchers at Stanford have designed a more broadly useful DNA device that mimics a transistor (Bonnet, Yin, Ortiz, Subsoontorn, & Endy, 2013). They were able to string several together to form the kinds of logic circuits used in computers, but the real value of DNA transistors is that they amplify small signals and could improve the ability to detect disease. Another obvious application is data storage; large scientific institutions archive data on magnetic tape, which must be replaced and rewritten every few years. DNA, on the other hand, can be stable for thousands of years if kept in a cool, dry place; by converting the usual binary 1s and 0s to DNA’s four-letter code, U.K. researchers have recorded data at a density equivalent to almost half a million DVDs per gram of DNA (Goldman

et al., 2013).

Genes and Behavior We have known from ancient times that animals could be bred for desirable

behavioral characteristics such as hunting ability or a mild temperament that made them suitable as pets. Charles Darwin helped establish the idea that behavioral traits can be inherited in humans as well, but the idea fell into disfavor as an emphasis on learning as the major influence on behavior became increasingly fashionable. But in the 1960s and 1970s, the tide of strict environmentalism began to ebb, and the perspective shifted toward a balanced view of the roles of nature and nurture (Plomin, Owen, & McGuffin, 1994). By 1992, the American Psychological Association was able to identify genetics as one of the themes that best represent the present and the future of psychology (Plomin & McClearn, 1993). FIGURE 1.10 Blood Types in the Offspring of Two Sets of Parents With Type A Blood. The circles in the boxes indicate the genotypes of the parents whose genes are indicated on the outside. Because the type A allele is dominant, all four parents have type A blood. On the left, one parent is homozygous for the A allele while the other is heterozygous, with an allele for each blood type. All of their offspring will receive at least one type A allele and will have type A blood, though about half will carry the type O allele. On the right, both parents are heterozygous for A and O. About three fourths of their offspring will receive the type O allele, but only about one fourth—those who receive two type O alleles—will have type O blood.

What are some of the inheritable behaviors? Of the behavioral traits that fall under genetic influence, intelligence is the most

investigated. Most of the behavioral disorders, including alcoholism and drug addiction, schizophrenia, major mood disorders, and anxiety, are partially hereditary as well (McGue & Bouchard, 1998). The same can be said for some personality characteristics (T. J. Bouchard, 1994) and sexual orientation (J. M. Bailey & Pillard, 1991; J. M. Bailey, Pillard, Neale, & Agyei, 1993; Kirk, Bailey, Dunne, & Martin,

2000). However, you should exercise caution in thinking about these genetic effects.

Genes do not provide a script for behaving intelligently or instructions for homosexual behavior. They control the production of proteins; the proteins in turn affect the development of brain structures, the production of neural transmitters and the receptors that respond to them, and the functioning of the glandular system. We will see specific examples in later chapters, where we will discuss this topic in more depth. The Human Genome Project After geneticists have determined that a behavior is influenced by genes, the next

step is to discover which genes are involved. The various techniques for identifying genes boil down to determining whether people who share a particular characteristic also share a particular gene or genes that other people don’t have. This task is extremely difficult if the researchers don’t know where to look, because the amount of DNA is so great. However, the gene search received a tremendous boost in 1990 when a consortium of geneticists at 20 laboratories around the world began a project to identify all the genes in our chromosomes, or the human genome.

What is the Human Genome Project, and how successful has it been? “

Landing a person on the moon gave us an extraterrestrial perspective on human life... and now the human genome sequence gives us a view of the internal genetic scaffold around which every human life is molded.

—Svante Pääbo

” The goal of the Human Genome Project was to map the location of all the genes on

the human chromosomes and to determine the genes’ codes—that is, the order of bases within each gene. In 2000—just 10 years after the project began—the project group and a private organization simultaneously announced “rough drafts” of the human genome (International Human Genome Sequencing Consortium, 2001; Venter et al., 2001). Within another 5 years, the entire human genome had been sequenced (Gregory et al., 2006). But when it comes to gene functioning, there is still more mystery than

enlightenment. Only 21,000 of our genes—just 3% of our DNA—have turned out to be protein encoding (The ENCODE Project Consortium, 2012). The lowly roundworm has 19,735 protein-coding genes (Hillier, Coulson, & Murray, 2005), so, clearly, the number of genes is not correlated with behavioral complexity. However, the amount of noncoding DNA—which we used to call “junk” DNA—does correlate

with behavioral complexity (Andolfatto, 2005; Siepel et al., 2005). So what is important about “junk” DNA? Some of it is, in fact, nonfunctional, remnants left behind during evolution; but much of the non-protein-coding DNA controls the expression of other genes—the translation of their encoded information into the production of proteins, thus controlling their functioning (Pennacchio et al., 2006). For example, when a stretch of noncoding DNA known as HACNS1—which is unique to humans—is inserted into a mouse embryo, it turns on genes in the “forearm” and “thumb” (Figure 1.11; Prabhakar et al., 2008). DNA taken from the same area in chimpanzees and rhesus monkeys does not have that effect. The researchers speculate that the genes that HACNS1 turns on led to the evolutionarily important dexterity of the human thumb. FIGURE 1.11 Human Junk DNA Turns on Genes in a Mouse Embryo’s Paw. To determine where the DNA was having an effect, it was paired with a gene that produces a blue protein when activated. The blue area indicates that HACNS1 is targeting genes in the area analogous to the human thumb.

SOURCE: From “Human-Specific Gain of Function in a Developmental Enhancer,” by S. Prabhakar et al., 2008, Science, 321, p. 1348. Reprinted with permission from AAAS. A second question is what the genes do. The gene map doesn’t answer that

question, but it does make it easier to find the genes responsible for a particular disorder or behavior. For example, when geneticists were searching for the gene that causes Huntington’s disease in the early 1980s, they found that most of the affected individuals in a large extended family shared a couple of previously identified genes with known locations on chromosome 4 while the disease-free family members didn’t. This meant that the Huntington’s gene was on chromosome 4 and near these

two marker genes (Gusella et al., 1983). Actually finding the Huntington gene still took another 10 years; now the gene map is dramatically reducing the time required to identify genes.

2 Gene Research Site Identifying the genes and their functions will improve our understanding of human

behavior and psychological as well as medical disorders. We will be able to treat disorders genetically, counsel vulnerable individuals about preventive measures, and determine whether a patient will benefit from a drug or have an adverse reaction, thus eliminating delays from trying one treatment after another. (See the accompanying Application.)

APPLICATION

Beyond the Human Genome Project Now that the human genome has been mapped, logical next steps include figuring out the functions of the genes and the remaining 97% of DNA, and then turning this knowledge into applications that can benefit individual humans. Two general directions of research in pursuit of these goals have been especially newsworthy lately. When the Human Genome Project ended in 2003, it was replaced by The

Encyclopedia of DNA Elements (ENCODE) Project; its purpose is to determine all the functional elements of the human genome and make an initial assessment of what their functions are. The project’s research teams at 32 institutions around the world have so far churned out more than 400 publications (Maher, 2012; Pennisi, 2012); one of their surprising revelations was that 80% of the genome is biochemically active. ENCODE data are already giving researchers new tools for understanding the etiology of a variety of diseases. The Human Genome and ENCODE projects have catapulted us into a new

era of genetic understanding, but some geneticists believe that now it is more efficient to focus on the exome, the complement of exons, or short sequences of DNA that actually direct protein production. The 180,000 exons of the human exome constitute only about 1% of the entire genome, so sequencing them is faster and cheaper, and scientists believe they contain 85% of all disease-causing mutations. Dutch scientists at the annual meeting of the European Society of Human Genetics in 2012 reported that sequencing the exomes of 262 patients detected disease-causing mutations in half of the cases of blindness; 20% of the patients with intellectual disability; 20% of the

deafness cases; and 15% to 20% of patients with movement disorders (European Society of Human Genetics, 2012). Lead researcher Marcel Nelen says that most of these patients have had “a long and worrying journey through different doctors and hospitals before they are diagnosed,” and exome sequencing can shorten that route.

3 The Human Exome

Heredity: Destiny or Predisposition? To many people, the idea that several, if not most, of their behavioral characteristics

are hereditary implies that they are clones of their parents and their future is engraved in stone by their genes. This is neither a popular nor a comfortable view and creates considerable resistance to the concept of behavioral genetics. The view is also misleading; a hallmark of genetic influence is actually diversity.

Do genes lock a person into a particular outcome in life? Genes and Individuality Although family members do tend to be similar to each other, children share only

half of their genes with each of their parents or with each other. A sex cell receives a random half of the parent’s chromosomes; as a result, a parent can produce 223, or 8 million, different combinations of chromosomes. Add to this the uncertainty of which sperm will unite with which egg, and the number of genetic combinations that can be passed on to offspring rises to 60 or 70 trillion! So sexual reproduction increases individuality in spite of the inheritability of traits. This variability powers what Darwin (Figure 1.12) called natural selection, which means that those whose genes endow them with more adaptive capabilities are more likely to survive and transmit their genes to more offspring (Darwin, 1859). FIGURE 1.12 Charles Darwin (1809–1882).

SOURCE: From Origins, Richard Leakey and Roger Lewin. The effects of the genes themselves are not rigid; they can be variable over time

and circumstances. Genes are turned on and turned off, or their activity is upregulated and downregulated, so they produce more or less of their proteins or different proteins at different times. If the activity of genes were constant, there would be no smoothly flowing sequence of developmental changes from conception to adulthood. A large number of genes change their functioning late in life, apparently accounting for many of the changes common to aging (Ly, Lockhart, Lerner, & Schultz, 2000), as well as the onset of diseases such as Alzheimer’s (Breitner, Folstein, & Murphy, 1986). The functioning of some genes is even controlled by experience, which explains some of the changes in the brain that constitute learning (C. H. Bailey, Bartsch, & Kandel, 1996). For the past quarter century, researchers have puzzled over why humans are so different from chimpanzees, our closest relatives, considering that 95% to 98% of our DNA sequences are identical (R. J. Britten, 2002; M.-C. King & Wilson, 1975). Now, it appears that part of the answer is that we differ more dramatically in which genes are expressed—actually producing proteins—in the brain (Enard, Khaitovich, et al., 2002). Genes also have varying degrees of effects; some determine the person’s

characteristics, while others only influence them. A person with the mutant form of the huntingtin gene will develop Huntington’s disease, but most behavioral traits depend on many genes; a single gene will account for only a slight increase in intelligence or in the risk for schizophrenia. The idea of risk raises the issue of vulnerability and returns us to our original question, the relative importance of heredity and environment. Heredity, Environment, and Vulnerability To assess the relative contributions of heredity and environment, we need to be able

to quantify the two influences. Heritability is the percentage of the variation in a

characteristic that can be attributed to genetic factors. There are various ways of estimating heritability of a characteristic; one technique involves a comparison of how often identical twins share the characteristic with how often fraternal twins share the characteristic. The reason for this comparison is that identical twins develop from a single egg and therefore have the same genes, while fraternal twins develop from separate eggs and share just 50% of their genes, like nontwin siblings. Heritability estimates are around 50% for intelligence (Plomin, 1990), which means that about half of the population’s differences in intelligence are due to heredity. Heritability has been estimated at 60% to 90% for schizophrenia (Tsuang, Gilbertson, & Faraone, 1991) and 40% to 50% for personality characteristics and occupational interests (Plomin et al., 1994). The heritability for height is approximately 90% (Plomin, 1990), which makes the values for behavioral characteristics seem modest. On the other hand, the genetic influence on behavioral characteristics is typically stronger than it is for common medical disorders, as Figure 1.13 shows (Plomin et al., 1994). Since about half of the differences in behavioral characteristics among people are

attributable to heredity, approximately half are due to environmental influences. Keep in mind that heritability is not an absolute measure but tells us the proportion of variability that is due to genetic influence; the measure depends on the environmental circumstances of the group we’re looking at as much as its genetic characteristics. For example, adoption studies tend to overestimate the heritability of intelligence because adopting parents are disproportionately from the middle class. Because the children’s environments are unusually similar, environmental influence will appear to be lower and heritability higher than typical (McGue & Bouchard, 1998). Similarly, heritability will appear to be lower if we look only at a group of closely related individuals.

What do we mean by “genetic predisposition”? Researchers caution us that “we inherit dispositions, not destinies” (R. J. Rose,

1995, p. 648). This is because the influence of genes is only partial. This idea is formalized in the vulnerability model, which has been applied to disorders such as schizophrenia (Zubin & Spring, 1977). Vulnerability means that genes contribute a predisposition for a disorder, which may or may not exceed the threshold required to produce the disorder; environmental challenges such as neglect or emotional trauma may combine with a person’s hereditary susceptibility to exceed that threshold. The general concept applies to behavior and abilities as well, though we wouldn’t use the term vulnerability. For example, the combination of genes a person receives determines a broad range for the person’s potential intelligence; environmental influences then will determine where in that range the person’s capability will fall. Psychologists no longer talk about heredity versus environment, as if the two are competing with each other for importance. Both are required, and they work together to make us what we are. As an earlier psychologist put it, “To ask whether heredity or

Concept Check

environment is more important to life is like asking whether fuel or oxygen is more necessary for making a fire” (Woodworth, 1941, p. 1). FIGURE 1.13 Twin Studies of Behavioral and Medical Disorders. The concordance of (a) behavioral disorders and (b) medical disorders in identical and fraternal twins. Concordance is the proportion of twin pairs in which both twins have the disorder. Note the greater concordance in identical twins and the generally higher concordance for behavioral disorders than for medical disorders.

SOURCE: From “The Genetic Basis of Complex Human Behavior,” by R. Plomin, M. J. Owen, and P. McGuffin, Science, 264, p. 1734. © 1994 American Association for the Advancement of Science. Reprinted with permission from AAAS.

Take a Minute to Check Your Knowledge and Understanding

Why is it inappropriate to ask whether heredity or environment is more important for behavior?

When we say that a person inherits a certain personality characteristic, what do we really mean?

Explain how two parents who have the same characteristic produce children who are different from them in that characteristic. Use appropriate terminology.

Explain how genes influence behavior.

With increasing understanding of genetics, we are now in the position to change our very being. This kind of capability carries with it a tremendous responsibility. The knowledge of our genetic makeup raises the question whether it is better for a person to know about a risk that may never materialize, such as susceptibility to Alzheimer’s disease. In addition, many worry that the ability to do genetic testing on our unborn children means that some parents will choose to abort a fetus because it has genes for a trait they consider undesirable. Our ability to plumb the depths of the brain and of

the genome is increasing faster than our grasp of either its implications or how to resolve the ethical questions that will arise. We will consider some of the ethical issues of genetic research in Chapter 4. In Perspective In the first issue of the journal Nature Neuroscience, the editors observed that brain science still has a “frontier” feel to it (“From Neurons to Thoughts,” 1998). The excitement Kay Jamison talked about is real and tangible, and the accomplishments are remarkable for such a young discipline. The successes come from many sources: the genius of our intellectual ancestors, the development of new technologies, the adoption of empiricism, and, I believe, a coming to terms with the concept of the mind. Evidence of all these influences will be apparent in the following chapters.

4 More Useful Websites Neuroscience and biopsychology still have a long way to go. For all our successes,

we do not fully understand what causes schizophrenia, exactly how the brain is changed by learning, or why some people are more intelligent than others. Near the end of the Decade of the Brain, Torsten Wiesel (whose landmark research in vision you will read about later) scoffed at the idea of dedicating a decade to the brain as “foolish.... We need at least a century, maybe even a millennium” (quoted in Horgan, 1999, p. 18). As you read the rest of this book, keep in mind that you are on the threshold of that century’s journey, that millennium of discovery. Summary The Origins of Biopsychology • Biopsychology developed out of physiology and philosophy as early psychologists adopted empiricism.

• Most psychologists and neuroscientists treat mind as a product of the brain, believing that mental activity can be explained in terms of the brain’s functions.

• Localization describes brain functioning better than equipotentiality, but a brain process is more likely to be carried out by a network of structures than by a single structure.

Nature and Nurture • We are learning that a number of behaviors are genetically influenced. One does not inherit a behavior itself, but genes influence structure and function in the brain and body in a way that influences behavior.

• Behavior is a product of both genes and environment. In many cases, genes produce a predisposition, and environment further determines the outcome.

• With the knowledge of the genome map, we stand on the threshold of unbelievable opportunity for identifying causes of behavior and diseases, but we face daunting ethical challenges as well. ■ Study Resources

For Further Thought • Why, in the view of most neuroscientists, is materialistic monism the more productive approach for understanding the functions of the mind? What will be the best test of the correctness of this approach?

• Scientists were working just as hard on the problems of the brain a half century ago as they are now; why were the dramatic discoveries of recent years not made then?

• What are the implications of knowing what all the genes do and of being able to do a scan that will reveal which genes an individual has?

• If you were told that you had a gene that made it 50% likely that you would develop a certain disease later in life, would there be anything you could do?

Quiz: Testing Your Understanding 1. How would a monist and a dualist pursue the study of biopsychology

differently? 2. What was the impact of the early electrical stimulation studies and the

evidence that specific parts of the brain were responsible for specific behaviors?

3. The allele for type B blood is, like the one for type A, dominant over the allele for type O. Make a matrix like the one in Figure 1.10 to show the genotypes and phenotypes of the offspring of an AO parent and a BO parent.

4. A person has a gene that is linked with a disease but does not have the disease. We have mentioned three reasons why this could occur; describe two of them.

5. Discuss the interaction between heredity and environment in influencing behavior, including the concept of vulnerability.

Select the best answer: 1. The idea that mind and brain are both physical is known as

a. idealistic monism. b. materialistic monism. c. idealistic dualism. d. materialistic dualism.

2. A model is a. an organism or a system used to understand a more complex one. b. a hypothesis about the outcome of a study. c. an analogy, not intended to be entirely realistic. d. a plan for investigating a phenomenon.

3. Descartes’s most important contribution was in

a. increasing knowledge of brain anatomy. b. suggesting the physical control of behavior. c. emphasizing the importance of nerves. d. explaining how movement is produced.

4. Helmholtz showed that a. nerves are not like electrical wires because they conduct too slowly. b. nerves operate electrically. c. nerves do not conduct animal spirits. d. language, emotion, movement, and so on depend on the activity of

nerves. 5. In the mid-1800s, studies of brain-damaged patients convinced researchers

that a. the brain’s activity was electrical. b. the mind was not located in the brain. c. behaviors originated in specific parts of the brain. d. the pineal gland could not serve the role Descartes described.

6. Localization means that a. specific functions are found in specific parts of the brain. b. the most sophisticated functions are located in the highest parts of the

brain. c. any part of the brain can take over other functions after damage. d. brain functions are located in widespread networks.

7. X-linked characteristics affect males more than females because a. the X chromosome is shorter than the Y chromosome. b. unlike males, females have only one X chromosome. c. the responsible gene is not paired with another gene on the Y

chromosome. d. the male internal environment exaggerates effects of the genes.

8. Two parents are heterozygous for a dominant characteristic. They can produce a child with the recessive characteristic: a. if the child receives a dominant gene and a recessive gene. b. if the child receives two recessive genes. c. if the child receives two dominant genes. d. under no circumstance.

9. The Human Genome Project has a. counted the number of human genes. b. made a map of the human genes. c. determined the functions of most genes. d. cloned most of the human genes.

10. Heritability is greatest for

a. intelligence. b. schizophrenia. c. personality. d. height.

11. If we all had identical genes, the estimated heritability for a characteristic would be a. 0%. b. 50%. c. 100%. d. impossible to determine.

Answers: 1. b, 2. a, 3. b, 4. a, 5. c, 6. a, 7. c, 8. b, 9. b, 10. d, 11. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Web links from the text • Web resources On the Web The following websites are coordinated with this chapter’s content. (See the numbered WWW icons in the margins.) To access these sites: On the Chapter Resources page, select this chapter and then click on Web links from the text. (Bold items are links.) Also, be sure to look at the other study aids, as well as the Updates from the Author (located above the list of chapters). 1. Mind and Body covers the history of the idea from René Descartes to

William James. Most pertinent sections are I: 1–5 and II: 1–2. 2. You can search Online Mendelian Inheritance in Man by

characteristic/disorder (e.g., schizophrenia), chromosomal location (e.g., 1q21–q22), or gene symbol (e.g., SCZD9) to get useful genetic information and summaries of research articles.

3. The Wikipedia article Exome includes links to descriptions of several research projects using exome sequencing.

4. The following journals are major sources of neuroscience articles (those that are not open access may require a subscription or university access): Behavioral Sciences (open access) Brain and Behavior (open access) Brain, Behavior, and Evolution

Frontiers in Neuroscience (open access) Journal of Neuroscience Nature Nature Neuroscience Nature Reviews Neuroscience New Scientist (for the general reader) PLoS Biology (open access) PLoS Genetics (open access) Science Scientific American Mind (for the general reader) The Scientist (for the general reader) Trends in Neurosciences

General information sites: Brain Briefings (various topics in neuroscience) Brain in the News (neuroscience news from media sources) The Human Brain (a collection of brain-related articles published in the magazine New Scientist) Neuroguide (a small but growing offering of resources) Science Daily (latest developments in science; see “Mind & Brain” and “Health & Medicine”)

Chapter Updates and Biopsychology News

For Further Reading 1. “The Emergence of Modern Neuroscience: Some Implications for

Neurology and Psychiatry,” by W. Maxwell Cowan, Donald H. Harter, and Eric R. Kandel (Annual Review of Neuroscience, 2000, 23, 343–391), describes the emergence of neuroscience as a separate discipline in the 1950s and 1960s, and details its most important accomplishments in understanding disorders.

2. “Neuroscience: Breaking Down Scientific Barriers to the Study of Brain and Mind,” by E. R. Kandel and Larry Squire (Science, 2000, 290, 1113– 1120), is a briefer treatment of the recent history of neuroscience, with an emphasis on psychological issues; a timeline of events over more than three centuries is included.

3. The Scientific American Brave New Brain, by Judith Horstman (Jossey- Bass, 2010), describes how today’s scientific breakthroughs will in the future help the blind see and the deaf hear, allow our brains to repair and improve themselves, help us postpone the mental ravages of aging, and give the paralyzed control of prosthetic devices and machinery through brain waves.

4. Behavioral Genetics, by Robert Plomin, John DeFries, Gerald McClearn, and Peter McGuffin (Worth, 2008, 5th ed.), is a textbook on that topic; another text, Evolutionary Psychology, by William Ray (SAGE, 2013), takes a neuroscience approach to the evolution of behavior.

5. “Tweaking the Genetics of Behavior,” by Dean Hamer (available at http://apbio.savithasastry.com/Units/Unit%208/articles/cle_review_genesandbehavior.pdf is a fanciful but thought-provoking story about a female couple in 2050 who have decided to have a child cloned and the decisions available to them for determining their baby’s sex and her physical and psychological characteristics through genetic manipulation.

Key Terms allele biopsychology deoxyribonucleic acid (DNA) dominant dualism embryo empiricism equipotentiality expression (of genes) fetus gene genome genotype heritability heterozygous homozygous Human Genome Project localization materialistic monism mind-brain problem model monism natural selection nature versus nurture neuroscience phenotype phrenology polygenic

recessive vulnerability X-linked zygote

PART I

Neural Foundations of Behavior: The Basic Equipment

Chapter 2. Communication Within the Nervous System Chapter 3. The Organization and Functions of the Nervous System Chapter 4. The Methods and Ethics of Research

T

2 Communication Within the Nervous System

In this chapter you will learn • How neurons are specialized to conduct information • How glial cells support the activity of neurons • How neurons communicate with each other • Strategies neurons use to increase their information capacity • The functions of some of the major chemical transmitters • How computer simulations of neural networks are duplicating many brain functions

The Cells That Make Us Who We Are Neurons APPLICATION: TARGETING ION CHANNELS

Glial Cells CONCEPT CHECK

How Neurons Communicate With Each Other Chemical Transmission at the Synapse Regulating Synaptic Activity Neurotransmitters APPLICATION: AGONISTS AND ANTAGONISTS IN THE REAL WORLD

Of Neuronal Codes, Neural Networks, and Computers IN THE NEWS: THE HUMAN BRAIN PROJECT CONCEPT CHECK

In Perspective Summary Study Resources

hings were looking good for Jim and his wife. She was pregnant with their first child, and they had just purchased and moved into a new home. After the exterminating company treated the house for termites by injecting the pesticide

chlordane under the concrete slab, Jim noticed that the carpet was wet and there was a chemical smell in the air. He dried the carpet with towels and thought no more about

it, not realizing that chlordane can be absorbed through the skin. A few days later, he developed headaches, fatigue, and numbness. Worse, he had problems with memory, attention, and reasoning. His physician referred him to the toxicology research center of a large university medical school. His intelligence test score was normal, but the deficiencies he was reporting showed up on more specific tests of cognitive ability. Jim and his wife had to move out of their home. At work, he had to accept reduced responsibilities because of his difficulties in concentration and adapting to novel situations. The chlordane had not damaged the structure of his brain as you might suspect, but it had interfered with the functioning of the brain cells by impairing a mechanism called the sodium-potassium pump (Zillmer & Spiers, 2001). Jim’s unfortunate case reminds us that the nervous system is as delicate as it is intricate. Only by understanding how it works will we be able to appreciate human behavior, to enhance human performance, and to treat behavioral problems such as drug addiction and psychosis. FIGURE 2.1 Estimated Numbers of Neurons in the Brain and Spinal Cord.

The Cells That Make Us Who We Are To understand human behavior and the disorders that affect it, you must understand

how the brain works. And to understand how the brain works, you must first have at least a basic understanding of the cells that carry messages back and forth in the brain and throughout the rest of the body. Neurons are specialized cells that convey sensory information into the brain; carry out the operations involved in thought, feeling, and action; and transmit commands out into the body to control muscles and organs. It is estimated that there are about 100 billion neurons in the human brain (Figure 2.1; R. W. Williams & Herrup, 2001). This means that there are more neurons in your brain than stars in our galaxy. But as numerous and as important as they are, neurons make up only 10% of the brain’s cells and about half its volume. The other 90% are glial cells, which we will discuss later in the chapter. Neurons Neurons have the responsibility for all the things we do—our movements, our

thoughts, our memories, and our emotions. It is difficult to believe that anything so simple as a cell can measure up to this task, and the burden is on the neuroscientist to demonstrate that this is true. As you will see, the neuron is deceptively simple in its action but impressively complex in its function.

What are the parts of the neuron? Basic Structure: The Motor Neuron First let’s look inside a neuron, because I want to show you that the neuron is a cell,

very much like other cells in the body. Figure 2.2 is an illustration of the most prominent part of the neuron, the cell body or soma. The cell body is filled with a watery liquid called cytoplasm and contains a number of organelles. The largest of these organelles is the nucleus, which contains the cell’s chromosomes. Other organelles are responsible for converting nutrients into fuel for the cell, constructing proteins, and removing waste materials. So far, this could be the description of any cell; now let’s look at the neuron’s specializations that enable it to carry out its unique role. Figure 2.3 illustrates a typical neuron. “Typical” is used guardedly here, because there are three major kinds of neurons and variations within those types. This particular type is a motor neuron, which carries commands to the muscles and organs. It is particularly useful for demonstrating the structure and functions that neurons have in common. FIGURE 2.2 Cell Body of a Neuron. Part of the membrane has been removed to show interior features.

Dendrites are extensions that branch out from the cell body to receive information from other neurons. Their branching structure allows them to collect information from many neurons. The axon extends like a tail from the cell body and carries information to other locations, sometimes across great distances. The myelin sheath that is shown wrapped around the axon supports the axon and provides other benefits that we will consider later. Branches at the end of the axon culminate in swellings called end bulbs or terminals. The terminals contain chemical neurotransmitters, which the neuron releases to communicate with a muscle or an organ or the next neuron in a chain. In our examples, we will talk as if neurons form a simple chain, with one cell sending messages to a single other neuron, and so on; in actuality, a neuron receives input from many neurons and sends its output to many others. Neurons are usually so small that they can be seen only with the aid of a

microscope. The cell body is the largest part of the neuron, ranging from 0.005 to 0.1 millimeter (mm) in diameter in mammals. (In case you are unfamiliar with metric measurements, a millimeter is about the thickness of a dime.) Even the giant neurons of the squid, favored by researchers for their conveniently large size, have axons that are only 1 mm in diameter. Typical axons are smaller; in mammals, they range from 0.002 to 0.02 mm in diameter. Axons can be anywhere from 0.1 mm to more than a meter in length. FIGURE 2.3 Components of a Neuron.

The illustration is of a motor neuron.

Other Types of Neurons The second type of neuron is the sensory neuron. Sensory neurons carry

information from the body and from the outside world into the brain and spinal cord. Motor and sensory neurons have the same components, but they are configured differently. A motor neuron’s axon and dendrites extend in several directions from the cell body, which is why it is called a multipolar neuron. Sensory neurons can be either unipolar or bipolar. The sensory neuron in Figure 2.4a is called a unipolar neuron because of the single short stalk from the cell body that divides into two branches. Bipolar neurons have an axon on one side of the cell body and a dendritic process on the other (Figure 2.4b). Motor and sensory neurons are specialized for transmission over long distances; their lengths are not shown here in the same scale as the rest of the cell. The third type is neither motor nor sensory. Interneurons connect one neuron to

another in the same part of the brain or spinal cord. Notice in Figure 2.4c that this neuron is also multipolar, but its axon appears to be missing; for some interneurons this is so, and when they do have axons, they are often so short that they are indistinguishable from dendrites. Because interneurons make connections over very short distances, they do not need the long axons that characterize their motor and sensory counterparts. In the spinal cord, interneurons bridge between sensory neurons and motor neurons to produce a reflex. In the brain, they connect adjacent neurons to carry out the complex processing that the brain is noted for. Considering the major role they play, it should come as no surprise that interneurons are the most numerous neurons.

How do the major types of neurons differ? FIGURE 2.4 Sensory Neurons and an Interneuron. Compare the location of the soma in relation to the dendrites and axon in these and in the motor neuron.

The different kinds of neurons operate similarly; they differ mostly in their shape, which fits them for their specialized tasks. We will examine how neurons work in the next few sections. The types of neurons and their characteristics are summarized in Table 2.1. TABLE 2.1 The Major Types of Neurons.

The Neural Membrane and Its Potentials The most critical factor in the neuron’s ability to communicate is the membrane

that encloses the cell. The membrane is exceptionally thin—only about 8 micrometers (millionths of a meter) thick—and is made up of lipid (fat) and protein (see Figure 2.5). Each lipid molecule has a “head” end and a “tail” end. The heads of the molecules are water soluble, so they are attracted to the seawater-like fluid around and inside cells. The tails are water insoluble, so they are repelled by the fluid. Therefore, as the heads orient toward the fluid and the tails orient away from the fluid, the molecules turn their tails toward each other and form a double-layer membrane. FIGURE 2.5 Cross Section of the Cell Membrane of a Neuron.

Notice how the lipid molecules form the membrane by orienting their heads toward the extracellular and intracellular fluids.

The membrane not only holds a cell together but also controls the environment within and around the cell. Some molecules, such as water, oxygen, and carbon dioxide, can pass through the membrane freely. Many other substances are barred from entry. Still others are allowed limited passage through protein channels (shown here in green) that open and close under different circumstances. This selective permeability contributes to the most fundamental characteristic of neurons, polarization, which means that there is a difference in electrical charge between the inside and outside of the cell. A difference in electrical charge between two points, such as the poles of a battery or the inside and outside of a cell, is also called a voltage. FIGURE 2.6 Recording Potentials in a Neuron. Potentials are being recorded in the axon of a neuron, with an electrode inside the cell and one in the fluid outside. Due to the size of neurons, the electrodes have microscopically small tips. On the right, a highly magnified view shows the size of a microelectrode relative to that of neurons. Electrodes for recording inside neurons are even smaller.

SOURCE: (right) © Bob Jacobs, Colorado College. The Resting Potential. Just as you would measure the voltage of a battery, you can

measure a neuron’s voltage (see Figure 2.6). By arbitrary convention, the voltage is expressed as a comparison of the inside of the neuron with the outside. The difference in charge between the inside and outside of the membrane of a neuron at rest is called the resting potential. This voltage is negative and varies anywhere from –40 to –80 millivolts (mV) in different neurons but is typically around –70 mV. You should understand that neither the inside of the neuron nor the outside has a voltage, because a voltage is a difference and is meaningful only in comparison with another location. Note that this voltage is quite small—the voltage of a 1.5-V flashlight battery is 25 times greater. No matter; we’re moving information, and very little power is required.

What accounts for the resting potential? The resting potential is due to the unequal distribution of electrical charges on the

two sides of the membrane. The charges come from ions, atoms that are charged because they have lost or gained one or more electrons. Sodium ions (Na+) and potassium ions (K+) are positively charged. Chloride ions (Cl–) are negative, and so are certain proteins and amino acids that make up the organic anions (A–). The fluid outside the neuron contains mostly Na+ and Cl– ions, and the ions inside the neuron are mostly K+ and A– (see Figure 2.7). The inside of the neuron has more negative ions than positive ions, while the ions on the outside are mostly positive, and this makes the resting potential negative. If you remember from grade-school science that molecules tend to diffuse from an

area of high concentration to one of low concentration, then you are probably wondering how this imbalance in ion distribution can continue to exist. In fact, two forces do work to balance the location of the ions. Because of the force of diffusion, ions move through the membrane to the side where they are less concentrated. And, as a result of electrostatic pressure, ions are repelled from the side that is similarly charged and attracted to the side that is oppositely charged. FIGURE 2.7 Distribution of Ions Inside and Outside the Resting Neuron. Ions on the outside are mostly Na+ and Cl– ions; inside, the ions are mostly K+ ions

and organic anions. In the middle, a sodium channel is closed; on the left, a sodium-potassium pump is discharging three Na+ ions outside the neuron, while on the right another is returning two K+ ions to the inside.

In spite of these two forces, a variety of other influences keep the membrane polarized. Both forces would move the organic anions out, but they are too large to pass through the membrane. Their negative charge then repels the chloride ions, so the force of diffusion is unable to move those ions inside. As a result, the “real players” then become the potassium and sodium ions. There is a slightly greater tendency for potassium to move outward (because its force of diffusion is stronger than its electrostatic pressure), while the force of both gradients attracts sodium inside. However, ions may cross the membrane only through channels like those in Figures 2.7 and 2.8, which are selective for particular ions. In the neuron’s resting state, both the sodium channel and the potassium channel are closed, so only a few ions trickle through. The few ions that do make it through are returned by the sodium-potassium pump,

which consists of large protein molecules that move sodium ions through the cell membrane to the outside and potassium ions back inside. Its exchange rate of three sodium ions for every two potassium ions helps keep the inside of the membrane more negative than the outside. The pump is a metabolic process, which means that it uses energy; in fact, it accounts for an estimated 40% of the neuron’s energy expenditure. But you will soon see that this energy is well spent, because the resting potential stores the energy to power the action potential. The Action Potential. A neuron is usually excited by input that arrives on the

neuron’s dendrites and cell body from another neuron or from a sensory receptor. An excitatory signal causes a partial depolarization, which means that the polarity in a

small area of the membrane is shifted toward zero. This partial depolarization disturbs the ion balance in the adjacent membrane, so the disturbance flows down the dendrites and across the cell membrane. This looks at first like the way the neuron might communicate its messages through the nervous system; however, because a partial depolarization is decremental—it dies out over distance—it is effective only over very short distances. For this reason, the partial depolarization is often called the local potential. Fortunately, the membrane of the axon has unique physical properties. If the local potential exceeds the threshold for activating that neuron, typically about 10 mV more positive than the resting potential, it will cause the normally closed sodium channels in that area to open, which triggers an action potential. FIGURE 2.8 Ion Movement and Voltages During the Neural Impulse. At point of (a), the membrane voltage is at the neuron’s resting potential, –70 mV; as indicated in (b), there is an abundance of sodium ions (red) on the outside of the membrane and an abundance of potassium ions (blue) on the inside. (Chloride ions and organic anions are not shown here.) At a local potential has arrived at the axon hillock, partially depolarizing a small area of the axon membrane. At this partial depolarization has reached the neuron’s threshold, which triggers the opening of sodium channels (c); sodium ions rush in, completely depolarizing the membrane. At the potassium channels begin to open, and potassium ions start flowing out (d); shortly after, at sodium channels close (d, also d). With no more sodium ions entering the membrane and with potassium ions leaving, the membrane begins recovering its resting potential at . At the membrane voltage continues to fluctuate around the resting potential for several milliseconds (unless there is another action potential).

The action potential is an abrupt depolarization of the membrane that allows the neuron to communicate over long distances. (The following discussion is illustrated in Figure 2.8.) The voltage across the resting neuron membrane is stored energy, just as the term resting potential implies. Imagine countless sodium ions being held outside the neuron against the combined forces of diffusion and electrostatic pressure. Opening the sodium channels allows the sodium ions in that area to rush into the axon at a rate 500 times greater than normal; they are propelled into the cell’s interior so rapidly that the movement is often described as explosive. A small area inside the membrane becomes fully depolarized to zero; the potential even overshoots to around +30 or +40 mV, making the interior at that location temporarily positive.

1 Resting and Action Potentials Just as abruptly as the neuron “fired,” it begins to recover its resting potential. At

the peak of the action potential, the sodium channels close, so there is no further depolarization. By that time the potassium channels have opened; the positive charge and the concentration of potassium ions inside the membrane combine to move potassium ions out. This outward flow of potassium ions returns the axon to its resting potential. The action potential requires about 1 millisecond (ms; one thousandth of a

second) or so to complete; the actual duration varies among individual neurons. The action potential causes nearby sodium channels to open as well. Thus, a new

action potential is triggered right next to the first one. That action potential in turn triggers another farther along, creating a chain reaction of action potentials that move through the axon; thus, a signal flows from one end of the neuron to the other. Nothing physically moves down the axon. Instead, a series of events occurs in succession along the axon’s length, much as a line of dominoes standing on end knock each other over when you tip the first one. When the action potential reaches the terminals, they pass the signal on to the next neuron in the chain (or to an organ or a muscle). The transmission from neuron to neuron is covered later; for now, the action potential needs to be examined a bit further. Although the neuron has returned to its resting potential, a number of extra sodium

ions remain inside, and there is an excess of potassium ions on the outside. Actually, only the ions in a very thin layer on either side of the membrane have participated in the action potential, so the dislocated ions are able to diffuse into the surrounding fluid. Eventually, though, the ions must be replaced or the neuron cannot continue firing. The sodium-potassium pump takes care of this chore. (Perhaps you can see now why Jim was in such a bad way after his bout with chlordane.)

What is the role of the sodium-potassium pump following an action potential? The action potential differs in two important ways from the local potential that

initiates it. First, the local potential is a graded potential, which means that it varies in magnitude with the strength of the stimulus that produced it. The action potential, on the other hand, is ungraded; it operates according to the all-or-none law, which means that it occurs at full strength or it does not occur at all. A larger graded potential does not produce a larger action potential; like the fuse of a firecracker, the action potential depends on the energy stored in the neuron. A second difference is that the action potential is nondecremental ; it travels down the axon without any decrease in size, propagated anew and at full strength at each successive point along the way. The action potential thus makes it possible for the neuron to conduct information over long distances.

How is an action potential different from a graded potential? However, because the action potential is all-or-none, its size cannot carry

information about the intensity of the initiating stimulus. One way stimulus intensity is represented is in the number of neurons firing, because a more intense stimulus will recruit firing in neurons with higher thresholds. There is, though, a way in which the individual neuron can encode stimulus strength, as you will see in the discussion of refractory periods.

APPLICATION

Targeting Ion Channels The Japanese delicacy fugu, or puffer fish, produces an exciting tingling sensation in the diner’s mouth; improperly prepared, it causes numbness and weakness and, in some cases, a paralysis of the respiratory muscles that has claimed the lives of a few thousand culinary risk takers. The fish’s natural poison, tetrodotoxin (TDT), blocks sodium channels and prevents neurons from firing (Kandel & Siegelbaum, 2000a). Other neurotoxins (neuron poisons) are found in snake venoms, which block either sodium or potassium channels (Benoit & Dubois, 1986; Fertuck & Salpeter, 1974), and scorpion venom, which keeps sodium channels open, prolonging the action potential (Catterall, 1984; Chuang, Jaffe, Cribbs, Perez-Reyes, & Swartz, 1998; Pappone & Cahalan, 1987). Interfering with neuron functioning can be useful, though; for example,

most local anesthetics prevent neuron firing by blocking sodium channels (Ragsdale, McPhee, Scheuer, & Catterall, 1994), and some general anesthetics hyperpolarize the neuron by opening potassium channels and allowing the potassium ions to leak out (Nicoll & Madison, 1982; A. J. Patel et al., 1999). The cone snail of the South Seas can penetrate a wet suit with its proboscis and inject toxins that will kill a human in half an hour, but its hundred or so toxins that target sodium, potassium, or calcium channels or block neurotransmitter receptors are in demand by researchers developing pain relievers and drugs for epilepsy (L. Nelson, 2004). An exciting new research strategy known as optogenetics involves creating

light-responsive ion channels in the membrane of neurons so the neurons can be controlled by light. Typically, the channels are proteins controlled by opsin genes, which are found in many members of the plant and animal kingdoms; their normal functional roles include orientation to light, circadian rhythms, and vision (F. Zhang et al., 2011). Some of the channels allow positive ions to enter the neuron, depolarizing it, and others move negative ions inside, hyperpolarizing it. The channels are triggered by different wavelengths of light, allowing the researcher either to accelerate or to inhibit firing. In a different technique, glutamate receptors can be modified without the use of opsins so that green light and ultraviolet light have opposing effects, turning the receptor into a neuronal on-off switch (Levitz et al., 2013). Optogenetic modifications can be targeted to specific types of neurons, so the procedure offers more precise control than electrical stimulation, which activates all neurons in the area. In a living animal, stimulation can be delivered through a

transparent window in the skull or deeper in the brain via a fiber-optic probe. Though the procedure is not ready for human applications, its use in animal models is helping us understand the circuitry involved in human disorders, such as Parkinson’s disease and depression.

Modified Membrane Enables Light Control of Neuron Activity. (a) Blue light activates a channel from green algae; the channel allows positive ions to flow inward, triggering neural impulses. (b) Yellow light activates a chloride pump from bacteria; chloride ions hyperpolarize the neuron. SOURCE: Adapted from “Controlling Neural Circuits With Light,” by M. Häusser and S. L. Smith, 2007, Nature, 446, pp. 617–619 (Figure 1a, p. 617).

Refractory Periods Right after the action potential occurs, the neuron goes through the absolute

refractory period, a brief time during which it cannot fire again; this occurs because the sodium channels cannot reopen. This delay in responsiveness has two important effects. First, the absolute refractory period limits how frequently the neuron can fire. If a neuron takes a full millisecond to recover to the point where it can fire again, then the neuron can fire, at most, a thousand times a second; many neurons have much lower firing rate limits. A second effect of this recovery period is that the action potential will set off new action potentials only in front of it (the side toward the terminals), not on the side it has just passed. This is critical, because backward- moving potentials would block responses to newly arriving messages. A second refractory period plays a role in intensity coding in the axon. The

potassium channels remain open for a few milliseconds following the absolute refractory period, and the continued exit of potassium makes the inside of the neuron slightly more negative than usual (the “dip” in Figure 2.8). During the relative refractory period, the neuron can be fired again, but only by a stronger-than-threshold

stimulus. A stimulus that is greater than threshold will cause the neuron to fire again earlier and thus more frequently. The axon encodes stimulus intensity not in the size of its action potential but in its firing rate, an effect called the rate law.

What are the absolute and relative refractory periods? Glial Cells Glial cells are nonneural cells that provide a number of supporting functions to

neurons. The name glia is derived from the Greek word for glue, which gives you some idea how the role of glial cells has been viewed in the past. However, glial cells do much more than hold neurons together. One of their most important functions is to increase the speed of conduction in neurons. Myelination and Conduction Speed Survival depends in part on how rapidly messages can move through the nervous

system, enabling the organism to pounce on its prey, outrun a predator, or process spoken language quickly. The speed with which neurons conduct their impulses varies from 1 to 120 meters (m) per second (s), or about 270 miles per hour. This is much slower than the flow of electricity through a wire, the analogy sometimes mistakenly used to describe neural conduction. Because conduction speed is so critical to survival, strategies have evolved for increasing it. One way is to develop larger axons, which provide less resistance to the flow of electrical potentials. By evolving motor neurons with 0.5 mm thick axons, the squid has achieved conduction speeds of 30 m/s, compared with 1 m/s in the smallest neurons.

What are the functions of glial cells? However, conduction speed does not increase in direct proportion to axon size. To

reach our four-times-greater maximum conduction speed of 120 m/s, our axons would have to be 42 = 16 times larger than the squid axon, or 8 mm in diameter! Obviously, your brain would be larger than you could carry around. In other words, if axon size were the only way to achieve fast conduction speed, you would not exist. Vertebrates (animals with backbones) have developed another solution, myelination. Glial cells produce myelin, a fatty tissue that wraps around the axon to insulate it from the surrounding fluid and from other neurons. Only the axon is covered, not the cell body. Myelin is produced in the brain and spinal cord by a type of glial cell called oligodendrocytes and in the rest of the nervous system by Schwann cells (see Figure 2.9). Because there are very few sodium channels under the myelin sheath, action

potentials cannot occur there; conduction in myelinated areas is by graded potential (Waxman & Ritchie, 1985). However, myelin appears in segments about 1 mm long, with a gap of one or two thousandths of a millimeter between segments. The gaps in the myelin sheath are called nodes of Ranvier (see Figure 2.9 again). At each node of

Ranvier, where the membrane is exposed and there are plenty of sodium channels, the graded potential triggers an action potential; action potentials thus jump from node to node in a form of transmission called saltatory conduction. This arrangement has three benefits. First, the insulating effect of myelin reduces

an electrical effect of the membrane called capacitance. Because capacitance slows the movement of ions down the axon, the graded potential gets a big boost in speed. The overall effect of myelination is the equivalent of increasing the axon diameter 100 times (Koester & Siegelbaum, 2000). Second, the breaks in the myelination mean that the signal is renewed by an action potential at every node of Ranvier. Third, myelinated neurons use much less energy because there is less work for the sodium- potassium pump to do.

2 Myelination and Conduction Speed FIGURE 2.9 Glial Cells Produce Myelin for Axons. A single oligodendrocyte provides myelin for multiple segments of the axon and for multiple neurons. A Schwann cell covers only one segment of an axon.

Some diseases, such as multiple sclerosis, destroy myelin. As myelin is lost, the capacitance rises, reducing the distance that graded potentials can travel before dying out. The individual is worse off than if the neurons had never been myelinated; due to the reduced number of sodium channels, action potentials may not be generated in the previously myelinated area. Conduction slows or stops in affected neurons. FIGURE 2.10 Glial Cells Increase the Number of Connections Between Neurons.

Neurons were cultured for 5 days in the absence of glial cells (a) and in the presence of glia (b). The number of neurons was similar in both cultures; the greater density on the right is due to increased connections among the neurons.

SOURCE: From “Synaptic Efficacy Enhanced by Glial Cells In Vitro,” by F. W. Pfrieger and B. A. Barres, Science, 277, p. 1684. © 1997. Reprinted with permission from AAAS. FIGURE 2.11 Number of Astrocytes per Neuron in Various Species. The ratio of astrocytes per neuron increases as behavioral complexity increases. Notice that the leech, frog, mouse, and rat all have less than one astrocyte per neuron, while the cat and humans have more astrocytes than neurons.

SOURCE: Based on data from “New Roles for Astrocytes: Redefining the Functional Architecture of the Brain,” by M. Nedergaard, B. Ransom, and S. A. Goldman, Trends in Neurosciences, 26, pp. 523–530. © 2003. Used with permission from Elsevier. Other Glial Functions During fetal development, one kind of glial cell forms a scaffold that guides new

neurons to their destination. Later on, glial cells provide energy to neurons and respond to injury and disease by removing cellular debris. Others contribute to the development and maintenance of connections between neurons. Neurons form seven times as many connections in the presence of glial cells, and if glial cells are removed from a laboratory dish, the neurons start to lose their synapses (Pfrieger & Barres,

Concept Check

1997; Ullian, Sapperstein, Christopherson, & Barres, 2001; see Figure 2.10). You will see later that glia play an important role in neural activity as well. An indication of the importance of glial cells is that as brain complexity increases across species, there is also a progressive increase in the ratio of astrocytes to neurons; astrocytes are the glial cells most intimately involved with neural activity (Figure 2.11).

Take a Minute to Check Your Knowledge and Understanding

How is information conducted in the axon? How does the all-or-none law limit information transmission? What benefits do the refractory periods provide? How does myelin speed up conduction in axons?

How Neurons Communicate With Each Other Before the late 1800s, microscopic examination suggested that the brain consisted of a continuous web. At that point, however, Camillo Golgi developed a new tissue- staining method that helped anatomists see individual neurons by randomly staining some entire cells without staining others (see the discussion of staining methods in Chapter 4). With this technique, the Spanish anatomist Santiago Ramón y Cajal (1937/1989) was able to see that each neuron is a separate cell. The connection between two neurons is called a synapse, a term derived from the Latin word that means “to grasp.” The neurons are not in direct physical contact at the synapse but are separated by a small gap called the synaptic cleft. Two terms will be useful to us in the following discussion: The neuron that is transmitting to another is called the presynaptic neuron; the receiving neuron is the postsynaptic neuron (see Figure 2.12). FIGURE 2.12 The Synapse Between a Presynaptic Neuron and a Postsynaptic Neuron. Notice the separation between the presynaptic axon terminal and the postsynaptic neuron.

“

I awoke again, at three o’clock, and I remembered what it was.... I got up immediately, went to the laboratory, made the experiment... and at five o’clock the chemical transmission of the nervous impulse was conclusively proved.

—Otto Loewi

” Chemical Transmission at the Synapse Until the 1920s, physiologists assumed that neurons communicated by an electrical

current that bridged the gap to the next neuron. The German physiologist Otto Loewi believed that synaptic transmission was chemical, but he did not know how to test his hypothesis. One night Loewi awoke from sleep with the solution to his problem (Loewi, 1953). He wrote his idea down so he would not forget it, but the next morning he could not read his own writing. He recalled that day as the most “desperate of my whole scientific life” (p. 33). But the following night he awoke again with the same idea; taking no chances, he rushed to his laboratory. There he isolated the hearts of two frogs. He applied electrical stimulation to the vagus nerve attached to one of the hearts, which slowed the heartbeat. Then he extracted a salt solution that he had placed in the heart beforehand to capture any chemical that might have been released. When he placed this salt solution in the second heart, that heart

slowed, too, just as Loewi expected. Then he stimulated the accelerator nerve of the first heart, which caused the heart to beat faster. When he transferred salt solution from the first heart to the second, this time it speeded up (see Figure 2.13). So Loewi demonstrated that transmission at the synapse is chemical and that there are at least two different chemicals that carry out different functions. It turned out later that some neurons do communicate electrically by passing ions

through channels that connect one neuron to the next; their main function appears to be synchronizing activity in nearby neurons (Bennett & Zukin, 2004). In addition, some neurons release a gas transmitter. Still, Loewi was essentially correct because most synapses are chemical. By the way, if this example suggests to you that the best way to solve a problem is to “sleep on it,” keep in mind that such insight occurs only when people have paid their dues in hard work beforehand! At chemical synapses, the neurotransmitter is stored in the terminals in membrane-

enclosed containers called vesicles; the term means, appropriately, “little bladders.” When the action potential arrives at the terminals, it opens channels that allow calcium ions to enter the terminals from the extracellular fluid. The calcium ions cause the vesicles clustered nearest the membrane to fuse with the membrane. The membrane opens there, and the transmitter spills out and diffuses across the cleft in a process called exocitosis (see Figure 2.14).

How does synaptic transmission differ from transmission in the axon? On the postsynaptic neuron, the molecules of neurotransmitter dock with

specialized chemical receptors that match the molecular shape of the transmitter molecules (Figure 2.14). Activation of these receptors causes ion channels in the membrane to open. Ionotropic receptors open the channels directly to produce the immediate reactions required for muscle activity and sensory processing; metabotropic receptors open channels indirectly and slowly to produce longer-lasting effects. Opening the channels is what sets off the graded potential that initiates the action potential. You will see in the next section that the effect this has on the postsynaptic neuron depends on which receptors are activated. FIGURE 2.13 Loewi’s Experiment Demonstrating Chemical Transmission in Neurons. Loewi stimulated the first frog heart. When he transferred fluid from it to the second heart, it produced the same effect there as the stimulation did in the first heart.

The chemical jump across the synapse takes a couple of milliseconds; that is a significant slowing compared with transmission in the axon. In a system that places a premium on speed, inserting these gaps in the neural pathway must have some compensating benefit. As you will see in the following sections, synapses add important complexity to the simple all-or-none response in the axon. Excitation and Inhibition Opening ion channels on the dendrites and cell body has one of two effects: It can

cause the local membrane potential to shift in a positive direction toward zero, partially depolarizing the membrane, or it can shift the potential farther in the negative direction. Partial depolarization, or hypopolarization, is excitatory and facilitates the occurrence of an action potential; increased polarization, or hyperpolarization, is inhibitory and makes an action potential less likely to occur. The value of excitation is obvious, but inhibition can communicate just as much information as excitation does. Also, the message becomes more complex because input from one source can partially or completely negate input from another. In addition, inhibition helps prevent runaway excitation; one cause of the uncontrolled neural storms that sweep across the brain during an epileptic seizure is a deficiency in receptors for an inhibitory transmitter (Baulac et al., 2001).

FIGURE 2.14 A Presynaptic Terminal Releases the Neurotransmitter at the Synapse.

What determines whether the effect on the postsynaptic neuron is facilitating or inhibiting? It depends on which transmitter is released and the type of receptors on the postsynaptic neuron. A particular transmitter can have an excitatory effect at one location in the nervous system and an inhibitory effect at another; however, some transmitters typically produce excitation, and others most often produce inhibition. If the receptors open sodium channels, this produces hypopolarization of the dendrites and cell body, which is an excitatory postsynaptic potential (EPSP). Other receptors open potassium channels, chloride channels, or both; as potassium moves out of the cell or chloride moves in, it produces a hyperpolarization of the dendrites and cell body, or an inhibitory postsynaptic potential (IPSP).

What are the differences between an EPSP and an IPSP?

At this point, there is only a graded local potential. This potential spreads down the dendrites and across the cell body to the axon hillock (where the axon joins the cell body). At the axon, a positive graded potential that reaches threshold will produce an action potential; a negative graded potential makes it harder for the axon to fire. Most neurons fire spontaneously all the time, so EPSPs will increase the rate of firing and IPSPs will decrease the rate of firing (Figure 2.15). So now another form of complexity has been added at the synapse: The message to the postsynaptic neuron can be bidirectional, not just off-on. You should not assume that excitation of neurons always corresponds to activation

of behavior or that inhibition necessarily suppresses behavior. An EPSP may activate a neuron that has an inhibitory effect on other neurons, and an IPSP may reduce activity in an inhibitory neuron. An example of this paradox at the behavioral level is the effect of Ritalin. Ritalin and many other medications used to treat hyperactivity in children are in a class of drugs called stimulants, which increase activity in the nervous system. Yet, they calm hyperactive individuals and improve their ability to concentrate and focus attention (D. J. Cox, Merkel, Kovatchev, & Seward, 2000; Mattay et al., 1996). They probably have this effect by stimulating frontal areas of the brain where activity has been found to be abnormally low (Faigel, Szuajderman, Tishby, Turel, & Pinus, 1995). FIGURE 2.15 Effect of Excitation and Inhibition on Spontaneous Firing Rate.

SOURCE: Adapted from Principles of Neural Science, 4th ed., by E. R. Kandel et al., pp. 207–208. © 2002, McGraw-Hill Companies, Inc. Used with permission. Next you will see that the ability to combine the inputs of large numbers of neurons

expands the synapse’s contribution to complexity even further. Postsynaptic Integration The output of a single neuron is not enough by itself to cause a postsynaptic neuron

to fire or to prevent it from firing. In fact, an excitatory neuron may depolarize the membrane of the postsynaptic neuron by as little as 0.2 to 0.4 mV (Kandel & Siegelbaum, 2000b); remember that it takes an approximately 10-mV depolarization to trigger an action potential. However, a typical neuron receives input from approximately one thousand other neurons (Figure 2.16); because each neuron has numerous terminals, this amounts to as many as 10,000 synaptic connections in most parts of the brain and up to 100,000 in the cerebellum (Kandel & Siegelbaum, 2000a).

FIGURE 2.16 A Cell Body Virtually Covered With Axon Terminals.

SOURCE: © Science VU/Lewis-Everhart-Zeevi/Visuals Unlimited/Corbis. Because a single neuron has such a small effect, the postsynaptic neuron must

combine potentials from many neurons to fire. This requirement is actually advantageous: It ensures that a neuron will not be fired by the spontaneous activity of a single presynaptic neuron, and it allows the neuron to combine multiple inputs into a more complex message. These potentials are combined at the axon hillock in two ways. Spatial summation combines potentials occurring simultaneously at different locations on the dendrites and cell body. Temporal summation combines potentials arriving a short time apart. Temporal summation is possible because it takes a few milliseconds for a potential to die out. Spatial summation and temporal summation occur differently, but they have the same result. Summation is illustrated in Figure 2.17.

What are summation and integration? As you can see in Figure 2.18, summation combines EPSPs so that an action

potential is more likely to occur. Alternatively, summation of IPSPs drives the membrane’s interior even more negative and makes it more difficult for incoming EPSPs to trigger an action potential. When both excitatory and inhibitory impulses arrive on a neuron, they will also summate, but algebraically. The combined effect will equal the difference between the sum of the hypopolarizations and the sum of the hyperpolarizations. Spatial summation of two excitatory inputs and one inhibitory input is illustrated in Figure 2.19. The effect from temporal summation would be similar. FIGURE 2.17 Spatial and Temporal Summation.

Because the neuron can summate inputs from multiple sources, it rises above the role of a simple message conductor—it is an information integrator. And, using that information, it functions as a decision maker, determining whether to fire or not. Thus, the nervous system becomes less like a bunch of telephone lines and more like a computer. In subsequent chapters, you will come to appreciate how important the synapse is in understanding how we see, how we learn, and how we succumb to mental illness. FIGURE 2.18 Temporal and Spatial Summation. (1) An EPSP; (2) temporal summation of 2 EPSPs; (3) temporal summation of 3 EPSPs reaches threshold; (4) spatial summation of EPSPs reaches threshold; (5) an IPSP; (6) temporal summation of 2 IPSPs.

Terminating Synaptic Activity The neurotransmitter’s story does not end when it has activated the postsynaptic

neuron’s receptors. Usually, the transmitter must be inactivated; otherwise, it might “lock up” a circuit that must respond frequently, or leak over to other synapses and interfere with their function. Typically, the transmitter is taken back into the terminals by membrane proteins called transporters in a process called reuptake ; it is repackaged in vesicles and used again. At some synapses, the transmitter in the cleft is absorbed by glial cells. The neurotransmitter acetylcholine (ACh), on the other hand, is deactivated by acetylcholinesterase, an enzyme that splits the molecule into its components of choline and acetate. Choline is then taken back into the terminals and used to make more acetylcholine. FIGURE 2.19 Spatial Summation of Excitatory and Inhibitory Potentials. Note that inhibitory potentials cancel out excitatory potentials of equal strength (and vice versa).

Controlling how much neurotransmitter remains in the synapse is one way to vary behavior, and many drugs capitalize on this mechanism. Cocaine blocks the uptake of dopamine; some antidepressant medications block the reuptake of serotonin, norepinephrine, or both, while others (MAO inhibitors) prevent monoamine oxidase from degrading those transmitters as well as dopamine and epinephrine; and drugs for treating the muscular disorder myasthenia gravis increase ACh availability by inhibiting the action of acetylcholinesterase. Regulating Synaptic Activity The previous description has been of a system that amounts to “neuron A stimulates

neuron B, neuron B stimulates neuron C,” and so on. However, such a simple system cannot transmit the complex information required to solve a math equation, write a symphony, or care for a newborn. Not only that, but as messages flow from neuron to neuron, activity would soon drift out of control; some activity would fade out, while other activity would escalate until it engulfed an entire area of the brain. A nervous system that controls complex behavior must have several ways to regulate its activity. One of the ways is through axoaxonic synapses. The synapses described so far are

referred to as axodendritic and axosomatic synapses, because their targets are dendrites and cell bodies. At axoaxonic synapses, a third neuron releases transmitter

onto the terminals of the presynaptic neuron (see #1 in Figure 2.20). The result is presynaptic excitation or presynaptic inhibition, which increases or decreases, respectively, the presynaptic neuron’s release of neurotransmitter onto the postsynaptic neuron. One way an axoaxonic synapse adjusts a presynaptic terminal’s activity is by regulating the amount of calcium entering the terminal, which, you will remember, triggers neurotransmitter release.

What are the three ways of regulating synaptic activity? Neurons also regulate their own synaptic activity in two ways. Autoreceptors on the

presynaptic terminals sense the amount of transmitter in the cleft; if the amount is excessive, the presynaptic neuron reduces its output (Figure 2.20, #2). Postsynaptic neurons participate in regulation of synaptic activity as well. When there are unusual increases or decreases in neurotransmitter release, postsynaptic receptors change their sensitivity or even their numbers to compensate (Figure 2.20, #3). You will see in Chapter 14 that receptor changes figure prominently in psychological disorders such as schizophrenia. Glial cells also contribute to the regulation of synaptic activity. They surround the

synapse and prevent neurotransmitter from spreading to other synapses, but some also absorb neurotransmitter in the synaptic cleft and recycle it for the neuron’s reuse (Figure 2.21); by varying the amount of transmitter they absorb, they influence postsynaptic excitability (Oliet, Piet, & Poulain, 2001). They can even respond to the neurotransmitter level in the synapse by releasing transmitters of their own. These gliotransmitters regulate transmitter release from the presynaptic neuron or directly stimulate the postsynaptic neuron to excite or inhibit it (M. Anderson & Hanse, 2010; E. A. Newman, 2003). Thus, rather than simpy being neural “glue” as the name implies, glia should be considered active partners in neural transmission. FIGURE 2.20 Regulating Activity at the Synapse.

Neurotransmitters Table 2.2 on page 44 lists several transmitters, grouped according to their chemical

structure. This is an abbreviated list; there are other known or suspected transmitters, and there are doubtless additional transmitters yet to be discovered. This summary is intended to illustrate the variety in neurotransmitters and to give you some familiarity with the functions of a few of the major ones. You will encounter most of them again as various behaviors are discussed in later chapters. Having a variety of neurotransmitters multiplies the effects that can be produced at

synapses; the fact that there are different subtypes of the receptors adds even more. For example, two types of receptors detect acetylcholine: the nicotinic receptor, so called because it is also activated by nicotine, and the muscarinic receptor, named for the mushroom derivative that can stimulate it. Nicotinic receptors are excitatory; they

are found on muscles and, in lesser numbers, in the brain. Muscarinic receptors are more frequent in the brain, where they have an excitatory effect at some locations and an inhibitory one at others. Other transmitters have many more receptor subtypes than acetylcholine does. FIGURE 2.21 Glial Cell Interacting With Neurons at the Synapse. An astrocyte, a type of glial cell, encloses the synapse, where it absorbs the neurotransmitter glutamate (Glu) from the synaptic cleft. It recycles the transmitter into its precursor glutamine (Gln) and returns the Gln to the presynaptic terminal for reuse. The glial cell can influence synaptic activity by granting or withholding transmitter absorption and by releasing its own transmitter in response to the neurotransmitter level in the synapse.

SOURCE: Adapted with permission from “Energy on Demand,” by P. J. Magistretti et al., 1999, Science, 283, p. 497. Copyright © 1999. Reprinted with permission from AAAS. For decades, neurophysiologists labored under the erroneous belief, known as

Dale’s principle, that a neuron was capable of releasing only one neurotransmitter. We learned only fairly recently that many neurons ply their postsynaptic partners with two to four and perhaps even more neurotransmitters. Since then, most researchers have thought that the combination invariably consisted of a single fast-acting “classical” neurotransmitter and one or more slower-acting neuropeptides that prolong and enhance the effect of the main transmitter (Hökfelt, Johansson, & Goldstein, 1984). Peptides are chains of amino acids (longer chains are called proteins); neuropeptides, of course, are peptides that act as neurotransmitters.

What are two additional ways synapses add information complexity?

3 Origin of the Brain Recent studies have found that some neurons release two fast transmitters (Rekling,

Funk, Bayliss, Dong, & Feldman, 2000). Even more surprising, we have learned that the same neuron can release both an excitatory transmitter and an inhibitory transmitter (Duarte, Santos, & Carvalho, 1999; Jo & Schlichter, 1999). It appears that the two types of transmitters are released at different terminals (Duarte et al., 1999; Sulzer & Rayport, 2000). This co-release suggests that a neuron can act as a two-way switch (Jo & Schlichter, 1999). One example is in cells in the eye that produce excitation when a viewed object moves in one direction and inhibition when movement is in the opposite direction (Duarte et al., 1999). Another is in neurons that release the excitatory transmitter glutamate, but can also release the inhibitor gamma- aminobutyric acid (GABA) as a means of limiting excitability and avoiding seizure activity (Trudeau & Gutiérrez, 2007). It now appears that this co-release of transmitters is the rule, rather than the exception. TABLE 2.2 Some Representative Neurotransmitters.

APPLICATION

Agonists and Antagonists in the Real World Neurotransmitters are not the only substances that affect transmitters. Many drugs, as well as other compounds, mimic or increase the effect of a neurotransmitter and are called agonists. Any substance that reduces the effect of a neurotransmitter is called an antagonist. Practically all drugs that have a psychological effect interact with a neurotransmitter system in the brain, and many of them do so by mimicking or blocking the effect of neurotransmitters (S. H. Snyder, 1984). You have already seen that the effect of acetylcholine is duplicated by

nicotine and by muscarine at the two kinds of receptors. Opiate drugs such as heroin and morphine also act as agonists, stimulating receptors for opiate-like transmitters in the body. The drug naloxone acts as an antagonist to opiates, occupying the receptor sites without activating them; consequently, naloxone can be used to counteract an overdose.

Amazonian Indians Tip Their Darts With the Plant Neurotoxin Curare. SOURCE: © Jack Fields/Corbis.

The plant toxin curare blocks acetylcholine receptors at the muscle, causing paralysis (Trautmann, 1983). South American Indians in the Amazon River basin tip their darts with curare to disable their game. A synthetic version of curare was used as a muscle relaxant during surgery before safer and more effective drugs were found (M. Goldberg & Rosenberg, 1987). Ironically, it has even been used in the treatment of tetanus (lockjaw), which is caused by another neurotoxin; a patient receiving this treatment has to be artificially respirated for weeks to prevent suffocation until recovery occurs.

Of Neuronal Codes, Neural Networks, and Computers Underlying this discussion has been the assumption that we can explain behavior

by understanding what neurons do. But we cannot make good on that promise as long as we talk as if neural communication is limited to single chains of neurons that either fire or don’t fire. In fact, neurons are capable of generating complex messages, which they send across intricate networks. Coding of Neural Messages Neurons don’t just produce a train of equally spaced impulses: They vary the

intervals between spikes, they produce bursts of varying lengths, and the bursts can be separated by different intervals (Cariani, 2004). But do these temporal (time-related) variations in firing pattern form a code that the brain can use, or are they just “noise” in the system? The best way to answer this question is to look at sensory processes, because the researcher can correlate firing patterns with sensory input on one end and behavior on the other. A good example is an early study done by Patricia Di Lorenzo and her colleague Gerald Hecht (1993). First, they recorded the firing patterns in individual taste neurons of rats during stimulation with a sucrose (sugar) solution and quinine; as you can see in Figure 2.22a, these flavors produce different neural activity. Then they duplicated the temporal patterns in the form of electrical pulses (Figure

2.22b) and used these to stimulate the taste pathways of other rats. The assumption was that if the brain uses this information, the unanesthetized rats would behave as if they were actually tasting sweet sucrose or bitter quinine. As Figure 2.22c shows, that is exactly what happened: the rats licked a water tube at a high rate when they were receiving stimulation patterned after sucrose, but almost stopped licking—even though they were water deprived—when the stimulation was patterned after quinine. FIGURE 2.22 Response of Rats to Neural Stimulation Simulating the Taste of Sucrose and Quinine. (a) Recordings from individual neurons during stimulation with sucrose and quinine. (b) Electrical stimulation mimicking the recorded neuronal activity; each dot represents a single neural impulse. (c) The average number of times the rats licked a drinking tube for water during delivery of the quinine simulation and the sucrose simulation.

SOURCES: (a) and (b) Adapted from Figure 7 of “Temporal Coding in the Gustatory System,” by R. M. Hallock and P. M. Di Lorenzo, 2006, Neuroscience and Biobehavioral Reviews, 30, p. 1156. Used with permission from Elsevier. (c) Adapted from Figure 4 of “Perceptual Consequences of Electrical Stimulation in the Gustatory System,” by P. M. Di Lorenzo and G. S. Hecht, 1993, Behavioral Neuroscience, 107, p. 135. However, this coding apparently is not sufficient by itself to carry the complex

information involved in brain communication. An additional opportunity for coding is provided by the fact that neural information often travels over specialized pathways. For example, taste information is carried by at least five types of specialized fibers; Di Lorenzo and Hecht (1993) recorded the sucrose firing pattern from a “labeled line” specialized for sweet stimuli and the quinine pattern from another specialized for bitter stimuli. In later chapters, you will see that not only taste but also information about color and about the higher sound frequencies is transmitted over a limited number of labeled lines. However, even with temporal coding and labeled lines, a significant burden remains for the brain if it is to make sense of this information; this leads us to the topic of neural networks. Neural Networks Individual neurons cannot carry enough information to determine the taste of a bite

of food or the color of an object. Color processing, for example, depends on just four

“labeled lines” carrying information about red, green, blue, and yellow light. However, we can distinguish millions of colors by comparing the relative activity in these four pathways. This kind of analysis requires complex interactions among a network of neurons. Neural networks are groups of neurons that function together to carry out a process; they are where the most complex neural processing—the “computing” work of the brain—occurs. Sometimes these networks involve a relatively small number of neurons in a single area, such as groups of neurons in a part of the rat’s brain called the hippocampus. During an experimenter-imposed delay in maze running, these networks store the rat’s preceding choices and calculate its next choice. They perform so reliably that the researcher can use their activity to predict which way the rat will turn after the delay (Pastalkova, Itskov, Amarasingham, & Buzsáki, 2008). But as you will see in later chapters, other networks combine the activity of widespread brain areas to perform language functions (Chapter 9), to identify an object visually and locate it in space (Chapter 10), and, some researchers believe, to produce conscious awareness (Chapter 15). FIGURE 2.23 Image of White Matter Fiber Tracts. This image is from the brain of an infant at risk for autism, based on having older siblings with autism. Those who were diagnosed with autism at 24 months had already begun to differ in tract development by the age of 6 months (Wolff et al., 2012). The study used a white matter imaging technique called diffusion tensor imaging; colors represent varying strengths of connection.

SOURCE: Courtesy of Jason Wolff, PhD, University of North Carolina at Chapel Hill. Understanding these networks is the next big frontier in brain research. Their

complexity and relative inaccessibility are challenging researchers’ resolve and ingenuity, but recent developments in brain imaging capabilities make the goal more realistic. The Human Connectome Project is a large-scale, multi-university effort to

map the brain’s circuits. Its researchers are using a combination of four scanning techniques, behavioral measures, and genetic analysis to determine the brain’s anatomical and functional connectivity (Van Essen et al., 2013). The maps will help researchers understand normal brain functioning in realms such as learning and consciousness, as well as disorders in functioning, including autism and schizophrenia (see Figure 2.23). By the way, it took over a decade to map the roundworm’s brain, with just 300 neurons and 7,000 connections, so attempting it for the human brain is a very tall order. Another approach uses computers to simulate brain circuits. In the last couple of

decades this effort has been dominated by work with artificial neural networks, computer programs that mimic the brain’s neural networks; rather than being programmed to perform in a specific way, these networks learn how to carry out their task, much as we do. The network is trained by repeatedly giving it feedback about correct responses, and its neurons respond by adjusting the stimulating and inhibiting effects they have on their neighbors. As with the brain, the network’s performance at first is random, but it improves with practice. The real-world applications have been numerous, including robotics, stock market prediction, medical diagnosis, and face recognition, but artificial networks are also helping neuroscientists understand how the brain works. For example, after a network had been trained to navigate a maze, the researchers were able to inspect the modified connections and learn how it accomplished the task (Fleischer, Gally, Edelman, & Krichmar, 2007). Networks can also be used to test hypotheses about neural functioning; one that was trained to play games that allow cooperation or “cheating” and was also endowed with the ability to “evolve” (by adding new neurons) lent support to the hypothesis that intelligence and cooperative behavior evolved together (McNally, Brown, & Jackson, 2012). With increasing successes, the projects are becoming more ambitious; a network with 500 million synapses accurately modeled neural activity across wide areas of the brain (Izhikevich & Edelman, 2008), and another with 2.5 million neurons accomplished basic cognitive tasks, such as solving number sequence problems (Eliasmith et al., 2012). Now people in the field are becoming confident enough to tackle the whole brain, which is the subject of the accompanying In the News. While we’re waiting for neuroscientists to explain how the brain works, the idea of

neural networks provides a useful way of thinking about mental processes. The next time you are trying to remember a person’s name that is “on the tip of your tongue,” imagine your brain activating individual components of a neural network until one produces the name you’re looking for. If you visualize the person’s face as a reminder, imagine that the name and the image of the face are stored in related networks so that activating one memory activates the other. This is not just speculation: Electrode recordings from patients preparing for brain surgery show that the information triggered by the photo of a familiar person and by the person’s written name converge

Concept Check

on the same neurons in a critical memory area of the brain (Quiroga, Kraskov, Koch, & Fried, 2009)—thanks, of course, to neural networks.

The Human Brain Project In October 2013, neuroscientists, computer scientists, medical doctors, and roboticists from 130 research institutions throughout Europe launched a 10-year program to model the entire brain with computers. The idea for the Human Brain Project originated with neuroscientist Henry Markram, who was inspired to seek a broader understanding of the brain after his son was diagnosed with autism. The project has attracted a one-billion euro grant from the European Union and a gift from the Swiss government of an IBM Blue Gene computer,

currently the world’s fastest supercomputer. A few months earlier, the United States announced that it would conduct a

similar project. Its combination of government and private funding promises to equal that of the European effort and, if President Obama is successful in convincing Congress to appropriate $3 billion, greatly exceed it. The BRAIN Initiative is aimed at a better understanding of human brain functioning in order to treat, prevent, and cure disorders such as autism, schizophrenia, Alzheimer’s disease, and traumatic brain injury. Two additional projects are creating brain maps by slicing brains extremely thin, photographing the slices, and reassembling the images into 3-D maps that will be available to researchers on the Internet. BigBrain’s slices are one-fifth the diameter of a human hair, and The Brain Observatory’s are 40 times thinner; their resolution will be so high that researchers can see individual cell bodies and the connections between the neurons. Whether the goals of the Human Brain Project and the BRAIN Initiative are

realistic or, as critics say, too grandiose to be achievable, bringing together this much research power is sure to have a profound effect on how we think about the brain. For links to these news sources, see On the Web #4 at the end of this chapter.

4 Neural Networks & News Sources

Take a Minute to Check Your Knowledge and Understanding

How is information transmitted at the synapse? It can be said that integration transforms neurons from a “telephone line” to a computer. Explain.

What difference would it make if there were no regulation of activity at the synapse?

What is Dale’s principle, and in what way is it incorrect? How successful have artificial neural networks been in simulating human brain activity? What does this tell us about whether they work the same way the brain does?

In Perspective It is impossible to understand the brain and impossible to understand behavior without first knowing the capabilities and the limitations of the neuron. Although more complexity is added at the synapse, a relatively simple device is the basis for our most sophisticated capabilities and behaviors. However, what happens at the individual neuron is not enough to account for human behavior; neurons work in concert with each other, in both local and brainwide networks. Some researchers are using artificial neural networks to understand how neurons work together to produce thought, memory, emotion, and consciousness. In the next chapter, you will learn about some of the functional structures in the brain that are formed by the interconnection of neurons. Summary The Cells That Make Us Who We Are • There are three major kinds of neurons: motor neurons, sensory neurons, and interneurons. Although they play different roles, they have the same basic components and operate the same way.

• The neural membrane is electrically polarized. This polarity is the resting potential, which is maintained by forces of diffusion and electrostatic pressure in the short term and by the sodium-potassium pump in the long term.

• Polarization is the basis for the neuron’s responsiveness to stimulation, in the form of the graded potential and the action potential.

• The neuron is limited in firing rate by the absolute refractory period and in its ability to respond to differing strengths of stimuli by the all-or-none law. More intense stimuli cause the neuron to fire earlier during the relative refractory period, providing a way to encode stimulus intensity (the rate law).

• Glial cells provide the myelination that enables neurons to conduct rapidly while remaining small. They also help regulate activity in the neurons and provide several supporting functions for neurons.

How Neurons Communicate With Each Other • Transmission from neuron to neuron is usually chemical in vertebrates, involving neurotransmitters released onto receptors on the postsynaptic dendrites and cell

body. • The neurotransmitter can create an excitatory postsynaptic potential, which increases the chance that the postsynaptic neuron will fire, or it can create an inhibitory postsynaptic potential, which decreases the likelihood of firing.

• Through temporal and spatial summation, the postsynaptic neuron integrates its many excitatory and inhibitory inputs.

• Regulation of synaptic activity is produced by axoaxonic synapses from other neurons, adjustment of transmitter output by autoreceptors, and change in the number or sensitivity of postsynaptic receptors.

• Leftover neurotransmitter may be taken back into the presynaptic terminals, absorbed by glial cells, or broken down by an enzyme.

• The human nervous system contains a large number of neurotransmitters, detected by an even greater variety of receptors. A neuron can release combinations of two or more neurotransmitters.

• The computing work of the brain is done in complex neural networks, and artificial neural networks are helping us to understand these networks. ■ Study Resources

For Further Thought • What would be the effect if there were no constraints on the free flow of ions across the neuron membrane?

• What effect would it have on neural conduction if the action potential were decremental?

• Sports drinks replenish electrolytes that are lost during exercise. Electrolytes are compounds that separate into ions; for example, sodium chloride (table salt) dissociates into sodium and chloride ions. What implication do you think electrolyte loss might have for the nervous system? Why?

• Imagine what the effect would be if the nervous system used only one neurotransmitter.

• How similar to humans do you think computers are capable of becoming? How much is your answer based on how you think human behavior is controlled versus how capable you think computers are?

Quiz: Testing Your Understanding 1. Describe the ion movements and voltage changes that make up the neural

impulse, from graded potential (at the axon hillock) to recovery. 2. Discuss the ways in which the synapse increases the neuron’s capacity for

transmitting information. 3. Describe how artificial neural networks function like the brain and what

humanlike behaviors they have produced. Select the best answer:

1. The inside of the neuron is relatively poor in _____ ions and rich in _____ ions. a. chloride, phosphate b. sodium, potassium c. potassium, sodium d. calcium, sodium

2. The rate law a. explains how the intensity of stimuli is represented. b. does not apply to neurons outside the brain. c. describes transmission in myelinated axons. d. describes the process of postsynaptic integration.

3. Without the sodium-potassium pump, the neuron would become a. more sensitive because of accumulation of sodium ions. b. more sensitive because of accumulation of potassium ions. c. overfilled with sodium ions and unable to fire. d. overfilled with potassium ions and unable to fire.

4. There is a limit to how rapidly a neuron can produce action potentials. This is due to a. inhibition. b. facilitation. c. the absolute refractory period. d. the relative refractory period.

5. Saltatory conduction results in a. less speed and the use of more energy. b. greater speed with the use of less energy. c. less speed but with the use of less energy. d. greater speed but with the use of more energy.

6. General anesthetics open potassium channels, allowing potassium ions to leak out of the neuron. This a. increases firing in pain-inhibiting centers in the brain. b. increases firing in the neuron until it is fatigued. c. hypopolarizes the neuron, preventing firing. d. hyperpolarizes the neuron, preventing firing.

7. When the action potential arrives at the terminal button, entry of _____ ions stimulates release of transmitter. a. potassium b. sodium c. calcium d. chloride

8. All the following neurotransmitters are deactivated by reuptake except

a. acetylcholine. b. norepinephrine. c. serotonin. d. dopamine.

9. An inhibitory neurotransmitter causes the inside of the postsynaptic neuron to become a. more positive. b. more negative. c. more depolarized. d. neutral in charge.

10. Excitatory postsynaptic potentials are typically produced by movement of _____ ions, whereas inhibitory postsynaptic potentials are typically produced by movement of _____ ions. a. potassium; sodium or chloride b. potassium; sodium or calcium c. sodium; calcium or chloride d. sodium; potassium or chloride

11. Which of the following is not an example of regulation of synaptic activity? a. A neuron has its synapse on the terminals of another and affects its

transmitter release. b. Autoreceptors reduce the amount of transmitter released. c. A presynaptic neuron inhibits a postsynaptic neuron. d. Postsynaptic receptors change in numbers or sensitivity.

12. The graph below shows three graded potentials occurring at the same time.

Assume that the resting potential is –70 mV and that each graded potential individually produces a 5-mV change. What is the membrane’s voltage after the graded potentials arrive? a. –65 mV b. –70 mV c. –75 mV d. +75 mV

13. The presence of synapses in a neuron chain provides the opportunity for a. increases in conduction speed. b. modification of neural activity. c. two-way communication in a pathway. d. regeneration of damaged neurons.

14. Artificial neural networks

a. rely on prewired “neural” connections. b. solve problems in a couple of trials by insight. c. are preprogrammed. d. learn how to carry out the task themselves.

Answers: 1. b, 2. a, 3. c, 4. c, 5. b, 6. d, 7. c, 8. a, 9. b, 10. d, 11. c, 12. a, 13. b, 14. d.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. Neuroscience for Kids (don’t be put off by the name!) has a review of the

resting and action potentials and an animation of their electrical recording. A YouTube animation of the sodium-potassium pump is an instructive

illustration of how the mechanism works. 2. The Schwann Cell and Action Potential is a visually appealing animation of

myelination and how it speeds conduction. 3. The animated video The Origin of the Brain describes how (and why)

neurons and synapses evolved and ends with a demonstration of how simple circuits can “remember” and make “decisions.”

4. The Symphony Inside Your Brain describes the Human Connectome Project and features a rotating scan of the major pathways of one hemisphere. Osaka University’s Intelligent Robotics Laboratory site offers videos of

several of its lifelike androids. The American Association for Artificial Intelligence site covers a wide

variety of topics, from robots to cognitive science to ethical and social issues. Read the original news articles about the Human Brain Project, the Brain

Initiative, and BigBrain and the Brain Observatory. Animations • The Neural Impulse (Figure 2.8)

• Transmission at the Synapse (Figure 2.14) • Spatial and Temporal Summation (Figure 2.17) Chapter Updates and Biopsychology News

For Further Reading 1. Synaptic Self, by Joseph LeDoux (Penguin Books, 2003), takes the position

that “your ‘self,’ the essence of who you are, reflects patterns of interconnectivity between neurons in your brain.” A good read by a noted neuroscientist.

2. “Understanding Synapses: Past, Present, and Future,” by Thomas Südhoff and Robert Malenka (Neuron, 2008, 60, 469–476), will convince you of the importance of synapses and will provide a useful reference throughout the course.

3. “Tripartite Synapses: Astrocytes Process and Control Synaptic Information,” by Gertrudis Perea, Marta Navarrete, and Alfonso Araque (Trends in Neurosciences, 2006, 32, 421–431), reviews what we know about glial influence on synaptic activity.

4. “All My Circuits: Using Multiple Electrodes to Understand Functioning Neural Networks,” by Earl Miller and Matthew Wilson (Neuron, 2008, 60, 483–488), gives a good description of brainwide neural networks that play a variety of roles.

5. Written by well-known neuroscientist John E. Dowling (you will see some of his work in Chapter 10), Neurons and Networks: An Introduction to Behavioral Neuroscience (Harvard University Press, 2001) elaborates on the topics in this chapter. According to one student, the book “goes into depth without becoming murky.”

6. Sebastian Seung’s book Connectome (Houghton Mifflin Harcourt, 2012) describes the effort to map the brain using computers and artificial intelligence; you can read a summary and review in New Scientist, February 4, 2012, p. 46.

7. “The Human Brain Project,” by Henry Markram (Scientific American, June 2012, 50–55), describes the author’s plan to model the entire brain on a computer, along with the scientific and medical benefits and the awesome computing demands.

Key Terms absolute refractory period action potential agonist

all-or-none law antagonist autoreceptor axon cell body Dale’s principle dendrite electrostatic pressure excitatory postsynaptic potential (EPSP) force of diffusion glial cell graded potential Human Connectome Project hyperpolarization hypopolarization inhibitory postsynaptic potential (IPSP) interneuron ion ionotropic receptor metabotropic receptor motor neuron myelin neural network neuron neurotoxin neurotransmitter node of Ranvier nondecremental oligodendrocyte optogenetics polarization postsynaptic presynaptic presynaptic excitation presynaptic inhibition rate law relative refractory period resting potential reuptake saltatory conduction

Schwann cell sensory neuron sodium-potassium pump spatial summation synapse synaptic cleft temporal summation terminal vesicle voltage

K

3 The Organization and Functions of the Nervous System

In this chapter you will learn • The major structures of the nervous system and some of their functions • How the nervous system develops and how it changes with experience • Strategies for repairing damaged brains and spinal cords, and the obstacles

The Central Nervous System The Forebrain APPLICATION: THE CASE OF PHINEAS GAGE

The Midbrain and Hindbrain The Spinal Cord Protecting the Central Nervous System CONCEPT CHECK

The Peripheral Nervous System The Cranial Nerves The Autonomic Nervous System CONCEPT CHECK

Development and Change in the Nervous System The Stages of Development How Experience Modifies the Nervous System Damage and Recovery in the Central Nervous System IN THE NEWS: IS THE BRAIN TOO FRAGILE FOR SPORTS? IN THE NEWS: NUCLEAR TESTING REVEALS ADULT NEUROGENESIS IN HUMANS APPLICATION: MENDING THE BRAIN WITH COMPUTER CHIPS CONCEPT CHECK

In Perspective Summary Study Resources

aren is a college graduate and holds a job with considerable responsibility. She is married and leads a normal life except for occasional epileptic seizures. When her doctors ordered a brain scan to find the cause of her seizures, they were

astounded. The normal person’s brain has many folds on its surface, so it is wrinkled like a walnut; Karen’s is perfectly smooth, like the one on the right in Figure 3.1. Notice, too, that the dark areas in the middle of the brain (ventricles) are enlarged, indicating a deficiency in the amount of brain tissue. People with her disorder are

usually not only lissencephalic (literally, smooth-brained) and epileptic like Karen, but severely impaired intellectually as well (Barinaga, 1996; Eksioglu et al., 1996). So what really amazed Karen’s doctors was not how abnormal her brain is, but that she functions not just normally but well above average. How do we explain why some people are able to escape the consequences of what is usually a devastating developmental error? The answer is that we do not know why; it is one of the mysteries that neuroscientists are attempting to solve in order to understand the brain’s remarkable resilience. “

The brain is wider than the sky, For, put them side by side, The one the other will include With ease, and you beside.

—Emily Dickinson

” SOURCE: Reprinted by permission of the publishers and the Trustees of Amherst College from The Poems of Emily Dickinson, Thomas H. Johnson, ed., Cambridge, Mass.: The Belknap Press of Harvard University Press, Copyright © 1951, 1955, 1979, 1983 by the President and Fellows of Harvard College. You are now well versed in the functioning of neurons and how they interact with

each other. What you need to understand next is how neurons are grouped into the functional components that make up the nervous system. In the next few pages, we will review the physical structure of the nervous system so that you will have a road map for more detailed study in later chapters. And we will include an overview of major functions to prepare you for the more detailed treatments to come in later chapters. We will look first at the two divisions of the nervous system before turning our attention to issues such as brain development. FIGURE 3.1 A Normal Brain and a Lissencephalic Brain.

SOURCE: Courtesy of Dr. Joseph Gleeson, University of California San Diego School of Medicine. The Central Nervous System The nervous system is divided into two subunits. The central nervous system (CNS) includes the brain and the spinal cord. The second part is the peripheral nervous system, which we will examine later in the chapter. Before we go any further, we need to be sure you understand a couple of terms correctly. As we talk about the nervous system, be careful not to confuse nerve and neuron. A neuron is a single neural cell; a nerve is a bundle of axons running together like a multiwire cable. However, the term nerve is used only in the peripheral nervous system; inside the CNS, bundles of axons are called tracts. Most of the neurons’ cell bodies are also clustered in groups; a group of cell bodies is called a nucleus in the CNS and a ganglion in the peripheral nervous system. Table 3.1 should help you keep these terms straight. TABLE 3.1 Terms for Axons and Cell Bodies in the Nervous System.

FIGURE 3.2 View of a Human Brain.

SOURCE: © Dr. Fred Hossler/Visuals Unlimited/Getty Images. FIGURE 3.3 The Brain Develops From a Tubular Structure.

Figure 3.2 is a photograph of a human brain. It will be easier to visualize the various structures of the brain if you understand that the CNS begins as a hollow tube and preserves that shape as it develops (Figure 3.3). The upper end of the tube develops three swellings, which will become the forebrain, midbrain, and hindbrain; the lower part of the tube develops into the spinal cord. The forebrain appears to be perched on top of the lower structures as it enlarges and almost completely engulfs them. By comparing the four drawings in this series, you can see that the mature forebrain obscures much of the lower brain from view. You will get a better idea of these hidden structures later when we look at an interior view of the brain. The Forebrain

The major structures of the forebrain are the two cerebral hemispheres, the thalamus, and the hypothalamus. The outer layer of the hemispheres, the cortex, is where the highest-level processing occurs in the brain. The Cerebral Hemispheres The large, wrinkled cerebral hemispheres dominate the brain’s appearance (Figure

3.4). Not only are they large in relation to the rest of the brain, but they are also disproportionately larger than in other primates (Deacon, 1990). The longitudinal fissure that runs the length of the brain separates the two cerebral hemispheres, which are nearly mirror images of each other in appearance. Often the same area in each hemisphere has identical functions as well, but you will see that this is not always the case. The simplest form of asymmetry is that each hemisphere receives most of its sensory input from the opposite side of the body (or of the world, in the case of hearing and vision) and provides most of the control of the opposite side of the body. “

One of the key strategies of the nervous system is localization of functions: specific types of information are processed in particular regions.

—Eric Kandel

” Look again at Figures 3.2 and 3.4. The brain’s surface has many ridges and grooves

that give it a very wrinkled appearance; the term we use is convoluted. Each ridge is called a gyrus; the groove or space between two gyri is called a sulcus or, if it is large, a fissure. You can see how the gyri are structured in the cross section of a brain in Figure 3.5. The outer surface is the cortex (literally, “bark”), which is made up mostly of the cell bodies of neurons; because cell bodies are not myelinated, the cortex looks grayish in color, which is why it is referred to as gray matter. Remember that neural processing occurs where neurons synapse on the cell bodies of other neurons, which indicates why the cortex is so important. The cortex is only 1.5 to 4 millimeters (mm) thick, but the convolutions increase the amount of cortex by tripling the surface area. The convolutions also provide the axons with easier access to the cell bodies than if the developing cortex thickened instead of wrinkling. The axons come together in the central core of each gyrus, where their myelination gives the area a whitish appearance. Notice how the white matter of each gyrus joins with the white matter of the next gyrus, creating the large bands of axons that serve as communication routes, both within each hemisphere and between the two hemispheres.

Why is a wrinkled brain better than a smooth one? You find yourself running to your early morning test, fretting about being late while

rehearsing answers to the questions you expect on the exam. You interrupt your

thoughts only to greet a fellow student, doing your best to conceal your disdain because of the silly questions he asks in class. Do you ever wonder how your brain pulls all this off? FIGURE 3.4 Human Brain Viewed From Above. This photo shows the cerebral hemisphere and longitudinal fissure. The blood vessels have been removed from the right hemisphere.

SOURCE: © David Bassett/Science Source.

1 Brain Atlas and Tutorial FIGURE 3.5 Section of Human Brain Showing Gyri and Sulci.

SOURCE: Reproduced with permission from http://www.brains.rad.msu.edu, and http://brainmuseum.org, supported by the U.S. National Science Foundation. It will take the rest of this book to start answering that question, but this is a good

time to mention two ways the brain’s organization helps it to be more efficient. First, the cortex in humans and most mammals is arranged in layers; the number of layers is usually six, though a particular layer may be absent in some areas. The layers stand

out from each other because they are separated by fibers that serve the cell bodies, but they also differ in appearance: They vary in type and size of cells and in the concentration of cell bodies versus axons (see Figure 3.6a). There are differences in function as well. Some researchers have concluded that layers II and III are associational, IV is sensory, and V and VI have motor functions (Buxhoeveden & Casanova, 2002). FIGURE 3.6 Layers and Columns of the Cortex. (a) Photograph of a section of cortex, revealing its layered organization. (b) Photograph showing the columnar arrangement of cells in the cortex; the numbers on the left identify the cortical layers.

SOURCE: (a) “Human-specific Organization of Primary Visual Cortex: Alternating Compartments of Dense Cat-301 and Calbindin Immunoreactivity in Layer 4A,” by Todd M. Preuss and Ghislaine Q. Coleman, Cerebral Cortex, 12(7), pp. 671–691, doi: 10.1093/cercor/12.7.671. (b) Reconstructed neurons from the Blue Brain Project © BBP/EPFL. Second, the cells of the cortex are organized into groups of 80 to 100

interconnected neurons, which are arranged in columns running perpendicular to the cortical surface (Figure 3.6b; Buxhoeveden & Casanova, 2002). They provide a vertical unification of the cortex’s horizontal layers, which contributes to their role as the primary information-processing unit in the cortex (Torii, Hashimoto-Torii, Levitt, & Rakic, 2009). The cells in a column have a similar function; for example, they may receive input from the same area on the skin’s surface, while surrounding columns serve adjacent locations. In the visual cortex, the cells in a column may detect object edges at a particular orientation, while surrounding columns respond to edges at a slightly different orientation. Having similar functions grouped close together in well- connected columns helps the brain work quickly and efficiently. FIGURE 3.7 Brains of Three Different Species.

SOURCE: Reproduced with permission from http://www.brains.rad.msu.edu, and http://brainmuseum.org, supported by the U.S. National Science Foundation. Students often ask whether intelligent people have bigger brains. Bischoff, the

leading European anatomist in the 19th century, argued that the greater average weight of men’s brains was infallible proof of their intellectual superiority over women. When he died, his brain was removed and added to his extensive collection as his will had specified; ironically, it weighed only 1,245 grams (g), less than the average of about 1,250 g for women (“Proof?” 1942). There actually is a tendency for people with larger brains to be more intelligent (Willerman, Schultz, Rutledge, & Bigler, 1991), but the relationship is small and highly variable. What this means is that factors other than brain size are more important; otherwise, women would be less intelligent than men as Bischoff claimed, but we know from research that this is not

the case. When we look at brain size more closely in the chapter on intelligence, you will learn that Einstein’s brain was even smaller than Bischoff’s. Across species, brain size is more related to body size than to intelligence; the

brains of elephants and sperm whales are five or six times larger than ours. It is a brain’s complexity, not its size, that determines its intellectual power. Look at the brains in Figure 3.7, and then compare them with the human brain in Figure 3.2. You can see two features that distinguish more complex, more highly evolved brains from less complex ones. One is that the higher brains are more convoluted; the greater number of gyri means more cortex. The other is that the cerebral hemispheres are larger in proportion to the lower parts of the brain. It is no accident that the cerebral hemispheres are perched atop the rest of the brain and the spinal cord. The CNS is arranged in a hierarchy; as you ascend from the spinal cord through the hindbrain and midbrain to the forebrain, the neural structures become more complex, and so do the behaviors they control. FIGURE 3.8 Lobes and Functional Areas on the Surface of the Hemispheres.

The Four Lobes The hemispheres are divided into four lobes—frontal, parietal, occipital, and

temporal—each named after the bone of the skull covering it. The lobes are illustrated in Figure 3.8, along with the major functions located within them. These divisions are somewhat arbitrary, but they are very useful for locating structures and functions, so we will organize our discussion around them. Sometimes we need additional precision in locating structures, so you should get used to seeing the standard terms that are

used; the most important ones are illustrated in Figure 3.9a. Also, throughout this text you will be seeing illustrations of the nervous system from a variety of perspectives; until you get more comfortable with the structure of the nervous system, it may be difficult to tell what you are seeing. The images in Figure 3.9b will serve as a guide for understanding the orientation of most of these illustrations. FIGURE 3.9 Terms Used to Indicate Direction and Orientation in the Nervous System. (a) Dorsal means toward the back, and ventral means toward the stomach.S (This terminology was developed with other animals and becomes more meaningful when you imagine the human on all fours, face forward. Anterior means toward the front, and posterior means toward the rear . Superior is a location above another structure, and inferior means below another structure. Lateral means toward the side; medial indicates toward the middle. (b) The coronal plane divides the brain vertically from side to side, while the sagittal plane divides it vertically in an anterior-posterior direction, and the horizontal plane divides it between the top and bottom. We use these terms when we refer to an image (e.g., a sagittal view) or when the brain is cut along one of these planes (e.g., a horizontal section).

The frontal lobe is the area anterior to (in front of) the central sulcus and superior to (above) the lateral fissure. The functions here are complex and include some of the highest human capabilities. A considerable portion of the frontal lobes is also involved with the control of movement. And because the primary motor area is located along the posterior boundary of the frontal lobe, we will start our discussion there. (You should continue to refer to Figure 3.8.)

What functions are found in the frontal lobes? The precentral gyrus, which extends the length of the central sulcus, is the location

of the primary motor cortex, which controls voluntary (nonreflexive) movement. The motor area in one hemisphere controls the opposite side of the body, though it does exert a lesser control over the same side of the body. The parts of the body are “mapped onto” the motor area of each hemisphere in the form of a homunculus, which means “little man.” All this means is that the cells that control the muscles of the hand are adjacent to the cells controlling the muscles of the arm, which are next to those controlling the shoulder, and so on (see Figure 3.10). The homunculus is distorted in shape, however; the parts of the body that make precise movements, such as the hands and fingers, have more cortex devoted to their control. The primary

motor cortex, like other functional areas of the brain, carries out its work in concert with adjacent secondary areas. The secondary motor areas are located just anterior to the primary area. Subcortical (below the cortex) structures, such as the basal ganglia, also contribute to motor behavior. FIGURE 3.10 The Motor Cortex. This view shows a cross section (coronal) of the precentral gyrus. The distorted body proportions and facial features of the homunculus indicate the relative amount of motor cortex devoted to those body areas.

SOURCE: Adapted from Penfield/Rasmussen. The Cerebral Cortex of Man. © 1950 Gale, a part of Cengage Learning, Inc. Reproduced by permission. Looking back at Figure 3.8, locate Broca’s area anterior to the motor area and along

the lateral fissure. Broca’s area controls speech production, contributing the movements involved in speech and grammatical structure. A patient with damage to this area was asked about a dental appointment; he replied, haltingly, “Yes... Monday... Dad and Dick... Wednesday 9 o’clock... 10 o’clock... doctors... and... teeth” (Geschwind, 1979). Similar problems occur in reading and writing. In another example of hemispheric asymmetry, language activity is mostly controlled by the left hemisphere in 9 out of 10 people. The more anterior part of the frontal lobes—the prefrontal cortex in Figure 3.8—is

functionally complex. It is the largest region in the human brain, twice as large as in chimpanzees, and it accounts for 29% of the total cortex (Andreasen et al., 1992; Deacon, 1990). The prefrontal cortex is involved in planning and organization, impulse control, adjusting behavior in response to rewards and punishments, and

some forms of decision making (Bechara, Damasio, Tranel, & Damasio, 1997; Fuster, 1989; Kast, 2001). Symptoms of impairment are varied, depending on which part of the prefrontal area is affected (Mesulam, 1986), but malfunction often strikes at the capabilities we consider most human. Schizophrenia and depression, for example, involve dysfunction in the prefrontal cortex. People with prefrontal damage often engage in behavior that normal individuals

readily recognize will get them into trouble. In clinical interviews, they show good understanding of social and moral standards and the consequences of behavior—for example, they can describe several valid ways to develop a friendship, maintain a romantic relationship, or resolve an occupational difficulty—but they are unable to choose among the options. So in real life, they suffer loss of friends, financial disaster, and divorce (A. Damasio, 1994). Research indicates that prefrontal damage impairs the ability to learn from reward and punishment and to control impulses (Bechara et al., 1997). In spite of the effects of frontal lobe damage, during the 1940s and 1950s, surgeons

performed tens of thousands of lobotomies, a surgical procedure that disconnects the prefrontal area from the rest of the brain. Initially, the surgeries were performed on patients with severe schizophrenia, but many overly enthusiastic doctors lobotomized patients with much milder problems. Walter Freeman, shown in Figure 3.11, did more than his share of the 40,000 lobotomies performed in the United States and zealously trained other psychiatrists in the technique (Valenstein, 1986). The surgery calmed agitated patients, but the benefits came at a high price; the patients often became emotionally blunted, distractible, and childlike in behavior. In a follow-up study of patient outcomes, 49% were still hospitalized, and less than a fourth of the others were living independently (A. Miller, 1967). Lack of success with lobotomy and the introduction of psychiatric drugs in the 1950s made the surgery a rare therapeutic choice. Now psychosurgery, the use of surgical intervention to treat cognitive and emotional disorders, is generally held in disfavor, unlike brain surgery to treat problems such as tumors. The accompanying Application describes the most famous case of accidental lobotomy.

2 History of Psychosurgery FIGURE 3.11 Lobotomy Procedure and a Lobotomized Brain. (a) Walter Freeman inserts his instrument between the eyelid and the eyeball, drives it through the skull with a mallet, and moves it back and forth to sever the connections between the prefrontal area and the rest of the brain. (b) A horizontal view of a brain shows the gaps (arrows) produced by a lobotomy.

SOURCE: (a) © Bettmann/Corbis. (b) © Living Art Enterprises, LLC/Science Source.

APPLICATION

The Case of Phineas Gage In 1848, Phineas Gage, a 25-year-old railroad construction foreman in Cavendish, Vermont, was tamping explosive powder into a blasting hole when the charge ignited prematurely and drove the 3½-foot-long (1.15-m) tamping iron through his left cheek and out the top of his skull. Gage not only regained consciousness immediately and was able to talk and to walk with the aid of his men, but he also survived the accident with no impairment of speech, motor abilities, learning, memory, or intelligence. However, his personality was changed dramatically. He became irreverent and profane, and although Gage previously was the most capable man employed by the railroad, he no longer was dependable and had to be dismissed. He wandered about for a dozen years, never able to live fully independently, and died under the care of his family. Almost a century and a half later, Hanna Damasio and her colleagues

carried out a belated postmortem examination of the skull (H. Damasio et al., 1994). Combining measurements from the skull with a three-dimensional computer rendering of a human brain, they were able to reconstruct the path of the tamping iron through Gage’s brain (see the accompanying figure). They concluded that the accident damaged the part of both frontal lobes involved in processing emotion and making rational decisions in personal and social matters. At the time of Gage’s accident, physiologists were debating whether different parts of the brain have specific functions or are equally competent in carrying out functions. Gage’s experience had such an important influence in tipping the balance toward localization of function that in 1998 scientists from

around the world gathered in Cavendish to commemorate the 150th anniversary of the event (Vogel, 1998).

Reconstruction of the Damage to Phineas Gage’s Brain. The image of a normal brain (on the right) shows the area where Gage’s was damaged; the colors indicate motor, language, and body sensory areas that were unharmed. SOURCE: Reprinted with permission from “The Return of Phineas Gage: Clues About the Brain From a Famous Patient,” by H. Damasio, T. Grabowski, R. Frank, A. M. Galaburda, and A. R. Damasio, Science, 264, pp. 1102–1105. © 1994. Reprinted by permission from AAAS.

The parietal lobes are located superior to the lateral fissure and between the central sulcus and the occipital lobe. The primary somatosensory cortex, located on the postcentral gyrus, processes the skin senses (touch, warmth, cold, and pain) and the senses that inform us about body position and movement (see Figure 3.8 again). Like the motor cortex, the somatosensory area serves primarily the opposite side of the body. The somatosensory cortex also is organized as a homunculus, but in this case, the size of each area depends on the sensitivity in that part of the body. As you look at the senses of vision and hearing later, you will learn that this mapping is a principle of brain organization. Also, this is a good place to point out that the sensory areas of the brain are often referred to as projection areas, as in somatosensory projection area.

What functions are found in the parietal lobes? Each of the lobes contains association areas, which carry out further processing

beyond what the primary area does, often combining information from other senses. Parietal lobe association areas receive input from the body senses and from vision; they help the person identify objects by touch, determine the location of the limbs, and locate objects in space. Damage to the posterior parietal cortex may produce neglect, a disorder in which the person ignores objects, people, and activity on the side opposite the damage. This occurs much more frequently when the damage is in the right parietal lobe. The person may fail to shave or apply makeup on the left side of the face. In some cases, a stroke patient with a paralyzed arm or leg will deny that anything is wrong and even claim that the affected limb belongs to someone else. The lateral fissure separates the temporal lobe from the frontal and parietal lobes.

The temporal lobes contain the auditory projection area, visual and auditory association areas, and an additional language area (Figure 3.8). The auditory cortex, which receives sound information from the ears, lies on the superior (uppermost) gyrus of the temporal lobe, mostly hidden from view within the lateral fissure. Just posterior to the auditory cortex is Wernicke’s area, an association area that interprets language input arriving from the nearby auditory and visual areas; it also generates spoken language through Broca’s area and written language by way of the motor cortex. When Wernicke’s area is damaged, the person has trouble understanding speech or writing; the person can still speak, but the speech is mostly meaningless. Like Broca’s area, this structure is found in the left hemisphere in most people.

What functions are found in the temporal lobes? The inferior temporal cortex, in the lower part of the lobe as the name implies,

plays a major role in the visual identification of objects. People with damage in this area have difficulty recognizing familiar objects by sight, even though they can give detailed descriptions of the objects. They have no difficulty identifying the same items by touch. They may also fail to recognize the faces of friends and family members, though they can identify people by their voices. The neurologist Oliver Sacks (1990) described a patient who talked to parking meters, thinking they were children. Considering his strange behavior, it seems remarkable that he was unimpaired intellectually. Perhaps as you read about cases like this one and hear of patients who do things like denying ownership of their paralyzed leg, you will begin to appreciate the fact that human capabilities are somewhat independent of each other because they depend on different parts of the brain. FIGURE 3.12 Brain of One of Penfield’s Patients. The numbered tags allowed Penfield to relate areas to patients’ responses.

SOURCE: From The Excitable Cortex in Conscious Man, by Wilder Penfield, 1958. Courtesy of Dennis Coon and Liverpool University Press, Liverpool, UK © 1958. Used with permission. When the neurosurgeon Wilder Penfield (1955) stimulated patients’ temporal lobes,

he often elicited what appeared to be memories of visual and auditory experiences. Penfield was doing surgery to remove malfunctioning tissue that was causing epileptic seizures. Before the surgery, Penfield would stimulate the area with a weak electrical current and observe the effect; this allowed him to distinguish healthy tissue and important functional areas from the diseased tissue he wished to remove (see Figure 3.12). The patients were awake because their verbal report was needed for carrying out

this mapping; since brain tissue has no pain receptors, the patient requires only a local anesthetic for the surgery. Stimulation of primary sensory areas provoked only unorganized, meaningless sensations, such as tingling, lights, or buzzing sounds. But when Penfield stimulated the association areas of the temporal cortex, 25% of the patients reported hearing music or familiar voices or, occasionally, reliving a familiar event. One time, the patient hummed along with the music she was “hearing,” and the nurse, recognizing the tune, joined in by supplying the lyrics. (Does this not sound like a scene from a Monty Python movie—a sing-along during brain surgery?) People with epileptic activity or brain damage in their temporal lobes sometimes hear familiar tunes as well. The composer Shostakovich reportedly heard music when he tilted his head, shifting the location of a tiny wartime shell fragment in his temporal lobe; he refused to have the sliver removed, saying he used the melodies when composing (Sacks, 1990). Unfortunately, Penfield made no attempt to verify whether the apparent memories were factual or a sort of electrically induced dream; we will see in Chapter 12, however, that part of the temporal lobe has an important role in memory.

What functions are found in the occipital lobes? Finally, the occipital lobes are the location of the visual cortex, which is where

visual information is processed (see Figure 3.8). The primary projection area occupies the posterior tip of each lobe; anterior to the primary area are four association areas that detect individual components of a scene, such as color, movement, and form; this information is then combined and further processed in additional association areas, particularly in the temporal and parietal lobes. Just as the somatosensory and motor areas are organized to represent the shape of the body, the visual cortex contains a map of visual space because adjacent receptors in the back of the eye send neurons to adjacent cells in the visual cortex. Now that you are familiar with the four lobes and some of the functions located in

the cortex, we will direct our tour to structures below the surface. The Thalamus and Hypothalamus Deep within the brain, the thalamus lies just below the lateral ventricles, where it

receives information from all the sensory systems except olfaction (smell) and relays it to the respective cortical projection areas. (Figure 3.13 is a sagittal view of a brain sliced down the middle to show the structures described in this section.) Many other neurons from the thalamus project more diffusely throughout the cortex and help arouse the cortex when appropriate. You will see additional functions for the thalamus in later chapters. Actually there are two thalami, a right and a left, lying side by side.

What functions do the thalamus and hypothalamus perform? The hypothalamus, a smaller structure just inferior to the thalamus, plays a major

role in controlling emotion and motivated behaviors such as eating, drinking, and sexual activity (Figure 3.13). The hypothalamus exerts this influence largely through its control of the autonomic nervous system, which we will consider shortly. The hypothalamus also influences the body’s hormonal environment through its control over the pituitary gland. In Figure 3.13, the pituitary appears to be hanging down on its stalk just below the hypothalamus. The pituitary is known as the master gland because its hormones control other glands in the body. The hypothalamus, which is paired like the thalamus, contains perhaps the largest concentration of nuclei important to behavior in the entire brain. Just posterior to the thalamus is the pineal gland. You can see in Figure 3.13 why it

was Descartes’s best candidate for the seat of the soul (see Chapter 1): it is a single, unpaired structure, attached by its flexible stalk just below the hemispheres. In reality, the pineal gland secretes melatonin, a hormone that induces sleep. It controls seasonal cycles in nonhuman animals and participates with other structures in controlling daily rhythms in humans. FIGURE 3.13 Sagittal View of the Interior Features of the Human Brain.

In this view, the cut has been made between the cerebral hemispheres. Everything above the midbrain is forebrain; everything below is hindbrain.

The Corpus Callosum If you were to look inside the longitudinal fissure between the two cerebral

hemispheres, you would see that the hemispheres are distinctly separate from each other. A couple of inches below the brain’s surface, the longitudinal fissure ends in the corpus callosum, a dense band of fibers that carry information between the hemispheres. The corpus callosum is visible in Figure 3.13; you can see it from another perspective, along with a smaller band of crossing fibers, the anterior commissure, by looking back at Figure 3.5. You know that the two hemispheres carry out somewhat different functions, so you can imagine that they must communicate with each other constantly to integrate their activities. In addition, incoming information is often directed to one hemisphere—visual information appearing to one side of your field of view goes to the hemisphere on the opposite side, just as information from one side of your body does. This information is “shared” with the other hemisphere through the crossing fibers, especially the corpus callosum; the car that is too close on your left is registered in your right hemisphere, but if you are steering with your right hand, it is your left hemisphere that must react. Occasionally, surgeons have to sever the corpus callosum in patients with

incapacitating epileptic seizures that cannot be controlled by drugs. The surgery prevents the out-of-control neural activity in one hemisphere from engulfing the other hemisphere as well. The patient is then able to maintain consciousness during seizures and to lead a more normal life. These patients have been very useful for studying differences in the functions of the two hemispheres, because a stimulus can be presented to one hemisphere and the information will not be shared with the other hemisphere. Studies of these individuals have helped establish, for example, that the

left hemisphere is more specialized for language than the right hemisphere and the right hemisphere is better at spatial tasks and recognizing faces (Gazzaniga, 1967; Nebes, 1974). An example is shown in Figure 3.14; we will explore this topic further when we discuss consciousness in the final chapter. FIGURE 3.14 A Patient With Severed Corpus Callosum Identifying Objects by Touch. He cannot say what the object is because the right hemisphere, which receives the information from the hand, has been disconnected from the more verbal left hemisphere. Results are similar for visually presented stimuli and sound information.

The Ventricles During development, the hollow interior of the nervous system develops into

cavities called ventricles in the brain and the central canal in the spinal cord. The ventricles are filled with cerebrospinal fluid, which carries material from the blood vessels to the CNS and transports waste materials in the other direction. The lateral ventricles (Figures 3.13 and 3.15) extend forward deeply into the frontal lobes and in the other direction into the occipital lobes before they curve around into the temporal lobes. Below the lateral ventricles and connected to them is the third ventricle; it is located between the two thalami and the two halves of the hypothalamus, which form the ventricle’s walls. The fourth ventricle is not in the forebrain, so we will locate it later. FIGURE 3.15 The Ventricles of the Brain.

The Midbrain and Hindbrain The midbrain contains structures that have secondary roles in vision, hearing, and

movement (Figures 3.13 and 3.16). The superior colliculi, for example, help guide eye movements and fixation of gaze, and the inferior colliculi help locate the direction of sounds. One of the structures involved in movement is the substantia nigra, which projects to the basal ganglia to integrate movements; its dopamine-releasing cells degenerate in Parkinson’s disease (Chapter 11). Another is the ventral tegmental area, which we will see in Chapter 5 plays a role in the rewarding effects of food, sex, drugs, and so on. The midbrain also contains part of the reticular formation, which is described below. Passing through the midbrain is the cerebral aqueduct, which connects the third ventricle above with the fourth ventricle below (see Figure 3.15). Notice in Figure 3.16 that the brain takes on a more obvious tubular shape here, reminding us of the CNS’s origins. Considering the shape of these structures and the appearance of the cerebral hemispheres perched on top, you can see why this part of the brain is referred to as the brain stem. The hindbrain is composed of the pons, the medulla, and the cerebellum (Figures

3.13 and 3.16). The pons contains centers related to sleep and arousal, which are part of the reticular formation. The reticular formation is a collection of many nuclei running through the middle of the hindbrain and the midbrain; besides its role in sleep and arousal, it contributes to attention and to aspects of motor activity, including reflexes and muscle tone. The word pons means “bridge” in Latin, which reflects not only its appearance but also the fact that its fibers connect the two hemispheres of the cerebellum; the pons also has pathways connecting higher areas of the brain with the brain stem. The medulla forms the lower part of the hindbrain; its nuclei are involved with control of essential life processes, such as cardiovascular activity and respiration (breathing).

FIGURE 3.16 The Brain Stem. The brain stem includes posterior parts of the forebrain (thalamus, hypothalamus, etc.), the midbrain, and the hindbrain. The cerebellum has been removed to reveal the other structures. This is a dorsal view of the brain stem. Refer to Figure 3.13 for its orientation with respect to the entire brain.

The cerebellum is the second most distinctive-appearing brain structure (see Figures 3.2, 3.8, 3.13, and 3.20). Perched on the back of the brain stem, it is wrinkled and divided down the middle like the cerebral hemispheres—thus its name, which means “little brain.” The most obvious function of the cerebellum is refining movements initiated by the motor cortex by controlling their speed, intensity, and direction. A person whose cerebellum is damaged has trouble making precise reaching movements and walks with difficulty because the automatic patterning of movement routines has been lost. It is not unusual for individuals with cerebellar damage to be arrested by the police because their uncoordinated gait is easily mistaken for drunkenness. The cerebellum also plays a role in motor learning, and research implicates it in other cognitive processes and in emotion (Fiez, 1996). With 70% of the brain’s neurons in its fist-sized volume, it would be surprising if it did not hold a number of mysteries waiting to be solved. We have admittedly covered a large number of structures. It may help to see them

and their major functions summarized in Table 3.2. But as you review these functions, remember the caveat about localization from Chapter 1 that a behavior is seldom the province of a single brain location, but results from the interplay of a whole network of structures.

3 How the Brain Works The Spinal Cord The spinal cord is a finger-sized cable of neurons that carries commands from the

brain to the muscles and organs and sensory information into the brain. Its role is more complicated than that, though. It controls the rapid reflexive response when you withdraw your hand from a hot stove, and it contains pattern generators that help control routine behaviors such as walking. Notice the appearance of the interior of the spinal cord in Figure 3.17; it is arranged just the opposite of the brain, with the white matter on the outside and the gray matter in the interior. The white exterior is made up of axons—ascending sensory tracts on their way to the brain and descending motor tracts on their way to the muscles and organs. TABLE 3.2 Major Structures of the Brain and Their Functions.

Sensory neurons enter the spinal cord through the dorsal root of each spinal nerve.

The sensory neurons are unipolar; clustering of their cell bodies in the dorsal root ganglion explains the dorsal root’s enlargement. The sensory neuron in the illustration could be as much as 1 meter (m) long, with its other end out in a fingertip or a toe. The H-shaped structure in the middle of the spinal cord is made up mostly of unmyelinated cell bodies. The cell bodies of motor neurons are located in the ventral horns, which is why the ventral horns are enlarged. The axons of the motor neurons pass out of the spinal cord through the ventral root. The dorsal root and the ventral root on the same side of the cord join to form a spinal nerve that exits the spine between adjacent vertebrae (the bones that make up the spine). FIGURE 3.17 Horizontal Cross Section of the Spinal Cord, With Reflex Circuit. A sensory neuron from the hand transmits signals (1) via the dorsal root of the spinal nerve into the spinal cord, where it (2) forms a reflex arc with a motor neuron that (3) exits through the ventral root and (4) activates the biceps muscle to flex the arm and withdraw the hand. The sensory input also travels (5) up to the brain to produce a sensation. (6) A motor neuron from the brain connects to the motor neuron in the ventral horn; this adds a voluntary activation of the muscle, though more slowly. (In reality, many neurons would be involved.)

What is the structure of the spinal cord? Most of the motor neurons receive their input from the brain, either from the motor

cortex or from nuclei that control the activity of the internal organs. Notice in Figure 3.17, however, that in some cases sensory neurons from the dorsal side connect with motor neurons, either directly or through an interneuron. This pathway produces a simple, automatic movement in response to a sensory stimulus; this is called a reflex. For example, when you touch a lighted match with your hand, input travels to the spinal cord, where signals are directed out to the muscles of the arm to produce reflexive withdrawal. Many people use the term reflex incorrectly to refer to any action a person takes without apparent thought; however, the term is limited to behaviors that are controlled by these direct sensory-motor connections. Besides not requiring thought, reflexive acts occur much more rapidly than the same response produced voluntarily. Reflexes originate in the brain as well as in the spinal cord, and reflexes also affect the internal environment—for example, reducing blood pressure when it goes too high. Protecting the Central Nervous System The brain and the spinal cord are delicate organs, vulnerable to damage from blows

and jostling, to poisoning by toxins, and to disruption by mislocated or excessive neurotransmitters. Both structures are enclosed in a protective three-layered membrane called the meninges. The space between the meninges and the CNS is filled with cerebrospinal fluid, which cushions the neural tissue from the trauma of blows and sudden movement. The brain and spinal cord literally float in the cerebrospinal fluid, so the weight of a 1,200- to 1,400-g brain is in effect reduced to less than 100 g. The tough meninges and the cerebrospinal fluid afford the brain some protection from occasional trauma, but the blood-brain barrier, which limits passage between the bloodstream and the brain, provides constant protection from toxic substances and from neurotransmitters circulating in the blood such as norepinephrine, which increases during stress. FIGURE 3.18 The Blood-Brain Barrier. The tight junctions of the capillary walls prevent passage of large molecules into the brain. Small molecules, such as oxygen and carbon dioxide, pass through freely, as do fat-soluble substances, including most drugs. Water-soluble substances such as amino acids and glucose must be transported through.

Concept Check

Outside the brain, the cells that compose the walls of the capillaries (small blood vessels) have gaps between them that allow most substances to pass rather freely. In the brain, these cells are joined so tightly that easy passage is limited to small molecules such as carbon dioxide and oxygen and to substances that can dissolve in the lipid (fat) of the capillary walls (Figure 3.18). Fat solubility accounts for the effectiveness of most drugs, both therapeutic and abused. Most substances needed by the brain are water soluble and cannot pass through on their own, so glucose, iron, amino acids (the building block that proteins are made of), and many vitamins must be actively carried through the walls by specialized transporters. Not all brain areas are protected by the barrier, however. This is particularly true of

brain structures surrounding the ventricles. One of them is the area postrema; when you ingest something toxic, such as an excess of alcohol, the substance passes from the bloodstream into the area postrema. Because the area postrema induces vomiting, your stomach empties quickly—ideally before too much harm is done.

Take a Minute to Check Your Knowledge and Understanding

What is the advantage of the convoluted structure of the cortex? What has been the fate of psychosurgery; what clue from past experience did doctors have that lobotomy in particular might have undesirable consequences?

Select one of the lobes or the midbrain or the hindbrain and describe the structures and functions located there.

Describe the pathway of a reflex, identifying the neurons and the parts of the spinal cord involved.

The Peripheral Nervous System The peripheral nervous system (PNS) is made up of the cranial nerves, which enter and leave the underside of the brain, and the spinal nerves, which connect to the sides of the spinal cord at each vertebra. From a functional perspective, the PNS can be divided into the somatic nervous system and the autonomic nervous system. The somatic nervous system includes the motor neurons that operate the skeletal muscles —that is, the ones that move the body—and the sensory neurons that bring information into the CNS from the body and the outside world. The autonomic nervous system (ANS) controls smooth muscle (stomach, blood vessels, etc.), the glands, and the heart and other organs. The diagram in Figure 3.19 will help you keep track of these divisions and relate them to the CNS. We dealt with the spinal nerves when we discussed the spinal cord, and we have said all we need to for now about the somatic system, so we will give the rest of our attention to the cranial nerves and the ANS. FIGURE 3.19 Divisions of the Nervous System.

SOURCE: Adapted from Biological Foundations of Human Behavior, by J. Wilson, 2003, Belmont, CA: Wadsworth. The Cranial Nerves The cranial nerves enter and exit on the ventral side of the brain (Figure 3.20).

While the spinal nerves are concerned exclusively with sensory and motor activities within the body, some of the cranial nerves convey sensory information to the brain from the outside world. Two of these, the olfactory nerves and the optic nerves, have the special status of often being considered part of the brain. One reason is the brainlike complexity of the olfactory bulb and of the retina at the back of the eye; another is that their receptor cells originate in the brain during development and

migrate to their final locations. As a consequence, you will sometimes see the olfactory and optic nerves referred to as tracts.

What are the functions of the autonomic nervous system? The Autonomic Nervous System The functions of the ANS are primarily motor; its sensory pathways provide

internal information for regulating its own operations. The ANS is composed of two branches. The sympathetic nervous system activates the body in ways that help it cope with demands such as emotional stress and physical emergencies. Your most recent emergency may have been when you overslept on the morning of a big exam. As you raced to class, your heart and breathing sped up to provide your body the resources it needed. Your blood pressure increased as well, and your peripheral blood vessels constricted, shifting blood supply to the internal organs, including your brain. Your muscles tensed to help you fight or flee, and your sweat glands started pouring out sweat to cool your overheating body. All this activity was just the sympathetic nervous system at work. The parasympathetic nervous system not only slows the activity of most organs to conserve energy, but also activates digestion to renew energy. FIGURE 3.20 Ventral View of the Brain Showing the Cranial Nerves and Their Major Functions. Brain landmarks are labeled on the right to help you locate the nerves.

The sympathetic branch rises from the middle (thoracic and lumbar) areas of the spinal cord (see Figure 3.21). Most sympathetic neurons pass through the sympathetic ganglion chain, which runs along each side of the spine; there they synapse with postsynaptic neurons that rejoin the spinal nerve and go out to the muscles or glands they serve. (The others pass directly to ganglia in the body cavity before synapsing.) Because most of the sympathetic ganglia are highly interconnected in the sympathetic ganglion chain, this system tends to respond as a unit. Thus, when you were rushing to your exam, your whole body went into hyperdrive. As you can see in the illustration, the parasympathetic branch rises from the extreme ends of the PNS—in the cranial nerves and in the spinal nerves at the lower (sacral) end of the spinal cord. The parasympathetic ganglia are not interconnected but are located on or near the muscles and glands they control; as a result, the components of the parasympathetic system operate more independently than those of the sympathetic system. FIGURE 3.21 The Autonomic Nervous System. A diagrammatic view of the parasympathetic and sympathetic nerves and their

functions. The nerves exit both sides of the brain and spinal cord through the paired cranial and spinal nerves but are shown on one side for simplicity.

Organs are innervated by both branches of the ANS, with the exception of the sweat glands, the adrenal glands, and the muscles that constrict blood vessels, which receive only sympathetic activation. It is not accurate to assume that one branch is active at a time and the other completely shuts down; rather, both are active to some degree all the time, and the body’s general activity reflects the balance between sympathetic and parasympathetic stimulation.

Concept Check Take a Minute to Check YourKnowledge and Understanding Which cranial nerves are sometimes referred to as tracts, and why? Why does the sympathetic system operate more as a unit than the parasympathetic system does?

How do the branches of the ANS interact to regulate internal activity?

Development and Change in the Nervous System Nothing rivals the human brain in complexity, which makes the development of the brain the most remarkable construction project that you or I can imagine. During development, its 100 billion neurons must find their way to destinations throughout the brain and the spinal cord; then they must make precise connections to an average of a thousand target cells each (Tessier-Lavigne & Goodman, 1996). How this is accomplished is one of the most intriguing mysteries of neurology, but a mystery that is being solved a little at a time.

4 BrainWork News The Stages of Development You already know that the nervous system begins as a hollow tube that later

becomes the brain and the spinal cord. The nervous system begins development when the surface of the embryo forms a groove (see Figure 3.22); the edges of this groove curl upward until they meet, turning the groove into a tube. Development of the nervous system then proceeds in four distinct stages: cell proliferation, migration, circuit formation, and circuit pruning. Proliferation and Migration During proliferation, the cells that will become neurons divide and multiply at the

rate of 250,000 new cells every minute. Proliferation occurs in the ventricular zone, the area surrounding the hollow tube that will later become the ventricles and the central canal. During migration, these newly formed neurons move from the ventricular zone outward to their final location. They do so with the aid of specialized radial glial cells (Figure 3.23 on page 78). Remember Karen from the beginning of the chapter? This is where development went awry in her brain. The neurons that would have formed her cortex failed to migrate properly and got off their radial glial cell scaffolds too early (J. W. Fox et al., 1998).

How do neurons find their correct destination?

The functional role that a neuron will play depends on its location and the time of its “birth”; different structures form during different stages of fetal development. Prior to birth and for a time afterward, the neurons retain considerable functional flexibility, however. In fact, fetal brain tissue can be transplanted into a different part of an adult brain, and the transplanted neurons will form synapses and assume the function of their new location. FIGURE 3.22 Development of the Neural Tube. (a) Photographs of neural tube development as the embryo’s surface forms a groove, which closes to form a tube. (b) Diagrammatic representation of the events. The photographs show an end view of the developing tube; the drawings show the entire structure.

SOURCE: Photos by Kathryn Tosney. Circuit Formation During circuit formation, the axons of developing neurons grow toward their target

cells and form functional connections. For example, axons of motor neurons grow toward the spinal cord, and cells in the retina of the eye send their axons to the thalamus, where they form synapses with other neurons. To find their way, axons form growth cones at their tip, which sample the environment for directional cues (Figure 3.24 on page 79). Chemical and molecular signposts attract or repel the advancing axon, coaxing it along the way (Tessier-Lavigne & Goodman, 1996). By pushing, pulling, and hemming neurons in from the side, the chemical and molecular

forces guide the neuron to intermediate stations and past inappropriate targets until they reach their final destinations. The path to the developing axon’s destination is not necessarily direct, but thanks to

changing genetic control, it is able to make direction changes along the way. This is illustrated by an axon whose destination is on the opposite side of the brain’s midline. Ordinarily, a migrating axon will grow parallel to the midline without crossing over, because it is repelled by a midline chemical that is under the control of the gene Robo1. But at the appropriate location, the gene Robo3 becomes active; the axon is then attracted to the midline and turns and enters it. At that point, Robo3 is downregulated; the axon is repelled again and, continuing in the same direction, exits the midline and will not recross (C. G. Woods, 2004). FIGURE 3.23 A Neuron Migrates Along Glial Scaffolding. (a) Immature neurons migrate from the inner layer, where they were “born,” to their destination between there and the outer layer. (b) A close-up of one of the neurons climbing a radial glial cell scaffold.

SOURCE: Adapted from illustration by Lydia Kibiuk, © 1995. Circuit Pruning

The brain produces extra neurons, apparently as a means of compensating for the errors that occur in reaching targets. This overproduction is not trivial: The monkey’s visual cortex contains 35% more neurons at the time of birth than in adulthood, and the number of axons crossing the corpus callosum is four times what it will be later in life (LaMantia & Rakic, 1990; R. W. Williams, Ryder, & Rakic, 1987). The next stage of neural development, circuit pruning, involves the elimination of excess neurons and synapses. Neurons that are unsuccessful in finding a place on a target cell, or that arrive late, die; the monkey’s corpus callosum alone loses 8 million neurons a day during the first 3 weeks after birth. In a second step of circuit pruning, the nervous system refines its organization and

continues to correct errors by eliminating large numbers of excessive synapses. For example, in mature mammals, neurons from the left and right eyes project to alternating columns of cells in the visual cortex, but the connections made during development are indiscriminate. Synapses are strengthened or weakened depending on whether the presynaptic neuron and the postsynaptic neuron fire together. Because a single neuron cannot by itself cause another neuron to fire, this is likely to happen when neighboring neurons are also firing and adding summating inputs through overlapping terminals. If a neuron is not firing at the same time as its neighbors, it has probably made its connection in the wrong neighborhood. It is thought that the postsynaptic neuron sends feedback to the presynaptic terminals in the form of neurotrophins, chemicals that enhance the development and survival of neurons.

What determines which synapses will survive? In the visual system, sensory stimulation provides neuronal activation that

contributes to this refinement. However, pruning of synapses begins in some parts of the visual system even before birth. How can this stimulation occur when visual input is impossible? The answer is that waves of spontaneous neural firing sweep across the fetal retina, providing the activation that selects which synapses will survive and which will not (Hooks & Chen, 2007; Huberman, 2007). In the first few years of the rhesus monkey’s life, 40% of the synapses in the primary visual cortex are eliminated, at the stunning rate of 5,000 per second (Bourgeois & Rakic, 1993). This process of producing synapses that will later be eliminated seems wasteful, but targeting neurons’ destinations more precisely would require prohibitively complex chemical and molecular codes. Later, the plasticity (ability to be modified) of these synapses decreases; a practical example is that recovery from injury to the language areas of the brain is greatly reduced in adulthood. However, the synapses in the cortical association areas are more likely to retain their plasticity, permitting later modification by experience—in other words, learning (Kandel & O’Dell, 1992; W. Singer, 1995). FIGURE 3.24 Neurons With Growth Cones.

SOURCE: Steven Rothman, MD.

5 Preiventricular Heterotopia and Fetal Alcohol Syndrome As impressive as the brain’s ability to organize itself during development is,

mistakes do occur, and for a variety of reasons. Periventricular heterotopia, the problem Karen had (see beginning of the chapter), is caused by any one of a variety of gene mutations that cause developing neurons to clump near the ventricles rather than migrating to the cortex. Fetal alcohol syndrome, which often produces intellectual disability, is caused by the mother’s use of alcohol during a critical period of brain development. The brains of individuals with fetal alcohol syndrome are often small and malformed, and neurons are dislocated (Figure 3.25). During migration, many cortical neurons fail to line up in columns as they normally would because the radial glial cells revert to their more typical glial form prematurely; other neurons continue migrating beyond the usual boundary of the cortex (Clarren, Alvord, Sumi, Streissguth, & Smith, 1978; Gressens, Lammens, Picard, & Evrard, 1992; P. D. Lewis, 1985). Exposure to ionizing radiation, such as that produced by nuclear accidents and atomic blasts, also causes intellectual impairment by interfering with both proliferation and migration. The offspring of women who were in the 8th through 15th weeks of pregnancy during the bombing of Hiroshima and Nagasaki and during the meltdowns at the Chernobyl and Fukushima nuclear generating stations were the most vulnerable, because the rates of proliferation and migration are highest then (Schull, Norton, & Jensh, 1990). An additional step is required for full maturation of the nervous system—

myelination. In the brain, it begins with the lower structures and then proceeds to the cerebral hemispheres, moving from occipital lobes to frontal lobes. Myelination starts around the end of the third trimester of fetal development but is not complete until late adolescence or beyond (Sowell, Thompson, Holmes, Jernigan, & Toga, 1999). This slow process has behavioral implications—for instance, contributing to the

improvement through adolescence on cognitive tasks that require the frontal lobes (H. S. Levin et al., 1991). Considering the role of the prefrontal cortex in impulse control and the fact that this area is the last to mature (Sowell et al., 1999), it should come as no surprise that parents are often baffled by their adolescents’ behavior. “

The top 10 causes of death in young people—including motor vehicle accidents, homicides and suicides—are all preventable issues relating to judgment, not illness.

—Melinda Beck, Wall Street Journal

” How Experience Modifies the Nervous System Stimulation continues to shape synaptic construction and reconstruction throughout

the individual’s life. For example, training rats to find their way through a maze or just exposing them to a complex living environment causes increased branching of synapses in the cortex (Greenough, 1975). Humans lose neurons as they age, but they develop more synapses (Buell & Coleman, 1979), presumably as the result of experience. FIGURE 3.25 Fetal Alcohol Syndrome In the Mouse Brain. (a) In this cross section of the normal cortex, the neurons (the dark spots) tend to line up in vertical columns. (b) In the alcohol-exposed brain, the neurons are arranged randomly.

SOURCE: From “Ethanol Induced Disturbances of Gliogenesis and Neurogenesis in

the Developing Murine Brain: An in vitro and an in vivo Immunohistochemical and Ultrastructural Study,” by P. Gressens, M. Lammans, J. J. Picard, and P. Evrard, Alcohol and Alcoholism, 27, pp. 219–226. © 1992. Used by permission of Oxford University Press. Experience-induced change can involve reorganization, a shift in connections that

changes the function of an area of the brain. For example, in blind people who read Braille, the space in the brain devoted to the index (reading) finger increases, at the expense of the area corresponding to the other fingers on the same hand (Pascual- Leone & Torres, 1993). In a brain scan study, it was discovered that blind individuals who excel at sound localization had recruited the unused visual area of their brains to aid in the task (Gougoux, Zatorre, Lassonde, Voss, & Lepore, 2005). This rewiring is not random: In blind individuals, trying to locate sounds or touch activated the area normally involved in visual localization; when cats deaf from birth located objects or detected motion visually they used areas that ordinarily perform those functions with sounds (Lomber, Meredith, & Kral, 2010; Renier et al., 2010). Much of our brain plasticity is lost after the age of two or three (Bedny, Konkle, Pelphrey, Saxe, & Pascual-Leone, 2010), but dramatic changes can occur in adulthood. And some of them take place rapidly, as we see in a study of individuals born with a condition called syndactyly, in which the fingers are attached to each other by a web of skin. Use of the fingers is severely limited, and the fingers are represented by overlapping areas in the somatosensory cortex. Figure 3.26 shows that after surgery, the representations of the fingers in the cortex became separate and distinct in just 7 days (Mogilner et al., 1993). The 19th-century philosopher and psychologist William James speculated that if a

surgeon could switch your optic nerves with your auditory nerves, you would then see thunder and hear lightning (James, 1893). James was expressing Johannes Müller’s doctrine of specific nerve energies from a half century earlier—that each sensory projection area produces its own unique experience regardless of the kind of stimulation it receives. This is why you “see stars” when your Rollerblades shoot out from under you and the back of your head (where the visual cortex is located) hits the pavement. But during early development, even this basic principle of brain operation can fall

victim to reorganization. In people blind from birth, the visual cortex has nothing to do; as a result, some of the somatosensory pathways take over part of the area, so the visual cortex is activated by touch. But in this case, does the visual cortex produce a visual experience, or one of touch? To find out, researchers stimulated the visual cortex of blind individuals by applying an electromagnetic field to the scalp over the occipital area (L. G. Cohen et al., 1997). In sighted people, this disrupts visual performance, but in the blind individuals, the procedure distorted their sense of touch and interfered with their ability to identify Braille letters. Apparently, their visual area

was actually processing information about touch in a meaningful way!

What kinds of changes occur in the brain due to experience? Reorganization does not always produce a beneficial outcome. When kittens were

reared in an environment with no visual stimulation except horizontal stripes or vertical stripes, they didn’t develop the ability to respond to objects in the other orientation. A cat reared, for example, with vertical stripes would play with a rod held vertically and ignore the rod when it was horizontal. Electrical recording indicated that the cells in the visual cortex that would have responded to horizontally oriented stimuli had reorganized their connections in response to the limited stimulation. In Chapter 11, you will see that people who have a limb amputated often experience phantom pain, pain that seems to be located in the missing limb. It appears to be caused by sensory neurons from a nearby part of the body growing into the somatosensory area that had served the lost limb (Flor et al., 1995). FIGURE 3.26 Changes in the Somatosensory Area Following Surgery for Syndactyly. (a) The hand before (top) and after (bottom) surgery. (b) Images (coronal) showing brain areas responsive to stimulation of the fingers before and after surgery. (c) Graphic representation of the relative size and location of the responsive areas.

SOURCE: From “Somatosensory Cortical Plasticity in Adult Humans Revealed by Magnetoencephalography,” by A. Mogilner et al., 1993, Proceedings of the National Academy of Sciences, 90, pp. 3593–3597. “

In the adult centres the nerve paths are something fixed, ended and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.

—Santiago Ramón y Cajal, 1928

” Damage and Recovery in the Central Nervous System One reason neuroscientists are interested in the development of the nervous system

is because they hope to find clues about how to repair the nervous system when it is damaged by injury, disease, or developmental error. It is difficult to convey the impairment and suffering that results from brain disorders, but the staggering financial costs in Table 3.3 will give you some idea. We will focus mostly on stroke and trauma and leave the other sources of injury for later chapters. TABLE 3.3 Annual Costs of Brain Damage and Disorders in the United States.

SOURCES: Olesen et al. (2011); Uhl and Grow (2004). NOTE: Includes direct costs of care and treatment and indirect costs such as crime, lost wages, and financial assistance. Differences between the U.S. and European data are due to a variety of factors, including incidence rate, greater cost of direct health care in the United States, and which indirect costs were included in each study. Stroke, also known as cerebrovascular accident, is caused by a loss of blood flow in

the brain. Most strokes are ischemic, caused by blockage of an artery by a blood clot or other obstruction; hemorrhagic strokes occur when an artery ruptures. The neurons are deprived of oxygen and glucose, of course, but most of the damage is due to excitotosis (not to be confused with exocitosis, mentioned in Chapter 2); dying neurons release excess glutamate, which overstimulates the surrounding neurons, which then die as large amounts of calcium enter the cells. Further impairment is caused by edema, an accumulation of fluid that causes increased pressure on the brain. Stroke is the third leading cause of death in the United States and a leading cause of long-term disability, including paralysis and loss of language and other functions (Heron et al., 2009). Traumatic brain injury (TBI) is caused by an external mechanical force such as a

blow to the head, sudden acceleration or deceleration, or penetration. TBIs are the cause of 52,000 deaths each year in the United States; about 35% of TBIs are caused by falls, and another 17% result from traffic accidents (Faul, Xu, Wald, & Coronado, 2010). Besides the direct damage to neurons, edema and ischemia (loss of blood supply due to blood clots) take an additional toll. Mild traumatic injury, or concussion as it is more commonly known, is the most common TBI; it results from blows and acceleration-deceleration that occur in automobile accidents, sports activities, and battlefield explosions. Whether or not these traumas are sufficient to cause loss of consciousness, they are often followed by headache, drowsiness, and memory loss, which usually go away if the individual rests during the following 3 weeks. Repeated concussions can cause cumulative brain damage; the expression “punch-drunk” actually refers to dementia pugilistica, the impairment suffered by boxers who didn’t know when to quit. However, even a single concussion severe enough to cause brief unconsciousness or amnesia produces brain atrophy that is detectable 1 year later, and which is correlated with memory and attention deficits (Zhou et al., 2013). We may expect such effects from car wrecks, violent gridiron hits, and roadside bombs, but we’re learning that more benign sports also can be dangerous for the brain (see In the News).

What limits central nervous system repair? How might repair be encouraged? Limitations on Recovery Nervous system repair is no problem for some species, particularly amphibians. For

example, when Sperry (1943, 1945) severed the optic nerves of frogs, the eyes made functional reconnections to the brain even when the disconnected eye was turned upside down or transplanted into the other eye socket. Regeneration, the growth of severed axons, also occurs in mammals, at least in the PNS. So when you fell Rollerblading, if you broke your arm so badly that a nerve was severed, the disconnected part of the cut axon would have died, but the part connected to the cell body would have survived and regrown. Myelin provides a guide tube for the sprouting end of a severed neuron to grow through (W. J. Freed, de Medinaceli, & Wyatt, 1985), and the extending axon is guided to its destination much as it would be during development (Horner & Gage, 2000).

Is the Brain Too Fragile for Sports?

Two years after 4,500 football players and their families sued the National Football League (NFL) over accusations that it concealed what it knew about the dangers of repeated hits to the head, the parties agreed to a settlement of $765 million. If approved by the judge, most of the money will go to players or the families of players who experienced cognitive impairments, with the rest supporting baseline medical exams and research. Nearly every former player who has been autopsied has had chronic traumatic encephalopathy, a degenerative brain

condition similar to Alzheimer’s disease believed to be caused only by repeated head trauma; three of those players committed suicide. Now the Institute of Medicine, which advises the government on health issues,

has released a report cautioning that too little research is being done on concussions in youth. They concluded that 10% to 20% of concussions in youth result in symptoms lasting for weeks to years and that we lack information about how vulnerable their developing brains are to outcomes like those in NFL players. The data we do have are unsettling, because it appears that brain damage can be incurred without even sustaining a concussion. Researchers who presented their work at the Radiological Society of North America’s annual meeting initially planned to see if soccer injuries produce noticeable brain changes, but their brain scans showed that players who headed the ball more often than their fellow players had brain injuries similar to those in patients with concussions. The impact from heading a ball isn’t believed to be enough to tear nerve tissue, but repeated heading may set off a cascade of responses that lead to degeneration of cells.

6 Sports and Traumatic Brain Injury

But in the mammalian CNS, damaged neurons encounter a hostile environment. If your Rollerblading accident severed neurons in your spinal cord, the axon stumps would sprout new growth, but they would make little progress toward their former target. This is partly because the CNS in adult mammals no longer produces the chemical and molecular conditions that stimulate and guide neuronal growth. In addition, scar tissue produced by glial cells blocks the original pathway, glial cells also produce axon growth inhibitors, and immune cells move into the area and possibly interfere with regrowth (D. F. Chen, Schneider, Martinou, & Tonegawa, 1997; Horner & Gage, 2000; Thallmair et al., 1998). Another way the nervous system could repair itself is by neurogenesis, the birth of

new neurons. While neurogenesis has been detected in several areas of the nonhuman brain (C. D. Fowler, Liu, & Wang, 2007), it appears to be most extensive in two areas; one is the hippocampus, and the other is near the lateral ventricles, supplying the

olfactory bulb (Gage, 2000). These new neurons apparently contribute to the neural plasticity required in learning: Blocking neurogenesis in the hippocampus interferes with certain types of learning that involve that structure, and doing so in the olfactory bulbs impairs learning associations with odors (Lazarini & Lledo, 2011; Ming & Song, 2011). There is no guarantee that this neurogenesis contributes to brain repair following injury. On the other hand, neural precursor cells migrate to damaged areas in rats’ brains following experimentally induced stroke and appear to replace damaged neurons (Parent, 2003). Furthermore, increased neurogenesis has been observed at damage sites in the brains of deceased Alzheimer’s patients and Huntington’s disease patients (Curtis et al., 2003; Jin et al., 2004). Results such as these suggest that if we could enhance neurogenesis, it might provide a means of self-repair; this assumes that neurogenesis occurs postnatally in humans and that it is extensive enough to work with, a question that has been answered in a unique way (see In the News). Compensation and Reorganization Although axons do not regenerate and neuron replacement is limited at best,

considerable recovery of function can occur in the damaged mammalian CNS. Much of the improvement in function following injury is nonneural in nature and comes about as swelling diminishes and glia remove dead neurons (Bach-y-Rita, 1990). The simplest recovery that is neural in nature involves compensation as uninjured tissue takes over the functions of lost neurons. Presynaptic neurons sprout more terminals to form additional synapses with their targets (Fritschy & Grzanna, 1992; Goodman, Bogdasarian, & Horel, 1973), and postsynaptic neurons add more receptors (Bach-y- Rita, 1990). In addition, normally silent side branches from other neurons in the area become active within minutes of the injury (Das & Gilbert, 1995; Gilbert, 1993). These synaptic changes are similar to those occurring during learning; this would explain why physical therapy can be effective in promoting recovery after brain injury.

What forms of recovery are possible in the human CNS? A more dramatic form of neural recovery involves reorganization of other brain

areas. During recovery of language ability following brain damage or surgery, the functions apparently are assumed by nearby brain areas or, in the case of massive damage, by the other hemisphere (Guerreiro, Castro-Caldas, & Martins, 1995). Occasionally, an entire hemisphere must be removed because it is diseased. The patients typically do not reach normal levels of performance after the surgery, but they often recover their language and other cognitive skills and motor control to a remarkable degree (Glees, 1980; Ogden, 1989). In these cases, malfunction in the removed hemisphere dated back to infancy, so presumably the reorganization began then rather than at the time of surgery in late adolescence or early adulthood. In rare instances, people are born entirely lacking a corpus callosum. A further tribute to the

brain’s plasticity is that 75% of these individuals develop normally and fewer than 12% are severely impaired (Sotiriadis & Makrydimas, 2012).

Nuclear Testing Reveals Adult Neurogenesis in Humans We know a great deal about neurogenesis in mice, and very little when it comes to humans. Fifteen years ago, researchers in Sweden reported evidence of adult neurogenesis in the human hippocampus (Erikkson et al., 1998). At that time the chemical bromodeoxyuridine (BrdU), which enters cells while they are dividing, was being used in cancer patients to track the spread of tumors. In a group of deceased patients, BrdU was also found in some of the neurons in the hippocampus, which meant that they had been formed during the patients’ treatment.

But the use of BrdU was banned shortly after that, which made it difficult to repeat the study and left some researchers doubting the results. Then another research team at Stockholm’s Karolinska Institute came up with a

brilliant alternative strategy. From 1945 to 1963, above-ground nuclear testing by the United States, the United Kingdom, and the Soviet Union doubled the amount of carbon 14 (C 14) in the atmosphere around the entire globe. C 14 atoms enter the food chain and, like BrdU, are incorporated into cellular DNA as the cells are dividing. When the researchers applied this technique to human hippocampal tissue, some of the neurons were found to have elevated C 14 levels. Because C 14 in cells corresponds closely to levels in the atmosphere, and that has been diminishing at a known rate since 1963, the researchers were able to date the birth of neurons to within one year. This allowed them to conclude that our hippocampi add 1,400 new neurons every day. Also, neurogenesis continued throughout life; the rate did diminish with age, but not nearly as much as it does in mice.

7 Human Neurogenesis In two earlier studies by the group, C 14 testing yielded no evidence of adult

neurogenesis in the human cortex (Bhardwaj et al., 2006) or olfactory bulbs (Bergman et al., 2012). Assuming that hippocampal neurogenesis contributes to memory, we might be able to enhance that process to help Alzheimer’s patients; but repairing damage in the cortex is another matter, unless we can find a way to initiate neurogenesis where it doesn’t normally occur.

FIGURE 3.27 Normal Brain and Hydrocephalic Brain. The ventricles are greatly enlarged and brain tissue is reduced in the brain on the right, compared to the normal brain on the left. The individual has an IQ of 75 (above the cutoff for intellectual impairment), is employed as a civil servant, and

has a wife and two children.

SOURCE: Reprinted “Brain of a White-Collar Worker,” by L. Feuillet, H. Dufour, and J. Pelletier, 2007, The Lancet, 370, p. 262. © 2007, with permission from Elsevier. Recovery from aphasia and periventricular heterotopia challenges our

understanding of how the brain works. Hydrocephalus provides another such example. Hydrocephalus occurs when the circulation of cerebrospinal fluid is blocked and the accumulating fluid interferes with the brain’s growth, producing severe intellectual impairment. If detected in time, the condition can be treated by installing a drain that shunts the excess fluid into the bloodstream. However, the occasional individual somehow avoids impairment without this treatment. The British neurologist John Lorber described a 26-year-old college student with hydrocephalus whose ventricles were so enlarged that the cerebral walls (between his ventricles and the outer surface of his brain) were less than 1 mm thick, compared with the usual 45 mm (see Figure 3.27). Yet he had a superior IQ of 126, had earned an honors degree in mathematics, and was socially normal (Lewin, 1980). It is unclear how these individuals can function normally in the face of such enormous brain deficits. What is clear is that somewhere in this remarkable plasticity lies the key to new revelations about brain function. FIGURE 3.28 Christopher Reeve (1952–2004).

SOURCE: © Wally McNamee/CORBIS. Possibilities for CNS Repair In 1995, Christopher Reeve, the movie actor best known for his role as Superman,

was paralyzed from the neck down when he was thrown from his horse during a competition (Figure 3.28). Three quarters of his spinal cord was destroyed at the level of the injury (J. W. McDonald et al., 2002). He had no motor control and almost no sensation below the neck; like 90% of similarly injured patients, he experienced no functional improvement over the next several years. In spite of Ramón y Cajal’s declaration that there is no regeneration in the CNS,

scientists nearly a century later are pursuing several strategies for inducing self-repair following damage like Reeve’s. These efforts include minimizing the initial damage, encouraging regrowth and new connections, and—the holy grail of stroke and spinal cord treatment—replacing lost neurons. As one example, administering a newly developed molecule shortly after induced stroke in rats reduced glutamate-induced excitotoxicity, which in turn reduced the area of damage by 40% and minimized the loss of motor functions (Bach et al., 2012). Although the brain releases gamma- aminobutyric acid (GABA) to defend against excitotoxicity, GABA’s effect at receptors elsewhere on the neuron is to reduce later plasticity. Researchers at UCLA have found a way to block GABA’s effect outside the synapse, while leaving its synaptic inhibition intact; as a result, mice treated with the drug recovered 50% more motor function than controls (Clarkson, Huang, MacIsaac, Mody, & Carmichael, 2010).

Several strategies for encouraging axon regrowth are under investigation. One option is to block receptors for the protein Nogo-A, which inhibits regeneration following injury. In monkeys with surgically induced spinal cord damage, a Nogo-A inhibitor produced axon growth across the injured area, and the monkeys recovered 80% of the use of their paralyzed hands (Freund et al., 2006; Freund et al., 2007). In rats with induced stroke, combining this Nogo-A blocker with inosine doubled the compensatory growth of axon branches into the spinal cord from the intact hemisphere; this restored the rats’ skilled reaching to preoperative levels (Zai et al., 2011). The drug company Novartis has begun a phase 2 clinical trial to test the effectiveness of a Nogo-A blocker, indicating that its phase 1 safety trial was successful, though those results have not been published yet. “

The word impossible is not in the vocabulary of contemporary neuroscience. —Pasko Rakic

”

The most graphic axon regrowth results were in a study with rats whose severed spinal cords were treated with electrical stimulation and drugs that increased neural excitability (van den Brand et al., 2012). When the rats were suspended in a sling, circuits in the lower spinal cord enabled them to step in response to a moving treadmill but not to walk voluntarily. But when the electrochemical stimulation was combined with the temptation of a chocolate treat, they were able after 4 to 5 weeks of training not only to walk but to sprint up rat-sized stairs. Compared with untrained rats and rats trained on the treadmill alone, they had an increase in axonal projections around the lesion site that equaled 45% of the original fibers, plus an almost fourfold increase in projections from the cortex to brain-stem motor areas.

8 Curing Paralysis The most exciting possibility involves the use of stem cells to replace injured

neurons. Stem cells are undifferentiated cells that can develop into specialized cells such as neurons, muscle, or blood cells. Stem cells in the embryo (Figure 3.29) are pluripotent, which means that they can differentiate into any cell in the body; the developing cell’s fate is determined by chemical signals from its environment that turn on specific genes and silence others. Later in life, stem cells lose most of their flexibility and are confined to areas with a high demand for cell replacement, such as the skin, the intestine, and bone marrow (the source of blood cells). In the brain, stem cells are the source of the neurogenesis we discussed earlier. When embryonic stem cells are placed into an adult nervous system, they tend to differentiate into neurons appropriate to that area; researchers are also learning how to coax adult stem cells to

do the same. Researchers in Portugal and an international team operating in Panama have reported encouraging improvements in spinal cord patients treated with stem cells, including the ability to transfer to and from a wheelchair, the ability to step with assistance, and return of bowel and urinary control and sexual function (Ichim, 2010; Lima et al., 2006). On the other hand, the U.S. biotech company Geron has called off its stem cell clinical trial; they cited financial reasons, but critics have suggested that at this stage of our understanding it is too early even to venture into this form of treatment (Coghlan, 2011). FIGURE 3.29 Embryonic Stem Cells. Because they can develop into any type of cell, stem cells offer tremendous therapeutic possibilities.

SOURCE: © Professor Miodrag Stojkovic/Science Source. Five years after his injury, Christopher Reeve undertook an intensive rehabilitation

program called activity-based recovery (J. W. McDonald et al., 2002). The therapy involved using electrical stimulation to exercise critical muscle groups. For example, electrodes placed over three muscles of each leg were activated sequentially to allow him to pedal a customized exercise bike. This effort appeared futile; no spinal cord patient classified as Grade A (the category of greatest impairment) had ever recovered more than one grade after 2 years. But after 3 years of this therapy, two thirds of his touch sensation had returned, and he was able to walk in an aquatherapy pool and make swimming movements with his arms; as a result, he was reclassified to Grade C. It even seemed possible that Reeve might achieve his goal of walking again, but he died of heart failure in October 2004. The Christopher Reeve Paralysis Foundation continues his work toward lifting Ramón y Cajal’s decree. But since that day appears far off, researchers in the meantime are merging neurons with electronics to give back to patients control of their bodies (see the accompanying Application).

APPLICATION

Mending the Brain With Computer Chips Faced with the daunting challenge of coaxing axons to regrow and stem cells to take over the duties of brain cells, some researchers are turning to computer chips, and their results have been encouraging. For example, neuroscientists at Northwestern University simulated spinal injury in two monkeys by temporarily anesthetizing nerves in their arms at the elbow. Then they used a 100-electrode array to pick up signals from the hand area of the motor cortex, which were then amplified and delivered to muscles in the forearm. With this arrangement the monkeys were able to grasp and pick up a ball and drop it into an opening almost as well as they had done before the anesthesia (Figure a; Ethier, Oby, Bauman, & Miller, 2012). This approach cannot produce entirely normal movement, in part because

the spinal cord contains central pattern generators that produce rhythmic movements required for complex actions such as walking. To meet this need, a U.S.–Canadian team has designed a central pattern generator on a computer chip; it delivers rhythmic electrical stimulation to the hip, knee, and ankle muscles and adjusts the stimulation according to feedback it receives from sensors. With it, anesthetized cats that were suspended in a sling were able to walk with their hind legs (Mazurek et al., 2012). However, other work may have already surpassed that achievement. Rob Summers was left paralyzed by a hit-and-run accident, with no motor function in his trunk and leg muscles and no bladder control. Surgeons implanted electrodes on his spinal cord and used a programmable electronic device to tap into central pattern generators below the injury; now Summers is able to stand for several minutes at a time and to make stepping movements. And even with the stimulation turned off he shows some voluntary movement as well as improved bladder and sexual functioning, presumably because the activity stimulated the growth of new connections or activation of silent ones (Harkema et al., 2011).

9 BrainGate Videos

(a) A Monkey Uses Its Paralyzed Arm to Pick Up and Manipulate a Ball. SOURCE: Adapted from Figure 1 of “Restoration of Grasp Following Paralysis Through Brain-Controlled Stimulation of Muscles,” by C. Ethier, E. R. Oby, M. J. Bauman, and l. E. Miller,” Nature, 485, pp. 368– 371.

(b) Paralyzed Woman Gives Herself a Drink for the First Time in 15 Years. SOURCE: Figure 2 of “Reach and Grasp by People With Tetraplegia Using a Neurally Controlled Robotic Arm.” by L. R. Hochberg et al., Nature, 485, pp. 372–377.

Moving these experimental accomplishments out of the laboratory and into the patient’s everyday life will take years; in the meantime, the possibility of using thought to control external devices promises some degree of independence. After implantation of an array of 96 electrodes in the arm area of his motor cortex, a 25-year-old quadriplegic (both arms and legs paralyzed) was able to move a cursor on a computer screen to read e-mails and to play a simple computer game (Hochberg et al., 2006). Later refinements have allowed two patients to control a robotic arm to pick up and manipulate objects, including drinking from a water bottle (see Figure b; Hochberg et al., 2012). The BrainGate device they used is now in clinical trials with volunteers to determine safety and feasibility (“Clinical Trials,” 2012).

Concept Check Take a Minute to Check YourKnowledge and Understanding Describe the four steps of nervous system development and the fifth step of maturation.

Give three examples of changes in the brain resulting from experience. What are the obstacles to recovery from injury in the CNS and the strategies for overcoming them?

In Perspective I could end this chapter by talking about how much we know about the brain and its functions. Or I could tell you about how little we know. Either point of view would be correct; it is the classic case of whether the glass is half full or half empty. As I said in Chapter 1, we have made remarkable progress during the past few years. We know the functions of most areas of the brain. We have a good idea how the brain develops and how neurons find their way to their destinations and make functional connections. And we’re getting closer to understanding how the neurons form complex networks that carry out the brain’s work. “

If the human brain were so simple that we could understand it, we would be so simple that we couldn’t.

—Emerson Pugh

” But we do not know just how the brain combines activity from widespread areas to

bring about an action or a decision or an experience. We don’t know what a thought is. And we don’t know how to fix a broken brain. But, of course, there is hope, and for good reason. You will see in the following chapters that our knowledge is vast and that we have a solid foundation for making remarkable advances in my lifetime and revolutionary ones in yours. Summary The Central Nervous System • The CNS consists of the brain and the spinal cord. • The CNS is arranged in a hierarchy, with physically higher structures carrying out more sophisticated functions.

• The cortex is the location of the most sophisticated functions; the convoluted structure of the cerebral hemispheres provides for the maximum amount of cortex.

• See Table 3.2 for the major structures of the brain and their functions. • Although localization is an important functional principle in the brain, most functions depend on the interaction of several brain areas.

• The spinal cord contains pathways between the brain and the body below the head and provides for sensory-motor reflexes.

• The meninges and the cerebrospinal fluid protect the brain from trauma; the blood- brain barrier blocks toxins and blood-borne neurotransmitters from entering the brain. The Peripheral Nervous System • See Figure 3.19 for a summary of the divisions of the nervous system.

The PNS consists of the cranial and spinal nerves or, alternatively, the somatic nervous system and the ANS.

The somatic nervous system consists of the sensory nerves and the nerves controlling the skeletal muscles.

The sympathetic branch of the ANS prepares the body for action; the parasympathetic branch conserves and renews energy.

• Interconnection in the sympathetic ganglion chain means that the sympathetic nervous system tends to function as a whole, unlike the parasympathetic branch.

Development and Change in the Nervous System • Prenatal development of the nervous system involves

proliferation, the multiplication of neurons by division; migration, in which neurons travel to their destination; circuit formation, the growth of axons to, and their connection to, their targets; and

circuit pruning, the elimination of excess neurons and incorrect synapses. • Myelination continues through adolescence or later, with higher brain levels myelinating last.

• Experience can produce changes in brain structure and function. • Although some recovery of function occurs in the mammalian CNS, there is little or no true repair of damage by either neurogenesis or regeneration; enhancing repair is a major research focus. ■

Study Resources

For Further Thought • Patients with damage to the right parietal lobe, the temporal lobe, or the prefrontal cortex may have little or no impairment in their intellectual capabilities, yet they show deficits in behavior that seem inconsistent for an otherwise intelligent individual. Does this modify your ideas about how we govern our behavior?

• Like the heroes in the 1966 science fiction movie Fantastic Voyage, you and

your crew will enter a small submarine to be shrunk to microscopic size and injected into the carotid artery of an eminent scientist who is in a coma. Your mission is to navigate through the bloodstream to deliver a lifesaving drug to a specific area in the scientist’s brain. The drug can be designed to your specifications, and you can decide where in the vascular system you will release it. What are some of the strategies you could consider to ensure that the drug will enter the brain and be effective?

• What strategy do you think has the greatest potential for restoring function in brain-damaged patients? Why?

Quiz: Testing Your Understanding 1. Describe the specific behaviors you would expect to see in a person with

prefrontal cortex damage. 2. Describe compensation and reorganization in recovery from brain damage,

giving examples. 3. In what ways does the brain show plasticity after birth? Select the best answer: 1. Groups of cell bodies in the CNS are called

a. tracts. b. ganglia. c. nerves. d. nuclei.

2. The prefrontal cortex is involved in all but which one of the following functions? a. Responding to rewards b. Orienting the body in space c. Making decisions d. Behaving in socially appropriate ways

3. Because the speech center is usually located in the left hemisphere of the brain, a person with the corpus callosum severed is unable to describe stimuli that are a. seen in the left visual field. b. seen in the right visual field. c. presented directly in front of him or her. d. felt with the right hand.

4. A person with damage to the inferior temporal cortex would most likely be unable to a. see. b. remember previously seen objects. c. recognize familiar objects visually. d. solve visual problems, such as mazes.

5. A particular behavior is typically controlled by a. a single structure. b. one or two structures working together. c. a network of structures. d. the entire brain.

6. When the police have a drunk-driving suspect walk a straight line and touch his nose with his finger, they are assessing the effect of alcohol on the a. motor cortex. b. corpus callosum. c. cerebellum. d. medulla.

7. Cardiovascular activity and respiration are controlled by the a. pons. b. medulla. c. thalamus. d. reticular formation.

8. All the following are involved in producing movement, except the a. hippocampus. b. cerebellum. c. frontal lobes. d. basal ganglia.

9. Damage would be most devastating to humans if it destroyed the a. pineal gland. b. inferior colliculi. c. corpus callosum. d. medulla.

10. If the ventral root of a spinal nerve is severed, the person will experience a. loss of sensory input from a part of the body. b. loss of motor control of a part of the body. c. loss of both sensory input and motor control. d. none of the above.

11. During a difficult exam, your heart races, your mouth is dry, and your hands are icy. In your room later, you fall limply into a deep sleep. Activation has shifted from primarily _______ to primarily _______. a. somatic, autonomic b. autonomic, somatic c. parasympathetic, sympathetic d. sympathetic, parasympathetic

12. In the circuit formation stage of nervous system development,

a. correct connection of each neuron is necessary, since barely enough neurons are produced.

b. axons grow to their targets and form connections. c. neurons continue dividing around a central neuron, and those neurons

form a circuit. d. neurons that fail to make functional connections die.

13. Fetal alcohol syndrome involves a. loss of myelin. b. overproduction of neurons. c. errors in neuron migration. d. excessive growth of glial cells.

14. The study in which kittens reared in an environment with only horizontal or vertical lines were later able to respond only to stimuli at the same orientation is an example of a. compensation. b. reorientation. c. reorganization. d. regeneration.

15. If a peripheral nerve were transplanted into a severed spinal cord, it would a. fail to grow across the gap. b. grow across the gap but fail to make connections. c. grow across the gap and make connections but fail to function. d. bridge the gap and replace the function of the lost neurons.

Answers: 1. d, 2. b, 3. a, 4. c, 5. c, 6. c, 7. b, 8. a, 9. d, 10. b, 11. d, 12. b, 13. c, 14. c, 15. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The Whole Brain Atlas has images of normal and diseased or damaged

brains. The HOPES Brain Tutorial will help you visualize how the brain is organized. The final segment, Build a Brain, is best.

2. The History of Psychosurgery, from trephining (drilling holes in the skull to let evil spirits out) to lobotomy to more recent experimental attempts, is the subject of this sometimes less than professional but very interesting website. At Lobotomy’s Hall of Fame you will learn, for example, that sisters of the playwright Tennessee Williams and President John F. Kennedy had lobotomies (the story that actress Frances Farmer had a lobotomy turned out to be a fabrication).

3. How the Human Brain Works provides an interactive tour of brain functions and the areas responsible.

4. The Dana Foundation’s BrainWork offers regular updates on the latest findings in neuroscience research.

5. Genetics Home Reference gives a good description of periventricular heterotopia and its genetic causes. The National Organization on Fetal Alcohol Syndrome has information and statistics on the disorder.

6. Read the original news articles about the NFL Player Settlement, the judge’s concerns, the report on youth concussions, and the study of brain damage in soccer players.

7. Read the news article about the use of carbon 14 nuclear fallout to document human adult neurogenesis. 8. The Miami Project to Cure Paralysis at the University of Miami School of Medicine has summaries of basic and clinical research on central nervous system damage. The Christopher and Dana Reeve Foundation site provides information about spinal cord damage research. The National Institutes of Health’s Stem Cell Information site is a good resource for information about stem cells and their potential.

9. BrainGate Lets Your Brain Control the Computer is a video explanation of the BrainGate system, which shows the patient controlling a computer and a prosthetic hand. A second video shows a paralyzed woman controlling a robotic arm to drink coffee.

Animations • The Spinal Cord (Figure 3.17) Chapter Updates and Biopsychology News

For Further Reading 1. In The New Executive Brain (Oxford University Press, 2009), Elkhonon

Goldberg draws from recent discoveries and fascinating case studies to explore how the brain engages in complex decision making, deals with ambiguity, makes moral choices, and controls emotion.

2. The Human Brain Book by award-winning science writer Rita Carter (DK Publishing, 2009) ranges from brain anatomy and neural transmission to explorations of behavior, sensory processing, dreaming, and genius.

3. The Scientific American Day in the Life of Your Brain, by Judith Horstman (Scientific American, 2009), in 130 articles tackles the brain bases of creativity, hunger, sex, addictions, dreaming, biological clocks, and more.

4. The Man Who Mistook His Wife for a Hat and Other Clinical Tales, by Oliver Sacks (Harper Perennial, 1990), a collection of case studies, is as entertaining as it is informative, as it treats the human side of brain damage and disorder.

5. Pictures of the Mind: What the New Neuroscience Tells Us About Who We Are, by Miriam Boleyn-Fitzgerald (FT Press, 2010), uses brain imaging technology to reveal how resilient and flexible the brain is. Its topics range from brain damage to emotional disorders to addiction.

Key Terms anterior association area auditory cortex autonomic nervous system (ANS) blood-brain barrier Broca’s area central nervous system (CNS) central sulcus cerebellum cerebral hemispheres cerebrospinal fluid circuit formation circuit pruning compensation corpus callosum cortex cranial nerves dorsal dorsal root fetal alcohol syndrome fissure

frontal lobe ganglion growth cone gyrus hydrocephalus hypothalamus inferior inferior colliculi inferior temporal cortex lateral lateral fissure lobotomy longitudinal fissure medial medulla meninges midbrain migration motor cortex neglect nerve neurogenesis neurotrophins nucleus occipital lobe parasympathetic nervous system parietal lobe peripheral nervous system (PNS) pineal gland plasticity pons posterior precentral gyrus prefrontal cortex primary somatosensory cortex proliferation psychosurgery radial glial cells reflex regeneration

reorganization reticular formation somatic nervous system spinal cord spinal nerves stem cell stroke sulcus superior superior colliculi sympathetic ganglion chain sympathetic nervous system temporal lobe thalamus tract traumatic brain injury (TBI) ventral ventral root ventricle visual cortex Wernicke’s area

A

4 The Methods and Ethics of Research

In this chapter you will learn • The value of theory in science and the relative advantages of experiments and correlational studies

• Some of the ways biopsychologists do research • Why research in biopsychology creates ethical concerns

Science, Research, and Theory Theory and Tentativeness in Science Experimental Versus Correlational Studies CONCEPT CHECK

Research Techniques Staining and Imaging Neurons Light and Electron Microscopy Measuring and Manipulating Brain Activity IN THE NEWS: LOOKING INTO THE BRAIN

Brain Imaging Techniques APPLICATION: SCANNING KING TUT IN THE NEWS: GROWING A MODEL BRAIN FROM STEM CELLS

Investigating Heredity CONCEPT CHECK

Research Ethics Plagiarism and Fabrication Protecting the Welfare of Research Participants IN THE NEWS: NIH IS RETIRING MOST OF ITS RESEARCH CHIMPS

Gene Therapy Stem Cell Therapy CONCEPT CHECK

In Perspective Summary Study Resources

shanthi DeSilva developed her first infection just 2 days after her birth. There would be many more. At the age of 2, her frequent illnesses and poor growth were diagnosed as due to severe combined immunodeficiency (SCID)—better known as

the “bubble-boy disease” after an earlier victim who had to live in a sterile

environment in a plastic tent (Figure 4.1). Her immune system was so compromised that she suffered from frequent infections and gained weight slowly; because traditional enzyme treatments were inadequate, at the age of 4 her parents enrolled her in a revolutionary experimental therapy. SCID is caused by a faulty gene, so the doctors transferred healthy genes into her immune cells (Blaese et al., 1995). Ashanthi is a grown woman now and living a normal life in suburban Cleveland (Springen, 2004), her health and normal resistance to disease a silent testimonial to the power of genetic research. Just a few years ago, cures like Ashanthi’s and the gene therapies and stem cell

therapies that you will read about in this chapter and others seemed like miracles. These breakthroughs are products of the ingenuity of medical and neuroscience researchers, who have built on the accumulated knowledge of their predecessors. Their accomplishments are also the result of more powerful research methods, including research design as well as technology. This is the story of the role that research methodology plays in the field of biopsychology, and of the increasing ethical implications of our advancing knowledge. But first, we need to take a few minutes to review some important points about research; you have most likely seen them before, but they are worth reemphasizing in the context of biological psychology. FIGURE 4.1 The Original “Bubble Boy.” The most famous patient with SCID was so vulnerable to life-threatening infections that he had to live in a sterile plastic tent. Thanks to research advances, genetic treatment is offering new hope.

SOURCE: ASSOCIATED PRESS.

Science, Research, and Theory Science is not distinguished by the knowledge it produces but by its method of acquiring knowledge. We learned in Chapter 1 that scientists’ primary method is empiricism; this means that they rely on observation for their information rather than on intuition, tradition, or logic (alone). Descartes started out with the traditional assumption that there was a soul, and then he located the soul in the pineal gland because it seemed the logical place for the soul to control the brain. Aristotle, using equally good logic, had located the soul in the heart because the heart is so vital to life. (He thought that the brain’s function was to cool the blood!) Observation—which is a much more formal activity in science than the term suggests—is more objective than alternative ways of acquiring knowledge; this means that two observers are more likely to reach the same conclusion about what is being observed (though not necessarily about its interpretation) than if they were using intuition or logic. Biopsychologists, and scientists in general, have great confidence in observation

and all the methods in their arsenal. But in scientific writings, you will often see statements beginning with “It appears that...,” “Perhaps...,” or “The results suggest....” So you might well wonder, Why do scientists always sound so tentative? Theory and Tentativeness in Science One reason is that the field is very complex, so it is always possible that a study is

flawed or that new data will come along that will change how we interpret previous studies. A second reason is that we base our conclusions on samples of subjects and samples of data from those subjects; the laws of probability tell us that even in well- designed research, we will occasionally end up with a few unusual participants in our study or there will be a slight but important shift in behavior that has nothing to do with the variable we are studying.

Why are scientists so tentative? Scientists recognize that knowledge is changing rapidly and the cherished ideas of

today may be discarded tomorrow. A case in point is that, until recently, no one accepted that there was regrowth of severed axons or any neurogenesis in the mammalian central nervous system (Rakic, 1985), a belief that you now know was incorrect. You seldom hear scientists using the words truth and proof, because these terms suggest final answers. Such uncertainty may feel uncomfortable to you, but centuries of experience have shown that certainty about truth can be just as uncomfortable; “certainty” has an ugly way of stifling the pursuit of knowledge. One way the researcher has of making sense out of ambiguity is through theory. A

theory integrates and interprets diverse observations in an attempt to explain some phenomenon. For example, schizophrenia researchers noticed that people who overdosed on the drug amphetamine were being misdiagnosed as having schizophrenia when they were admitted to emergency rooms with hallucinations and

paranoia. They also knew that amphetamine increases activity in neurons that release dopamine as the neurotransmitter. This led several researchers to propose that schizophrenia is due to excess dopamine activity in the brain. A theory explains existing facts, but it also generates hypotheses that guide further

research. One hypothesis that came from dopamine theory was that drugs that decrease dopamine activity would improve functioning in schizophrenia. This hypothesis was testable, which is a requirement for a good theory. The hypothesis was supported in many cases of schizophrenia, but not in others. We now realize that the dopamine theory is an incomplete explanation for schizophrenia. However, even a flawed theory inspires further research that will yield more knowledge and additional hypotheses. But remember that the best theory is still only a theory; theory and empiricism are the basis of science’s ability for self-correction and its openness to change and renewal. Now we will examine one of the knottiest issues of research, one that you will need

to think about often as you evaluate the research evidence discussed throughout this text. Experimental Versus Correlational Studies Observation has a broad meaning in science. A biological psychologist might

observe aggressive behavior in children on the playground to see if there are differences between boys and girls (naturalistic observation), report on the brain scan of a patient who had violent outbursts following a car accident that caused brain injury (case study), use a questionnaire to find out whether some women are more aggressive during the premenstrual period (survey), or stimulate a part of rats’ brains with electricity to see what parts of the brain control aggressive behavior (experiment). These different research strategies fall into the broad categories of experimental and correlational studies.

What is the advantage of experimental studies over correlational studies? An experiment is a study in which the researcher manipulates a condition (the

independent variable) that is expected to produce a change in the subject’s behavior (the dependent variable). The experimenter also eliminates extraneous variables that might influence the behavior or equates them across subjects—for example, by removing environmental distractions, instructing participants not to use caffeine or other stimulants beforehand, and “running” subjects at the same time of day. In a correlational study, the researcher does not control an independent variable but observes whether two variables are related to each other. When we use brain scans to determine that violent criminals more often have impaired frontal lobe activity, we are doing a correlational study; if we induce the impairment in monkeys (independent variable) and then observe whether this increases aggression (dependent variable), we are doing an experiment.

FIGURE 4.2 Correlational Versus Experimental Studies. In a correlational study (a), we cannot tell whether A influences B, B influences A, or a third variable affects both. In an experimental study (b), the researcher manipulates the independent variable (IV), which increases assurance that it is the cause of the change in the dependent variable (DV). (The red arrows indicate possible interpretations of causation.)

Figure 4.2 illustrates some of the differences between a correlational and an experimental study of aggressive behavior. Based on observations that violent criminals often have impaired frontal lobe functioning, we might identify a large group of impaired individuals (using brain scans or behavioral and cognitive tests) and see if they have a record of violent crimes. We would very likely find that they do, but Figure 4.2a reveals a problem with interpretation: For all we know, the individuals’ brain damage may have been incurred in the process of committing their criminal acts rather than the other way around. Or both frontal lobe damage and violent behavior could stem from any number of third variables, such as physical abuse during childhood or long-term drug use. These variables are potentially confounded with each other, so we cannot separate their effects. In other words, we cannot draw conclusions about cause and effect from a correlational study. What about doing this research as an experimental study? For ethical reasons, of

course, we would not induce brain damage in humans, but remember that in Chapter 3 we saw that researchers used an electromagnetic field to disrupt activity in the visual cortex of blind individuals. So let’s use this transcranial magnetic stimulation to disrupt temporarily our hypothetical volunteers’ frontal lobe functioning. Granted, we won’t see them become physically violent in the laboratory, but we can borrow a technique from a similar study we will see later in the chapter on emotion: We will

Concept Check

administer several mild shocks to the subject under the pretense that the shocks are being controlled by another (fictitious) player, and we will record the intensity of shocks our participant delivers in retaliation. Because we selected our research participants and induced the brain impairment, we have controlled the confounding variables that plagued us in the correlational study; that is, they are likely to be similar between the impaired group and an unimpaired control group. Now if we see higher levels of shock administered by subjects while their frontal activity is being disrupted, we can be fairly confident that the frontal lobe impairment is causing the increase in the aggressive behavior. Of course, we could quibble about how well this study mirrors real brain damage

and violent aggression; the greater control afforded by experimental studies often carries a cost of some artificiality. Experimentation is the most powerful research strategy, but correlational studies also provide unique and valuable information, such as the observation that children of parents who have schizophrenia have a high incidence of the disorder even when they are reared in normal adoptive homes. To advance our understanding in biopsychology, we need correlational studies as well as experimental research, but we equally need to be careful about interpreting their results—a point you should keep in mind as we explore the following research techniques and as we look at research in later chapters.

Take a Minute to Check Your Knowledge and Understanding

What is the value of empiricism? What is the value of theory? A scientist speaking to a group of students says, “I do not expect my research to find the truth.” Why?

What advantages do correlational studies have over experiments? You hear the newscaster say, “Physicians are urging people to stay active in retirement, because researchers have found that people who are more physically and socially active are less likely to develop Alzheimer’s disease.” What should you be thinking?

Research Techniques The brain does not give up its secrets easily. If we remove a clock from its case and observe the gears turn and the spring expand, we can get a pretty good idea how a clock measures time; but if we open the skull, how the brain works remains just as much a mystery as before. This is where research technique comes in, extending the scientist’s observation beyond what is readily accessible. Your understanding of the information that fills the rest of this book—and of the limitations of that information

—will require some knowledge of how the researchers came to their conclusions. The following review of a few major research methods is abbreviated, but it will help you navigate through the rest of the book, and we will add other methods as we go along.

What major discovery did Golgi staining enable? Staining and Imaging Neurons It didn’t take long to exhaust the possibilities for viewing the nervous system with

the naked eye, but the invention of the microscope took researchers many steps beyond what the pioneers in gross anatomy could do. Unfortunately, neurons are greatly intertwined and are difficult to distinguish from each other, even when magnified. The Golgi stain method randomly stains about 5% of neurons, placing them in relief against the background of seeming neural chaos (Figure 4.3a). As we saw in Chapter 2, the Italian anatomist Camillo Golgi developed this technique in 1875 and, shortly after, his Spanish contemporary Santiago Ramón y Cajal used it to discover that neurons are separate cells. Golgi and Cajal jointly received the 1906 Nobel Prize in physiology and medicine for their contributions. Other staining methods add important dimensions to the researcher’s ability to

study the nervous system. Myelin stains are taken up by the fatty myelin that wraps and insulates axons; the stain thus identifies neural pathways. In Figure 4.3b, the slice of brain tissue is heavily stained in the inner areas where many pathways converge, but it is stained lightly or not at all in the perimeter where mostly cell bodies are located. Nissl stains do the opposite; they identify cell bodies of neurons (Figure 4.3c). Later-generation techniques are used to trace pathways to determine their origin or

their destination—that is, which part of the brain is communicating with another. These procedures take advantage of the fact that neurons move materials up and down the axon constantly. For example, if we inject the chemical fluorogold into a part of the brain, it will be taken up by the terminals of neurons and transported up the axons to the cell bodies. Under light of the appropriate wavelength, fluorogold will fluoresce —radiate light—so it will show up under a microscope and tell us which brain areas receive neural input from the area we injected. For example, fluorogold injected into a rat’s superior colliculi will show up a few days later among the neurons at the back of the eye. FIGURE 4.3 Three Staining Techniques. (a) Golgi stains highlight individual neurons. (b) Myelin stains emphasize white matter and, therefore, neural pathways (stained blue here). (c) Nissl stains emphasize the cell bodies of neurons (stained dark).

SOURCES: (a) © Dr. John D. Cunningham/Visuals Unlimited/Corbis. (b) © Biophoto/Science Source. (c) Reproduced with permission from http://www.brains.rad.msu.edu, and http://brainmuseum.org, supported by the U.S. National Science Foundation.

What advantage does autoradiography have? These staining and tracing procedures reveal fine anatomy, but they do not tell us

anything about function. Autoradiography makes neurons stand out visibly just as staining does, but it also reveals which neurons are active, and this information can be correlated with the behavior the animal was engaged in. In this procedure, the animal is injected with a substance that has been made radioactive, such as a type of sugar called 2-deoxyglucose (2-DG). Then, the researcher usually stimulates the animal, for instance, by presenting a visual pattern or requiring the subject to learn a task. Active neurons take up more glucose, and because 2-DG is similar to glucose, the neurons involved in the activity become radioactively “labeled.” In Chapter 10, we will see an example of this technique, where vision researchers mapped the projections to the visual cortex from light-receptive cells in the eye (Tootell, Silverman, Switkes, & De Valois, 1982). After injecting monkeys with radioactive 2-DG, they presented the subjects with a geometric visual stimulus. The animals were euthanized (killed painlessly), and a section of their visual cortical tissue placed on photographic film. The radioactive areas exposed the film and produced an image of the original stimulus. This confirmed that just as the somatosensory projection area contains a map of the body, the visual cortex maps the visual-sensitive retina and, thus, the visual world (Figure 4.4a). FIGURE 4.4 Autoradiographs.

(a) Monkeys were injected with radioactive 2-DG before they were presented with a geometric visual stimulus. The monkeys were euthanized, and a slice of their brain was placed on photographic film; the pattern of radioactivity produced the image you see here. (b) An autoradiograph of a horizontal slice from a rat’s brain that was soaked in a radioactive opiate antagonist, naloxone. White areas indicated opiate receptors. The slice is at the level of the thalamus; the front of the brain is at the top of the picture.

SOURCES: (a) From “Deoxyglucose Analysis of Retinotopic Organization in Primate Striate Cortex,” by R. B. H. Tootell et al., Science, 218, pp. 902–904. Reprinted with permission from AAAS. (b) Republished with permission of The Society for Neuroscience, from “Light Microscopic Localization of Brain Opiate Receptors: A General Autoradiographic Method Which Preserves Tissue Quality,” by M. A. Herkenham and C. B. Pert, 1982, Journal of Neuroscience, 2, pp. 1129– 1149. A variation of this method is used to determine the location and quantity of

receptors for a particular drug or neurotransmitter. Candace Pert used this procedure to find out whether there are receptors in the brain for opiate drugs (a class containing

opium, morphine, and heroin), which seemed like the best explanation for the drugs’ potency in relieving pain (Herkenham & Pert, 1982; Pert & Snyder, 1973). First, she soaked rat brains in radioactive naloxone, a drug that she knew counteracts the effects of opiates, on the assumption that it does so by blocking the hypothesized receptors. She then placed thinly sliced sections of the brains on photographic film. Sure enough, an image of the brain formed, highlighting the locations of opiate receptors (Figure 4.4b). This procedure not only established that the receptors exist, but implied that the brain makes its own opiates! Instead of using radioactivity, immunocytochemistry uses antibodies attached to a

dye to identify cellular components such as receptors, neurotransmitters, or enzymes. The technique takes advantage of the fact that antibodies, which attack foreign intruders in the body, can be custom designed to be specific to any cellular component. The dye, which is usually fluorescent, makes the antibodies’ targets visible when the tissue is removed and examined under a microscope. Night- migrating birds use the earth’s magnetic field to navigate, and earlier evidence suggested that the magnetic detectors might be cryptochromes, which are molecules found in some neurons in the birds’ retinas. Henrik Mouritsen and his colleagues (2004) in Germany have provided strong supporting evidence. Using immunocytochemistry, they found that during the day, cryptochromes were plentiful in the retinas of both garden warblers and zebra finches; at night, however, cryptochromes diminished virtually to zero in the nonmigratory finches but increased in the eyes of the night-migrating warblers (Figure 4.5). But before they could do this study, Mouritsen’s team had to decide which of two

kinds of cryptochrome to focus their efforts on, CRY1 or CRY2. So they used another powerful research technique that determines where particular genes are active, in this case the cry1 and cry2 genes. Remember from Chapter 1 that genes control the production of proteins; the instructions for protein production are carried from the nucleus into the cytoplasm of a cell by messenger ribonucleic acid (RNA), which is a copy of one strand of the gene’s DNA. So, when we locate specific messenger RNA, we know that the gene is active in that place; this is done by in situ hybridization. In situ hybridization involves constructing strands of complementary DNA, which will dock with strands of messenger RNA. Because the complementary DNA is first made radioactive, autoradiography can then be used to determine the location of gene activity (see Figure 4.6). The researchers found that the protein product CRY2 was being constructed in cell nuclei, while CRY1 was being constructed outside the nucleus; because a magnetoreceptor was more likely to function outside the nucleus, they limited their study to that cryptochrome. Light and Electron Microscopy For more than three centuries, the progress of biological research closely paralleled

the development of the light microscope. The microscope evolved from a device that

used a drop of water as the magnifier, through the simple microscope with a single lens, to the compound microscope with multiple lenses. At that point, investigators were able to see the gross details of neurons: cell bodies, dendrites, axons, and the largest organelles. But the capability of the light microscope is limited, not due to the skills of the lens maker but due to the nature of light; increases in magnification beyond about 1,500 times yield little additional information. FIGURE 4.5 Immunocytochemistry Reveals Cryptochromes in the Eyes of Migrating Birds. Neurons that contain cryptochromes and are currently active are labeled in orange. The larger type of neurons (indicated by arrows) project to a brain area that responds to magnetic field stimulation.

SOURCE: From “Cryptochromes and Neuronal-Activity Markers Colocalize in the Retina of Migratory Birds During Magnetic Orientation,” by H. Mouritsen et al., PNAS, 101, pp. 14294–14299. © 2004 H. Mouritsen. Used with permission. The electron microscope, on the other hand, magnifies up to about 250,000 times

and can distinguish features as small as a few hundred millionths of a centimeter. The electron microscope works by passing a beam of electrons through a thin slice of tissue onto a photographic film; different parts of the tissue block or pass electrons to different degrees, so the electrons produce an image of the object on the film. The electron microscope’s high resolution allows us to see details such as the synaptic vesicles in an axon terminal. Engineers have enhanced the technique in the scanning electron microscope. The beam of electrons induces the specimen to emit electrons itself, and these are captured like the conventional microscope collects reflected light. Magnification is not as great as with the electron microscope, but the images have a three-dimensional (3-D) appearance that is very helpful in visualizing details. You can see this feature in Figure 4.7, as well as in Figure 2.16. Microscopic technology continues to evolve, for example, in the confocal laser

scanning microscope and the two-photon microscope. These microscopes image specific kinds of tissue, depending on the fluorescent dye the tissue is stained with (a fluorescent dye emits light when radiated with light within a specific range of

wavelengths). These microscopes have the advantage that they are not limited to very thin slices of tissue. They can be used with thicker tissue samples and can even image details in the upper layers of the exposed living brain; with optical probes, they can image neurons as deep as 1 cm below the surface. As an example, researchers using a dye specific for calcium were able to measure movement-related neural activity in the brains of mice running on a treadmill (Dombeck, Khabbaz, Collman, Adelman, & Tank, 2007). As In the News reveals, techniques for viewing the brain are about to get a significant boost. FIGURE 4.6 DNA, Proteins, and in Situ Hybridization. Messenger RNA copies a strand of the DNA and then moves out into the cytoplasm, where it controls the development of proteins. Complementary radioactive DNA helps researchers locate gene activity.

Measuring and Manipulating Brain Activity You learned in previous chapters that it is easy to stimulate the surface of the brain

with electricity to produce movement, sensations, and even apparent memories. We can also record electrical activity from the surface of the brain or even from the scalp. Studying deeper structures will require more inventive techniques, which we will look at after we discuss electroencephalography. Electroencephalography In 1929, the German psychiatrist Hans Berger invented the electroencephalograph

and used it to record the first electroencephalogram from his young son’s brain. Since then, the technique has proved indispensable in diagnosing brain disorders such as epilepsy and brain tumors; it has also been valuable for studying brain activity during various kinds of behavior, from sleep to learning. The electroencephalogram (EEG) is recorded from two electrodes on the scalp over the area of interest; an electronic amplifier detects the combined electrical activity of all the neurons between the two electrodes (popularly known as “brain waves”; see Figure 4.8). Usually, the researcher applies a number of electrodes and monitors activity in multiple brain areas at the same time.

FIGURE 4.7 Scanning Electron Micrograph of a Neuron. Notice the depth and detail this kind of imaging provides. (The white structures on and around the cell body are glial cells.)

SOURCE: © Dr. Robert Berdan, 2007. The temporal (time) resolution of the EEG is one of its best features; it can

distinguish events only 1 millisecond (ms) apart in time, so it can track the brain’s responses to rapidly changing events. However, its spatial resolution, or ability to detect precisely where in the brain the signal is coming from, is poor. This problem can be alleviated somewhat by applying electrodes directly to the brain, which removes the interference of the skull. Of course, this procedure is used only with animals or with humans undergoing surgery. So although the EEG provides relatively gross measurements, its advantages are good time resolution, ease of use, and, compared with the imaging techniques we will consider shortly, low cost. FIGURE 4.8 An Electroencephalograph and a Sample EEG. An electroencephalograph records the electrical activity of the brain through electrodes applied to the scalp (a). The up-and-down fluctuations of the tracings on the computer screen (b) indicate the EEG frequency, and the height indicates the voltage. The computer does precise analyses of the signal for research or diagnostic purposes.

SOURCES: (a) Courtesy of National Institute of Neurological Disorders and Stroke. (b) From Current Concepts: The Sleep Disorders, by P. Hauri, 1982, Kalamazoo, MI: Upjohn. EEGs are most useful for detecting changes in arousal, as in the example in Figure

4.8. They are not good at detecting the response to a brief stimulus, such as a spoken word; the time resolution is adequate, but the “noise” of the brain’s other ongoing activity drowns out the response, so the tracing looks much like the “awake” recording in the figure. However, by combining electroencephalography with the computer, the researcher can average the EEG over several presentations of the stimulus to produce an event-related potential, like the one in Figure 4.9. Averaging over many trials cancels out the ongoing noise, leaving only the unique response to the stimulus. In this example, Shirley Hill (1995) repeatedly presented a low-pitched tone to her research participants and occasionally interjected a high-pitched tone. Averaging showed a large dip in the electrical potential following the novel (high- pitched) stimulus. In Chapter 5, you will learn that this dip is smaller in alcoholics than in nonalcoholics, as well as in the young children of alcoholics, which suggests an inherited vulnerability to alcoholism. Another example is that biopsychologists have used the technique to confirm that spoken words produce a greater response in the left hemisphere, just as you would expect, than in the right hemisphere.

Looking Into the Brain Neuroscientists have many holy grails, and one of them is the ability to peer into the brain, to visualize the neurons and their all-important connections. You saw in Chapter 2 that we have ways to image white-matter pathways, but the resolution is poorer than researchers would like. Light microscopy provides more detail, but brain tissue is mostly opaque so it must be sliced into very thin sections that limit ability to trace pathways. There have been attempts to make brain tissue transparent by extracting the lipids that make up the cell membranes, but the

process also removes proteins and the cells fall apart. Now a team at Stanford University led by psychiatrist and bioengineer Karl

Deisseroth has come up with a solution in the form of a process they call,

appropriately, CLARITY. First, the brain is immersed in a solution of acrylamide, which binds to the brain’s proteins and holds them together. Then, in a process called electrophoresis, an electric field is used to move detergent molecules through the sample, flushing out lipids along the way. By then the tissue is totally transparent, as you can see in the figure. In the next step, the neurons are “labeled” with fluorescent antibodies, which attach to specific proteins and make particular structures visible; the third panel of the figure shows the neurons in an intact mouse hippocampus (the curved structure in the image). And because the acrylamide increases the tissue’s resilience, the labels can be removed and replaced with others to highlight different types of neurons. This means that the precious few brains available from people with particular disorders can be used over and over again.

1 CLARITY in the News

The first two images compare a mouse brain before and after clarification. The third image is a three-dimensional view of a hippocampus (the curved structure) stained to reveal neurons (green), connecting interneurons (red), and glia (blue). SOURCE: Reprinted by permission from Macmillan Publishers Ltd. From “Structural and Molecular Interrogation of Intact Biological Systems,” by Kwanghun Chung et al., Nature, 497, pp. 332–337, doi: 10.1038/nature1210. Copyright 2013.

What can EEGs and event-related potentials tell us? Stereotaxic Techniques When the area of interest is below the surface, the researcher must use probes that

can penetrate deep into the brain. Two important aids make this task feasible. The first is a map of the brain called a stereotaxic atlas. A large number of brains are sliced into very thin coronal sections; drawings are prepared that show the (average) location of brain structures on each section. Figure 4.10 is one of these drawings from a stereotaxic atlas of the rat brain. Each drawing is numbered to indicate the anterior/posterior location of the slice, and the scales on the side and the bottom of the drawing tell the researcher how far from the midline and how deep to insert the probe. FIGURE 4.9 Event-Related Potential Produced by a Novel Tone.

A research participant responds to a novel stimulus, such as an occasional high- pitched tone among low-pitched tones, with a large dip in the event-related potential. Without averaging over several stimulus presentations, all we would see would be an EEG like the “awake” recording in Figure 4.8.

A stereotaxic instrument is a device used for the precise positioning in the brain of an electrode or other device. Figure 4.11 shows a stereotaxic instrument for rats; the instrument secures the anesthetized rat’s head and allows the investigator to insert the probe through a small hole drilled in the skull at the precise location and depth specified by the atlas. Often the probe is a fine-wire electrode, electrically insulated except at its tip, that is used to activate the structure with very low voltage electricity. While the still-anesthetized animal’s brain is being stimulated, the researcher can monitor responses in other parts of the brain or in the body. If the animal must be awake to test the effect, the electrode can be anchored to the skull; the wound is closed, and after a couple of days of recovery, the rat’s behavior can be observed during stimulation. In Chapter 5, you will see research in which animals were willing to press a lever to deliver electrical stimulation to certain parts of their own brains. (The stimulation isn’t painful, because the brain lacks pain receptors.)

What are the different ways a stereotaxic instrument is used? A similar electrode arrangement is used to record neural activity; the

biopsychologist might subject the animal to a learning task, present visual or auditory stimuli, or introduce a member of the other sex while monitoring activity in an appropriate brain location. Electrodes ordinarily will record from all the surrounding neurons, but microelectrodes have tips so fine that they can record from a single neuron. The electrodes may be placed in the brain temporarily in an anesthetized animal, or they may be mounted in a socket cemented to the animal’s skull to permit recording in the unanesthetized, behaving subject. FIGURE 4.10 A Plate From a Stereotaxic Atlas.

SOURCE: From A Stereotaxic Atlas of the Rat Brain, 2nd edition, by L. J. Pellegrino, A. S. Pellegrino, and A. J. Cushman, New York: Kluwer Academic/Plenum Publishers. © 1979; with kind permission from Springer Science+Business Media B.V. The stereotaxic instrument can also be used to insert a small-diameter tube called a

cannula for injecting chemicals. Chemical stimulation has a special advantage over electrical stimulation in that it acts only at the dendrites and cell bodies of neurons. This means that the researcher can simulate the effects of a neurotransmitter or block a transmitter’s effects at the synapses. Often the tube is not used to deliver the drug but is cemented in place and used later as a guide for inserting a smaller drug-delivery cannula; this arrangement can be used for stimulation later on multiple occasions. The same technique is used for microdialysis, in which brain fluids are extracted for analysis, but a more elaborate dual cannula is required. As Figure 4.12 shows, the brain fluids seep through a porous membrane into the lower chamber of the cannula; a biologically neutral fluid (very similar to seawater) is pumped through one of the dual tubes, and it flushes the brain fluid out the other tube for analysis. In Chapter 5, you will see results from both of these techniques, when researchers deliver abused drugs to rats’ brains or monitor the release of brain neurotransmitters after an animal is injected with a drug. FIGURE 4.11 A Stereotaxic Instrument. This device allows the researcher to locate an electrode precisely at the right horizontal position and depth in the animal’s brain. (Although its eyes are open, the rat is deeply anesthetized.)

Ablation and Lesioning Historically, one of the most profitable avenues of brain research has been the study

of patients who have sustained brain damage. Brain damage can occur in a variety of ways: gunshot wounds, blows to the head, tumors, infection, toxins, and strokes. Although these “natural experiments” have been extremely valuable to neuroscientists, they also have major disadvantages. Most important, the damage doesn’t coincide neatly with the functional area; it will affect a smaller area or overlap with other functional areas. Fortunately, the pattern of damage varies from patient to patient, so if the neuroscientist studies a large number of patients, it may be possible to identify the location of damage common to people with the same deficits. FIGURE 4.12 A Cannula for Microdialysis. Neurochemicals in the surrounding fluid diffuse into the cannula through the porous membrane. Fluid is pumped in through the outer tube and flows out through the inside tube, carrying the neurochemicals with it.

Because of these and other difficulties in studying patients with brain damage, researchers often resort to producing the damage themselves in animals. In some cases, a whole area of the brain may be removed; removal of brain tissue is called ablation. Ablation can be done with a scalpel, but aspiration is a more precise technique, and it allows access to deeper structures. The skull is opened, and a fine- tipped glass micropipette connected to a vacuum pump is used to suck out neural tissue. Usually, however, lesioning is preferred in place of ablation because the damage can be more precisely controlled. Lesions, or damage to neural tissue , can be produced by electrical current, heat, or injection of a neurotoxin (using a stereotaxic instrument) or by using a knife or a fine wire to sever connections between areas. “Reversible lesions” can be produced by chilling a brain area or by injecting certain chemicals; this means that the animal’s behavior can be observed before and during treatment and again after recovery. Occasionally there is reason to insert a cannula or an electrode into a human’s

brain. This is done for clinical purposes—for example, to identify functional areas by recording electrical activity prior to brain surgery, to lesion malfunctioning tissue in patients with epilepsy, or to stimulate the brain in patients with Parkinson’s disease. Stereotaxic atlases of the human brain are published for this purpose, and there are human stereotaxic instruments as well, usually designed to mount on the head, as shown in Figure 4.13. Transcranial Magnetic Stimulation Transcranial magnetic stimulation(TMS) is a relatively new noninvasive brain

stimulation technique that uses a magnetic coil to induce a voltage in brain tissue. The device is held close to the scalp over the target area, as in Figure 4.14. TMS is pulsed at varying rates; frequencies of 1/s or less decrease brain excitability, and frequencies of 5/s and higher increase excitability.

FIGURE 4.13 A Human Stereotaxic Instrument.

SOURCE: Adapted from Biological Foundations of Human Behavior, by J. Wilson, 2003, Belmont, CA: Wadsworth. TMS has demonstrated its usefulness mostly as a research instrument. By making

clever combination of TMS stimulation and brain-imaging techniques (described in the next section), researchers have teased out the neural modifications that account for recovery in stroke patients (Gerloff et al., 2006); they have also determined that making visual-spatial judgments involves not just the parietal area but a broader network that includes frontal regions (Sack et al., 2007). TMS is also a promising candidate as a therapeutic tool, showing potential usefulness in alleviating symptoms of Parkinson’s disease, depression, and autism (Hallett, 2007). A simpler and less expensive alternative, transcranial direct current stimulation

(tDCS), involves application of direct current electrical stimulation through electrodes placed on the scalp (Sparing & Mottaghy, 2008). Unlike TMS, tDCS does not excite neurons to fire, but increases their spontaneous firing rate; still, it can produce effects that last for a few hours by affecting membrane potentials and receptor functioning. A drawback is that its effects cannot be localized as precisely as TMS. Most often, tDCS is used to enhance learning; for example, the U.S. military is using it experimentally to improve the training of snipers and drone operators (Bullard et al., 2011; Fields, 2011). Brain Imaging Techniques In Broca’s day, and in fact until fairly recently, a researcher had to wait for a brain-

damaged patient to die in order to pinpoint the location of the damage. There was little motivation to do exhaustive observations of the patient’s behavior when the patient might outlive the researcher or the body might not be available to the researcher at death. All that changed with the invention of imaging equipment that

could produce a picture of the living brain showing the location of damage. The first modern medical imaging technique came into use in the early 1970s.

Computed tomography (CT) scanning produces a series of X-rays taken from different angles; a computer combines the series of two-dimensional horizontal cross sections, or “slices,” so the researcher can scan through them as if they are a 3-D image of the entire organ (Figure 4.15). Imaging soft tissue such as the brain requires injecting a dye that will show up on an X-ray; the dye diffuses throughout the tiny blood vessels of the brain, so it is really the differing density of blood vessels that forms the image. A major drawback of earlier equipment was its extreme slowness, but newer models of CT scanners are fast, and they provide detailed images. CT scans are also popularly known as CAT scans. FIGURE 4.14 A Therapist Uses TMS With a Patient.

SOURCE: “Using Magnets as a Depression Treatment,” Design News, October 11, 2010. Retrieved from http://www.designnews.com/document.asp?doc_id=229440. Another imaging technique, magnetic resonance imaging (MRI), works by

measuring the radio-frequency waves emitted by the nuclei of hydrogen atoms when they are subjected to a strong magnetic field. Most of that hydrogen is in the water that composes 78% of the brain, but the water content varies in different brain structures, so these emissions from hydrogen nuclei can be used to form a detailed image of the brain (Figure 4.16a). The MRI is reasonably fast, and it can image small areas. Recent increases in power permit more versatile imaging by detecting elements other than hydrogen, including sodium, phosphorus, carbon, nitrogen, and oxygen. MRI scanners in the future should also be small enough to be portable and cost a few thousand dollars rather than a million or more. A variant of MRI, diffusion tensor imaging, measures the movement of water molecules; because water moves easily along the length of axons, this technique is very useful for imaging brain pathways and measuring their quality (Figure 4.16b). As you read through the rest of this text, you will see just how much the ability to quantify white matter is helping us understand mental disorders and psychological functions such as intelligence and learning. CT and MRI added tremendous capability for detecting tumors and correlating

brain damage with behavioral symptoms. However, CT and MRI lack the ability to detect changing brain activity (as EEG does, for instance); the two remaining techniques add that capability. Positron emission tomography (PET) involves injecting a radioactive substance

into the bloodstream, which is taken up by parts of the brain according to how active they are. The scanner captures the positrons emitted by the radioactive substance to form an image that is color coded to show the relative amounts of activity (see Figure 4.17). Radioactive 2-DG is often the substance that is injected because increased uptake of 2-DG by active neurons provides a measure of metabolic activity. Other radioactive substances can be used to monitor blood flow or oxygen uptake, and if a neurotransmitter is made radioactive, it can be used to determine the locations and numbers of receptors for the transmitter. Usually, the researcher produces a “difference scan” by subtracting the activity occurring during a neutral control condition from the activity that occurred during the test condition; this produces an image that uses a color scale to show where activity increased or decreased in the brain. FIGURE 4.15 Computed Tomography Scanning Procedure. (a) The patient’s head is positioned in a large cylinder, as shown here. (b) An X-ray beam and X-ray detector rotate around the patient’s head, taking multiple X-rays of a horizontal slice of the patient’s brain. (c) A computer combines X-rays to create an image of a horizontal slice of the brain. The scan reveals a tumor on the right side of the brain.

SOURCES: (a) Alvis Upitis/The Image Bank. (b) From Weiten. Psychology: Themes and Variations (with InfoTrac), 5E. © 2001 South-Western, a part of Cengage Learning, Inc. Reproduced by permission. (c) © RGB Ventures LLC dba SuperStock/Alamy. PET equipment is expensive and requires a sophisticated staff to operate it; the

facility must also be near a cyclotron, which produces the radioactive substance, and there are few of those around. The advantage that justifies this expense is that PET is able to track changing activity in the brain. The speed is not what a biopsychologist might wish, though, because PET cannot detect changes during behaviors that are briefer than 45 seconds. PET also does not image the brain tissue itself, so the results are often displayed overlaid on a brain image produced by another means, such as MRI. FIGURE 4.16 Magnetic Resonance and Diffusion Tensor Images. (a) A magnetic resonance image, which has detected a tumor (red arrow). (b) A diffusion tensor image reveals fibers connecting frontal, parietal, temporal, and occipital areas. Colors have been added to provide three-dimensional information; for example, the yellow fibers are ascending or descending vertically.

SOURCES: (a) © Living Art Enterprises/Photo Researchers/Getty Images. (b) Courtesy of Aaron Filer, MD, PhD.

What advantage do PET and fMRI have over CT and MRI? A modification of MRI takes advantage of the fact that oxygenated blood has

magnetic properties that are different from those of blood that has given up its oxygen to cells; functional magnetic resonance imaging (fMRI) measures brain activation by

detecting the increase in oxygen levels in active neural structures (Figure 4.18). MRI and fMRI have the advantage over PET and CT that they involve no radiation, so they are safe to use in studies that require repeated measurements. In addition, fMRI measures activity, like PET, and produces an image of the brain with good spatial resolution, like MRI; researchers can detect activity in cortical areas as small as 1 millimeter (Barinaga, 1997). The fMRI machines are particularly pricey though, which limits their usefulness for research. FIGURE 4.17 Positron Emission Tomography. A PET scan detects concentrations of radioactivity where neural activity is high; the computer produces a color-coded image, shown here superimposed over a separate scan of a brain. Traditionally, red indicates the greatest amount of activity, followed by yellow, green, and then blue. The individual was working on a verbal task, so areas involved in language processing were activated.

SOURCE: © Science Source/SPL. Brain imaging has been referred to as “the predominant technique in behavioral and

cognitive neuroscience” (Friston, 2009, p. 399). That said, you will not be surprised to see many examples of its use throughout this text—though none will be as unusual as the one in the accompanying Application. However, some investigators are urging caution in interpreting results; their focus has been mostly on fMRI, but their criticisms apply more broadly. For one thing, comparison of fMRI data with data from electrode recording in monkeys showed that fMRI misses a great deal of information; this is due to its lower sensitivity as well as to chance factors such as the distance of the neurons from a blood vessel (Logothetis, 2002). A related problem is less-than- perfect test–retest reliability. For example, when researchers showed volunteers pictures of fearful faces, correlations of amygdala activity in sessions 2 weeks apart ranged from.4 to.7, indicating a disappointing level of consistency (Johnstone et al., 2005). Perhaps more important, some researchers have been criticized for the way they

select their data. Ideally, researchers should decide in advance to obtain data from a

specific area, such as the amygdala, but often researchers do not have enough information to make this selection beforehand and therefore scan the whole brain. Then they divide the scan into tiny cube-shaped areas called voxels and determine which voxels’ activity is correlated with performance on a task or with a characteristic of the subjects. This involves calculating literally thousands of correlations; if you have even a basic understanding of probability, you know that this procedure guarantees finding several voxels whose activity correlates with the dependent variable even when no relationship exists. Thus, to ensure reliability of the results, the researcher should repeat the experiment focusing only on those areas to rule out the possibility the original correlations occurred by chance. However, researchers sometimes choose the easier approach of simply reporting the

correlations they found in that one session. In an analysis of 53 studies that reported correlations of fMRI activity with social or emotional measures (such as distress from social rejection), over half used the flawed nonindependent approach, and they accounted almost entirely for the highest correlations (Vul, Harris, Winkielman, & Pashler, 2009; see also the similar results of Kriegeskorte, Simmons, Bellgowan, & Baker, 2009). Nikos Logothetis has warned that erroneous claims of brain areas specialized for everything from empathy to neuroticism are leading to a phrenology that is even more dangerous than the 19th-century variety because it is cloaked in the respectability of brain imaging (Spinney, 2002).

2 Brain Imaging Still, these problems do not undermine the potential of imaging studies for

understanding behavior. The fact that five people won Nobel Prizes for their work in developing scanning technology indicates the importance of imaging techniques, and you can be sure that many important future developments in neuroscience will depend on brain imaging, just as they have for the past 20 years. The techniques described here are summarized in Table 4.1. FIGURE 4.18 An FMRI Scan. The colored areas were more active when research participants were processing words that were later remembered than when they processed words that were not remembered.

SOURCE: From “Building Memories: Remembering and Forgetting of Verbal Experiences as Predicted by Brain Activity,” by A. D. Wagner et al., Science, 281, pp. 1188–1191. © 1998 American Association for the Advancement of Science. Reprinted by permission from AAAS. “

The single most critical piece of equipment is still the researcher’s own brain.... What is badly needed now, with all these scanners whirring away, is an understanding of exactly what we are observing, and seeing, and measuring, and wondering about.

—Endel Tulving

”

APPLICATION

Scanning King Tut In January 2005, King Tutankhamun, pharaoh of Egypt 3,000 years ago, was removed from his tomb in the Valley of the Kings for the first time in almost 80 years. The trip was a short one, to a nearby van where his mummified body was subjected to a CT scan to determine whether Tut’s death at the age of 19 might have resulted from murderous intrigue within the royal family. An X-ray conducted in the tomb 30 years ago found pieces of his skull

inside the cranium, adding to the murder theory. But if Tut had died from a blow to the head, the bone fragments would have been caught up in the embalming material. Instead, the scan showed them lodged between the skull and the now solidified embalming fluid; more likely the archaeologist Howard Carter, who discovered Tut’s tomb in 1922, damaged the skull while prying away the golden mask that was stuck to the skull by solidified resins. The scans also found no mineral deposits in the bone, which some poisons would

leave behind, though other poisons could not be ruled out. The most promising evidence was that one leg had been broken, within days of his death judging by the lack of healing. The break was severe enough to cause an open wound, so King Tut’s death could have been caused by an infection.

Egypt’s Vice Minister of Culture Zahi Hawass Readies Tut for Scanning. SOURCE: © Supreme Council of Antiquities/epa/Corbis.

A deficiency of all these technologies is that they show what the brain is doing at the current time. To understand many brain processes and disorders such as schizophrenia, we also need to watch the brain as it develops. In the News describes an important step in that direction. TABLE 4.1 Comparison of EEG and Imaging Techniques.

Growing a Model Brain From Stem Cells

Animal models are extremely useful for studying the human brain, but animal brains are less complex and they sometimes don’t perform the same as a human brain. For example, manipulating genes in mice that in humans cause microcephaly —a disorder characterized by a smaller than normal brain— fails to produce full-blown symptoms. If we could grow a human brain and observe its development, we could learn so much more. That was the goal of researchers in Austria. They suspended

human stem cells in droplets of gel and floated the droplets in a nutrient bath. The stem cells had been induced to become neurons and glial cells, which they did; then over the course of 3 to 4 weeks, the neurons migrated into layers and differentiated into regions reminiscent of cerebral cortex, retina, and meninges, as well as cell types characteristic of hippocampus. Without a blood supply coursing among its cells, this cerebral organoid doesn’t grow beyond about 4 mm, but it has proved useful nevertheless. The researchers used stem cells from a patient with microcephaly to grow additional organoids, and these grew to a lesser size. Dissecting the organoids, the team discovered why: The stem cells differentiated into neurons early, when they should have still been replicating themselves; as a result, the brains developed fewer neurons and ended up small. Researchers have suspected that the switch is controlled by the protein CDK5RAP2, which is deficient in microcephaly because of mutations in its gene; when the team added the protein to the developing organoids, they grew normally.

3 Growing a Model Brain

Investigating Heredity We looked at the interplay of heredity and environment in shaping behavior in

Chapter 1; now we need to understand some of the techniques scientists use to do genetic research. The idea that behavior can be inherited is an ancient one, but most of the methods for doing genetic research were introduced or came into maturity in the past three or four decades. Until then, the work was not much more sophisticated than observing that a characteristic runs in families. Genetic Similarities: The Correlational Approach In a family study, which determines how strongly a characteristic is shared among

relatives, we would find that intelligent parents usually have intelligent children. However, as one researcher put it, “Cake recipes run in families, but not because of genes” (Goodwin, 1986, p. 3). This is a good example of the problem with correlational research. People who have similar genes often share a similar environment, so the effects of heredity are confounded with the effects of

environment. Still, the fact that family members are similar in a characteristic tells researchers that it would be worthwhile to pursue more complicated and costly research strategies. We will look at ways to reduce the confounding of heredity with environment, but first we need a way to quantify the results. Quantification is a simple matter for characteristics that can be treated as present or

absent, such as schizophrenia. We can say, for instance, that the rate of schizophrenia is about 1% in the general population but increases to around 13% among the offspring of a schizophrenic parent (Gottesman, 1991). For variables that are measured on a numerical scale, such as height and IQ (intelligence quotient, a measure of intelligence), we express the relationship with a statistic called the correlation coefficient. Correlation is the degree of relationship between two variables, measured on a scale between 0.0 and ±1.0. The strength of the relationship is indicated by the absolute value—how close the correlation is to either1.0 or −1.0. A positive correlation means that when one variable is high, the other tends to be high as well. For example, the correlation between the IQs of parents and their children averages about.42 across studies, and the correlation between brothers and sisters in the same family is about.47 (T. J. Bouchard & McGue, 1981). A negative value indicates the opposite tendency—when one value is high, the other tends to be low— not that the relationship is weaker. Now we can consider how to separate the effects of heredity from those of the environment. Adoption studies eliminate much of the confounding of heredity and environment

that occurs in family studies. Adoption studies compare the similarity between adopted children and their biological parents with their similarity to their adoptive parents. This kind of study is often called a natural experiment, but it lacks the control of a real experiment because we do not manipulate the adoption variable. As a result, environmental confounding can still occur; for example, families that must be split up by adoption may differ from the control families in important ways. Additional confounding occurs because children are often adopted into similar family environments and because adoption is frequently delayed until after critical developmental periods have passed. Nevertheless, the technique has yielded extremely valuable information, such as the fact that rearing children apart from their biological parents results in a drop in the correlation between their IQs from.42 to about.22 (T. J. Bouchard & McGue, 1981). The drop in correlation indicates a substantial influence of environment, while the remaining correlation indicates genetic influence. An environmental confound that adoption studies don’t control is the prenatal

environment, which can bring about long-term alterations in nervous system functioning. Animal researchers get around this problem by cross-fostering, implanting a fetus or an egg into another female. Of course, this strategy is unavailable in human research, or at least it was until in vitro fertilization became so

widespread. British researchers examined the medical records of 800 children conceived by in vitro fertilization; in one fourth of the cases, the egg or embryo was donated by another woman, so the offspring was unrelated to the mother. With this strategy, the researchers were able to conclude that the low birth weight previously observed in babies whose mothers smoked during pregnancy is environmental, while antisocial behavior (tantrums, fighting, lying, etc.) in children of smoking mothers has a genetic origin (F. Rice et al., 2009). Twin studies assess how similar twins are in some characteristic; their similarity is

then compared with that of nontwin siblings, or the similarity between identical twins is compared with the similarity between fraternal twins. Remember that fraternal twins are produced from two separately fertilized eggs (dizygotic), while identical twins result from a single egg that splits and develops into two individuals (monozygotic). Fraternal twins, like nontwin siblings, share only half their genes with each other; identical twins share 100% of their genes. Because both identical twins and fraternal twins share a common environment for the most part, a greater similarity between identical twins in a characteristic is probably due to their greater genetic similarity. Investigations of intelligence provide particularly good examples of the value of twin studies. For example, the correlation between fraternal twins’ IQs is about.60, and for identical twins it increases to around.86 (T. J. Bouchard & McGue, 1981). (Of course, we have to select fraternal pairs that are of the same sex, because identical twins are of the same sex.) Criticisms of twin studies include the possibility that identical twins might be treated more similarly than fraternal twins and the fact that sharing an umbilical cord makes their prenatal environment more similar.

How are adoption and twin studies superior to family studies? A useful measure for identifying genetic influence is concordance rate, the

frequency with which relatives are alike in a characteristic. An example of this measure is that when one fraternal twin is schizophrenic, the second twin will also be diagnosed with schizophrenia about 17% of the time; in identical twins this measure almost triples, to 48% (see Figure 4.19; Gottesman, 1991). But, because the correlation falls short of a perfect 1.0, even the identical twin of a person with schizophrenia escapes schizophrenia about half of the time; for the same reason, identical twins will rarely have exactly the same IQ. The incomplete influence of heredity means that environmental effects are also operating. Family, adoption, and twin studies are compared in Table 4.2. FIGURE 4.19 The Genain Quadruplets. Identical quadruplets, the sisters all became schizophrenic later in life. The chances of any four unrelated individuals all being schizophrenic is 1 in 100 million. The name Genain is a nickname derived from the Greek word meaning “dreadful gene.”

SOURCE: ASSOCIATED PRESS. Genetic Engineering: The Experimental Approach Although adoption and twin studies reduce confounding, they still share some of

the disadvantages of correlational studies. Genetic engineering involves actual manipulation of the organism’s genes or their functioning; studies using this technology qualify as experiments. At present, genetic engineering is employed mostly with mice, because their genetic makeup is well known and their embryos are more successfully manipulated.

What advantage does genetic engineering have over adoption and twin studies? An obvious way to find out what a gene does is to disable it and see what effect this

has on the animal. In the knockout technique, a nonfunctioning mutation is introduced into the isolated gene, and the altered gene is transferred into embryos. Subsequent mating of the resulting animals is required to produce animals that are homozygous for the gene. Another strategy is to disable the gene by interfering with its messenger RNA. The antisense RNA procedure blocks the participation of messenger RNA in protein construction. This is accomplished by inserting strands of complementary RNA into the animal, which dock with the gene’s messenger RNA (Figure 4.20). The cell recognizes this newly formed molecule as abnormal and releases an enzyme that destroys the RNA. TABLE 4.2 Comparison of Relationship Studies.

In gene transfer, a gene from another organism is inserted into the recipient’s cells. An important research tool is the transgenic animal, created by inserting the gene into the developing embryo. Again, mating of these animals is required to integrate the gene into all the cells. Researchers observe the effects in recipient animals to determine the transferred gene’s function. The technique also has potential for treating human disease. In this case, transfer must occur after the disease has been diagnosed, and is limited to the tissue involved in the disease. The gene is usually placed within a harmless virus, which then infects the cells. FIGURE 4.20 Antisense RNA. Antisense RNA is a strand of RNA that is complementary to a particular messenger RNA. The two will dock with each other, which disables the messenger RNA and halts production of its protein. The researcher observes differences in the animal to determine the gene’s function.

“

There will be a gene-based treatment for essentially every disease within 50 years. —W. French Anderson

”

Genetic engineering is becoming a therapeutic reality. Between 1999 and 2005, gene therapy was used successfully to treat at least 17 children with SCID, the disease Ashanthi had (“Gene Therapy Notches Another Victory,” 2005). Researchers recently used stem cells from two 7-year-old boys to carry a corrective gene into their bloodstream and halt the progress of a demyelinating brain disorder (the disease that was the subject of the movie Lorenzo’s Oil; Cartier et al., 2009). In Chapter 12, you will see that doctors are having some success using gene transfer to treat Alzheimer’s disease. While these results are promising, the ability to manipulate our genome carries tremendous risks and raises important ethical questions.

Concept Check Take a Minute to Check YourKnowledge and Understanding Organize your knowledge: Make a table of the staining and labeling techniques and their functions.

What different ways could be used to determine the function of a part of the brain?

Name three procedures that can be used to identify receptors. What are the advantages and disadvantages of experimental studies and correlational studies?

Describe the different genetic manipulation strategies discussed in this chapter.

Research Ethics As important as research ethics is, the topic usually gets pushed into the background by the excitement of scientific accomplishments and therapeutic promise. To place ethics at the forefront where it belongs, the major scientific and medical organizations have adopted strict guidelines for conducting research, for the treatment of subjects, and for communicating the results of research (see, e.g., American Psychological Association, 2010; “Policies on the Use of Animals and Humans in Neuroscience Research,” n.d.; “Public Health Service Policy on Humane Care and Use of Laboratory Animals,” 2002; “Research Involving Human Subjects,” n.d.).

What are the main issues in research integrity? Plagiarism and Fabrication The success of research in answering questions and solving problems depends not

only on the researchers’ skill in designing studies and collecting data but also on their accuracy and integrity in communicating results. Unfortunately, research is sometimes misrepresented intentionally; the two cardinal sins of research are plagiarism and the fabrication of data. Plagiarism is the theft of another’s work or ideas. Plagiarism denies individuals the

credit they deserve and erodes trust among the research community. The infraction may be as simple as failing to give appropriate credit through citations and references (like those you see throughout this text), but occasionally a researcher literally steals another’s work. In a recent high-profile case, for example, German education minister Annette Schavan resigned after the University of Düsseldorf revoked her Ph.D. due to plagiarism. According to the university, large parts of her 1980 dissertation were closely paraphrased from other sources without crediting those sources (“German Education Minister Quits,” 2013).

Fabrication, or faking, of results is more serious than plagiarism because it introduces erroneous information into the body of scientific knowledge. As a result, the pursuit of false leads by others consumes scarce resources and sidetracks researchers from more fruitful lines of research. More important, fabrication in clinical research can slow therapeutic progress and harm lives. In 1998, Andrew Wakefield published a study implicating a preservative in some vaccines as a cause of autism. No one could replicate the results, and later investigation revealed numerous instances of data fabrication and misrepresentation in the research (Deer, 2011). The article was retracted and Wakefield lost his medical license, but the repercussions continue today; many parents have become suspicious of vaccines and are failing to have their children immunized, putting them and others at risk of potentially deadly childhood diseases. “

Falsification is far more serious because it always corrupts the scientific record. It is a crime against science, indeed a crime against all humanity, when it legitimizes science that is false.

—David Crowe

” Although such cases are rare (E. Marshall, 2000b), they undermine confidence in

scientific and medical research. Increasingly, concerned government agencies are taking steps to educate researchers about research ethics (R. Dalton, 2000), setting aside $1 million of grant money to support studies on research integrity (E. Marshall, 2000c) and discouraging ties between scientists and the companies whose products they are testing (Agnew, 2000). In a fascinating new development, a social psychologist at the University of Pennsylvania has devised a statistical method to detect suspicious patterns in research data; using it, he accused a psychologist at the University of Rotterdam of data tampering, which led to a university investigation, withdrawal of two papers, and the psychologist’s resignation (Enserink, 2012).

4 Official Ethics Policies Protecting the Welfare of Research Participants All the scientific disciplines that use live subjects in their research have adopted

strict codes for the humane treatment of both humans and animals. The specifics of the treatment of human research participants and even the legitimacy of animal research are controversial, however. These are not abstract issues. As a student, you are a consumer of the knowledge that human and animal research produce, and you benefit personally from the medical and psychological advances, so you are more than just a neutral observer.

Research With Humans In 1953, the psychologist Albert Ax performed a study that was as significant for

its ethical implications as for its scientific results. He was attempting to determine whether all emotions result in the same general bodily arousal or each emotion produces a unique pattern of activation. To do so, he measured several physiological variables sensitive to emotional arousal, such as heart rate, breathing rate, and skin temperature, while inducing anger in the individuals at one time and fear at another. If Ax had told the research participants what would happen during the study, it would have altered their behavior, so he said he was doing a study of blood pressure.

What are the principal ethical concerns in human research? In the “anger” condition, the research participant was insulted by Ax’s assistant,

who complained at length that the person was not a very good experimental subject. The “fear” situation was more intense. During the recordings the individual received a mild electrical shock through the recording electrodes, while sparks jumped from nearby equipment. The experimenter acted alarmed as he explained that there was a dangerous high-voltage short circuit. Later interviews indicated that both ruses worked. Ax (1953) reported that one participant kept pleading during the fear treatment, “Please take the wires off. Oh! Please help me.” Another said of the anger treatment, “I was just about to punch that character on the nose” (p. 435). You will find the results of Ax’s research in Chapter 8; for now, we will look at the issues of informed consent and deception in relation to his study. Occasionally, research involves some pain, discomfort, or even risk. Before

proceeding with a study, current standards require the researcher to obtain the participant’s informed consent. Informed consent means that the individual voluntarily agrees to participate after receiving information about any risks, discomfort, or other adverse effects that might occur. However, sometimes the nature of a study requires the researcher to use deception, failing to tell the participants the exact purpose of the research or what will happen during the study or actively misinforming them. According to the American Psychological Association (APA), deception is acceptable only when the value of the study justifies it, alternative procedures are not available, and the individuals are correctly informed afterward. The APA’s guidelines are also clear that psychologists should not deceive subjects about research that is reasonably expected to cause physical pain or severe emotional distress (American Psychological Association, 2010). Some researchers and subjects’ rights advocates believe that deception is never justified. Ax’s study would probably not be permitted today, but we will see in Chapter 8 that researchers have found interesting alternatives for doing this kind of research.

What are the opposing views on animal research?

Research With Animals Psychological and medical researchers have perhaps no more important resource

than the laboratory animal. As the American Medical Association (1992) concluded, “Virtually every advance in medical science in the twentieth century, from antibiotics and vaccines to anti-depressant drugs and organ transplants, has been achieved either directly or indirectly through the use of animals in laboratory experiments” (p. 11). Psychologists have used animals to investigate behavior, aging, pain, stress, and cognitive functions such as learning and perception (Blum, 1994; F. A. King, Yarbrough, Anderson, Gordon, & Gould, 1988; N. F. Miller, 1985). It may seem that the best subjects for that purpose would be humans, but animals are useful because they live in a controlled environment and have a homogeneous history of experience, as well as a briefer development and life span. In addition, researchers feel that it is more ethical to use procedures that are painful or physically or psychologically risky on other animals rather than humans. As a result, in the mid-1980s, U.S. scientists were using 20 million animals a year: 90% of them were rodents, mostly mice and rats, and around 3.5% were primates, mostly monkeys and chimpanzees (U.S. Congress Office of Technology Assessment, 1986). The preference for inflicting discomfort or danger on nonhuman animals rather

than on humans is based on the assumption that the well-being of animals is less important than that of humans. Animal rights activists have called this dual ethical standard speciesism (H. A. Herzog, 1998), a term chosen to be intentionally similar to racism. Some activists work hand in hand with researchers to improve conditions for research animals; others have been more aggressive, breaking into labs, destroying equipment and records, and releasing animals (typically resulting in the animals’ death). In Europe and Britain, death threats have forced some researchers to move their work behind high fences (Koenig, 1999; Schiermeier, 1998); at the University of California at Santa Cruz, one animal researcher’s home was firebombed, and another’s car was burned (G. Miller, 2008). Activists have been shifting their attacks from laboratories to the researchers themselves; since the 1990s, attacks on individuals have risen from 9% of incidents to 46% (“Animal Rights Extremists... ”, 2014). “

Every one has heard of the dog suffering under vivisection, who licked the hand of the operator: this man, unless he had a heart of stone, must have felt remorse to the last hour of his life.

—Charles Darwin, The Descent of Man and Selection in Relation to Sex, 1871

” Animal research guidelines provide for humane housing of animals, attention to

their health, and minimization of discomfort and stress during research (American Psychological Association, 2010; “Guidelines for Ethical Conduct in the Care and Use of Animals,” n.d.; “Policies on the Use of Animals and Humans in Neuroscience Research,” n.d.). But critics point out that researchers sometimes do not live up to the standards of their professional organizations. The Behavioral Biology Center in Silver Spring, Maryland, was engaged in research that involved severing the sensory nerve in one arm of monkeys to study the reorganization that occurs in the brain. The lab’s contributions drew the praise of neuroscientists and led to the design of routines for extensive exercise of an afflicted limb to help people recover from brain injuries. But in 1981, a student summer employee informed the police of what he considered to be abuse of the lab’s animals, and the police carried out the first raid on a research laboratory in the United States (“A Brighter Day for Edward Taub,” 1997; Orlans, 1993). The director, Edward Taub, was convicted of animal abuse because of poor postoperative care, but the conviction was overturned because the state lacked jurisdiction over federally supported scientific research. The National Institutes of Health withdrew Taub’s funding, and Congress enacted more stringent animal protection laws. In spite of the controversy, Taub received the William James Award from the American Psychological Society. However, he points out that the award was for work that is no longer permitted and that animal welfare rules enacted by Congress prevent him from taking measurements in the brain of the one remaining monkey for the length of time that would be needed. The conflict between animal welfare and research needs is obviously not a simple

issue and is strongly felt on both sides (Figure 4.21). Although psychologists and neuroscientists do not condone mistreatment of research animals, most of them argue that the distress that does occur is justified by the benefits animal research has produced. The 2000 Nobel Prize in physiology or medicine was shared by three neuroscientists: Arvid Carlsson, for his discovery of the role of dopamine as a neurotransmitter in the brain; Paul Greengard, for identifying how dopamine and related neurotransmitters produce their effect on neurons; and Eric Kandel, for his work on the molecular changes that occur in the brain during learning. The work of all three prize winners relied heavily on animal research. It is unlikely that animal research will be banned as the more extreme activists

demand, but animal care and use guidelines have been tightened and outside monitoring increased, and states have passed more stringent laws. In addition, researchers have become more sensitive to the welfare of animals, adopting more humane methods of treatment and turning to tissue cultures and computer simulations in place of live animals when possible. In a survey of articles published in major biomedical journals between 1970 and 2000, the proportion of studies using animal subjects had fallen by one third, and in the studies that did use animals, the average number had decreased by half (Carlsson, Hagelin, & Hau, 2004). The National

Institutes of Health is furthering that trend by taking most of its chimpanzees out of research (see In the News).

5 Benefits and Ethics of Animal Research Human research has typically generated less controversy than the use of animals,

largely because scientists are more restrained in their treatment of humans, and humans are able to refuse to participate and to bring lawsuits. The balance of concern is shifting, though, particularly as treatments move from the research lab to the clinic. FIGURE 4.21 Animal Research Controversy. The poster (a) and the demonstration (b) illustrate the contrasting views on animal research.

SOURCES: (a) Foundation for Biomedical Research. (b) © Paul Conklin/PhotoEdit.

NIH Is Retiring Most of Its Research Chimps In mid-2013, the National Institutes of Health (NIH) announced it will retire most of its 360 research chimpanzees. The decision came after an Institute of Medicine report concluded that recent advances have made most research on chimpanzees unnecessary. Following the report’s recommendations, NIH will now use chimps only in studies that will advance human health and when the work cannot be done on humans or other animals. Fifty animals will remain available for research but will be housed in groups in large outdoor spaces. The 310

others will be relocated to appropriate sanctuaries. To support the chimps’ retirement, the U.S. Congress voted to allow NIH to spend up to $12 million a year on the national sanctuary, Chimp Haven.

SOURCE: © Chimp Haven, Inc.

6 NIH Chimps Retire

Gene Therapy Gene therapy, the treatment of disorders by manipulating genes, has enjoyed

glowing press reviews because of its potential for correcting humanity’s greatest handicaps and deadly diseases. But a distinct chill fell over the research in 1999, when Jesse Gelsinger, an 18-year-old volunteer, became the first human to die as the direct result of gene research (Lehrman, 1999; E. Marshall, 2000a). The study was using a deactivated form of adenovirus, which causes the common cold, to transport a gene into the liver in an experimental attempt to correct a genetic liver enzyme deficiency. Gelsinger developed an immune reaction to the adenovirus, which resulted in his death.

What are the problems with gene research and gene therapy? The Food and Drug Administration (FDA), which was overseeing the study,

reprimanded the researchers for not consulting with the FDA when most of the patients developed mild adverse reactions and for not informing the research participants that two monkeys had died in an earlier study after receiving much larger doses of adenovirus (“U.S. Government Shuts Down Pennsylvania Gene Therapy Trials,” 2000). The university was assessed a $1 million fine, and the three principal investigators had restrictions placed on their human research until 2010 (Check, 2004). The case has slowed gene therapy research across the country, but a positive outcome is that it has led to stricter supervision of human studies.

7 Gene Therapy There are additional concerns that gene manipulation could affect the reproductive

cells and change the genome of nonconsenting future generations, a questionable outcome at least when survival is not at stake. As a result, the American Association for the Advancement of Science (2000) has called for a moratorium on research that might produce inheritable modifications. There are social and ethical issues as well,

including the potential abuse of information in a person’s DNA. In the United States, it is now illegal for insurers and employers to discriminate against people based on their DNA (“Genetic Information Nondiscrimination Act of 2008,” n.d.). U.K. lawmakers took privacy a step further by making it illegal to analyze a person’s DNA without the person’s consent (“Sneaky DNA Analysis to Be Outlawed,” 2004); unfortunately, that protection is available only in a handful of states in the United States (Joh, 2011). An additional concern is that, because gene therapy is very expensive, it is likely to increase inequalities further between the haves and have-nots in our society. Some worry that its application will not be limited to correcting disabilities and disease but will be used to enhance the beauty, brawn, and intelligence of the offspring of well-to-do parents. The science fiction movie Gattaca (whose title is a play on the four letters of the genetic code) depicts a society in which privilege and opportunity are reserved for genetically enhanced “superior” individuals. Fortunately, the U.S. Congress wisely set aside 5% of the Human Genome Project budget to fund the study of the ethical, legal, and social implications of genetic research (Jeffords & Daschle, 2001).

What is the promise of stem cells?

8 Stem Cell Research Stem Cell Therapy You learned in Chapter 3 that embryonic stem cells are undifferentiated cells that

have the potential for developing into any other body cell. Stem cells have been used successfully to treat spinal cord damage (J. W. McDonald et al., 1999) and brain damage (Ren et al., 2000) in rats; they have also tracked down tumors in the brains of mice and delivered interleukin 12, making it easier for immune cells to kill the tumors (Ehtesham et al., 2002). In humans, heart functioning improved in patients with congestive heart failure after injection of stem cells (A. N. Patel et al., 2004). Medical researchers hope that stem cells can eventually be used to grow human organs in the laboratory to supply organ transplants and to allow genetic researchers to watch a gene produce a diseased organ rather than working backward from the diseased patient to the gene. An estimated 28 million people in the United States alone have diseases that are potentially treatable by stem cell therapy (Perry, 2000). So if stem cells hold such wonderful potential, why are they being discussed under

the topic of ethics? Extracting stem cells destroys the embryo, so right-to-life advocates oppose this use of human embryos, even though most are “extras” resulting from fertility treatment and would otherwise be discarded (Figure 4.22). Stem cell research was crippled for years in the United States by the Bush administration’s refusal to fund research on stem cell lines derived from embryos after August 2001; however, the earlier lines were too contaminated for human use (M. J. Martin, Muotri,

Gage, & Varki, 2005). This policy was reversed in 2009 by President Obama and, after a 3-year court battle, a federal appeals court ruled that government funding of research with human embryonic stem cells does not violate existing U.S. law (Kaiser, 2012). But research with embryonic stem cells is still controversial in the United States, and views differ across the European Union’s 28 member nations as much as they do in the United States (Drumi, 2009). Due to this controversy and the limited availability of embryonic stem cells, other sources are being sought; for example, the stem cells used to treat the heart patients were taken from their own bone marrow. Mature cells can be turned into embryonic-like induced pluripotent stem cells by increasing the expression of four genes, but only about 10% of cells are transformed in this procedure. Israeli scientists discovered that the protein Mbd3 acts as a brake on reprogramming; by mutating the Mbd3 gene or decreasing its expression, they have been able to increase the transformation rate to almost 100% (Rais et al., 2013). FIGURE 4.22 Injecting Cells Into a Damaged Brain. (a) Although the procedure is promising, it is controversial because of where the cells come from, which is usually (b) human embryos.

SOURCES: (a) From Coon. Introduction to Psychology, 9E. © 2001 South-Western, a part of Cengage Learning, Inc. Reproduced by permission. (b) © Science

Concept Check

Source/SPL. Some critics are calling for a slower pace in implementing gene and stem cell

therapies, pointing to incidents like the Jesse Gelsinger case. More recently, three children being treated for SCID with gene therapy developed leukemia, and one died (“Therapy Setback,” 2005). Apparently the retrovirus used to transfer the gene triggered the leukemia by activating a gene involved in cell proliferation. Critics suggest that there are unknown dangers as well; for example, sometimes stem cells injected into animals have found their way into tissues throughout the body, and we don’t know what all the consequences might be. In the case of the patients treated for heart disease, there is some question whether the stem cells repaired the patients’ hearts or some other factor, such as the chemicals used in the bone marrow preparation, accounted for the improvement (Check, 2004). Many scientists are reluctant to undertake large clinical trials until there is more information about the benefits as well as the risks of stem cell therapies. When the implications of research are so far-reaching, restraint is as valuable as enthusiasm and commitment.

Take a Minute to Check Your Knowledge and Understanding

What are the effects of dishonesty in research? How do researchers justify their use of animals in research? Why is there an ethical issue with human stem cell research; how might it be resolved?

In Perspective Early progress in psychology and in biopsychology relied on the wit and perspiration of the pioneering researchers. Now they are aided by sophisticated equipment and methods that are escalating discovery at an unprecedented pace and taking research into areas that were barely conceivable a few decades ago. Knowledge is power, and with power comes responsibility. For the scientists who

study behavior, that responsibility is to the humans and animals that provide the source of our knowledge and to the people who may be healed or harmed by the new treatments resulting from research. Summary Science, Research, and Theory • Researchers respect uncertainty but try to reduce it through research and the use of theory.

• Of the many research strategies at their disposal, biopsychologists favor the experimental approach because of the control it offers and the ability to determine

cause and effect. • Correlational techniques have value as well, particularly when the researcher cannot control the situation.

Research Techniques • Staining and labeling techniques make neurons more visible, emphasize cell bodies or axons, trace pathways to or from a location, and identify active areas or specific structures such as receptors.

• Light microscopy is extremely useful, but electron microscopy reveals more detail, scanning electron microscopy adds three-dimensionality, and confocal and two- photon microscopy produce images at greater depths.

• The EEG sums the neural activity between two electrodes to assess arousal level and detect damage and some brain disorders. Event-related potentials measure averaged responses to brief stimuli.

• Brain functioning can be studied by observation of brain-damaged individuals, electrical and chemical stimulation (using stereotaxic techniques), destruction of neural tissue (ablation and lesioning), and microdialysis of brain chemicals.

• Brain imaging using CT and MRI depicts structure, for example, to assess damage, while PET and fMRI are capable of measuring activity.

• Family studies, adoption studies, and twin studies are correlational strategies for investigating heredity. Family studies determine whether a characteristic runs in families, while adoption studies assess whether adopted children are more like their adoptive parents or their biological parents in a characteristic. Twin studies contrast the similarity of fraternal twins with the similarity of identical twins.

• Genetic engineering includes gene transfer and gene-disabling techniques (knockout and antisense RNA). Although experimental, it is already showing therapeutic promise.

Research Ethics • A major concern in biopsychology is maintaining the integrity of research; plagiarism and fabrication of data are particularly serious infractions.

• Both the public and the scientific community are increasingly concerned about protecting the welfare of humans and animals in research. The various disciplines have standards for subject welfare, but the need for more monitoring and training is evident.

• Stem cell technology is promising for treating brain and spinal cord damage and a variety of diseases, but it is controversial because obtaining stem cells often involves destroying embryos. Gene therapy also holds much promise, but it has dangers and could be abused. ■ Study Resources

For Further Thought • Pay close attention as you read through this text, and you will notice that

human studies are more likely than animal studies to be correlational. Why do you think this is so?

• Genetic engineering is mostly a research technique now; what practical uses can you imagine in the future?

• Is it unreasonable coercion to (a) require a student in an Introduction to Psychology course to participate in research, (b) require a student in a Research Methods course to participate in research exercises during the laboratory sessions as a part of the educational experience, or (c) offer money and a month’s housing and meals to a homeless person to participate in a risky drug study?

• Do you think the rights of humans and animals are adequately protected in research? Why or why not? What do you think would be the effect of eliminating the use of animal subjects?

Quiz: Testing Your Understanding 1. Describe the four imaging techniques, including method, uses, and

advantages/disadvantages. 2. Discuss the relative merits of experimental and correlational research,

using family/twin/adoption studies versus genetic engineering as the example.

3. Discuss the conflicts between research needs and animal rights. 4. In spite of their promise, stem cell research and gene therapy are

controversial. Why? Select the best answer: 1. You could best identify receptors for acetylcholine by using

a. Golgi stain. b. Nissl stain. c. immunocytochemistry. d. electron microscopy.

2. If you needed to measure brain activity that changes in less than 1 s, your best choice would be a. EEG. b. CT. c. MRI. d. PET.

3. Your study calls for daily measurement of activity changes in emotional areas of the brain. You would prefer to use a. CT. b. MRI. c. PET. d. fMRI.

4. Science is most distinguished from other disciplines by a. the topics it studies. b. the way it acquires knowledge. c. its precision of measurement. d. its reliance on naturalistic observation.

5. Experiments are considered superior to other research procedures because they a. involve control over the variable of interest. b. permit control of variables not of interest. c. permit cause-and-effect conclusions. d. All of the above e. None of the above

6. A theory a. is the first step in research. b. is the final stage of research. c. generates further research. d. is an opinion widely accepted among researchers.

7. The best way to assess the relative contributions of heredity and environment would be to compare the similarity in behavior of a. fraternal versus identical twins. b. relatives versus nonrelatives. c. siblings reared together versus those reared apart. d. fraternal versus identical twins, half of whom have been adopted out.

8. The most sensitive way to determine whether a particular gene produces a particular behavior would be to a. compare the behavior in identical and fraternal twins. b. compare the behavior in people with and without the gene. c. use genetic engineering to manipulate the gene and note the behavior

change. d. find out whether people with the behavior have the gene more often

than people without the behavior. 9. Antisense RNA technology involves

a. inserting a gene into the subject’s cells. b. interfering with protein construction controlled by the gene. c. introducing a nonfunctioning mutation into the subject’s genes. d. All of the above

10. The most popular research animals among the following are a. rats. b. pigeons. c. monkeys.

d. chimpanzees. 11. Speciesism refers to the belief that

a. humans are better research subjects than animals. b. it is more ethical to do risky experiments on lower animals than on

humans. c. humans are the superior species. d. All of the above e. None of the above

12. The biggest obstacle to using stem cells would be eliminated if researchers could a. get adult stem cells to work as well as embryonic ones. b. get stem cells to differentiate into neurons. c. get stem cells to survive longer. d. get stem cells to multiply faster.

Answers: 1. c, 2. a, 3. d, 4. b, 5. d, 6. c, 7. d, 8. c, 9. b, 10. a, 11. b, 12. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. CLARITY is described in a Stanford School of Medicine press release. 2. Brain Imaging compares the advantages and disadvantages of different

imaging techniques, along with sample images. fMRI 4 Newbies is the whimsical title of a site filled with images and information, as well as humor (such as “Ten Things Sex and Brain Imaging Have in Common”).

3. News about the model human brain appeared in The Economist and The Scientist.

4. The American Psychological Association establishes Ethical Principles of Psychologists and Code of Conduct, covering research and publication, therapeutic practice, and conflict of interest, as well as numerous other

areas. The National Institutes of Health publishes its policies on the use of human and animal research.

5. You can download several Scientific American articles expressing contrasting opinions on the Benefits and Ethics of Animal Research. Research With Animals in Psychology is a rationale for the use of animals in behavioral research, provided by the Committee on Animal Research and Ethics of the American Psychological Association.

6. Science Insider has the news articles about the retirement of NIH chimps and their support at Chimp Haven.

7. The Wikipedia article Gene Therapy describes the strategy and the successes of the technique and provides a timeline history of developments from 1990 to the present.

8. The International Society for Stem Cell Research website has news, recent research, photos and movie clips, and ethics essays related to stem cell research. Tristem Corporation is dedicated to creating stem cells from mature adult cells, and its website has informative articles and press releases along with several colorful images of stem cells.

Chapter Updates and Biopsychology News

For Further Reading 1. “Remote Control Brains,” by Douglas Fox (New Scientist, July 27, 2007,

30–34), is a nontechnical review of the field of optogenetics, the strategy described in Chapter 2 for controlling neurons with light; “The Optogenetic Catechism,” by Gero Miesenböck (Science, 2009, 326, 395–399), is a more thorough treatment.

2. “Why You Should Be Skeptical of Brain Scans,” by Michael Shermer (Scientific American Mind, Oct/Nov 2008, 66–71), is the layperson’s guide to understanding why interpretations of brain scan research can be misleading.

3. Transgenic animals have almost exclusively been mice, but now the marmoset has become the first transgenic primate, enabling research with a subject considerably closer to humans (“Generation of Transgenic Non- human Primates With Germline Transmission,” by Erika Sasaki et al., Nature, 2009, 459, 523–528).

4. Opposing views of several writers on research deception are presented in the American Psychologist, July 1997, 746–747, and July 1998, 803–807.

5. The Scientific American article “The World’s First Neural Stem Cell Transplant,” by K. Mossman, describes some of the promise of stem cell therapy, while “Reality Check: The Inevitable Disappointments From Stem

Cells” addresses technical, social, and political challenges that remain. Search for these two titles at www.scientificamerican.com

6. “Doctors Offer Unapproved Stem Cell Therapies,” by Steve Sternberg (USA Today, June 29, 2011), describes numerous unproven stem cell treatments offered by doctors who are either uninformed or outright charlatans. (Search for this title at usatoday.com.)

Key Terms ablation adoption study antisense RNA autoradiography computed tomography (CT) concordance rate correlation correlational study deception diffusion tensor imaging electroencephalogram (EEG) electron microscope event-related potential experiment fabrication family study functional magnetic resonance imaging (fMRI) gene therapy gene transfer genetic engineering Golgi stain immunocytochemistry in situ hybridization informed consent knockout lesion magnetic resonance imaging (MRI) messenger ribonucleic acid (RNA) myelin stain Nissl stain plagiarism positron emission tomography (PET)

stereotaxic instrument theory transcranial magnetic stimulation twin study

PART II

Motivation and Emotion: What Makes Us Go

Chapter 5. Drugs, Addiction, and Reward Chapter 6. Motivation and the Regulation of Internal States Chapter 7. The Biology of Sex and Gender Chapter 8. Emotion and Health

H

5 Drugs, Addiction, and Reward

In this chapter you will learn • The major classifications of drugs and some of their effects • What happens in the brain during addiction • How addiction is treated pharmacologically • How heredity influences addiction

Psychoactive Drugs Opiates Depressants Stimulants Psychedelics Marijuana IN THE NEWS: CHANGING ATTITUDES TOWARD MARIJUANA CONCEPT CHECK

Addiction The Neural Basis of Addiction and Reward Dopamine and Reward Dopamine, Learning, and Brain Plasticity Treating Drug Addiction APPLICATION: PREVENTING ADDICTION BY TARGETING THE IMMUNE SYSTEM CONCEPT CHECK

The Role of Genes in Addiction Separating Genetic and Environmental Influences What Is Inherited? Implications of Addiction Research CONCEPT CHECK

In Perspective Summary Study Resources

onoré de Balzac (Figure 5.1) wrote a phenomenal 45 novels in 20 years. He was aided in his long writing marathons by large amounts of a stimulant drug whose effects pleased him so much that he advocated its use to others. However, he died

at the age of 51 in part because of this unrelenting stimulation. What was the powerful drug that contributed both to his success and to his untimely death? According to his physician, Balzac died from a heart condition, aggravated by “the use or rather the abuse of coffee, to which he had recourse in order to counteract man’s natural propensity to sleep” (“French Roast,” 1996, p. 28). “

You illustrious Human Candles... who consume your own brilliant selves with the heat and light of your minds... I have discovered a horrible, rather brutal method that I recommend only to men of excessive vigor, men with thick black hair and skin covered with liver spots, men with big square hands and with legs shaped like bowling pins.

—Balzac (1839/1996)

” There is good reason to consider caffeine an addictive drug. Coffee may have

milder effects than the other drugs coming out of Colombia, but strength of effect and illegality are not the criteria for classifying a substance as addictive. As you will see, a drug’s effect on the brain is the telling feature, and that is our reason for discussing drugs at this particular point: It provides the opportunity to tie together our preceding discussions of brain structures and neural (particularly synaptic) functioning. Psychoactive Drugs A drug is a substance that on entering the body changes the body or its functioning. Drugs fall into one of two general classes, according to their effect on a transmitter system. As we saw in Chapter 2, an agonist mimics or enhances the effect of a neurotransmitter. It can accomplish this by having the same effect on the receptor as the neurotransmitter, by increasing the transmitter’s effect on the receptor, or by blocking the reuptake or the degradation of the transmitter. An antagonist may occupy the receptors without activating them, simultaneously blocking the transmitter from binding to the receptors. Or it may decrease the availability of the neurotransmitter, for example, by reducing its production or its release from the presynaptic terminals. FIGURE 5.1 Honoré de Balzac.

SOURCE: © The Print Collector/Alamy. Psychoactive drugs are those that have psychological effects, such as anxiety relief

or hallucinations. The focus of this chapter is on abused psychoactive drugs, although many of the principles discussed here are applicable more generally. We will discuss several psychotherapeutic drugs later, in the chapter on psychological disorders (see Chapter 14). The effects of abused drugs are extremely varied, but whether they arouse or relax, expand the consciousness or dull the senses, addictive drugs initially produce a sense of pleasure in one form or another. They also have several other effects in common; reviewing those effects will give us the language we need for a discussion of how the drugs work. Most of the abused drugs produce addiction; addiction is identified by

preoccupation with obtaining a drug, compulsive use of the drug in spite of adverse consequences, and a high tendency to relapse after quitting. Many abused drugs also produce withdrawal reactions. Withdrawal is a negative reaction that occurs when drug use is stopped. Withdrawal symptoms are due at least in part to the nervous system’s having adapted to the drug’s effects, so they are typically the opposite of the effects the drug produces. For example, the relaxation, constipation, chills, and positive mood of heroin are replaced by agitation, diarrhea, fever, and depression during withdrawal. Regular use of most abused drugs results in tolerance; tolerance means that the

individual becomes less responsive to the drug and requires increasing amounts of the drug to produce the same results. Like withdrawal, tolerance results from compensatory adaptation in the nervous system, mostly a reduction in receptor number or sensitivity. Tolerance is one reason for overdose. Tolerance can occur to

some of a drug’s effects without occurring to others. Thus, if the drug abuser takes larger doses of heroin to achieve the original sense of ecstasy while the tendency to produce sleep and respiratory arrest are undiminished, overdose is nearly inevitable, and the consequences can be deadly. Opiates The opiates are drugs derived from the opium poppy (see Figure 5.2). Opiates have

a variety of effects: They are analgesic (pain relieving) and hypnotic (sleep inducing), and they produce a strong euphoria (sense of happiness or ecstasy). Their downside is their addictive potential. Opium has been in use since around 4000 BCE (Berridge & Edwards, 1981); originally it was eaten, but when explorers carried the American Indians’ practice of pipe smoking of tobacco back to their native countries, opium users adopted this technique. Morphine was extracted at the beginning of the early 1800s and has been extremely valuable as a treatment for the pain of surgery, battle wounds, and cancer. Heroin was synthesized from morphine in the late 1800s; at the turn of the century, it was marketed by the Bayer Drug Company of Germany as an over-the-counter analgesic until its dangers were recognized. It is now an illegal drug in the United States but is prescribed as a pain reliever in Great Britain and is used there and in a few European countries as a replacement drug in addiction treatment. Codeine, another ingredient of opium, has been used as a cough suppressant, and dilute solutions of opium, in the form of paregoric and laudanum (literally, “something to be praised”), were once used to treat diarrhea and to alleviate pain; paregoric was even used to quiet fretful children. Morphine continues to be used with cancer patients and is showing promise of safe use with milder pain in a time-release form that virtually eliminates the risk of addiction. Aside from morphine, opiates have mostly been replaced by synthetics. These are called opioids, to indicate that they are not derived from opium, at least not directly, though the term is increasingly used to include all substances that affect the endogenous receptors. Although the synthetic opioids are safer, they also are subject to abuse; you probably recognize OxyContin because of its reputation for abuse rather than for its pain-relieving ability.

Do opiates have any legitimate use? Heroin is the most notoriously abused opiate, due to its intense effect: a glowing,

orgasm-like sensation that occurs within seconds, followed by drowsy relaxation and contentment. Because heroin is highly soluble in lipids, it passes the blood-brain barrier easily; the rapid effect increases its addictive potential. The major danger of heroin use comes from overdose—either from the attempt to maintain the pleasant effects in the face of increasing tolerance or because the user unknowingly obtains the drug in a purer form than usual. In a 33-year study of 581 male heroin addicts, 49% were dead at the end of the study, with an average age at death of 46 years (Hser, Hoffman, Grella, & Anglin, 2001). Nearly a fourth of those had died of drug

overdoses (mostly from heroin); 19.5% died from homicide, suicide, or accident; and 15% died from chronic liver disease. Half of the survivors who could be interviewed were still using heroin, and the high likelihood of returning to usage even after 5 years or more of abstinence suggested to the researchers that heroin addiction may be a lifelong condition. In spite of the representation of the horrors of heroin withdrawal in movies, it is best described as similar to a bad case of flu, so apparently fear of withdrawal is not the prime motivator for continued heroin addiction. FIGURE 5.2 An Opium Poppy.

SOURCE: © iStockphoto/SERDAR YAGCI.

1 Effects of Heroin and Other Drugs As tolerance to a drug develops, it also becomes associated with the person’s drug-

taking surroundings and circumstances. This learned or conditioned tolerance does not generalize completely to a new setting; when the person buys and takes the drug in a different neighborhood, the usual dose can lead to overdose (Macrae, Scoles, & Siegel, 1987; S. Siegel, 1984). Heroin is a particularly good example; an amount of heroin that killed 32% of rats injected in their customary drug-taking environment killed 64% of rats injected in a novel environment (S. Siegel, Hinson, Krank, & McCully, 1982). We saw in Chapter 4 that neuroscientist Candace Pert discovered why opioid drugs

are so effective as pain relievers: The body has receptors that are specific for these drugs, because it manufactures its own endogenous (generated within the body)

opioids, known as endorphins. One effect of endorphins is pain relief, as we will see in Chapter 11. Stimulation of endorphin receptors triggers some of the positive effects of opiates; others occur from indirect activation of dopamine pathways. Depressants Depressants are drugs that reduce central nervous system activity. The group

includes sedative (calming) drugs, anxiolytic (anxiety-reducing) drugs, and hypnotic drugs. Alcohol, of course, is the most common and is the most abused in this class, so we will start there.

What are the uses and dangers of depressant drugs? Alcohol Ethanol, or alcohol, is a drug fermented from fruits, grains, and other plant

products; it acts at many brain sites to produce euphoria, anxiety reduction, sedation, motor incoordination, and cognitive impairment (Koob & Bloom, 1988). It is the oldest of the abused drugs; its origin is unknown, but it was probably discovered when primitive people found that eating naturally fermented fruit had a pleasant effect. (Even elephants sometimes congregate under trees to eat fallen and fermenting fruits until they become intoxicated!) Alcohol has historically played a cultural role in celebrations and ceremonies, provided a means of achieving religious ecstasy, and, especially in primitive societies, permitted socially sanctioned temporary indulgence in hostility and sexual misbehavior. In modern societies, controlled group drinking has been replaced by uncontrolled individual abuse. “

I had booze, and when I was drinking, I felt warm and pretty and loved—at least for a while.

—Gloria, a recovering alcoholic

” Alcohol is valued by moderate users as a social lubricant and as a disinhibitor of

social constraints, owing largely to its anxiety-reducing effect. Like many drugs, its effects are complex. At low doses, say a couple of drinks, it turns off the inhibition the cortex normally exerts over behavior, resulting in behavioral stimulation, but it also has a direct stimulatory effect by increasing dopamine release (Hendler, Ramchandani, Gilman, & Hammer, 2013). As intake increases, alcohol begins to have a sedative or even hypnotic effect; behavior moves from relaxation to sleep or unconsciousness. Later, after the bout of drinking has ended, the alcohol is metabolized back to a low blood level and it becomes a stimulant again. That is why a few drinks in the evening may help you get to sleep at bedtime only to awaken you later in the night.

Because it interferes with cognitive and motor functioning as well as judgment, alcohol is involved in one third of all U.S. traffic fatalities (National Highway Traffic Safety Administration, 2006). In the United States and Canada, a person is legally considered too impaired to drive when the blood alcohol concentration (BAC) reaches 0.08%. As you well know, alcohol is also closely linked with violent crime; in fact, it is involved in 38% of incarcerations for violence (K. L. Greenfeld & Henneberg, 2001). Besides affecting judgment, alcohol reduces the anxiety that normally inhibits aggression (Pihl & Peterson, 1993).

2 Alcoholics Anonymous Alcohol carries with it a host of health and behavioral problems. High levels of any

depressant drug have the potential to shut down the brain stem, resulting in coma or death; a blood alcohol level of 0.5% is adequate to put the drinker at risk. A common result of chronic alcoholism is cirrhosis of the liver, which in its severest form is fatal. In addition, the vitamin B1 deficiency that is associated with chronic alcoholism can produce brain damage and Korsakoff’s syndrome, which involves severe memory loss along with sensory and motor impairment (Figure 5.3). Binge drinkers are more likely to be impulsive and to have learning and memory impairments (Stephens & Duka, 2008). Alcohol is the fifth leading cause of premature death and disability, which has led the World Health Organization to launch a worldwide campaign to reduce alcohol’s toll on health (World Health Organization, 2009). Even abstinence can be dangerous for the alcoholic. Alcohol withdrawal involves tremors, anxiety, and mood and sleep disturbances; more severe reactions are known as delirium tremens— hallucinations, delusions, confusion, and, in extreme cases, seizures and possible death. FIGURE 5.3 A Normal Brain and an Alcoholic Brain. Both brains are from 53-year-old men. In the alcoholic brain note the smaller corpus callosum, as well as the enlarged ventricles, sulci, and fissures, which indicate reduced brain tissue.

SOURCE: From “Magnetic Resonance Imaging of the Living Brain,” by Margaret J. Rosenbloom and Adolf Pfefferbaum, 2008, Alcohol Research and Health, 31, pp. 362–376. Considering the health risks, violence, and disruption of homes and livelihood,

alcohol is more costly to society than any of the illegal drugs. According to the Centers for Disease Control and Prevention (2011), for example, excessive alcohol use accounts for more than 79,000 deaths annually in the United States. In view of all the dangers of drinking, it seems amazing now that in 1961 a speaker at a symposium of psychiatrists and physicians on drinking expressed the group’s consensus that “alcohol is the safest, most available tranquilizer we have” (“Paean to Nepenthe,” 1961, p. 68). Alcohol provides a good example of the complex effects that drugs have on

multiple receptor and neurotransmitter systems. First, it inhibits the release of glutamate (Hoffman & Tabakoff, 1993; G. Tsai, Gastfriend, & Coyle, 1995). You may remember from Chapter 2, Table 2.2, that glutamate is the most prevalent excitatory neurotransmitter. Glutamate reduction produces a sedating effect; then there is a compensatory increase in the number of glutamate receptors, which probably accounts for the seizures that sometimes occur during withdrawal. Alcohol also increases the release of gamma-aminobutyric acid (GABA), the most prevalent inhibitory neurotransmitter (Wan, Berton, Madamba, Francesconi, & Siggins, 1996). The combined effect at these two receptors is sedation, anxiety reduction, muscle relaxation, and inhibition of cognitive and motor skills. Alcohol also affects opiate receptors (in turn increasing dopamine release), serotonin receptors, and cannabinoid receptors, which are also excited by marijuana (Julien, 2008); these actions likely account for the pleasurable aspects of drinking. FIGURE 5.4 The GABAA Receptor Complex. The complex has binding sites for GABA, barbiturates, benzodiazepines, and alcohol.

Alcohol specifically affects the A subtype of GABA receptor; because the GABAA receptor is important in the action of other drugs, we will give it special attention. It is actually a receptor complex, composed of five different kinds of receptor sites (Figure 5.4). One receptor, of course, responds to GABA. Its activation opens the receptor’s chloride channel, and the influx of chloride ions hyperpolarizes the neuron. Other receptors in the complex respond to alcohol, to barbiturates, and to benzodiazepines; these drugs enhance the binding of GABA to its receptor and thus its ability to open the chloride channel. Now you can understand why it is so dangerous to mix alcohol with barbiturates or benzodiazepines.

What prenatal effects does alcohol have? Alcohol passes easily through the placenta, raising the BAC of a fetus to about the

same level as the mother’s. You saw in Chapter 3 that prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS; see Figure 5.5), which is the leading cause of intellectual impairment in the Western world (Abel & Sokol, 1986). Besides being intellectually impaired, FAS children are irritable and have trouble maintaining attention. Regular alcohol abuse apparently is not required to produce damage. In one study, mothers who had FAS children did not drink much more on average than the mothers of normal children, but they did report occasional binges of five or more drinks at a time (Streissguth, Barr, Bookstein, Sampson, & Olson, 1999). Just having three or more drinks at any one time during pregnancy more than doubles the offspring’s risk of a drinking disorder during adulthood (Alati et al., 2006). No safe level of alcohol intake during pregnancy has been established, so most authorities recommend total abstention. (Refer to Figure 3.25 to see the developmental effects of FAS on a mouse brain.) FIGURE 5.5 Child With Fetal Alcohol Syndrome.

Besides intellectual impairment and behavioral problems, FAS individuals often have facial irregularities, including a short, upturned nose that is flattened between the eyes, thin upper lip, and lack of a groove between the nose and upper lip.

SOURCE: © George Steinmetz. Barbiturates and Benzodiazepines Like alcohol, barbiturates in small amounts act selectively on higher cortical

centers, especially those involved in inhibiting behavior; in low doses, they produce talkativeness and increased social interaction, and in higher doses, they are sedatives and hypnotics. Barbiturates have been used to treat insomnia and prevent epileptic seizures, and from 1912 to 1960, they were the drug of choice for treating anxiety and insomnia (Julien, 2008). They are not addictive in prescribed doses, but tolerance leads the person to increase the dosage, resulting in addictive symptoms similar to those of alcoholism. Like alcohol, barbiturates act at the GABAA complex, though at the barbiturate receptor, but unlike alcohol, they can open chloride channels on their own in the absence of GABA. As a result, the line between therapeutic and toxic levels is a fine one, and their use has been fraught with accidental and intentional overdose (including famous cases such as Marilyn Monroe, Judy Garland, and 1960s peace activist Abbie Hoffman). As a result, barbiturates were mostly replaced by much safer benzodiazepines. Benzodiazepines act at the benzodiazepine receptor on the GABA A complex to

produce anxiety reduction, sedation, and muscle relaxation. They reduce anxiety by suppressing activity in the limbic system, a network of structures we will consider in more detail in the chapter on emotion (Chapter 8). Their effect in the brain stem produces relaxation, while GABA activation in the cortex and hippocampus results in confusion and amnesia (Julien, 2008). There are several benzodiazepine drugs, the best known of which are Valium

(diazepam), Xanax (alprazolam), and Halcion (triazolam). Because benzodiazepines

are addictive and can produce mental confusion, they have been replaced in many cases by newer drugs. One of the benzodiazepines, Rohypnol (roofies or rophies), has gained notoriety as the date rape drug.

3 Cocaine Anonymous Stimulants Stimulants activate the central nervous system to produce arousal, increased

alertness, and elevated mood. They include a wide range of drugs, from cocaine to caffeine, which vary in the degree of risk they pose. The greatest danger lies in how they are used. Cocaine Cocaine, which is extracted from the South American coca plant, produces

euphoria, decreases appetite, increases alertness, and relieves fatigue. It is processed with hydrochloric acid into cocaine hydrochloride, the familiar white powder that is “snorted” (inhaled) or mixed with water and injected. Pure cocaine, or freebase, can be extracted from cocaine hydrochloride by chemically removing the hydrochloric acid. When freebase is smoked, the cocaine enters the bloodstream and reaches the brain rapidly. A simpler chemical procedure yields crack, which is less pure but produces pure cocaine in the vapor when it is smoked. The low cost of crack has spread its use into poor urban communities that could not afford cocaine before. FIGURE 5.6 Advertisement From Around 1900.

SOURCE: The National Library of Medicine. Cocaine has not always been viewed as a dangerous drug. The coca leaf has been

chewed by South American Indians for centuries as a means of enduring hardship and privation. When cocaine was isolated in the late 1800s, it was initially used as a local anesthetic. It soon found its way into over-the-counter medications (Figure 5.6), and until 1906, even Coca-Cola owed much of its refreshment to 60 milligrams of cocaine in every serving (M. S. Gold, 1997). Sigmund Freud, the father of psychoanalysis,

championed the use of cocaine, giving it to his fiancée, sisters, friends, and colleagues and prescribing it to his patients. He even wrote an essay, which he called a “song of praise” to cocaine’s virtues. He gave up the use of the drug, both personally and professionally, when he realized its dangers (Brecher, 1972). Cocaine blocks the reuptake of dopamine and serotonin at synapses, potentiating

their effect. Dopamine usually has an inhibitory effect, so cocaine reduces activity in much of the brain, as the positron emission tomography (PET) scans in Figure 5.7 show (London et al., 1990). Presumably, cocaine produces euphoria and excitement because dopamine removes the inhibition the cortex usually exerts on lower structures. Reduced cortical activity is typical of drugs that produce euphoria, including benzodiazepines, barbiturates, amphetamines, alcohol, and morphine, although localized activation is often reported in frontal areas (R. Z. Goldstein & Volkow, 2002; London et al., 1990). Brain metabolism rises briefly during the first week of abstinence, but then falls again during prolonged withdrawal; however, during craving, activity increases in several areas, as we will see later (R. Z. Goldstein & Volkow; S. Grant et al., 1996; Volkow et al., 1991, 1999). FIGURE 5.7 A Normal Brain and a Brain on Cocaine. The upper two scans show activity in a cocaine-free individual. The remaining scans show reduced activity in the brain of a cocaine abuser 10 days and 100 days after last cocaine use.

SOURCE: Photo courtesy of Nora Volkow, PhD, from “Long-term Frontal Brain Metabolic Changes in Cocaine Abusers,” N. D. Volkow, R. Hitzemann, G.-J. Wang, J. S. Fowler, A. P. Wolf, and S. L. Dewey, 1992, Synapse, 11, pp. 184–190. Injection and smoking produce an immediate and intense euphoria, which increases

the addictive potential of cocaine. After the end of a cocaine binge, the user crashes into a state of depression, anxiety, and cocaine craving that motivates a cycle of continued use. Withdrawal effects are typically mild, involving anxiety, lack of motivation, boredom, and lack of pleasure. Three decades ago, addiction was defined in terms of a drug’s ability to produce withdrawal, and because cocaine’s withdrawal symptoms are so mild, it was not believed to be addictive (Gawin, 1991). As usage increased in the population, we learned that cocaine is actually one of the most addictive of the abused drugs. The intensity of the drug’s effect makes treatment for addiction very difficult, and no treatment is generally accepted as successful. Complicating rehabilitation is the fact that cocaine addicts typically abuse other drugs, and they have a very high rate of psychological disorders, including depression, anxiety, bipolar disorder, and posttraumatic stress disorder (Julien, 2008). Cocaine provides a good example of selective tolerance: While increasing amounts

of the drug are required to produce the desired psychological effects, the person becomes supersensitive to the effect that produces seizures. It is possible that the risks of cocaine relative to other drugs have been underestimated. In one study, rats were allowed to press a lever that caused heroin or cocaine to be injected into their bloodstream; after 1 month, 90% of rats receiving cocaine had died of self- administered overdose, compared with 36% of rats receiving heroin (Bozarth & Wise, 1985).

What neurotransmitter system is involved in the effects of all stimulant drugs? Cocaine users have impairments in memory and in executive functions, including

impulse control, decision making, and assessment of emotional stimuli. These deficits are accompanied by reduced activity in the prefrontal cortex (Beveridge, Gill, Hanlon, & Porrino, 2008), and by a loss of gray matter in prefrontal and temporal areas during middle age that is almost twice as fast as in nonusers (3.1 ml/year versus 1.7 ml/year; Ersche, Jones, Williams, Robbins, & Bullmore, 2012). Also, like alcohol, cocaine passes through the placenta easily, where it interferes with fetal development. It is difficult to separate the effects of alcohol and cocaine on the children’s development from the effects of poverty and neglect often seen in the homes, but a Toronto group was able to control environmental factors by studying 26 cocaine-exposed children who had been adopted. Compared with control children matched for the mother’s IQ and socioeconomic status, the cocaine-exposed children had lower IQs, poorer language development, and greater distractibility (Nulman et al., 2001). In addition, we have evidence from animal studies that prenatal exposure to alcohol causes brain damage in mice (see Chapter 3), and that exposure to cocaine results in abnormal circuit formation among dopamine neurons (L. B. Jones, 2000). Amphetamines Amphetamines are a group of synthetic drugs that produce euphoria and increase

confidence and concentration. The group includes amphetamine sulfate (marketed as Benzedrine), the three to four times more potent dextroamphetamine sulfate (marketed as Dexedrine), and the still more powerful methamphetamine (known on the street as meth, speed, crank, and crystal). Like cocaine, it can be purified to its freebase form called ice, which is smokable. Because they dull the appetite, reduce fatigue, and increase alertness, amphetamines have shown up in weight-loss drugs and have been used by truck drivers, pilots, and students to postpone sleep. They have been useful in treating ailments like narcolepsy, a disorder of uncontrollable daytime sleepiness. Amphetamines increase the release of norepinephrine and dopamine. Increased

release of dopamine exhausts the store of transmitter in the vesicles, which accounts for the period of depression that follows. The effects of amphetamine injection are so similar to those of cocaine that individuals cannot tell the difference between the two (A. K. Cho, 1990). Heavy use can cause hallucinations and delusions of persecution that are so similar

to the symptoms of paranoid schizophrenia that even trained professionals cannot recognize the difference (resulting in occasional emergency room mistreatment). In laboratory studies, psychotic symptoms develop after 1 to 4 days of chronic amphetamine administration. In one study, a volunteer on amphetamine was convinced that a “giant oscillator” in the ceiling was controlling his thoughts. Another believed his ex-wife had hired an assassin to kill him and was perturbed when the doctor would not guard the window while he stood watch at the door (Griffith et al., 1972; S. H. Snyder, 1972). After an amphetamine psychosis subsides, the person may be left with a permanently increased sensitivity to the drug so that using even a small amount years later can revive symptoms (Sato, 1986). An amphetamine-like drug that is creating new concern is bath salts, a variety of

synthetic derivatives of the catha edulis plant (khat). Chewing khat leaves is popular in Middle Eastern countries for its stimulant effects; in the movie Captain Phillips, it was the mainstay of the Somali pirates as they held the captain of the Maersk Alabama for ransom. Synthetic drugs are a special problem because the ingredients themselves are often legal and their use is disguised, for example, by labeling them as “bath salts” and including the warning “not for human consumption.” While bath salts produce positive effects similar to those of amphetamines, they can also lead to hallucinations, delusions, paranoia, anxiety, or depression, as well as impaired memory, attention, and concentration; seizures and death have also been reported. As the popularity of bath salts has increased, there have been several media reports linking them to violent and sometimes bizarre crimes (Dolak, 2012). Nicotine Nicotine is the primary psychoactive and addictive agent in tobacco. Tobacco is

ingested by smoking, chewing, and inhaling (as snuff, a finely powdered form).

Nicotine has an almost unique effect (Schelling, 1992): When tobacco is smoked in short puffs, it has a stimulating effect; when inhaled deeply, it has a tranquilizing or depressant effect. In large doses, nicotine can cause nausea, vomiting, and headaches; in extremely high doses, it is powerful enough to produce convulsions and even death in laboratory animals.

4 Nicotine Effects and Addiction The withdrawal reactions are well known because smokers “quit” so often; the

most prominent symptoms are nervousness and anxiety, drowsiness, lightheadedness, and headaches. The United Kingdom annually observes a “No Smoking Day,” similar to the “Great American Smokeout,” in which people voluntarily abstain from smoking for a day; apparently as a result of impairment from withdrawal symptoms, workplace accidents go up by 7% (Waters, Jarvis, & Sutton, 1998). People who try to give up smoking are usually able to abstain for a while but then relapse; only about 20% of attempts to stop are successful after 2 years. Before bans on public and workplace smoking, about 80% of male smokers and two thirds of female smokers smoked at least one cigarette per waking hour (Brecher, 1972). “

Because of the 400,000 deaths produced each year by smoking [in the U.S.], including 50,000 in non-smokers due to passive inhalation of secondhand smoke, it can reasonably be argued that nicotine is the most important drug of abuse. Heroin and cocaine combined produce no more than 6,000 deaths per year in contrast.

—Charles O’Brien

” In part because usage is more continuous with tobacco than with other drugs, the

health risks are particularly high. The health risks from smoking are not the result of nicotine but of some of the 4,000 other compounds present in tobacco smoke. For example, a metabolite of benzo-[a]pyrene damages a cancer-suppressing gene, resulting in lung cancer (Denissenko, Pao, Tang, & Pfeifer, 1996). Other cancers resulting from smoking occur in the larynx, mouth, esophagus, liver, and pancreas. Smoking can also cause Buerger’s disease, constriction of the blood vessels that may lead to gangrene in the lower extremities, requiring progressively higher amputations. Although abstinence almost guarantees a halt in the disease’s progress, surgeons report that it is not uncommon to find a patient smoking in the hospital bed after a second or third amputation (Brecher, 1972). Smoking is the largest cause of preventable death, accounting for 443,000 premature deaths annually in the United States and 5 million worldwide; the health and lost-productivity costs in the United States add up to $193 billion (Centers for Disease Control and Prevention, 2008;

World Health Organization, 2004). Cigarette package warnings aimed at expectant mothers are not just propaganda.

Infants born to mothers who smoked during pregnancy have lower birth weight, a higher incidence of asthma, and up to 56% greater mortality (Gilliland, Li, & Peters, 2001; Kleinman, Pierre, Madans, Land, & Schramm, 1987; F. Rice et al., 2009). One study of 6- to 8-year-old children whose mothers smoked throughout pregnancy found reductions in cortical gray matter and overall brain volume, cortical thinning in prefrontal areas, and a tendency for depression (El Marroun et al., 2013). We cannot be sure from these results alone that maternal smoking caused the problems in offspring. We saw in Chapter 4 that a unique study of cross-fostered children confirmed a causal relationship between maternal smoking and low birth weight but determined that the link with conduct disorder is genetic (F. Rice et al.). The association with conduct disorder probably arises because women with a genetic predisposition for impulse control problems are also more likely to smoke. In the study of 6- to 8-year-olds, a causal relationship receives some credibility from the fact that children of women who quit smoking when they learned they were pregnant were no different from the children of nonsmoking mothers (El Marroun et al.); however, there may be important genetic differences between mothers who were able to give up smoking and those who weren’t. All this illustrates why we shouldn’t be too quick to accept the “obvious” interpretation when two variables are correlated. As you saw in Chapter 2, nicotine stimulates nicotinic acetylcholine receptors. In

the periphery, it activates muscles and may cause twitching. Centrally, it produces increased alertness and faster response to stimulation. Neurons that release dopamine contain nicotinic receptors, so they are also activated, resulting in a positive mood effect (Svensson, Grenhoff, & Aston-Jones, 1986). Caffeine Caffeine, the active ingredient in coffee, produces arousal, increased alertness, and

decreased sleepiness. It is hardly the drug that amphetamine and cocaine are, but as you saw in Balzac’s case, it is subject to abuse. It blocks receptors for the neuromodulator adenosine, increasing the release of dopamine and acetylcholine (Silinsky, 1989; S. H. Snyder, 1997). Because adenosine has sedative and depressive effects, blocking its receptors contributes to arousal. Withdrawal symptoms include headaches, fatigue, anxiety, shakiness, and craving, which last about a week. Withdrawal is not a significant problem, because coffee is in plentiful supply, but heavy drinkers may wake up with a headache just from abstaining overnight. Because 80% of Americans drink coffee, researchers at the Mayo Clinic once recommended intravenous administration of caffeine to patients recovering from surgery to eliminate postoperative withdrawal headaches (“Caffeine Prevents Post-op Headaches,” 1996).

5 LSD, Ecstasy, and PCP

Psychedelics Psychedelic drugs are compounds that cause perceptual distortions in the user. The

term comes from the Greek words psyche (“mind”) and delos (“visible”). “Visible mind” refers to the expansion of the senses and the sense of increased insight that users of these drugs report. Although the drugs are often referred to as hallucinogenic, they are most noted for producing perceptual distortions: Light, color, and details are intensified; objects may change shape; sounds may evoke visual experiences; and light may produce auditory sensations. Psychedelics may affect the perception of time, as well as self-perception; the body may seem to float or to change shape, size, or identity. These experiences are often accompanied by a sense of ecstasy. The best-known psychedelic, lysergic acid diethylamide (LSD), was popularized in

the student peace movement of the 1960s. LSD is structurally similar to serotonin and stimulates serotonin receptors (Jacobs, 1987). As you will see in this chapter and in later chapters, serotonin has a wide variety of psychological functions. Other serotonin-like drugs include psilocybin and psilocin, LSD-like drugs from the mushroom Psilocybe mexicana; peyote, the “button” on the top of the peyote cactus; and mescaline, the active ingredient in peyote. Peyote is used in religious ceremonies by the Native American Church, and that use is protected by the U.S. federal government and by 23 states (Julien, 2008). FIGURE 5.8 Brain Damage Produced by the Drug “Ecstasy.” These brain sections have been stained with a chemical that makes neurons containing serotonin turn white. Photos in the top row are from a normal monkey; those below are from a monkey given MDMA a year earlier.

SOURCE: From “Long-Lasting Effects of Recreational Drugs of Abuse on the Central Nervous System,” by U. D. McCann, K. A. Lowe, and G. A. Ricaurte, 1997, The Neuroscientist, 3, pp. 399–411. Ecstasy is the street name of a drug developed as a weight-loss compound called

methylenedioxymethamphetamine (let’s just call it MDMA!); it is a popular drug among young people, especially at dance clubs and “raves.” Similar to amphetamine in structure, at low doses it is a psychomotor stimulant, increasing energy, sociability, and sexual arousal; at higher doses it produces hallucinatory effects like those produced by LSD. MDMA stimulates the release of dopamine; one of dopamine’s roles is as a psychomotor stimulant. MDMA also stimulates the release of serotonin, which probably accounts for the hallucinatory effects (Liechti & Vollenweider, 2000). The disturbing news is that high doses of MDMA destroy serotonergic neurons in monkeys (Figure 5.8; McCann, Lowe, & Ricaurte, 1997). A study of human users found widespread reduction in serotonin functioning; this impairment decreased over a period of abstinence (McCann et al., 2005). A review of 422 studies showed persistent but small effects on cognitive performance, especially memory deficits (Rogers et al., 2009). Although health effects are usually minimal, several deaths are reported annually. Phencyclidine (PCP) was developed as an anesthetic, but its use was abandoned

because it produced disorientation and hallucinations that were almost

indistinguishable from the symptoms of schizophrenia (Murray, 2002). It has found recreational popularity as angel dust or crystal. Monkeys and rats will self-administer PCP, and humans show compulsive use, indicating that PCP is addictive (Carlezon & Wise, 1996). PCP increases activity in dopamine pathways, but blocking dopamine activity does not eliminate self-administration in rats; the drug’s motivating properties apparently are partly due to its inhibition of a subtype of glutamate receptors (Carlezon & Wise, 1996; E. D. French, 1994). Scientists became interested in psychedelic drugs at the beginning of the 20th

century because some of the effects resemble psychotic symptoms. This suggested that a chemical imbalance might be the cause of psychosis, so researchers tried to produce “model psychoses” that could be studied in the laboratory. Early research was unproductive, but more recent experience with PCP has led researchers to revise their theories of schizophrenia (Jentsch & Roth, 1999). Marijuana Marijuana is the dried and crushed leaves and flowers of the Indian hemp plant,

Cannabis sativa (Figure 5.9). The hemp plant was heavily cultivated in the United States during World War II as a source of material for making rope, and it is still found occasionally growing wild along midwestern roadsides. Marijuana is usually smoked but can be mixed in food and eaten. The major psychoactive ingredient is delta-9-tetrahydrocannabinol (THC). THC is particularly concentrated in the dried resin from the plant, called hashish. FIGURE 5.9 A Marijuana Plant.

SOURCE: © Tina Lorien/iStockphoto.com. THC is a cannabinoid, a group of compounds that includes two known endogenous

cannabinoids, anandamide and 2-arachidonyl glycerol, or 2-AG (Devane et al., 1992;

di Tomaso, Beltramo, & Piomelli, 1996; Mechoulam et al., 1995). Cannabinoid receptors are found on axon terminals; cannabinoids are released by postsynaptic neurons and act as retrograde messengers, regulating the presynaptic neuron’s release of neurotransmitter (R. L. Wilson & Nicoll, 2001). The receptors are widely distributed in the brain and spinal cord, which probably accounts for the variety of effects marijuana has on behavior. The pleasurable sensation is likely due to its ability to increase dopamine levels (Tanda, Pontieri, & Di Chiara, 1997). Receptors in the frontal cortex probably account for impaired cognitive functioning and distortions of time sense and sensory perception, receptors in the hippocampus disrupt memory, and those in the basal ganglia and cerebellum impair movement and coordination (Herkenham, 1992; Howlett et al., 1990; Ong & Mackie, 1999). This is a good time to point out that although drugs may reveal a great deal about brain functioning, the pattern of effects they produce is usually unlike normal functioning; drugs affect wide areas of the brain indiscriminately, whereas normal activation tends to be more discrete and localized. Marijuana’s impact on users may be greater than previously thought. Long-term

heavy users have various brain anomalies, including reduced volume in the hippocampus and amygdala and impaired white matter connectivity in the hippocampus and corpus callosum (Yücel et al., 2008; Zalesky et al., 2012). These findings are correlational, leaving open the possibility that the deficits were preexisting and contributed to excessive marijuana use; however, several animal studies have shown that cannabis does have neurotoxic effects on the hippocampus (cited in Yücel et al., 2008). Longitudinal studies also get around the correlational issue; one showed that individuals who smoked five joints a day had an average 4- point decline in IQ from childhood to young adulthood (Fried, Watkinson, James, & Gray, 2002). In another study, individuals who used marijuana from their teens to age 38 lost an average of 6 IQ points (Meier et al., 2012). Abstinence apparently led to recovery of the losses in the first study but not in the second, probably due to longer use. There has been much less research on prenatal effects of marijuana, most likely

because the impairments are not as obvious as those caused by prenatal cocaine and alcohol. Indeed, the studies that have been done found no deficits until about 4 years of age. Then, and through adolescence, data reveal behavioral problems, including impulsiveness and hyperactivity; decreased performance on visual-spatial tasks; and deficits in attention, memory, and language comprehension (Fried, 1995; C.-S. Wu, Jew, & Lu, 2011). These studies also suffer from being correlational, but experiments with animals have produced similar results.

Changing Attitudes Toward Marijuana

When the Gallup polling organization first asked the question in 1969, only 12% of Americans favored the legalization of marijuana. In 2010 that number was at 46%, and by 2013 it had risen to 58%. By then, 19 states and the District of Columbia had approved the use of medical marijuana, Colorado and Washington had decriminalized its recreational use, and California was considering following suit. There are various motivations for legalizing marijuana, including elimination of the criminal element, freeing up crowded jails and courtrooms,

increasing tax revenues, and reducing demand for synthetic marijuana (“spice” or “K2”), which has such dangerous side effects it accounted for 11,000 emergency room visits in one year. Although any use of marijuana remains illegal under federal law, beginning in

2009 the Department of Justice has mostly turned a blind eye to its medical use, and in 2013 it announced that it would not challenge legalized recreational use so long as the states maintain strict procedures for the sale of the drug. It is not clear what the future holds, but the Justice Department seems inclined to let the experiment play out, and growing public acceptance suggests that further changes are in store.

6 Marijuana and Its Controversies

Legalization is the major controversy surrounding marijuana; it is a battle that is being waged on two very different fronts. Because of its mild effects, many contend that its use should be unrestricted. Others, citing reports that it reduces pain, the nausea of chemotherapy, and the severity of the eye disease glaucoma, believe it should be available by a doctor’s prescription. The medical claims have been controversial but are gaining acceptance, and both public and governmental attitudes are changing, as In the News indicates.

What are the two controversies about marijuana? Another controversy concerns whether marijuana is addictive. The importance of

this debate is that it requires us to define just what we mean by the term. Addiction has traditionally been equated with a drug’s ability to produce withdrawal symptoms; because marijuana’s withdrawal symptoms are very mild, its compulsive use was attributed to “psychological dependence,” a concept also invoked to explain the habitual use of other drugs that do not produce dramatic withdrawal symptoms, like nicotine and caffeine. Withdrawal symptoms are mild because cannabinoids dissolve in body fats and leave the body slowly. However, monkeys will press a lever to inject THC into their bloodstream in amounts similar to doses in marijuana smoke inhaled

Concept Check

by humans (Tanda, Munzar, & Goldberg, 2000). Researchers are reluctant to attribute drug self-administration in animals to psychological dependence and usually consider it evidence of addiction. Earlier we defined addiction in terms of the drug’s hold on the individual, without reference to its ability to produce withdrawal symptoms. Next, we will examine the reasons for taking this position.

Take a Minute to Check Your Knowledge and Understanding

How does tolerance develop, and how does it increase a drug’s danger? Why does alcohol increase the danger of barbiturates? How are the effects of amphetamine and cocaine at the synapse alike? How are they different?

Addiction It is an oversimplification to assume that chronic drug use is motivated primarily by the pleasurable effects of the drug; in fact, individuals who engage in compulsive drug taking often report that they no longer enjoy their drug experience. Their casual drug use has progressed into the compulsive disorder of addiction. The common belief that addiction is fueled by the drug user’s desire to avoid withdrawal symptoms also has several flaws. One is that it does not explain what motivates the person to use the drug until addiction develops. Second, we know that many addicts go through withdrawal fairly regularly to reset their tolerance level so they can get by with lower and less costly amounts of the drug. Third, it does not explain why many addicts return to a drug after a long period of abstinence and long after withdrawal symptoms have subsided. Finally, the addictiveness of a drug is unrelated to the severity of withdrawal symptoms (Leshner, 1997). Cocaine is a good example of severe addictiveness but mild withdrawal, while a number of drugs—including some asthma inhalers, nasal decongestants, and drugs for hypertension and angina pain—produce withdrawal symptoms but are not addictive (S. E. Hyman & Malenka, 2001).

Why does the avoidance of withdrawal symptoms fail to explain addiction? “

It is as if drugs have hijacked the brain’s natural motivational control circuits. —Alan Leshner

”

The Neural Basis of Addiction and Reward

Research indicates that addiction and withdrawal take place in different parts of the brain and that they are independent of each other. When Bozarth and Wise (1984) allowed rats to press a lever to inject morphine directly into the ventral tegmental area (Figure 5.10), the rats did so reliably, suggesting that the area is involved in addiction. Then the researchers tried to induce withdrawal by blocking the opiate receptors there with injections of naloxone, but no signs of withdrawal occurred. Rats would not press a lever for morphine injections into a nearby area called the periventricular gray, which meant that it is not involved in addiction. But when the researchers gave the rats regular morphine injections in the periventricular gray and then injected naloxone, the rats showed classic signs of withdrawal, including teeth chattering, “wet dog” shakes, and attempts to escape from the test apparatus. This independence of addiction and withdrawal does not mean that addicts never take drugs to avoid withdrawal symptoms; rather it means that withdrawal is not necessary for addiction and avoidance of withdrawal is not an explanation of addiction. Addiction depends on something else; one hypothesis is that that something is reward. FIGURE 5.10 The Mesolimbocortical Dopamine System. The system is made up of two components. The mesolimbic system projects from dopamine (DA) neurons in the ventral tegmental area (VTA) to the nucleus accumbens, via the medial forebrain bundle; the mesocortical system projects from DA neurons in the VTA to frontal cortex.

Reward refers to the positive effect an object or a condition—such as a drug, food, sexual contact, or warmth—has on the user. This effect is primarily on behavior, but it is typically accompanied by feelings of pleasure. Drug researchers have traditionally

identified the mesolimbocortical dopamine system as the location of the major drug reward system (Wise & Rompre, 1989); it takes its name from the fact that it begins in the midbrain (mesencephalon) and projects to the limbic system and prefrontal cortex. As you can see in Figure 5.10, the most important structures in the system are the nucleus accumbens, the medial forebrain bundle, and the ventral tegmental area. (Other structures also participate in reward, including the amygdala and the hippocampus, but they have been accorded less importance.) Rats will learn to press a lever to inject abused drugs into these areas (Bozarth & Wise, 1984; Hoebel et al., 1983), and lesioning the nucleus accumbens reduces reward effects for many drugs (Kelsey, Carlezon, & Falls, 1989). Dopamine and Reward Virtually all the abused drugs increase dopamine levels in the nucleus accumbens,

including opiates, barbiturates, alcohol, THC, PCP, MDMA, nicotine, and even caffeine (Di Chiara, 1995; Grigson, 2002). There is considerable evidence that this increase in dopamine level plays an important role in addiction. For example, rats given drugs that block dopamine activity do not learn to press a lever for amphetamine or cocaine injections; if they have learned previously, they do not continue lever pressing after receiving the dopamine-blocking drug (Wise, 2004). In PET scan studies, human volunteers who had the greatest increase in dopamine in the general area of the nucleus accumbens also experienced the most intense “highs” (Volkow, Fowler, & Wang, 2003). In one study, participants began reporting that they felt “high” when cocaine had blocked 47% of the dopamine reuptake sites in the nucleus accumbens (Volkow et al., 1997).

What is the reward hypothesis of addiction? But the mesolimbocortical dopamine system’s reward function is not limited to

drugs; microdialysis studies show that food, water, and sexual stimulation also increase dopamine levels in the nucleus accumbens of rats (Carelli, 2002; Damsma, Pfaus, Wenkstern, & Phillips, 1992). The same can be said for electrical stimulation (Fibiger, LePiane, Jakubovic, & Phillips, 1987). In electrical stimulation of the brain (ESB), animals and, sometimes, humans learn to press a lever to deliver mild electrical stimulation to brain areas where the stimulation is rewarding. Drugs that block dopamine receptors interfere with learning to press a lever to obtain this stimulation (Wise, 2004). ESB is thought to reflect “natural” reward processes, because effective sites are often in areas where experimenter-delivered stimulation evokes eating or sexual activity and because self-stimulation rate in the posterior hypothalamus varies with experimenter-induced sexual motivation (Caggiula, 1970). The most sensitive areas are where the density of dopaminergic neurons is greatest, especially in the medial forebrain bundle (Corbett & Wise, 1980). “

Drugs of abuse create a signal in the brain that indicates, falsely, the arrival of a huge fitness benefit.

—Randolph Nesse and Kent Berridge

” Both electrical stimulation and drugs are especially powerful motivators of

behavior. Animals will ignore food and water and tolerate painful shock to stimulate their brains with electricity, sometimes pressing a lever thousands of times in an hour. Humans will sacrifice their careers, relationships, and lives in the interest of acquiring and using drugs. While food and sex increase dopamine in the nucleus accumbens by 50% to 100%, drugs and electrical stimulation can have a three- to sixfold greater effect, depending on dosage (A. G. Phillips et al., 1992; Wise, 2002). Many researchers are interested in drugs and electrical stimulation because they seem to provide a more direct access to the brain’s motivational systems. But there is an intriguing paradox in the dopamine research: PET imaging reveals

that chronic drug users have diminished dopamine release and numbers of dopamine receptors (Figure 5.11; Volkow, Fowler, Wang, & Swanson, 2004). This decreased dopamine activity may not be the consequence of chronic abuse. Non-drug-abusing subjects who reported the greatest “liking” for the effects of the cocaine-like stimulant methylphenidate (Ritalin) also had low numbers of the D2 type of dopamine receptors; those with the highest numbers of receptors found the drug unpleasant (Volkow et al., 2002). Thus, lowered dopamine receptors probably precedes drug experience and creates a “reward deficiency syndrome” that accounts for addicts’ decreased sensitivity to rewards in general (Volkow et al., 2003) and predisposes the individual to seek stronger stimulation. This view has received experimental support. Thanos and his colleagues trained rats to self-administer alcohol and then used a virus to insert the D2 gene into the rats’ nucleus accumbens; this increased the number of dopamine receptors, and the rats reduced their alcohol preference and alcohol intake (Thanos et al., 2001). FIGURE 5.11 Reduced Dopamine D2 Receptors in Drug Abusers. The researchers imaged the brains using PET and an agent that binds to dopamine D2 receptors. The predominance of yellow in place of red in the scans of the drug abusers’ brains indicates fewer of the D2 receptors than in the control subjects’ brains.

SOURCE: From “Role of Dopamine, the Frontal Cortex, and Memory Circuits in Drug Addiction: Insight From Imaging Studies,” by N. D. Volkow et al., Neurobiology of Learning and Memory, 78, pp. 610–624. © 2002 Nora Volkow. Used with permission from Elsevier. And now an important caveat: While most of the abused drugs trigger the release of

dopamine, dopamine cannot account for all reward. The rewarding effect of alcohol, for example, depends partly on opiate receptors; in fact, opiate blockers such as naloxone and naltrexone are effective in preventing relapse in alcoholics (Garbutt, West, Carey, Lohr, & Crews, 1999). PCP produces rewarding effects by blocking glutamate receptors, likely on the same neurons that mediate dopamine-based reward (Figure 5.12; Carlezon & Wise, 1996). According to Wise (2004), dopamine is crucial for the rewarding effects of cocaine and amphetamine; important but perhaps not crucial for the effects of the opiates, nicotine, cannabis, and ethanol; and questionable in the case of benzodiazepines, barbiturates, and caffeine. Dopamine, Learning, and Brain Plasticity While most researchers agree that reward is an essential factor in early drug taking,

it is doubtful that reward maintains long-term drug abuse (Volkow & Fowler, 2000; Wise, 2004). Rather, researchers now believe that the intense craving and withdrawal symptoms seen in later stages of addiction are due to potentially lifelong changes in brain functioning that are brought about by dopamine’s effects during the earlier stages. Our first clues came from animal learning research; as learning proceeds, a rewarding stimulus initially produces dopamine release and then ceases to do so. Instead, that capability shifts to stimuli that precede the reward, such as an auditory tone that signals the period when lever pressing will produce the reward. In addition, dopamine release occurs when an expected reward is omitted. In humans, fMRI scans showed greater activity in the nucleus accumbens when a drop of juice was delivered unpredictably than when it was delivered on a predictable schedule (Figure 5.13;

Berns, McClure, Pagnoni, & Montague, 2001). Observations such as these indicate that dopamine signals not only rewards but errors in prediction (Schultz, 2002). FIGURE 5.12 Dopamine and Glutamate Neurons Converge on the Same Neurons in the Nucleus Accumbens.

According to contemporary theory, learning occurs only when the reward is unexpected or better than expected, or when the reward is omitted or is worse than expected; therefore, the ability to detect errors in prediction is critical for learning. Learning changes behavior by modifying connections in the brain, and the focus of addiction research has shifted toward understanding those changes. A part of that research has found that some dopamine neurons encode motivational value, which supports either seeking or avoiding a stimulus; others encode the salience of a stimulus, based on its attention-getting properties (such as a loud sound) or its motivational significance (Bromberg-Martin, Matsumoto, & Hikosaka, 2010). Researchers at Stanford University found evidence for three distinct dopamine circuits in the mesolimbocortical system. One of these projects to the prefrontal cortex and responds to aversive (painful) stimuli, one projects to the nucleus accumbens and responds to a rewarding stimulus (cocaine), and the third projects to another part of the nucleus accumbens and responds to both rewarding and aversive stimuli, presumably indicating saliency (Lammel, Ion, Roper, & Malenka, 2011).

What alternative role besides reward has been suggested for dopamine? FIGURE 5.13 Brain Responses to Predictable and Unpredictable Rewards. In these fMRI scans, unexpected liquid delivery increased activity in the nucleus accumbens (NAC) (a). When delivery occurred predictably every 10 seconds, there was a smaller response in the temporal lobe (b).

SOURCE: From “Predictability Modulates Human Brain Response to Reward,” by Berns et al., Journal of Neuroscience, 21, pp. 2793–2798, fig. 3. © 2001 Society for Neuroscience. Used with permission. Learning involves more or less persistent neural changes, and the brief rewarding

and aversive stimuli used in the study increased synaptic strength up to 3 weeks. Chronic administration of amphetamine or cocaine produces more enduring effects, in the form of increased dendrite length and greater synaptic complexity in the nucleus accumbens and prefrontal cortex (T. E. Robinson, Gorny, Mitton, & Kolb, 2001; T. E. Robinson & Kolb, 1997). The power of drug-induced learning is most obvious in craving, especially in its ability to persist years after drug use has ceased. Even viewing drug paraphernalia is enough to evoke craving in addicts (Garavan et al., 2000; S. Grant et al., 1996; Maas et al., 1998); PET scans show that the sight of drug- related stimuli shifts the addict’s typically low brain metabolism to hyperactive in areas that are involved in learning and emotion (R. Z. Goldstein & Volkow, 2002; S. Grant et al., 1996; Volkow, Fowler, & Wayne, 2004; Figure 5.14). The hippocampus is particularly important in learning associations with environmental stimuli like those involved in drug taking; after rats have given up pressing a lever because the drug delivery mechanism has been disconnected, electrical stimulation of the hippocampus results in a 30-minute-long release of dopamine in the nucleus accumbens and a return to lever pressing (Vorel, Liu, Hayes, Spector, & Gardner, 2001). “

The proneness to relapse is based on changes in brain function that continue for

months or years after the last use of the drug. —Charles O’Brien

”

Learning cannot explain all the changes in the addict’s brain or the accompanying alterations in behavior; some drug-induced changes are better characterized as neural pathology. When T. E. Robinson et al. (2001) studied the changes in prefrontal cortex in their cocaine-abusing rats, they found malformed dendrites. This suggested a possible basis for the frontal dysfunction observed in cocaine addicts, which includes impaired judgment and decision making. Disrupted prefrontal functioning could account for the addicts’ loss of control over their behavior, even while expressing a desire to abstain from drugs (Volkow et al., 2003). PET imaging has also verified dysfunction in the orbitofrontal cortex, an area that monitors the relative value of reinforcers and where pathology has also been reported in patients with obsessive- compulsive disorders (Volkow et al., 2003; Volkow & Fowler, 2000). According to Nora Volkow and her colleagues, the transition from controlled drug use to compulsive drug intake involves pathological changes in communication between the prefrontal cortex and the nucleus accumbens (Kalivas, Volkow, & Seamans, 2005). The addict returns to drug taking when stress or drug-related stimuli trigger increases in dopamine release in the prefrontal cortex and glutamate release in the nucleus accumbens. The first of these increases produces a compulsive focus on drugs at the expense of other reinforcers, while the latter cranks up the drive to engage in drug seeking. FIGURE 5.14 The Brain of a Cocaine Abuser During Craving. PET scans are shown at two depths in the brain. Notice the increased activity during presentation of cocaine-related stimuli. Frontal areas (DL, MO) and temporal areas (TL, PH) are involved in learning and emotion.

SOURCE: From “Activation of Memory Circuits During Cue-Elicited Cocaine

Craving,” by S. Grant et al., 1996, Proceedings of the National Academy of Sciences, USA, 93, pp. 12040–12045. © 1996. National Academy of Sciences, U.S.A. Treating Drug Addiction Synanon, the residential community for the treatment of addictions, supplied its

residents with all their food, clothing, and other necessities including, until 1970, cigarettes—which alone cost $200,000 annually (Brecher, 1972). But then Synanon’s founder and head Charles Dederich had a chest X-ray that showed a cloudy area in his lungs. He quit smoking and, realizing that residents as young as 15 were learning to smoke under his watch, stopped supplying cigarettes and banned their use on the premises. Giving up smoking was more difficult for the residents than expected. About 100 people left during the first 6 months rather than do without cigarettes. Some of the residents who quit smoking noticed that they got over withdrawal symptoms from other drugs in less than a week but the symptoms from smoking hung around for at least 6 months. As one resident said, it was easier to quit heroin than cigarettes. Freud had a similarly difficult experience (see Figure 5.15). He smoked as many as

20 cigars a day and commented that his passion for smoking interfered with his work. Although he quit cocaine with apparent ease, each time he gave up smoking, he relapsed. He developed cancer of the mouth and jaw, which required 33 surgeries, but he continued smoking. After replacement of his jaw with an artificial one, he was in constant pain and sometimes unable to speak, chew, or swallow, but still he smoked. He quit smoking when he died of cancer in 1939 (Brecher, 1972). The first step in quitting drug use is detoxification. This means giving up the drug

and allowing the body to cleanse itself of the drug residues. This is admittedly difficult with nicotine or opiates, but withdrawal from alcohol is potentially life threatening; medical intervention with benzodiazepines to suppress the withdrawal syndrome may be necessary (O’Brien, 1997). Still, withdrawal is often easier than the subsequent battle against relapse. The addict’s impulsiveness, accompanied by atrophy and reduced activity in the orbitofrontal cortex, are even more pronounced in those who relapse (Beck et al., 2012; Dom, Sabbe, Hulstijn, & van den Brink, 2005), making therapy all the more difficult. However, in spite of the challenges for addicts and those who treat them, the relapse rate is no higher than that of other chronic diseases such as hypertension, asthma, and type 2 diabetes (McLellan, Lewis, O’Brien, & Kleber, 2000). Fortunately, the number of treatment options is increasing; as you will see, they reflect our improving knowledge of how addiction works. FIGURE 5.15 Sigmund Freud and Relapse of Smoking Addiction. Notice in the graph that the two legal drugs have relapse rates equal to that of heroin.

SOURCE: (a) Bettmann/CORBIS; (b) Adapted with permission from “Nicotine Becomes Addictive,” by R. Kanigel, 1988, Science Illustrated, Oct/Nov, pp. 12–14, 19–21. © 1988 Science Illustrated. Treatment Strategies Agonist treatments replace an addicting drug with another drug that has a similar

effect; this approach is the most common defense against drug craving and relapse. Nicotine gum and nicotine patches provide controlled amounts of the drug without the dangers of smoking, and their use can be systematically reduced over time. Opiate addiction is often treated with a synthetic opioid called methadone. This treatment is controversial because it substitutes one addiction for another, but methadone is a milder and safer drug and the person does not have to resort to crime to satisfy the habit. As a side note, methadone was developed in World War II Germany as a pain- relieving replacement for morphine, which was not available; it was called adolphine, after Adolph Hitler (Bellis, 1981).

7 Web of Addictions Antagonist treatments, as the name implies, involve drugs that block the effects of

the addicting drug. Drugs that block opiate receptors, such as naltrexone, are used to treat opiate addictions and alcoholism because they reduce the pleasurable effects of the drug. The potential for this type of treatment is illustrated dramatically in Figure 5.16 (Suzdak et al., 1986). However, antagonist treatment has a distinct disadvantage compared with agonist treatment. Because the treatment offers no replacement for the abused drug’s benefit, success depends entirely on the addict’s motivation to quit.

APPLICATION

Preventing Addiction by Targeting the Immune System

Researchers have long assumed that opioid drugs exert their reinforcing influence through opioid receptors; now researchers from the University of Colorado and the University of Adelaide in Australia have learned that a key factor in opioid addiction is an immune system receptor in the brain, the toll- like receptor 4 (TLR4). Linda Watkins and her colleagues used (+)-naloxone (plus-naloxone), a synthesized molecular mirror image of naloxone, to block TLR4 in rats (Hutchinson et al., 2012). When rats were given a dose of (+)- naloxone beforehand, morphine no longer produced a dopamine increase in the nucleus accumbens; the rats also did not develop a preference for the compartment where morphine was administered and they showed little interest in pressing a lever that administered another opioid drug. The most important benefit of (+)-naloxone is that it should allow patients

to take opioid pain relievers, and at higher doses, without fear of becoming addicted. On top of that, (+)-naloxone actually increases the degree of pain relief from the drugs. The researchers believe (+)-naloxone could enter clinical trials within 18 months.

Other receptor-targeting strategies are in the experimental stage. For example, the muscle relaxant baclofen activates GABAB receptors on dopaminergic neurons and dampens the reward system (Addolorato et al., 2011; Bock, 2010); drugs that enhance activity at glutamate receptors help addicts “unlearn” the association between drug- related stimuli and craving (Cleva, Gass, Widholm, & Olive, 2010; “Cognitive Enhancement and Relapse Prevention...,” 2012). Genetic intervention is another possibility for turning down receptor functioning. Rats trained to binge drink stopped drinking almost immediately after researchers blocked a gene for the GABAA receptor in their amygdalas (Liu et al., 2012). As the accompanying Application shows, even more novel receptor-blocking approaches may be on the horizon. Rather than blocking the effects of a drug, aversive treatments cause a negative

reaction when the person takes the drug. Antabuse interferes with alcohol metabolism, so drinking alcohol makes the person ill. Similarly, adding silver nitrate to chewing gum or lozenges makes tobacco taste bad. As with antagonist treatments, success depends on the addict’s motivation and treatment compliance. FIGURE 5.16 Effects of a GABAA Receptor Blocker. The two rats received the same amount of alcohol, but the one on the right received a drug that blocks the effect of alcohol at the GABAA receptor.

SOURCE: From “New Drug Counters Alcohol Intoxication,” by G. Kolata, 1986, Science, 234(4781), p. 1198. Reprinted with permission from AAAS. All of these approaches have problems: Alcoholics often fail to take Antabuse;

methadone is itself addictive; naltrexone works only with a subset of addicts; and the anti-nicotine drugs Chantix and Zyban have been associated with hostility, depression, and suicidal thoughts. An attractive alternative is antidrug vaccines. Antidrug vaccines consist of molecules that attach to the drug and stimulate the immune system to make antibodies that will degrade the drug. Vaccines of this sort reduce the amount of cocaine that reaches the brain by 80% (Carrera et al., 1995) and the amount of nicotine by 65% (Pentel et al., 2000). A few anti-nicotine vaccines have shown early promise, and the cocaine vaccine TA-CD performed well in phase 2 clinical trials (Esterlis et al., 2013; Shorter & Kosten, 2011). These treatments avoid the side effects that occur when receptors in the brain are manipulated. Another benefit is that the antibodies are expected to last from weeks to years, which means that therapeutic success will not depend on the addict’s decision every morning to take an anti- addiction drug. Because addiction is so resistant to treatment, researchers are constantly looking for new approaches, and one effort is particularly interesting. There is evidence that abused drugs cause inflammation in glial cells, which alters their ability to regulate neural transmission and contributes to addiction. The drug ibudilast (MN-166) tones down glial activity; in a UCLA study it reduced craving and improved cognitive functioning in methamphetamine addicts, and in a study at Columbia University it eased the symptoms of heroin withdrawal (K. Miles, 2013). These results are preliminary, but both efforts have received the go-ahead for phase 2 trials and they promise to give us an additional way of thinking about addiction. “

Addiction will eventually be seen as analogous to other medical illnesses—as complex constructs of genetic, environmental, and psychosocial factors that require multiple levels of intervention for their treatment and prevention.

—Eric Nestor and George Aghajanian

” Before we leave this topic we need to raise two additional points. One is that

diminished serotonin activity has been found across several addictions, as well as a variety of other disorders. As a consequence, drugs that increase serotonin levels have shown some usefulness in treating smoking (S. M. Hall et al., 1998) and one form of alcoholism, identified in the next section as Type 1 (Dundon, Lynch, Pettinati, & Lipkin, 2004). Part of the effectiveness of the serotonin-potentiating drugs can be attributed to the fact that serotonin helps regulate activity in the mesolimbocortical dopamine system (Melichar, Daglish, & Nutt, 2001) and is also important in impulse control. This brings us to the second point, that the various neurotransmitter systems are highly interconnected. This interconnection provides additional windows of access to the neural mechanism we want to manipulate and may allow us to choose a more powerful drug or one with fewer side effects. Table 5.1 lists the drugs that are currently approved for treating the major addictions. TABLE 5.1 Medications Approved by the U.S. Food and Drug Administration for Treating Drug Addictions.

SOURCES: Julien (2008); Volkow and Li (2004). Effectiveness and Acceptance of Pharmacological Treatment Pharmacological intervention increases treatment effectiveness dramatically.

Methadone combined with counseling produces abstinence rates of 60% to 80% in heroin addicts, compared with 10% to 30% for programs that rely on behavioral management alone (Landry, 1997). This is not an argument for pharmacological treatment alone; drug addiction is almost always accompanied by environmental problems and emotional baggage that must be dealt with, and treating addiction as a purely biological or a purely environmental problem has not been very successful (Volkow et al., 2003). “

Concept Check

Science has yet to defeat the mind/body problem—or those who view psychological problems as failures of will and values.

—Maia Szalavitz

” A major difficulty for treating addiction is comorbidity with personality disorders,

either mental or emotional. This means that drug abusers are likely to have other problems that complicate their rehabilitation. In a study of 43,000 people, 18% of drug abusers had an anxiety disorder, 20% had a mood disorder (most often depression), and 48% had a personality disorder (most often antisocial personality disorder) (B. F. Grant et al., 2004a, 2004b). These symptoms could be partly a by- product of the ravages of addiction, but drug abuse can also be the result of another disorder, for instance, when the person uses drugs as an escape or as a way of self- medicating the symptoms. However, it is more likely that the addiction and the personality disorder have a common genetic, neurological, or environmental cause. In spite of the promise of pharmacological treatment of addiction, giving a drug to

combat a drug is controversial in some segments of society. Some people believe that recovery from addiction should involve the exercise of will and that recovery should not be easy; Antabuse is okay because it causes the backslider to suffer, but methadone is not okay because it continues the pleasures of drug taking (Szalavitz, 2000). The counterargument is that the bottom line in drug treatment is effectiveness. Addiction costs an estimated $600 billion each year in the United States alone (National Institute on Drug Abuse, 2012), but every dollar invested in treatment saves $4 to $12, depending on the drug and the type of treatment (O’Brien, 1997).

Take a Minute to Check Your Knowledge and Understanding

What is wrong with the withdrawal explanation of addiction? Where does the reward hypothesis of addiction run into trouble? What are the strengths and weaknesses of the different types of pharmacological treatment of addiction?

The Role of Genes in Addiction Much of the research on what predisposes a person to addiction has focused on alcoholism to the neglect of other drugs. This is understandable, because alcoholism is such a pervasive problem in our society; also, alcoholics are readily accessible to researchers because their drug use is legal. We are beginning to accumulate the same kind of information for other drugs, but as you will see, the study of alcoholism has

served as a good model for other addiction research. Separating Genetic and Environmental Influences The heritability of addiction was first established with alcoholism. However, for a

long time heredity’s role in alcoholism was controversial, because studies yielded inconsistent results. One reason is that researchers typically treated alcoholism as a unitary disorder; they would study whatever group they had access to, such as hospitalized alcoholics, and generalize to all alcoholics. An important breakthrough came when Robert Cloninger and his colleagues included all 862 men and 913 women who had been adopted by nonrelatives at an early age (average, 4 months) in Stockholm, Sweden, between 1930 and 1949 (Bohman, 1978).

How do hereditary and environmental contributions differ in the two types of alcoholism? They divided the alcoholics among those adoptees into two groups, based on

drinking behaviors and personality (see Table 5.2). Type 1 alcoholics typically begin their problem drinking after the age of 25, after a long period of exposure to socially encouraged drinking, such as at lunch with coworkers; I will refer to them as late- onset alcoholics. They are able to abstain from drinking for long periods of time, but when they do drink, they have difficulty stopping (binge drinking), and they experience guilt about their behavior. Their associated personality traits make them cautious and emotionally dependent. Type 2 alcoholics begin drinking at a young age, so I will call them early-onset alcoholics. They drink frequently and feel little guilt about their drinking. They have a tendency toward antisocial behavior and often get into fights in bars and are arrested for reckless driving. They are typically impulsive and uninhibited, confident, and socially and emotionally detached. In other words, their behavior resembles the description of antisocial personality disorder. Apparently, the personality characteristics appear early; novelty seeking and low harm avoidance in 6- and 10-year-olds predicted drug and alcohol use in adolescence (Mâsse & Tremblay, 1997). Early-onset alcoholics are almost entirely male, and most of the men who are hospitalized for alcoholism fall in this category. TABLE 5.2 Distinguishing Characteristics of Two Types of Alcoholism.

SOURCE: From “Neurogenetic Adaptive Mechanisms in Alcoholism,” by C. Robert Cloninger, 24 April 1987, Science, 236(4800), pp. 410–416. Reprinted with permission from AAAS. As Cloninger examined the offspring from these two groups, differences emerged

that helped explain the disagreement among earlier studies. For the offspring of early- onset alcoholics, the rearing environment made no difference in whether they also became alcoholic, which indicated a strong genetic influence. Offspring of late-onset alcoholics, on the other hand, were likely to become alcoholic only if they were reared in a home where there was alcohol abuse. Interactions between genetic and environmental influences can be complex and seemingly contradictory. A good example is the Met158 allele of the COMT gene; the gene is responsible for an enzyme that metabolizes dopamine, and Met158 is associated with an anxious, sensitive, and cautious personality. This greater anxiety and cautiousness apparently confers some protection from alcoholism in American Plains Indians; but among European Caucasian men, who tend to drink socially on a daily basis as a means of relaxing, Met158 predisposes them to late-onset alcoholism (Enoch, 2006). FIGURE 5.17 Evoked Potentials in Children at High Risk and low Risk for Alcoholism. Evoked potentials were elicited by high-pitched tones occurring among low-pitched tones. The usual dip of the P300 wave is diminished in the high-risk children.

SOURCE: Reprinted by permission of Elsevier Science from S. Y. Hill, D. Muka, S. Steinhauer, and J. Locke. “P300 Amplitude Decrements in Children From Families of Alcoholic Female Probands,” Biological Psychiatry, 38, pp. 622–632. © 1995 Society of Biological Psychiatry. Used with permission from Elsevier. What Is Inherited? Twin and adoption studies indicate that the heritability for alcoholism is around

50% to 60% (Heath et al., 1997; Köhnke, 2008). Other heritabilities range from 50% for hallucinogens to 72% for cocaine (Goldman, Oroszi, & Ducci, 2005). If genetics plays such an important role in addiction, just what is it that is inherited? The majority of addiction genetics research has focused on neurotransmitters and their receptors, and it has implicated most of the major neurotransmitter systems (Dick & Agrawal, 2008). For example, knockout mice lacking either of two Homer genes, which regulate glutamate transmitter activity, are more susceptible to the rewarding effects of drugs (Szumlinski, Ary, & Lominac, 2008; Szumlinski et al., 2004). Mice lacking the Clock gene, which regulates sleep-wakefulness cycles, release more dopamine in the ventral tegmental area and are more vulnerable to the effects of cocaine (McClung et al., 2005). Individuals with certain alleles of the GABRA2 gene, which influences GABAA receptor functioning, have more symptoms of alcohol dependence and are higher in the impulsiveness trait that characterizes most alcoholics (Villafuerte et al., 2012). Studies of drug abusers’ brains have revealed a variety of functional and structural

anomalies. In people addicted to stimulant drugs, these include abnormal white fiber connectivity in prefrontal areas associated with impulse control, gray matter increases in temporal lobe areas involved in both addiction and learning, and gray matter reduction in other areas (Ersche, Jones, Williams, Turton, et al., 2012). The same characteristics are found in the addicts’ nonaddicted siblings and are probably hereditary rather than the result of drug abuse. When anticipating a reward or a loss, Villafuerte’s addicts showed more activity than nonaddicts in the insular cortex, an area involved in food and drug craving. Alcoholics have a diminished P300 (P3)

response, which is a dip in the EEG event-related potential that occurs about 300 milliseconds after an unexpected stimulus (Figure 5.17; Hesselbrock, Begleiter, Porjesz, O’Connor, & Bauer, 2001; S. Hill, 1995; W. G. Iacono, Carlson, Malone, & McGue, 2002). They share this characteristic with their nonalcoholic relatives, and heritability is estimated at 64% (Hicks, et al., 2007). Lowered P3 amplitude in boys at age 17 predicts the development of drug abuse disorders by the age of 20 (W. G. Iacono et al., 2002). Reduced P3 amplitude is seen in a variety of disorders characterized by behavioral

disinhibition, whose most distinctive characteristic is impulsivity. These include additional forms of drug abuse, as well as childhood conduct disorder and adult antisocial behavior. The heritability of behavioral disinhibition is around 80% (Hicks et al., 2007). In addition, the various personality characteristics associated with drug experimentation and addiction—impulsivity, risk taking, novelty seeking, and stress responsiveness—have been linked to genes that are also implicated in drug dependence (Dalley et al., 2007; Kreek, Nielsen, Butelman, & LaForge, 2005; Sinha et al., 2003).

8 Additional Drug Information Obviously, not everyone who tries a drug becomes addicted; percentages run about

4% for inhalants, 9% for marijuana, 15% for alcohol, 17% for cocaine, 23% for heroin, and 32% for tobacco (Anthony, Warner, & Kessler, 1994). Whether drug use will lead to addiction depends largely on how the individual reacts to the drug. For example, people who get a pleasurable rush during early experimenting with smoking are more likely to become heavy smokers; the “buzz” is due to an allele of one of the acetylcholine receptor genes (Sherva et al., 2008). Similarly, people who experience greater euphoria from drinking have three times the risk for alcohol abuse (L. A. Ray & Hutchison, 2004); vulnerability due to the positive effects is associated with an allele of the opioid receptor gene OPRMI. Resistance to the negative effects— intoxication, nausea, and motor impairment—quadruples the risk (Schuckit, 1994). Many Asians are protected from alcoholism because they experience intense flushing, nausea, and increased heart rate. Alcohol is removed from the system by being metabolized to acetaldehyde, which is further metabolized and then eliminated. Variants of three genes that are prevalent in Asians result in either excess production of acetaldehyde, which is toxic, or reduced metabolism of the acetaldehyde (Eng, Luczak, & Wall, 2007). Reduction in alcohol dependence ranges from fourfold to ninefold in individuals who possess one or more of these gene variants. Implications of Addiction Research The study of drug abuse and addiction has practical societal importance, but it is

worthwhile for other reasons as well, particularly in shedding light on other kinds of vulnerability and principles of behavioral inheritance. For example, the fact that

Concept Check

genetic and environmental influences operate differently in different types of alcoholism and in different cultural settings illustrates the fact that no behavior is simple or simply explained. Even after we understand the relative roles of heredity and environment, there is further complexity, because we must also understand the mechanisms—the neurotransmitters, receptors, pathways, enzymes, and so on. In other words, the causes of addiction, and of behavior in general, are many and complex. Finally, we must look beyond simple appeals to willpower in explaining the self-defeating behavior of the addict, just as we must do when we try to understand other kinds of behavior. Our brief look at addiction is a good preparation for our inquiries into the physiological systems behind other human behaviors and misbehaviors.

Take a Minute to Check Your Knowledge and Understanding

How did the failure to recognize two types of alcoholism create misunderstandings about hereditary and environmental influences and gender distribution in alcoholism?

How can lowered sensitivity to a drug increase the chances of addiction? What are two kinds of evidence that some people are predisposed to alcoholism from birth?

In Perspective The costs of drug abuse include untold suffering; loss of health, productivity, and life; and billions of dollars in expenses for treatment and incarceration. The only upsides are that the study of drug abuse reveals the workings of the synapses and brain networks and helps us recognize that powerful biological forces are molding our behavior. This knowledge in turn helps us understand the behaviors that are the subject of the remaining chapters, including the disorders covered there, and guides research into developing therapeutic drugs. Summary Psychoactive Drugs • Most abused drugs produce addiction, which is usually (but not always) accompanied by withdrawal symptoms when drug use is stopped.

• Tolerance can increase the dangers of drugs because life-threatening effects may not show tolerance.

• The opiates have their own receptors, which are normally stimulated by endorphins. • The opiates are particularly addictive and dangerous. • Depressants reduce activity in the nervous system. Some of them have important

uses, but they are also highly abused. • Stimulants increase activity in the nervous system. They encompass the widest range of effects and include nicotine, most notable for its addictiveness and its association with deadly tobacco.

• Psychedelic drugs are interesting for their perceptual/hallucinatory effects, which result from their transmitter-like structures.

• Marijuana is controversial not just in terms of the legalization issue but because it raises questions about what constitutes addiction.

Addiction • The mesolimbocortical dopamine system is implicated by several lines of research as a reward center that plays a role in drug addiction, feeding, sex, and other behaviors.

• Dopamine may also contribute to addiction through its role in learning by modifying neural functioning.

• Treatment of addiction is very difficult; effective programs combine psychological support with pharmacological strategies, including agonist, antagonist, and aversive treatments and, potentially, drug vaccines, and genetic intervention.

The Role of Genes in Addiction • Research suggests that addiction is partially hereditary and that the inherited vulnerability is not necessarily drug specific.

• Heredity research indicates that there are at least two kinds of alcoholism, with different genetic and environmental backgrounds.

• Alcoholics often have dopamine and serotonin irregularities that may account for the susceptibility, and some have a deficiency in evoked potentials that appears to be inherited.

• Addicts have transmitter and receptor irregularities and structural and functional brain anomalies that appear to be genetic in origin.■

Study Resources

For Further Thought • Is the legality or illegality of a drug a good indication of its potential for abuse?

• Is it morally right to treat addictions with drug antagonists, aversive drugs, and antidrug vaccines? Is your opinion the same for drug agonists?

• You work for an agency that has the goal of substantially reducing the rate of drug abuse in your state through education, family support, and individualized treatment. Based on your knowledge of addiction, what should the program consist of?

Quiz: Testing Your Understanding 1. Describe the two proposed roles for dopamine in addiction and give two

pieces of evidence for each. 2. What are the practical and ethical considerations in using drugs to treat

addiction? 3. Sally and Sam are alcoholics. Sally seldom drinks but binges when she does

and feels guilty later. Sam drinks regularly and feels no remorse. What other characteristics would you expect to see in them, and what speculations can you make about their environments?

Select the best answer: 1. In the study of conditioned tolerance to heroin,

a. human subjects failed to show the usual withdrawal symptoms. b. human subjects increased their drug intake. c. rats were unresponsive to the drug. d. rats tolerated the drug less in a novel environment.

2. Withdrawal from alcohol a. can be life threatening. b. is about like a bad case of flu. c. is slightly milder than with most drugs. d. is usually barely noticeable.

3. The reason alcohol, barbiturates, and benzodiazepines are deadly taken together is that they a. affect the thalamus to produce almost total brain shutdown. b. have a cumulative effect on the periaqueductal gray. c. affect the same receptor complex. d. increase dopamine release to dangerous levels.

4. Psychedelic drugs often produce hallucinations by a. inhibiting serotonin neurons. b. stimulating serotonin receptors. c. stimulating dopamine receptors. d. blocking dopamine reuptake.

5. Marijuana was the subject of disagreement among researchers because some of them a. believed it is more dangerous than alcohol or tobacco. b. believed it is highly addictive. c. thought it failed to meet the standard test for addictiveness. d. overstated its withdrawal effects.

6. Evidence that addiction does not depend on the drug’s ability to produce withdrawal symptoms is that a. they don’t usually occur together with the same drug. b. they are produced in different parts of the brain. c. either can be produced without the other in the lab.

d. a and b e. b and c

7. When rats trained to press a lever for electrical stimulation of the brain are given a drug that blocks dopamine receptors, lever pressing a. increases. b. decreases. c. increases briefly and then decreases. d. remains the same.

8. The best argument that caffeine is an addictive drug like alcohol and nicotine is that a. it is used regularly by most of the population. b. quitting produces withdrawal. c. it affects the same processes in the brain. d. it stimulates dopamine receptors directly.

9. Evidence that dopamine’s contribution to addiction may be its effect on learning includes a study in which a. blocking dopamine receptors interfered with learning to self-inject

cocaine. b. hippocampal stimulation released dopamine and restored learned lever

pressing. c. rats learned to press a lever for injections of dopamine into the nucleus

accumbens. d. rats learned a maze for food reward faster if given a dopamine uptake

blocker. 10. Agonist treatments for drug addiction

a. mimic the drug’s effect. b. block the drug’s effect. c. make the person sick after taking the drug. d. reduce anxiety so that there is less need for the drug.

11. Critics of treating drug addiction with drugs believe that a. getting over addiction should not be easy. b. it is wrong to give an addict another addictive drug. c. the drugs are not very effective and delay effective treatment. d. a and b e. b and c

12. The type of alcoholism in which the individual drinks regularly is associated with a. behavioral rigidity. b. perfectionism. c. feelings of guilt.

d. antisocial personality disorder. 13. Alcoholics often

a. have reduced serotonin and dopamine functioning. b. are more sensitive to the effects of alcohol. c. are unusually lethargic and use alcohol as a stimulant. d. have an inherited preference for the taste of alcohol.

Answers: 1. d, 2. a, 3. c, 4. b, 5. c, 6. e, 7. b, 8. c, 9. b, 10. a, 11. d, 12. d, 13. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The National Institute on Drug Abuse’s (NIDA) Heroin page is a good

source for research and other information on heroin and its effects. Check The Effects of Drugs on the Nervous System at the Neuroscience for Kids site for information on more than a dozen drugs.

2. The Alcoholics Anonymous site has information about AA, testimonials from members, and a quiz for teenagers (or anybody else) to help them decide if they have a drinking problem.

3. Cocaine Anonymous offers news, information, a self-test for addiction, and a directory of local groups.

4. NIDA’s Tobacco/Nicotine page provides facts, publications, and links to other sites.

5. NIDA also has information on LSD, Ecstasy, and PCP. 6. There’s even a Marijuana Anonymous, and its site offers a variety of

publications for the person who wants to stop using marijuana or for the student who wants to learn more. Of course, NIDA has its Marijuana page, too. And ProCon.org’s Medical Marijuana page has arguments for and against the medical use of marijuana, along with discussions of legal issues and marijuana’s use with each of 16 different diseases. Read the original news articles about attitudes toward marijuana legalization,

the Justice Department’s hands-off policy, and legalization for recreational use.

7. The Web of Addictions provides fact sheets, links to a variety of other information sites, contact information for support organizations and other organizations concerned with drug problems, and in-depth reports on special topics.

8. The Substance Abuse and Mental Health Services Administration website has a broad range of information for the general public and for professionals. The NIDA site provides news; research information; and information on prevention for parents, teachers, and students.

Chapter Updates and Biopsychology News

For Further Reading 1. Often used as a text in psychopharmacology and upper-level biopsychology

courses, A Primer of Drug Action, by Robert M. Julien, Claire Advokat, and Joseph Comaty (Worth, 2010), covers principles of drug action, properties of specific drugs, pharmacotherapy for various disorders, and societal issues. It is a #1 Best Seller in Medicine and Psychology at Amazon, where it receives good reviews from students.

2. Buzzed: The Straight Facts About the Most Used and Abused Drugs From Alcohol to Ecstasy, by Cynthia Kuhn, Scott Swartzwelder, Wilkie Wilson, Leigh Heather Wilson, and Jeremy Foster (W. W. Norton, 3rd ed., 2008), gives technical information about drugs written in a style appropriate for college students. It covers drug characteristics, histories of the drugs, addiction, the workings of the brain, and legal issues.

3. Formatted as a reference book, The Encyclopedia of Psychoactive Substances, by Richard Rudgley (St. Martins, 2000), devotes just a few pages to each of more than 100 drugs but includes historical information as well as information about changing social attitudes. Coverage ranges from traditional drugs to exotic ones, including hallucinogenic fish.

Key Terms addiction agonist treatment alcohol amphetamine analgesic antagonist treatment antidrug vaccine anxiolytic

aversive treatment barbiturate bath salts benzodiazepine caffeine cannabinoids cocaine delirium tremens depressant drug early-onset alcoholism electrical stimulation of the brain (ESB) endogenous endorphins euphoria heroin hypnotic late-onset alcoholism marijuana medial forebrain bundle mesolimbocortical dopamine system methadone nicotine nucleus accumbens opiate psychedelic drug psychoactive drug reward sedative stimulant tolerance ventral tegmental area withdrawal

6 Motivation and the Regulation of Internal States

In this chapter you will learn • Some of the ways psychologists have viewed motivation • How the concepts of drive and homeostasis explain the regulation of internal body states

• How taste helps us select a safe and nutritious diet • How we regulate the amount of food we eat • What some of the causes of obesity are • What we know about anorexia and bulimia

Motivation and Homeostasis Theoretical Approaches to Motivation Simple Homeostatic Drives CONCEPT CHECK

Hunger: A Complex Drive The Role of Taste APPLICATION: PREDATOR CONTROL THROUGH LEARNED TASTE AVERSION

Digestion and the Two Phases of Metabolism Signals That Start a Meal Signals That End a Meal Long-Term Controls APPLICATION: HOW NICOTINE AND MARIJUANA AFFECT APPETITE CONCEPT CHECK

Obesity The Myths of Obesity The Contributions of Heredity and Environment IN THE NEWS: HOW THE FTO GENE MAKES US OBESE APPLICATION: THE SWEET TASTE OF OBESITY

Obesity and Reduced Metabolism Treating Obesity CONCEPT CHECK

W

ANOREXIA, BULIMIA, AND BINGE EATING DISORDER Environmental and Genetic Contributions The Role of Serotonin, Dopamine, and Cannabinoids CONCEPT CHECK

In Perspective Summary Study Resources

hen Christopher was born, it was obvious there was something wrong (Lyons, 2001). He was a “floppy baby,” lying with his arms and legs splayed lifelessly on the bed, and he didn’t cry. Doctors thought he might never walk or talk, but he

seemed to progress all right until grade school, when he was diagnosed with Prader- Willi syndrome. The disorder occurs when a small section of the father’s chromosome 15 fails to transfer during fertilization. The exact contribution of those genes is not known, but the symptoms are clearly defined, and Christopher had most of them. He stopped growing at 5 feet, 3 inches (1.6 meters), he had learning difficulties, and he had difficulty with impulse control. “

I can stuff my face for a long time and I won’t feel full. —Christopher Theros

”

More obviously, Christopher could never seem to recognize when he had eaten enough, so he ate constantly. He even stole his brother’s paper-route money to buy snacks at the corner store. At school, he would retrieve food from the cafeteria garbage can and wolf it down; his classmates would taunt him by throwing a piece of food in the trash to watch him dive for it. The only way to protect a person like Christopher is to manage his life completely, from locking the kitchen to institutionalization. State law did not permit institutionalization for Chris, because his average-level IQ did not fit the criterion for inability to manage his affairs. He lived in a series of group homes but was thrown out of each one for rebelliousness and violence, behaviors that are characteristic of the disorder. When he died at the age of 28, he weighed 500 lb (227 kg; Figure 6.1).

1 Prader-Willi Syndrome In the previous chapter, we puzzled over why people continue to take drugs that are

obviously harming them. Now we are forced to wonder why a person would be so out of control that he would literally eat himself to death. When we ask why people (and animals) do what they do, we are asking about their motivation.

Motivation and Homeostasis Motivation, which literally means “to set in motion,” refers to the set of factors that initiate, sustain, and direct behaviors. The need for the concept was prompted by psychologists’ inability to explain behavior solely in terms of outside stimuli. Assuming various kinds of motivation, such as hunger or achievement need, helped make sense of differing responses to the same environmental conditions. FIGURE 6.1 Christopher During a Hospital Stay.

SOURCE: Courtesy of the San Luis Obispo County Tribune. Keep in mind, though, that motivation is a concept psychologists have invented and

imposed on behavior; we should not expect to find a single “motivation center” in the brain or even a network whose primary function is motivation. The fact that we sometimes cannot distinguish motivation from other aspects of behavior, like emotion, is evidence of how arbitrary the term can be. Still, it is a useful concept for organizing ideas about the sources of behavior. After a brief overview of some of the ways psychologists have approached the

problem of motivation, we will take a closer look at temperature regulation, thirst, and hunger as examples before taking up the topics of sexual behavior in Chapter 7 and emotion and aggression in Chapter 8. Theoretical Approaches to Motivation Greeks relied heavily on the concept of instinct in their attempts to explain human

behavior. An instinct is a complex behavior that is automatic and unlearned and occurs in all the members of a species. Migration and maternal behavior are good examples of instinctive behaviors in animals. According to early instinct theorists, humans were guided by instincts, too, waging war because of an aggressive instinct, caring for their young because of a maternal instinct, and so on. At first blush, these

explanations sound meaningful. But if we say that a person is combative because of an aggressive instinct, we know little more about what makes the person fight than we did before; if we cannot then analyze the supposed aggressive instinct, we have simply dodged the explanation. The idea of instincts as an explanation of human motivation was popularized in

modern times by the psychologist William McDougall (1908), who proposed that human behaviors such as reproduction, gregariousness, and parenting are instinctive. It wasn’t long until one writer was able to count 10,000 names of instincts in the literature; this led him to suggest, tongue firmly in cheek, that there must also be an “instinct to produce instincts” (Bernard, 1924). Apparently the instinct explanation provided too many theorists an easy way out; the idea of human instincts fell into disrepute. Contemporary students of behavior have used stringent requirements of evidence to identify a few instincts in animals, such as homing and maternal care. But most psychologists believe that in human evolution instincts have either dropped out or weakened. At any rate, we need to be extremely careful about how we use the term instinct and to avoid the temptation to label any behavior that is difficult to explain as an instinct. Drive theory has fared much better than instinct theory, at least in explaining

motivation that involves physical conditions such as hunger, thirst, and body temperature. According to drive theory, the body maintains a condition of homeostasis, in which any particular system is in balance or equilibrium (C. L. Hull, 1951). Any departure from homeostasis, such as depletion of nutrients or a drop in temperature, produces an aroused condition, or drive, which impels the individual to engage in appropriate action such as eating, drinking, or seeking warmth. As the body’s need is met, the drive and associated arousal subside. This is a temporary state, of course; soon the individual will be hungry or thirsty or cold again, and the cycle will continue.

What do homeostasis and drive mean? Critics of drive theory point out that it does not explain all kinds of motivation;

many motivated behaviors seem to have nothing to do with satisfying tissue needs. For example, a student may be motivated by grades, some people struggle to achieve fame, and others work long hours to earn more money than they need for food and shelter. Incentive theory recognizes that people are motivated by external stimuli, not just internal needs (Bolles, 1975). In this respect, money and grades act as incentives. Incentives can even be a factor in physiological motivation; consider, for example, the effect of the smell of chocolate chip cookies baking or the sight of a sexually attractive individual. My wife recently jumped out of an airplane for the thrill of plummeting toward the

earth, hoping to be saved at the last minute by a flimsy parachute; there is no tissue

need, and no obvious drive involved here. Observations like this have led to the arousal theory, which says that people behave in ways that keep them at their preferred level of arousal (Fiske & Maddi, 1961). Different people have different optimum levels of arousal, and some seem to have a need for varied experiences or the thrill of confronting danger (Zuckerman, 1971). This sensation seeking finds expression in anything from travel and unconventional dress to skydiving, drug use, armed robbery, and eating fugu (see Chapter 2). In the face of challenges to drive theory, psychologists have shifted their emphasis

to drives as states of the brain rather than as conditions of the tissues (Stellar & Stellar, 1985). This approach nicely accommodates sexual behavior, which troubled drive theorists because it does not involve a tissue deficit. Even eating behavior is better understood as the result of a brain state. Hunger ordinarily occurs when a lack of nutrients in the body triggers activity in the brain. However, an incentive like the smell of a steak on the grill can also cause hunger, apparently by activating the same brain mechanisms as tissue deficits do. In addition, the person feels satisfied and stops eating long before the nutrients have reached the deficient body cells. Similarly, if the brain is not “satisfied,” it little matters how much the person has eaten. In other words, if the information that reserves are excessive fails to reach the brain or to have its usual effect there, the person may, like Christopher, eat to obesity and still feel hungry. In the following pages, we will look at the regulation of body temperature, fluid levels, and energy supply from the perspective of drive and homeostasis. Simple Homeostatic Drives To sustain life, a number of conditions, such as body temperature, fluid levels, and

energy reserves, must be held within a fairly narrow range. Accomplishing that requires a control system. A mechanical control system that serves as a good analogy is a home heating and cooling system. Control systems have a set point, which is the point of equilibrium the system returns to. For the heating and cooling system, the set point is the temperature selected on the thermostat. The result of a departure in the room temperature from the set point is analogous to a drive; the thermostat initiates an action, turning on the furnace or the air conditioner. When the room temperature returns to the preset level, the system is “satisfied” in the technical sense of the word; homeostasis has been achieved, so the system goes into a quieter state until there is another departure from the set point.

How is body temperature regulated? Temperature Regulation Not only is the regulation of body temperature superficially similar to our

thermostat analogy; it is almost as simple. All animals have to maintain internal temperature within certain limits to survive, and they operate more effectively within an even narrower range; this is their set point. How they respond to departures from

homeostasis is much more variable than with the home heating and cooling system, however. Ectothermic animals, such as snakes and lizards, are unable to regulate their body temperature internally, so they adjust their temperature behaviorally by sunning themselves, finding shade, burrowing in the ground, and so on. Endothermic animals, which include mammals and birds, use some of the same strategies along with others that are functionally similar, such as building nests or houses, turning up the thermostat, and wearing clothing. However, endotherms are also able to use their energy reserves to maintain a nearly constant body temperature automatically. In hot weather, their temperature regulatory system reduces body heat by causing sweating, reduced metabolism, and dilation of peripheral blood vessels. In cold weather, it induces shivering, increased metabolism, and constriction of the peripheral blood vessels. To say that we make these adjustments because we feel hot or cold suggests that the responses are intentional behaviors, but, of course, that is not the case. So how do these behaviors occur? FIGURE 6.2 Selected Nuclei of the Hypothalamus. The illustration shows only the right hypothalamus. The hypothalamus is a bilaterally symmetrical structure, which means that the left and right halves (separated by the third ventricle) are duplicates of each other. (The pituitary, optic chiasm, and pons have been identified for use as landmarks.)

SOURCE: Adapted from The Human Central Nervous System (3rd rev. ed.), by R. Nieuwenhuys, J. Voogd, and C. vanHuijzen, 1988, Berlin, Germany: Springer-

Verlag. In mammals, the major “thermostat” is located in the preoptic area of the

hypothalamus, which contains separate warmth-sensitive and cold-sensitive cells (Figure 6.2; Nakashima, Pierau, Simon, & Hori, 1987). Some of these neurons respond directly to the temperature of the blood flowing through the area; others receive input from temperature receptors in other parts of the body, including the skin. The preoptic area integrates information from these two sources and initiates temperature regulatory responses, such as panting, sweating, and shivering (Boulant, 1981; Kupferman, Kandel, & Iversen, 2000). We will be talking about several nuclei in the hypothalamus in this chapter, so you may want to refer to Figure 6.2 often. Thirst The body is about 70% water, so it seems obvious that maintaining the water

balance is critical to life. Water is needed to maintain the cells of the body, to keep the blood flowing through the veins and arteries, and to digest food. You can live for weeks without eating but only for a few days without water, in part because of the constant loss through sweating, urination, and defecation. The design of your nose, which could have been just a pair of nostrils on your face, is testimonial to the body’s efforts to conserve water. As you breathe, you exhale valuable moisture; but as your breath passes through the much cooler nose, some of the moisture condenses and is reabsorbed. The next time you get a runny nose when you step outside on a cold day, you will get some idea how much water the nose recycles.

How does the body regulate its water reserves? It is obvious that you drink when your mouth and throat feel dry, but at most a dry

mouth and throat determine only when you drink, not how much you drink. There are two types of thirst, one generated by the water level inside the body’s cells and the other reflecting the water content of the blood. Water deprivation affects both kinds of deficit, but the fluid levels in the two compartments can vary independently and so the brain manages them separately. Osmotic thirst occurs when the fluid content decreases inside the cells. This happens when the blood becomes more concentrated than usual, usually because the individual has not taken in enough water to compensate for food intake; eating a salty meal adds to the effect by making the blood more concentrated. As a result, water is drawn from the cells into the bloodstream by osmotic pressure. Hypovolemic thirst occurs when the blood volume drops due to a loss of extracellular water. This can be due to sweating, vomiting, and diarrhea. Of course, another cause is blood loss; that is why you feel thirsty after giving blood. The reduced water content of cells that contributes to osmotic thirst is detected

primarily in areas bordering the third ventricle, particularly in the organum vasculosum lamina terminalis (OVLT; see Figure 6.3). Injecting saline (salt solution) into the bloodstream draws water out of the cells and induces drinking, but this effect

is dramatically reduced when the OVLT is lesioned beforehand (Thrasher & Keil, 1987). The OVLT communicates the water deficit to the median preoptic nucleus of the hypothalamus, which initiates drinking. Hypovolemia is detected by receptors located where the large veins enter the atrium

of the heart; these receptors respond to stretching of the vascular walls by the volume of blood passing through (Fitzsimons & Moore-Gillon, 1980). The reduced blood volume in the heart that accompanies hypovolemia is signaled by the vagus nerve to the nucleus of the solitary tract (NST) in the medulla. From there, the signal goes to the median preoptic area of the hypothalamus (Figure 6.3; Stricker & Sved, 2000). Lowered blood volume is also detected by receptors in the kidneys, which trigger

the release of the hormone renin. Renin then increases production of the hormone angiotensin II. Angiotensin II circulating in the bloodstream informs the brain of the drop in blood volume. It stimulates the subfornical organ (SFO), a structure bordering the third ventricle and one of the areas that is not protected by the blood-brain barrier (Figure 6.3). Again, drinking is induced by the nearby median preoptic nucleus (Fitzsimons, 1998; Stricker & Sved, 2000). Injecting angiotensin into the SFO increases drinking; lesioning the SFO blocks this effect but has no effect on drinking in response to osmotic thirst (J. B. Simpson, Epstein, & Camardo, 1978). FIGURE 6.3 Thirst Control Signals and Brain Centers.

Concept Check

Thirst is more complicated than the operation of a furnace or body temperature regulation because there is a significant time lag between drinking and the arrival of water in the tissues. The individual must stop drinking well before tissue need is satisfied. The satiety (satisfaction of appetite) mechanism is not well understood, but there is evidence that receptors in the stomach monitor the presence of water (Rolls, Wood, & Rolls, 1980). Also, infusion of water into the liver reduces drinking, which suggests that either water receptors or pressure receptors are there (Kozlowski & Drzewiecki, 1973). We know more about satiety when it comes to hunger and will take up the issue again later.

Take a Minute to Check Your Knowledge and Understanding

How do temperature regulation and thirst qualify as homeostatic drives?

Receptors are able to do their jobs because they are specialized for specific types of stimuli; what are the specializations of the receptors we have seen so far?

Hunger: A Complex Drive Although hunger can be described in terms of drive and homeostasis just like temperature regulation and thirst, the differences almost overshadow the similarities. Hunger is more complicated in a variety of ways. Eating provides energy for activity, fuel for maintaining body temperature, and materials needed for growth and repair of the tissues. In addition, the set point is so variable that you might think there is none. This is not surprising, because the demands on our resources change with exercise, stress, growth, and so on. A changing set point is not unique to hunger, of course. For example, our temperature set point changes daily, decreasing during our normal sleep period (even if we fly to Europe and are awake during normal sleep time). It also increases during illness to produce a fever to kill invading bacteria. What is unusual about hunger is that the set point can undergo dramatic and prolonged shifts, for instance in obesity. Another difference is that the needs in temperature regulation and thirst are unitary,

while hunger involves the need for a variety of different and specific kinds of nutrients. Making choices about what foods to eat can be more difficult than knowing when to eat and when to stop eating. The Role of Taste Selecting the right foods is no problem for some animals. Some herbivores (plant-

eating animals) can get all the nutrients they need from a single source; koalas, for instance, eat only eucalyptus leaves, and giant pandas eat nothing but the shoots of the bamboo plant. Carnivores (meat eaters) also have it rather easy; they depend on their prey to eat a balanced diet. We are omnivores; we are able to get the nutrients we need from a variety of plants and animals. Being able to eat almost anything is liberating but simultaneously a burden: We must distinguish among foods that may be nutritious, nonnutritious, or toxic, and we must vary our diet among several sources to meet all our nutritional requirements. Choosing the right foods and in the right amounts can be a real challenge. “

You are what you eat. —popular adage

”

It is possible that you plan your diet around nutritional guidelines, but probably you rely more on what you learned at the family table about which foods and what combinations of foods make an “appropriate” meal in your culture. Have you ever wondered where these traditions came from, or why they survive when each new

generation seems to delight in defying society’s other customs? Long before humans understood the need for vitamins, minerals, proteins, and carbohydrates, your ancestors were using a “wisdom of the body” to choose a reasonably balanced diet that ensured their survival and your existence. That wisdom is reflected in cultural food traditions, which usually provide a balanced diet (Rozin, 1976), sometimes by dictating unattractive (to us) choices such as grub worms or cow’s blood. As you will see, the internal forces that guide our selection of a balanced diet are more automatic than the term choice usually suggests, but they are also subtle and easily overcome by the allure of modern processed foods, which emphasize taste over nutrition. The simplest form of dietary selection involves distinguishing between foods that

are safe and nutritious and those that are either useless or dangerous. This is where the sense of taste comes in. In humans, all taste experience is the result of just five taste sensations: sour, sweet, bitter, salty, and the more recently discovered umami (Kurihara & Kashiwayanagi, 1998). The first four need no explanation; umami is often described as “meaty” or “savory.” These five sensations are called primaries; more complex taste sensations are made up of combinations of the primaries. There may be other taste primaries; for example, researchers have long suspected we have the ability to detect fat directly, and a team in Australia has found evidence for a receptor (Stewart et al., 2010) and one in the United States has identified a gene (CD36) that influences sensitivity (Pepino, Love-Gregory, Klein, & Abumrad, 2012). FIGURE 6.4 A Microscopic Photo of a Papilla With Taste Buds.

SOURCE: © Southern Illinois University/Science Source. It is easy to see why we have evolved taste receptors with these particular

sensitivities, because they correspond closely to our dietary needs. We will readily eat foods that are sweet, which include fruits and carbohydrates. We also prefer foods that are a bit salty; salt provides the sodium and chloride ions needed for cellular functioning and for neural transmission. Mountain gorillas get 95% of their sodium by eating decaying wood—while avoiding similar wood with lower sodium content (Rothman, Van Soest, & Pell, 2006). Umami receptors aid in our selection of proteins. One type responds to amino acids and two respond to glutamate (Chaudhari, Pereira, & Roper, 2009), which is found in meats, cheese, and soy products (as well as in the flavor enhancer monosodium glutamate). Just as we are attracted to useful foods by taste, we avoid others. Overly sour foods are likely to be spoiled, and bitter foods are

likely to be toxic. You do not have to understand these relationships, much less think about them; they operate quietly, in the neural background.

In what ways does taste contribute to selection of a proper diet? Taste receptors are located on taste buds, which in turn are found on the surface of

papillae; papillae are small bumps on the tongue and elsewhere in the mouth (see Figure 6.4). Taste neurons travel through the thalamus to the insula, the primary gustatory (taste) area in the frontal lobes. But on their way, they pass through the NST in the medulla, which we saw in Figure 6.3 in relation to drinking and will soon see plays an important role in feeding behavior. Back in Chapter 2, you saw research indicating that taste neurons encode different taste stimuli in unique time patterns of impulses, but there is another, more important, way the system informs the brain of what we are tasting. Each of the primary taste stimuli is detected by receptors that are specialized for that stimulus; information from the different receptors travels to the brain via separate pathways to distinct areas in the insular cortex (X, Chen, Gabitto, Peng, Ryba, & Zuker, 2011; Schoenfeld et al., 2004; see Figure 6.5). You will see in later chapters that other sensory systems exploit this labeled line coding of stimuli and that the brain combines primary sensations into more complex sensory experiences. Besides the nutritional and safety benefits we have already mentioned, the taste

sense contributes to dietary selection in three additional ways: sensory-specific satiety, learned taste aversion, and learned taste preferences. FIGURE 6.5 Localization of Taste Responses in the Cortex. The color-coded areas on this fMRI scan indicate where the insular cortex was activated as the subject tasted various liquids. The locations differed among subjects but were consistent over time for each subject. The location of the insular cortex is shown in the lower image.

SOURCE: From “Functional Magnetic Resonance Tomography Correlates of Taste Perception in the Human Primary Taste Cortex,” by M. A. Schoenfeld et al., 2004, Neuroscience, 127, pp. 347–353. Used with permission from Elsevier. Sensory-Specific Satiety: Varying the Choices One day when I was a youngster, a neighbor child joined our family for lunch. At

the end of the meal, she enjoyed a bowl of my mother’s homemade apple cobbler, then another, and another. Halfway through the third serving, she observed in puzzlement that the last serving wasn’t nearly as good as the first. Barbara and Edmund Rolls call this experience sensory-specific satiety. Sensory-specific satiety means that the more of a particular food an individual eats, the less appealing the food becomes. Humans rate a food less favorably after they have consumed it, and they eat more if they are offered a variety of foods instead of a single food (Rolls, Rolls, Rowe, & Sweeney, 1981). The effect sounds trivial, but it is not; sensory-specific satiety is the brain’s way of

encouraging you to vary your food choices, which is necessary for a balanced diet. Back in the 1920s, Clara Davis (1928) allowed three newly weaned infants to choose all their meals from a tray of about 20 healthy foods. They usually selected only two or three foods at one meal and continued choosing the same foods for about a week. Then they would switch to another two or three foods for a similar period. Their self- selected diet was adequate to prevent any deficiencies from developing over a period of 6 months. Sensory-specific satiety takes place in the NST. Place a little glucose (one of the

sugars) on a rat’s tongue, and it produces a neural response there. But if glucose is injected into the rat’s bloodstream first, sugar placed on the tongue has less effect in the NST (Giza, Scott, & Vanderweele, 1992). The brain automatically motivates the rat—or you—to switch to a new flavor and a different nutrient. Learned Taste Aversion: Avoiding Dangerous Foods Learned taste aversion, the avoidance of foods associated with illness or poor

nutrition, was discovered when researchers were studying bait shyness in rats. Farmers know that if they put out poisoned bait in the barn, they will kill a few rats at first but the surviving rats will soon start avoiding the bait (thus the term bait shyness). Rats eat small amounts of a new food; a poison will more likely make them ill instead of killing them, and they will avoid that food in the future. Learned aversion is studied in the laboratory by giving rats a specific food and then making them nauseous with a chemical like lithium chloride or with a dose of X-ray radiation. Later they refuse to eat that food. Learned taste aversion helps wild animals and primitive-living humans avoid

dangerous foods (see the accompanying Application). Modern-living humans experience learned taste aversions, too. In a study of people with strong aversions to particular foods, 89% could remember getting sick after eating the food, most often between the ages of 6 and 12 (Garb & Stunkard, 1974). However, in civilized settings, learned aversions have little value in identifying dangerous foods. Instead, we usually get sick following a meal because we left the food out of the refrigerator too long or because we happened to come down with stomach flu. Learned taste aversion appears to be one reason chemotherapy patients lose their appetite. Among children who were

given a uniquely flavored ice cream before a chemo session, 79% later refused that flavor, compared with 33% of children receiving chemotherapy without the ice cream; the effect was just as strong 4 months later (I. L. Bernstein, 1978).

APPLICATION

Predator Control Through Learned Taste Aversion Learned taste aversion has been put to practical use in an unlikely context: predator control. As a novel and humane (compared with extermination) means of controlling sheep killing by wolves and coyotes, Carl Gustavson and colleagues fed captive predators sheep carcasses laced with lithium chloride (see the photo), which made them sick. When they were placed in a pen with sheep, the wolves and coyotes avoided the sheep instead of attacking them. One coyote threw up just from smelling a lamb, and two hesitant wolves were chased away by a lamb that turned on them (Gustavson, Garcia, Hankins, & Rusiniak, 1974; Gustavson, Kelly, Sweeney, & Garcia, 1976). In a 3-year study on 10 ranches in Saskatchewan, coyote predation of sheep decreased 87% (Gustavson, Jowsey, & Milligan, 1982).

One of Gustavson’s Coyotes Undergoing Conditioning. SOURCE: © Janet Haas/Rainbow.

Learned taste aversion may not be very useful to modern humans for avoiding dangerous foods, but it may help us avoid nonnutritious ones. When rats are fed a diet that is deficient in a particular nutrient, such as thiamine (vitamin B), they start showing an aversion to their food; they eat less of it, and they spill the food from its container in spite of indications they are hungry, like chewing on the wire sides of their cage (Rozin, 1967). Even after recovery from the deficit, the rats prefer to go hungry rather than eat the previously deficient food. But aversion to a nutrient- deficient food is just the first step toward selecting a nutritious diet.

Learned Taste Preferences: Selecting Nutritious Foods Although rats, and presumably humans, can detect salt, sugars, and fat directly by

their taste (Beck & Galef, 1989), they must learn to select the foods containing other necessary nutrients. This apparently requires the development of a learned taste preference, which is a preference not for the nutrient itself but for the flavor of a food that contains the nutrient. In an early study, rats were fed a diet deficient in one of three vitamins (thiamine, riboflavin, or pyridoxine); later they learned to prefer a food enriched with that vitamin, which was flavored distinctively by adding anise (which tastes like licorice). When the anise was switched to the vitamin-deficient food, the rats began eating that food instead (E. M. Scott & Verney, 1947). This type of learning requires pairing of a taste with some benefit, such as recovery from a dietary deficiency, and usually requires constant pairing over a period of several days (T. R. Scott, 2011). A diet-deficient rat enhances its chances of learning which foods are beneficial by eating a single food at a time (Rozin, 1969). (Notice how similar this is to the sampling behavior of Davis’s infants who were allowed to choose their own food.) How much humans are able to make use of these abilities is unclear; certainly we

often choose an unhealthy diet over a healthy one. These bad selections may not be due so much to a lack of ability to make good choices as it is to the distraction of tasty, high-calorie foods that are not found in nature. Even rats have trouble selecting the foods that are good for them when the competing foods are flavored with cinnamon or cocoa (Beck & Galef, 1989), and they become obese when they are offered human junk food (Rolls, Rowe, & Turner, 1980). Wisdom of the body is inadequate in the face of the temptation of french fries and ice cream. Now a caveat. You have most likely read that taste is largely a matter of smell, and

perhaps even tested the idea by holding your nose while tasting familiar foods. In this context, it is important to distinguish between taste, which is the experience you get from your taste receptors, and flavor, which depends on a combination of taste and smell. Smell does have a significant effect; how much depends on the specific food and, to my knowledge, has never actually been quantified (in spite of authoritative- sounding statements to the contrary). We will take up the topic of the sense of smell in Chapter 7. Digestion and the Two Phases of Metabolism Here, we confront a significant inadequacy in our thermostat analogy. To maintain

consistent temperature, the thermostat calls on the furnace to cycle on and off frequently. Some species of animals do behave like the home furnace; they have to eat steadily, with only brief pauses, to provide the constant supply of nutrients the body needs. Humans do not; we eat a few discrete meals and fast in between. Eating discrete meals leaves us free to do other things with our time, but it requires a complex system for storing nutrient reserves, allocating the reserves during the fasting

periods, and monitoring the reserves to determine the timing and size of the next meal. The Digestive Process Digestion begins in the mouth, where food is ground fine and mixed with saliva.

Saliva provides lubrication and contains an enzyme that starts the breakdown of food. Digestion proceeds in the stomach as food is mixed with the gastric juices hydrochloric acid and pepsin. The partially processed food is then released gradually so that the small intestine has time to do its job. (Figure 6.6 shows the organs of the digestive system.) FIGURE 6.6 The Digestive System.

The stomach provides another opportunity for screening toxic or spoiled food that gets past the taste test. If the food irritates the stomach lining sufficiently, the stomach responds by regurgitating the meal. Some toxins don’t irritate the stomach, and they make their way into the bloodstream. If so, a part of the brain often takes care of this problem; the area postrema is one of the places in the brain that is outside the blood- brain barrier, so toxins can activate it to induce vomiting. The result can be surprisingly forceful; projectile vomiting usually means that you’ve got hold of something really bad. On the other hand, college students have been known to

incorporate this adaptive response into a drinking game called “boot tag,” the details of which I will leave to your imagination. Digestion occurs primarily in the small intestine, particularly the initial 25 cm of

the small intestine called the duodenum. There food is broken down into usable forms. Carbohydrates are metabolized into simple sugars, particularly glucose. Proteins are converted to amino acids. Fats are transformed into fatty acids and glycerol, either in the intestine or in the liver. The products of digestion are absorbed through the intestinal wall into the blood and transported to the liver via the hepatic portal vein. Digestion requires the food to be in a semiliquid mix, and the body can ill afford to give up the fluid; the large intestine’s primary job is retrieving the excess water. This process is under the control of the autonomic nervous system, so digestion is

affected by stress or excitement, as you probably well know. If too much acid is secreted into the stomach, you’ll take your course exam with an upset stomach. If food moves too slowly through the system, constipation will be the result. Too fast, and there isn’t time to remove the excess water, so you may be asking to leave the room in the middle of your exam to go to the bathroom. Because diarrhea causes the body to lose water, you may have to drink more liquids to avoid dehydration. You also lose electrolytes, compounds that provide the ions your neurons and other cells need, which is why your doctor may recommend a sports drink as the replacement liquid.

What happens during the absorptive and fasting phases? The Absorptive Phase The feeding cycle is divided into two phases, the absorptive phase and the fasting

phase. For a few hours following a meal, the body lives off the nutrients arriving from the digestive system; this period is called the absorptive phase. Following a meal, the blood level of glucose, our primary source of energy, rises. The brain detects the increased glucose and shifts the autonomic system from predominantly sympathetic activation to predominantly parasympathetic activity. As a result, the pancreas starts secreting insulin, a hormone that enables body cells to take up glucose for energy and certain cells to store excess nutrients. (Actually, because of conditioning, just the sight and smell of food is enough to trigger insulin secretion, increased salivation, and release of digestive fluids into the stomach. Remember the incentive theory?) The cells contain insulin receptors, which activate transporters that carry glucose

into the cells. Diabetes results when the pancreas is unable to produce enough insulin (type 1 diabetes) or the body’s tissues are relatively unresponsive to insulin (type 2 diabetes). The diabetic’s blood contains plenty of glucose following a meal but, due to insulin resistance, the cells of the body are unable to make use of it and the diabetic is chronically hungry. FIGURE 6.7 Summary of the Absorptive and Fasting Phases.

During the absorptive phase, the body is also busy storing some of the nutrients as a hedge against the upcoming period of fasting. Some of the glucose is converted into glycogen and stored in a short-term reservoir in the liver and the muscles. Any remaining glucose is converted into fats and stored in fat cells, also known as adipose tissue. Fats arriving directly from the digestive system are stored there as well. Storage of both glucose and fat is under the control of insulin. After a small proportion of amino acids is used to construct proteins and peptides needed by the body, the rest is converted to fats and stored. The Fasting Phase Eventually the glucose level in the blood drops. Now the body must fall back on its

energy stores, which is why this is called the fasting phase. The autonomic system shifts to sympathetic activity. The pancreas ceases secretion of insulin and starts secreting the hormone glucagon, which causes the liver to transform stored glycogen back into glucose. Because the insulin level is low now, this glucose is available only to the nervous system. To meet the rest of the body’s needs, glucagon triggers the breakdown of stored fat into fatty acids and glycerol. The fatty acids are used by the muscles and organs, while the liver converts glycerol to more glucose for the brain. During starvation, muscle proteins can be broken down again into amino acids, which are converted into glucose by the liver. The two phases of metabolism are summarized in Figure 6.7. The oscillations of eating and fasting and the shifts in metabolism that accompany

them are orchestrated for the most part by two particularly important areas in the hypothalamus. The lateral hypothalamus initiates eating and controls several aspects of feeding behavior as well as metabolic responses. It controls chewing and swallowing through its brainstem connections; salivation, acid secretion, and insulin production through autonomic pathways in the medulla and spinal cord; and cortical arousal, which likely increases locomotion and the possibility of encountering food (Currie & Coscina, 1996; Saper, Chou, & Elmquist, 2002; Willie, Chemelli, Sinton, & Yanagisawa, 2001). The paraventricular nucleus (PVN) initiates eating, though less

effectively than the lateral hypothalamus, and regulates metabolic processes such as body temperature, fat storage, and cellular metabolism (Broberger & Hökfelt, 2001; Sawchenko, 1998). You can see where these structures are located in the brain in Figure 6.8, which we will refer to throughout this discussion.

What stimuli initiate eating? After the body has lived for a few hours off of its stores, the falling level of

nutrients signals the brain that it is time to eat again. However, by then you probably have already headed for lunch, cued by the clock rather than a brain center. In the modern, highly structured world, physiological motivations have been so incorporated into social customs that it is difficult to tell where the influence of one leaves off and the other begins. We will turn the power of research to answering the questions “What makes a person eat?” “How does a person know when to stop eating?” and “How does a person regulate weight?” As you will learn, the answers are not simple ones; even what you see here will be an abbreviated treatment. FIGURE 6.8 Hunger Control Signals and Brain Centers.

NOTE: PVN = paraventricular nucleus; LH = lateral hypothalamus; Arc = arcuate nucleus; NST = nucleus of the solitary tract; PYY = paraventricular nucleus; CCK = cholecystokinin Signals That Start a Meal When I ask students in class what being hungry means, the favorite answer is that

their stomach feels empty. Your stomach often does feel empty when you are hungry, but we don’t eat to satisfy the stomach. The stomach is not even necessary for hunger to occur; people who have their stomach removed because of cancer still report feeling hungry and still eat much like everybody else, though they have to take smaller meals (Ingelfinger, 1944). So what does make us feel hungry? FIGURE 6.9 Immunohistochemical Labeling Highlights the Arcuate Nucleus.

NPY-releasing neurons in the arcuate nucleus send output to the PVN and the lateral hypothalamus, but they also inhibit neurons within the nucleus that ordinarily block eating. A fluorescent antigen has bound to the NPY receptors, making them appear white in this photograph; doing so has also defined the shape of the arcuate nucleus. (The dark space between the two nuclei is the third ventricle.)

SOURCE: From Figure 1 of “Hypothalamic and Vagal Neuropeptide Circuitries Regulating Food Intake,” by C. Broberger and T. Hokfelt, 2001, Physiology and Behavior, 74, p. 670. Used with permission from Elsevier. There are three major signals for hunger. One tells the brain of a low supply of

glucose, or glucoprivic hunger; the second indicates a deficit in fatty acids, or lipoprivic hunger; and the third does inform us that the stomach’s store of nutrients has been depleted. The liver monitors the glucose level and the fatty acids in the blood passing to it from the small intestine via the hepatic portal vein (see Figure 6.8). Novin, VanderWeele, and Rezek (1973) demonstrated glucose monitoring by injecting 2-deoxyglucose into the hepatic portal vein of rabbits. You may remember from Chapter 4 that 2-deoxyglucose (2-DG) resembles glucose and is absorbed by cells; it takes the place of glucose in the cells but provides no energy, so it creates a glucose deficiency. The injection caused the rabbits to start eating within 10 minutes and to eat three times as much as animals that were injected with saline. A compound that blocks the metabolism of fatty acids (mercaptoacetate) also increases the amount eaten (S. Ritter & Taylor, 1990); injecting mercaptoacetate into the hepatic portal vein increases activity in the vagus nerve, sending a signal to the brain. As you can see in Figure 6.8, signals of glucose and fatty acid deficits are carried

by the vagus nerve from the liver to the NST in the medulla (see #1). If the NST is lesioned or the vagus is cut, low glucose and fatty acid levels no longer affect feeding (S. Ritter & Taylor, 1990). The animals do increase their rate of eating 3 hours after a 2-DG infusion (Novin et al., 1973), however, because the brain has its own glucose receptors near the fourth ventricle (R. C. Ritter, Slusser, & Stone, 1981). This suggests that the medulla keeps track of nutrient levels in the rest of the body via the vagus nerve but monitors the brain’s supply of glucose directly (Figure 6.8, #2).

FIGURE 6.10 Ghrelin Levels in a Human Over a 24-Hour Period. Notice that the ghrelin level started rising just before, and peaked at, the customary mealtimes.

SOURCE: From “A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans,” by D. E. Cummings et al., 2001, Diabetes, 50, p. 1716, fig. 2A. © 2001 American Diabetes Association. The hypothalamus, however, is the master regulator of the energy system.

Information about glucose and fatty acid levels is relayed from the NST to the arcuate nucleus, a vital hypothalamic structure for monitoring the body’s nutrient condition (Figures 6.2, 6.8, 6.9; Saper et al., 2002; Sawchenko, 1998). The arcuate nucleus sends neurons to the PVN and the lateral hypothalamus to regulate both feeding and metabolism. The third major signal for hunger is ghrelin, a hormone that is synthesized in the

stomach and released into the bloodstream as the stomach empties during fasting. Circulating ghrelin reaches the arcuate nucleus because it passes readily through the blood-brain barrier (Broberger & Hökfelt, 2001). Injecting ghrelin into rats’ ventricles caused them to eat more and to gain weight four times faster than rats injected with saline (Kamegai et al., 2001). In humans, ghrelin levels in the blood rose almost 80% before each meal and dropped sharply after eating (Figure 6.10; Cummings et al., 2001). Ghrelin may account for the uncontrollable appetite of people like Christopher; it is 2.5 times higher in individuals with Prader-Willi syndrome than in lean controls and 4.5 times higher than the depressed levels found in equally obese individuals without the syndrome (Cummings et al., 2002). All three of these hunger signals exert their influence through NPY/AgRP neurons

in the arcuate nucleus; these neurons release neuropeptide Y (NPY) and agouti-related protein (AgRP), both of which excite the PVN and the lateral hypothalamus to increase eating and reduce metabolism (Figure 6.8, #3; Horvath & Diano, 2004; Kamegai et al., 2001). Rats that receive NPY injections in the paraventricular nucleus

double their rate of eating and increase their rate of weight gain sixfold (B. G. Stanley, Kyrkouli, Lampert, & Leibowitz, 1986). They are so motivated for food that they will tolerate shock to the tongue to drink milk and they will drink milk adulterated with bitter quinine (Flood & Morley, 1991). The fact that their weight gain is three times greater than their increase in food intake attests to NPY’s ability to reduce metabolism. During extreme deprivation, NPY conserves energy further by reducing body temperature (Billington & Levine, 1992) and suppressing sexual motivation (J. T. Clark, Kalra, & Kalra, 1985). If you think about it, sexual activity is a particularly unnecessary luxury during food shortage because it expends energy and produces offspring that compete for the limited resources. FIGURE 6.11 Effect of Nutrient Concentration on Later Meal Size. In all trials except the baseline, the stomach was preloaded with 5 milliliters of saline or glucose solution before the subject was offered a glucose solution to drink. The connection between the stomach and small intestine (the pylorus) could be closed by inflating a small cuff. (a) With the pylorus closed, nutrient value made no difference. (b) With the pylorus open, the amount consumed diminished as nutrient values increased.

SOURCE: Adapted from “Gastric Volume Rather Than Nutrient Content Inhibits Food Intake,” by R. J. Phillips and T. L. Powley, American Journal of Physiology, 271, pp. R766 -R799. © 1996 American Physiological Society. Used with permission. Signals That End a Meal Just as with drinking, there must be a satiety mechanism that ends a meal well

before nutrients reach the tissues. It might seem obvious that we stop eating when we feel “full,” and that answer is partly right. R. J. Phillips and Powley (1996) used a

small inflatable cuff to close the connection between the stomach and intestines of rats. Infusing glucose into the stomach reduced the amount of food the rats ate later, but saline had just as much effect as glucose; this meant that in the stomach volume and not nutrient value is important. Distension of the stomach activates stretch receptors that send a signal by way of the vagus nerve to the NST (Figure 6.8, #4; Broberger & Hökfelt, 2001; B. R. Olson et al., 1993). But a full stomach cannot produce satiation by itself; otherwise, drinking water

would satisfy us. Humans and other animals also adjust the amount of food they eat according to the food’s nutritional value. To a small extent, this involves mouth factors and learning. A high-calorie soup produces a greater reduction in hunger if it is drunk than if it is infused into the stomach, and high-calorie drinks are more satisfying than noncaloric drinks (S. E. French & Cecil, 2001).

What stimuli terminate eating? Optimal satiation, however, requires the interaction of mouth, stomach, and

intestinal factors. When R. J. Phillips and Powley (1996) opened the cuff so that the stomach’s contents could flow into the intestines, nutrient value did make a difference. Glucose reduced subsequent eating more than saline did, and higher concentrations of the glucose had a greater effect (see Figure 6.11). The stomach and intestines respond to food by releasing peptides, which the brain uses to monitor nutrients. About a dozen different peptides have this function; different peptides are released in response to carbohydrates, fats, proteins, or mixtures of these nutrients. They induce the pancreas, liver, and gallbladder to secrete the appropriate enzymes into the duodenum to digest the specific nutrient, and at least some of them inform the brain as to which nutrient needs are being met (S. C. Woods, 2004), via either the vagus nerve or the bloodstream. The best known of these satiety signals is cholecystokinin (CCK), a peptide

hormone released as food passes into the duodenum. CCK detects fats and causes the gallbladder to inject bile into the duodenum; the bile breaks down the fat so that it can be absorbed. When Xavier Pi-Sunyer and his colleagues injected CCK into the bloodstream of obese humans, they ate less at the next meal (Pi-Sunyer, Kissileff, Thornton, & Smith, 1982). CCK stimulates receptors on the vagus nerve; as Figure 6.8 (#5) indicates, the vagus conveys the signal to the NST, and from there it passes to the hypothalamus (S. C. Woods, 2004). FIGURE 6.12 A Rat With Lesioned Ventromedial Hypothalamus.

SOURCE: Neal Miller, Yale University. However, don’t look for CCK to appear on the market as a weight loss drug.

Although rats given CCK eat smaller meals, they eat more often and maintain their weight (West, Fey, & Woods, 1984). This means that CCK’s role is limited to meal size; there must be other controls that exert a more long-term effect. Long-Term Controls Another appetite-suppressing peptide hormone released in the intestines in response

to food is peptide YY 3–36 (PYY). PYY is carried by the bloodstream to the arcuate nucleus, where it inhibits the NPY-releasing neurons (Figure 6.8, #6; Batterham et al., 2002). Unlike CCK, PYY’s nonneural route to the brain means that its action is too slow to limit the current meal; instead, it decreases caloric intake by about a third over the following 12 hours. We will see later that this hormone is receiving serious consideration as an antiobesity drug. Over longer periods, humans and animals regulate their eating behavior by

monitoring their body weight or, more precisely, their body fat. But how they sense their fat level has not always been clear. In 1952, G. R. Hervey surgically joined pairs of rats so that they shared a very small amount of blood circulation; animals joined like this are called parabiotic. Then Hervey operated on one member of each pair to destroy the ventromedial hypothalamus. This surgery increases parasympathetic activity in the vagus nerve and enhances insulin release (Weingarten, Chang, & McDonald, 1985). This creates a kind of persistent absorptive phase in which most incoming nutrients are stored rather than being available for use; as a result, the animal has to overeat to maintain a normal energy level. The rat becomes obese, sometimes tripling its weight (see Figure 6.12). Hervey’s lesioned rats overate and became obese as expected, but their pairmates began to undereat and lose weight. In fact, in two of the pairs the lean rat starved to death. The message was clear: The obese rat was producing a blood-borne signal that suppressed eating in the other rat, a signal to which the brain-damaged obese rat was insensitive.

What are the signals for controlling body weight?

Concept Check

What that signal was remained a mystery until a half-century later, when researchers discovered that fat cells secrete a hormone called leptin that inhibits eating. The amount of leptin in the blood is proportional to body fat; it is about four times higher in obese than nonobese individuals (Considine et al., 1996). Like cholecystokinin, leptin helps regulate meal size, but it does so in response to the long- term stores of fat rather than the nutrients contained in the meal. Insulin levels also are proportional to the size of fat reserves (M. W. Schwartz &

Seeley, 1997) and provide a similar function. Together, leptin and insulin put the brakes on feeding in the arcuate nucleus, in part by inhibiting the NPY/AgRP neurons (Berthoud & Morrison, 2008). At the same time, they activate a second population of arcuate neurons known as POMC cells (because they release proopiomelanocortin); these neurons reduce feeding by inhibiting the PVN and lateral hypothalamus (Figure 6.8, #7 and #8; Elmquist, 2001; Gao & Horvath, 2007; M. W. Schwartz & Morton, 2002). We now understand that when Hervey destroyed the ventromedial hypothalamus in rats, he also severed fibers passing through it and disconnected the arcuate nucleus from the PVN (see Figure 6.2 again to see how this could happen). An additional contributor to the control of feeding and body weight that is not

illustrated in Figure 6.8 is orexin, a neuropeptide that increases appetite and induces eating. Some researchers prefer to use the alternate term, hypocretin, but because the name orexin is derived from orexis, the Greek word for “appetite,” it seems more appropriate here. Its neurons are activated when leptin or glucose is low and when ghrelin is high (Sakurai, 2007; Tsujino & Sakurai, 2009); thus, orexin is a hybrid that responds to both short-term and long-term indicators of nutrient reserves. Orexin- releasing neurons are located in the lateral hypothalamus; they project to the arcuate nucleus, where they increase feeding by activating NPY neurons and inhibiting POMC neurons. Table 6.1 summarizes the factors that influence hunger and feeding that we have

just covered, and the accompanying Application makes the point that these pathways respond to more than just energy needs. Until now, we have been considering the ideal situation, the regulation of feeding

and weight when all goes well. But in many cases, people eat too much, they eat the wrong kinds of foods, or they eat too little. As we will see, these behaviors are not just personal preferences or inconvenient quirks of behavior; too often, they are health- threatening disorders.

Take a Minute to Check Your Knowledge and Understanding

What is the advantage of the ability to access stored nutrients between meals?

How important are feeling “empty” and feeling “full” in the regulation of eating? Explain.

You have lost weight during a long illness and now you are ravenous. What are your likely levels of glucose, fatty acids, ghrelin, insulin, and leptin?

TABLE 6.1 Summary of Feeding Signals.

NOTE: Numbers refer to items in Figure 6.8 and in text. NST = nucleus of the solitary tract; CCK = cholecystokinin; PYY = peptide YY3-36; NPY = neuropeptide Y.

APPLICATION

How Nicotine and Marijuana Affect Appetite Monitoring the body’s energy reserves is a complex task requiring intricately complex mechanisms. But this system is made up of multipurpose components, so they also respond to signals from a number of unrelated sources. That is why smoking tobacco helps people keep their weight down and cancer and AIDS patients smoke marijuana to keep theirs up. Researchers at Yale and Baylor colleges of medicine traced nicotine’s

appetite-suppressing effects to a particular variety of nicotinic acetylcholine receptor in the arcuate nucleus, called a3ß4 (Mineur et al., 2011). Stimulating these receptors activates POMC neurons to curtail appetite; mice given a drug that targets a3ß4 ate half as much as untreated mice in the next 2 hours, and over a month their body fat dropped 15% to 20%. Areas important in hunger and feeding—the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus—also have an abundance of cannabinoid receptors, and injecting anandamide or THC into these areas caused satiated

mice to resume eating (Di Marzo, Ligresti, & Cristino, 2009). In human subjects, smoking marijuana cigarettes produced hunger-inducing increases in ghrelin levels and decreases in PYY. There are several reasons for not smoking tobacco or marijuana, but now

that we’ve identified the specific nicotinic receptor, pharmaceutical researchers should be able to develop a safer drug, and there are already alternative ways of administering THC, such as with inhalers. These may not be the best approaches to weight loss, but the problem has been so daunting that researchers are always looking for alternatives.

Obesity Two thirds of adults in the United States are overweight, and over one third of those individuals are obese (Flegal, Carroll, Ogden, & Curtin, 2010). This problem is not unique to the United States. According to a survey of 9 million people, obesity rates have almost doubled worldwide since 1980 (Finucane et al., 2011); this escalation has led the World Health Organization to declare obesity a global epidemic. For the first time in history, the number of people in the world who are overfed and overweight exceeds the number who are hungry and underweight (Figure 6.13; World Health Organization, 2003). However, the number of people who are malnourished is almost double the number who are under nourished, in part because many of those overweight are getting their calories from junk foods that are low in nutritional value (G. Gardner & Halweil, 2000). FIGURE 6.13 Underweight and Obesity According to the Country’s Level of Development.

SOURCE: From “Controlling the Global Obesity Epidemic,” by World Health

Organization (2003). Most researchers use the World Health Organization’s BMI calculation to quantify

leanness and obesity. Body mass index (BMI) is calculated by dividing the person’s weight in kilograms by the squared height in meters. (If you’re uncomfortable with metric measures, you can read your BMI from Figure 6.14.) People with BMIs between 25 and 29 are considered overweight, those whose BMIs are between 30 and 39 are considered obese, and those with BMIs of 40 and above qualify as morbidly obese. BMI is an inaccurate measure in some individuals; because muscle is heavier than fat, a healthy, bulked-up athlete will have a high BMI score. A more complete analysis would include a body fat measure and the waist-to-hip ratio. FIGURE 6.14 Body Mass Index Calculation Chart. BMIs in green are considered normal, yellow indicates overweight, and red signifies obesity.

SOURCE: Adapted from “Obesity: How Big a Problem?” by I. Wickelgren, Science, 280, pp. 1364–1367. Copyright 1998 American Association for the Advancement of Science. Reprinted with permission from AAAS. Obesity is most important because of its health risks. As overweight and obesity

increase, so does the incidence of diabetes; researchers estimate that the prevalence of diabetes will increase from 14% of the population in 2010 to 21% in 2050, and possibly run as high as 33% (Boyle, Thompson, Gregg, Barker, & Williamson, 2010). Being overweight also increases the likelihood of high blood pressure, heart disease, stroke, and colon cancer (Field et al., 2001; Must et al., 1999). Obesity is also linked to cognitive decline and risk for Alzheimer’s disease. Swedish researchers found that in women with lifelong obesity, for every one-point increase in BMI, there was a 13% to 16% increase in the risk of temporal lobe shrinkage due to cell loss (Gustafson,

Lissner, Bengtsson, Björkelund, & Skoog, 2004). The degeneration could have been the result of impaired blood flow to the brain or excess release of the stress hormone cortisol. In the United States, obesity accounts for 9% of all medical costs, or $150 billion annually (Finkelstein, Trogdon, Cohen, & Dietz, 2009). Health declines mean more than reduced quality of life. For every 5-point increase

in BMI over 25, the risk of death increases by 31% (de Gonzalez et al., 2010); the result is a shortening of lifespan between 2 and 10 years, depending on the degree of overweight (Prospective Studies Collaboration, 2009). Between 1990 and 2008, longevity declined, likely due to the effects of obesity and drug use; this was the first time in a century that life expectancy failed to increase (Olshansky et al., 2012). While the average loss was only a tenth of a year, among people with less than a high school education the loss rose to 3 years for men and a full 5 years for women. Just as obesity is detrimental to health, dietary restriction appears to be beneficial,

even in people who aren’t obese. As you would expect, limiting the number of calories by around 30% reduces cholesterol, triglycerides, and circulating levels of insulin and glucose. But it also lowers blood pressure and improves heart health and functioning (P. K. Stein et al., 2012; Trepanowski, Canale, Marshall, Kabir, & Bloomer, 2011), and in elderly subjects verbal memory improved 20% (Witte, Fobker, Gellner, Knecht, & Flöbel, 2009). Feeding restriction increases the lifespan of rats and mice by 20% to 60% (Kennedy, Steffen, & Kaeberlein, 2007), and some people believe the health benefits of dietary restriction will translate into longer lives for humans as well. But because humans have such a long lifespan, we’ll have to wait a few more years to find out whether they’re right. A 2009 study reported that calorie restriction extended the lives of monkeys, but a more recent one produced negative results; the two studies did agree that the deprived animals were healthier than the control subjects (Colman et al., 2009; Mattison et al., 2012). Few people are willing to undergo the required diet restriction, so biogerontologists are experimenting with drugs that produce similar changes in gene expression and improved health measures (Magalhães, Wuttke, Wood, Plank, & Vora, 2011). The Myths of Obesity Because obesity is dangerous to the person’s health as well as the occasion for

social and career discrimination, it is important to ask why people become overweight and why obesity rates are rising so dramatically. Although the causes have been difficult to document, most authorities believe that the global increase in obesity has a simple explanation: People are eating more and richer foods and exercising less (J. O. Hill & Peters, 1998; J. O. Hill, Wyatt, Reed, & Peters, 2003). The cause of obesity seems straightforward enough, then: Energy in exceeds energy out, and the person gains weight. But we would miss the point entirely if we assumed that people become obese just because they cannot resist the temptation to overeat. Research has not supported the popular opinion that obesity is completely under voluntary control

(Volkow & Wise, 2005) or that it can be characterized simply as lack of impulse control, inability to delay gratification, or maladaptive eating style (Rodin, Schank, & Striegel-Moore, 1989). In fact, as we will see later, obesity has a number of features in common with drug addiction.

Is obesity due to a lack of willpower? “

Most forms of obesity are likely to result not from an overwhelming lust for food or lack of willpower, but from biochemical defects at one or more points in the system responsible for the control of body weight.

—Michael Schwartz and Randy Seeley

” Another popular belief is that obese children learn overindulgence from their

family. Obesity does run in families, and body mass index and other measures are moderately related among family members. However, the evidence consistently points to genetic rather than environmental influences as more important (Grilo & Pogue- Geile, 1991). To the extent that environment does play a role, it is mostly from outside the family.

Is obesity hereditary? The Contributions of Heredity and Environment Two environmental influences on weight and obesity are obvious—diet and activity

level. During the last three decades of the 20th century, advancing prosperity and improved agricultural production led to greater food availability, and per-capita calorie consumption increased by 1% or more per year in most areas of the world (Rosen, 1999). But this abundance turned out to be a mixed blessing, due to unhealthy dietary choices; for example, by the year 2000, half of calorie consumption in the United States consisted of carbohydrates, and fat made up another third (Wright, Kennedy-Stephenson, Wang, & Johnson, 2004). This increased consumption added about 200 calories a day to the average U.S. diet (Wright et al., 2004), while decreasing energy demands on the job reduced daily energy expenditure by more than 100 calories (Church et al., 2011). As people drive rather than walk and spend more time in front of computers and televisions, activity levels are decreasing to the point that most world populations could be classified as sedentary within the next few years (Ng & Popkin, 2012). Physical activity begins to decline in adolescence, and reduced physical activity during that time is a strong predictor of obesity at age 25 (Pietiläinen et al., 2008). A less obvious influence is sleep deprivation. Over the last century, average sleep

time has decreased from around 9 hours per night to 6 hours and 40 minutes, a loss of 35%. Adults who sleep less than 6 hours a night on workdays have a 41% obesity rate, compared with 28% for 8-hour sleepers, and each hour of lost sleep during adolescence increases the risk of obesity by 80% (reviewed in McAllister et al., 2009). Sleep loss reduces leptin levels and increases ghrelin secretion, both of which cause a craving for high-calorie foods (Greer, Goldstein, & Walker, 2013). Remember that these hormone shifts also trigger the release of orexin, which is an additional reason appetite increases.

2 Calorie Intake by Country More surprising than the sleep connection is the possibility that some obesity is the

result of infection. The human adenovirus-36, which causes respiratory and eye infections, is three times more prevalent among obese individuals (Atkinson et al., 2005), and in one study the presence of antibodies for four common viruses accounted for 9% of subjects’ fat mass (Fernandez-Real et al., 2007). Animal research tells us that the viruses increase glucose uptake by fat cells; and because animals can be made obese by infecting them with the viruses, the viruses likely cause obesity in humans rather than being a result of it (McAllister et al., 2009). Bacteria also appear to play a role. When researchers transferred gut bacteria from obese humans to mice that had no gut microbes of their own, the mice increased their body fat by 10%, even though they were eating the same amount of food as mice that received microbes from the human donors’ lean twins (Ridaura et al., 2013). Bacteria of the phylum Firmicutes are the likely culprit; animal studies suggest they enhance the ability to harvest energy from nutrients. In a study of childhood obesity, obese children had a higher ratio of Firmicutes to Bacteriodetes, the other major phylum of gut bacteria (Bervoets et al., 2013). Bacteriodetes, on the other hand, may have a protective function. Cohousing the two mice treated with human microbes later in the study allowed them to eat each other’s feces, which they have the unsavory habit of doing. In this situation, Bacteriodetes invaded the intestines of the overweight mice, dominated the Firmicutes in number, and prevented the mice from gaining further weight. However, that happened only in mice fed the usual high-fiber/low-fat lab chow, not a high-fat diet. Genetic analysis indicated the likely reason: The lean mice had more genes expressed that are involved in breaking down dietary fiber. Both adoption studies and twin studies demonstrate the influence of heredity on

body weight. Adopted children show a moderate relationship with their biological parents’ weights and BMIs, and little or no similarity to their adoptive parents (Grilo & Pogue-Geile, 1991). In a compilation of studies involving 75,000 individuals, correlations for BMI averaged.74 for identical twins and.32 for fraternal twins (Maes, Neale, & Eaves, 1997). Even when identical twins are reared apart, the correlation drops only to.62 (Grilo & Pogue-Geile, 1991), still almost double that for fraternals

reared together (see Figure 6.15). Across 88 estimates from twin studies, heritability of BMI varied from.47 to.90, largely due to methodological differences (Elks et al., 2012). Interestingly, the correlation increased during childhood, likely due to increasing gene expression, and decreased through adulthood, possibly as subjects adopted individual dietary and exercise habits. FIGURE 6.15 Correlations of Body Mass Index Among Twins. Notice that the correlation is higher for identical twins than for fraternal twins, even when the identicals are reared apart and the fraternals are reared together.

SOURCE: Based on data from “The Nature of Environmental Influences on Weight and Obesity: A Behavior Genetic Analysis,” by C. M. Grilo and M. F. Pogue-Geile, 1991, Psychological Bulletin, 110, pp. 520–537. Forty years ago, it was known that the so-called obesity gene on chromosome 6 and

the diabetes gene on chromosome 4 cause obesity in mice. Mice that are homozygous for the recessive obesity gene (ob/ob) or the recessive diabetes gene (db/db) have the same symptoms: overeating, obesity, and susceptibility to diabetes (see Figure 6.16). To find out how the two genes produced these symptoms, D. L. Coleman (1973) used parabiotic pairings of the two kinds of mice and normals (Figure 6.17). When a db/db mouse was paired with a normal mouse, the normal mouse starved to death. The same thing happened to the ob/ob mouse when it was paired with the db/db mouse. These results suggested that the db/db mice were producing a fat signal but that they were not themselves sensitive to it. The ob/ob mouse had no effect on a normal mouse, but its own rate of weight gain slowed. The ob/ob mouse apparently was sensitive to a fat signal that it did not produce. It was another 20 years before researchers discovered that the fat signal in Coleman’s study (and Hervey’s 1952 lesioning study) was leptin. Following that discovery, they were able to test Coleman’s hypothesis. Injecting leptin into ob/ob mice reduced their weight 30% in just 2 weeks, while db/db mice were not affected by the injections (Halaas et al., 1995). We now understand that the ob gene encodes the production of leptin, and the db gene is responsible for the receptor. FIGURE 6.16 The Mouse on the Right is an ob/ob Mouse.

SOURCE: From “Positional Cloning of the Mouse Obese Gene and Its Human Homologue,” by Y. Zhang et al., 1994, Nature, 335, pp. 11–16. Reprinted by permission of Nature, copyright 1994. Those genes are rare in the population, however, and account for relatively few

cases of obesity. Sixteen percent of the population, on the other hand, have two copies of the A allele of the FTO gene, and this increases their risk of obesity by nearly 70%; even a single copy ups the risk by 30% (Frayling et al., 2007; see the accompanying In the News for the latest development). Variants of the MC4R gene add 12% to the risk for obesity in women (Loos et al., 2008) and account for 6% of cases of severe childhood obesity (Farooqi et al., 2003). Both of these genes promote obesity by increasing calorie intake (Loos et al.; Speakman, Rance, & Johnstone, 2008). A gene recently linked with obesity appears to have a combination of effects. Four variants of the Mrap2 gene found in severely obese individuals apparently interfere with functioning of the receptor for Mc4r, a protein involved in regulating appetite and energy expenditure (Asai et al., 2013). These mutations likely account for less than 1% of cases of obesity, however. More than 40 genetic variants are known to contribute to obesity and fat distribution (Herrera, Keildson, & Lindgren, 2011), and additional candidates turn up regularly. The research reminds us that there are many paths to obesity, including increased appetite, diminished satiety, reduced metabolism, and increased fat storage; accordingly, obesity results from the contributions of many genes. FIGURE 6.17 Effects of Leptin on ob/ob, db/db, and Normal Mice.

SOURCE: Based on the results of Coleman (1973). All the known genes account for only a small proportion of obesity, and heritability

measures leave room for significant environmental influence; indeed, we must recognize that the recent surge in obesity is due to nongenetic factors, such as diet and activity level. Even the tendency of overweight women to give birth to overweight babies cannot be attributed entirely to inheritance (Black, Sacks, Xiang, & Lawrence, 2013; Hochner et al., 2012); children born to women after they have lost weight through bariatric surgery are only one third as likely to be obese, compared with their siblings born before the surgery (J. Smith et al., 2009). The reason this discussion is occurring here is that environmental influences often work by altering gene activity; we call these effects epigenetic. Epigenetic characteristics are inheritable traits that result from modifications of gene expression rather than changes in the individual’s DNA sequence. One mechanism of epigenetic change is methylation, the attachment of molecules called methyl groups to a gene, which makes it more difficult for the gene to function. A recent study found that body mass index is correlated with methylation of a handful of genes that had previously been linked to obesity and diabetes (Feinberg et al., 2010). In another study, methylation of the RXRA gene at birth accounted for more than 25% of variation in childhood weight; the methylation apparently was due to low carbohydrate intake by the mothers during early pregnancy (Godfrey et al., 2011).

How the FTO Gene Makes Us Obese

Researchers have known about the FTO-obesity link for several years, but no one knew how the gene made people gain weight. But now Rachel Batterham and her colleagues at University College London have found that people with a single copy of the A allele have higher levels of ghrelin in their blood before a meal and their ghrelin levels don’t drop as much after eating, so they continue to feel hungry. After eating an 1,800-calorie meal, men with the A allele didn’t find food any more attractive overall than did the control subjects, but they rated pictures of

rich foods 50% higher. While they were viewing images of the rich foods, fMRI scans revealed increased activity in the same brain areas as in addicts when they are asked to think about their next drink or drug hit.

3 How FTO Causes Obesity

FIGURE 6.18 Methylation Counters Effects of a Mutant Gene. Both mice have a mutation in the agouti gene, but the mother of the mouse on the right received supplements high in methyl groups; the resulting methylation reduced expression of the mutant gene.

SOURCE: Courtesy of Randy L. Jirtle, Duke University Medical Center. You can see a graphic demonstration of the effects of methylation in Figure 6.18.

Both mice have a mutation in the agouti gene, which is responsible for the agouti- related peptide mentioned earlier; the mutation produces obesity and an atypical yellow coat. But during pregnancy, the mother of the mouse on the right was fed supplements high in methyl groups (folic acid and vitamin B12); the resulting methylation downregulated the mutant gene (Waterland & Jirtle, 2003). But the most dramatic example comes from the Dutch hunger winter of 1944–1945, when Germany blockaded food shipments to western Holland and 20,000 people died from starvation. A study of young men whose mothers were exposed to famine during early

pregnancy found that they were more often obese than unexposed control subjects (Ravelli, Stein, & Susser, 1976). More recent follow-up studies discovered the likely reason: In individuals exposed during early gestation, several genes that control prenatal growth showed modest increases or decreases in methylation, the remnants of epigenetic changes that occurred six decades earlier (Tobi et al., 2009; Tobi et al., 2012). Hunger winter offspring also had twice the typical rate of schizophrenia (Susser et al., 1996). In the following chapters, we will see growing evidence of the role of epigenetic influences on our lives and in our well-being. Meanwhile, the accompanying Application describes another influence on eating and weight gain that will likely also turn out to be epigenetic.

APPLICATION

The Sweet Taste of Obesity People who are obese like sweet and fatty foods more than lean people do (Bartoshuk, Duffy, Hayes, Moskowitz, & Snyder, 2006). That’s no surprise, but the fact that they are less sensitive to these tastes than the rest of us might surprise you. When asked to rate sweet stimuli, obese children rate them lower in flavor than other children do, plus they have trouble identifying all of the primary flavors (Overberg, Hummel, Krude, & Wiegand, 2012). In addition, adults with lower sensitivity to the taste of fat consume more fatty foods and have higher BMIs (Stewart et al., 2010). This might remind you of what we saw in Chapter 5: Liking for cocaine and

chronic drug use are associated with a less sensitive dopamine reward system, and evidence suggests that this reduced sensitivity is a cause rather than a result of drug abuse. So, do people eat more sweet and fatty foods because their taste is blunted, or has a high-calorie diet modified the obese person’s palate? Whereas taste ability is largely innate, personal taste preferences begin developing during the prenatal and postnatal periods (Beauchamp & Menella, 2009); for example, children whose mothers drank carrot juice regularly during either late pregnancy or initial breast, feeding ate more carrot-flavored cereal than other children (Menella, Jagnow, & Beauchamp, 2001). According to a study with rats, exposure to novel flavors produces long-term changes in the gustatory projection area (Swank & Sweatt, 2001). So, experience can influence taste, but to answer our question about what

causes the obesity-taste relationship, we need to look at a study in which researchers induced lean rats to become obese by offering them access to a high-fat diet. After 10 weeks, the mice were 30% to 40% heavier than their littermates; they also were less sensitive to sweet tastes, and fewer of their taste cells were physiologically responsive to the sweet stimuli (Maliphol,

Garth, & Medler, 2013). The critical study hasn’t been done yet, but the evidence we’ve seen for diet-induced epigenetic effects on obesity suggests we look for epigenetic influences of diet on taste in obese individuals. This could be important because of the likelihood that once taste sensitivity

shifts downward, it contributes to further overeating. In fact, the lead researcher suggests that the mice had to eat more to get the same taste-cued satisfaction as their lean brothers and sisters (Hsu, 2013). It’s very conceivable that obesity involves a cycle of overeating due to genetic and/or environmental influences, leading to reduced taste sensitivity, which encourages more overeating, and so on.

Obesity and Reduced Metabolism Accounts of dieting are all too often stories of failure; overweight people report

slavishly following rigorous diets without appreciable weight loss, or they lose weight and then gain it back within a year’s time. One factor in the failures may be dieters’ misrepresentation of their efforts, whether intentional or not. One group of diet- resistant obese individuals underreported the amount of food they consumed by 47% and overreported their physical activity by 51% (Lichtman et al., 1992). But another critical element that can make weight loss difficult is a person’s rate of

energy expenditure. In the average sedentary adult, about 75% of daily energy expenditure goes into resting or basal metabolism, the energy required to fuel the brain and other organs and to maintain body temperature; the remainder is spent about equally in physical activity and in digesting food (Bogardus et al., 1986). Differences in basal metabolism may be a key element in explaining differences in

weight. When 29 women who claimed they could not lose weight were isolated and monitored closely while they were restricted to a diet of 1,500 kilocalories (kcal; a measure of food’s energy value, popularly called calorie), 19 did lose weight, but 10 did not (D. S. Miller & Parsonage, 1975). The 10 who failed to lose weight turned out to have a low basal metabolism rate (BMR). Heredity accounts for about 40% of people’s differences in BMR (C. Bouchard, 1989). When identical twins were overfed 1,000 calories a day for 3 months, the differences in weight gain within pairs of twins were only one third as great as the differences across pairs (C. Bouchard et al., 1990). However, a person’s metabolism can shift when the person gains or loses weight. In

an unusual experimental manipulation, researchers had both obese and never-obese individuals either lose weight or gain weight (Leibel, Rosenbaum, & Hirsch, 1995). Those who lost weight shifted to reduced levels of energy expenditure (resting plus nonresting), and the ones who gained weight increased their energy expenditure. This was expected, because your weight affects how much energy is required to move around and even to sit or stand. However, the energy expenditure changes were greater than the weight changes would require, suggesting that the individuals’ bodies

were defending their original weight (see Keesey & Powley, 1986). So why doesn’t this defense of body weight prevent people from becoming obese?

One reason is that the body defends less against weight gain than against weight loss (J. O. Hill et al., 2003; J. O. Hill & Peters, 1998). Humans evolved in an environment in which food was sometimes scarce, so it made sense for the body to store excess nutrients during times of plenty and to protect those reserves during famine. Such a system is adaptive when humans are at the mercy of nature, but it is a liability when modern agriculture and global transportation provide a constant supply of more food than we need. “

What is a wisdom of the body in times of deprivation becomes a foolishness in our modern environment.

—Xavier Pi-Sunyer

” A second reason is that people vary tremendously in the strength of their defense

response, making some people more vulnerable to becoming overweight than others. When volunteers were overfed 1,000 calories a day, on average only 40% of the excess calories were stored as fat and the remaining 60% were burned off by increased energy expenditure (F. R. Levine, Eberhardt, & Jensen, 1999). But some individuals had smaller increases in energy expenditure, and they gained 10 times as much weight as others. Two thirds of the volunteers’ increases in energy expenditure were due to nonexercise physical activity—casual walking, fidgeting, spontaneous muscle contraction, and posture maintenance. Researchers are beginning to think that spontaneous activity may be as important as basal metabolism in resisting obesity. Prolonged weight gain may actually reset the set point at a higher level. Barbara

Rolls and her colleagues fattened rats on highly palatable, high-energy junk food (chocolate chip cookies, potato chips, and cheese crackers) for 90 days (Rolls, Rowe, et al., 1980). Surprisingly, when the rats were returned to their usual lab chow they did not lose weight. The rats maintained their increased weight for the 4-month duration of the study—while eating the same amount of food as the control rats. They were defending a new set point. The researchers suggested that the variety of the foods offered, the length of the fattening period, and lack of exercise all contributed to the rats’ failure to defend their original weight. In view of the difficulties in shedding excess weight, one obesity researcher suggested that returning to normal weight may not be a reasonable goal, and a goal of 10% weight reduction is more practical (Pi- Sunyer, 2003).

How can obesity be treated?

Treating Obesity There is no greater testimony to the difficulty of losing weight than the lengths to

which patients and doctors have gone to bring about weight loss. These include wiring the jaws shut, surgically reducing the stomach’s capacity, and removing fat tissue. The standard treatment for obesity, of course, is dietary restriction. However, we have seen that the body defends against weight loss, and dieters are usually frustrated. Exercise burns fat, but it takes a great deal of effort to use just a few hundred calories. On the other hand, exercise during dieting may increase resting metabolic rate or at least prevent it from dropping (Calles-Escandón & Horton, 1992). Dieters who exercise lose more weight than dieters who do not exercise (see Figure 6.19; J. O. Hill et al., 1989). In a study of formerly obese women, 90% of those who maintained their weight loss exercised, compared with 34% of those who regained their lost weight (Kayman, Bruvold, & Stern, 1990). “

Obesity is the most dangerous epidemic facing mankind, and we are relatively unprepared for it.

—George Yancopoulos

” Another option in the treatment of obesity is medication. However, it has not been a

particularly promising alternative; lack of effectiveness is one problem, and because the drugs manipulate metabolic and other important body systems, they often have adverse side effects. The approval of dexfenfluramine in 1996 was the first by the Food and Drug Administration (FDA) in 20 years. But just a year later, both dexfenfluramine and the older fenfluramine (used in the now-notorious combination called fen-phen) were withdrawn from the market by the manufacturer after reports that they caused heart valve leakage (Campfield, Smith, & Burn, 1998). Abbott Laboratories withdrew sibutramine (marketed as Meridia) because of increased risk of heart attack and stroke (“Abbott Laboratories Agrees to Withdraw...,” 2010), and rimonabant, which was never approved in the United States, was withdrawn from the European market after it was linked to serious psychiatric disorders (Taylor, 2009). In the United States, only orlistat (marketed as Xenical and Alli) remained available. Orlistat blocks fat absorption, and as a result produces digestive discomfort in some individuals; it also requires a label warning about rare reports of liver damage (“FDA Drug Safety... Injury,” 2010). After 13 years without any new drugs being approved for long-term weight loss, two reached the market in the summer of 2012. Belviq, which activates serotonin 2C receptors in the brain, led to a 5% loss in body weight in 38% of patients, compared with 16% of patients on placebo (“FDA Approves Belviq...,” 2012). The second, Qsymia, is thought to work by increasing leptin; 69%

of patients lost 5% of their body weight, compared with 20% treated with placebo (“FDA Approves Weight-Management Drug Qsymia,” 2012).

4 Overeaters Anonymous FIGURE 6.19 The Effect of Exercise on Weight Loss. Dieters who also exercised lost 32% more weight than those who did not, and they lost 40% more body fat.

SOURCE: Based on data from J. O. Hill et al. (1989). Four of the seven drugs mentioned above increase serotonin activity, either by

activating serotonin receptors or by increasing transmitter levels, and serotonin plays an interesting role in weight control. Carbohydrate regulation involves a feedback loop; eating carbohydrates increases serotonin levels, which inhibits a person’s appetite for carbohydrates (Leibowitz & Alexander, 1998), apparently by reducing NPY activity (Dryden, Wang, Frankish, Pickavance, & Williams, 1995). Drugs that block serotonin reuptake reduce carbohydrate intake, but only in the group of obese individuals who crave carbohydrates and eat a large proportion of their diet in carbohydrates (Lieberman, Wurtman, & Chew, 1986; J. J. Wurtman, Wurtman, Reynolds, Tsay, & Chew, 1987). Serotonin also enhances mood in some people, and people who have trouble maintaining weight loss often say that they use food to make themselves feel better when they are upset (Kayman et al., 1990). A high- carbohydrate meal also improves mood only in carbohydrate cravers; it actually lowers the mood of noncravers and makes them feel fatigued and sleepy (Lieberman et al., 1986). So serotonin dysregulation may be important in obesity, but only in a subset of people. FIGURE 6.20 A Leptin-Deficient Boy Before and After Treatment. (a) At age 3.5 years when treatment began and (b) at age 8 and at normal weight.

SOURCE: Courtesy of Sadaf Farooqi and Stephen O'Rahilly. By now you should be asking, “Why not try the body’s own hormones as weight-

loss drugs?” And, of course, researchers have thought of that as well. Attempts to use PYY have so far been unsuccessful, because of either a lack of effect or extreme nausea (De Silva & Bloom, 2012). Leptin is particularly attractive to obesity researchers because, unlike food restriction, it increases metabolism (N. Levin et al., 1996), and it targets fat reduction while sparing lean mass (P. Cohen & Friedman, 2004). Leptin was administered to three severely obese children who produced no leptin at all due to a mutation in the ob gene (Farooqi et al., 2002). Their body weights decreased throughout treatment although they were increasing in age; more than 98% of the weight loss was in fat mass, while lean mass increased. Figure 6.20 shows how dramatic the effects were in one of the children. Unfortunately, leptin treatment benefits only the 5% to 10% of obese people who are leptin deficient; the rest are resistant to leptin’s effects, apparently as a result of long-term high-fat consumption (Enriori et al., 2007; Maffei et al., 1995). Many obesity researchers now believe that leptin’s main role is in protecting the individual against weight loss during times of deprivation rather than against weight gain during times of plenty (Marx, 2003). FIGURE 6.21 Diminished Number of Dopamine D2 Receptors in Obese Individuals. Less intense colors in the PET scan of obese individuals (showing the group average) reveal that D2 receptors are reduced in the same areas as in individuals with drug addictions.

SOURCE: Reprinted from “Brain Dopamine and Obesity,” by G.-J. Wang et al., 2001, Lancet, 357, pp. 354–357, with permission from Elsevier. A more recent therapeutic approach involves treating obesity as an addictive

behavior. Compulsive overeating and drug addiction share several behavioral and neurophysiological similarities, including high relapse rate, responsiveness to stress, dopamine release in response to cues, reduced numbers of dopamine D2 receptors (Figure 6.21) with associated decreases in metabolism in prefrontal areas involved in impulse control, and continued drug taking and compulsive eating when the behaviors are self-destructive and no longer pleasurable (V. H. Taylor, Curtis, & Davis, 2009; Trinko, Sears, Guarnieri, & DiLeone, 2007; Volkow, Wang, Fowler, & Telang, 2008). In addition, signals that influence eating—orexin, insulin, leptin, and ghrelin—also increase or decrease activity in the reward system (Volkow, Wang, Tomasi, & Baler, 2013). Some drugs used in addiction treatment have shown promise for treating obesity as well. Obese patients taking Contrave, a combination of the antiaddiction drugs bupropion and naltrexone, lost 50% more weight than patients receiving a placebo; the manufacturer is in the final stages of obtaining FDA approval (“Orexigen Has Another Go,” 2013; “Orexigen Therapeutics,” 2009). FIGURE 6.22 Gastric Bypass Procedure. A small area of the stomach is isolated from the rest. Then the small intestine is severed, and the cut end is attached to the pouch, reducing the length of the intestine and the amount of nutrient absorption.

SOURCE: Adapted from Ainsworth (2009). Unfortunately, lifestyle modification and approved drug therapies reduce body

weight by only 5% to 10% (Mitka, 2006), and most dieters regain their weight within a year (Bray, 1992). That much weight reduction can lead to significant health gains, but it is not enough for the morbidly obese, who are increasingly turning to bariatric surgery. The cost is substantial—about $28,000 on average for the surgery, plus a death rate of 1 in 200 patients within 6 months (Encinosa, Bernard, Du, & Steiner, 2009)—but the benefits can be remarkable. The most effective procedure, gastric bypass, reduces the stomach to a small pouch, which is then reconnected at a lower point on the intestine (see Figure 6.22). This both limits meal size and reduces nutrient absorption in the digestive tract. The resulting weight loss averages 32% after 1 or 2 years and is maintained at 25% 10 years later (Sjöström et al., 2007). The weight loss engenders a cascade of additional benefits: remission of type 2 diabetes in 77% of patients, hypertension in 66%, and sleep apnea in 88% (Buchwald et al., 2004), as well as a 27% reduction in mortality at 15 years (Sjöström et al.). An additional benefit of reducing the amount of functional digestive tract is that postmeal levels of ghrelin are decreased and GLP-1 and PYY are increased (Pournaras & le Roux, 2009), so the individual doesn’t feel hungry. Surgery is a last resort, though, and its downsides highlight the need for obesity prevention and new strategies for weight management. Not everyone with an eating disorder is overweight or obese. Some try so hard to

control their weight that they eat less than is needed to maintain health, or they eat normal or excess amounts and then vomit or use laxatives to avoid gaining weight. As you will see, anorexia and bulimia are as puzzling to researchers as obesity and often

Concept Check

more deadly for the victims.

Take a Minute to Check Your Knowledge and Understanding

What are the causes of obesity? Of the current surge in obesity? How does defense of body weight contribute to obesity? What are the problems in treating obesity?

Anorexia, Bulimia, and Binge Eating Disorder Difficulties with eating and weight regulation affect women much more often than they do men. Though men are overrepresented among U.S. adults who are overweight or obese, women outnumber men two to one among the extremely obese (U.S. Department of Health and Human Services, 2012). Similarly, women are three times as likely to be diagnosed with anorexia nervosa or bulimia nervosa, and twice as likely to suffer from binge eating disorder (Figure 6.23; Hudson, Hiripi, Pope, & Kessler, 2007). The reasons are not well understood, so they will not be addressed here, but you should understand why the following discussion often refers only to women or girls. FIGURE 6.23 Prevalence by Sex of Overweight, Obesity, and Eating Disorders.

SOURCE: Based on data from Hudson, Hiripi, Pope, and Kessler (2007); U.S. Department of Health and Human Services (2012). Anorexia nervosa is known as the “starving disease” because the individual restricts

food intake to maintain weight at a level so low that it is threatening to health (see Figure 6.24; Walsh & Devlin, 1998). The person may also exercise for hours a day or resort to vomiting to control weight loss. Anorexics often see themselves as fat even when they are emaciated. They are likely to deny the need for treatment and fail to

comprehend the medical consequences of their disorder. There are two subgroups of anorexics. Restrictors rely only on reducing food intake to control their weight. Binge-purgers restrict their calorie intake as well, but they also resort to vomiting or using laxatives. If anorexia continues long enough, it leads to cessation of ovulation, loss of muscle

mass, heart damage, and reduction in bone density. The death rate among anorexics is more than double that for female psychiatric patients; half of the deaths are from complications of the disease and another quarter from suicide (Sullivan, 1995). Brain scans show deficits in brain volume, which appear to be only partially reversible following weight recovery (Castro-Fornieles et al., 2009; Lambe, Katzman, Mikulis, Kennedy, & Zipursky, 1997; Mainz, Schulte-Rüther, Fink, Herpertz-Dahlmann, & Konrad, 2012). Brain scans also reveal dysfunction in areas involved in reward, emotion, and processing of bodily information, including those responsible for body image (Kaye, Fudge, & Paulus, 2009). The studies do not tell us whether these brain anomalies are due to starvation or represent conditions that precede and contribute to the anorexia. However, the poor performance of anorexics on a behavioral test of frontal cortex functioning continues after recovery and is found in healthy sisters (Attia, 2009). In addition, the presence of obsessive-compulsive traits, harm avoidance, and perfectionism during childhood as well as after recovery suggests the presence of predisposing factors before the onset of illness (Kaye et al.).

What are anorexia, bulimia, and binge eating disorder?

5 Eating Disorders FIGURE 6.24 French Model Isabelle Caro in Late Stages of Anorexia. Caro, who suffered from anorexia from the age of 13, fell into a coma when her weight dropped to 55 pounds. That experience led her to pose for photos that appeared in newspapers and on billboards as part of an Italian anti-anorexia campaign. She died 3 years later at the age of 28; her mother committed suicide over the guilt she felt.

SOURCE: © Agencia el Universal/El Universal de Mexico/Newscom. The anorexic individual’s unwillingness to eat does not necessarily imply a lack of

hunger. NPY and ghrelin are elevated and leptin levels are diminished (Kaye, Berrettini, Gwitsman, & George, 1990; Mantzoros, Flier, Lesem, Brewerton, & Jimerson, 1997; Shiiya et al., 2009), so apparently anorexics are “hungry” whether they realize it or not. The sight of attractive food increases their insulin levels more than it does in lean people; lean subjects eat the food when it is offered, but the anorexics do not in spite of overnight fasting, saying they aren’t hungry (Broberg & Bernstein, 1989). Bulimia nervosa also involves weight control, but the behavior is limited to

bingeing and purging. If the bulimic restricts food intake, it is only for a few days at a time, and restricting takes a backseat to bingeing and purging. In fact, only 19% of bulimic women consume fewer calories than normal controls, while 44% overeat (Weltzin, Hsu, Pollice, & Kaye, 1991). Unlike anorexics, most bulimic women are of normal weight (Walsh & Devlin, 1998). However, there are indications that, like anorexics, they might also be battling hunger. Their ghrelin levels between meals are a third higher than in control subjects and decrease less following a meal; in addition, PYY levels do not rise as much following a meal (Kojima et al., 2005). Like anorexia, bulimia is also a dangerous disorder. Both anorexia and bulimia are difficult to treat; although three quarters of bulimics and a third of anorexics appear to be fully recovered after 8 years, a third of these relapse (D. B. Herzog et al., 1999). People with binge eating disorder frequently eat large amounts of food during a

short period of time, and they feel they cannot control what or how much they eat. Because the individuals do not attempt to control weight by fasting, purging, or exercising, they typically are overweight, but this is not a requirement for diagnosis. They usually feel disgust and shame about their overeating, so they often choose to eat separately from others and do their bingeing in seclusion. Binge eating disorder has been recognized clinically only during the past two decades, and was included as a disorder for the first time in the 2013 revision of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013). For this

reason, there has been much less research on this disorder than on anorexia and bulimia.

What is the evidence for social and genetic influences in anorexia and bulimia? Environmental and Genetic Contributions Both anorexics and bulimics are preoccupied with weight and body shape. Because

increases in anorexia and bulimia seem to have paralleled an increasing cultural emphasis on thinness and beauty, some researchers have concluded that the cause is social. The male–female difference is consistent with this argument, because women are under more pressure to be slim while men are encouraged to “bulk up.” Cases are more common in Western, industrialized countries, where an impractical level of thinness is promoted by actors, models, and advertisers. Anne Becker of Harvard Medical School has been studying eating habits in the Pacific islands of Fiji since 1988 (Becker, Burwell, Gilman, Herzog, & Hamburg, 2002). Traditionally, a robust, muscled body has been valued for both sexes there. But when satellite television arrived in 1995, the tall, slim actors in shows like Beverly Hills 90210 became teenage Fiji’s new role models. By 1998, 74% of young island girls considered themselves too big or fat, even though they were not more overweight than others. Young girls who lived in homes that owned a TV were three times more likely to have an eating problem. Among 17-year-old girls, 11% admitted they had vomited to control weight, compared with just 3% in 1995. There is little doubt that social pressure contributes to anorexia and bulimia. But the

disorders are not unknown in non-Westernized societies, and anorexia has been reported for 300 years, long before the cultural emphasis on thinness. One indication that a sociocultural explanation is an oversimplification is that several studies show a genetic influence. Relatives of patients have a higher than usual incidence of the disorders, and the concordances for anorexia and bulimia are about three times greater for identical twins than for fraternals (Kendler et al., 1991; Kipman, Gorwood, Mouren-Simeoni, & Ad’es, 1999). Heritability has been estimated at 56% for anorexia (Bulik, Sullivan, Tozzi, Furberg, Lichtenstein, & Pedersen, 2006), 54% to 83% for bulimia (Bulik et al., 2003), and 45% for binge eating disorder (Mitchell et al., 2010). There has been no shortage of candidate genes, but definitive results have been

elusive; this is due to a variety of reasons, including the apparent involvement of many small-effect genes, difficulty acquiring adequate numbers of patient volunteers, and the failure of studies to distinguish between the two subtypes of anorexia. The most promising results so far implicate a serotonin receptor gene and a dopamine receptor gene in anorexia; estrogen and cannabinoid genes that influence food intake in bulimia; and a serotonin transporter gene in binge eating disorder (Trace, Baker, Peñas-Lledó, & Bulik, 2013).

When researchers followed 772 female twins through adolescence, they made a surprising discovery (Klump, Burt, McGue, & Iacono, 2007). At age 11, genetic factors accounted for just 6% of disordered eating symptoms, such as weight preoccupation, body dissatisfaction, and binge eating, but by age 14 they accounted for 46% of the variance. Almost all of the nongenetic influence is unique to the individual (Bulik et al., 2006; Bulik, Sullivan, Wade, & Kendler, 2000; Mitchell et al., 2010), which suggests the possibility that adolescent hormonal changes, stress, and dieting (and, possibly, prenatal conditions) produce epigenetic changes in the genes that play a role in anorexia and bulimia. There has been relatively little research in this area, but epigenetic dysregulation of dopamine genes has been reported in women with anorexia and bulimia (Frieling et al., 2010). Eating disorders typically are accompanied by comorbid psychological disorders;

in a study of 2,436 female inpatients, almost all were diagnosed with depression, more than half had anxiety disorders, 22% had substance abuse disorders, and obsessive- compulsive disorder varied from 15% to 29% across the groups (Blinder, Cumella, & Sanathara, 2006). Studies have also confirmed genetic associations of eating disorders with depression and obsessive-compulsive disorder (Scherag, Hebebrand, & Hinney, 2009). Because you know the limitations of correlational studies, you should be thinking that there are three possible reasons for this relationship: The psychological disorders could trigger disordered eating, starvation or overeating could precipitate an emotional disorder, or both of these could be the result of a third underlying cause. For us, the immediate value is that this correlation leads us to look at transmitters involved in the two emotional disorders and in reward and substance abuse.

What role does serotonin appear to have in anorexia and bulimia? The Role of Serotonin, Dopamine, and Cannabinoids The involvement of serotonin and dopamine has been suggested by a large number

of genetic studies. Researchers have focused most on serotonin, largely because it is involved so intimately in eating behavior and in the anxiety, depression, obsessiveness, and impulsive behavior that typically accompany anorexia and bulimia (Kaye, Gendall, & Strober, 1998). Antidepressants that block the reuptake of serotonin at synapses reduce bingeing and purging in patients with bulimia, and they lower the chance of relapse after recovery from anorexia. This finding led researchers to look for evidence of decreased serotonin activity. Instead, levels of serotonin metabolites in the cerebrospinal fluid were normal in the ill bulimia patients and they rose to above normal after recovery (see Figure 6.25). Levels did turn out to be low in patients with anorexia, but only during illness when their starvation diet provided too little tryptophan, the precursor to serotonin. After weight recovery (the only time antidepressants help them), metabolite levels were higher than normal. In addition, symptom improvement was unrelated to any reduction in depression, or even whether

depression was present. The key might not be in the general level of serotonin activity but in which of two

types of serotonin receptor is more abundant. The 5HT1A receptor responds to serotonin by inhibiting neural activity, while the 5HT2A receptor increases activation. A preponderance of 5HT1A receptors in the subgenual prefrontal cortex appears to interfere with the area’s executive control over the amygdala; individuals with a higher ratio of 1A receptors respond more to photos depicting fearful or angry facial expressions than do subjects with a higher 2A ratio (Fisher et al., 2011). Imaging studies indicate that anorexia and bulimia patients have an imbalance in activity at serotonin receptors, with increased transmitter binding at the 5HT1A receptors and diminished binding at 5HT2A receptors in both groups (Bailer & Kaye, 2010). These receptors are of interest because of their role in anxiety, depression, compulsive behavior, and harm avoidance, and because 1A/2A imbalance is found in brain areas known to be involved in these symptoms. Bailer and Kaye also think this imbalance explains why people with anorexia have such a compelling urge to starve themselves. They point to evidence that experimentally depleting tryptophan reduces anxiety in both ill and recovered subjects and suggest that food restriction serves to reduce anxiety by depriving 5HT1A receptors of serotonin. FIGURE 6.25 Cerebrospinal Fluid 5-HIAA in Anorexia and Bulimia Values are compared to levels in healthy control women, which are set at 100%. 5- HIAA (5-hydroxyindoleacetic acid) is a metabolite of serotonin and the level found in cerebrospinal fluid is used to estimate serotonin activity.

SOURCE: Adapted from Figure 1 of “Serotonin Neuronal Function and Selective Serotonin Reuptake Inhibiitor Treatment in Anorexia and Bulimia Nervosa,” by W. Kaye, K. Gendall, and M. Strober, Biological Psychiatry, 44, pp. 825–838. Copyright, 1998. Used with permission from Elsevier. Anorexia patients’ distinctive lack of enjoyment and ability to deny themselves not

only food but other pleasures of life suggest that disordered reward systems might

Concept Check

also be at work (Cassin & von Ranson, 2005). Individuals ill with and recovered from anorexia have low levels of dopamine metabolites in the cerebrospinal fluid, and evidence indicates that dopamine activity may be diminished in the ventral striatum, one of the areas important in reward. Similar measures in another brain area are associated with higher levels of harm avoidance in weight-recovered patients (Kaye et al., 2009). In addition, increasing dopamine activity by administering amphetamine produced euphoria in control subjects but increased anxiety in subjects recovered from anorexia (Bailer et al., 2012). Because eating increases dopamine release, this finding lends additional support to the idea that food restriction serves to reduce anxiety. The cannabinoid system, which plays a role in food intake and reward, also appears to be involved (Gérard, Pieters, Goffin, Bormans, & Van Laere, 2011). Both anorexic and bulimic patients have larger numbers of cannabinoid receptors in the insula, whose functions include the rewarding effects of food and responses to hunger; viewing pictures of food invokes atypical activity there in both groups.

Take a Minute to Check Your Knowledge and Understanding

What are the likely causes of anorexia and bulimia? How are anorexics and bulimics alike and different? (Don’t forget the two types of anorexics.)

In Perspective Temperature regulation, thirst, and hunger provide good examples of drive, homeostasis, and physiological motivation in general. Although they are explained best by drive theory, they also illustrate the point that it is ultimately the balance or imbalance in certain brain centers that determines motivated behaviors. In addition, hunger in particular demonstrates that homeostasis alone does not

explain all the facets of motivated behavior. For instance, we saw that the incentives of the sight and smell of food are enough to start the physiological processes involved in the absorptive phase. This suggests that incentives operate through physiological mechanisms and are themselves physiological in nature. We also know that there are important social influences on what and how much people eat, and sensation seeking may explain why some people are gourmets or enjoy the risks of eating puffer fish. Most of the factors that determine our eating behavior are in turn influenced by

genes. If it is true that we are what we eat, it is equally true that what we eat (and how much) is the result of who we are. But we will be reminded time and again throughout this text that heredity is not destiny, that we are the products of countless interactions between our genetic propensities and the environment.

Our interest in the motivation of hunger would be mostly theoretical if it were not for eating disorders, which can have life-threatening consequences. But in spite of their importance, we are unsure about the causes of obesity, anorexia, bulimia, and binge eating disorder, as well as what the best treatments are. We do know that, like the motivation of hunger itself, they are complex and have a number of causes. This chapter has given you an overview of what we mean by motivation. We will

broaden that view in the next two chapters by looking at sexuality, emotion, and aggression. Summary Motivation and Homeostasis • Homeostasis and drive theory are key to understanding physiological motivation, but they are not adequate alone.

• Temperature regulation involves a simple mechanism for control around a set point. • Thirst is a bit more complex, compensating for deficits both in the cells (osmotic thirst) and outside the cells (hypovolemic thirst).

Hunger: A Complex Drive • Hunger is a more complex motivation, involving a variety of nutrients and regulation of both short-term and long-term nutrient supplies.

• Taste helps an individual select nutritious foods, avoid dangerous ones, and vary the diet.

• The feeding cycle consists of an absorptive phase, a period of living off nutrients from the last meal, and the fasting phase, when reliance shifts to stored nutrients.

• Eating is initiated when low blood levels of glucose and fatty acids are detected in the liver. The information is sent to the medulla and to the paraventricular nucleus of the hypothalamus, where neuropeptide Y is released to initiate eating.

• Feeding stops when stretch signals from the stomach, increasing glucose levels in the liver, and cholecystokinin released in the duodenum indicate that satiety has occurred.

• How much we eat at a meal is also regulated by the amount of fat we have stored, indicated by leptin and insulin levels.

Obesity • Obesity is associated with malnutrition and with a variety of illnesses. • A variety of factors, many of them outside the person’s control, contribute to obesity.

• Obesity is partly inheritable, and the environmental influences that exist are not primarily from the family.

• As calorie intake decreases, metabolism decreases to defend against weight loss. • Obesity is difficult to treat, but drugs that increase serotonin activity appear most promising, and bariatric surgery is beneficial for more extreme obesity.

Anorexia, Bulimia, and Binge Eating Disorder

• Anorexia involves restriction of food intake, and sometimes bingeing and purging, to reduce weight. Bulimia is a bingeing disease; weight increase is limited by purging or exercise.

• Social pressure and heredity both appear to be important in anorexia and bulimia. • People with binge eating disorder eat excessively during a brief period of time; they are typically, but not always, overweight.

• Family and twin studies indicate a strong hereditary component, though few genes have been reliably identified. The large amount of individually unique environmental influence suggests epigenetic effects.

• Anomalies in serotonin, dopamine, and cannabinoid systems also are implicated. ■ Study Resources

For Further Thought • If a group of nuclei in the brain control a particular homeostatic need, what functions must those nuclei carry out?

• What do you think would happen if the brain had no way of monitoring stored fat levels?

• Several of the controls of eating seem to duplicate themselves. Is this wasteful or useful? Explain.

• What do you think a complete program of obesity treatment would look like? • Can you propose another way to organize the three subgroups that make up anorexics and bulimics—perhaps even renaming the disorders?

Quiz: Testing Your Understanding 1. Describe either temperature regulation or thirst in terms of homeostasis,

drive, and satisfaction, including the signals and brain structures involved in the process.

2. Describe the absorptive and fasting phases of the feeding cycle; be specific about what nutrients are available, how nutrients are stored, and how they are retrieved from storage.

3. Describe obesity as a problem of metabolism. Select the best answer: 1. A problem that makes some question drive theory is that

a. an animal remains aroused after the need is satisfied. b. some people have stronger drives than others. c. not all motivation involves tissue needs. d. soon after a drive is satisfied, the system goes out of equilibrium again.

2. An animal is said to be in homeostasis when it a. recognizes that it is satisfied. b. feels a surge of pleasure from taking a drink. c. is in the middle of a high-calorie meal.

d. is at its set point temperature. 3. Osmotic thirst is due to

a. dryness of the mouth and throat. b. lack of fluid in the cells. c. reduced volume of the blood. d. stimulation of pressure receptors.

4. A structure in the medulla that is involved in taste as well as in hunger and eating is the a. nucleus of the solitary tract. b. paraventricular nucleus. c. area postrema. d. subfornical organ.

5. You have trouble with rabbits eating your garden. Several sprays are available, but they are washed off each day by the sprinklers. The solution with the best combination of kindness, effectiveness, and ease for you would be to a. spray the plants daily with a substance that tastes too bad to eat. b. spray the plants occasionally with a substance that makes the rabbits sick. c. spray the plants with a poison until all the rabbits are gone. d. forget about spraying; run outside and chase the rabbits away.

6. During the absorptive phase a. fat is broken down into glycerol and fatty acids. b. insulin levels are low. c. glucagon converts glycogen to glucose. d. glucose from the stomach is the main energy source.

7. Neurons in the arcuate nucleus release NPY, which a. increases eating. b. increases drinking. c. breaks down fat. d. causes shivering.

8. A long-term signal that influences eating is a. glucose. b. 2-deoxyglucose. c. cholecystokinin. d. leptin.

9. Regarding environmental influences on weight, a. smoking increases appetite. b. the influence of infection appears to be minimal. c. sleep loss increases appetite. d. social influence is mostly from the family.

10. When we say that the body defends weight during dieting, we mean primarily that a. the person’s metabolism decreases. b. the person eats less but selects richer foods. c. the person eats lower-calorie foods but eats larger servings. d. the body releases less NPY.

11. Studies comparing the weights of adopted children with their biological parents and their adoptive parents a. show that weight is influenced most by environment. b. show that weight is influenced most by heredity. c. show that heredity and environment have about equal influence. d. have not been in agreement.

12. If a db/db mouse is parabiotically attached to a normal mouse, the db/db mouse will a. gain weight while the normal loses. b. lose weight while the normal gains. c. be unaffected while the normal loses. d. be unaffected while the normal gains.

13. Epigenetic effects on offspring weight have resulted from the mother’s a. drug use. b. activity level. c. diet. d. smoking.

14. Which of the following was not discussed as a factor in anorexia and/or bulimia? a. Increased numbers of nicotinic acetylcholine receptors. b. An imbalance in types of 5HT receptors. c. Reduced dopamine activity. d. Increased numbers of cannabinoid receptors.

15. Regarding anorexia and bulimia, a. both are characterized by a deficiency in hunger. b. evidence indicates that epigenetic changes occur during adolescence. c. they appear to be uniquely distinct from other disorders. d. antidepressants help with anorexia, but not bulimia.

Answers: 1. c, 2. d, 3. b, 4. a, 5. b, 6. d, 7. a, 8. d, 9. c, 10. a, 11. b, 12. c, 13. c, 14. a, 15. b.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The National Institutes of Health site Prader-Willi Syndrome is a valuable

resource for practical as well as technical information about the disorder. The Prader-Willi Association site has information about the association, facts about the disorder, and research information.

2. ChartsBin has a world map that is color coded to show the daily calorie intake per person in each country. Mouse over the country to see its name, calorie count, and changes since 1990.

3. The news article on how the FTO gene causes obesity appeared in New Scientist.

4. You’ve seen Alcoholics Anonymous’s 12-step program applied to all the other drug addictions; now it’s being used to manage compulsive overeating. Overeaters Anonymous has information about its organization and links to the sites of local help organizations.

5. The National Eating Disorders Association provides information about anorexia, bulimia, obesity, compulsive eating disorder, and other disorders, as well as information about treatments. Internet Mental Health has information on diagnosis, treatment, and research related to anorexia and bulimia (click on Disorders on the left side of the page).

Animations • Hunger, Satiation, and the Regulation of Fat Reserves (Figure 6.8)

Chapter Updates and Biopsychology News

For Further Reading 1. “Making Sense of Taste,” by David V. Smith and Robert F. Margolskee

(Scientific American, March 2001, 32–39) or search for the title at www.scientificamerican.com) elaborates on taste receptors, the umami flavor, and taste processing in the brain.

2. “Common Sense About Taste: From Mammals to Insects”, by David

Yarmolinsky, Charles Zuker, and J. P. Ryba (Cell, 2009, 139, 234–243), is a more technical review of taste emphasizing the genes and receptors that account for the different primary tastes.

3. “Extreme Obesity: A New Medical Crisis in the United States,” by Donald Hensrud and Samuel Klein (Mayo Clinic Proceedings, 2006, 8 [10 suppl.], S5–S10), details prevalence, causes, and cost of obesity in the United States.

4. “Genetic Factors in Human Obesity,” by I. S. Farooqi and S. O’Rahilly (Obesity Reviews, 2007, 8 [Suppl. 1], 37–40), describes the progress made over the past decade in identifying genes that contribute to obesity.

5. “Unfinished Symphony,” by Jane Qiu (Nature, 2006, 441, 143–145), gives a clear description of how epigenetic inheritance works and discusses possible drugs to reverse epigenetic effects and the efforts of the Human Epigenome Project to crack the epigenetic code.

6. “Full Without Food,” by Claire Ainsworth (New Scientist, September 5, 2009, 30–33), describes surgery for obesity and emphasizes its benefits for diabetics, as well as the possibility of creating drugs that mimic the effects of GLP-1, which is increased following the surgery.

Key Terms absorptive phase agouti-related protein (AgRP) amino acids angiotensin II anorexia nervosa arcuate nucleus area postrema arousal theory basal metabolism binge eating disorder body mass index (BMI) bulimia nervosa cholecystokinin (CCK) diabetes diabetes gene drive drive theory duodenum epigenetic fasting phase fatty acids

ghrelin glucagon glucose glycerol glycogen homeostasis hypovolemic thirst incentive theory instinct insulin lateral hypothalamus learned taste aversion learned taste preference leptin median preoptic nucleus motivation neuropeptide Y (NPY) nucleus of the solitary tract (NST) obesity gene organum vasculosum lamina terminalis (OVLT) orexin osmotic thirst paraventricular nucleus (PVN) peptide YY3–36 (PYY) preoptic area satiety sensory-specific satiety set point subfornical organ (SFO)

7 The Biology of Sex and Gender

In this chapter you will learn • How sex is similar to and different from other drives • How hormones and brain structures control sexual development and behavior • Some of the differences between males and females and what causes them • How deviations in sexual development affect the body, the brain, and behavior • How prenatal development may help explain heterosexuality and homosexuality

Sex as a Form of Motivation Arousal and Satiation The Role of Testosterone Brain Structures and Neurotransmitters Odors, Pheromones, and Sexual Attraction APPLICATION: OF LOVE AND BONDING CONCEPT CHECK

The Biological Determination of Sex Chromosomes and Hormones Prenatal Hormones and the Brain CONCEPT CHECK

Gender-Related Behavioral and Cognitive Differences Some Demonstrated Male–Female Differences Origins of Male–Female Differences CONCEPT CHECK

Biological Origins of Gender Identity Gender Identity Reversal 46 XY Difference in Sexual Development 46 XX Difference in Sexual Development Cognitive and Behavioral Effects Ablatio Penis: A Natural Experiment APPLICATION: SEX, GENDER, AND SPORTS IN THE NEWS: WHO CHOOSES A CHILD’S SEX? CONCEPT CHECK

Sexual Orientation The Social Influence Hypothesis

F

Genetic and Epigenetic Influences Prenatal Influences on Brain Structure and Function Social Implications of the Biological Model CONCEPT CHECK

In Perspective Summary Study Resources

ourteen-year-old Jan went to her family physician complaining of a persistent hoarse voice. As is often the case, other concerns surfaced during the course of the examination. At puberty, she had failed to develop breasts or to menstruate;

instead, her voice deepened, and her body became muscular. Once comfortable with her tomboyishness, she was now embarrassed by her appearance and increasingly masculine mannerisms; she withdrew from peers, and her school performance began to suffer. But there was an even more significant change at puberty: Her clitoris started growing and was 4 centimeters (1½ inches) long when she was examined by the doctor; in addition, her labia (vaginal lips) had partially closed, giving the appearance of a male scrotum. To everyone’s surprise, Jan’s included, the doctor discovered that she had two undescended testes in her abdomen and no ovaries. Further testing showed that her sex chromosomes were XY, which meant that genetically she was a male. After a psychiatric evaluation, Jan’s parents and doctors decided that she should be

offered the opportunity to change to a male sexual identity. She immediately went home and changed into boy’s clothing and got a boy’s haircut. The family moved to another neighborhood where they were unknown. At the new high school, Jack became an athlete, excelled as a student, was well accepted socially, and began dating girls. Surgeons finished closing the labia and moved the testes into the newly formed scrotum. He developed into a muscular, 6-foot-tall male with a deep voice and a heavy beard. At the age of 25 he married, and he and his wife reported a mutually satisfactory sexual relationship (Imperato-McGinley, Peterson, Stoller, & Goodwin, 1979). Humans have a great affinity for dichotomies, dividing their world into blacks and

whites with few grays in between. No dichotomy is more significant for human existence than that of male and female: One’s sex is often the basis for deciding how the person should behave, what the person is capable of doing, and with whom the person should fall in love. Not only are many of the differences between males and females imposed on them by society, but Jan’s experience suggests that typing people as male or female may not be as simple or as appropriate as we think. We will encounter even more puzzling cases later as we take a critical look at the designation of male versus female and the expectations that go with it. In the meantime, we need to continue our discussion of motivation by considering how sex is like and unlike

other drives. Sex as a Form of Motivation To say that sex is a motivated behavior like hunger may be stating the obvious. But theorists have had difficulty categorizing sex with other physiological drives because it does not fit the pattern of a homeostatic tissue need. If you fail to eat or if you cannot maintain body temperature within reasonable limits, you will die. But no harm will come from forgoing sex; sex ensures the survival of the species, but not of the individual. There are, however, several similarities with other drives like hunger and thirst.

They include arousal and satiation, the involvement of hormones, and control by specific areas in the brain. We will explore these similarities as well as some differences in the following pages. Arousal and Satiation The cycle of arousal and satiation is the most obvious similarity between sexual

motivation and other motivated behaviors. In the 1960s, William Masters and Virginia Johnson conducted groundbreaking research on the human sexual response. Until then, research had been limited to observing sexual behavior in animals or interviewing humans about their sexual activity. Masters and Johnson (1966) observed 312 men and 382 women and recorded their physiological responses during 10,000 episodes of sexual activity in the laboratory. This kind of research was unheard of at the time; in fact, the researchers had trouble finding journals that would publish their work.

How is sex like and unlike other drives? Masters and Johnson identified four phases of sexual response (see Figure 7.1). The

excitement phase is a period of arousal and preparation for intercourse. Both sexes experience increased heart rate, respiration rate, blood pressure, and muscle tension. The male’s penis becomes engorged with blood and becomes erect. The female’s clitoris becomes erect as well, her vaginal lips swell and open, the vagina lubricates, her breasts enlarge, and the nipples become erect. Hunger is a function mostly of time since the last meal. Sexual arousal, though, is

more influenced by opportunity and sexual stimuli, such as explicit conversation or the presence of a sexually attractive person. (In many other animal species, sexual arousal is a regular event triggered by a surge in hormones.) Another difference between sex and other drives is that we usually are motivated to reduce hunger, thirst, and temperature deviations, but we seek sexual arousal. This difference is not unique, though; for example, we skip lunch to increase the enjoyment of a gourmet dinner. During the plateau phase, the increase in sexual arousal levels off; arousal is

maintained at a high level for seconds or minutes, though it is possible to prolong this period. The testes rise in the scrotum in preparation for ejaculation; vaginal

lubrication increases and the vaginal entrance tightens on the penis. During orgasm, rhythmic contractions in the penis are accompanied by ejaculation of seminal fluid containing sperm into the vagina. Similar contractions occur in the vagina. This period lasts just a few seconds but involves an intense experience of pleasure. Resolution follows as arousal decreases and the body returns to its previous state. Orgasm is similar to the pleasure one feels after eating or when warmed after a

deep chill, but it is unique in its intensity; the resolution that follows is reminiscent of the period of quiet following return to homeostasis with other drives. FIGURE 7.1 Phases of the Sexual Response Cycle. This is a typical response for a male; most females are capable of multiple orgasms.

SOURCE: From Psychology: The Adaptive Mind (2nd ed.), by J. S. Nairne, 2000, Wadsworth, a part of Cengage Learning, Inc. Males have a refractory phase, during which they are unable to become aroused or

have another orgasm for minutes, hours, or even days, depending on the individual and the circumstances. Females do not experience a refractory period and are able to have additional orgasms anytime during the resolution phase. When comparing the sex drive with other kinds of motivation, the male refractory period has an interesting parallel with sensory-specific satiety (see Chapter 6); it is called the Coolidge effect. According to a popular but probably apocryphal story, President Coolidge and his wife were touring a farm when Mrs. Coolidge asked the farmer whether the flurry of sexual activity among the chickens was the work of one rooster. The farmer answered yes, that the rooster copulated dozens of times each day, and Mrs. Coolidge said, “You might point that out to Mr. Coolidge.” President Coolidge, so the story goes, then asked the farmer, “Is it a different hen each time?” The answer again was yes. “Tell that to Mrs. Coolidge,” the president replied. Whether the story is true or not, the Coolidge effect —a quicker return to sexual arousal when a new partner is introduced —has been observed in a wide variety of species; we will visit the subject again shortly. The Role of Testosterone As important as sex is to humans, it is ironic that so much of what we know about

the topic comes from the study of other species. One reason is that research into human sexual behavior was for a long time considered off-limits and funding was hard to come by. Another reason is that sexual behavior is more “accessible” in nonhuman animals; rats have sex as often as 20 times a day and are not at all embarrassed to perform in front of the experimenter. In addition, we can manipulate their sexual behavior in ways that would be considered unethical with humans. Hormonal control in particular is more often studied in animals because hormones have a clearer role in animal sexual behavior. Castration, or removal of the gonads (testes or ovaries), is one technique used to

study hormonal effects because it removes the major source of sex hormones; castration results in a loss of sexual motivation in nonhuman mammals of both sexes. Sexual behavior may not disappear completely, because the adrenal glands continue to produce both male and female hormones, though at a lesser rate than the gonads. The time course of the decline is also variable, ranging from a few weeks to 5 months in male rats (J. M. Davidson, 1966); across several species, animals who are sexually experienced are impaired the least and decline the slowest (Hart, 1968; Sachs & Meisel, 1994). Humans are less at the mercy of fluctuating hormone levels than other animals, but when they are castrated (usually for medical reasons, such as cancer), sexual interest and functioning decrease in both males and females (Bremer, 1959; Heim, 1981; Sherwin & Gelfand, 1987; Shifren et al., 2000). The decline takes longer in humans than in rats, but the rate is similarly variable.

What is the role of testosterone in sexual behavior? Castration has been elected by some male criminals in the hope of controlling

aggression or sexual predation, sometimes in exchange for shorter prison sentences. Castration is an extreme therapy; drugs that counter the effects of androgens (a class of hormones responsible for a number of male characteristics and functions) are a more attractive alternative. Those that block the production of the androgen testosterone, the major sex hormone in males, have been 80% to 100% effective in eliminating deviant sexual behavior such as exhibitionism and pedophilia (sexual contact with children), along with sexual fantasies and urges (A. Rösler & Witztum, 1998; F. Thibaut, Cordier, & Kuhn, 1996). The effects of castration indicate that testosterone is necessary for male sexual behavior, but the amount of testosterone required appears to be minimal; men with very low testosterone levels can be as sexually active as other men (Raboch & Stárka, 1973). Frequency of sexual activity does vary with testosterone levels within an individual,

but the testosterone increases appear to be the result of sexual activity rather than the cause. For example, testosterone levels are high in males at the end of a period in which intercourse occurred, not before (J. M. Dabbs & Mohammed, 1992; Kraemer et al., 1976). A case report (which is anecdotal and does not permit us to draw

conclusions) suggests that just the anticipation of sex can increase the testosterone level. Knowing that beard growth is related to testosterone level, a researcher working in near isolation on a remote island weighed the daily clippings from his electric razor. He found that the amount of beard growth increased just before planned visits to the mainland and the opportunity for sexual activity (Anonymous, 1970)! In most species, females are unwilling to engage in sex except during estrus, a

period when the female is ovulating, sex hormone levels are high, and the animal is said to be in heat. Human females and females of some other primate species engage in sex throughout the reproductive cycle. Studies of sexual frequency in women have not shown a clear peak at the time of ovulation. However, initiation of sex is a better gauge of the female’s sexual motivation than is her willingness to have sex; women do initiate sexual activity more often during the middle of the menstrual cycle, which is when ovulation occurs (Figure 7.2; D. B. Adams, Gold, & Burt, 1978; Harvey, 1987). The researchers attributed the effect to estrogen, a class of hormones responsible for a number of female characteristics and functions. Their reasons were that estrogen peaks at midcycle and the women did not increase in sexual activity if they were taking birth control pills, which level out estrogen release over the cycle. FIGURE 7.2 Female-Initiated Activity During the Menstrual Cycle. Activity initiated by women peaks around the middle of the menstrual cycle, which is when ovulation occurs.

SOURCE: From figure 2 from “Rise in Female-Initiated Sexual Activity at Ovulation and Its Suppression by Oral Contraceptives,” by D. B. Adams, A. R. Gold, and A. D. Burt, 1978, New England Journal of Medicine, 299(21), pp. 1145– 1150. However, testosterone peaks at the same time, and the frequency of intercourse

during midcycle corresponds to the woman’s testosterone level (N. M. Morris, Udry, Khan-Dawood, & Dawood, 1987). At menopause, when both estrogen and testosterone levels decline, testosterone levels show the most consistent relationship with intercourse frequency (McCoy & Davidson, 1985). How to interpret these observations is unclear, because testosterone increases in women as a result of sexual

activity, just as it does in men (Figure 7.3; J. M. Dabbs & Mohammed, 1992). However, studies in which testosterone level was manipulated demonstrate that it also contributes to women’s sexual behavior. Giving a dose of testosterone to women increases their arousal during an erotic film (Tuiten et al., 2000). More important, in women who had their ovaries removed, testosterone treatment increased sexual arousal, sexual fantasies, and intercourse frequency, but estrogen treatment did not (Sherwin & Gelfand, 1987; Shifren et al., 2000). FIGURE 7.3 Relationship Between Sexual Behavior and Salivary Testosterone Levels in Men and Women.

SOURCE: From “Male and Female Salivary Testosterone Concentrations Before and After Sexual Activity,” by J. M. Dabbs, Jr. and S. Mohammed, Physiology and Behavior, 52, pp. 195–197, Fig. 1. © 1992. Reprinted with permission from Elsevier Science. Brain Structures and Neurotransmitters As neuroscientists developed a clearer understanding of the roles of various brain

structures, motivation researchers began to shift their focus from drive as a tissue need to drive as a condition in particular parts of the brain. Sexual activity, like other drives and behaviors, involves a network of brain structures. This almost seems inevitable, because sexual activity involves reaction to a variety of stimuli, activation of several physiological systems, postural and movement responses, a reward experience, and so on. We do not understand yet how the sexual network operates as a whole, but we do know something about the functioning of several of its components. In this section, you will see some familiar terms, the names of hypothalamic structures you learned about in the previous chapter. This illustrates an important principle of brain functioning, that a particular brain area, even a very small one, often has multiple functions.

The medial preoptic area (MPOA) of the hypothalamus is one of the more significant brain structures involved in male and female sexual behavior. (The general preoptic area can be located in Figure 6.2, in the previous chapter. Be careful not to confuse the medial preoptic area with the median preoptic nucleus, discussed in that chapter.) Stimulation of the MPOA increases copulation in rats of both sexes (Bloch, Butler, & Kohlert, 1996; Bloch, Butler, Kohlert, & Bloch, 1993), and the MPOA is active when they copulate spontaneously (Pfaus, Kleopoulos, Mobbs, Gibbs, & Pfaff, 1993; Shimura & Shimokochi, 1990). The MPOA appears to be more responsible for performance than for sexual motivation; when it was destroyed in male monkeys, they no longer tried to copulate, but instead they would often masturbate in the presence of a female (Slimp, Hart, & Goy, 1978).

What brain structures are involved in sexual behavior? Especially significant for males is the sexually dimorphic nucleus (SDN), located in

the MPOA (de Jonge et al., 1989). The SDN is five times larger in male rats than in females (see Figure 7.4; Gorski, Gordon, Shryne, & Southam, 1978), and a male’s level of sexual activity is related to the size of the SDN, which in turn depends on prenatal (before birth) exposure to testosterone (R. H. Anderson, Fleming, Rhees, & Kinghorn, 1986). Destruction of the SDN reduces male sexual activity (de Jonge et al., 1989). The SDN’s connections to other sex-related areas of the brain suggest that it integrates sensory and hormonal information and coordinates behavioral and physiological responses to sensory cues (Roselli, Larkin, Resko, Stellflug, & Stormshak, 2004). Two other hypothalamic structures are also important. The paraventricular nucleus

(Figure 6.2 in the previous chapter) is important for male sexual performance and, particularly, for penile erections (Argiolas, 1999). The ventromedial hypothalamus is active in females during copulation (Pfaus et al., 1993), and its destruction reduces the female’s responsiveness to a male’s advances (Pfaff & Sakuma, 1979). FIGURE 7.4 The Sexually Dimorphic Nuclei of the Rat. (a) The SDN in the male is larger than (b) the SDN in the female. (c) The effects of testosterone and a masculinizing synthetic hormone on the female SDN.

SOURCE: From “The Neuroendocrine Regulation of Sexual Behavior,” by R. A. Gorski, pp. 1–58, in G. Newton and A. H. Riesen (Eds.) Advances in Psychobiology (Vol. 2), 1974, New York: Wiley. Reprinted with permission of John Wiley & Sons, Inc. A part of the amygdala known as the medial amygdala also contributes to sexual

behavior in rats of both sexes. Located near the lateral ventricle in each temporal lobe, the amygdala is involved not only in sexual behavior but also in aggression and emotions. The medial amygdala is active while rats copulate (Pfaus et al., 1993), and stimulation causes the release of dopamine in the MPOA (Dominguez & Hull, 2001; Matuszewich, Lorrain, & Hull, 2000). The medial amygdala’s role apparently is to respond to sexually exciting stimuli, such as the presence of a potential sex partner (de Jonge, Oldenburger, Louwerse, & Van de Poll, 1992). For obvious reasons, we know much less about the brain structures involved in

human sexual behavior. Functional MRI (fMRI) recording during masturbation has confirmed the involvement of the medial amygdala and paraventricular nucleus in human sexual activity (Komisaruk et al., 2004). Neurons of the paraventricular nucleus are known to secrete the hormone/neuromodulator oxytocin, which contributes to male and female orgasm and the intensity of its pleasure (Carmichael, Warburton, Dixen, & Davidson, 1994). We will see additional results from human research in the discussion of neurotransmitters. We also know that a few brain

structures in humans differ in size between males and females. Because their contribution to sexual behavior is not clear and the size differences may also distinguish homosexuals from heterosexuals, I will defer discussion of these structures until we take up the subject of sexual orientation. FIGURE 7.5 Dopamine Levels in the Nucleus Accumbens During the Coolidge Effect. Activity was recorded until the male lost interest in Female 1; then, Female 2 was presented. During the periods represented by the orange bars, the female was separated from the male by a clear screen. The line graph shows dopamine levels. Bars show the number of vaginal penetrations. SOURCE: From “Dynamic Changes in Nucleus Accumbens Dopamine Efflux During the Coolidge Effect in Male Rats,” by D. F. Fiorino, A. Coury, and A. G. Phillips, 1997, Journal of Neuroscience, 17, p. 4852. © 1997 Society for Neuroscience. Reprinted with permission.

Sexual behavior involves several neurotransmitters, but dopamine is the one that has received the most attention. You saw in Chapter 5 that dopamine level increases in the nucleus accumbens during sexual activity and in this chapter that stimulation of the medial amygdala releases dopamine in the MPOA. Dopamine activity in the MPOA contributes to sexual motivation in males and females of several species (E. M. Hull et al., 1999). In males, dopamine is critical for sexual performance: Initially, it stimulates D1 receptors, activating the parasympathetic system and increasing motivation and erection; as dopamine increases it activates D2 receptors, which shifts autonomic balance to the sympathetic system, resulting in ejaculation. D2 activity also

inhibits erection, which probably accounts in part for the sexual refractory period. Interestingly, dopamine release parallels sexual behavior during the Coolidge effect. As you can see in Figure 7.5, it increased in the male rat’s nucleus accumbens in the presence of a female, dropped back to baseline as interest waned, and then increased again with a new female (Fiorino, Coury, & Phillips, 1997). The changes occurred even when the male and female were separated by a clear panel, so the dopamine level reflects the male’s interest rather than the effects of sexual activity. Our knowledge about the role of dopamine in human sexual behavior is less

precise, but nevertheless intriguing. Drugs that increase dopamine levels, such as those used in treating Parkinson’s disease, increase sexual activity in humans (Meston & Frolich, 2000). The dopamine system has been reported to be active in the ventral tegmental area in males during ejaculation (Holstege et al., 2003) and in the nucleus accumbens in females during orgasm (Komisaruk et al., 2004). This activity likely reflects a reward response, but, significantly, the activated areas also have strong motor output to the pelvic floor muscles, which are important in orgasmic activity. Variations in the gene for the D4 receptor (DRD4) are associated with sexual arousal and functioning (Ben Zion et al., 2006), and one variant is correlated with promiscuity and sexual infidelity (Garcia et al., 2010). Ejaculation is also accompanied by serotonin increases in the lateral hypothalamus,

which apparently contributes further to the refractory period (E. M. Hull et al., 1999). Injecting a drug that inhibits serotonin reuptake into the lateral hypothalamus increases the length of time before male rats will attempt to copulate again, and their ability to ejaculate when they do return to sexual activity. Humans take serotonin reuptake blockers to treat anxiety and depression, and they often complain that the drugs interfere with their ability to have orgasms. The antianxiety drug buspirone, on the other hand, decreases the release of serotonin and facilitates orgasms (Komisaruk, Beyer, & Whipple, 2008). Odors, Pheromones, and Sexual Attraction Sexual behavior results from an interplay of internal conditions, particularly

hormone levels, with external stimuli. Sexual stimuli can be anything from brightly colored plumage or an attractive body shape to particular odors. Here we will examine the role of odors and pheromones in sexual attraction, with emphasis on how important they might be for humans. The Nose as a Sex Organ Each human gives off a distinctive, genetically determined odor (Axel, 1995), and

people can distinguish clothing worn by family members from clothing worn by strangers just by smelling them (Porter & Moore, 1981; Schaal & Porter, 1991). It is possible that, like other mammals, we use this ability to identify and bond with family members, and there is evidence that it influences mate choice; women prefer the odor of dominant men, but only during the fertile phase of their menstrual cycle (Havlicek,

Roberts, & Flegr, 2005). Some studies suggest that animals and humans are influenced in their mate choices by the odor of individuals who differ in the major histocompatibility complex (MHC), a group of genes that contributes to the functioning of the immune system (Chaix, Cao, & Donnelly, 2008). For example, women reported more sexual satisfaction and fewer outside sex partners when their romantic partners were dissimilar in MHC (Garver-Apgar, Gangestad, Thornhill, Miller, & Olp, 2006). The idea makes good sense, because couples similar in MHC tend to be less fertile and have more spontaneous abortions; supposedly, MHC-based mate choices help avoid genetic inbreeding and increase disease resistance. However, there have been negative studies as well, so no conclusions can be drawn yet. In some cases, pheromones are more important than odors, at least in nonhuman

animals. Pheromones are airborne chemicals released by an animal that have physiological or behavioral effects on another animal of the same species. Pheromones can be very powerful, as you know if your yard has ever been besieged by all the male cats in the neighborhood when your female cat was “in heat.” The female gypsy moth can attract males from as far as 2 miles away (Hopson, 1979). But, to understand the role pheromones play, we need to have a basic understanding

of the olfactory (smell) system. Olfaction is one of the two chemical senses, along with taste. Airborne odorous materials entering the nasal cavity must dissolve in the mucous layer overlying the receptor cells; the odorant then stimulates a receptor cell when it comes in contact with receptor sites on the cell’s dendrites (see Figure 7.6). Axons from the olfactory receptors pass through openings in the base of the skull to enter the olfactory bulbs, which lie over the nasal cavity. From there, neurons follow the olfactory nerves to the nearby olfactory cortex tucked into the inner surfaces of the temporal lobes. By varying the number of components in odor mixtures, researchers have

calculated that humans can distinguish a trillion odors (Bushdid, Magnasco, Vosshall, & Keller, 2014). But we do not have a different receptor for each odor, and an individual neuron cannot produce the variety of signals required to distinguish among so many different stimuli. Researchers have discovered that about 1,000 genes produce an equal number of olfactory receptor types in rats and mice; humans have between 500 and 750 odor receptor genes, although only one fourth to three fourths of these appear to be functional (Mombaerts, 1999). It is believed that each neuron has a single type of odor receptor, but whether each neuron has one or several receptor types, the brain must distinguish among the 10,000 different odors by the combination of neurons that are active. Most pheromones are detected by the vomeronasal organ (VNO), a cluster of

receptors also located in the nasal cavity (Figure 7.6). The two systems are separate, and the VNO’s receptors are produced by a different family of genes (P. J. Hines, 1997). Not surprisingly, in animals the VNO sends its signals to the MPOA and the

ventromedial nucleus of the hypothalamus, as well as to the amygdala (Keverne, 1999). The VNO is detectable in humans, but it has evolved to a diminished, often microscopic size (Garcia-Velasco & Mondragon, 1991). Although genes for the VNO have been identified in humans (Mundy & Cook, 2003), some claim the genes are no longer functional (J. Zhang & Webb, 2003). They suggest that as color vision evolved, our ancestors abandoned pheromones in favor of visual sexual signals, and this led to the VNO’s functional demise (I. Rodriguez, 2004). Nevertheless, a VNO may not be required for detecting pheromones. Recent research has identified two groups of receptors that detect airborne alarm signals and other pheromones in the olfactory system of mice; humans have at least one of the receptor types and genes for the other (Brechbühl, Klaey, & Broillet, 2008; Liberles & Buck, 2006).

What is the evidence for pheromones in human sexual behavior? Interest in the possibility of human pheromones increased following reports that

women living together in dorms tended to have synchronized menstrual periods and that this was caused by sweat-borne compounds that altered the frequency of luteinizing hormone release (Preti, Cutler, Garcia, Huggins, & Lawley, 1986; Preti, Wysocki, Barnhart, Sondheimer, & Leyden, 2003; K. Stern & McClintock, 1998). Later studies have failed to demonstrate menstrual synchrony almost as often as they have succeeded, and the results have been questioned on methodological grounds (Z. Yang & Schank, 2006), but other evidence of pheromonal influence continues to filter in. Both men and women have reported increased sexual intercourse when using

aftershave or perfume laced with underarm extracts from members of their own sex (Cutler, Friedman, & McCoy, 1998; McCoy & Pitino, 2002). Neither group increased their frequency of masturbation, so enhanced motivation for sex on their part did not appear to be the explanation. In another study, men rated the scent of women’s T- shirts as more attractive when the women were in the middle of the menstrual cycle, when they would be expected to be ovulating and, therefore, fertile; this did not happen with women taking birth control pills, which suppress ovulation (Kuukasjärvi et al., 2004). PET scans suggest that these presumed pheromones activate the anterior hypothalamic area, where structures important in animal sexual behavior are located (Savic, Berglund, Gulyas, & Roland, 2001). Additional brain areas responded when females sniffed underarm pads worn by males while they watched an explicit and sexually arousing video (W. Zhou & Chen, 2008). Further evidence for human pheromones has been found in nonsexual contexts: Subjects were able to distinguish between underarm pads worn by others during a fear-provoking film and a neutral film (Ackerl, Atzmueller, & Grammer, 2002), and fMRI showed that sniffing underarm pads worn by first-time skydivers activated the amygdala, while the sweat of people engaged in strenuous exercise did not (Mujica-Parodi et al., 2009).

FIGURE 7.6 The Olfactory and Vomeronasal Systems.

In most animals, attraction is fleeting, lasting only through copulation or, at best, till the end of the mating season. For a few species, though, pair bonding occurs for years or for a lifetime, as we see in the accompanying Application.

APPLICATION

Of Love and Bonding Prairie voles are a rare exception among mammals; they mate for life, and if they lose a mate they rarely take another partner. The bonding process (as reviewed in L. J. Young & Wang, 2004) begins with the release of dopamine in reward areas during mating. If dopamine activity is blocked by a receptor antagonist, partner preference fails to develop. Sexual activity also releases the neuropeptides oxytocin and vasopressin, which are likewise required for bonding to take place. Either can facilitate bonding in males or females, but oxytocin is more effective with females and vasopressin with males. Meadow voles and montane, or mountain, voles also release these neuropeptides, but they are not monogamous. At least a part of the reason lies in the AVPR1A gene, which is responsible for a type of vasopressin receptor. When the prairie vole’s version of the gene was inserted into male meadow voles, these animals showed uncharacteristically increased preference for a female they had

copulated with. So does any of this apply to humans, who are also monogamous (more or

less)? The most apparent parallel involves oxytocin. Oxytocin not only facilitates bonding but also causes smooth muscle contractions, such as those involved in orgasm and in milk ejection during breast-feeding. Blood levels of oxytocin increase dramatically as males and females masturbate to orgasm (M. R. Murphy, Checkley, Seckl, & Lightman, 1990). The increase in oxytocin is probably responsible for the muscle contractions involved in orgasm and likely explains why lactating women sometimes eject a small amount of milk from their nipples during orgasm. Oxytocin also contributes to social recognition, which is necessary for developing mate preferences. Male mice without the oxytocin gene fail to recognize females from one encounter to the next (J. N. Ferguson et al., 2000), and human males are better at recognizing previously seen photos of women while using a nasal spray containing oxytocin (Rimmele, Hediger, Heinrichs, & Klaver, 2009); men getting the nasal spray also had more activity in the nucleus accumbens while viewing photos of their partners, and they increased their attractiveness ratings of their partners, but not of other women they knew (Scheele et al., 2013). More convincing, men with two copies of a particular allele of the AVPR1a gene were twice as likely to report a marital crisis during the prior year, and twice as likely to be unmarried, compared with males without the allele (Walum et al., 2008). Oxytocin’s bonding effects are not limited to mates and sex partners.

Mother-infant bonding is correlated with oxytocin levels during pregnancy and following birth (Feldman, Weller, Zagoory-Sharon, & Levine, 2007), and a gene for the oxytocin receptor is related to parenting sensitivity (Bakermans- Kranenburg & van IJzendoorn, 2008). Another receptor gene appears to affect empathy levels in adults (Rodrigues, Saslow, Garcia, John, & Keltner, 2009).

Prairie Voles Mate for Life and Share Parenting Duties. SOURCE: Todd Ahern/Emory University.

Concept Check Take a Minute to Check YourKnowledge and Understanding What change in thinking helped researchers see sex as similar to other biological drives?

What roles do estrogen and testosterone play in sexual behavior in humans? In what ways do sensory stimuli influence sexual behavior?

The Biological Determination of Sex Now we need to talk about differences between the sexes and the anomalies (exceptions) that occur. Sex is the term for the biological characteristics that divide humans and other animals into the categories of male and female. Gender refers to the behavioral characteristics associated with being male or female. For our purposes, it will be useful to make two further distinctions : Gender role is the set of behaviors society considers appropriate for people of a given biological sex, while gender identity is the person’s subjective feeling of being male or female. The term sex cannot be used to refer to all these concepts, because the characteristics are not always consistent with each other. Thus, classifying a person as male or female can sometimes be difficult. You might think that the absolute criterion for identifying a person’s sex would be a matter of chromosomes, but you will soon see that it is not that simple. FIGURE 7.7 Female and Male X and Y Chromosomes.

Chromosomes and Hormones You may remember from Chapter 1 that when cells divide to produce sex cells, the

pairs of chromosomes separate, and each gamete—the sperm or egg—receives only 23 chromosomes. This means that a sex cell has only one of the two sex chromosomes. In mammals, an egg will always have an X chromosome, but a sperm

may have either an X chromosome or a Y chromosome. The procreative function of sexual intercourse is to bring the male’s sperm into contact with the female’s egg, or ovum. When the male ejaculates into the female’s vagina, the sperm use their tail-like flagella to swim through the uterus and up the fallopian tubes, where the ovum is descending. As soon as one sperm penetrates and enters the ovum, the ovum’s membrane immediately becomes impenetrable so that only that sperm is allowed to fertilize the egg. The sperm makes its way to the nucleus of the ovum, where the two sets of chromosomes are combined into a full complement of 23 pairs. After fertilization, the ovum begins dividing, producing the billions of cells that make up the human fetus. If the sperm that fertilizes the ovum carries an X sex chromosome, the fetus will develop into a female; if the sperm’s sex chromosome is Y, the child will be a male (see Figure 7.7).

What makes a person male or female? FIGURE 7.8 Development of Male and Female Internal Organs.

SOURCE: Adapted from Our Sexuality (7ed.), by R. Crooks and K. Baur, 1999, Fig. 3.2 p. 46. Stamford, CT: Cengage Learning. For the first month, XX and XY fetuses are identical. Later, the primitive gonads

(testes and ovaries, the primary reproductive organs) in the XX individual develop into ovaries, where the ova (eggs) develop. The Müllerian ducts develop into the uterus, the fallopian tubes, and the inner vagina, while the Wolffian ducts, which would become the male organs, wither and are absorbed (Figure 7.8). The undifferentiated external genitals become the clitoris, the outer segment of the vagina, and the labia, which partially enclose the entrance to the vagina (Figure 7.9). FIGURE 7.9 Differentiation of Male and Female Genitals.

SOURCE: Based on Netter (1983). If the fetus receives a Y chromosome from the father, the SRY gene on that

chromosome produces the Sry protein, which causes the primitive gonads to develop into testes, the organs that will produce sperm. The testes begin secreting two types of hormones (Haqq et al., 1994). Müllerian inhibiting hormone defeminizes the fetus by causing the Müllerian ducts to degenerate. Testosterone, the most prominent of the androgens, masculinizes the internal organs: The Wolffian ducts develop into the seminal vesicles, which store semen, and the vas deferens, which carry semen from the testes to the penis. A derivative of testosterone, dihydrotestosterone, masculinizes the external genitals; the same structures that produce the clitoris and the labia in the female become the penis and the scrotum, into which the testes descend during

childhood. In the absence of the SRY gene, the primitive gonads of the XX fetus develop into

ovaries. The ovaries won’t begin producing estrogens until later, but the default sex is female, and the uterus, vagina, clitoris, and labia will all develop without benefit of hormones. You should understand that it is not entirely accurate to speak of hormones as being “male” or “female.” The testes and ovaries each secrete both androgens and estrogens, although in differing amounts; the adrenal glands also secrete small amounts of both kinds of hormones. The hormonal effects we have been discussing are called organizing effects.

Organizing effects mostly occur prenatally and shortly after birth; they affect structure and are lifelong in nature. Organizing effects are not limited to the reproductive organs; they include sex-specific changes in the brains of males and females as well, at least in nonhuman mammals. Activating effects can occur at any time in the individual’s life; they may come and go with hormonal fluctuations or be long lasting, but they are reversible. Some of the changes that occur during puberty are examples of activating effects. During childhood, differences between boys and girls other than in the genitals are

relatively minimal. Boys tend to be heavier and stronger, but there is considerable overlap. Boys also are usually more active and more aggressive, and interests diverge at an early age. Marked differences appear about the time the child enters puberty, usually during the preteen years. At puberty, a surge of estrogens from the ovaries and testosterone from the testes completes the process of sexual differentiation that began during prenatal development. Organizing effects include maturation of the genitals and changes in stature. Activating effects include breast development in the girl and muscle increases and beard growth in the boy. In addition, the girl’s ovaries begin releasing the ova that have been there since birth (i.e., she begins to ovulate), and she starts to menstruate. Boys’ testes start producing sperm, and ejaculation becomes possible. More important from a behavioral perspective, sexual interest increases dramatically, and in the majority of cases, preference for same-sex company shifts to an attraction to the other sex, along with an interest in sexual intimacy. Prenatal Hormones and the Brain Several characteristics and behaviors can be identified as male typical and others as

female typical. This does not mean that the behaviors are somehow more appropriate for that sex but simply that they occur more frequently in one sex than in the other. These differences are not absolute. For example, consider the stereotypical sexual behavior of rats: The male mounts the female from behind, while the female curves her back and presents her hindquarters in a posture called lordosis. However, females occasionally mount other females, and males will sometimes show lordosis when approached by another male.

What is the effect of “sexualizing” the brain? The same hormonal influence responsible for the development of male gonads and

genitals affects behavior as well. A male rat will display lordosis and accept the sexual advances of other males if he was castrated shortly after birth or if he was given a chemical that blocks androgens just before birth and for a short time postnatally (after birth). Similarly, a female rat given testosterone during this critical period will mount other females at a higher rate than usual as an adult (Figure 7.10; Gorski, 1974). These behaviors apparently result from testosterone’s influence on the size and function of several brain structures; in other words, the presence of testosterone masculinizes certain brain structures. That statement is somewhat misleading, though, because it is estradiol, the principal estrogen hormone, that carries out the final step of masculinization. When testosterone enters the neurons, it is converted to estradiol by a chemical process called aromatization. At the critical time when brain masculinization occurs, aromatase increases in the areas that are to be masculinized (Horvath & Wikler, 1999). FIGURE 7.10 A Female Rat Mounting a Male.

SOURCE: From “Sex-Hormone-Dependent Brain Differentiation and Sexual Functions,” in G. Dörner (Ed.), Endocrinology of sex (pp. 30–37). Leipzig: J. A. Barth. Copyright © 1974 Gunther Dörner. Used with permission. Until recently, it was believed that feminization of the brain, like the sex organs,

required only the absence of testosterone; now we know that just as masculinization of the male brain requires estradiol, so does feminization of the female brain. Female knockout mice born unable to produce estradiol display less sexual interest and receptivity toward males or females as adults than do other mice, even when they are given replacement estrogens (Bakker, Honda, Harada, & Balthazart, 2002, 2003). Just as the male brain must be masculinized and the female brain feminized, the male brain must also be defeminized. Again, estrogens are necessary; male knockout mice lacking the estrogen receptor showed normal male sexual behavior but also were receptive to advances of other males (Kudwa, Bodo, Gustafsson, & Rissman, 2005). This sexualization of the brain is reflected in behavioral differences, affecting not

only sexual activity but also play behavior, spatial activity, and learning performance

Concept Check

(see Collaer & Hines, 1995). Do hormones have a similar influence in humans? In the following pages we will try to answer that question.

Take a Minute to Check Your Knowledge and Understanding

How is the sex of a fetus determined, and what affects prenatal and postnatal sexual development?

What effect do sex hormones have on differentiation of the brain and behavior?

Gender-Related Behavioral and Cognitive Differences In his popular book Men Are From Mars, Women Are From Venus, John Gray (1992) said that men and women communicate, think, feel, perceive, respond, love, and need differently, as if they are from different planets and speaking different languages. How different are men and women? This question is not easily answered, but it is not for lack of research on the topic. The results of studies are often ambiguous and contradictory. One reason is that different researchers measure the same characteristic in different ways. Also, the research samples are often too small to yield reliable results, and the subjects are usually not selected in a manner that ensures accurate representation of the population. Whether the differences that do exist are influenced by biology or are solely the product of experience is controversial. Contemporary parents make efforts to rear their children equally, but parents who claim to do so have been found to verbalize differently and play differently with a child dressed as a girl than when the same child is dressed as a boy (Culp, Cook, & Housley, 1983). Differential rearing, of course, could account for marked differences in behavior, temperament, and self-expectations. FIGURE 7.11 A Spatial Rotation Task. People are presented several pairs of drawings like these and asked whether the first could be rotated so that it looks like the second. Males are typically better at this kind of task than females. (In case you’re wondering, the answer in this case is no.)

Some Demonstrated Male–Female Differences Back in 1974, Eleanor Maccoby and Carol Jacklin reviewed more than 2,000

studies and concluded that the evidence firmly supported three differences in

cognitive performance and one difference in social behavior: (1) Girls have greater verbal ability than boys, (2) boys excel in visual-spatial ability, (3) boys excel in mathematical ability, and (4) boys are more aggressive than girls. Later research has supported these differences, but we should add two qualifications. First, there is considerable overlap between males and females in these characteristics. Second, the differences are rather specific. For example, females excel in verbal fluency and writing but not in reading comprehension or vocabulary (Eagly, 1995; Hedges & Nowell, 1995), and male spatial performance exceeds females’ most on tasks requiring mental rotation of a three-dimensional object (like the one in Figure 7.11) and less on other spatial tasks (Hyde, 1996). Origins of Male–Female Differences The best evidence that the three cognitive differences mentioned above are

influenced by experience is that they have decreased over the years, presumably as gender roles have changed (Hedges & Nowell, 1995; Hyde, 1996; Voyer, Voyer, & Bryden, 1995). In fact, testing of 7 million students indicates that the gender difference in average mathematical performance has disappeared in the United States, although boys are slightly overrepresented at both the lower and higher extremes (Hyde, Lindberg, Linn, Ellis, & Williams, 2008). Similar trends were found in a study of 89 countries, and data suggested that progress is due to increasing gender equality (Kane & Mertz, 2012). In addition, the dramatic variation in murder rate in different countries suggests there is also a strong cultural influence on aggression; for example, the murder rate in 2008 was 52 per 100,000 of population in Venezuela, 5.4 in the United States, 2.03 in the United Kingdom, and 0.44 in Japan (“List of Countries,” n.d.).

How do we explain the differences in verbal and spatial abilities and in aggression? Although environmental influences play a significant role, gender differences in

cognition and behavior also owe a great deal to biology. Most often, researchers attribute the differences to the effects of estrogen and testosterone, particularly on the organizational development of the brain during gestation. This view gets support from the fact that gender differences in the volume of different brain areas correspond to the density of sex hormone receptors in those areas (J. M. Goldstein et al., 2001). Because the effects of sex hormones on brain development are most evident in people with atypical sexual development, we will hold that discussion for the next section and focus here on activating effects occurring after birth. Males who produce low amounts of testosterone during the developmental years

are impaired later in spatial ability (Hier & Crowley, 1982), and testosterone replacement in older men improves their spatial functioning (Janowsky, Oviatt, & Orwoll, 1994). Men who take estrogens because they identify sexually as females

(transsexual males) increase their scores on verbal fluency tasks, but they lose spatial performance; transsexual females taking testosterone lose verbal ability but improve in spatial performance (for references, see Hulshoff Pol et al., 2006). Men kill 30 times as often as women do (Daly & Wilson, 1988), and testosterone is usually blamed for this difference. However, whether testosterone is the cause or the result of aggression is questioned because a variety of studies show, for example, that winning a sports competition increases testosterone and losing decreases it (Archer, 1991). Aggression in males is partly inheritable; genetic effects account for about half the variance in aggression, and aggression is moderately correlated in identical twins even when they are reared apart (Rushton, Fulker, Neale, Nias, & Eysenck, 1986; Tellegen et al., 1988). The source of aggression is a complex subject, and we will deal with it more thoroughly in Chapter 8.

1 Sex Differences in the Brain Differences in brain anatomy and organization are also cited as bases for gender

differences. Jerre Levy (1969) hypothesized that women outperform men on verbal tests because they are able to use both hemispheres of the brain in solving verbal problems rather than mostly the left hemisphere. This idea has been controversial, but there is some fMRI evidence that males process language tasks primarily in the left temporal area, while females engage both temporal areas equally (Kansaku, Yamaura, & Kitazawa, 2000). According to imaging studies, men use parietal areas to perform spatial rotations, while women rely more on frontal areas (reviewed in Andreano & Cahill, 2009); men have more cortical surface in the parietal lobes, and their scores on a spatial rotation task are correlated with the amount of cortical surface (Koscik, O’Leary, Moser, Andreasen, & Nopoulos, 2009). There are also several other indications that male and female brains work differently: Males and females have different patterns of brain activation during learning (Andreano & Cahill, 2009), pain (Naliboff et al., 2003), and stress (J. Wang et al., 2007); males are genetically more resistant to pain, and males and females respond differently to different pain medications (J. Bradbury, 2003); men are less affected by stress (Matud, 2004); and, as you will see in subsequent chapters, males are more susceptible to autism, Tourette’s syndrome, and attention-deficit/hyperactivity disorder, while women are more likely to suffer from depression. There are numerous differences between the sexes in brain activation patterns and anatomy, and though some translate to behavioral differences, others do not. In those cases, the brain differences may ensure equal functioning in spite of hormonal differences that would disadvantage one sex (Cahill, 2006; de Vries, 2004). The value of studying these differences is not to label one sex as smarter or more

aggressive but to understand what contributes to the characteristics. Keep in mind that aside from physical strength and possibly aggressiveness, the differences are small

Concept Check

and do not justify discrimination in society or in the workplace. We are far more alike than we are different; this is a reason to use the term other sex instead of opposite sex. There are real differences, though, and an understanding of their origins could help us enhance intellectual development or reduce violence. From a scientific perspective, that knowledge also helps us understand how the brain develops, an issue that we will continue to pursue in the next two sections.

Take a Minute to Check Your Knowledge and Understanding

What are the origins of male–female differences in verbal and spatial abilities? What are the arguments for environmental origins and for biological origins of male–female differences in cognitive abilities and behaviors?

Biological Origins of Gender Identity For decades, sex researchers have argued about what shapes an individual’s gender identity, with some believing it is formed in the first few years of life by a combination of rearing practices and genital appearance (Money & Ehrhardt, 1972) and others claiming that chromosomes and hormones are more important (M. Diamond, 1965). Our earlier discussion of the effects of XY and XX chromosomes was the simple version of the sex-determination story; in reality, development sometimes takes an unexpected turn. As you will soon see, the results not only challenge our definition of what is male and what is female, but they also tell us a great deal about the influence of biology on gender. “

There is no one biological parameter that clearly defines sex. —Eric Vilain

”

Gender Identity Reversal Individuals who believe they have been born into the wrong sex are referred to as

transsexual. They may dress and live as the other sex or undergo surgery for sex reassignment. Gender identity reversal is rare, with estimates ranging between 1 and 5 per 1,000 people (Collaer & Hines, 1995). Gender dissatisfaction can appear as early as 3 or 4 years of age; a twin study indicated that at that age, heritability is moderate, and shared (family) environmental influence is stronger (Knafo, Iervolino, & Plomin, 2005). Persistence into adolescence occurs less frequently; in those cases, heritability is estimated at 62%, with the remaining 38% due to nonshared environmental

influence (Coolidge, Thede, & Young, 2002). Specific genes that have been identified are alleles of the CYP17 gene and the AR gene. The first increases testosterone levels in female-to-male transsexuals (Bentz et al., 2008) and the second reduces sensitivity to androgen in male-to-female transsexual individuals (Hare et al., 2009); the researchers believe these genes lead to masculinization of the female brain and a failure to masculinize the male brain.

What influences affect gender identity and gender-related behavior?

2 Variations in Sex Development How could an individual’s genitals and brain develop at variance with each other?

They differentiate sexually at different times during gestation, the genitals during the first 2 months and the brain during the last half, presumably allowing them to fall under the influence of independent processes (Bao & Swaab, 2011). Whatever the mechanism, physiological evidence does suggest that the brains of transsexual individuals have followed a different developmental path. Male-to-female transsexuals—who are studied more often because they are more plentiful—have been reported to resemble females rather than males in the size of the third interstitial nucleus of the hypothalamus, or INAH3 (Garcia-Falgueras & Swaab, 2008); in brain response to the presumed pheromones AND, an androgen derivative found in male sweat, and EST, an estrogen-like compound found in female urine (Berglund, Lindström, Dhejne-Helmy, & Savic, 2008); and in brain activation patterns in response to an erotic video (Gizewski et al., 2009). In spite of that last finding, note that transsexuals are not necessarily homosexual; in nine studies, the rate of homosexuality and bisexuality among male transsexuals averaged 62% (Lawrence, 2005). One characteristic may distinguish the brains of transsexual individuals from those of homosexuals: The central bed nucleus of the stria terminalis (BSTc) of the hypothalamus is smaller in women than in men and has been reported to be female sized in male transsexuals and male sized in the one available female transsexual (Figure 7.12; Kruijver et al., 2000; J. N. Zhou, Hofman, Gooren, & Swaab, 1995). This difference was specific to transsexuality; it occurred whether or not the individual was homosexual. FIGURE 7.12 BSTc Size in a Male-to-Female Transsexual. Representative images of the stained BSTc in a (a) heterosexual male, (b) heterosexual female, (c) homosexual male, and (d) male-to-female transsexual male.

SOURCE: Figure 2, “A Sex Difference in the Human Brain and Its Relation to Transsexuality,” by J.-N. Zhou, M. A. Hofman, L. J. Gooren, and D. F. Swaab, 1995, Nature, 378, pp. 68–70. Reprinted by permission of Nature, copyright 1995. For a variety of reasons, obtaining reliable data on gender identity has not been

easy; the sexual variations described in the sections that follow serve as “natural experiments” that provide valuable, and sometimes dramatic, additional information. 46 XY Difference in Sexual Development The Jan who became Jack at the beginning of the chapter would, in today’s

terminology, be described as having 46 XY difference in sexual development (DSD), meaning that he had a typical number of chromosomes, including an X and a Y chromosome, but he had a variation in sexual development. In 2006, practitioners in the field of sexual development adopted the term disorder of sexual development. This terminology is appropriate from a medical perspective, but some contend that sexual development is a continuum, and prefer the term difference in place of disorder. In respect for that view, I will use DSD here to mean “difference in sexual development.” These variations in development have a variety of causes. The reason for Jan’s unusual development was a deficiency in an enzyme (17α-hydroxysteroid) that converts testosterone into dihydrotestosterone; dihydrotestosterone masculinizes the external genitalia before birth. The large surge of testosterone at puberty enabled her body partially to carry out that process. A deficiency in another enzyme, 5α-reductase, also reduces dihydrotestosterone

levels and delays genital development; this deficiency is genetic and is most likely to

occur when there is frequent intermarriage among relatives. Of 18 such individuals in the Dominican Republic who were reared unambiguously as girls, all but one made the transition to a male gender identity after puberty, and 15 were living or had lived with women (Imperato-McGinley, Peterson, Gautier, & Sturla, 1979). The men said they realized they were different from girls and began questioning their sex between the ages of 7 and 12. Although their transition argues for the influence of genes and hormones on gender identity, such a conclusion must be tentative because the individuals had a great deal to gain from the switch in a society that puts a high premium on maleness. Eden Atwood (Figure 7.13) is a widely acclaimed jazz singer. She has recorded and

performed all over the world and with the biggest names in jazz. Ms. Atwood is also remarkable for having been born with XY chromosomes and two testes. Androgen insensitivity syndrome, a form of 46 XY DSD, is caused by a genetic absence of androgen receptors, which results in insensitivity to androgen. Müllerian inhibiting hormone suppresses development of most of the female internal organs, but because the individual is unaffected by androgens, the testes do not descend and the external genitals develop as more or less feminine (depending on the degree of insensitivity), with a shallow vagina. If the genitals are mostly feminine, the child is reared as a girl, and at puberty her body is further feminized by estrogen from the testes and adrenal glands. The condition may not be recognized until menstruation fails to occur at puberty or when unsuccessful attempts to become pregnant lead to a more complete medical examination. In the absence of testosterone’s influence, androgen-insensitive individuals tend to have well-developed breasts and a flawless complexion. Because these characteristics are often combined with long, slender legs, androgen-insensitive males repeatedly turn up among female fashion models (J. Diamond, 1992). FIGURE 7.13 Eden Atwood.

SOURCE: Photo courtesy of Terry Cyr. Used with permission of Eden Atwood.

3 Profiles of AIS 46 XX Difference in Sexual Development A female fetus may be partially masculinized by excess androgen and by some

hormone treatments during fetal development, resulting in 46 XX difference in sexual development. The internal organs are female, because no Müllerian inhibiting hormone is released, but the external genitals are virilized to some extent; that is, they have some degree of masculine appearance. In extreme cases, the clitoris is as large as a newborn male’s penis, and the external labia are partially or completely fused to give the appearance of an empty scrotum. FIGURE 7.14 Female Infant With Congenital Adrenal Hyperplasia. Parents of children with ambiguous genitalia often have difficulty knowing whether to rear them as boys or as girls. (The unusual pigmentation of the skin is due to excess excretion of sodium, or salt wasting, which often occurs with CAH.)

SOURCE: Used with permission of Thomas A. Wilson, MD, The School of Medicine at Stony Brook University Medical Center. Figure 7.14 illustrates one cause of 46 XX DSD; congenital adrenal hyperplasia

(CAH), which results from an enzyme defect that causes the individual’s adrenal glands to produce large amounts of androgen during fetal development and after birth until the problem is treated. Postnatal hormone levels can be normalized by administering corticosteroids, and the parents often choose reconstructive surgery to reduce the size of the clitoris and eliminate labial fusion, giving the genitals a more feminine appearance. If masculinization is more pronounced, the parents may decide to rear the child as a boy; in that case, the surgeons usually finish closing the labia and insert artificial testes in the scrotum to enhance the masculine appearance Recent work indicates that the most common cause of CAH, 21-hydroxylase deficiency, can be detected in the womb and treated with a synthetic corticosteroid to reduce genital ambiguity (Nimkarn & New, 2010). Obviously, sex cannot always be neatly divided between male and female. Some

experts believe that two categories are not sufficient to describe the variations in masculinity and femininity. Anne Fausto-Sterling (1993) advocates at least five sexual categories. The ones between male and female are often referred to as intersex conditions, a term that is not used in the medical profession but is preferred by many individuals. It would be easy to get caught up in the unusual physical characteristics of these individuals and to be distracted from our question: What makes a person male or female? This question is the topic of the accompanying Application as well as the next few pages. Cognitive and Behavioral Effects As mentioned earlier, reversing the sex hormone balance during prenatal

development changes the brain and later behavior in nonhuman animals. Is it possible that masculinization and feminization of the developing brain account for sex differences in behavior and cognitive abilities in humans as well? If so, then we would expect the behavior and abilities of individuals who have experienced an excess or a deficit of androgen during prenatal development to be at odds with their chromosomal sex.

4 Intersex Conditions That is indeed the case. Androgen-insensitive males are like females in that their

verbal ability is higher than their spatial performance, and their spatial performance is lower than that of other males (Imperato-McGinley, Pichardo, Gautier, Voyer, & Bryden, 1991; Masica, Money, Ehrhardt, & Lewis, 1969). And though there have been contradictory results, evidence favors increased spatial ability in CAH women (Puts, McDaniel, Jordan, & Breedlove, 2008). Androgen-insensitive 46 XY individuals also are typically feminine in behavior, have a strong childbearing urge,

and are decidedly female in their sexual orientation (M. Hines, 1982; Money, Schwartz, & Lewis, 1984; J. M. Morris, 1953). Although 95% of CAH women reared as girls accept a female identity, they also show behavioral shifts in the masculine direction (Dessens, Slijper, & Drop, 2005). They have been reported to be tomboyish in childhood (M. Hines); to prefer boys’ toys, such as trucks and building blocks (Berenbaum, Duck, & Bryk, 2000); and to draw pictures more typical of boys, using darker colors and including mechanical objects and excluding people (Iijima, Arisaka, Minamoto, & Arai, 2001). They also more often report male-dominated occupational choices (30% vs. 13%), interest in rough sports (74% vs. 50%), and interest in motor vehicles (14% vs. 0%; Frisén et al., 2009). There is evidence that these effects are due to androgen levels before birth rather than during postnatal development (Berenbaum et al.). Homosexual or bisexual orientation has been reported to be as high as 37% (Money et al.) and at 19% in a recent larger study (Frisén et al.). “

The evidence accumulated so far strongly suggests that man is no exception with regard to the influence of sex steroids on the developing brain and subsequent behavior.

—Anke Ehrhardt and Heino Meyer-Bahlburg

” Some critics claim that humans are sexually neutral at birth and they attribute the

cognitive and behavioral effects we have just seen to feminine or ambiguous rearing in response to the child’s genital appearance. (You may be beginning to appreciate the deficiencies of natural experiments.) However, some of the findings are difficult to explain from a socialization perspective. For example, the anti-miscarriage drug diethylstilbestrol (DES) given to women in the 1950s and 1960s has an androgen-like effect in the brain but does not virilize the genitals, yet DES-exposed daughters reported increased homosexual fantasy and behavior (Ehrhardt et al., 1985; Meyer- Bahlburg et al., 1995). In another study, girls exposed to a similar drug and who had nonvirilized genitals scored higher in aggression than their unexposed sisters (Reinisch, 1981). In addition, the fact that androgen-insensitive 46 XY individuals perform even lower on spatial tests than their unaffected sisters and female controls (Imperato-McGinley et al., 1991) can be explained by insensitivity to androgens but not by “feminine rearing.”

What are the behavioral implications of 46 XX and 46 XX DSD? Ablatio Penis: A Natural Experiment The “neutral-at-birth” theorists claim that individuals reared in opposition to their

chromosomal sex generally accept their sex of rearing and that this demonstrates that

rearing has more effect on gender role behavior than chromosomes or hormones (studies reviewed in M. Diamond, 1965). Diamond, who advocates a “sexuality-at- birth” hypothesis, argues that the reason individuals with ambiguous genitals accept their assigned gender is that sex of rearing is usually decided by whether the genital appearance is predominantly masculine or feminine, which in turn reflects the influence of prenatal hormones. According to Diamond, there is no case in the literature where an unambiguously male or female individual was successfully reared in opposition to the biological sex. He and others (Money, Devore, & Norman, 1986) have described several instances in which individuals assigned as one sex successfully shifted to their chromosomal and gonadal sex in later years, long after Money’s window for forming gender identity (the first few years of life) supposedly had closed. Failures in predicting the later gender identity of a child with ambiguous genitals has led several experts (along with the advocacy group Accord Alliance) to advocate waiting until the child can give informed consent, or at least indicates a clear gender preference; others are reluctant to see the child subjected to the social difficulties that result from an ambiguous appearance.

APPLICATION

Sex, Gender, and Sports When Caster Semenya of South Africa won the gold medal in the 800-meter race at the 2009 World Championships in Athletics, her strong performance and masculine physique aroused suspicions about her gender. Fueled by years of media reports that some female competitors might actually be men, the International Association of Athletics Federations (IAAF) and the International Olympic Committee (IOC) had introduced routine gender testing in the 1960s (J. L. Simpson et al., 1993). However, physical examination was soon rejected as unacceptable to many women, and chromosome testing turned out to be inadequate as a measure of performance advantage. For example, Barr body analysis, which identifies cells with XX chromosomes, rejects androgen-insensitive XY individuals though they receive no benefit from testosterone, but it would pass XXY males, who do benefit. The IOC and the IAAF ended routine testing in the 1990s, though both reserved the authority to request gender identification on an individual basis. Semenya agreed to an IAAF request to undergo extensive gender testing,

and a panel of experts spent months evaluating the results. In the meantime, reports were leaked that Semenya had two testes and triple the normal level of testosterone for a female. The IAAF said that if the reports turned out to be accurate, it would pay for corrective surgery; the surgery would remove the internal testes, which have a high risk for cancer, and eliminate the source of

the extra testosterone. When the IAAF received the report, it did not reveal the results to the public, but nearly a year after the championships, Semenya was cleared to compete again—as a woman. Some sexual activists argue that if society would place less emphasis on gender, whether a person is male or female wouldn’t matter, but this case suggests there is a need for better understanding of what it means to be male or female. The IOC is now skirting the gender issue, announcing in June 2012 that it will bar athletes from competing as females if they have normal male levels of androgens and are responsive to androgens. What is normal was left unspecified, and the IOC indicated that it expected participating countries to verify their own athletes for the 2012 London Olympics, so the new policy has not been tested.

SOURCES: “Caster Semenya Must Wait,” 2010; Hart, 2009; Macur, 2012; O’Reilly, 2010; Powers, 2010. SOURCE: © ASSOCIATED PRESS/Anja Niedringhaus.

“

Gender identity is sufficiently incompletely differentiated at birth as to permit successful assignment of a genetic male as a girl.

—John Money An extensive search of the literature reveals no case where a male or female without some sort of biological abnormality... accepted an imposed gender role opposite to that of his or her phenotype.

—Milton Diamond

” In 1966, an 8-month-old boy became the most famous example of resistance to

sexual reassignment when the surgeon using electrocautery to perform a circumcision turned the voltage too high and destroyed the boy’s penis. At that time, it was not possible to fashion a satisfactory replacement surgically, so after months of consultation and agonizing, Bruce’s parents decided to let surgeons transform his

genitals to feminine ones. The neutral-at-birth view was widely accepted then, and the psychologist John Money counseled the parents that they could expect their son to adopt a female gender identity (M. Diamond & Sigmundson, 1997). Bruce would be renamed Brenda, and “she” would be reared as a girl. This case study had two characteristics lacking in other “natural experiments”: The child was normal before the accident, and he happened to have an identical twin who served as a control. FIGURE 7.15 David Reimer, 1965–2004.

SOURCE: © STR/REUTERS/Newscom. Over the next several years, Money (1968; Money & Ehrhardt, 1972) reported that

Brenda was growing up feminine, enjoying her dresses and hairdos, and choosing to help her mother in the house, while her “typical boy” brother played outside. But developmental progress was not nearly as smooth as Money claimed (M. Diamond & Sigmundson, 1997). Brenda was in fact a tomboy who played rough-and-tumble sports and fought, and she preferred her brother’s toys and trucks over her dolls. She looked feminine, but her movements betrayed her, and her classmates called her “caveman.” When the girls barred her from the restroom because she often urinated in a standing position, she went to the boys’ restroom instead. She had private doubts about her sex beginning in the second grade, and by the age of 11 had decided she was a boy. At age 14, she decided to switch to living as a male. Only then did Brenda’s father tell her the story of her sexual transition in infancy. Then, said Brenda, “everything clicked. For the first time things made sense and I understood who and what I was” (p. 300). Brenda changed her name to David and requested treatment with testosterone,

removal of the breasts that had developed under estrogen treatment, and construction of a penis. The child who was isolated and teased as a girl was accepted and popular as a boy, and he attracted girlfriends. At age 25, he married Jane and adopted her three children. Although he was limited in sexual performance, he and Jane engaged in

sexual play and occasional intercourse. But life was still not ideal. He brooded about his childhood and was often angry or

depressed; after 14 years, Jane told him they should separate for a while. Troubled by his past and his present, and perhaps a victim of heredity—his mother had attempted suicide, his father became an alcoholic, and his twin brother died of an overdose of antidepressants—one spring day in 2004 David Reimer took his own life (Figure 7.15; Colapinto, 2004). Ablatio penis (“removed penis”) during infancy is rare; only two other cases of

female reassignment with follow-up have been reported in the literature. In one, the individual chose reassignment as a male at the age of 14 (Ochoa, 1998). In the third case, the individual reported no uncertainty about her feminine identity in adulthood (Bradley, Oliver, Chernick, & Zucker, 1998). This more positive outcome could be due to any of a number of factors, including early gender reassignment and minimal family ambivalence about the female assignment. However, in spite of her commitment to a female gender identity, she reported being a tomboy during childhood, and as an adult she chose a traditionally masculine “blue collar” occupation. At age 26, her sexual activity was evenly divided between men and women, and her sexual fantasies were predominantly about women. Meyer-Bahlburg (1999) points out that “a given gender identity can accommodate wide variations in gender role behavior” (p. 3455). These three cases do not permit firm conclusions, but they also do not support the view that gender behavior is primarily a result of upbringing. A recent case emphasizes the need for better understanding of this issue (see the accompanying In the News).

Who Chooses a Child’s Sex? After M.C. was born his mother was declared unfit and his father abandoned him, so he became a ward of the state of South Carolina. M.C. was born with both male and female genitals, so at the age of 16 months doctors performed reconstructive surgery and the child was assigned to be reared as a girl just 3 months before being adopted by Mark and Pam Crawford. Now 8 years old, M.C. lives as a boy and refuses to be called

a girl; his family, friends, school, pediatrician, and religious leaders all support his identity. In the first case of its kind in the United States, his adoptive parents are suing the three doctors and several staff members from the South Carolina Department of Social Services. The parents say that the doctors should not have made the decision, and that any surgery should have been delayed until M.C. was able to choose his own identity. M.C.’s chromosomal sex has not been disclosed.

Concept Check

5 The Case of M.C.

Take a Minute to Check Your Knowledge and Understanding

How do the sexual anomalies require you to rethink the meaning of male and female?

What reasons can you give for thinking that the brains of people with sexual anomalies have been masculinized or feminized contrary to their chromosomal sex?

Sexual Orientation Sex researchers, along with the rest of us, spend a great deal of time arguing about why some people are attracted to members of the same sex. Whether we know it or not, we are also asking why most people are heterosexual. The answer to that question may seem obvious, but the fact that a behavior is nearly universal and widely accepted does not mean that it requires no explanation. People who are attracted to members of their own sex may be able to tell us not only about homosexuality but also about the basis for sexual orientation in general. It is difficult to estimate how many people are homosexual; the numbers vary from

study to study and from one country to another, due to differences in definition and sampling methods, as well as reluctance to admit membership in a stigmatized group. In a review of nine studies, the average rate in the United States was 3.5%, with Canada, Australia, the United Kingdom, and Norway ranging from 1.2% to 2.1% (Gates, 2011). In the United States, prevalence was equally divided between men and women; however, while almost two thirds of the nonheterosexual men identified themselves as exclusively homosexual, only one third of nonheterosexual women did so. Homosexual experiences are fairly common, especially during adolescence and in the absence of heterosexual opportunities. Almost 8% of the population have had at least one same-sex sexual encounter and as many as 11% report same-sex attraction (Gates, 2011); but as Ellis and Ames (1987) point out, these experiences do not make a person homosexual any more than occasional heterosexual activity makes a person heterosexual. Interestingly, about 1% of people express no interest in sex at all (Bogaert, 2004). Asexuality is gaining acceptance as an additional category of preference. Research does not support the belief that gay men are necessarily feminine and

lesbians are masculine; only about 44% of gays and 54% of lesbians fit those

descriptions (Bell, Weinberg, & Hammersmith, 1981). Even then, they usually identify with their biological sex, so gender role, gender identity, and sexual orientation are somewhat independent of each other and probably have different origins.

6 Homosexuality and Asexuality It is not clear what causes homosexuality, which means that we do not know how to

explain heterosexuality either. There is considerable evidence for biological influences on sexual orientation, or else the topic would not appear in this chapter. But because social influences are commonly believed to be more important, we will consider this position first. The Social Influence Hypothesis It has been argued that homosexuality arises from parental influences or is caused

by early sexual experiences. Bell and his colleagues (1981) expected to confirm these influences when they studied 979 gay and 477 heterosexual men. But they found no support for frequently hypothesized environmental influences, such as seduction by an older male or a dominant mother and a weak father. Several developmental experiences do seem to differentiate homosexuals from

heterosexuals, and these have been considered evidence for a social learning hypothesis (Van Wyk & Geist, 1984). But these experiences—such as spending more time with other-sex playmates in childhood, learning to masturbate by being masturbated by a member of the same sex, and homosexual contact by age 18—can just as easily be interpreted as reflecting an early predisposition to homosexuality. In fact, Bell and his associates (1981) concluded that adult homosexuality “is just a continuation of the earlier homosexual feelings and behaviors from which it can be so successfully predicted” (p. 186; italics in the original). However, they did find more evidence for an influence of learning on bisexuality than on exclusive homosexuality. This suggests that there might be a biological influence that varies in degree, with experience making the final decision in the individuals with weaker predispositions for homosexuality. Seventy percent of homosexuals remember feeling “different” as early as 4 or 5

years of age (Bell et al., 1981; Savin-Williams, 1996). Memories of feelings are suspect, because they are easily distorted in light of today’s circumstances; memories of behavior are somewhat more reliable, and home videos from childhood are better yet. These behavioral measures show a high rate of gender nonconformity, including mannerisms and dress typical of the other sex, a tendency to engage in activities usually preferred by the other sex, and an atypical preference for other-sex playmates and companions while growing up (Bell et al., 1981; Rieger, Linsenmeier, Gygax, & Bailey, 2008). If we are to entertain a biological hypothesis of sexual orientation, though, we must come up with some reasonable explanation for how it is formed and

how it is altered. There are three biological approaches to the question: genetic, hormonal, and neural. Genetic and Epigenetic Influences Twin and family studies provide the most documented evidence for a biological

basis for sexual orientation. Homosexuality is seen two to seven times more often among the siblings of homosexuals than it is in the general population (J. M. Bailey & Bell, 1993; J. M. Bailey & Benishay, 1993; Hamer, Hu, Magnuson, Hu, & Pattatucci, 1993). Studies in the early 1990s reported concordances of about 50% in identical twins for both men and women (J. M. Bailey & Pillard, 1991; J. M. Bailey et al., 1993). However, when subjects were recruited without regard to their sexual preference, concordances for men fell to 37% in one study and 18% in another, and women’s concordances dropped to 30% and 22% (J. M. Bailey, Dunne, & Martin, 2000; Långström, Rahman, Carlström, & Lichtenstein, 2010). Presumably the earlier data suffered from volunteer bias, due to homosexual individuals’ greater willingness to volunteer if they had a homosexual sibling.

What is the evidence for a biological basis for homosexuality? The search for specific genes has been frustrating, which is not uncommon when

multiple genes are involved; because any number of combinations of the genes can produce the behavior, a particular gene can have a significant effect in one study and go undetected in the next. Dean Hamer and his associates (1993) focused their attention on the X chromosome; their reasoning was that gay men have more gay relatives on the mother’s side of the family than on the father’s side, and the mother contributes only X chromosomes to her sons. They found that 64% of the pairs of gay brothers they studied shared identical genetic material at one end of the X chromosome, in the region designated as Xq28 (Figure 7.16a). However, results of subsequent studies have been only suggestive of a gene related to homosexuality in that area (Mustanski et al., 2005). A whole-genome study implicated a stretch of DNA on chromosome 7 in the 7q36 region (Mustanski et al.), and a later study of Chinese homosexual men implicated an allele of the SHH gene there (Figure 7.16b; Wang et al., 2012). SHH contributes to the patterning of organ development, from growth of fingers to organization of the brain, but it is also involved in male–male sexual activity, at least in fruit flies. FIGURE 7.16 Possible Locations of Genes for Male Homosexuality. (a) The X chromosome, showing the Xq28 region. (b) Chromosome 7, indicating region 7q36 and the relative location of the SHH gene.

Evidence that homosexuality is influenced by genes presents a Darwinian contradiction; how could homosexuality survive when its genes are unlikely to be passed on by the homosexual individual? Italian researchers have offered an intriguing proposal; the birth rate is higher in women on the mother’s side of the family of male homosexuals, so they conclude that genes responsible for homosexuality also increase the women’s birth rate—compensating for the homosexual’s lack of productivity (Camperio Ciani, Corna, & Capiluppi, 2004; Iemmola & Camperio Ciani, 2009). A later analysis indicated that this effect is best explained by two genes, at least one of which is on the X chromosome; the researchers also suggested that the genes increase attraction to men, in both men and women (Camperio Ciani, Cermelli, & Zanzotto, 2008). In the face of recent data indicating that environmental influences are stronger than

previously thought, we need to look further for the sources. As you can see in Figure 7.17, unique environmental factors are much greater than shared influences (Långström et al., 2010). At the age of 3 or 4, when prehomosexual feelings and behaviors typically appear, there has been very little opportunity for social influences outside the family to come into play; this means that the prenatal environment is the more likely source of these unique influences. One proposed mechanism is an epigenetic process known as imprinting. In females, one of each pair of X chromosomes is turned off in every cell. Which of the two X chromosomes gets turned off usually varies randomly from cell to cell, but in the mothers of gay sons one X chromosome is more likely to be favored over the other (Bocklandt, Horvath, Vilain, & Hamer, 2006). Only 4% of women with no gay sons showed “extreme skewing”—defined as inactivation of the same chromosome in 90% of their cells— compared with 13% of women with a homosexual son and 23% of the mothers of two or more gay sons. A study at the University of Pennsylvania supports the idea that environmental

influences can have epigenetic effects on sexual development (Morgan & Bale, 2011). Male offspring of mice that were subjected to stress during the early prenatal period had a variety of female-typical characteristics, including gene expression patterns in the brain, passivity during restraint, and alterations in genital development. A research team from the United States and Sweden has proposed that epigenetic modifications of testosterone sensitivity contribute to the development of sexual orientation (W. R. Rice, Friberg, & Gravilets, 2012). According to them, these sensitivity shifts

ordinarily occur when testosterone levels are a bit off the mark, helping to ensure normal development. These effects usually are not passed on to the next generation, but if a man with low testosterone transfers his increased sensitivity to a daughter, or a woman with high testosterone transfers her decreased sensitivity to a son, it can have significant effects on the offspring’s sexual and gender development. FIGURE 7.17 Genetic and Environmental Contributions to Sexual Orientation.

SOURCE: Based on data from “Genetic and Environmental Effects on Same-Sex Sexual Behavior: A Population Study of Twins in Sweden,” by N. Långström, Q. Rahman, E. Carlström, and P. Lichtenstein, 2010, Archives of Sexual Behavior, 39, pp. 75–80. Prenatal Influences on Brain Structure and Function For early researchers, the most obvious biological explanation was that

homosexuality is due to atypical sex hormone levels. Their attempts to reverse male homosexuality by administering testosterone not only were not successful, but they often increased homosexual activity (for references, see A. C. Kinsey, Pomeroy, Martin, & Gebbard, 1953). Later studies measured hormonal levels and found no evidence of either a deficit or an excess of sex hormones (Gartrell, 1982; Meyer- Bahlburg, 1984). However, by manipulating hormonal levels during gestation and shortly after birth researchers were able to produce same-sex preference in rats, hamsters, ferrets, pigs, and zebra finches (for references, see LeVay, 1996).

Which brain structures are different in homosexual males? Critics say this effect has no bearing on human behavior, claiming that spontaneous

homosexual behavior occurs in animals only when members of the other sex are unavailable and that it does not represent a shift in sexual orientation. However, about 10% of male sheep prefer other males as sex partners, and some form pair bonds in which they take turns mounting and copulating anally with each other (Perkins & Fitzgerald, 1992). A few female gulls observed on Santa Barbara Island off the coast of California form “lesbian” pairs—courting, attempting copulation, taking turns

sitting on their nest, and sharing parenting if some of the eggs were fertilized during an “unfaithful” interlude with a male (Hunt & Hunt, 1977; Hunt, Newman, Warner, Wingfield, & Kaiwi, 1984). A shortage of males could be a contributing factor, but the gulls’ behavior is atypical of opportunistic homosexuality in that the majority stay paired for more than one season. If sex hormones play a role in human sexual orientation, they probably do so by

altering brain development during gestation. It is difficult to measure prenatal hormone levels in humans, so researchers have looked at cognitive and brain differences, which are known to be influenced by sex hormones during development. Homosexual men perform as well as or better than heterosexual females on verbal tests, but underperform heterosexual men on spatial tests (Figure 7.18; Collaer, Reimers, & Manning, 2007; C. M. McCormick & Witelson, 1991; Rahman, Abrahams, & Wilson, 2003). Some studies have reported male-typical spatial and verbal capabilities in homosexual women, but results have been inconsistent (Collaer et al.; Rahman et al.; Gladue, Beatty, Larson, & Staton, 1990). Male spatial superiority appears to be due to a right hemisphere that is larger than the left and specialized for spatial processing, while females gain their advantage by sharing verbal functions across both hemispheres. Savic and Lindström (2008) found that homosexual men, like heterosexual women, have equal-sized left and right hemispheres, while homosexual women have a male-typical larger right hemisphere. FIGURE 7.18 Sex-Atypical Cognitive Performance in Homosexual Men and Women. (a) Spatial performance of gay men was lower than that of heterosexual men; the homosexual women’s performance was slightly, but significantly, higher than that of heterosexual women. (b) Verbal fluency was higher in homosexual males than in all others, including heterosexual females; performance was lower for both heterosexual males and homosexual females, who did not differ significantly from each other.

SOURCE: (a) Based on data from “Sexual-Orientation-Related Differences in Verbal Fluency,” by Q. Rahman, S. Abrahams, and G. D. Wilson, 2003, Neuropsychology,

17, pp. 240–246. (b) Based on data from “Visuospatial Performance on an Internet Line Judgment Task and Potential Hormonal Markers: Sex, Sexual Orientation, and 2D:4D,” by M. L. Collaer, S. Reimers, and J. T. Manning, Archives of Sexual Behavior, 36, pp. 177–192. FIGURE 7.19 Responses of Heterosexual Women, Homosexual Men, and Heterosexual Men to a Presumed Male Pheromone. Heterosexual women and homosexual men responded to the testosterone derivative AND in the MPOA/anterior hypothalamus, while heterosexual men did not.

SOURCE: From “Smelling of Odorous Sex Hormone-Like Compounds Causes Sex- Differentiated Hypothalamic Activations in Humans,” by I. Savic et al., Neuron, 31, pp. 661–668, fig. 1. © 2002. Another indication of functional brain differences is that homosexual individuals,

like male-to-female transsexuals, respond atypically to AND and EST. In a study by Swedish researchers, homosexual men did not respond to EST, but did respond to AND, and in the same areas as the women did (Figure 7.19; Savic, Berglund, & Lindström, 2005). Likewise, lesbian women’s responses to AND and EST were more similar to those of heterosexual men than to those of heterosexual women (Berglund, Lindström, & Savic, 2006). Studies have also found size differences between gay males and heterosexuals in

two brain structures. Simon LeVay (1991) reported that the third interstitial nucleus of the anterior hypothalamus (INAH3) is half the size in gay men and heterosexual women as in heterosexual men (Figure 7.20; you can locate the anterior hypothalamus in Figure 6.2). Earlier we saw this difference in male-to-female transsexuals, and it has also been reported in sheep (Roselli et al., 2004); another human study found a difference in the same direction, but it failed to reach statistical significance (Byne et al., 2001). Though INAH3 is located in the same area as the sexually dimorphic nucleus in animals, its role in human sexual behavior is unknown. In other research, the suprachiasmatic nucleus (SCN) was larger in gay men than in heterosexual men and contained almost twice as many cells that secrete the neuropeptide vasopressin (Swaab & Hofman, 1990). The SCN is also shown in Figure 6.2, lying, as its name implies, just above the optic chiasm. Besides controlling daily cycles of activity in rats and humans, the SCN regulates the reproductive cycle in female rats. Blocking the effects of testosterone in male rats during the prenatal period and for the first few

days after birth increased the number of vasopressin-secreting cells in their SCNs; as adults, they preferred the company of a sexually active male rather than an estrous female, and they showed lordosis and accepted mounting from the male (Swaab, Slob, Houtsmuller, Brand, & Zhou, 1995). FIGURE 7.20 INAH3 in a Heterosexual Man (Left) and a Homosexual Man (Right). The arrows indicate the boundaries of the structure. Note the smaller size in the homosexual brain.

SOURCE: From “A Difference in Hypothalamic Structure Between Heterosexual and Homosexual Men,” by S. LeVay Science, 253, pp. 1034–1047. © 1991, American Association for the Advancement of Science (AAAS). Reprinted with permission from AAAS. You may have noticed that there is less evidence for masculinization in homosexual

women than there is for its failure in homosexual men. A major reason is that studies of homosexuality have focused disproportionately on men, but there have also been negative findings when lesbians were studied. Two physical characteristics do distinguish homosexual from heterosexual women; though they seem trivial, they are widely accepted as measures of prenatal androgen exposure. First, the ratio of index finger length to ring finger length is smaller in lesbians than in control women, and similar to those in men, both heterosexual and homosexual (T. J. Williams et al., 2000). The second difference involves a peculiar, faint sound given off by the inner ear when it is stimulated, called evoked otoacoustic emissions. The response is weaker in lesbians and men (both heterosexual and homosexual) than in heterosexual women (McFadden & Pasanen, 1998). “

The most powerful sex organ is between the ears, not between the legs. —Milton Diamond

”

An alternative hypothesis about how the brain might be altered comes from the fact that homosexual males tend to have more older brothers than heterosexual males do;

the effect is so strong that it is estimated that one gay man in seven owes his sexual orientation to birth order (Cantor, Blanchard, Paterson, & Bogaert, 2002). The effect can’t be attributed to social influence, because the presence of older nonbiological brothers in the home has no effect on orientation (Bogaert, 2006). Some researchers have proposed that previous male births expose later-born males to elevated testosterone in the womb (T. J. Williams et al., 2000), citing the fact that gay men exaggerate some male-typical traits, such as left-handedness (reviewed in Rahman, 2005a). This explanation runs into trouble because CAH males do not have a high level of homosexuality (Cohen-Bendahan, van de Beek, & Berenbaum, 2005), and fraternal birth order is not correlated with spatial ability or a general measure of masculinity (Rahman, 2005b). Ray Blanchard (2001) proposed the maternal immunity hypothesis: With each male birth, the mother develops increasing antibodies to male- specific proteins in the brain, and these affect the development of sex-related traits. The hypothesis is speculative, but one protein coded in the brain by a gene on the Y chromosome (SMCY) does produce an immune reaction in mothers that increases with subsequent male births, and three other candidate proteins have been proposed (Bogaert & Skorska, 2011). Social Implications of the Biological Model As is often the case, the research we have been discussing has important social

implications. If homosexuality is a choice, as argued by some, then U.S. civil rights legislation does not apply to homosexuals, because protection for minorities depends on the criterion of unalterable or inborn characteristics (Ernulf, Innala, & Whitam, 1989). About 75% of homosexuals believe that homosexuality is inborn, and that they have no choice (Leland & Miller, 1998). When Congressman Barney Frank of Massachusetts (Figure 7.21) was asked if he ever considered whether switching to the straight life was a possibility, he replied, “I wished it was. But it wasn’t. I can’t imagine that anybody believes that a 13-year-old in 1953 thinks, ‘Boy, it would be really great to be a part of this minority that everybody hates and to have a really restricted life’” (Dreifus, 1996, p. 25).

Why is the search for a biological basis of homosexuality a social issue? But some in the gay community think that promoting this view is not in their best

interest. For them, the biological model is associated too closely with the old medical “disease” explanation of homosexuality. They fear that homosexuals will be branded as defective, or even that science may find ways to identify homosexual predisposition in fetuses and that parents will have the “problem” corrected through genetic manipulation or abortion. Emotions are so strong among some homosexuals that the researcher Dick Swaab was physically attacked in Amsterdam by members of the Dutch gay movement, who felt threatened by his biological findings (Swaab, 1996).

Concept Check

FIGURE 7.21 U.S. Congressman Barney Frank. In 2012, Frank became the first member of Congress to marry someone of the same gender while in office.

SOURCE: © SAUL LOEB/AFP/Getty Images/Newscom. “

As for being gay, I never felt I had much choice.... I am who I am. I have no idea why. —Congressman Barney Frank

”

Other gay and lesbian rights activists welcome the biological findings because they think that belief in biological causation will increase public acceptance of homosexuality. Polls indicate they are right; in a survey of four different cultures, 56% to 85% of people who believed homosexuals are “born that way” held significantly more positive views (Ernulf et al., 1989). In the United States, moral acceptance of homosexuality has increased from 38% in 2002 to 54% in 2012 (Saad, 2012), and the number favoring same-sex marriage rose from 40% in 2004 to 53% in 2013 (S. Dutton, De Pinto, Salvanto, & Backus, 2013). The nature-nurture debate will not be settled to everyone’s satisfaction anytime soon, but most researchers believe that when we understand the origins of homosexuality and heterosexuality, they will include a combination of heredity, hormones, neural structures, and experience (LeVay, 1996).

Take a Minute to Check Your Knowledge and Understanding

How has the social influence hypothesis fared in explaining homosexuality? What is the evidence that homosexuality has a biological cause? Organize your knowledge: Make a table of the structural and functional brain differences that may distinguish homosexual from heterosexual individuals. Include a brief explanation.

In Perspective The fact that sex is not motivated by any tissue deficit caused researchers to look to the brain for its basis. What they found was a model for all drives that focused on the brain rather than on tissue that lacked nutrients or water or was too cold. This view changed the approach to biological motivation, and it meant that gender identity and gender-specific behavior and abilities might all be understood from the perspective of the brain. The fact that a person’s sexual appearance, gender identity, and behavior are

sometimes in contradiction with each other or with the chromosomes makes sex an elusive concept. Research is helping us understand that many differences between the sexes are cultural inventions and that many differences thought to be a matter of choice have biological origins. As a result, society is slowly coming around to the idea that distinctions should not be made on the basis of a person’s sex, sexual appearance, or sexual orientation. These issues are emotional, as are the important questions behind them: Why are we attracted to a particular person? Why are we attracted to one sex and not the other? Why do we feel male or female? The emotion involved often obscures an important point: that the answers keep leading us back to the brain, which is why some have called the brain the primary sex organ. Summary Sex as a Form of Motivation • Although there is no tissue deficit, sex involves arousal and satiation like other drives, as well as hormonal and neural control. Also like the other drives, sex can be thought of as a need of the brain.

• The key elements in human sexual behavior are testosterone, structures in the hypothalamus, and sensory stimuli such as certain physical characteristics and pheromones.

The Biological Determination of Sex • Differentiation as a male or a female depends on the combination of X and Y chromosomes and the presence or absence of testosterone.

• Testosterone controls the differentiation not only of the genitals and internal sex organs but also of the brain.

Gender-Related Behavioral and Cognitive Differences • Evidence indicates that females exceed males in verbal abilities and that males are more aggressive and score higher in visual-spatial abilities. Males also score more often at the extremes of mathematical ability.

• With the possible exception of mathematical ability, it appears that these differences are at least partly due to differences in the brain and in hormones.

Biological Origins of Gender Identity • People with sexual variations and those with gender identity reversal challenge our idea of male and female.

• The cognitive abilities and altered sexual preferences of people with sexual anomalies suggest that the human brain is masculinized or feminized before birth.

Sexual Orientation • The idea that sexual orientation is entirely learned has not fared well. • Evidence indicates that homosexuality, and thus heterosexuality, is influenced by genes, prenatal hormones (and possibly other factors), and brain structures.

• The biological view is controversial among homosexuals, but most believe that it promotes greater acceptance, and research suggests that this is the case. ■

Study Resources

For Further Thought • Do you think the cognitive differences between males and females will completely disappear in time? If not, would they in an ideal society? Explain your reasons.

• Some believe that parents should have their child’s ambiguous genitals corrected early, and others think it is better to see what gender identity the child develops. What do you think, and why?

• Do you think neuroscientists have made the case yet for a biological basis for homosexuality? Why or why not?

Quiz: Testing Your Understanding 1. Compare sex with other biological drives. 2. Describe the processes that make a person male or female (limit your answer

to typical development). 3. Discuss sex as a continuum of gradations between male and female rather

than a male versus female dichotomy. Give examples to illustrate. 4. Identify any weak points in the evidence for a biological basis for

homosexuality (ambiguous results, gaps in information, and so on) and indicate what research needs to be done to correct the weaknesses.

Select the best answer: 1. The chapter opened with the story of a boy born with female genitals. At

puberty he grew a penis; developed muscles, a deep voice, and a beard; and became more masculine in behavior. The changes at puberty were _____ effects. a. activating b. organizing

c. activating and organizing d. none of the above

2. Of the following, the best argument that sex is a drive like hunger and thirst is that a. almost everyone is interested in sex. b. sexual motivation is so strong. c. sexual behavior involves arousal and satiation. d. sexual interest varies from one time to another.

3. Evidence has been most positive for a pheromone-like effect on _____ in humans. a. menstrual cycles b. sexual attraction c. the VNO d. a and b e. a, b, and c

4. A likely result of the Coolidge effect is that an individual will a. be monogamous. b. have more sex partners. c. prolong a sexual encounter. d. prefer attractive mates.

5. The part of the sexual response cycle that most resembles homeostasis is a. excitement. b. the plateau phase. c. orgasm. d. resolution.

6. The increase in testosterone on nights that couples have intercourse is an example of a. an organizing effect. b. an activating effect. c. cause. d. effect.

7. The sex difference in the size of the sexually dimorphic nucleus is due to a. experience after birth. b. genes. c. sex hormones. d. both genes and experience.

8. The most prominent structure in the sexual behavior of female rats is the a. MPOA. b. medial amygdala. c. ventromedial

d. sexually dimorphic nucleus. nucleus. 9. The chromosomal sex of a fetus is determined

a. by the sperm. b. by the egg. c. by a combination of effects from the two. d. in an unpredictable manner.

10. The main point of the discussion of cognitive and behavioral differences between the sexes was to a. illustrate the importance of experience. b. make a case for masculinization and feminization of the brain. c. make the point that men and women are suited for different roles. d. explain why men usually are dominant over women.

11. The term that describes a person with XX chromosomes and masculine genitals is a. homosexual. b. XX SCID c. androgen-insensitive male. d. XX DSD.

12. The best evidence that the brains of people with sexual variations have been masculinized or feminized contrary to their chromosomal sex is (are) their a. behavior and cognitive abilities. b. genital appearance. c. physical appearance. d. adult hormone levels.

13. Testosterone injections in a gay man would most likely a. have no effect. b. increase his sexual activity. c. make him temporarily bisexual. d. reverse his sexual preference briefly.

14. Evidence that lesbianism is biologically influenced is a. that there is a high concordance among identical twins. b. that lesbians have a couple of distinctive physical features. c. that a brain structure is larger in lesbians and men than in heterosexual

women. d. both a and b e. both b and c

15. Environmental influences on sexual orientation are a. insignificant in size. b. mostly from peers. c. mostly within the family.

d. most likely prenatal. Answers: 1. c, 2. c, 3. b, 4. b, 5. d, 6. d, 7. c, 8. c, 9. a, 10. b, 11. d, 12. a, 13. b, 14. b, 15. d.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The Society for Women’s Health Research describes a number of sex

differences in brain structure and cognitive function, with references. 2. The Johns Hopkins Children’s Center’s Disorders of Sex Differentiation

provides information on a variety of variations in sexual development. 3. Profiles of Two Women With AIS is a video interview with Eden Atwood

and a young girl about living with androgen insensitivity syndrome. 4. Intersex and Intersex Initiative are two sites that provide a wealth of

information about intersex conditions and treatment. The Interface Project presents the stories of people with intersex conditions, including Eden Atwood.

5. CNNHealth posted the story of M.C. and his family’s suit against the doctors who performed his sex reassignment surgery.

6. Facts About Homosexuality and Mental Health describes research and changing attitudes regarding the mental health of homosexual individuals. Also available are links to additional information. Asexual Visibility and Education Network (AVEN) provides information about asexuality and the opportunity to chat on a variety of related topics.

Chapter Updates and Biopsychology News

For Further Reading 1. Why Is Sex Fun? The Evolution of Human Sexuality, by Jared Diamond

(Basic Books, 1997), takes an evolutionary approach to answer questions such as why humans have sex with no intention of procreating and why the

human penis is proportionately larger than in other animals. 2. Sex Differences in Cognitive Abilities, 4th ed., by Diane Halpern

(Psychology Press, 2011), updates research on cognitive differences and attempts to separate well-reasoned, data-supported conclusions from politicized pseudoscience.

3. “His Brain, Her Brain,” by Larry Cahill (Scientific American, May 2005, 40– 47, or www.bio.uci.edu/public/press/2005/hisherbrain.pdf), is a nicely illustrated and popularly written tour of sex differences in brain and behavior.

4. Your Sexual Mind, a special issue of Scientific American Mind, contains several relevant articles. They include (with references for their original issues of publication, which might be more readily available): “The Orgasmic Mind” (brain activity during orgasm; Apr/May, 2008, 66–71); “Bisexual Species” (same-sex behavior in other animals; June/July, 2008, 68–73); “Sex and the Secret Nerve” (pheromone detection; Feb/Mar, 2007, 20–27); “Abnormal Attraction” (pedophilia; Feb/Mar, 2007, 58–63); “Misunderstood Crimes” (sex offenders; Apr/May, 2008, 78–79); and “Do Gays Have a Choice?” (gays who have adopted the straight life; Feb/Mar, 2006, 50–57).

5. In Sexing the Body: Gender Politics and the Construction of Sexuality, by Anne Fausto-Sterling (Basic Books, 1999), and Intersex in the Age of Ethics, by Alice Domurat Dreger (University Publishing Group, 1999), the authors argue for a more flexible view of sex and gender than our traditional either/or approach, including accepting gradations between male and female and allowing intersexed individuals to make their own gender selection.

6. As Nature Made Him: The Boy Who Was Raised as a Girl, by John Colapinto (HarperCollins, 2000), tells the story of the boy whose penis was damaged during circumcision. Described by reviewers as “riveting,” with a touching description of his suffering and of his parents’ and brother’s support of him.

7. “The Pheromone Myth: Sniffing Out the Truth,” by Richard Doty (New Scientist, February 24, 2010, 28–29), is based on the author’s book The Great Pheromone Myth (Johns Hopkins University Press, 2010), in which he dismisses pheromones in mammals as nothing more than learned odor preferences or, in some cases, the result of bad research.

Key Terms activating effects amygdala androgen insensitivity syndrome androgens

castration central bed nucleus of the stria terminalis (BSTc) congenital adrenal hyperplasia (CAH) Coolidge effect dihydrotestosterone estrogen estrus 46 XY difference in sexual development 46 XX difference in sexual development gender gender identity gender nonconformity gender role gonads major histocompatibility complex (MHC) medial amygdala medial preoptic area (MPOA) Müllerian ducts Müllerian inhibiting hormone organizing effects ovaries oxytocin pheromones sex sexually dimorphic nucleus (SDN) suprachiasmatic nucleus (SCN) testes testosterone third interstitial nucleus of the anterior hypothalamus (INAH3) transsexual ventromedial hypothalamus vomeronasal organ (VNO) Wolffian ducts

8 Emotion and Health

In this chapter you will learn • How the brain and the rest of the body participate in emotion • How stress affects health and immune functioning • Why pain is an emotion as well as a sensation • The role of hormones, brain structures, and heredity in aggression

Emotion and the Nervous System Autonomic and Muscular Involvement in Emotion The Emotional Brain The Prefrontal Cortex APPLICATION: WHY I DON’T JUMP OUT OF AIRPLANES

The Amygdala Hemispheric Specialization in Emotion CONCEPT CHECK

Stress, Immunity, and Health Stress as an Adaptive Response Negative Effects of Stress IN THE NEWS: KEEPING ODD HOURS COULD MAKE YOU SICK APPLICATION: ONE AFTERMATH OF 9/11 IS STRESS-RELATED BRAIN DAMAGE

Social, Personality, and Genetic Factors Pain as an Adaptive Emotion CONCEPT CHECK

Biological Origins of Aggression Hormones and Aggression The Brain’s Role in Aggression Neurotransmitters and Aggression APPLICATION: NEUROCRIMINOLOGY, RESPONSIBILITY, AND THE LAW

Heredity and Environment CONCEPT CHECK

In Perspective Summary Study Resources

When Jane was 15 months old, she was run over by a vehicle. The injuries seemedminor, and she appeared to recover fully within days of the accident. By the age of 3, however, her parents noticed that she was largely unresponsive to verbal or

physical punishment. Her behavior became progressively disruptive, and by the age of 14 she had to be placed in the first of several treatment facilities. Although her intelligence was normal, she often failed to complete school assignments. She was verbally and physically abusive to others, she stole from her family and shoplifted frequently, and she engaged in early and risky sexual behavior that resulted in pregnancy at the age of 18. She showed little if any guilt or remorse; empathy was also absent, which made her dangerously insensitive to her infant’s needs. Because her behavior put her at physical and financial risk, she became entirely dependent on her family and social agencies for financial support and management of her personal affairs. “

My own brain is to me the most unaccountable of machinery—always buzzing, humming, soaring, roaring, diving, and then buried in mud. And why? What’s this passion for?

—Virginia Woolf

” Magnetic resonance imaging (MRI) revealed that there was damage to Jane’s

prefrontal cortex, which is necessary for making judgments about behavior and its consequences. People who sustain damage to this area later in life show an understanding of moral and social rules in hypothetical situations, but they are unable to apply these rules in real-world situations, so they regularly make choices that lead to financial losses and the loss of friends and family relationships (Bechara, Damasio, Damasio, & Lee, 1999). People like Jane, whose injury occurred in infancy, cannot even verbalize these rules when confronted with a hypothetical situation, and their moral development never progresses beyond the motivation to avoid punishment; they not only make a mess of their own lives but also engage in behavior that harms others as well, like stealing (S. W. Anderson, Bechara, Damasio, Tranel, & Damasio, 1999).

1 Brain and Emotion Videos Emotion enriches our lives with its “buzzing, humming, soaring, and roaring.” It

also motivates our behavior: Anger intensifies our defensive behavior, fear accelerates flight, and happiness encourages the behaviors that produce it. Emotion adds emphasis to experiences as they are processed in the brain, making them more memorable (A. K. Anderson & Phelps, 2001); as a result, we are likely to repeat the behaviors that bring joy and avoid the ones that produce danger or pain. Although

Jane was intelligent, she was unable to learn from her emotional experiences because of her injury. According to Antonio Damasio (1994), reason without emotion is inadequate for making the decisions that guide our lives and, in fact, make up our lives. Emotion and the Nervous System If asked what emotion means, you would probably think first of what we call “feelings”—the sense of happiness or excitement or fear or sadness. Then you might think of the facial expressions that go along with these feelings: the curled-up corners of the mouth during a smile, the knit brow and red face of anger. Next you would probably visualize the person acting out the emotion by fleeing, striking, embracing, and so on. Emotion is all these and more; a working definition might be that emotion is an increase or a decrease in physiological activity that is accompanied by feelings that are characteristic of the emotion and often accompanied by a characteristic behavior or facial expression. Having said that mouthful, I suspect you will understand why Joseph LeDoux (1996) wrote that we all know what emotion is until we attempt to define it. We will talk about these different facets of emotion in the following pages, along with some practical implications in the form of aggression and health.

What effect does the autonomic nervous system have during emotions? Autonomic and Muscular Involvement in Emotion To the neuroscientist, the most obvious component of emotional response is

sympathetic nervous system activation. You may remember from Chapter 3 that the sympathetic system activates the body during arousal; it increases heart rate and respiration rate, increases sweat gland activity, shuts down digestion, and constricts the peripheral blood vessels, which raises the blood pressure and diverts blood to the muscles. As you will see in the section on stress, the sympathetic system also stimulates the adrenal glands to release various hormones, particularly cortisol. At the end of arousal, the parasympathetic system puts the brakes on most bodily activity, with the exception that it activates digestion. In other words, the sympathetic nervous system prepares the body for “fight or flight”; in contrast, the parasympathetic system generally reduces activity and conserves and restores energy (Figure 8.1). FIGURE 8.1 Comparison of Sympathetic Activity During Emotional Arousal With Parasympathetic Activity During Relaxation.

Of course, muscular activation is involved in the external expression of emotion, such as smiling or fleeing or attacking; it is also a part of the less obvious responses of emotion, such as the bodily tension that not only prepares us to act but also produces a headache and aching muscles when we try to write a paper the night before it is due. Autonomic and muscular arousal are adaptive, because they prepare the body for an emergency and help it carry out an appropriate response. They are also a very important part of the emotion itself, though the exact nature of their contribution has been the subject of controversy. Fortunately, as you can see from the following discussion, competing theories are one of the engines driving research and scientific advancement.

How do the James-Lange and cognitive theories disagree? What evidence is there? The Role of Feedback From the Body A bit over a century ago, the American psychologist William James (1893) and

Danish physiologist Carl Lange independently proposed what has come to be known as the James-Lange theory: Emotional experience results from the physiological arousal that precedes it, and different emotions are the result of different patterns of arousal. In our discussion of research ethics in Chapter 4, we talked about an experiment by Albert Ax (1953) in which subjects either were made angry by an insulting experimenter or were frightened by the possibility of a dangerous electric shock. Consistent with the James-Lange theory, the two emotions were accompanied by different patterns of physiological activity. Seventy years later, Stanley Schacter and Jerome Singer (1962) took a contrary position in their cognitive theory; they stated that the identity of the emotion is based on the cognitive assessment of the situation, and physiological arousal contributes only to the emotion’s intensity. Their research demonstrated how easily people could misidentify emotions depending on the environmental context. For example, young men who were interviewed by an

attractive woman while crossing a swaying footbridge 230 feet above a rocky river included more sexual content in brief stories they wrote and were more likely to call the phone number the young woman gave them than were men who were interviewed 10 minutes after crossing the bridge (D. G. Dutton & Aron, 1974). “

We feel sorry because we cry, angry because we strike, afraid because we tremble. —William James, 1893

”

FIGURE 8.2 Emotional Expressions Posed Using Ekman’s Instructions.

SOURCE: © Don Francis/Mardan Photography. Studies like these have not determined that one theory is right and the other is

wrong. Barlassina and Newen (2013) argue that neither is adequate; in their integrative embodiment theory of emotions they maintain that bodily sensations are a critical component of emotions, but these perceptions must be integrated with cognitive information. Nevertheless, incorrect theories can be useful if they generate research, and the competition between these two has produced valuable insights into emotion; a good example is the contribution of facial expressions to emotional experience. Experimenters have had to be very inventive in doing facial expression studies; obviously, they can’t just tell a person to smile or frown and then ask them what emotion they’re feeling. Paul Ekman and his colleagues (Levenson, Ekman, & Friesen, 1990) instructed subjects to contract specific facial muscles to produce different expressions (Figure 8.2); for example, to produce an angry expression, subjects were told to pull their eyebrows down and together, raise the upper eyelid, and push the lower lip up with the lips pressed together (p. 365). The posed facial expressions for happiness, fear, anger, disgust, sadness, and surprise each resulted in the experience of the intended emotion, along with a distinct pattern of physiological arousal. FIGURE 8.3 Disabling Corrugator Muscle Reduces Amygdala Response to Simulated Anger. A woman treated with Botox (a) is unable to produce the facial expression of anger

and shows little activation of the amygdala (b). A control subject makes the expected facial expression (c) and produces much greater amygdala activation (d).

SOURCE: Adapted from “The Link Between Facial Feedback and Neural Activity Within Central Circuitries of Emotion—New Insights from Botulinum Toxin- Induced Denervation of Frown Muscles,” by A. Hennenlotter et al., 2009, Cerebral Cortex, 19, pp. 537–542. By permission of Oxford University Press. Induced facial poses also influence how the person interprets the environment.

Volunteers rate a stimulus as more painful when they are making a sad face than a happy or neutral one (Salomons, Coan, Hunt, Backonja, & Davidson, 2008), and college students rate Far Side cartoons as more amusing when they are holding a pen between the teeth, which induces a sort of smile, than when they hold the pen between the lips, producing a frown (Strack, Martin, & Stepper, 1988). More strikingly, women who have had their corrugator muscles paralyzed by injecting botulinum toxin (Botox) to remove frown lines are unable to frown, and they report less negative mood—even if they don’t perceive themselves as more attractive (M. B. Lewis & Bowler, 2009). In addition, when these women attempt to imitate angry expressions, they produce less activation of the amygdala than women who have not had Botox treatment (Figure 8.3; Hennenlotter et al., 2009). Some researchers suggest that feedback from emotional expressions has another

role besides contributing to our emotional experience in that it also helps us understand other people’s emotions; this ability to recognize others’ emotions is critical to social communication and to societal success. To appreciate this point of view, you need to understand the concept of mirror neurons. Mirror neurons are neurons that respond both when we engage in a specific act and while observing the same act in others. They were first discovered when researchers noticed that neurons that were active while monkeys reached for food also responded when the monkeys saw the researcher picking up a piece of food (di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992); similar correlations have been observed in other brain areas, including those involved in emotions (see review in Bastiaansen, Thioux, & Keysers, 2009). Observing another person’s emotional expressions activates emotional areas in our own brains, and the amount of activity is related to scores on a measure of

empathy (Chakrabarti, Bullmore, & Baron-Cohen, 2006). Our observation of other people’s emotions is not entirely passive; we also mimic

their facial expressions and their gestures, body posture, and tone of voice (Bastiaansen et al., 2009). Just as feedback during our own emotional activity adds to our own emotional experience, feedback from imitated expressions may help us empathize with the emotions of others. Indeed, interfering with facial mimicry by engaging the required muscles in other activities (such as chewing gum) impairs subjects’ ability to recognize happiness and disgust in photos (Oberman, Winkielman, & Ramachandran, 2007). One of the characteristics of autism is difficulty in understanding other people’s emotions; autistic children imitate emotional expressions, but their mimicry is delayed by about 160 milliseconds (Oberman, Winkielman, & Ramachandran, 2009). A system this complex requires an equally complex control system. We will turn

our attention now to the brain structures responsible for emotion.

What are some of the brain structures involved in emotions, and what are their functions? The Emotional Brain In the late 1930s and 1940s, researchers proposed that emotions originated in the

limbic system, a network of structures arranged around the upper brain stem (Figure 8.4). As complex as this system is with its looping interconnections, we now know that it is an oversimplification; emotion involves structures at all levels of the brain, from the prefrontal area to the brain stem (A. R. Damasio et al., 2000). Also, we know that some of the limbic structures are more involved in nonemotional functions. For example, the hippocampus and mammillary bodies have major roles in learning. The concept of a limbic system is less important as a description of how emotion works than for spawning a tremendous volume of research that has taken us in diverse directions, which we will explore over the next several pages. FIGURE 8.4 Structures of the Limbic System.

Much of what we know about the brain’s role in emotion comes from lesioning and stimulation studies with animals; this research is limited because we do not know what the animal is experiencing. Robert Heath did some of the earliest probing of the limbic system in humans in 1964 when he implanted electrodes in the brains of patients in an attempt to treat epilepsy, sleep disorders, or pain that had failed to respond to conventional treatments. Researchers knew from animal studies that the hypothalamus has primary control over the autonomic system and that it produces a variety of emotional expressions, such as the threatened cat’s hissing and bared teeth and claws. Stimulation of the hypothalamus in Heath’s patients produced general autonomic discharge and sensations such as a pounding heart and feelings of warmth, but it also evoked feelings of fear, rage, or pleasure, depending on the location of the electrode in the hypothalamus. Septal area stimulation also produced a sense of pleasure, but in this case the feeling was accompanied by sexual fantasies and arousal. During septal stimulation one patient went from near tears while talking about his father’s illness to a broad smile as he described how he planned to take his girlfriend out and seduce her. When asked why he changed the subject, he replied that the thought just came into his head.

2 Emotion Research Labs Now researchers are more likely to use one of the scanning techniques to study the

brain centers of emotion. Typically, they do MRI scans to determine the location of damage in patients with emotional deficits, or they use positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) while healthy subjects relive an emotional experience, examine facial expressions of emotion, or view an emotional video. Two of the most reliable brain–emotion associations have been the amygdala’s role in fear and the location of disgust in the insular cortex and the basal ganglia (Figure 8.5; F. C. Murphy, Nimmo-Smith, & Lawrence, 2003; Phan, Wager,

Taylor, & Liberzon, 2002). We will consider the amygdala in some detail later. The insula is the area we identified in Chapter 6 as the cortical projection site for taste; a number of writers have remarked on the fact that taste and disgust share the same brain area and that dis-gust means, roughly, bad taste. In Chapter 3, we identified the basal ganglia as being involved in motor functions. Interestingly, people with Huntington’s disease or obsessive compulsive disorder, both of which involve abnormalities in the basal ganglia, have trouble recognizing facial expressions of disgust (Phan et al., 2002). FIGURE 8.5 Location of the Amygdala, Insula, and Basal Ganglia.

SOURCE: Photo courtesy of Dana Copeland. Another important structure in emotion is the anterior cingulate cortex, a part of

the cingulate gyrus important in attention, cognitive processing, emotion, and possibly consciousness. You can see the cingulate gyrus in Figure 8.4 and the anterior cingulate gyrus in Figure 8.6. The anterior cingulate cortex is believed to combine emotional, attentional, and bodily information to bring about conscious emotional experience (Dalgleish, 2004). Consequently, it is involved in emotional activity regardless of which emotion is being experienced, although some studies have also linked parts of the structure to specific emotions, such as sadness and happiness (F. C. Murphy et al., 2003; Phan et al., 2002). Interestingly, an MRI investigation found that the right anterior cingulate was larger in people with high scores on harm avoidance, which involves worry about possible problems, fearfulness in the face of uncertainty, and shyness with strangers (Pujol et al., 2002). Before we go too far in assigning emotions to specific brain structures, we need to

understand that any specific emotion involves activity in a network that includes many brain areas. This is well illustrated in a study that combined the results of 55 PET and fMRI investigations (Phan et al., 2002). As you can see in Figure 8.7, places

activated during a specific emotion cluster somewhat in particular areas, but they are also scattered across wide areas of the brain. This is partly due to different methods of inducing the emotions in the studies, but it also reflects the complexity of emotion. With the understanding that no emotion can be relegated to a single part of the brain, we will look more closely at three areas that have particularly important roles in emotional experience and behavior: the prefrontal cortex, the amygdala, and the right hemisphere. FIGURE 8.6 Size Differences in the Anterior Cingulate Gyrus. A larger anterior cingulate gyrus (highlighted in red) is associated with a higher level of the personality characteristic of harm avoidance.

SOURCE: From “Anatomical Variability of the Anterior Cingulated Gyrus and Basic Dimensions of Human Personality,” by J. Pujol et al., Neuroimage, 15, pp. 847–855, fig. 1, p. 848. © 2002. Used with permission from Elsevier. The Prefrontal Cortex The prefrontal cortex (see Figure 3.8 for location) is the final destination for much

of the brain’s information about emotion before action is taken. You saw in Chapter 3 that damage to the prefrontal area or severing its connections with the rest of the brain impairs people’s ability to make rational judgments. Later in this chapter you will learn that people with deficiencies in the area are unable to restrain violent urges, and in Chapter 14 you will see that abnormalities in the prefrontal area also figure prominently in depression and schizophrenia. These deficits have a variety of causes, including injury, infection, tumors, strokes, and developmental errors. What the victims have in common is damage to the prefrontal area that includes the ventromedial cortex and the orbitofrontal cortex (see Figure 8.8). FIGURE 8.7 Brain Areas Activated During Different Emotions. Each colored square represents the location identified in a single study for a particular emotion.

SOURCE: Reprinted from “Functional Neuroanatomy of Emotion: A Meta-Analysis of Emotion Activation Studies in PET and fMRI,” by K. L. Phan, T. Wager, S. F. Taylor, and I. Liberzon, Neuroimage, 16, pp. 331–348. Copyright 2002, with permission from Elsevier. FIGURE 8.8 Location of Damage That Impairs Emotion-Based Decision Making. In (a) the location of the ventromedial cortex and the orbitofrontal cortex is shown. In (b) you can see where damage occurred in four patients who showed judgment problems. The horizontal line shows where the scan in (c) was taken. In (b) and (c), the different colors indicate the number of patients with damage in the area, according to the code on the color bar. All shared damage in the ventromedial cortex, but some had damage in the orbitofrontal cortex as well.

SOURCE: (b) and (c) from “Different Contributions of the Human Amygdala and Ventromedial Prefrontal Cortex to Decision-Making,” by A. Bechara, H. Damasio, A. R. Damasio, & G. P. Lee, 1999, Journal of Neuroscience, 19, pp. 5473–5481. Antoine Bechara and his colleagues took a group of patients with ventromedial

damage into the laboratory to test their responses on the gambling task (Bechara et al., 1999). In this task, the individual chooses cards from four decks. Two “risky” decks contain cards that result in high rewards of play money, along with a few cards that carry a high penalty, for an overall loss; cards in the other two “safe” decks result in lower rewards and smaller penalties for an overall gain. Initially both patients and volunteers without ventromedial damage (controls) prefer the risky decks. As they encounter more penalties, the controls gradually shift their preference to the more

advantageous safe decks; the patients usually do not make the shift, even after they have figured out how the game works (Figure 8.9a). The reason the patients failed to make good choices appears to be that they were

unable to make use of the emotional information elicited by their bad choices. To assess emotion, the researchers used the skin conductance response (SCR), which is a measure of sweat gland activation and, thus, of sympathetic nervous system activity. The technique involves passing a very small electrical current through the individual’s skin; during arousal, the skin conducts electricity more readily. Both the patients and control subjects showed conductance increases when their card choices resulted in wins or losses. Over time, the control subjects began to show anticipatory SCRs just before drawing a card from a risky deck, and they did so even before they were able to verbalize that those stacks were risky. (This is the example of unaware emotional influence I promised earlier.) The patients, however, did not produce different SCRs to the four decks (Figure 8.9b). The researchers determined that the patients didn’t have any learning impairment; apparently they were unable to process the consequences of risky behavior and use that information to guide their choices.

How does loss of emotion impair “rational” decision making? In the rest of us, who like to think of ourselves as normal, the prefrontal cortex’s

connections to other parts of the brain determine whether we are novelty-seeking adventurers or are more restrained, as the Application explains. FIGURE 8.9 Comparison of Gambling Task Behavior in Controls and Patients With Damage to the Prefrontal Cortex. (a) The controls shifted from preferring cards from the risky decks to preferring cards from the safe decks, but the patients did not. (b) Also, as the task progressed, only the controls showed anticipatory skin conductance responses (SCR) before choosing from the risky decks.

APPLICATION

Why I Don’t Jump Out of Airplanes In our discussion of sensation seeking in Chapter 6, I mentioned my wife’s skydiving adventure. Why does she enjoy leaping out of a perfectly good airplane at 14,000 feet, while I prefer to stay on the ground and take photos of her descent? Why does she like to travel to exotic places, like Thailand and Patagonia, while I would rather stay at home and write about biopsychology? Once again, research comes to the rescue. Psychologists at the University of Arizona (M. X. Cohen, Schoene-Bake, Elger, & Weber, 2009) used a questionnaire to categorize 20 volunteers as novelty seekers (agreeing to statements like “I like to try new things just for fun.”) or reward dependent (agreeing to statements like “I’d rather stay home than go out.”). Novelty seekers are higher in exploratory drive and impulsivity, while those who are reward dependent are particularly sensitive to rewards and spend a lot of time pursuing activities that have been rewarding in the past. Next, the researchers used diffusion tensor imaging to measure the density

of the subjects’ white-matter tracts. Their analysis focused on the hippocampus, amygdala, and striatum, because animal research has indicated that these structures form a looping circuit that is important in novelty seeking. There were strong white-matter connections within this loop in the human novelty seekers, but the reward-dependent volunteers’ strongest connections were between the striatum and prefrontal areas, which tend to put the brakes on risky behavior. Just before my wife’s skydiving experience, the jump and videographer interviewed her about why she was making the jump, then turned the camera on me and asked why I chose not to. I answered lamely, “I just don’t need to.” Today, armed with the results of this study, my answer would be, “My prefrontal cortex won’t let me!”

The Amygdala The prefrontal areas receive much of their emotional input from the amygdala (see

Figure 8.4 again), a small limbic system structure in each temporal lobe that is involved in emotions, especially negative ones. The amygdala has other functions as well. In Chapter 12, we will see that it participates in memory formation, especially when emotion is involved. It also responds to pictures of happy faces and the recall of pleasant information and, as we saw in Chapter 7, sexually exciting stimuli. So the amygdala’s role may involve responding to emotionally significant stimuli in general (Phan et al., 2002). FIGURE 8.10 Activity in the Right Amygdala While Viewing Facial

Expressions of Fear. The individual on the left has the short allele of the SLC6A4 gene, which reduces serotonin activity and increases fear responsiveness; the one on the right has two copies of the long allele.

SOURCE: From “Serotonin Transporter Genetic Variation and the Response of the Human Amygdala,” by Hariri et al., Science, 297, pp. 400–403. Copyright 2002. Reprinted by permission of AAAS. Although the amygdala participates in other emotions, its role in fear and anxiety

has been researched the most thoroughly. Fear is an emotional reaction to a specific immediate threat; anxiety is an apprehension about a future, and often uncertain, event. Stimulating the amygdala produces fear in human subjects (Gloor, Olivier, Quesney, Andermann, & Horowitz, 1982). The amygdala contains receptors for benzodiazepines, which are used to treat anxiety, and injection of this type of drug directly into the amygdala reduces signs of both fear and anxiety in animals (M. Davis, 1992). People with one version of the SLC6A4 gene have decreased serotonin activity; as a result, they are prone to fear and anxiety and, as Figure 8.10 shows, their amygdalas are hyperreactive to fear stimuli (Hariri et al., 2002). Rats with both amygdalas destroyed are so fearless they will not only approach a

sedated cat but also climb all over its back and head (D. C. Blanchard & Blanchard, 1972). One rat even nibbled on the stuporous cat’s ear, provoking an attack—and after the attack ended, the rat climbed right back onto the cat. A few humans have sustained damage to both amygdalas, usually as a result of infection or disease, and they also show a variety of deficits; like the rats, for example, they are unusually trusting of strangers (Adolphs, Tranel, & Damasio, 1998). Bechara’s study of prefrontal patients included a group of patients with bilateral amygdala damage (Bechara et al., 1999). The two groups performed similarly in most ways, with one notable exception: While neither group produced anticipatory SCRs when choosing from the risky decks, the amygdala patients also didn’t respond to monetary gains and losses. Apparently the ventromedial patients were unable to make use of emotional information from the amygdala, but the amygdala patients couldn’t even generate an emotional response to rewards and punishments. As a result, patients with bilateral amygdala damage often live in supervised care, because their actions can easily bring harm to themselves and others. Ventromedial patients are less impaired, which suggests that the amygdala sends its information to additional decision-making areas, suggesting a broad scope to

this network. FIGURE 8.11 SM’s Brain, Compared With a Normal Brain. In SM’s brain (left), you see only two dark voids (in the red circles) where the amygdalas were before disease caused their deterioration. The brain on the right is normal, for comparison.

SOURCE: From “Human Brain Is Divided on Fear and Panic: New Study Contends Different Areas of Brain Responsible for External Versus Internal Threats,” by John Riehl, April 2, 2013, Iowa Now, retrieved from http://now.uiowa.edu/2013/01/human-brain-divided-fear-and-panic. SM is one of the best characterized patients with bilateral amygdala damage

(Figure 8.11); she reports very little feeling of fear and—in spite of having been held up at knifepoint, nearly killed in an act of domestic violence, and threatened with death on other occasions—her behavior never reflected any sense of desperation or urgency (Feinstein, Adolphs, Damasio, & Tranel, 2011). Researchers were unable to find any stimulus that could evoke fear in her; she was undisturbed by horror movies or a haunted house that produced screams in her companions, and she showed an unusual compulsion to touch snakes she had been told were deadly. Interestingly, during a test that involved inhaling carbon dioxide, which produces a feeling of suffocation, she and a similar patient experienced full-blown panic attacks (Feinstein et al., 2013). The researchers’ interpretation was that the amygdala monitors external threats from the environment, and that fear triggered internally—in this case by the sense of suffocation—has another neural basis. Hemispheric Specialization in Emotion The specialization of the cerebral hemispheres we have seen in other functions is

also evident in emotion. Although both hemispheres are involved in the experience of emotions, the left frontal area is more active when the person is experiencing positive emotions, and the right frontal area is more active during negative emotion (R. J. Davidson, 1992). People with damage to the left hemisphere often express more anxiety and sadness about their situation, while those with right-hemisphere damage are more likely to be unperturbed or even euphoric, even when dealing with an

Concept Check

associated paralysis of an arm or a leg (Gainotti, 1972; Gainotti, Caltagirone, & Zoccolotti, 1993; Heller, Miller, & Nitschke, 1998). The same difference in emotions occurs when each of the cerebral hemispheres is anesthetized briefly in turn by injecting a short-acting barbiturate into the right or left carotid artery (Rossi & Rosadini, 1967). (This technique is sometimes used in evaluating patients prior to brain surgery.) In fact, when the right hemisphere is anesthetized, individuals can describe negative events in their lives but can barely recall having felt sad or angry or fearful, even with incidents as intense as their mother’s death, the discovery of a spouse’s affair, or the wife’s threatening to kill the individual (E. D. Ross, Homan, & Buck, 1994). Although both hemispheres are involved in experiencing emotion, the right is more

specialized for its expression (Heller et al., 1998). Autonomic responses to emotional stimuli such as facial expressions and emotional scenes are greater when the stimuli are presented to the right hemisphere (using the strategy described by Spence, Shapiro, & Zaidel, 1996, p. 298). Much of the emotional suppression in patients with right-hemisphere damage is due to decreased autonomic response (Gainotti et al., 1993). Perception of nonverbal aspects of emotion is impaired in patients with right-

hemisphere damage; for example, they often have difficulty recognizing emotion in others’ facial expressions (Adolphs, Damasio, Tranel, & Damasio, 1996). Verbal aspects are unimpaired, however; the same patients can understand the emotion in a verbal description like “Your team’s ball went through the hoop with one second left to go in the game,” but they have trouble identifying the emotion in descriptions of facial or gestural expressions such as “Tears fell from her eyes” or “He shook his fist” (Blonder, Bowers, & Heilman, 1991). Patients with right-hemisphere damage also have trouble recognizing emotion from the tone of the speaker’s voice (Gorelick & Ross, 1987), and their own speech is usually emotionless as well (Heilman, Watson, & Bowers, 1983). When asked to say a neutral sentence like “The boy went to the store” in a happy, sad, or angry tone, they speak instead in a monotone and often add the designated emotion to the sentence verbally, for example, “... and he was sad.”

Take a Minute to Check Your Knowledge and Understanding

Describe the role of the autonomic nervous system in emotion (including the possible identification of emotions).

Organize your knowledge: List the major parts of the brain described in this section that are involved in emotion, along with their functions.

How are the effects of prefrontal and amygdala damage alike and different?

Stress, Immunity, and Health Stress is a rather ambiguous term that has two meanings in psychology. Stress is a

condition in the environment that makes unusual demands on the organism, such as threat, failure, or bereavement. Stress is also an internal condition, your response to a stressful situation; you feel stressed, and your body reacts in several ways. Whether a situation is stressful to the person is often a matter of individual differences, either in perception of the situation or in physiological reactivity. For some, even the normal events of daily life are stressful, while others thrive on excitement and would feel stressed if they were deprived of regular challenges. In other words, stress in this sense of the term is in the eye of the beholder. Stress as an Adaptive Response Ordinarily, the body’s response to a stressful situation is positive and adaptive. In

Chapter 3, you saw that the stress response includes activation of the sympathetic branch of the autonomic nervous system, which is largely under the control of the hypothalamus. The resulting increases in heart rate, blood flow, and respiration rate help the person deal with the stressful situation. Stress also activates the hypothalamus-pituitary-adrenal axis, a group of structures that help the body cope with stress (Figure 8.12). The hypothalamus activates the pituitary gland, which in turn releases hormones that stimulate the adrenal glands to release the stress hormones epinephrine, norepinephrine, and cortisol. The first two hormones increase output from the heart and liberate glucose from the muscles for additional energy. The hormone cortisol also increases energy levels by converting proteins to glucose, increasing fat availability, and increasing metabolism. Cortisol provides a more sustained release of energy than the sympathetic nervous system does, for coping with prolonged stress.

What are the positive effects of stress? FIGURE 8.12 The Hypothalamus-Pituitary-Adrenal Axis.

Brief stress increases activity in the immune system (Herbert et al., 1994), the cells and cell products that kill infected and malignant cells and protect the body against foreign substances, including bacteria and viruses. Of course, this is highly adaptive because it helps protect the person from any infections that might result from the threatening situation. The immune response involves two major types of cells. Leukocytes, or white blood cells, recognize invaders by the unique proteins that every cell has on its surface and kills them. These proteins in foreign cells are called antigens. A type of leukocyte called a macrophage ingests intruders (Figure 8.13). Then it displays the intruder’s antigens on its own cell surface; this attracts T cells, another type of leukocyte that is specific for particular antigens, which kill the invaders. B cells, a third type of leukocyte, fight intruders by producing antibodies that attack a particular cell type. Natural killer cells, the second type of immune cells, attack and destroy certain kinds of cancer cells and cells infected with viruses; they are less specific in their targets than T or B cells. The brain and spinal cord are considered “immune privileged,” in that the central nervous system is protected from most infectious agents by the blood-brain barrier. When these agents do make their way in, they are dealt with by microglia, which act in most ways like macrophages. Table 8.1 summarizes the characteristics of these immune cells. Some antibodies are transferred from mother to child during the prenatal period or

postnatally through the mother’s milk. Most antibodies, though, result from a direct encounter with invading cells, for example, during exposure to measles. Vaccinations work because injection of a weakened form of the disease-causing bacteria or virus triggers the B cells to make antibodies for that disease. FIGURE 8.13 Macrophages Preparing to Engulf Bacteria.

SOURCE: © KAGE Microphotography. The preceding is a description of what happens when all goes well. In the immune

deficiency disease AIDS (acquired immune deficiency syndrome), on the other hand, T cells fail to detect invaders, and the person dies of an infectious disease. In autoimmune disorders, the immune system runs amok and attacks the body’s own cells. In the autoimmune disorder multiple sclerosis, for instance, the immune system destroys myelin in the central nervous system. Negative Effects of Stress We are better equipped to deal with brief stress than with prolonged stress. Chronic

stress can interfere with memory, increase or decrease appetite, diminish sexual desire and performance, deplete energy, and cause mood disruptions. Although brief stress enhances immune activity, prolonged stress compromises the immune system. After the nuclear accident at the Three Mile Island electric generating plant, nearby residents had elevated stress symptoms and performed less well on tasks requiring concentration, compared with people who lived outside the area (Baum, Gatchel, & Schaeffer, 1983). Amid concerns about continued radioactivity and the long-term effects of the initial exposure, they had reduced numbers of B cells, T cells, and natural killer cells as long as 6 years after the accident (McKinnon, Weisse, Reynolds, Bowles, & Baum, 1989).

3 Stress Less TABLE 8.1 Major Types of Immune Cells.

Disease symptoms were not measured at Three Mile Island, but other studies have shown that health is compromised when stress impairs immune functioning. Recently widowed women experienced decreased immunity and marked health deterioration in the year following the spouse’s death (Maddison & Viola, 1968). Also, students had reduced immune responses, more infectious illnesses, and slower wound healing at exam times than other times of the year (Glaser et al., 1987; Marucha, Kiecolt-Glaser, & Favagehi, 1998). In a rare experimental study, healthy individuals were given nasal drops containing common cold viruses and then were quarantined and observed for infections. In Figure 8.14, you can see that their chance of catching a cold depended on the level of stress they reported on a questionnaire at the beginning of the study (S. Cohen, Tyrrell, & Smith, 1991). In a follow-up study, it turned out that only stresses that had lasted longer than a month increased the risk of infection (S. Cohen et al., 1998). In the News addresses one more way that stress affects the immune system. The cardiovascular system is particularly vulnerable to stress. Stress increases

blood pressure, and prolonged high blood pressure can damage the heart or cause a stroke. Some people are more vulnerable to health effects from stress than others. Researchers classified young children as normal reactors or excessive reactors based on their blood pressure increases while one hand was immersed in ice water. Forty- five years later, 71% of the excessive reactors had high blood pressure, compared with 19% of the normal reactors (Wood, Sheps, Elveback, & Schirger, 1984). FIGURE 8.14 Relationship Between Stress and Vulnerability to Colds.

SOURCE: Adapted from “Psychological Stress and Susceptibility To the Common Cold,” by S Cohen, A. D. Tyrrell, and A. P. Smith, New England Journal of Medicine, 325, pp. 606–612. © 1991 Massachusetts Medical Society. All rights reserved. Stress can even produce death. This fact has not always been accepted in the

scientific and medical communities, but in 1942 the physiologist Walter Cannon determined that reports of apparent stress-related deaths were legitimate. He even suggested that voodoo death, which has been reported to occur within hours of a person being “hexed” by a practitioner of this folk cult, is also due to stress. We now know that fear, loss of a loved one, humiliation, or even extreme joy can result in sudden cardiac death. In sudden cardiac death, stress causes excessive sympathetic activity that sends the heart into fibrillation, contracting so rapidly that it pumps little or no blood. When one of the largest earthquakes ever recorded in a major North American city struck the Los Angeles area in 1994, the number of deaths from heart attacks increased fivefold (Figure 8.15; Leor, Poole, & Kloner, 1996). The stress doesn’t have to be as extreme as an earthquake: During the 2006 soccer World Cup games in Germany, cardiac emergencies in that country tripled in men and almost doubled in women (Wilbert-Lampen et al., 2008); and when the Los Angeles Rams were defeated in the 1980 Super Bowl, cardiac deaths in the team’s hometown increased 15% in men and 27% in women (Kloner, McDonald, Leeka, & Poole, 2011). Heart attacks even increase during the first 3 days following the spring change to daylight savings time, as people cope with minor sleep deprivation and an earlier wake time, and then drop slightly when the autumn transition gives them an extra hour of sleep (T. S. Janszky & Ljung, 2008).

Keeping Odd Hours Could Make You Sick

People whose work or lifestyle has them on a nocturnal schedule for long periods are at greater risk for heart disease, diabetes, gastrointestinal illnesses, and, in extreme cases, even cancer. Now, researchers at the University of Texas Southwestern Medical Center may have found out why your mom was right when she told you to turn off the light and go to sleep. T helper 17 cells (TH17) patrol the intestinal lining and other

mucosal surfaces, detecting and fighting bacterial and fungal infections; but if TH17 cells become too numerous, they can cause serious inflammatory problems, such as inflammatory bowel disease. Conversion of T cells into TH17 cells is under the control of the NFIL3 gene, which, the researchers discovered, is in turn regulated by the CLOCK gene; and CLOCK happens to be one of the genes that controls our day-night cycle, influencing not only our sleep but also the activity levels of many of our physiological systems. To see if disrupting the day-night cycle would affect this part of the immune

system, the researchers first turned the lights on 6 hours earlier each day in the room where mice were housed; they gave the mice 4 days to adjust, then advanced the clock another 6 hours, and so on—the equivalent of flying from the United States to Europe, India, and Japan and spending 4 days in each country. At the end of the study, the mice had twice as many TH17 cells, compared with control subjects, and they had a greater inflammatory response to a chemical irritant. The results indicate that sleep-cycle disruption could be one cause of inflammatory diseases and suggest that the body’s internal clock system might be a window into treatments for autoimmune disorders, gastrointestinal disorders, and other inflammation-based disorders, such as heart disease, asthma, and chronic pain.

4 Sleep and Immunity

Extreme stress can also lead to brain damage (Figure 8.16). Hippocampal volume was reduced in Vietnam combat veterans suffering from posttraumatic stress disorder (Bremner et al., 1995) and in victims of childhood abuse (Bremner et al., 1997), and cortical tissue was reduced in torture victims (T. S. Jensen et al., 1982). The abused individuals had short-term memory deficits, and some of the torture victims showed slight intellectual impairment. There is some evidence that the damage is caused by cortisol; implanting cortisol pellets in monkeys’ brains damaged their hippocampi (Sapolsky, Uno, Rebert, & Finch, 1990), and elderly humans who had elevated cortisol levels over a 5-year period had an average 14% decrease in hippocampal volume (Lupien et al., 1998). However, individuals with posttraumatic stress disorder

have lowered cortisol levels. Rachel Yehuda (2001) points out that they also have an increased number and sensitivity of the glucocorticoid receptors that respond to cortisol. She suggests that posttraumatic stress disorder involves increased sensitivity to cortisol rather than an increase in cortisol level; although there is a compensatory decrease in cortisol release, it is not adequate to protect the hippocampus. Researchers are learning that stress that is inadequate to produce posttraumatic stress disorder can also damage the brain, as the Application shows.

5 Stress and Health FIGURE 8.15 Increase in Cardiac Deaths on the Day of an Earthquake.

SOURCE: Reprinted from “Sudden Cardiac Death Triggered by an Earthquake,” by J. Leor, W. K. Poole, and R. A. Kloner, New England Journal of Medicine, 334, pp. 413–419. © 1996 Massachusetts Medical Society. All rights reserved. “

In [emotional] pain there is as much wisdom as in pleasure. —Friedrich Nietzsche

”

FIGURE 8.16 Hippocampal Damage in a Stressed Monkey. Compare the number of cells between the arrows in the hippocampus of a control monkey (a) and the number in the same area in a monkey that died spontaneously of apparent stress (b).

SOURCE: From “Hippocampal Damage Associated With Prolonged and Fatal Stress in Primates,” by H. Uno, R. Tarara, J. G. Else, M. A. Suleman, and R. M. Sapolsky, 1999, Journal of Neuroscience, 9, pp. 1705–1711.

In what ways do personality characteristics influence immune functioning? Several studies suggest that reducing stress can improve health. T cell counts

increased in AIDS patients after 20 hours of relaxation training (D. N. Taylor, 1995); similar training was associated with reduced death rates in elderly individuals (C. N. Alexander, Langer, Newman, Chandler, & Davies, 1989) and in cancer patients (Fawzy et al., 1993; Spiegel, 1996). However, evidence that survival rate in these studies is related to immune function improvement is sketchy (Fawzy et al., 1993); it is possible that participation in these studies led the elderly subjects and cancer patients to make lifestyle changes. At any rate, it may be more practical to block stress hormones and bolster immunity chemically. Researchers at Tel Aviv University have found that the psychological and physiological stress of cancer surgery suppresses immunity, allowing the spread of cancer during the postoperative period; combining an anti-anxiety drug with an anti-inflammatory drug greatly increased the survival rate of mice following tumor removal, and clinical trials are under way with humans (Glasner et al., 2010; “New Method to Manage...,” 2012).

APPLICATION

One Aftermath of 9/11 Is Stress-Related Brain Damage On September 11, 2001, terrorists flew two airliners into the World Trade Center in New York, taking the lives of more than 2,500 people. This was an obviously traumatic event for the people of the United States, and particularly for the victims’ relatives and for the people living in the vicinity of the Twin Towers. The stress was still measurable in residents 3 years later, which led a group of researchers to ask just how serious the continuing trauma was (Ganzel, Kim, Glover, & Temple, 2008). They used fMRI scans to compare the brains of a group of volunteers living within 1.5 miles (2.4 kilometers) of the towers with those of people living 200 miles (322 kilometers) away. The near residents exhibited some signs of posttraumatic stress disorder, but the symptoms were not severe enough for a diagnosis. Yet, they had reduced gray- matter volume in the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and insula; also, amygdala activation was greater when they viewed facial expressions of fear. The figure shows the location of these deficits. The same areas also lose gray matter with age, and the researchers suggest that much of the effect of aging on the brain is due to the lifelong accumulation of stress.

SOURCE: “Resilience After 9/11: Multimodal Neuroimaging Evidence for Stress-Related Change in the Healthy Adult Brain,” by B. L. Ganzel, P. Kim, G. H. Glover, and E. Temple, 2008, NeuroImage, 40, pp. 788– 795. Used with permission from Elsevier.

Social, Personality, and Genetic Factors Social support was associated with dramatically lower death rates in several

different populations (reviewed in House, Landis, & Umberson, 1988) and with lower stress and reduced stress hormone level among Three Mile Island residents (Fleming, Baum, Gisriel, & Gatchel, 1982). People who are hostile are at greater risk for heart disease (T. Q. Miller, Smith, Turner, Guijarro, & Hallet, 1996), while cancer patients who have a “fighting spirit” may live longer than patients who accept their illness or have an attitude of hopelessness (Derogatis, Abeloff, & Melisaratos, 1979; Greer, 1991; Temoshok, 1987). Because of the high association between mood disorder and cancer, some have suggested that depression is a predisposing factor; however, the opposite is more likely, because animal research indicates that immune system cytokines released by tumors can produce depressive-like behaviors (Pyter, Pineros, Galang, McClintock, & Prendergast, 2009). FIGURE 8.17 Differences in Postvaccine Antibody Levels in Relation to Prefrontal Hemispheric Activity.

SOURCE: From “Affective Style and In Vivo Immune Response,” by M. A. Rosenkranz et al., PNAS, 100, pp. 11148–11152. © 2003. Social and personality influences must work through physiological mechanisms,

which, unfortunately, are seldom assessed in these studies. An exception is an investigation of individual differences in immune response. Recall that there is a greater association of positive emotion with the left prefrontal area and negative emotion with the right. Six months after volunteers were given influenza vaccinations, the ones with higher EEG activity in the left prefrontal area had a five times greater increase in antibodies than those with higher activation on the right (Figure 8.17; Rosenkranz et al., 2003). In other research, men who had tested positive for human immunodeficiency virus (HIV) infection had HIV levels that were eight times higher if they were introverted (socially inhibited) rather than extroverted (S. W. Cole, Kemeny, Fahey, Zack, & Naliboff, 2003). The introverted patients’ HIV levels also decreased less during treatment and their T cells did not increase at all. The researchers point out that introverted individuals have elevated levels of

epinephrine and norepinephrine, which activate the sympathetic nervous system during stress, and that norepinephrine increases the rate at which the HIV virus multiplies in the laboratory. Unfortunately, they didn’t measure sympathetic activity specifically, but total autonomic activity (assessed from variability of heart rate, skin conductance, and other measures) was higher among the introverted HIV patients. This correlational study doesn’t tell us which among introversion, norepinephrine, and HIV infection is the initial cause, but it does suggest that norepinephrine is an important mediator of the effects. Personality characteristics such as introversion are moderately heritable, and so is

vulnerability to stress; for example, a study of 300 Swedish twins concluded that 32% of workplace stress is genetic (Judge, Ilies, & Zhang, 2012). One gene implicated in stress is NPY, which encodes the production of neuropeptide Y (which you know from its involvement in appetite); people with a low-functioning version of the gene show greater brain activity in response to negatively charged words, report more negative feelings in anticipation of a painful stimulus, and are more prone to depression (Mickey et al., 2011). But what may be as important as the genes we have is the ability of stress to modify the expression of those genes. German researchers took repeated blood samples from subjects undergoing a stressful interview and found that methylation of the oxytocin receptor gene OXTR increased during the first 10 minutes and then decreased below initial levels 90 minutes afterward, presumably increasing and then decreasing the number of oxytocin receptors (Unternaehrer et al., 2012). Besides playing a role in sexual experience and bonding, oxytocin increases during stress and reduces some of the physiological effects, including blood pressure and heart rate. The researchers suggest that the receptor changes observed would mobilize the body’s resources initially and then support longer-term coping with the effects of stress. Stress effects are known to sometimes carry over to the offspring, apparently due to epigenetic changes of this sort. Male mice repeatedly separated from their mothers during the first 14 days after birth showed depressive symptoms as

adults (passivity in response to stressful situations); the same behaviors were seen in the offspring, along with methylation changes in genes known to be involved in responses to stress (Franklin et al., 2010). Pain as an Adaptive Emotion Eighty percent of all visits to physicians are at least partly to seek relief from pain

(Gatchel, 1996), and we spend billions each year on nonprescription pain medications. These observations alone qualify pain as a major health problem. “

Pain is a more terrible lord of mankind than even death itself. —Albert Schweitzer

”

A world without pain might sound wonderful, but in spite of the suffering it causes, pain is valuable for its adaptive benefits. It warns us that the coffee is too hot, that our shoe is rubbing a blister, that we should take our skis back to the bunny slope for more practice . People with congenital insensitivity to pain are born unable to sense pain; they injure themselves repeatedly because they are not motivated to avoid dangerous situations, and they die from untreated conditions like a ruptured appendix. Mild pain tells us to change our posture regularly; a woman with congenital insensitivity to pain suffered damage to her spine because she could not respond to these signals, and resulting complications led to her death (Sternbach, 1968). Pain is one of the senses, a point we consider in more detail in Chapter 11. Here we

focus on the feature that makes pain unique among the senses: It is so intimately involved with emotion that we are justified in discussing it as an emotional response. In fact, when we tell someone about a pain experience, we are usually describing an emotional reaction; it is the emotional response that makes pain adaptive. FIGURE 8.18 Voluntary Ritualized Torture in Religious Practice. Cultural values help determine a person’s reaction to painful stimulation.

SOURCE: © Science Source/Alain Evrard. You know it, and Harvard psychologists have confirmed it: Pain someone inflicts

on you intentionally hurts more than pain you experience accidentally (K. Gray & Wegner, 2008). As Beecher (1956) observed, “The intensity of suffering is largely determined by what the pain means to the patient” (p. 1609). In our society, childbirth is considered a painful and debilitating ordeal; in other cultures, childbirth is a routine matter, and the woman returns to work in the fields almost immediately. After the landing at the Anzio beachhead in World War II, 68% of the wounded soldiers denied pain and refused morphine; only 17% of civilians with similar “wounds” from surgery accepted their pain so bravely (Beecher, 1956). The soldiers were not simply insensitive to pain, because they complained bitterly about rough treatment or inept blood draws. According to Beecher, who was the surgeon in command at Anzio, the surgery was a major annoyance for the civilians, but the soldiers’ wounds meant they had escaped the battlefield alive. Spiritual context can also have a powerful influence on the meaning of pain. Each spring in some remote villages of India, a man is suspended by a rope attached to steel hooks in his back; swinging above the cheering crowd, he blesses the children and the crops. Selection for this role is an honor, and the participant seems not only to be free of pain but also in a “state of exaltation” (Kosambi, 1967; Ghosh & Sinha, 2007). Figure 8.18 shows an example of culturally sanctioned self-torture.

What makes pain an emotional response? The pain pathway has rich interconnections with the limbic system, where pain

becomes an emotional phenomenon. Besides the somatosensory area, pain particularly activates the anterior cingulate cortex, which in turn is intimately connected with other limbic structures (D. D. Price, 2000; Talbot et al., 1991). The brain scan in Figure 8.19 shows increased activity in the anterior cingulate cortex as

well as the somatosensory area during painful heat stimulation. A hint that the anterior cingulate is involved in the emotional response of pain comes from microelectrode recordings in humans and monkeys; they revealed that some of the neurons respond not only to painful stimulation but to the anticipation of pain (Hutchison, Davis, Lozano, Tasker, & Dostrovsky, 1999; Koyama, Tanaka, & Mikami, 1998). FIGURE 8.19 PET Scan of Brain During Painful Heat Stimulation. The bright area near the midline is the cingulate gyrus; the one to the left is the somatosensory area. The four views were taken simultaneously at different depths in the same brain. (The frontal lobes are at the top of the figure.)

SOURCE: Reprinted with permission from “Multiple Representations of Pain in Human Cerebral Cortex,” J. D. Talbot et al., Science, 251, pp. 1355–1358. Copyright 1991. Reprinted by permission of AAAS. But how can we be sure that activity in the anterior cingulate cortex represents the

emotional aspect of pain? Fortunately, it is possible to separate the sensation of pain from its emotional effect. One way is to monitor changes in brain activity while the unpleasantness of pain increases with successive presentations of a painful stimulus. Another involves the use of hypnosis to increase pain unpleasantness without changing the intensity of the stimulus. With both strategies, activity increases in the anterior cingulate cortex but not in the somatosensory area, suggesting that its role in pain involves emotion rather than sensation (D. D. Price, 2000; Rainville, Duncan, Price, Carrier, & Bushnell, 1997). If pain continues, it also recruits activity in prefrontal areas where, presumably, the

pain is evaluated and responses to the painful situation are planned (D. D. Price, 2000). The location of pain emotion in separate structures may explain the experience of two groups of patients. In pain insensitivity disorders, it is the emotional response that is diminished rather than the sensation of pain; the person can recognize painful stimulation, but simply is not bothered by it (Melzack, 1973; D. D. Price, 2000). The same is true for people who underwent prefrontal lobotomy back when that surgery was used to manage untreatable pain; when questioned, the patients often said they

Concept Check

still felt the “little” pain but the “big” pain was gone.

Take a Minute to Check Your Knowledge and Understanding

Describe the positive and negative effects of stress, indicating why the effects become negative.

Discuss the emotional aspects of pain, including the brain structures involved.

Biological Origins of Aggression Both motivation and emotion reach a peak during aggression. Aggression can be adaptive, but it also takes many thousands of lives annually and maims countless others physically and emotionally. The systematic slaughter of millions in World War II concentration camps and the terrorist attack that destroyed the World Trade Center are dramatic examples, but we should not allow such catastrophic events as these to blind us to the more common thread of daily aggression running throughout society. Aggression is behavior that is intended to harm. Researchers agree that there is

more than one kind of aggression, but they do not agree on what the different kinds are, partly because the forms of aggression differ among species. Most often, researchers make a distinction between predatory aggression and affective aggression. Predatory aggression occurs when an animal attacks and kills its prey or when a human makes a premeditated, unprovoked attack on another. Predatory aggression is cold and emotionless, whereas affective aggression is characterized by its impulsiveness and emotional arousal. Researchers have also sometimes found it useful to distinguish between offensive and defensive affective aggression. Hormones and Aggression Although aggression is influenced by a person’s environment, it should come as no

surprise that such a powerful force has hormonal and neural roots. Hormones appear to influence offensive aggression more than other types, at least in rats (D. J. Albert, Walsh, & Jonik, 1993). In nonprimate animals, aggression is enhanced by testosterone in males and by both testosterone and estrogen in females.

How are testosterone and estrogen related to aggression? In primates, aggressiveness increases in female monkeys during the premenstrual

period (Rapkin et al., 1995), a time when estrogen and progesterone (a hormone that maintains pregnancy) are at their lowest. Studies have also reported a doubling of crimes (K. Dalton, 1961) and violent crimes (d’Orbán & Dalton, 1980) in women during this period. Anger responses to provocation increased in women during the premenstrual period, but only in those who had previously reported that they suffered

from premenstrual complaints (premenstrual syndrome, or PMS; Van Goozen, Frijda, Wiegant, Endert, & Van de Poll, 1996). Studies have reported reduced levels of progesterone in women with PMS, and that progesterone treatment reduces aggressive symptoms (K. Dalton, 1964, 1980; Monteleone et al., 2000). FIGURE 8.20 Testosterone Levels of Men Convicted of Various Crimes. The proportion of men with high testosterone levels compared with other prisoners is greater as the violence of the crime increases.

SOURCE: Based on J. M. Dabbs et al. (1995). Studies have also found a relationship between testosterone and violence in male

prison inmates. Male prisoners convicted of violent crimes like rape and murder and prisoners rated as tougher by their peers had higher testosterone levels than other prisoners (Figure 8.20; J. M. Dabbs, Carr, Frady, & Riad, 1995; J. J. Dabbs, Frady, Carr, & Besch, 1987). In women inmates as well, there appears to be a relationship between testosterone level and aggressive dominance while in prison (J. J. Dabbs & Hargrove, 1997). The prison results make sense intuitively, but the function of testosterone in human aggression is open to question, just as it was in sexual behavior. The studies are correlational, so we must look elsewhere for evidence that testosterone causes aggression. There is no clear evidence that aggression in humans is affected by manipulation of testosterone levels or by disorders that increase or decrease testosterone (D. J. Albert et al., 1993). For this reason, critics argue that aggression increases testosterone level rather than the other way around, and so far the research is on their side. Not only does testosterone increase after winning a sports event (Archer, 1991; Mazur & Lamb, 1980), but it also goes up while watching one’s team win a sporting event (Bernhardt, Dabbs, Fielden, & Lutter, 1998) and even after receiving an MD degree (Mazur & Lamb, 1980).

The Brain’s Role in Aggression Research with rats and cats indicates that defensive and predatory aggression are

distinct not only behaviorally but also neurally (D. J. Albert et al., 1993; A. Siegel, Roeling, Gregg, & Kruk, 1999). The highly emotional nature of defensive aggression, indicated by the cat’s familiar arched back, bristling fur, and hissing, contrasts sharply with the cold, emotionless stalking and killing of its prey. We know more about the brain structures involved in feline aggression and their connections than in any other animal. The two types of aggression have separate neural pathways, outlined in Figure 8.21. The defensive pathway begins in the medial nucleus of the amygdala, travels to the medial hypothalamus, and goes from there to the dorsal part of the periaqueductal gray in the brain stem. Control of predatory attack flows from the lateral nucleus and central nucleus of the amygdala to the lateral hypothalamus and the ventral periaqueductal gray (A. Siegel et al., 1999). Of course, threat does not always result in aggression; stimulation of another area in the periaqueductal gray produces flight (S. P. Zhang, Bandler, & Carrive, 1990).

What brain areas have a role in aggression? FIGURE 8.21 Brain Circuits for Defensive and Predatory Aggression in the Cat.

SOURCE: Based on A. Siegel et al. (1999). A predisposing factor for human aggression is a deficiency in prefrontal

functioning. Men have less gray matter in the prefrontal cortex than women, and this difference accounts for 77% of their greater antisocial behavior (Raine, Yang, Narr, & Toga, 2009). Reduced volume of gray matter in the prefrontal cortex is a characteristic of antisocial personality; people with antisocial personality disorder behave recklessly, violate social norms, and commit antisocial acts such as fighting, stealing, using drugs, and engaging in sexual promiscuity. However, deficiency in prefrontal functioning alone is not enough to produce violence; the prefrontal area ordinarily inhibits aggressive urges, but those urges originate in subcortical areas.

Aggression increases, for example, in people with seizure activity in the amygdala (D. J. Albert et al., 1993); in various studies, lesioning of the amygdala significantly reduced aggressive behavior in 33% to 100% of patients with severe aggressive disorders (Mpakopoulou, Gatos, Brotis, Paterakis, & Fountas, 2008). A PET scan study of male and female murderers found higher activity in right subcortical areas, including the amygdala, hippocampus, thalamus, and midbrain (Raine, Meloy, et al., 1998). The affective murderers in the group also had lower prefrontal activity than the control subjects, whereas the predatory murderers had essentially normal prefrontal activity. The predatory murderers’ lack of prefrontal deficit was something of a surprise, but a study of criminal psychopaths (distinctive for their lack of empathy and remorse) may help us understand the difference between the two types of murderers. Psychopaths who had been convicted of crimes had a 22% reduction in prefrontal gray matter, while those who admitted to crimes but had escaped detection had no deficit (Y. Yang et al., 2005). The prefrontal cortex deters most of us from aggressive and antisocial behavior, but in others with stronger urges, prefrontal functioning determines whether their aggression will be uncontrolled or planned and directed. This raises the question of responsibility, a topic discussed in the accompanying Application. Neurotransmitters and Aggression Aggression research has implicated three neurotransmitters more than any others:

dopamine, gamma aminobutyric acid (GABA), and serotonin. Dopamine and GABA have received far less attention than serotonin, so we will deal with them only briefly. Dopamine levels are high in the prefrontal cortex and nucleus accumbens of animals before, during, and after aggressive encounters, and dopamine antagonists are used to treat aggressive behavior in psychiatric patients (de Almeida, Ferrari, Parigiani, & Miczek, 2005; Miczek, Fish, de Bold, & de Almeida, 2002; R. J. Nelson & Trainor, 2007). However, dopamine’s lack of specificity as to type of aggression or timing during encounters suggests that its contribution is arousal, playing a facilitative role rather than initiating aggression.

APPLICATION

Neurocriminology, Responsibility, and the Law In 1999, Donta Page robbed a young Denver woman, and then raped her and killed her. During the trial, British psychologist Adrian Raine testified that Page had a “perfect storm” of predisposing factors: a family history of mental illness; a distinct lack of activation in the prefrontal cortex; and a childhood of poor nutrition, lead exposure, parental neglect, repeated physical and sexual abuse, and head injuries (Raine, 2013). As a result of Raine’s testimony, Page received a life sentence rather than the death penalty.

Raine (who is cited frequently in this chapter) is a pioneer in the emerging field of neurocriminology, which uses neuroscience to understand and prevent criminal behavior. He raises the question of whether we should hold criminals like Donta Page to the same level of accountability we expect of other people. For emphasis, he points out that violence in the United States has closely tracked the rise and fall of lead in gasoline, which can statistically account for 91% of the changes in violence from the 1970s to the present (“Criminologist Believes Violent Behavior...,” 2013). In spite of Page’s impairments, his crime didn’t have to happen. Earlier in

1999, he had come before the parole board while serving time for robbery. Had Raine been called on to testify then, he would have told the board that Page was at high risk for violence and should not be returned to society (Raine, 2013). Instead, Page was set free after serving 4 years of a 20-year term, and he murdered the young woman just 4 months later. Applying the expertise of neurocriminology earlier in a criminal’s career could reduce later violence through treatment and more enlightened decisions about sentencing and parole. Obstacles standing in the way of this approach are the lack of research funding and outmoded attitudes of officials and the public when it comes to brain disorders, mental illness, and responsibility. A positive outcome of the December 2012 Sandy Hook school shooting is that the parents of one victim, 6-year-old Avielle Richman, have established the Avielle Foundation to foster more constructive attitudes and encourage neuroscience research on the causes of violence (T. Smith, 2013).

Most research has indicated that GABA inhibits aggression. Several studies have found low levels of GABA in the brains of aggressive mice and rats (de Almeida et al., 2005) and men (Bjork et al., 2001), and another reported that low GABA activity was associated with impulsivity (Boy et al., 2011). Benzodiazepines, which enhance GABA activity, are used to reduce violent outbursts in psychiatric patients, but they sometimes produce a paradoxical increase in aggression (R. J. Nelson & Trainor, 2007). The variability in the effects of both benzodiazepines and alcohol, another GABA agonist, is likely due to the balance among the different types of receptors that make up the GABAA receptor complex and their distribution in different parts of the brain, as well as the context in which the aggression occurs (Miczek et al., 2002; R. J. Nelson & Trainor). Serotonin and the Inhibition of Aggression We have already seen some indication of the importance of serotonin in motivation.

Usually its role is inhibitory, suppressing motivated behaviors; when serotonin activity is low, appetite increases for food, water, sex, and drugs of abuse (Pihl & Peterson, 1993). Now we will add aggression to the list. Serotonin modulates activity

in dopamine neurons, so low serotonin is accompanied by dopamine increases (Seo, Patrick, & Kennedy, 2008); for example, prefrontal serotonin levels decreased 20% in rats during and after fights with intruder males, and dopamine levels increased by the same amount following the fights (Figure 8.22). Although these shifts persisted for more than an hour after a defensive confrontation, they appear to be an enduring characteristic in humans who are prone to violence, such as violent and sexual offenders with psychopathic traits.

How does serotonin affect aggression? FIGURE 8.22 Prefrontal Dopamine and Serotonin in Rats During and Following Fights.

SOURCE: Figure 2b from “Aggressive Behavior, Increased Accumbal Dopamine, and Decreased Cortical Serotonin in Rats,” by A. M. M. van Erp and K. A. Miczek, Journal of Neuroscience, 15, pp. 9320–9325. Copyright 2000. Persistently reduced serotonin activity is most characteristic of people whose

aggression is affective and impulsive rather than predatory (Miczek et al., 2002; R. J. Nelson & Trainor, 2007; Seo et al., 2008). PET studies have found that people with impulsive aggression have decreased serotonin activity in the prefrontal cortex (Meyer et al., 2008) and in the anterior cingulate gyrus, which also plays an important role in emotional regulation (Frankle et al., 2005). Of course, this doesn’t necessarily mean that low serotonin causes aggression; to find out, Moeller and his colleagues (1996) had males drink an amino acid mixture that lowered tryptophan, the precursor for serotonin. Then the men participated in a computer game in which one response earned points exchangeable for money and a different response subtracted points from a fictitious competitor. At random times during the game, the player’s screen indicated that some of his accumulated points had been deleted by the fictitious competitor. The men were more aggressive after drinking the tryptophan-depleting

mixture, deleting more of the fictitious competitor’s points. Drugs that block serotonin reuptake at neuron terminals reduce aggression in animals and in humans, providing additional causal evidence (Miczek et al.; R. J. Nelson & Trainor).

Does testosterone increase human aggression after all? Serotonin, Testosterone, and Alcohol Some research findings have reopened the possibility of a causal role for

testosterone in human aggression. Higley and his colleagues (1996) suggested that high testosterone and low serotonin interact to produce aggression, and their study of free-ranging male monkeys supported their position. Monkeys with high testosterone were more likely to engage in brief aggression that asserted dominance, such as threats and displacing another monkey from his position. Monkeys with low 5-HIAA levels were impulsive; they more frequently took dangerously long leaps among the treetops, and when they engaged in aggression it was more likely to accelerate into greater violence. The most aggressive monkeys of all had both low 5-HIAA and high testosterone levels. Human data suggest a similar relationship: Violent alcoholic offenders often have both low brain serotonin and high testosterone (Virkkunen, Goldman, & Linnoila, 1996; Virkkunen & Linnoila, 1993), and normal males with high testosterone and low serotonin levels score higher on questionnaires that assess hostility and aggression (Kuepper et al., 2010). If testosterone has any causal influence on human aggression, it may well occur only when serotonin’s inhibitory effect is reduced. We see a similar effect with alcohol. In a study of crime in 14 countries, 62% of

violent offenders were using alcohol at the time of their crime or shortly before (Murdoch, Pihl, & Ross, 1990), and evidence favors the commonsense interpretation that alcohol facilitates aggression rather than simply being a vice favored by aggressive people (Bushman & Cooper, 1990). However, alcohol appears to influence aggression only in people who also have low serotonin levels, such as early-onset alcoholics (see Chapter 5), who tend to be impulsively aggressive (Buydens- Branchey, Branchey, Noumair, & Lieber, 1989; Virkkunen & Linnoila, 1990, 1997). Serotonin has a dual influence on alcohol consumption and on aggression that makes for a deadly combination. After initially increasing serotonin activity, alcohol later depletes it below the original level, increasing craving for more alcohol (Pihl & Peterson, 1993); the alcohol abuser is caught in a vicious cycle as alcohol consumption increases both aggression and the desire for more alcohol. Drugs that inhibit serotonin uptake at the synapse, such as the antidepressant fluoxetine (trade name Prozac), reduce alcohol craving and intake (Naranjo, Poulos, Bremner, & Lanctot, 1994), and they also reduce hostility and aggressiveness (Coccaro & Kavoussi, 1997; Knutson et al., 1998). Heredity and Environment

From a review of 24 studies, it was estimated that up to 50% of the variation in aggression among people is genetic in origin (D. R. Miles & Carey, 1997). As you might expect, research has most often implicated genes that influence the dopamine, GABA, and serotonin neurotransmission systems (reviewed in Anholt & Mackay, 2012). These genes affect the amount of transmitter produced, how long it remains in the synapse before reuptake or degradation, and the sensitivity or number of receptors.

What roles do heredity and environment play in aggression? With only half of the variability in aggression accounted for by heredity, there is

still plenty of room for environmental influence. For example, men and women who were reared in homes with inadequate parenting have double the rate of violent criminality (Hodgins, Kratzer, & McNeil, 2001), and male and female murderers who do not have prefrontal deficits are more likely to have experienced psychological and social deprivation during childhood (Raine, Stoddard, Bihrle, & Buschbaum, 1998). Aggression research highlights the fact that the relationship between heredity and environment is often an active interaction, not simply the additive effects of two independent forces. FIGURE 8.23 Genetic Influence on Violent Behavior in Victims of Childhood Maltreatment. Low MAOA activity due to the MAOA-L allele, coupled with childhood maltreatment, results in increased violence.

SOURCE: Based on data from “Role of Genotype in the Cycle of Violence in Maltreated Children,” by A. Caspi et al., 2002, Science, 292, p. 852. The best known example is the association of the MAOA-L allele of the MAOA

gene with violence in males. Since its discovery in 1993, this association has been replicated more than any other aggression-gene link, most recently when the allele

Concept Check

was found to predict male membership in gangs and their use of weapons in fights (Beaver, DeLisi, Vaughn, & Barnes, 2010). And now the interaction: A later study found that the MAOA-L allele produced violence only in males who had been subjected to childhood physical abuse (see Figure 8.23; Caspi et al., 2002). In another study, violent offenders with a mutation that disables the HTR2B serotonin receptor gene committed 94% of their crimes under the influence of alcohol (Bevilacqua et al., 2010). We are already familiar with gene-environment interaction in the form of epigenetic influence. The SLC6A4 gene is involved not only in anxiety and fear, as we saw earlier, but also in aggression; adults who had been identified as highly aggressive during childhood had high levels of methylation of their SLC6A4 genes, and higher methylation was associated with decreased serotonin synthesis in the orbitofrontal cortex (D. Wang et al., 2012).

Take a Minute to Check Your Knowledge and Understanding

What is the evidence that the prefrontal cortex moderates aggression? How do serotonin, alcohol, and testosterone possibly interact to increase aggression?

In Perspective Emotion has been difficult for neuroscientists to get a handle on because it is so complex physiologically and because so much of emotion is a subjective, private experience. With improved research strategies and new technologies like PET scans, old questions about the role of brain structures are finally yielding to research. A good example is the ability to separate the emotion of pain from its sensory aspects at the neural level. On another front, research has confirmed the influence of emotion on health, a topic that was practically relegated to fringe psychology not too long ago. We have focused mostly on the negative aspects of emotion because they have

received the most attention from researchers and we know more about them. This focus of research interest acknowledges the fact that pain, anger, and aggression helped ensure the survival of our evolutionary ancestors, but now they are viewed as some of our greatest burdens. Not only does society need to ask whether modifying the environment might reduce schoolhouse shootings or violent crime in our streets; it also needs to appreciate the role of hormones, genes, and the brain when judging the accountability of a depressed mother who drowns all her children. In the meantime, if you find thoughts about the negative aspects of emotion a bit dismaying, you might want to take a short break while you hold your pen between your teeth; brightening your corner of the world is a good place to start.

Summary Emotion and the Nervous System • The autonomic nervous system increases bodily arousal during an emotional event and decreases it afterward.

• The James-Lange and cognitive theories differ as to the role of bodily feedback in emotional experience. There is evidence that feedback from facial expressions particularly contributes to emotions; also, mimicking other people’s expressions may help us understand others’ emotions.

• The limbic system is a network of several structures that have functions in emotion. We now know that emotion involves additional structures at all levels of the brain.

• The amygdala has a variety of functions, but its role in fear has received the most attention. Rats and humans with damage to both amygdalas lack fear and often fail to act in their own best interest.

• The prefrontal cortex combines emotional input with other information to make decisions. People with damage there have trouble following moral and social rules, and they have impaired ability to learn from the consequences of their behavior.

• Damage to the right hemisphere particularly blunts emotions and impairs the person’s ability to recognize emotion in faces and in voices.

Stress, Immunity, and Health • Stress is adaptive, mobilizing the body for action and increasing immune system activity.

• Prolonged stress interferes with mental, physical, and emotional functioning; compromises the immune system; and even damages the brain.

• Social support, personality, and attitudes are related to immune functioning and health, including cancer survival. However, these social and personality factors may not influence immune functioning; instead, they may be indicators of the individual’s physiological functioning.

• Pain is also an adaptive response; it informs us of danger to the body, and the emotion that accompanies it motivates us to take action.

Biological Origins of Aggression • Researchers usually distinguish two types of aggression in humans and animals, affective and predatory.

• Testosterone is involved in male aggression and both testosterone and estrogen in female aggression, although in humans the causal link for testosterone is questionable.

• The amygdala is one of the most important brain structures in aggression, both in lower animals and in humans. The prefrontal cortex suppresses aggression, and deficiency there is linked to antisocial personality and violent behavior.

• Dopamine contributes to aggression, likely by increasing arousal. Low GABA is associated with aggression and impulsivity. Drugs that reduce dopamine activity or

increase GABA activity reduce aggression. • Serotonin inhibits aggressive behavior, and low serotonin level is associated with aggression. Alcohol and a lowered serotonin level combine to increase aggression. Low serotonin and high testosterone levels may interact to increase aggression.

• Heredity is estimated to contribute half of the variability in aggression among humans; some genetic links with aggressive behavior involve serotonin receptors and serotonin metabolism. The other half of variation is due to the environment, including inadequate parenting. Heredity and environment interact, for example, in the combination of the MAOA-L allele with childhood abuse; some research implicates epigenetic effects as the mechanism in gene-environment interactions that increase aggression. ■

Study Resources

For Further Thought • Do you think we rely more on bodily feedback or the stimulus situation in identifying emotions? Why?

• Stress and pain involve considerable suffering, but they are necessary. Explain. What makes the difference between good and bad stress and pain?

• You are an adviser to a government official charged with reducing aggression in your country. From what you have learned in this chapter, what would you recommend?

• The legal plea of “not guilty by reason of insanity” has historically required that the defendant did not know right from wrong—as evidenced, for example, by the defendant’s failure to flee or try to conceal the crime. Critique this standard in terms of what you know about controlling behavior.

Quiz: Testing Your Understanding 1. Discuss the James-Lange and cognitive theories, including evidence for the

theories. 2. Explain the roles of the amygdala and the prefrontal cortex in guiding our

everyday decisions and behavior. 3. Describe the role the brain plays in animal and human aggression, including

structures and their functions. Select the best answer: 1. The James-Lange theory and the cognitive theory disagree on whether

a. specific brain centers are involved in specific emotions. b. there is any biological involvement in human emotions. c. bodily feedback determines which emotion is felt. d. individuals can judge their emotions accurately.

2. Some people with brain damage do not seem to learn from the consequences of their behavior and must have supervised care. Based on the location of

their damage, you would expect that they would particularly be lacking in a. sadness. b. joy. c. fear. d. motivation.

3. A person with partial paralysis seems remarkably undisturbed about the impairment. The paralysis a. probably is on the right side of the body. b. probably is on the left side of the body. c. probably involves both sides of the body. d. is as likely to be on one side as the other.

4. Stress can a. reduce immune system function. b. impair health. c. mobilize the immune system. d. both a and b e. a, b, and c

5. Long-term exposure to cortisol may affect memory by a. reducing blood flow to the brain. b. destroying neurons in the hippocampus. c. inhibiting neurons. d. redirecting energy resources to the internal organs.

6. AIDS is a deficiency of the a. immune system. b. autonomic system. c. central nervous system. d. motor system.

7. Indications are that if pain did not have an emotional component, we would probably a. be deficient in avoiding harm. b. avoid harm effectively, using learning and reasoning. c. be more aggressive. d. generally lead happier lives.

8. A structure described in the text as being involved in both aggression and flight is the a. amygdala. b. anterior cingulate cortex. c. lateral hypothalamus. d. periaqueductal gray.

9. According to research, you would have your best chance of showing that testosterone increases aggression in humans if you injected testosterone into a. males rather than females. b. people with prefrontal damage. c. people with low serotonin. d. people who were being confronted by another person.

10. Based on information in the text, the chance of violent criminal behavior is increased in males who a. have high testosterone. b. were abused as children. c. have a gene for low MAOA. d. both a and b e. both b and c

Answers: 1. c, 2. c, 3. b, 4. e, 5. b, 6. a, 7. a, 8. d, 9. c, 10. e.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. Here you can link to a variety of sites, from the University of California to

YouTube, to see Brain and Emotion Videos. 2. You can get a feel for what an active emotion research laboratory is like by

visiting lab sites at Boston College and the University of Maryland. You can read descriptions of their research programs and download published articles.

3. Stress Less features publications for sale, links to other websites on a broad variety of stress topics, and chat rooms organized by stress type.

4. The news articles about the effect of regular sleep on immunity came from Time and ScienceNOW.

5. The National Center for Posttraumatic Stress Disorder site has information on the disorder and on subtopics such as “Returning from War” and

“Specific to Women.” Various stress tests (some validated by research and some not) are available to assess the potential for stress to affect your health and well-being. You can take a test for Type A personality, which research indicates contributes to heart attacks; a stress test that assesses your stress level and your coping strategies; or the historically significant Holmes and Rahe Scale, designed to assess health risk from recent stressful events (positive as well as negative).

Chapter Updates and Biopsychology News

For Further Reading 1. Descartes’ Error, by Antonio Damasio (Quill, 2000), covers the various

topics of emotion but develops the premise that our rational decision making is largely dependent on input from emotions.

2. Why Zebras Don’t Get Ulcers (3rd ed.), by Robert Sapolsky (Freeman, 2004), is a lively discussion of emotion and its effects, including stress, immunity, ulcers, memory, and sex.

3. “Empathy Overkill,” by Helen Thomson (New Scientist, March 13, 2010, 43–45), describes research with people with “mirror synesthesia,” who intensely feel what they see others experiencing, and people with echopraxia, who greatly exaggerate the action mimicking that the rest of us engage in subtly.

4. “Health Psychology: Developing Biologically Plausible Models Linking the Social World and Physical Health,” by Gregory Miller, Edith Chen, and Steve W. Cole (Annual Review of Psychology, 2009, 501–524), is a detailed review of the interactions between emotion and health.

5. The Better Angels of Our Nature: Why Violence Has Declined, by Steven Pinker (Penguin Books, 2012), argues that in spite of what we see in the news, violence is declining worldwide and we may be living in the most peaceful era of human existence. Pinker attributes this in part to increasing empathy, as a result of literacy, travel, and a broader worldview.

6. The Anatomy of Violence: The Biological Roots of Crime, by Adrian Raine (Pantheon, 2013), describes his work and that of others over the past three decades, teasing out the biological causes of crime and what can be done, while establishing the new field of neurocriminology.

Key Terms affective aggression aggression anterior cingulate cortex antisocial personality disorder

autoimmune disorder B cell cognitive theory congenital insensitivity to pain cortisol emotion hypothalamus-pituitary-adrenal axis immune system James-Lange theory leukocytes limbic system macrophage microglia mirror neurons natural killer cell predatory aggression skin conductance response (SCR) stress sudden cardiac death T cell

PART III

Interacting With the World

Chapter 9. Hearing and Language Chapter 10. Vision and Visual Perception Chapter 11. The Body Senses and Movement

9 Hearing and Language

In this chapter you will learn • What the auditory (hearing) mechanism consists of and how it works • How the brain processes sounds, from pure tones to speech • Which brain structures account for language ability • The causes of some of the major language disorders • What we know about language abilities in nonhuman animals

Hearing The Stimulus for Hearing The Auditory Mechanism Frequency Analysis APPLICATION: RESTORING HEARING

Locating Sounds With Binaural Cues APPLICATION: I HEAR A TREE OVER THERE CONCEPT CHECK

Language Broca’s Area Wernicke’s Area The Wernicke-Geschwind Model Reading, Writing, and Their Impairment Mechanisms of Recovery From Aphasia A Language-Generating Mechanism? IN THE NEWS: LEARNING LANGUAGE STARTS BEFORE BIRTH

Language in Nonhumans Neural and Genetic Antecedents IN THE NEWS: THE LINK BETWEEN HUMAN LANGUAGE AND BIRDSONG CONCEPT CHECK

In Perspective Summary Study Resources

The only way Heather Whitestone knew the music had started for her ballet numberin the Miss America talent competition was because she could feel the vibrations through the floor. Heather was profoundly deaf, and she became the first person

with deafness or any other handicap to win the title of Miss America. “

To be deaf is a greater affliction than to be blind. —Helen Keller

”

Her hearing was normal until she contracted meningitis at the age of 18 months; the problem was not the meningitis but the strong antibiotics that destroyed the sound receptor cells in her ears. A hearing aid helped some, and she read lips and received twice weekly speech therapy. By the time she reached high school, she was able to participate in mainstream classes without a sign language interpreter, and she graduated with a 3.6 grade point average. A cochlear implant was an option, but since she had been deaf so long, it was possible she would not tolerate the strange new sounds. Besides, she was satisfied with her level of adjustment—that is, until she married and had a son. Heather realized she could not share many of his experiences because she could not hear what he was hearing. Then one day she saw her husband running to their son when the boy hurt himself and she had not even heard him crying. It was then she decided to have the surgery. FIGURE 9.1 Heather Whitestone Using Sign Language. Her communication and her quality of life improved when she received a cochlear implant.

SOURCE: Getty Images. The implant bypassed the dead receptor cells to stimulate the neurons in her inner

ear directly. After the surgery, she could understand her son’s speech much better, so he didn’t have to repeat himself so many times. Best of all, she could hear him cry, even when he was playing outside in the backyard. Nothing attests to the value of hearing more than the effects of losing it. Like

Heather, the person is cut off from much of the discourse that our social lives depend on. There is no music, no song of birds, and no warning from thunder or car horns. When hearing is lost abruptly in later life, the effect can be so depressing that it eventually leads to suicide. With the topics of hearing and language, we begin the discussion of how we carry

on transactions with the world. This communication involves acquiring information through the senses, processing the sensory information, communicating through language, moving about in the world, and acting on the world. We have already touched on the senses of taste, smell, and pain in the context of hunger, sexual behavior, and emotion. Before we explore additional sensory capabilities, we need to establish some basic concepts. First, a sensory system must have a specialized receptor. A receptor is a cell, often

a specialized neuron that is suited by its structure and function to respond to a particular form of energy, such as sound. A receptor’s function is to convert that

energy into a neural response. You will see examples of two kinds of receptors in this and the next chapter, but receptors come in a wide array of forms to carry out their functions.

How is a stimulus translated into information the brain can use? For a sensory receptor to do its job, there must also be an adequate stimulus. An

adequate stimulus is the energy form for which the receptor is specialized. Due to the imperfect specialization of receptors, other stimuli will often produce responses as well. For example, if you apply gentle pressure to the side of your eyeball (through the lid), you will see a circular dark spot. You will remember from Chapter 3 that, according to Müller’s doctrine of specific

nerve energies, the neural mechanism rather than the type of stimulus determines the kind of sensory experience you will have. A sensory system will register its peculiar type of experience even if the stimulus is inappropriate. So when the neurosurgeon stimulates the auditory cortex, the patient hears a buzzing sound or even voices or music, and when your skateboard shoots out from under you and your head hits the pavement, you really do see “stars.” You will learn in this and the next two chapters that it is the patterning of the stimulation—that is, the amplitude and timing of neural impulses—that makes sensory information meaningful.

What is the difference between sensation and perception? Most people consider audition and vision the most important senses. As a result,

there has been more research on these two senses than on others and we know more about them, so we will give them the most attention. Because audition is a more mechanical sensory mechanism than vision, it is a good place to begin our formal discussion of sensation, the acquisition of sensory information, and perception, the interpretation of sensory information. Hearing The fact that the auditory mechanism is less complex does not mean that hearing is a simple matter. The cochlea, where the auditory stimulus is converted into neural impulses, contains a million moving parts. Our range of sensitivity to intensity, from the softest sound we can hear to the point where sound becomes painful, is a million to one. Our ability to hear low-intensity sounds is limited more by interference from the sound of blood coursing through our veins and arteries than by the auditory mechanism itself. In addition, we are able to hear frequencies ranging from about 20 hertz (Hz, cycles per second) up to about 20000 Hz, and we can detect a difference in frequencies of only 2 or 3 Hz. To give you some idea of what these frequencies relate to in real life, the piano—the most versatile of musical instruments—has a range of about 27 to 4000 Hz. Upper ranges are more impressive for some animals: 60,000 Hz (60 kHz) for dogs, 79 kHz for cats, and an astonishing 200 kHz for bats—10 times

higher than for humans.

1 Hearing Loss The Stimulus for Hearing The adequate stimulus for audition is vibration in a conducting medium. Normally

the conducting medium is air, but we can also hear underwater and we hear sounds conducted through our skull. The air is set to vibrating by the vibration of the sound source—a person’s vocal cords, a bell that has been struck, or a stereo speaker. As the sound source vibrates, it alternately compresses and decompresses the air (Figure 9.2). FIGURE 9.2 Alternating Compression and Decompression of Air by a Sound Source. The surface of the speaker vibrates, alternately compressing and decompressing the surrounding air. The dark areas represent high pressure (a denser concentration of air molecules), and the light areas represent low pressure.

SOURCE: From Sensation and Perception, 5th ed., by E. B. Goldstein, 1999. Reprinted with permission of Wadsworth, a division of Thomson Learning. If we used a microphone to convert a sound to an electrical signal, we could display

the signal on an oscilloscope, like the one we used to measure the action potential in Chapter 2; the oscilloscope would form a graph of the compressions and decompressions, and we could see what the sound “looks like.” Look at Figure 9.3; the up-and-down squiggles represent the increasing and decreasing pressure of different sounds (over a brief fraction of a second). One way sounds differ is in frequency. Frequency refers to the number of cycles or waves of alternating compression and decompression of the vibrating medium that occur in a second (expressed in hertz). Figure 9.3a and b have the same frequency—indicated by the number of waves in the same time—so we would hear these two sounds as the same, or nearly the same, pitch. Figure 9.3c and d would also sound about the same as each other, but higher in pitch than Figure 9.3a and b. Pitch is our experience of the frequency of a sound.

What is the difference between frequency and pitch? Intensity and loudness?

Sounds also differ in amplitude. The sounds represented by Figure 9.3a and c have the same amplitude (the height of the wave), so they would sound about equally loud; Figure 9.3b and d would sound less loud but similar to each other. Amplitude, or intensity, is the term for the physical energy in a sound; loudness is the term for our experience of sound energy. Pitch does not correspond exactly to frequency, nor is the amplitude of a sound exactly the same as its loudness; this is due to the way our sensitivity varies across the range of sounds. For example, we are most sensitive to sounds between 2000 and 4000 Hz—the range within which most conversation occurs —and equally intense sounds outside this range would seem less loud to us. Similarly, the amplitude of a sound influences our experience of pitch. Because the physical stimulus and the psychological experience are not always perfectly related, we need to use the terms intensity versus loudness and frequency versus pitch carefully. The sounds we hear can also be classified as either pure tones or complex sounds.

A pure tone, generated for example by striking a tuning fork, would produce a tracing that looks like one of the graphs in Figure 9.3a to d. Notice that these four waveforms are a very regular shape, called a sine wave. They are pure tones: Each has only one frequency. Figure 9.3e and f are graphs of complex sounds: Each is a mixture of several frequencies. The random combination of frequencies in 9.3e would probably be described by most of us as “noise.” Depending on the combination and order of frequencies, a complex sound might seem musical like the last waveform, which was produced by a clarinet (Figure 9.3f). The two waveforms may not look very different to you, but they would certainly sound different. Although what is considered pleasantly musical depends on experience and culture (and one’s age!), we would recognize even the most foreign music as music. FIGURE 9.3 Examples of Pure and Complex Sounds. (a) and (b) are pure tones of the same frequency but different amplitudes, as are (c) and (d). (a) and (c) have the same amplitudes but different frequencies, as do (b) and (d). Both (e) and (f) are complex sounds—noise and a clarinet note, respectively.

The Auditory Mechanism To hear, we must get information about the sound to the auditory cortex. This

requires a series of events, including sound reception, amplification, and conversion into neural impulses that the brain can use. The Outer and Middle Ear The term ear refers generally to all the structures shown in Figure 9.4. The flap that

graces the side of your head is called the outer ear or pinna. The outer ear captures the sound and then amplifies it slightly by funneling it from the larger area of the pinna into the smaller area of the auditory canal. It also selects for sounds in front; this makes it easier to focus on a sound, such as the conversation you’re having, while excluding irrelevant sounds behind you. Dogs and cats have muscles that enable them to turn their ears toward a sound that is not directly in front of them; you may be able to wriggle your ears a bit (actually by twitching your scalp muscles), but you have to turn your head to orient toward a sound. The first part of the middle ear, the eardrum or tympanic membrane, is a very thin

membrane stretched across the end of the auditory canal; its vibration transmits the sound energy to the ossicles. A muscle called the tensor tympani can stretch the eardrum tighter or loosen it to adjust the sensitivity to changing sound levels. The tympanic membrane is very sensitive. Wilska (1935) ingeniously glued a small rod to the eardrum of a human volunteer (temporarily, of course) and used an electromagnetic coil to vibrate the rod back and forth. He determined that we can hear sounds when the eardrum moves as little as the diameter of a hydrogen atom! The experiment was remarkable for the time, and recent studies with more sophisticated equipment have shown that Wilska’s measurements were surprisingly accurate (Hudspeth, 1983). The second part of the middle ear is the ossicles, tiny bones that operate in lever

fashion to transfer vibration from the tympanic membrane to the cochlea. The malleus, incus, and stapes are named for their shapes, as you can see from their English equivalents hammer, anvil, and stirrup. The ossicles provide additional amplification by concentrating the energy collected from the larger tympanic membrane onto the much smaller base of the stirrup, which rests on the end of the cochlea. The amplification is enough to compensate for the loss of energy as the vibration passes from air to the denser liquid inside the cochlea. The ossicles are not passive players in the auditory process: The muscles attached to them tighten the joints to increase sensitivity to soft sounds and loosen the connections to dampen loud sounds. The Inner Ear You can also see the parts of the inner ear in Figure 9.4. The semicircular canals are

part of the vestibular organs and do not participate in hearing; we will talk about them in Chapter 11. The snail-shaped structure is the cochlea, where the ear’s sound-

analyzing structures are located. You can see from the cochlea’s shape where it got its name, which means “land snail” in Latin. Figure 9.5a shows a more highly magnified view. It is a tube that is about 35 millimeters (mm) long in humans and coiled 2½ times. It is subdivided by membranes into three fluid-filled chambers or canals (Figure 9.5b). In this illustration, the end of the cochlea has been removed, and you are looking down the three canals from the base end. The stirrup (Figure 9.5a) rests on the oval window, a thin, flexible membrane on the face of the vestibular canal. The vestibular canal (scala vestibuli) is the point of entry of sound energy into the cochlea. The vestibular canal connects with the tympanic canal at the far end of the cochlea through an opening called the helicotrema. (You might not need to remember this term, but it just sounds too wonderful to leave out!) The helicotrema allows the pressure waves to travel through the cochlear fluid into the tympanic canal more easily. Liquids are essentially incompressible; at the end of the tympanic canal another thin membrane, the round window, flexes outward with each sound wave and relieves the pressure. FIGURE 9.4 The Outer, Middle, and Inner Ear.

All this activity in the vestibular and tympanic canals bathes the cochlear canal, where the auditory receptors are located, in vibration. The vibration passes to the organ of Corti, the sound-analyzing structure that rests on the basilar membrane. The organ of Corti consists of four rows of specialized cells called hair cells, their supporting cells, and the tectorial membrane above the hair cells (Figure 9.5c). To

visualize these structures, remember you are looking down a long tube; imagine the four rows of hair cells as picket fences or rows of telephone poles and the tectorial membrane as a shelf overlying the hair cells. FIGURE 9.5 Structures of the Middle and Inner Ear. (a) The middle ear—tympanic membrane and ossicles—and the inner ear—the cochlea. (b) A section of the cochlea. (c) The organ of Corti.

The hair cells are the receptors for auditory stimulation. Vibration of the basilar membrane and the cochlear fluid bends the hair cells, opening potassium and calcium channels (not sodium channels, as in neurons) and depolarizing the hair cell membrane. This sets off impulses in the auditory neuron connected to the hair cell. When the hair cell moves back in the opposite direction, it relaxes and the potassium channels close. The hair cells are very sensitive; the amount of movement required to produce a sensation is equivalent to the Eiffel Tower leaning just the width of your thumb (Hudspeth, 1989), about the distance the tower sways in a strong wind.

How is the auditory stimulus converted to a neural impulse? The human cochlea has two sets of hair cells: a single row of about 3,500 inner hair

cells and three rows of about 12,000 outer hair cells (“inner” and “outer” refer to their location relative to the center of the coiled cochlea). The less numerous inner hair cells receive 90% to 95% of the auditory neurons, and they provide the majority of the information about auditory stimulation (Dallos & Cheatham, 1976). A strain of mouse lacking inner hair cells due to a mutant gene is unable to hear (Deol & Gluecksohn- Waelsch, 1979). The outer hair cells increase the cochlea’s sensitivity both by amplifying its output and by sharpening the frequency tuning at the location of peak vibration (Hudspeth, 2008; Xiao & Suga, 2002). Damage to the outer hair cells by noise or chemical ablation causes a dramatic loss of hearing, but also a loss of frequency selectivity along the basilar membrane. Why are these apparently nonsensory cells so important? Remember that the hair cells have their cilia embedded in the tectorial membrane. When the outer hair cells are deflected in one direction they depolarize, causing them to shorten. Shifting in the other direction causes hyperpolarization and lengthening; apparently the outer hair cells’ tugging on the tectorial membrane increases stimulation of the inner hair cells.

2 How Hearing Works & Dancing Hair Cell The Auditory Cortex Neurons from the two cochleas make up part of the auditory nerves (eighth cranial

nerves), one of which enters the brain on each side of the brain stem. The neurons pass through brain stem nuclei (see Figure 9.7a) to the inferior colliculi, to the medial geniculate nucleus of the thalamus, and finally to the auditory cortex in each temporal lobe. Neurons from each ear go to both temporal lobes, but there are more connections to the opposite side than to the same side. This means that a sound on your right side is registered primarily, but not exclusively, in the left hemisphere of the brain. Researchers interested in differences in function between the two hemispheres have used an interesting strategy, called the dichotic listening task, to stimulate one side of the brain. They present an auditory stimulus through headphones to one ear and present white noise (which contains all frequencies and sounds like radio static) to the other ear to occupy the nontargeted hemisphere. This technique has helped researchers determine that the left hemisphere is dominant for language in most people and that the right hemisphere is better at other tasks, such as identifying melodies. FIGURE 9.6 Electron Microscope View Showing the Hair Cells Attached to the Tectorial Membrane Above. (The colors are artificial.)

SOURCE: Dr. G. Oran Bredberg/SPI/Science Source. The auditory cortex is on the superior (upper) gyrus of the temporal lobe of each

hemisphere; part of it is hidden inside the lateral fissure, as you can see in Figure 9.7b. The area is topographically organized, which means that neurons from adjacent receptor locations project to adjacent cells in the cortex. In this case, the projections form a sort of map of the unrolled basilar membrane (Merzenich, Knight, & Roth, 1975), just as the somatosensory cortex contains a map of the body. We will see that this organization is typical in the senses when we study vision in Chapter 10. The work of the auditory system is hardly finished when we have heard a sound.

Beyond the primary auditory cortex are additional processing areas, as many as nine in some mammals; these secondary auditory areas are involved in processing complex sounds and understanding their meaning. For example, some of the cells adjacent to the monkey’s primary auditory area respond selectively to calls of their own species, and some of those react only to one type of call (Wollberg & Newman, 1972). The human primary auditory cortex has a secondary area surrounding it (Figure 9.7b), but auditory information also travels well beyond the auditory areas, following the dorsal stream or the ventral stream (Alain, Arnott, Hevenor, Graham, & Grady, 2001; Rauschecker & Tian, 2000). FIGURE 9.7 The Auditory Pathway and the Auditory Cortex. In (a) you can see that input to each ear goes to the auditory cortex in both hemispheres, but primarily to the opposite hemisphere. In (b) the temporal lobe has been pulled out to reveal the inner surface.

The dorsal stream flows from the auditory cortex through the parietal area, where the brain combines information from other senses to locate the sound in relation to the body and the visual scene. The information then proceeds to the frontal lobes, where it can be used for directing eye movements toward sound sources and for planning movements. The ventral stream is active when the individual is identifying sounds; the call-specific cells of the monkey’s auditory system are part of this system. Because of their specialties, the ventral and dorsal streams have been dubbed the what and where systems of audition. These two pathways are illustrated in Figure 9.8. We will see in Chapter 10 that vision has similar what and where systems. Frequency Analysis The sounds that are important to us, such as speech and music, vary greatly in

intensity and frequency, and they change intensity and frequency rapidly. It is the task of the cochlea and the auditory cortex to analyze these complex patterns and convert the raw information into a meaningful experience. We will concentrate on frequency analysis, which has received the lion’s share of

attention from researchers. More than 50 years ago, Ernest Wever (1949) described 17 versions of the two major theories of frequency analysis, which indicates the difficulty we have had in figuring out how people experience pitch. We will discuss a few versions that have been important historically. Besides introducing you to these two important theories, our discussion will describe what we know about how the auditory mechanism works and give you some idea of how theories develop in response to emerging evidence. FIGURE 9.8 The Dorsal “Where” and Ventral “What” Streams of Auditory Processing. The red areas were active when subjects determined the locations of sounds. Green areas were activated when they identified sounds. Localization and identification followed dorsal “where” and ventral “what” streams, respectively, with both terminating in frontal areas. (Functional MRI data were superimposed over a smoothed brain.)

SOURCE: From “Distinct Pathways Involved in Sound Recognition and Localization: A Human fMRI Study,” by P. P. Maeder, R. A. Meuli, M. Adriani, A. Bellmann, E. Fornari, J.-P. Thiran, A. Pittet, and S. Clarke, 2001, NeuroImage, 14, pp. 802–816. Used with permission from Elsevier. Frequency Theories The most obvious explanation of how the auditory system analyzes frequency is the

frequency theory, which assumes that the auditory mechanism transmits the actual frequency of a sound to the auditory cortex for analysis there. William Rutherford proposed an early version in 1886; it was called the telephone theory because he believed that individual neurons in the auditory nerve fired at the same frequency as the rate of vibration of the sound source. Half a century later, it was possible to test the theory with electrical recording equipment. Ernest Wever and Charles Bray (1930) performed one of the most intriguing investigations of auditory frequency analysis found in the scientific literature. They attached an electrode to the auditory nerve of an anesthetized cat and recorded from the nerve while they stimulated the cat’s ear with various sounds. Because the simple equipment used to record neural activity at that time was unable to respond to frequencies above 500 Hz, Wever and Bray ran the amplified neural responses into a telephone receiver in a soundproof room and listened to the output. Sounds produced by a whistle were transmitted with great fidelity. When someone spoke into the cat’s ear, the speech was intelligible, and the researchers could even identify who the speaker was. The auditory nerve was “following,” or firing at the same rate as the auditory stimulus. It appeared that the telephone theory was correct, but with the benefit of our more modern understanding of neural functioning, you and I know that neurons cannot fire at such high rates. (See the discussion of refractory periods in Chapter 2 if you don’t remember.)

How do the frequency and place theories explain frequency analysis?

3 Frequency Analysis Animation Wever and Bray were not recording from a single neuron, but from all the neurons

in contact with the hook-shaped copper electrode they placed around the auditory nerve. Thus, they were monitoring the combined activity of hundreds of neurons. Wever explained their finding later in his volley theory, which states that groups of neurons follow the frequency of a sound at higher frequencies, whereas a single neuron cannot (Wever, 1949). A group of neurons is able to follow high frequencies because different neurons “take turns” firing. The term volleying is an analogy to the practice of soldiers with muzzle-loading rifles, who would fire in squads and then reload while the other squads were firing. Volleying is illustrated in Figure 9.9, where each of the neurons synchronizes its firing to the waves of the tone; no single neuron can fire on every wave, but some neurons will be firing on each wave. In this theory, the brain is required to combine information from many neurons to determine the frequency. In Wever and Bray’s study, volleying in the auditory nerve was unable to keep up with the sound frequency beyond 5200 Hz, a figure that subsequent research has shown to be accurate (J. E. Rose, Brugge, Anderson, & Hind, 1967). So even with volleying, frequency following can account for only one fourth of the range of frequencies we hear. FIGURE 9.9 Illustration of Volleying in Neurons. No single neuron can follow the frequency of the sound, but a group of neurons can.

Place Theory In the 19th century, Hermann von Helmholtz (1863/1948) proposed that the basilar

membrane was like a series of piano strings, stretched progressively more loosely with distance down the membrane. Then he invoked a principle from physics called resonance to explain how we discriminate different frequencies. Resonance is the vibration of an object in sympathy with another vibrating object. If you hold a vibrating tuning fork near the strings of a piano or a guitar, you will notice that the strings begin to vibrate slightly. A high-frequency tuning fork causes the thinner, more tautly stretched strings to vibrate more than the others, and a low-frequency tuning fork causes the thicker, looser strings to vibrate most. According to Helmholtz, resonance would cause the narrow base end of the membrane to resonate more to high-frequency sounds, the middle portion to moderate frequencies, and the wider

apex (tip) to low frequencies. Helmholtz’s proposal was a type of place theory, which states that identifying the frequency of a sound depends on the location of maximal vibration on the basilar membrane and which neurons are firing most. Place theory in its various evolving versions has been the most influential explanation of frequency analysis for a century and a half. It is an example of a theory that has become almost universally accepted but continues to be referred to as a theory. A century later, Georg von Békésy, a communications engineer from Budapest,

began a series of innovative experiments that won him the Nobel Prize for physiology in 1961. Békésy constructed mechanical models of the cochlea and also observed the responses of the basilar membrane in cochleas he removed from deceased subjects as diverse as elephants and humans. When he stimulated these cochleas with a vibrating piston, he could see under the microscope that vibrations peaked at different locations along the basilar membrane; a wavelike peak hovered near the base when the frequency was high and moved toward the apex as Békésy (1951) decreased the frequency. But Helmholtz was wrong about the basilar membrane being like a series of piano strings; Békésy (1956) determined that its frequency selectivity is due to differences in elasticity, with the membrane near the stirrup 100 times stiffer than at the apical end. Figure 9.10 shows how frequency sensitivity is distributed along the membrane’s

length (see Figure 9.5 again for the location of the basilar membrane). Recordings from single auditory neurons have confirmed that place information about frequency is carried from the cochlea to the cortex. Because the auditory cortex is organized topographically, it also contains a tonotopic map, which means that each successive area responds to successively higher frequencies (Figure 9.11). FIGURE 9.10 Frequency Sensitivity on the Human Basilar Membrane. Notice that the basilar membrane is narrow at the base end of the cochlea and widens toward the apex, the opposite of the cochlea’s shape.

You can see from the tuning curves in Figure 9.12 that each neuron responds most to a narrow range of frequencies (Palmer, 1987), due to the neuron’s place of origin in the cochlea. However, each neuron also responds to a lesser extent to a range of frequencies around its “primary” frequency, mirroring the pattern of vibration in the basilar membrane. So how can neurons that make such imperfect discriminations inform the brain about the frequency of a sound with the 2- to 3-Hz sensitivity that has been observed? The answer is lateral inhibition; the more highly stimulated neurons inhibit activity in adjacent neurons with slightly different primary frequencies (G. Wu, Arbuckle, Liu, Tao, & Zhang, 2008). As a result, some neurons in the auditory cortex are many times more discriminating than neurons in the auditory nerve (Bartlett, Sadagopan, & Wang, 2011; Bitterman, Mukamel, Malach, Fried, & Nelken, 2008). This neural sharpening of information is a characteristic of the sensory systems, as we will see when we discuss sound localization and in Chapter 10 when we talk about vision. FIGURE 9.11 Tonotopic Map. The part of the auditory cortex at the lower end of the magnified view receives neurons from the apex of the cochlea, and the other end responds to signals from the base. The auditory cortex thus forms a “map” of the basilar membrane so that each successive area responds to progressively higher frequencies.

FIGURE 9.12 “Tuning Curves” of Auditory Neurons in the Cat. Curves are from three individual neurons in the cat auditory cortex. The lowest point of each curve indicates that neuron’s primary frequency and the lowest amplitude of sound that will activate the neuron. Other frequencies within the curve will also activate that neuron, but activation decreases with distance from the primary frequency. SOURCE: Figure 11.31 from Sensation and Perceptions (5th ed.; p. 331) by E. Bruce Goldstein, 1999, Pacific Grove, CA: Brooks-Cole. © 1999.

Place analysis is the reason we can hear with some clarity through bone conduction. The vibrations enter the cochlea from all sides during bone conduction, rather than through the oval window, but Békésy (1951) demonstrated with his cochleas that this does not disrupt the tonotopic response of the basilar membrane. As he moved his

vibrating piston from the base around to the side of the cochlea, or to the apex or anywhere else, the peak of vibration remained in the same location. Thomas Edison was nearly deaf, yet his second most famous invention was the phonograph. He compensated for his impaired hearing by grasping the edge of the phonograph’s wooden case between his teeth and listening to the recording through bone conduction. You can still see the bite marks on one of his phonographs in the museum at his winter home and laboratory in Fort Myers, Florida. Figure 9.13 shows another bite-to-listen device, and the accompanying Application explains how doctors took advantage of place analysis to restore Heather Whitestone’s ability to hear. FIGURE 9.13 A Musical Toy That Works by Bone Conduction. This is a musical lollipop holder. It has no speaker or earplug, but bite down on the lollipop and you literally hear the music in your head, thanks to bone conduction and place analysis. (Yes, it really works... but it won’t replace your iPod!)

SOURCE: Bob Garrett. At low frequencies, the whole basilar membrane vibrates about equally, and

researchers have been unable to find neurons that are specific for frequencies below 200 Hz (Kiang, 1965). Wever (1949) suggested a frequency-volley-place theory: individual neurons follow the frequency of sounds up to about 500 Hz by firing at the same rate as the sound’s frequency; then between 500 and 5000 Hz, the frequency is tracked by volleying, and place analysis takes over beyond that point. While volleying does occur in the auditory nerve, studies do not show that the brain uses that information in frequency analysis. Therefore, most researchers subscribe to a simpler frequency-place theory: Frequency following by individual neurons accounts for frequencies up to about 200 Hz and all remaining frequencies are represented by the place of greatest activity. Fortunately, we can sum up the auditory system’s handling of intensity coding

much more simply. As we learned in Chapter 2, a more intense stimulus causes a neuron to fire at a higher rate. The auditory system relies on this strategy for distinguishing among different intensities of sound. However, this is not possible at lower frequencies, where firing rate is the means of coding frequency. Researchers believe that at the lower frequencies, the brain relies on the number of neurons firing

as increases in stimulus intensity recruit progressively higher-threshold neurons into activity. Analyzing Complex Sounds You may have realized that we rarely hear a pure tone. The speech, music, and

noises that are so meaningful in our everyday life are complex, made up of many frequencies. Yet we have an auditory mechanism that appears to be specialized for responding to individual frequencies. But a solution to this enigma was suggested even before Helmholtz proposed his place theory. Forty years earlier, the French mathematician Fourier had demonstrated that any complex waveform—sound, electrical, or whatever—is in effect composed of two or more component sine waves. Fourier analysis is the analysis of a complex waveform into its sine wave components (see Figure 9.14). A few years later, Georg Ohm, better known for Ohm’s law of electricity, proposed that the ear performs a Fourier analysis of a complex sound and sends information about each of the component frequencies to the cortex. Current researchers agree that the basilar membrane acts as the auditory Fourier analyzer, responding simultaneously along its length to the sound’s component frequencies.

How does the auditory system handle complex sounds? Not only do we rarely hear a pure sound, but we also seldom hear a single complex

sound alone. At a party, we hear the music playing loudly, mixed in with several conversations going on all around us. In spite of the number of complex sounds assaulting our cochleas, we are able to separate the speech of our conversation partner from the other noises in the room. We do more than that; we sample the other sounds regularly enough to enjoy the music and to hear our name brought up in a conversation across the room. The ability to sort out meaningful auditory messages from a complex background of sounds is referred to as the cocktail party effect. FIGURE 9.14 Fourier Analysis of a Clarinet Note. The dominant component is a relatively high-amplitude, low-frequency sine wave; the other components are progressively higher frequencies at lower intensities. If we produced sounds at each of these frequencies and amplitudes at the same time, the combined waveform when displayed on an oscilloscope would look like the waveform at the top, and the result would sound like the clarinet note.

SOURCE: From “How Much Distraction Can You Hear?” by P. Milner,Stereo Review, June 1977, pp. 64–68. © 1977. The cocktail party effect is an example of selective attention; the brain must select

the important part of the auditory environment for emphasis and suppress irrelevant background information. When we look at attention more closely in the final chapter, we will see that selective attention actually enhances activity in one part of the sensory cortex and reduces it in others. To find out what happens in the brain during the cocktail party effect, researchers

turned to patients who had EEG electrodes placed directly on the cortex to determine where their seizure-causing lesions were located. When these subjects attended to one of two speech sources, that speech was tracked closely in the auditory cortex, while

the competing speech was somewhat suppressed; in higher-order areas, including those concerned with language, the unattended speech dropped out completely (Horton, D’Zmura, & Srinivasan, 2013; Zion Golumbic et al., 2013). Although outer hair cells have very few ascending connections to the brain, they receive many descending fibers; stimulating those fibers in bats increases hair cell activity in specific areas of the basilar membrane, which enhances frequency sensitivity in those areas (Xiao & Suga, 2002). By measuring evoked otoacoustic emissions in humans, French researchers confirmed that attention to a tone causes frequency-specific changes in outer hair cell activity (Maison, Micheyl, & Collet, 2001). Beyond distinguishing one sound from another, it is important to be able to identify

a sound; here it is useful to think in terms of an auditory object—a sound we identify as distinct from other sounds. Identifying an auditory object involves distinguishing characteristics such as pitch, rhythm, and tempo and depends on our ability to separate sounds by their directional location. Understand that identifying an auditory object does not imply that we recognize what the sound is; memory helps provide that function, enabling us to recognize an oncoming train or the voice of a friend. Dolphins can even recognize the signature whistle of former tank mates from as far back as 20 years, the typical dolphin lifespan in the wild (Bruck, 2013). Recognizing environmental sounds primarily requires posterior temporal areas and, to a lesser extent, the frontal cortex (J. W. Lewis et al., 2004), while recognizing individuals’ voices involves the secondary auditory cortex in the superior temporal area (Kriegstein & Giraud, 2004; Petkov et al., 2008). More generally speaking, these sound objects activate the “what” pathway (see Figures 9.15 and 9.8). In a few pages, you will see that these areas are also important in producing and understanding language.

APPLICATION

Restoring Hearing Ninety percent of cases of hearing impairment involve hair cell damage, and, because hair cells don’t regenerate, these individuals may be candidates for a cochlear implant, like Heather Whitestone’s and the ones worn by the two children in the opening photograph. An implant uses an external microphone to pick up sounds and send them to a speech processor located behind the ear; then a transmitter on the surface of the skin sends the signal to a receiver that is surgically mounted just beneath the skin (see the figure). From there, the signal travels through a wire to an electrode array threaded through the cochlea; the electrodes deliver signals representing the different frequencies of a sound to different locations along the length of the electrode. Activating different neurons with different frequencies mimics the functioning of the

basilar membrane and hair cells in an unimpaired individual; in other words, it relies on the principle of place analysis. Most cochlear implant recipients hear effectively enough to use a telephone,

which is more difficult than face-to-face conversation; most children can be mainstreamed in school, and they rate their quality of life comparably with their peers (Loy, Warner-Czyz, Tong, Tobey, & Roland, 2010). Early implantation works best, because adjustment to an enriched auditory world can be surprisingly difficult and because neurons from other sensory areas can take over the unused auditory cortex over time (D. S. Lee et al., 2001). In adults, success also depends on having learned language before deafness occurred. Children, on the other hand, are able to use the implants whether or not they learned language previously (Francis, Koch, Wyatt, & Niparko, 1999).

A Cochlear Implant Device.

4 Auditory Implants Because hearing is less than optimal with cochlear implants and they can’t

be used in some cases, researchers continue to search for alternatives. For those whose cochlea or auditory nerve is nonfunctional, a brainstem implant (in the cochlear nucleus) or a midbrain implant (in the inferior colliculus) may be possible. The neurons in both of these locations are frequency tuned and tonotopically organized, but the small number of electrodes—usually around 20—limits speech perception so much that most recipients rely on these implants only as an aid to lip reading (Lim, Lenarz, & Lenarz, 2009; M. S. Schwartz, Shannon, Hilselberger, & Brackmann, 2008). Gene replacement may be an option in the future. Inserting the ATOH1 gene improved hearing in

mice with experimentally damaged hair cells (Izymikawa et al., 2005), and replacement of the VGLUT3 gene improved glutamate transmission between the intact hair cells and auditory neurons in knockout mice (Akil et al., 2012). Gene therapy carries some risks that could prevent its use in humans, but a drug has produced similar results, coaxing supporting cells to develop into hair cells in deafened mice and improving their hearing (Mizutari et al., 2013). Another possibility is the use of stem cells, which can be induced to develop into hair cells or auditory neurons; inserting the latter into chemically nerve- deafened guinea pigs partially restored their hearing (W. Chen et al., 2012). A Phase 1 safety trial is now under way with infants, using stem cells from their own previously banked umbilical cord blood (“First FDA-Approved Study...,” 2012). It is important to note, however, that not everyone believes treatment of deafness is a good thing; for some nonhearing individuals, it implies that deafness is a disability, an idea they reject.

Locating Sounds With Binaural Cues The most obvious way to locate a sound is to turn your head until the sound is

loudest. This is not very effective, because the sound may be gone before the direction is located. Three additional cues permit us to locate sounds quickly and accurately, including those that are too brief to allow turning the head. All three of these cues are binaural, meaning that they involve the use of both ears; the brain determines the location of the sound based on differences between the sound at the two ears. These cues are useless when a sound source is in the median plane (equidistant from the person’s ears), but if the sound is slightly to one side, the stimulus will differ between the ears. Animals with ears that are very close together (such as mice) are at a disadvantage in locating sounds because the differences are so small. Grasshoppers and crickets have evolved a compensation for their small head size: Their auditory organs are on their legs, as far apart as possible. Nineteenth-century sailors used a novel application of this strategy when they needed to locate a distant foghorn: They listened through tubes attached to funnels at the ends of a long rod (Figure 9.16). The following paragraphs describe the three binaural differences: intensity, time of arrival, and phase. FIGURE 9.15 Areas Involved in Identifying Environmental Sounds. Recognized sounds activated the areas in yellow; unrecognized sounds activated other areas (blue), mostly in the right hemisphere. Notice that the activity occurs mostly in the ventral and frontal “what” pathway.

SOURCE: From “Human Brain Regions Involved in Recognizing Environmental Sounds,” by J. W. Lewis et al., 2004, Cerebral Cortex, 14, pp. 1008–1021, by permission of Oxford University Press.

How does the brain determine the locations of sounds? Binaural Cues When a sound source is to one side or the other, the head blocks some of the sound

energy. The sound shadow this creates produces a difference in intensity, so that the near ear receives a slightly more intense sound (Figure 9.17). Some of the neurons in the superior olivary nucleus (located in the brain stem) respond to differences in intensity at the two ears. Because low-frequency sounds tend to bend around obstacles, this cue works best when the sound is above 2000 or 3000 Hz. FIGURE 9.16 Sound Localizing Device Used by 19Th-Century Sailors. By listening through devices on a long rod, they effectively increased the distance between their ears and enhanced the binaural cues.

The second binaural cue for locating sounds is difference in time of arrival at the two ears. A sound that is directly to a person’s left or right takes about 0.5 millisecond to travel the additional distance to the second ear (see Figure 9.17 again); humans can

detect a difference in time of arrival as small as 10 microseconds (millionths of a second; Hudspeth, 2000), which means we can locate sounds even very near the midline of the head with good accuracy. We cannot distinguish such small intervals consciously, of course; this kind of precision involves automatic processing by specialized circuits, as we will see shortly. At low frequencies, a sound arriving from one side of the body will be at a different

phase of the wave at each ear, referred to as a phase difference (see Figure 9.18). As a result, at a given moment one eardrum will be pushed in more or less than the other or, at very low frequencies, one will be pushed in while the other is being pulled out. Some of the neurons in the superior olivary nucleus respond only when the inputs from the two ears are out of phase with each other. Above about 1500 Hz, a sound will have begun a new wave by the time it reaches the second ear, so phase difference is useless at higher frequencies. FIGURE 9.17 Differential Intensity and Time of Arrival as Cues for Sound Localization. The sound is reduced in intensity and arrives later at the distant ear.

A Brain Circuit for Detecting Time Differences Of the neural circuits for binaural sound localization, the one for time of arrival has

been studied most thoroughly. The circuit has been mapped in the barn owl, which is extremely good at sound localization; in fact, it can locate a mouse in darkness just from the sounds it makes rustling through the grass. The circuit is located in the nucleus laminaris, the avian (bird) counterpart of the mammalian superior olivary nucleus. Electrical recording has revealed the function of its coincidence detectors, neurons that fire most when they receive input from both ears at the same time (Carr & Konishi, 1990). Figure 9.19 is a simplified diagram of a coincidence detector

circuit, based on neuronal mapping in the barn owl. When the sound comes directly from the left side of the figure (Speaker A), Detector A will receive stimulation simultaneously from the two ears and will fire at a higher rate than the other detectors. This is because the length of the pathway from the right ear imposes a delay that equals the time required for the sound to travel through the air to the left ear. Likewise, Detector B will fire at its highest rate when the sound comes from Speaker B. When the sound source is equidistant from the two ears, Detector C is most active, and so on. Note that these relationships hold whether the sound comes from in front of the observer, behind, above, or below. This circuit is another example of the neural enhancement of small sensory differences that I referred to earlier. FIGURE 9.18 Phase Difference as a Cue for Sound Localization. (a) At lower frequencies, the sound reaches each ear at a different phase of the same pressure wave; the different stimulation of the two ears can be used to locate the sound’s direction. (b) At higher frequencies, the sound has begun a new wave by the time it reaches the second ear; the phase difference is useless for locating the sound.

These circuits can determine the direction of a sound, but that is not very useful by itself; it must be integrated with information from the visual environment and information about the position of the body in space. In Chapter 3, you learned that combining all this information is the function of association areas in the parietal lobes. So, unlike identifying sounds, locating sounds in space occurs in the dorsal “where” stream. The ultimate in sound localization is echolocation, a sort of sonar that bats,

dolphins, and some whales use to avoid obstacles and to detect prey and predators. Bats are so proficient that they can use the echoes of their ultrasonic chirps to capture insects while flying in total darkness. Humans also are able to use echolocation, which is the subject of the accompanying Application. If this were the end of our discussion of audition, it would also be the end of the

chapter, but obviously it is not. In humans, the most elaborate processing of auditory information occurs in language, which is our next topic. FIGURE 9.19 A Circuit for Detecting Difference in Time of Arrival at the Two Ears. The circuit’s arrangement compensates for the greater travel time to the more distant ear. Try tracing the flow of activity through this diagrammatic representation of the circuit to determine which detector will fire most when sound comes from each of the speakers. (The speakers are at the same horizontal level as the ears.)

SOURCE: Based on the results of Carr and Konishi (1990).

APPLICATION

I Hear a Tree Over There Some blind individuals have a remarkable ability to avoid obstacles in their paths, often without any awareness of how they do so. In 1749, the French philosopher Denis Diderot (1916) studied one of these adept individuals and concluded that he relied on air currents deflected by the obstacles. By the time Karl Dallenbach and his colleagues tackled the question at Cornell University, 14 theories had been proposed (Supa, Cotzin, & Dallenbach, 1944). One of their blind individuals could detect a wall 4 feet away and the other could do so at a distance of 17 feet. They concluded that the subjects accomplished this by listening to the sounds of their footsteps reflected by the obstacle as they approached. Their performance was still surprisingly good when they listened from another room through headphones as an experimenter carrying a

microphone walked toward the wall.

SOURCE: From “Neural Correlates of Natural Human Echolocation in Early and Late Blind Echolocation Experts,” by Thaler, L., Arnott, S. R., and Goodale, M. A., 2011, PLoS ONE 6(5), e20162, doi: 10.1371/journal.pone.0020162.

Blind individuals may use echolocation passively—simply listening for reflected sounds in their environment—or actively, by scuffing their feet or tapping a cane on the pavement, but these efforts can be thwarted by thick carpeting or a blanket of snow. Daniel Kish lost his eyes to cancer at the age of one, but he grew up surprisingly normally, even riding a bicycle to school (Kish, 2013). It wasn’t until he was 11 that a friend pointed out to him that he was using echolocation, clicking his tongue two to three times a second and listening for the echoes. As an adult, he bikes in busy traffic, travels by plane without assistance, and hikes in the woods, where he can recognize trees by the difference in the way the leaves and the trunks reflect the sounds. In a noisy environment, he simply clicks louder, his well-practiced ability to distinguish sound objects helping him to distinguish the echoes of his clicks. An fMRI study showed that blind individuals engage part of the visual cortex during echolocation, an area that is well suited for processing spatial information (see figure; Thaler, Arnott, & Goodale, 2011). Kish teaches others to use his technique, which he calls FlashSonar, and more than 500 people in 25 countries have received training through the organization World Access for the Blind (Kremer, 2012).

5 Daniel Kish

Concept Check Take a Minute to Check YourKnowledge and Understanding Trace an auditory stimulus from the pinna to the auditory neurons. Explain how, according to place theory, the frequency of sound is coded. How does the cochlea handle complex sounds?

Explain how the circuit for detecting difference in time of arrival of sounds at the two ears works.

Language Few would question the importance of language in human behavior. Keep in mind the meaning of the term language: It is not limited to speech but includes the generation and understanding of written, spoken, and gestural communication. Communication through language has important survival value and is inestimably important to human social relationships. A person who cannot communicate his or her thoughts to others suffers a high degree of isolation; one who cannot comprehend the communications of others is worse off still. These capabilities not only require learning; they also depend on specific structures of the brain, and damage to these structures can deprive a person of some or all of these functions. “

For humans, the most important aspect of hearing is its role in processing language. —A. J. Hudspeth

”

In 1861, the French physician Paul Broca reported his observations of a patient who for 21 years had been almost unable to speak. Tan, as he was known by the hospital staff because that was one of the few sounds he could make, died shortly after he came under Broca’s care. Autopsy revealed that Tan’s brain damage was located in the posterior portion of the left frontal lobe. After studying eight other patients, Broca concluded that aphasia —language impairment caused by damage to the brain— results from damage to the frontal area anterior to the motor cortex, now known as Broca’s area. Nine years later, a German doctor named Carl Wernicke identified a second site where damage produced a different form of aphasia. Located in the posterior portion of the left temporal lobe, this site is known as Wernicke’s area. See Figure 9.20 to locate Broca’s and Wernicke’s areas and the other structures to be discussed here. Most of our understanding of the brain structures involved in language comes from studies of brain-damaged individuals, so this is where we will start. FIGURE 9.20 Language-Related Areas of the Cortex.

Broca’s Area Broca’s aphasia is language impairment caused by damage to Broca’s area and

surrounding cortical and subcortical areas. The symptoms can best be understood by examining the speech of a stroke patient; as you read this interview, you will see why the disorder is also referred to as expressive aphasia. Doctor: Why are you in the hospital, Mr. Ford? Mr. Ford:

Arm no good. Speech... can’t say... talk, you see.

Doctor: What happened to make you lose your speech? Mr. Ford:

Head, fall, Jesus Christ, me no good, str, str... oh Jesus... stroke.

Doctor: I see. Could you tell me, Mr. Ford, what you’ve been doing in the hospital? Mr. Ford:

Yes, sure. Me go, er, uh, P.T. nine o’cot, speech... two times... read... wr... ripe, er rike, er, write... practice... getting better. (H. Gardner, 1975, p. 61)

Mr. Ford’s speech is not nearly as impaired as Tan’s; he can talk, and you can get a pretty good idea of his meaning, but he shows the classic symptoms associated with damage to Broca’s area. First, his speech is nonfluent; although well-practiced phrases such as “yes, sure” and “oh, Jesus” come out easily, his speech is halting, with many pauses between words. Second, he has trouble finding the right words, a symptom known as anomia (“without name”). He has difficulty with articulation; he mispronounces words, like “rike” for write. Finally, notice that his speech is agrammatic; it has content words (nouns and verbs) but lacks grammatical, or

function, words (articles, adjectives, adverbs, prepositions, and conjunctions). The hardest phrase for a Broca’s aphasic to repeat is “No ifs, ands, or buts” (Geschwind, 1972).

6 Aphasia Thelma was similarly impaired, but I had some enjoyable conversations when I

visited with her at the nursing home, mainly because I was willing to piece together her broken speech and to nod and smile when even that was impossible. She could usually manage only one or two words at a time: she showed me old photos of her parents, pointing and saying “Mother... Father.” But like Tan, who would occasionally express his frustration with the oath “sacre nom de Dieu!” (“holy name of God!”), Thelma would occasionally blurt out something meaningful. After a disagreement with an aide in which she was unable to express herself effectively, she exclaimed to me, “They can say anything they want to! I know everything. I just can’t say.” Broca believed that Broca’s aphasia impaired motor instructions for vocalizing words. But Mr. Ford was able to recite the days of the week and the letters of the alphabet, or to sing “Home on the Range,” and Thelma would entertain the group at dinner with a song she had composed before she was impaired. So vocalization is not lost, but the ability to translate information into speech patterns is compromised. The problem is “upstream” from speech in the brain, so reading and writing are

impaired as much as speech is. Comprehension is also as impaired as speech when the meaning depends on grammatical words. For example, the patient can answer questions like “Does a stone float on water?” but not the question “If I say, ‘The lion was killed by the tiger,’ which animal is dead?” (H. Gardner, 1975).

What are the differences between Broca’s aphasia and Wernicke’s aphasia? Wernicke’s Area In Wernicke’s aphasia, the person has difficulty understanding and producing

spoken and written language. This is often called receptive aphasia, but that term is misleading because the same problems with understanding language also show up in producing it. For example, the person’s speech is fluent but meaningless. A patient asked to describe a picture of two boys stealing cookies behind a woman’s back said, “Mother is away here working her work to get her better, but when she’s looking the two boys looking in the other part. She’s working another time” (Geschwind, 1979). This meaningless speech is called word salad, for obvious reasons.

What is the Wernicke-Geschwind model? Because the speech of the Wernicke’s patient is articulate and has the proper

rhythm, it sounds normal to the casual listener. The first time I met a person with Wernicke’s aphasia, I was knocking on the social worker’s door at the nursing home,

and I thought it was because my thoughts were elsewhere that I failed to understand one of the residents when she spoke. But then my “Pardon me” elicited “She’s in the frimfram,” and I realized the problem was hers rather than mine. I responded with a pleasantry, and she gave a classic word-salad reply. That began a long relationship of conversations, in some ways as enjoyable as those with Thelma. The difference was that neither of us ever understood the other; another difference was that it did not matter, because she seemed strangely unaware that anything was amiss. The Wernicke-Geschwind Model Wernicke suggested, and Norman Geschwind later elaborated on, a model for how

Broca’s area and Wernicke’s area interact to produce language (Geschwind, 1970, 1972, 1979). The model is illustrated in Figure 9.21 and in the following examples. Answering a verbal question involves a progression of activity from the auditory cortex to Wernicke’s area, and then to Broca’s area. Broca’s area then formulates articulation of the verbal response and sends the result to the facial area of the motor cortex, which produces the speech. If the response is to be written, Wernicke’s area sends output to the angular gyrus instead, where it elicits a visual pattern. When a person reads aloud, the visual information is translated into the auditory form by the angular gyrus and then passed to Wernicke’s area, where a response is generated and sent to Broca’s area. The idea that visual information must be converted to an auditory form for processing arose in part from the fact that language evolved long before writing was invented, and Wernicke’s area was believed to operate in an auditory fashion. FIGURE 9.21 The Wernicke-Geschwind Model of Language. Verbal input arrives in the auditory cortex and then travels to Wernicke’s area for interpretation. Written input arrives there via the visual cortex. If a verbal response is required, Wernicke’s area sends output to Broca’s area for articulation of the response, and the facial area of the motor cortex produces the speech.

SOURCE: Adapted from “Specializations of the Human Brain,” by N. Geschwind, Scientific American, 241(9), pp. 180–199. This system has long been the primary model for how language operates. It is

relatively simple and seems to make sense of the various aphasias. Modern imaging techniques have confirmed the participation of Broca’s and Wernicke’s areas in language; one study has actually traced the progression of activity while subjects produced a verbal response to written material, from the visual cortex to Wernicke’s area and then to Broca’s area (Dhond, Buckner, Dale, Marinkovic, & Halgren, 2001). However, there are problems. One is that language functions are not limited to Broca’s and Wernicke’s areas; damage to the basal ganglia, thalamus, and subcortical white matter also produce aphasia (Hécaen & Angelergues, 1964; Mazzocchi & Vignolo, 1979; Naeser et al., 1982). Broad cortical areas also play an important role, though possibly only because they are storage sites for information. For example, using nouns (naming objects) produces activity just below the auditory cortex and Wernicke’s area (H. Damasio, Grabowski, Tranel, Hichwa, & Damasio, 1996). Using verbs (describing what is happening in a picture) is impaired by damage to the left premotor cortex, which sends output to the motor cortex. This area is also activated while naming tools and by imagining hand movements (A. Martin, Wiggs, Ungerleider, & Haxby, 1996). Apparently when tool names are learned, they are stored near the brain structure that would produce the action. FIGURE 9.22 Frequency of Language Deficits Resulting From Damage in Each Area. Language functions are more widely distributed than originally thought.

SOURCE: Based on Hécaen and Angelergues (1964). Electrical stimulation studies (Mateer & Cameron, 1989; Ojemann, 1983) and

studies of brain damage (Hécaen & Angelergues, 1964) have also shown that the various components of language functioning are scattered throughout all four lobes (see Figure 9.22). This does not mean that there is no specialization of the cortical areas; for example, articulation errors are still more likely to result from frontal damage and comprehension problems from damage in the temporal lobes (Hécaen & Angelergues; Mazzocchi & Vignolo, 1979). However, it does mean that each function depends on a network of interconnected structures rather than a single structure. Other challenges to classic theory include studies that question, for example, how the language structures are interconnected (Dick & Tremblay, 2012) or indicate that spoken words are processed anterior to the auditory cortex rather than in Wernicke’s area (DeWitt & Rauschecker, 2012). The Wernicke-Geschwind view has turned out to be too simple, but it has also helped researchers organize their thinking about language and has generated volumes of research—which, after all, is how we make scientific sense of our world. Reading, Writing, and Their Impairment Although aphasia affects reading and writing, these functions can be impaired

independently of other language abilities. Alexia is the inability to read, and agraphia is the inability to write. Presumably, they are due to disruption of pathways in the angular gyrus that connect the visual projection area with the auditory and visual association areas in the temporal and parietal lobes (see Figure 9.20 again). The PET scans in Figure 9.23 show that activity increases in this area during reading.

What problems have been found in the brains of people with dyslexia?

FIGURE 9.23 Pet Scans During Reading. Viewing letterlike forms (a) and strings of consonants (b) did not activate the area between the primary visual cortex and language areas, but reading pronounceable nonwords (c) and real words (d) did.

SOURCE: From “Activation of Extrastriate and Frontal Cortical Areas By Visual Words and Word-Like Stimuli,” S. E. Petersen, P. T. Fox, A. Z. Snyderand, and M. E. Raichle, Science, 249, pp. 1049–1044. Reprinted with permission from AAAS. Reading and writing are also impaired in learning disorders. The most common

learning disorders are dyslexia, an impairment of reading; dysgraphia, difficulty in writing; and dyscalculia, a disability with arithmetic. Because of its importance and the amount of research that has been done, we will focus on dyslexia. Dyslexia can be acquired, through damage, but its origin is more often developmental. Developmental dyslexia is partially genetic, with an estimated heritability between 40% and 60% (Gayán & Olson, 2001). Of the seven most reliably identified genes (Scerri & Schulte-Körne, 2010), four are involved in neuron guidance and migration, and two contribute to cell functioning. The implications of impaired brain development are far-reaching. The public is

most familiar with the visual-perceptual symptoms of dyslexia: The individual reads words backwards (“now” becomes “won”), confuses mirror-image letters (p and q, b and d), and has trouble fixating on printed words, which seem to move around on the page. Some researchers have attributed this to slowness in responding to low-contrast, rapidly changing visual stimuli (Livingstone, Rosen, Drislane, & Galaburda, 1991); presumably, words jump around and reverse themselves because the reader has difficulty detecting and correcting for rapid, unintentional eye movements, which

affects both reading performance and learning to read in the first place. However, individuals with dyslexia also have trouble tracking the frequency and

amplitude changes that distinguish speech sounds from each other (J. Stein, 2001); supposedly this impairs the dyslexic’s ability to associate speech sounds with letters when learning to read and explains his or her slowness in reading nonwords. According to the phonological hypothesis, individuals with dyslexia have an impairment in processing, storing, and/or retrieving phonemes. Phonemes are small units of speech sound that distinguish one word from another, for example, the beginning sounds that distinguish book, took, and cook. When a group of dyslexic college students was administered a battery of tests, 10 had auditory deficits and 2 had a visual function deficit, but all 16 suffered from a phonological deficit (Ramus et al., 2003). Almost all researchers in the field now agree that phonological impairment is the crucial problem, and even suggest that at least some of the visual processing problems are a consequence, rather than a cause, of reading impairment (Habib, 2003; Olulade, Napollello, & Eden, 2013). FIGURE 9.24 Developmental Anomalies in the Brain of a Person With Dyslexia. (a) Cells in the left planum temporale of a normal brain. (b) In the dyslexic brain, cells lack the normal layering and arrangement in columns, and some of the cells have migrated into the outermost cortical layer, where they would not ordinarily be found. (Note the similarity with the fetal alcohol brain in Chapter 3.)

SOURCE: “Neurology of Developmental Dyslexia,” by A. M. Galaburda, 1993, Current Opinion in Neurobiology, 3, pp. 237–242. With permission from Elsevier. These difficulties are accompanied by a number of functional and structural

irregularities in the brain. Kindergartners who had a delayed EEG response when a string of repeated auditory or speech sounds was interrupted by a novel sound were more likely to have reading difficulties in the fifth grade (Maurer et al., 2009). In addition, kindergartners who scored poorly on a phonological awareness test used to measure risk for dyslexia had a smaller left arcuate fasciculus, which connects

Wernicke’s area with Broca’s area (Saygin et al., 2013). The planum temporale, where Wernicke’s area is located, averages about 13% larger in the left hemisphere than the right in nondyslexics, but is equal in the two hemispheres in people with dyslexia (Bloom, Garcia-Barrera, Miller, Miller, & Hynd, 2013). In at least some dyslexic brains, many of the neurons in the left planum temporale lack the usual orderly arrangement, and some of them have migrated past their normal destination and into the outermost layer of the cortex (Figure 9.24; Galaburda, 1993). These brain anomalies suggest that at least some of the origins of developmental dyslexia are prenatal.

7 Dyslexia The incidence of dyslexia is twice as great in some cultures as in others; this seems

to suggest a cultural explanation for the disorder, but in fact the discrepancies support a brain-based phonological hypothesis. Italian and Spanish are phonologically simpler languages, with an almost one-to-one correspondence between phonemes and spelling. Predictably, dyslexia is much rarer in Italy and Spain than in French- and English-speaking countries, where the same spelling may have several pronunciations (cough, tough, dough, slough). PET imaging shows that Italians suffering from dyslexia have the same brain impairments seen in French and English speakers (see Figure 9.25; Paulesu et al., 2001). FIGURE 9.25 Activation of Language Areas in Individuals With Dyslexia From Three Countries. Here (a) shows activation due to reading in control subjects; (b) shows activation due to reading in dyslexics; (c) indicates the area significantly less activated in dyslexics than in control subjects; and (d) shows that dyslexia is associated with the same deficiency in individuals from Italy, France, and the United Kingdom.

SOURCE: From “Dyslexia: Cultural Diversity and Biological Unity,” by E. Paulesu, J.-F. Démonet, F. Fazio, E. McCrory, V. Chanoine, N. Brunswick, S. F. Cappa, G. Cossu, M. Habib, C. D. Frith, and U. Frith, Science, 291, pp. 2165–2167. Reprinted with permission from AAAS. Mechanisms of Recovery From Aphasia There is usually some recovery from acquired aphasia during the first 1 or 2 years,

more so for Broca’s aphasia than for Wernicke’s aphasia (I. P. Martins & Ferro, 1992). Initial improvement is due to reduction of the swelling that often accompanies brain damage rather than to any neural reorganization. Just how the remaining recovery occurs is not well understood, but it is a testament to the brain’s plasticity. The right hemisphere can take over language functions following left-hemisphere

damage, as long as the injury occurs early in life. A 2-year-old girl had a left- hemisphere stroke (yes, it does occur); her language was impaired, but she developed normal language capability by the age of 7. Then at the age of 56 she had a right- hemisphere stroke, which resulted in a second aphasia from which she had only minimal recovery (Guerreiro et al., 1995). Right-hemisphere language was confirmed by fMRI in all five individuals of a group who had been born with inadequate blood supply to the language areas of the left hemisphere (Vikingstad et al., 2000). Rasmussen and Milner (1977) used the Wada technique and electrical stimulation to determine the location of language control in patients before removing lesioned tissue that was causing epileptic seizures. (The Wada technique involves anesthetizing one hemisphere at a time by injecting a drug into each carotid artery; when the injection is into the language-dominant hemisphere, language is impaired.) Individuals whose left-hemisphere injury occurred before the age of 5 were more likely to have language

control in the right hemisphere, supporting the hypothesis of right-hemisphere compensation. Patients whose left-hemisphere damage occurred later in life more often continued to have language control in the left hemisphere; there was, however, evidence in some cases that control had shifted into the border of the parietal lobe. Since language functions are scattered widely in the left hemisphere, perhaps the compensation involves enhancing already existing activity rather than establishing new functional areas. The ability of the right hemisphere to assume language functions may be partly due

to the fact that it normally makes several contributions to language processing. The most obvious right-hemisphere role in language is prosody, the use of intonation, emphasis, and rhythm to convey meaning in speech. An example of one aspect of prosody is the difference between “You put the cat out when it’s freezing” spoken as a statement and spoken as an emotion-filled question. We saw in Chapter 8 that people with right-hemisphere damage have trouble understanding emotion when it is indicated by speaking tone and in producing emotional speech the same way. An fMRI study found that right-hemisphere activity increased while individuals detected angry, happy, sad, or neutral emotions from the intonation of words (Buchanan et al., 2000). The right hemisphere also is important in understanding information from language

that is not specifically communicated by the meaning of the words, such as when the meaning must be inferred from an entire discourse or when the meaning is figurative rather than literal. For example, interpreting the moral of a story activates the right hemisphere (Nichelli et al., 1995), as does understanding a metaphor or determining the plausibility of statements such as “Tim used feathers as paperweights” (Bottini et al., 1994). Interestingly, the right-hemisphere regions involved in all these activities correspond generally to the structures we have identified in left-hemisphere language processing. “

Man has an instinctive tendency to speak, as we see in the babble of our young children.

—Charles Darwin

” A Language-Generating Mechanism? When Darwin suggested that we have an instinctive tendency to speak, what he

meant was that infants seem very ready to engage in language and can learn it with minimal instruction. Children learn language with such alacrity that by the age of 6 they understand about 13,000 words, and by the time they graduate from high school, their working vocabulary is at least 60,000 words (Dronkers, Pinker, & Damasio,

2000). This means that children learn a new word about every 90 waking minutes. The hearing children of deaf parents pick up language just about as fast as children with hearing parents (Lenneberg, 1969), in spite of minimal learning opportunities. Not only are preadolescent children particularly sensitive language learners, but they are also believed to be the driving force in the development of creole language (which combines elements of two languages, allowing communication between the cultures). In Nicaragua, children in the school for the deaf, where sign language is not taught, have devised their own sign language with unique gestures and grammar (Senghas, Kita, & Özyürek, 2004). FIGURE 9.26 Babies of Signing Parents Babble With Their Hands. Unlike the meaningless hand movements of other infants (which they also make at other times), their babbling is similar to their parents’ signing. Babbling hand movements are slower and restricted to the space in front of the infants’ bodies, and they correspond to the rhythmic patterning of adult sign-syllables.

SOURCE: From “Language Rhythms in Baby Hand Movements,” by L. A. Petitto, S. Holowka, L. E. Sergio, and D. Ostry, Nature, 413, pp. 35–36. Photo courtesy of Dr. Laura-Ann Petitto, University of Toronto. Noam Chomsky (1980) and later Steven Pinker (1994) interpreted children’s

readiness to learn language as evidence of a language acquisition device, a part of the brain hypothesized to be dedicated to learning and controlling language. Not all researchers agree with this idea, but most accept that there are biological reasons why language acquisition is so easy. This ease cuts across forms of language. For example, both hearing and deaf infants of signing parents babble in hand movements (Figure 9.26); the deaf infants’ babbling proceeds into signing through the same stages and at about the same pace that children of speaking parents learn vocal language (Petitto,

Holowka, Sergio, & Ostry, 2001; Petitto & Marentette, 1991). The researchers suggest that the ease of children’s language acquisition is due to a brain-based sensitivity to rhythmic language patterns, a sensitivity that does not depend on the form of the language. Innate Brain Specializations More than 90% of right-handed people are left-hemisphere dominant for language.

This is also true for two thirds to three quarters of left-handers; the remainder are about equally divided between right-hemisphere dominant and mixed (Knecht et al., 2000; D. W. Loring et al., 1990; B. Milner, 1974). In the large majority of autopsied brains, Broca’s area is larger (Falzi, Perrone, & Vignolo, 1982), and the lateral fissure (Yeni-Komshian & Benson, 1976) and planum temporale (Geschwind & Levitsky, 1968; Rubens, 1977; Wada, Clarke, & Hamm, 1975) are longer in the left than in the right hemisphere. These differences are not the result of usage. By the 20th week of gestation, the left temporal lobe is already beginning to enlarge relative to the right (Kasprian et al., 2010), and the left planum temporale is larger by the 29th week (Wada et al., 1975). At birth or shortly after, speech causes a greater increase in cerebral blood flow than nonspeech sounds, speech sounds activate the same left- hemisphere language areas as in adults, and sentence melody activates the right hemisphere (reviewed by Friederici, 2006). In the News makes the case that the brain is so well equipped for language acquisition that the child begins learning the patterns of speech even before birth.

8 Whistle and Click Languages Location of Other Languages Additional evidence for a language acquisition device comes from studies of

individuals who communicate with sign language. Left-hemisphere damage impairs sign-language ability more than right-hemisphere damage (Hickok, Bellugi, & Klima, 1996), and communicating in sign language activates the classical left-hemisphere language areas (Figure 9.27; Neville et al., 1998; Petitto et al., 2000). This was true of both congenitally deaf and normally hearing signers (all of whom had used sign language from infancy), but the finding is especially interesting in the deaf individuals, because it cannot be the result of the brain simply using pathways already established by an auditory language. It is also interesting because Wernicke’s area has traditionally been considered to be auditory in nature, which required the conversion of written words into an auditory form. Either the posterior language area is inherently more versatile than some theorists have thought, or the area underwent reorganization during infancy that enabled it to handle visual language. Either way, language seems to be a specialized capability of a limited subset of brain structures. But what happens if a person learns a second language after childhood, when the

brain is less plastic; will the brain then recruit other areas to handle the task? Two

imaging studies indicate that this does happen, to some extent. In the first study, bilingual individuals silently “described” events from the previous day in each of their two languages; the languages activated separate areas in the frontal lobes, with centers that were 4.5 to 9 mm apart in different individuals. This was not true of subjects who learned their second language simultaneously with the first (K. H. S. Kim, Relkin, Lee, & Hirsch, 1997). The second study produced similar results in the temporal lobe when subjects heard and read words in their two languages (Figure 9.28; Simos et al., 2001). This separation is so distinct that capability can be impaired in one of the languages while the other is unaffected (Gomez-Tortosa, Martin, Gaviria, Charbel, & Auman, 1995; M. S. Schwartz, 1994). A colleague who is originally from Lebanon told me an interesting story about his mother. She lives in the United States, and she was fluent in English until a stroke impaired her ability to speak English, but not Arabic. Her nearby family members spoke only English, so when they needed to talk with her they had to telephone a relative in another city to translate! These observations are not as inconsistent with the hypothesis of a single language acquisition device as they might seem; in both the Kim et al. (1997) and the Simos et al. (2001) studies, the second-language locations were in the same area as Broca’s and Wernicke’s areas, respectively. FIGURE 9.27 Language Areas in Hearing and Deaf Individuals. (a) fMRI results while hearing subjects read written English. (b) Activation in subjects deaf from birth while processing sign language. Yellow areas were significantly activated and those in red more so.

SOURCE: From “Cerebral Organizations for Language in Deaf and Hearing Subjects: Biological Constraints and Effects of Experience,” by H. J. Neville et al., 1998, Proceedings of the National Academy of Sciences, USA, 95, pp. 922–929. © 1998 National Academy of Sciences, U.S.A.

Learning Language Starts Before Birth

For the past few decades, researchers have been seeing evidence that children begin to learn the nuances of their culture’s language even before birth. For example, American newborns react to Swedish vowel sounds as unfamiliar, and Swedish babies respond the same way to English vowels. In the past, these studies have relied on the babies’ behaviors, such as sucking on a pacifier wired to a computer to hear more of the new sounds. Now a new study has manipulated the learning stimulus experimentally during gestation and then measured

brain activity after birth to confirm that learning in the womb gives babies a real jump on language acquisition (reported in Skwarecki, 2013). Several times a week during the final months of pregnancy, expectant mothers

played a recording of a voice repeating the nonword tatata; occasionally there would be a variation in the middle syllable, either a difference in pitch or a change in the vowel sound (tatota). By the time of birth, the baby had heard the pseudoword on average more than 25,000 times; infants in a control group did not hear the recordings. A few days after birth, the researchers fitted the infants with EEG electrodes and presented the pseudowords again. Event-related potentials showed that only the trained infants detected the frequency changes, and they were more responsive to the vowel changes. The trained infants also responded to variations they had not heard—changes in vowel intensity and lengthening of the vowel duration. These findings suggested that the infants’ enhanced prenatal experience had sensitized them to additional aspects of language.

FIGURE 9.28 Brain Areas Activated by Different Languages in Bilingual Individuals. Green circles represent areas activated by listening to English, and yellow circles indicate activation while listening to Spanish. These images are from different subjects, selected to represent the variability among 11 subjects. Although the patterns are different, in every case the languages activate separate areas.

SOURCE: From “Mapping of Receptive Language Cortex in Bilingual Volunteers by Using Magnetic Source Imaging,” by P. G. Simos, E. M. Castillo, J. M. Fletcher, D. J. Francis, F. Maestu, J. I. Breier, W. W. Maggio, and A.C. Papanicolaou, 2001, Journal of Neurosurgery, 95, pp. 76–81.

We still cannot say that the language structures evolved specifically to serve language functions, however. You will see in the next section that some primates show similar enlargements in the left hemisphere, and their possession of language is questionable at best. Another reasonable interpretation of these data is that the structures evolved to handle rapidly changing information and fine discriminations, which language in its various forms requires. Another view is that the language areas are primarily specialized for different aspects of learning: the frontal area for “procedural” or how-to learning that coincides with the rules of grammar and verb tenses, and the temporal area for “declarative” or informational learning and, thus, the storage of word meanings and information about irregular word forms (M. T. Ullman, 2001). Even if these structures have been “borrowed” by language and the concept of a dedicated language acquisition device isn’t meaningful, it is still clear that the human brain is uniquely well fitted for creating as well as learning language. We will explore the possible evolutionary roots of this ability in the context of animal language. Language in Nonhumans Research has refuted most of humans’ claims to uniqueness, including tool use, tool

making, and self-recognition. Determining whether humans have exclusive ownership of language has been more difficult. Animal language intrigues us both because we’re curious whether we have any company “at the top” and because we want to trace the evolutionary roots of language. Because language leaves no fossils behind, the origin of language is “a mystery with all the fingerprints wiped off” (Terrence Deacon, quoted by Holden, 2004a). Without this evidence, an alternative is to look to the behavior and brains of our nonhuman relatives. The rationale behind animal language research is that any behavior or brain mechanism we share with genetically related animals must have originated in common ancestors. Although dolphins, whales, and gorillas have been the subjects of research, the major contender for a copossessor of language has been the chimpanzee. The reason is that we and chimpanzees diverged from common ancestors a relatively recent 5 million years ago and we still share between 95% and 99% of our genetic material (R. J. Britten, Rowen, Williams, & Cameron, 2003; M.-C. King & Wilson, 1975). A major obstacle has been deciding what we mean by language. Linguists agree

that the vocalizations animals use to announce the availability of food or the presence of danger are only signals and have little to do with language. Even the human toddler’s request of “milk” may initially be just a learned signal to indicate hunger and, like the monkey’s alarm call, indicate no language understanding. As you will see in the following discussion, some of the results obtained in language research with animals are equally difficult to interpret.

What skills have chimps achieved in language studies?

An early study attempted to teach the home-reared chimpanzee Viki to talk, but after 6 years she had learned only “mama,” “papa,” and “cup” (Hayes & Hayes, 1953; Kellogg, 1968). Later, researchers concluded that chimpanzees lack the larynx for forming word sounds and, noting their tendency to communicate with a number of gestures, turned to American Sign Language. Over a 4-year period, the chimpanzee Washoe learned to use 132 signs; she was able to request food or to be tickled or to play a game, and she would sign “sorry” when she bit someone (Fouts, Fouts, & Schoenfeld, 1984). But critics argued that no chimpanzee had learned to form a sentence; they concluded that expressions such as “banana me eat banana” are just a “running-on” of words, and Washoe’s signing “water bird” in the presence of a swan was not the inventive characterization of “a bird that inhabits water” but the separate identification of the bird and the water it was on (Terrace, Petitto, Sanders, & Bever, 1979). However, animal language researchers received new encouragement when

Washoe’s adopted son, Loulis, learned 47 signs from her and three other chimps. The chimps regularly carried on sign-language conversations among themselves, most requesting hugs or tickling, asking to be chased, and signing “smile” (Fouts et al., 1984). Results have been more remarkable with bonobos, a near relative of chimpanzees. When Duane Rumbaugh and Sue Savage-Rumbaugh trained the bonobo Mutata to communicate by pressing symbols on a panel, her son Kanzi spontaneously began to communicate with the symbols and eventually learned 150 of them without any formal instruction (Figure 9.29; S. Savage-Rumbaugh, McDonald, Sevcik, Hopkins, & Rubert, 1986; S. Savage-Rumbaugh, 1987). Kanzi uses the board to request specific food items or to be taken to specific locations on the 55-acre research preserve, asks a particular person to chase a specific other person, and responds to similar requests from trainers. His communication skills have been estimated at the level of a 2-year-old child (Savage-Rumbaugh et al., 1993). Irene Pepperberg (1993) emphasized concept learning with her African gray parrot, Alex, but his communication skills turned out to be equally interesting. Using speech, Alex could tell his trainer how many items she was holding, the color of an item, or whether two items differed in shape or color. He also could respond to complex questions, such as “What shape is the green wood?”

9 Animal Language So do we share language ability with animals? The behavior of animals like Loulis,

Kanzi, and Alex requires us to rethink our assumptions about human uniqueness, but no animal has yet turned in the critical language performance, and as far as we know, no animals in the wild have developed anything resembling a true language. But what some researchers do see in the animals’ performance is evidence of evolutionary foundations of our language abilities (Gannon, Holloway, Broadfield, & Braun,

1998). FIGURE 9.29 Language Research With Chimpanzees and Bonobos. (a) A researcher converses with a chimp using American Sign Language. (b) A bonobo communicates through the symbol board.

SOURCES: (a) © Susan Kuklin/Science Source. (b) © Frans Lanting/Corbis. Neural and Genetic Antecedents An approach of some researchers has been to determine whether other animals

share with us any of the brain organization associated with human language. The results have been intriguing. In the chimpanzee, as with humans, there is a greater ratio of white to gray matter in the left hemisphere than in the right (Cantalupo et al., 2009), and the left lateral fissure is longer and the planum temporale is larger (Gannon et al., 1998; Yeni-Komshian & Benson, 1976). Japanese macaque monkeys respond better to calls of their own species when the recorded calls are presented through headphones to the right ear (and, therefore, primarily to the left hemisphere) than when they are presented to the left ear. There is no left-hemisphere advantage for the (nonmeaningful) calls of another monkey species (M. R. Petersen, Beecher, Zoloth, Moody, & Stebbins, 1978). Dolphins and the Rumbaughs’ chimps Austin and Sherman responded more quickly when symbols or command gestures were presented to their left hemisphere (Hopkins & Morris, 1993; Morrel-Samuels & Herman, 1993). Finally, lesions on the left side of the canary brain render its attempts at song unrecognizable, while birds with right-side lesions continue to sing nearly as well as intact birds (Nottebohm, 1977).

Do other animals share our brain structures for language? Many researchers consider hand and face gestures to be more analogous to human

speech than animal vocalizations are. They think that our ancestors communicated this way, aided in forming this simple but effective prelanguage by emerging language structures (Holden, 2004a; MacNeilage, 1998). Chimpanzees, our best living window into that ancestral past, communicate primarily through hand and face gestures (Figure 9.30), and one third of the hand gestures used by chimpanzees in the wild are similar to those used by humans, such as beckoning to an individual or waving an

individual away (E. M. Roberts, Vick, Roberts, Buchanan-Smith, & Zuberbühler, 2012). These researchers also believe that the ability to imitate gestures was critical to the development of language in humans; in fact, research indicates that children initially learn speech not by imitating sounds but by imitating the actions of the mouth (Goodell & Studdert-Kennedy, 1993), and the amount of gesturing at 14 months predicts vocabulary size at 54 months (Rowe & Goldin-Meadow, 2009). Now language theorists think that they have identified the mechanism for the imitative development of language in mirror neurons, which you learned about in Chapter 8. FIGURE 9.30 Chimpanzees Communicating With Face and Hand Gestures.

SOURCE: © Nigel J. Dennis/Science Source. Mirror neurons were first discovered in the area of the monkey brain that

corresponds to Broca’s area; they respond not only to monkeys’ hand movements but also to communicative mouth gestures such as lip smacking (Ferrari, Gallese, Rizzolatti, & Fogassi, 2003). In humans, they are located in Broca’s area and Wernicke’s area and in the parietal lobe (Grèzes, Armony, Rowe, & Passingham, 2003; Holden, 2004a). Human mirror neurons are most active during imitation of another’s movement (Iacoboni et al., 1999), which has encouraged the belief that they figure prominently in imitative ability and, thus, in the evolution of language (Figure 9.31). However, the fact that we share mirror neurons with monkeys and chimpanzees does not imply that monkeys and chimpanzees also share our language abilities. In fact, the evolutionary clues we do have suggest that language developed well after the split that led to humans and chimpanzees (Holden, 2004a). Whatever brain foundations of language we share with chimpanzees required extensive refinement, such as expansion of the brain, including the language areas; migration of the larynx lower in the throat, which increased vocalization range; and the development of imitative ability, which is poor in nonhuman primates (Holden, 2004a). FIGURE 9.31 Overlap Between Language Areas and Areas Involved in Imitation. Broca’s and Wernicke’s areas are shown in yellow on a model of a human brain; the

overlapping brown areas are also active during imitation of acts by others. Red indicates additional locations involved in imitation.

SOURCE: Image provided courtesy of Dr. Marco Iacoboni. From “The Origin of Speech,” by C. Holden, 2004, Science, 303, p. 1318. Suggesting that language is a product of evolution means, of course, that genes are

involved. KIAA0319, one of the genes contributing to dyslexia, also plays a role in the development of speech and language (M. L. Rice, Smith, & Gayán, 2009), and CNTNAP2 and ATP2C2 have been implicated in language impairment (Newbury, Fisher, & Monaco, 2010; Vernes et al., 2008). But the most researched and best understood language gene is FOXP2; a mutation of this gene results in reduced gray matter in Broca’s area, along with articulation difficulties, problems identifying basic speech sounds, grammatical difficulty, and trouble understanding sentences (Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Pinker, 2001; Vargha-Khadem, Gadian, Copp, & Mishkin, 2005). We also share this gene with chimpanzees, but the human version differs in two apparently very important amino acids. The human version has been found in Neanderthal remains (Krause et al., 2007), and other fossil and archaeological evidence suggests to some that the Neanderthals had the capacity for language. According to the researchers, the Neanderthals’ increased nerve supply (assessed from the size of the bony pathways) enabled the voluntary control of the tongue and respiratory muscles necessary for speech; their auditory system specialized them for sensitivity in the speech range; and the spread of complex tool designs implied the imitative ability involved in learning speech (Dediu & Levinson, 2013). While the evidence is circumstantial and the interpretation subjective, it does appear that modern language has roots in the far distant past. However, not all of the innovation has been in the human ancestral line, as the accompanying In the News reveals.

The Link Between Human Language and Birdsong

Concept Check

Researchers often look to songbirds for parallels with human language, and with good reason. Most animals are born already knowing the calls they will need in life, but songbirds share with humans and a few other species the ability to imitate and learn new vocalizations. They also share similar interconnected brain areas, for example, one involved in speaking/singing that is connected to brain stem circuits that control the muscles of the voice box. Animals incapable of vocal learning don’t have such connections.

Eric Jarvis and his colleagues at Duke University Medical Center have been looking for a genetic reason humans and songbirds are so different from most other animals. At the 2013 annual meeting of the American Association for the Advancement of Science, they reported that they have found similar patterns of expression in 40 genes in the vocalization area in songbirds and humans and another 40 genes with similar expression patterns in areas involved in imitation. Again, these patterns weren’t seen in other birds. It would be tempting to try to trace vocal learning back to a common ancestor,

but humans and birds went their separate evolutionary ways 300 million years ago, so this is almost certainly a case of independent evolution. Birds and humans are more similar in genes and physiology than they are different, so it’s not surprising that they would arrive at similar solutions to the same problem. What makes this information interesting is that it gives us a new window for understanding the language process, along with additional possibilities for genetic remedies for speech disorders. Jarvis believes the crucial moment in language development occurred when genetic mutations created a new pathway from the motor learning region to the vocal organs. He hopes to confirm this by identifying the specific genes and then using them to endow another animal—preferably a chimpanzee— with the same vocal learning capability.

10 Speech and Singing Birds

Take a Minute to Check Your Knowledge and Understanding

In what ways is the Wernicke-Geschwind model correct and incorrect? What are the different roles of the left and right hemispheres in language (in most people)? (See Chapter 8 for part of the answer.)

What clues are there in animal research for the possible origins of human language?

In Perspective My guess is that at the beginning of this chapter you would have said that vision is the most important sense. Perhaps now you can appreciate why Helen Keller thought her deafness was a greater handicap than her blindness. Hearing alerts us to danger, brings us music, and provides for the social interactions that bind humans together. Small wonder that during evolution, the body invested such resources in the intricate mechanisms of hearing. Hearing has important adaptive functions with or without the benefit of language,

but from our vantage point as language-endowed humans, it is easy to understand Hudspeth’s (2000) claim that audition’s most important role is in processing language. The person who is unable to talk is handicapped; the person who is unable to understand and to express language is nearly helpless. No wonder we put so much research effort into understanding how language works. One of the most exciting directions language research has taken has involved

attempts to communicate with our closest nonhuman relatives. Whether they possess language capabilities depends on how we define language. It is interesting how the capabilities we consider most characteristic of being human—such as language and consciousness—are the hardest to define. As so often happens, studying our animal relatives, however distant they may be, helps us understand ourselves. Summary • Sensation requires a receptor that is specialized for the particular kind of stimulus. Beyond sensation, the brain carries out further analysis, called perception.

Hearing • The auditory mechanism responds mostly to airborne vibrations, which vary in frequency and intensity.

• Sounds are captured and amplified by the outer ear and transformed into neural impulses in the inner ear by the hair cells on the basilar membrane. The signal is then transmitted through the brain stem and the thalamus to the auditory cortex in each temporal lobe.

• Frequency discrimination depends mostly on the basilar membrane’s differential vibration along its length to different frequencies, resulting in neurons from each location carrying frequency-specific information to the brain. At lower frequencies, neurons fire at the same rate as the sound’s frequency; it is possible that intermediate frequencies are represented by neurons firing in volleys, though research has not indicated that the brain utilizes this information.

• Although the cochlea is specialized for responding to pure tones, the basilar membrane apparently performs a Fourier analysis on complex sounds, breaking down a sound into its component frequencies.

• When different sounds must be distinguished from each other, stimulation from the brain probably adjusts the sensitivity of the hair cells to emphasize one sound at the expense of others. Selective attention also results in differential activity in areas of the cortex.

• Locating sounds helps us approach or avoid sound sources and to attend to them in spite of competition from other sounds.

• The brain has specialized circuitry for detecting the binaural cues of differences in intensity, time of arrival, and phase at the two ears.

Language • Researchers have identified two major language areas in the brain, with Broca’s area involved with speech production and grammatical functions and Wernicke’s area with comprehension.

• Damage to either area produces different symptoms of aphasia, and damage to connections with the visual cortex impairs reading and writing. Developmental dyslexia may involve planum temporale abnormalities, reduced activity in the posterior language area, or deficiencies in the auditory and visual pathways.

• Although damage to the left frontal or temporal lobes is more likely to produce the expected disruptions in language, studies have shown that control of the various components of language is distributed across the four lobes.

• Although some animals have language-like brain structures and have been taught to communicate in simple ways, it is controversial whether they possess true language. Their study suggests some possible evolutionary antecedents of language. Several genes with language functions have been identified, the best known being a variant of FOXP2, which was shared by Neanderthals. ■

Study Resources

For Further Thought • Write a modified Wernicke-Geschwind theory of language control, based on later evidence.

• Would you rather give up your hearing or your vision? Why? • Make the argument that chimps possess language, though at a low level. Then argue the opposite, that their behavior does not rise to the level of language.

Quiz: Testing Your Understanding 1. Describe the path that sound information takes from the outer ear to the

auditory neurons, telling what happens at each point along the way. 2. State the telephone theory, the volley theory, and the place theory. Indicate a

problem with each, and state the theory that is currently most widely accepted.

3. Summarize the Wernicke-Geschwind model of language function. Include structures, the effects of damage, and the steps in reading a word aloud and

in repeating a word that is heard. Select the best answer: 1. An adequate and an inadequate stimulus, such as light versus pressure on the

eyeball, will produce similar experiences because a. they both activate visual receptors and the visual cortex. b. the receptors for touch and vision are similar. c. touch and vision receptors lie side by side in the eye. d. our ability to discriminate is poor.

2. Frequency is to pitch as a. loudness is to intensity. b. intensity is to loudness. c. stimulus is to response. d. response is to stimulus.

3. The sequence of sound travel in the inner ear is a. oval window, ossicles, basilar membrane, eardrum. b. ossicles, oval window, basilar membrane, eardrum. c. eardrum, ossicles, oval window, basilar membrane. d. eardrum, ossicles, basilar membrane, oval window.

4. Place analysis depends most on the physical characteristics of the a. hair cells. b. basilar membrane. c. tectorial membrane. d. cochlear canal.

5. The fact that neurons are limited in their rate of firing by the refractory period is most damaging to which theory? a. telephone b. volley c. place d. volley-place

6. The place theory’s greatest problem is that a. neurons cannot fire as frequently as the highest frequency sounds. b. neurons specific for frequencies above 5000 Hz have not been found. c. the entire basilar membrane vibrates about equally at low frequencies. d. volleying does not follow sound frequencies above about 5000 Hz.

7. An auditory neuron’s tuning curve tells you a. which frequency it responds to. b. which part of the basilar membrane the neuron comes from. c. at what rate the neuron can fire. d. how much the neuron responds to different frequencies.

8. A cochlear implant works because

a. the tympanic membrane is intact. b. the hair cells are intact. c. it stimulates the auditory cortex directly. d. it stimulates auditory neurons.

9. An auditory object is a. a vibrating object in the environment. b. a sound recognized as distinct from others. c. the sound source the individual is paying attention to. d. None of the above

10. As a binaural sound location cue, difference in intensity works a. poorly at low frequencies. b. poorly at medium frequencies. c. poorly at high frequencies. d. about equally at all frequencies.

11. In the following diagram of coincidence detectors, which cell would respond most if the sound were directly to the person’s left?

12. On returning home from the hospital, an elderly neighbor drags one foot when he walks and uses almost exclusively nouns and verbs in his brief sentences. You guess that he has had a mild stroke located in his a. left temporal lobe. b. right temporal lobe. c. left frontal lobe. d. right frontal lobe.

13. Most researchers agree that dyslexia is primarily a problem of a. development in Broca’s area. b. development in the visual area. c. visual processing. d. phonological processing.

14. Evidence providing some support for a language acquisition device comes from studies showing that American Sign Language activates a. the left hemisphere. b. the left and right hemispheres. c. both frontal lobes. d. the occipital lobe.

15. The most reasonable conclusion regarding language in animals is that

a. they can use words or signs, but do not possess language. b. they can learn language to the level of a 6-year-old human. c. language is “built in” for humans, but can be learned by animals. d. some animals have brain structures similar to human language structures.

16. Mirror neurons’ role in language development is supposedly in the a. imitation of word sounds. b. imitation of gestures and mouth actions. c. development of grammar. d. use of prosody.

Answers: 1. a, 2. b, 3. c, 4. b, 5. a, 6. c, 7. d, 8. d, 9. b, 10. a, 11. e, 12. c, 13. d, 14. a, 15. d, 16. b.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flash Cards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. National Institute on Deafness and Other Communication Disorders, a

division of the National Institutes of Health, is an excellent resource site for information on deafness, language, and speech disorders, as well as information for student and teacher activities. The site Hereditary Hearing Loss provides an overview of the genetics of hereditary hearing loss.

2. Two animations, Hearing and How it Works and Auditory Transduction, give a good picture of what happens in the middle and inner ear. Dancing Hair Cell is a highly magnified video of an outer hair cell shortening and lengthening in rhythm with Linda Ronstadt’s “Quiéreme Mucho.”

3. Biointeractive: The Cochlea features an animation of the basilar membrane responding to pure tones and music. The video is a good demonstration of place analysis, although for simplicity’s sake it suggests that the basilar membrane around the area of greatest vibration does not vibrate at all.

4. Cochlear Implant is an animated explanation of the process of hearing and how cochlear implants restore hearing. Two YouTube videos capture the excitement of a young woman and a four- year-old girl when their new implants are turned on.

5. You can see a video of Daniel Kish using tongue clicks to navigate city streets, ride a bike, and even find a ball in an open field.

6. The National Aphasia Association has information about aphasia and about research on the disorder, as well as resources. Stroke Family has information about recovering speech after a stroke, including free mini guides, with emphasis on how the family can help.

7. The International Dyslexia Association provides information on the disorder. 8. To communicate over long distances on Isla Gomera, one of the Canary

Islands, people use complex whistles; you can see a video at Free Language. The whistles are processed in the left-hemisphere language areas by whistlers, but not by others (Carreiras, Lopez, Rivero, & Corina, 2005). !Kung hunters of the Kalihari Desert communicate solely with clicks while stalking game, and some researchers believe clicks formed the first vocal language. (! denotes a click, which is part of the name.) Hear South African singer Miriam Makeba demonstrate the click language and sing her famous “Click Song.”

9. At Friends of Washoe you can learn about the lives and personalities of Washoe and her family, including Loulis. Note especially Tatu’s signing and her awareness of time, including seasonal holidays. Sadly, Alex passed away in 2007, but Dr. Pepperberg continues her language research with four other parrots. See the Alex Foundation’s descriptions of the birds and the research, and a video of Alex performing. The site treehugger has a fascinating video about “language” research with prairie dogs.

10. The In the News about birdsong and language was based on two articles in ScienceNews, appearing in March and July of 2013.

Animations • Place Analysis of Auditory Frequency (Figure 9.10) • Sound Localization (Figure 9.19) • The Wernicke-Geschwind Model of Language (Figure 9.21) Chapter Updates and Biopsychology News

For Further Reading 1. In Auditory Neuroscience: Making Sense of Sound (MIT Press, 2012), Israel

Nelken and Andrew King draw on physics, psychophysics, and neuroscience to explain hearing, speech processing, sound localization, and auditory scene

analysis. They end with a description of auditory prostheses. 2. The Language Instinct (Harper Perennial, 2007) is a reprint of Stephen

Pinker’s classic on the evolution of language. Pinker’s expertise and lively writing style garnered one reviewer’s evaluation as “an excellent book full of wit and wisdom and sound judgment.”

3. W. Tecumseh Fitch’s The Evolution of Language (Cambridge University Press, 2010) presents evidence from paleontology, archaeology, and comparative biology and psychology to reconstruct the evolution of the neural and vocal equipment we use to produce language.

4. Principles of Animal Communication, 2nd ed., by Jack Bradbury and Sandra Vehrencamp (Sinauer Associates, 2011), treats the evolution of animal communication and then describes how animals communicate through auditory, visual, chemical, and tactile means.

5. “Genetics of Speech and Language Disorders,” by Changsoo Kang and Dennis Drayna (Annual Review of Genomics and Human Genetics, 2011, 12, 145–164), describes the progress made in identifying genes responsible for these disorders.

Key Terms adequate stimulus agraphia alexia amplitude angular gyrus aphasia auditory object basilar membrane binaural Broca’s aphasia cochlea cochlear canal cocktail party effect coincidence detectors complex sound difference in intensity difference in time of arrival dyslexia frequency frequency theory frequency-place theory

inner hair cells intensity language acquisition device loudness organ of Corti ossicles outer hair cells perception phase difference phonological hypothesis pinna pitch place theory planum temporale prosody pure tone receptor sensation tectorial membrane telephone theory tonotopic map topographical organization tympanic membrane volley theory Wernicke’s aphasia

10 Vision and Visual Perception

In this chapter you will learn • The structure of the eye • How the eye begins processing visual information even before it is sent to the brain

• The major theories of color and form vision • How color, form, movement, and spatial location are handled in the brain • Some of the visual disorders caused by brain damage and what they tell us about brain function

Light and the Visual Apparatus The Visible Spectrum The Eye and Its Receptors Pathways to the Brain APPLICATION: RESTORING LOST VISION CONCEPT CHECK

Color Vision Trichromatic Theory Opponent Process Theory A Combined Theory Color Blindness CONCEPT CHECK

Form Vision Contrast Enhancement and Edge Detection Hubel and Wiesel’s Theory Spatial Frequency Theory CONCEPT CHECK

The Perception of Objects, Color, and Movement The Two Pathways of Visual Analysis Disorders of Visual Perception The Problem of Final Integration APPLICATION: WHEN BINDING GOES TOO FAR CONCEPT CHECK

In Perspective

J

Summary Study Resources

onathan I. was in his car when it was hit by a small truck. In the emergency room, he was told that he had a concussion. For a few days, he was unable to read, saying that the letters looked like Greek, but fortunately this alexia soon disappeared.

Jonathan was a successful artist who had worked with the renowned Georgia O’Keeffe, and he was eager to return to his work. Driving to his studio, he noticed that everything appeared gray and misty, as if he were driving in a fog. When he arrived at his studio, he found that even his brilliantly colored paintings had become gray and lifeless. “

From the patterns of stimulation on the retina we perceive the world of objects and this is nothing short of a miracle.

—Richard Gregory

” His whole world changed. People’s appearance was repulsive to him, because their

skin appeared “rat-colored”; he lost interest in sex with his wife for that reason. Food was unattractive, and he came to prefer black and white foods (coffee, rice, yogurt, black olives). His enjoyment of music was diminished, too; before the accident, he used to experience synesthesia, in which musical tones evoked a sensation of changing colors, and this pleasure disappeared as well. Even his migraine headaches, which had been accompanied by brilliantly colored geometric hallucinations, became “dull.” He retained his vivid imagery, but it too was without color. Over the next 2 years, Jonathan seemed to forget that color once existed, and his

sorrow lifted. His wife no longer appeared rat colored, and they resumed sexual activity. He turned to drawing and sculpting and to painting dancers and race horses, rendered in black and white but characterized by movement, vitality, and sensuousness. However, he preferred the colorless world of darkness and would spend half the night wandering the streets (Sacks & Wasserman, 1987). Vision enables us to read and to absorb large amounts of complex information. It

helps us navigate in the world, build structures, and avoid danger. Color helps distinguish objects from their background, and it enriches our lives with natural beauty and works of art. I suspect that in contrast to Helen Keller’s belief that deafness was a greater affliction than blindness, most of you would consider vision the most important of our senses. Apparently, researchers share that opinion, because vision has received more research attention than the other senses combined. As a result, we understand a great deal about how the brain processes visual information. In addition, studies of vision are providing a valuable model for understanding

complex neural processing in general. Light and the Visual Apparatus Vision is an impressive capability. There are approximately 126 million light receptors in the human eye and a complex network of cells connecting them to each other and to the optic nerve. The optic nerve itself boasts a million neurons, compared with 30,000 in the auditory nerve. The optic nerve transmits information to the brain at an estimated 100 million bits per second, comparable to Ethernet data transmission rates (Koch et al., 2006). What our brain does with the information it receives from the eye is equally remarkable. The topics of vision and visual perception form an exciting story, one of high-tech research and conflicting theories and dedicated scientists’ lifelong struggles to understand our most amazing sense. The Visible Spectrum To understand vision, we need to start at the beginning by describing the adequate

stimulus, as we did with audition. To say that the stimulus for vision is light seems obvious, but the point needs some elaboration. Visible light is a part of the electromagnetic spectrum. The electromagnetic spectrum includes a variety of energy forms, ranging from gamma rays at one extreme of frequency to the radiations of alternating current circuits at the other (Figure 10.1); the portion of the electromagnetic spectrum that we can see is represented by the colored area in the figure. The visible part of the spectrum accounts for only 1/70 of the range. Most of the

energies in the spectrum are not useful for producing images; for instance, AM, FM, and analog television waves pass right through objects. Some of the other energy forms, such as X-rays and radar, can be used for producing images, but they require powerful energy sources and special equipment for detecting the images. Heat- producing objects give off infrared energy, which some nocturnal animals, such as the sidewinder rattlesnake, use to detect their prey in darkness. Humans can see infrared images only with the aid of specialized equipment, and this capability is very useful to the military and the police for detecting people and heat-producing vehicles and armament at night. (During the first Gulf War, the Iraqi army set up plywood silhouettes of tanks with heaters behind them to distract Allied airplanes.) But infrared images have blurred edges and fuzzy detail. The electromagnetic energy within our detectable range produces well-defined images because it is reflected from objects with minimal distortion. We are adapted to life in the daytime, and we sacrifice the ability to see in darkness in exchange for crisp, colorful images of faces and objects in daylight. In other words, our sensory equipment is adapted for detecting the energy that is most useful to us, just as the night-hunting sidewinder rattlesnake is equipped to detect the infrared radiation emitted by its prey and a bat’s ears are specialized for the high-frequency sound waves it bounces off small insects. FIGURE 10.1 The Electromagnetic Spectrum.

The visible part of the spectrum is the middle (colored) area, which has been expanded to show the color experiences usually associated with the wavelengths. Only 1/70 of the electromagnetic spectrum is visible to humans.

Light is a form of oscillating energy and travels in waves just as sounds do. We could specify visible light (and the rest of the electromagnetic spectrum) in terms of frequency, just as we did with sound energy, but the numbers would be extremely large. So we describe light in terms of its wavelength—the distance the oscillating energy travels before it reverses direction. (We could do the same with sound, but those numbers would be just as inconveniently small.) The unit of measurement is the nanometer (nm), which is a billionth of a meter; visible light ranges from about 400 to 800 nm. Notice in Figure 10.1 that different wavelengths correspond to different colors of light; for example, when light in the range of 500 to 570 nm strikes the receptors in our eye, we normally report seeing green. Later in the chapter, we will qualify this relationship when we examine why wavelength does not always correspond to the color we see.

1 Vision Info and Animations The Eye and Its Receptors The eye is a spherically shaped structure filled with a clear liquid (Figure 10.2).

The outer covering, or sclera, is opaque except for the cornea, which is transparent. Behind the cornea is the lens. Because the lens is a flexible tissue, the muscles attached to it can stretch it out flatter to focus the image of a distant object on the retina, or they can relax to focus the image of a near object. Notice in the figure that the lens inverts the image on the retina. The lens is partly covered by the iris, which is what gives your eye its color. The iris is actually a circular muscle whose opening forms the pupil; it controls the amount of light entering the eye by contracting reflexively in bright light and relaxing in dim light. You can observe this response in yourself by watching in a mirror while you change the level of light in the room. FIGURE 10.2 The Human Eye.

The retina, the light-sensitive structure at the rear of the eye, is made up of two main types of light-sensitive receptor cells, called rods and cones, and the neural cells that are connected to them. As you can see in Figures 10.2 and 10.3, the receptors— typically referred to as photoreceptors—are at the very back of the eye. Light must pass through the neural cells to reach the photoreceptors, but this presents little problem because the neural cells are transparent. The receptors connect to bipolar cells, which in turn connect to ganglion cells, whose fibers form the optic nerve. The photoreceptors are filled with light-sensitive chemicals called photopigments; light passing through the photopigment causes some of the molecules to break down into two components, and the ensuing chemical reaction ultimately results in a neural response. The two components then recombine to maintain the supply of photopigment.

How does the eye detect light? The rods and cones are named for their shapes, as you can see by looking at Figure

10.3 again. The human eye contains about 120 million rods and about 6 million cones. The two types of receptors contain different kinds of photopigments; rods and cones function similarly, but their chemical contents and their neural connections give them different specializations. The rod photopigment is called rhodopsin; the name refers to its color (from the

Latin rhodon, “rose”), not to its location in rods. Rhodopsin is more sensitive to light

than is cone photopigment. For this reason, rods function better in dim light than cones do; in fact, you rely solely on your rods for vision in dim light. In very bright light, the rhodopsin in your eyes remains broken down most of the time, so the rods barely function. The delay in adjusting to a darkened movie theater is due to the time it takes the rhodopsin to resynthesize. Iodopsin, the cone photopigment, requires a high level of light intensity to operate, so your cones are nonfunctional in dim light but function well in daylight. Three varieties of iodopsin, located in different cones, respond differentially to different wavelengths of light; this means that cones can distinguish among different wavelengths, whereas rods differentiate only among different levels of light and dark (which is why you cannot recognize colors in dim light). Rods and cones also differ in their location and in their amount of neural

interconnection. Cones are most concentrated in the fovea, a 1.5-millimeter-wide area in the middle of the retina, and drop off rapidly with distance from that point. Rods are most concentrated at 20 degrees from the fovea; from that point, they decrease in number in both directions and fall to zero in the middle of the fovea. In the center of the fovea, a single cone is connected to each ganglion cell; the number of cones per ganglion cell increases with distance from the center but still remains small compared with rods. Because few cones share ganglion cells, the fovea has higher visual acuity, or ability to distinguish details. Many rods share each ganglion cell; this reduces their resolution but enhances their already greater sensitivity to dim light. The area of the retina from which a ganglion cell (or any other cell in the visual system) receives its input is the cell’s receptive field. So, we can say that receptive fields are smaller in the fovea and larger in the periphery. Table 10.1 summarizes the characteristics of these two visual systems. FIGURE 10.3 The Cells of the Retina.

SOURCE: Adapted from “Organization of the Primate Retina,” by J. E. Dowling and B. B. Boycott, Proceedings of the Royal Society of London, B166, Fig. 23 on p. 104. Copyright 1966 by the Royal Society. The receptors’ response to light is different from what you might expect, because

they are most active when they are not being stimulated by light. In darkness, the photoreceptor’s sodium and calcium channels are open, allowing these ions to flow in freely. Thus, the membrane is partially depolarized; the receptor releases a continuous flow of glutamate, and this inhibits activity in the bipolar cells. The chemical response that occurs when light strikes the photopigments closes the sodium and calcium channels, reducing the release of glutamate in proportion to the amount of light. The bipolar cells release more neurotransmitter, which increases the firing rate in the ganglion cells. (The photoreceptors and bipolar cells do not produce action potentials.) If you look again at Figure 10.3, you can see that the rods and cones are highly

interconnected by horizontal cells. In addition, amacrine cells connect across many ganglion cells. This might suggest to you that the retina does more than transmit

information about points of light to the brain. You might also suspect that a great deal of processing goes on in the retina itself. You will soon see that both of these are true. With such complexity, no wonder most vision scientists consider the retina to be part of the brain and refer to the optic nerve as a tract. TABLE 10.1 Summary of the Characteristics of the Rod and Cone Systems.

Pathways to the Brain The axons of the ganglion cells join together and pass out of each eye to form the

two optic nerves (Figure 10.4). Where the nerve exits the eye, there are no receptors, so it is referred to as the blind spot (see Figure 10.2). The blind spots of the two eyes fall at different points in a visual scene, so you do not notice that any of your visual world is missing; besides, your brain is good at “filling in” missing information, even when a small part of the visual system is damaged. The two optic nerves run to a point just in front of the pituitary, where they join for a short distance at the optic chiasm before separating again and traveling to their first synapse in the lateral geniculate nuclei of the thalamus. At the optic chiasm, axons from the nasal sides of the eyes cross to the other side and go to the occipital lobe in the opposite hemisphere. Neurons from the outside half of the eyes (the temporal side) do not cross over but go to the same side of the brain.

How does information about an object on your right end up in your left hemisphere? It seems like splitting the output of each eye between the two hemispheres would

cause a major distortion of the image. However, if you look closely at Figure 10.4, you can see that the arrangement actually keeps related information together. Notice that the letter A, which appears in the person’s left visual field (the part of the environment being registered on the retina), casts an image on the right half of each retina. The information from the right half of each eye will be transmitted to the right hemisphere. An image in the right visual field will similarly be projected to the left hemisphere. This is how researchers who study differences in the functions of the two cerebral hemispheres are able to project a visual stimulus to one hemisphere. They present the stimulus slightly to the left or to the right of the midline; the exposure time is too brief to allow the subject to shift the eyes toward the stimulus, and with brief exposures the information does not transfer to the other hemisphere. There is a good reason you have two forward-facing eyes, instead of one like the

mythical Cyclops or one on each side of your head like many animals. The approximately 6-centimeter separation of your eyes produces retinal disparity, a discrepancy in the location of an object’s image on the two retinas. Figure 10.5 shows how the image of distant objects in a scene falls toward the nasal side of each retina and closer objects cast their image in the temporal half. Retinal disparity is detected in the visual cortex, where different neurons fire depending on the amount of lateral displacement. Then in the anterior parietal cortex this information is combined with information about an object’s shape and location to provide information about the distance of objects (J.-B. Durand et al., 2007). There are several good demonstrations of retinal disparity; the simplest is to hold your finger a foot (30 cm) in front of you and alternately close one eye and then the other while you notice how your finger moves relative to the background. The ViewMaster 3-D viewer you may have had as a child took advantage of your brain’s retinal disparity detectors by presenting each eye with an image photographed at a slightly different angle. 3-D movies use the same principle, but the two images are separated by differently polarized lenses in the special glasses. A striking 3-D effect can also be obtained without a viewer from stereograms such as those at Magic Eye (see On the Web 2).

How does retinal disparity help us see 3-D?

2 Stereograms and Illusions As the rest of the story of vision unfolds, you will notice three themes that will help

you understand how the visual system works: inhibition, modularity, and hierarchical processing. You will learn that neural inhibition is just as important as excitation, because it sharpens information beyond the processing capabilities of a system that depends on excitation alone. You will also learn that, like hearing and language, the visual system carries out its functions in discrete specialized structures, or modules, which pass information to each other in a serial, hierarchical fashion. FIGURE 10.4 Projections From the Retinas to the Cerebral Hemispheres. Notice how images of objects in the left and right sides of the visual field fall on the opposite sides of the two retinas; the information from the two eyes then travels to the visual cortex in the hemisphere opposite the object, where it is combined. (The distance between the two lateral geniculate nuclei is greatly exaggerated.)

FIGURE 10.5 Retinal Disparity. The image of an object to which the eyes are oriented (A) falls on the fovea, while the image of a more distant object (B) is displaced to the inside of each retina and the image of a closer object (C) is displaced to the outside. This provides information to the brain for depth perception.

APPLICATION

Restoring Lost Vision The World Health Organization (2013) estimates that 285 million people worldwide suffer from blindness or impaired vision, but researchers now have several promising new strategies for restoring vision. The U.S. Food and Drug Administration recently approved the Argus II as a retinal replacement in patients with retinitis pigmentosa (Sifferlin, 2013). With the Argus II, images from a small video camera mounted on a pair of glasses are processed and then transmitted wirelessly to an electronics package attached to the eyeball. That device activates a 60-electrode array in the back of the eye to stimulate the retinal neurons in a pattern that roughly duplicates the image (see figure). Vision is crude, but it allows some patients to read large letters, detect street curbs and people’s movement, and match clothing colors.

Source: Copyright © 2013 Second Sight Medical Products, Inc.

The Alpha IMS, which has won approval in Europe, skips the external camera in favor of a light-sensitive chip mounted behind the retina. This allows the recipient to look around by moving the eyes rather than turning the head, plus its 1,500 electrodes enable patients to read signs on doors and recognize faces (Stingl et al., 2013). While most blindness results from deterioration of retinal cells, in some instances the problem is in the optic nerve itself. Researchers hope someday to bypass the nerve electronically and stimulate the visual cortex with a chip implanted there. Of course, the ideal treatment would restore the visual mechanism itself,

and stem cell research is making impressive progress toward that goal. Researchers at the University of Oxford injected rod precursor cells into the eyes of mice that were completely blind due to loss of photoreceptors; after 2 weeks the cells had made functional connections and the nocturnal animals began avoiding light and seeking out dark spaces (Singh et al., 2013). This is a tiny early step toward curing blindness in humans, but Advanced Cell Technology is already engaged in clinical trials with humans. Their strategy involves using stem cells from human embryos to replace lost retinal pigment epithelial cells, which supply nutrients to photoreceptors. In a preliminary report, they announced that a patient’s vision had improved from 20/400— essentially blind—to 20/40, good enough to qualify him to receive a driver’s license (Coghlan, 2013).

3 Fixing Blindness

Concept Check Take a Minute to Check YourKnowledge and Understanding In what ways is human vision adapted for our environment? How are the rod and cone systems specialized for different tasks? The two visual pathways?

How does retinal disparity help us see 3-D?

Color Vision In Figure 10.1, you saw that there is a correspondence between color and wavelength; this would suggest that color is a property of the light reflected from an object and, therefore, of the object itself. However, wavelength does not always predict color, as Figure 10.6 illustrates. The circle on the left and the circle on the right appear to be different colors, although they reflect exactly the same wavelengths. Just as with the auditory terms pitch and loudness, the term color refers to the observer’s experience rather than a characteristic of the object. Thus, it is technically incorrect to say that the light is red or that a book is blue, because red and blue are experiences that are imposed by the brain. However, in the interest of simplicity, I will be rather casual about this point in future discussions, as long as we understand that “red” and “blue” are experiences rather than object characteristics. To understand the experience of color, we must now examine the neural equipment that we use to produce that experience. Our understanding of color vision has been guided over the past two centuries by two competing theories: the trichromatic theory and the opponent process theory. FIGURE 10.6 Independence of Wavelength and Color. Although the circles are identical, they appear to differ in color due to the color contrast with their backgrounds.

Trichromatic Theory After observing the effect of passing light through a prism, Sir Isaac Newton

proposed in 1672 that white light is composed of seven fundamental colors that cannot themselves be resolved into other colors. If there are seven “pure” colors, this

would suggest that there must be seven receptors and brain pathways for distinguishing color, just as there are five primary tastes (or six, if the fat receptor is confirmed). In 1852, Hermann von Helmholtz (whose place theory was discussed in Chapter 9) revived an idea of Thomas Young from a half-century earlier. Because any color can be produced by combining different amounts of just three colors of light, Young and Helmholtz recognized that this must be due to the nature of the visual mechanism rather than the nature of light. They proposed a trichromatic theory — now known as the Young-Helmholtz theory—that just three color processes account for all the colors we are able to distinguish. They chose red, green, and blue as the primary colors because observers cannot resolve these colors into separate components as, for example, you can see red and blue in the color purple. When you watch television or look at a computer monitor, you see an application of trichromatic color mixing: All the colors you see on the screen are made up of tiny red, green, and blue dots of light.

How do we distinguish colors? Opponent Process Theory The trichromatic theory accounted for some of the observations about color

perception very well, but it ran into trouble explaining why yellow also appears to observers to be a pure color. Ewald Hering (1878) “solved” this problem by adding yellow to the list of physiologically unique colors. But rather than assuming four color receptors, he asserted that there are only two—one for red and green and one for blue and yellow. Opponent process theory attempts to explain color vision in terms of opposing neural processes. In Hering’s version, the photochemical in the red-green receptor is broken down by red light and regenerates in the presence of green light. The chemical in the second type of receptor is broken down in the presence of yellow light and regenerates in the presence of blue light. Hering proposed this arrangement to explain the phenomenon of complementary

colors, colors that cancel each other out to produce a neutral gray or white. (Note the spelling of this term; complementary means “completing.”) In Figure 10.7, the visible spectrum is represented as a circle. This rearrangement of the spectrum makes sense, because violet at one end of the spectrum blends naturally into red at the other end just as easily as the colors adjacent to each other on the spectrum blend into each other. Another reason the color circle makes sense is that any two colors opposite each other on the circle are complementary; mixing equal amounts of light from across the circle results in the sensation of a neutral gray tending toward white, depending on the brightness. An exception to this rule is the combination of red and green; they produce yellow, for reasons you will understand shortly. FIGURE 10.7 The Color Circle. Colors opposite each other are complementary; that is, equal amounts of light in

those colors cancel each other out, producing a neutral gray.

Another indication of complementarity is that overstimulation of the eye with one light makes the eye more sensitive to its complement . Stare at a red stimulus for a minute, and you will begin to see a green edge around it; then look at a white wall or a sheet of paper, and you will see a green version of the original object. This experience is called a negative color aftereffect; the butcher decorates the inside of the meat case with parsley or other greenery to make the beef look redder. Negative color aftereffect is what one would expect if the wavelengths were affecting the same receptor in opposed directions, as Hering theorized. The flag in Figure 10.8 is a very good interactive demonstration of complementary colors and negative aftereffects. FIGURE 10.8 Complementary Colors and Negative Color Aftereffect. Stare at the dot in the center of the flag for about a minute, and then look at a white surface (the ceiling or a sheet of paper); you should see a traditional red, white, and blue flag.

If this discussion of color mixing seems inconsistent with what you understood in the past, it is probably because you learned the principles of color mixing in an art class. The topic of discussion there was pigment mixing, whereas we are talking about mixing light. An object appears red to us because it reflects mostly long-wavelength (red) light, while it absorbs other wavelengths of light. The effect of light mixing is additive, while pigment mixing is subtractive; if we mix lights, we add wavelengths to the stimulus, but as we mix paints more wavelengths are absorbed. For example, if you mix equal amounts of all wavelengths of light, the result will be white light; mixing paints in the same way produces black because each added pigment absorbs additional wavelengths of light until the result is total absorption and blackness (Figure 10.9). Now, back to color vision theory. Although Hering’s theory did a nice job of

explaining complementary colors and the uniqueness of yellow, it received little acceptance. One reason was that researchers had trouble with Hering’s assumption of a chemical that would break down in response to one light and regenerate in the presence of another. His theory was, in fact, in error on that point, but developments 100 years later would bring Hering’s thinking back to the forefront. FIGURE 10.9 Mixing Lights is Additive; Mixing Paints is Subtractive. The combination of all three primaries (or all colors) of light produces white; the same combination of pigments produces black, which is the lack of color.

A Combined Theory The trichromatic and opponent process theories appear to be contradictory.

Sometimes this means that one position is wrong and the other is right, but often it

means that each of the competing theories is partly correct but just too simple to accommodate all the known facts. Hurvich and Jameson (1957) resolved the conflict with a compromise: They proposed that three types of color receptors—red sensitive, green sensitive, and blue sensitive—are interconnected in an opponent process fashion at the ganglion cells. FIGURE 10.10 Hurvich and Jameson’s Proposed Interconnections of Cones Provide Four Color Responses and Complementary Colors. “+” indicates excitation; “–” indicates inhibition. For simplicity, cells between the cones and ganglion cells are not shown.

Figure 10.10 is a simplified version of how Hurvich and Jameson thought this combined color-processing strategy might work. Long-wavelength light excites “red” cones and the red-green ganglion cell to give the sensation of red. Medium- wavelength light excites the “green” cones and inhibits the red-green cell, reducing its firing rate below its spontaneous level and signaling green to the brain. Likewise, short-wavelength light excites “blue” cones and inhibits the yellow-blue ganglion cell, leading to a sensation of blue. Light midway between the sensitivities of the “red” and

“green” cones would stimulate both cone types. The firing rate in the red-green ganglion cell would not change, because equal stimulation and excitation from the two cones would cancel out; however, the cones’ connections to the yellow-blue ganglion cell are both excitatory, so their combined excitation would produce a sensation of yellow. According to this theory, there are three color processes at the receptors and four beyond the ganglion cells. This scheme does explain very nicely why yellow would appear pure just like red,

green, and blue do. Also, it is easy to understand why certain pairs of colors are complementary instead of producing a blended color. For example, you could have a color that is reddish blue (purple) or greenish yellow (chartreuse) but not a reddish green or a bluish yellow. Negative aftereffects can be explained as overstimulation “fatiguing” a ganglion cell’s response in one direction, causing a rebound in the opposite direction and a subtle experience of the opposing color. By the way, this is our first example of the significance of all that interconnectedness we saw back in Figure 10.3. FIGURE 10.11 Relative Absorption of Light of Various Wavelengths by Visual Receptors. Note that each type of cone responds best to wavelengths corresponding to blue, green, and red light, though each responds to other wavelengths as well.

SOURCE: Adapted from “Visual Pigments of Rods and Cones in Human Retina,” by Bowmaker and Dartnall, 1980, Journal of Physiology, 298, pp. 501–511. Copyright 1980, with permission from John Wiley & Sons, Inc. Evidence for this combined trichromatic/opponent process theory would be almost

a decade away, however, because it depended on the development of more precise measurement capabilities. Support came in two forms. First, researchers produced direct evidence for three color receptors in the retina (K. Brown & Wald, 1964; Dartnall, Bowmaker, & Mollon, 1983; Marks, Dobelle, & MacNichol, 1964). The researchers shone light of selected wavelengths through individual receptors in eyes

that had been removed from humans for medical reasons or shortly after their death; they measured the light that passed through to determine which wavelengths had been lost through absorption. The absorbed wavelengths indicated the ones the receptor’s photochemical was sensitive to. Figure 10.11 shows the results from a study of this type. Note that there are three distinct color response curves (plus a response curve for rods), just as Hurvich and Jameson predicted. I should point out that the “red” cone’s sensitivity is actually closer to orange, but tradition is tradition, so we continue to refer to its preferred color as red. There are two additional features of these results I want to call to your attention.

Like the tuning curves for frequency we saw in Chapter 9, these curves are not very sharp; each receptor has a sensitivity peak, but its response range is broad and overlaps with that of its neighbors. This means that the medium-wavelength cones could be active because the stimulus is “green” light or because they are being stimulated with intense “blue” light. The system must compare activity in all three types of cones to determine which wavelengths you are seeing. This “comparison” does not occur at the level of awareness; it is an automatic neural process, like the one that sharpens frequency discrimination and the activity of coincidence detectors in sound localization. The second feature is related to the evolution of color vision. Notice that the

medium- and long-wavelength curves are distant from the short-wavelength curve, but very close to each other. Genetic research indicates that the genes for the photopigments in the medium- and long-wavelength cones evolved from a common precursor gene relatively recently (only about 35 million years ago), but the genes for the short-wavelength cones and for the rod receptors split off from their precursor much earlier. Indeed, the “red” and “green” genes are adjacent to each other on the X chromosome, and they are 98% identical in DNA (Gegenfurtner & Kiper, 2003). Trichromatic vision is certainly beneficial in appreciating art, but we might well ask

what evolutionary benefits compelled its development. An obvious advantage was an enhanced ability to distinguish ripe fruit and to locate young, tender leaves. In addition, comparisons of primate genomes indicate intriguing parallels between the appearance of genes for trichromacy, the decreases in olfactory and pheromone receptor genes, and the development of visual signals such as the reddened and swollen sexual skin in female baboons and Old World monkeys (Gilad, Wiebe, Przeworski, Lancet, & Pääbo, 2004; J. Zhang & Webb, 2003). The importance of the red-green end of the spectrum is suggested by the fact that only 10% of human cones have their sensitivity in the blue end of the spectrum. Analyzing 5,000 photographs from the savannas of Botswana, researchers concluded that this balance matches the distribution of colors in the environment in which humans are believed to have evolved (Garrigan et al., 2010). Additional confirmation of the trichromatic/opponent process theory came when

researchers found color-opponent cells in monkeys, both in the retina and in the lateral geniculate nucleus of the thalamus (De Valois, 1960; De Valois, Abramov, & Jacobs, 1966; Gouras, 1968). Figure 10.10 shows two types of opponent cells, one that is excited by red and inhibited by green (R+G–) and one that is excited by yellow and inhibited by blue (Y+B–); Russell De Valois and his colleagues (1966) identified two additional types that were the inverse of the previous two: green excitatory/red inhibitory (G+R–) and blue excitatory/yellow inhibitory (B+Y–). A surprise was that some of the color-opponent ganglion cells receive their input

from cones that are arranged in two concentric circles (Gouras, 1968; Wiesel & Hubel, 1966). The cones in the center and those in the periphery have color- complementary sensitivities (see Figure 10.12). Of course, the yellow response is provided by the combined output of “red” and “green” cones. Why all this complexity? First, the opposition of cones at the ganglion cells provides wavelength discrimination that individual cones are incapable of producing (E. E. Goldstein, 1999)—an example of the “neural comparison” I referred to earlier. The concentric- circle receptor fields also enhance information about color contrast in objects. This mode of information sharpening will become clearer when we look at how the retina distinguishes the edge of an object. FIGURE 10.12 Receptive Fields of Color-Opponent Ganglion Cells. The cones in the center and the cones in the periphery respond to colors that are complementary to each other. The center cones excite the ganglion cell, and the cones in the periphery inhibit it.

SOURCE: Based on the findings of De Valois et al. (1966). A theory is considered successful if it is consistent with the known facts, can

explain those facts, and can predict new findings. The combined trichromatic and opponent process color theory meets all three criteria: (1) It is consistent with the observation that all colors can be produced by using red, green, and blue light. (2) It can explain why observers regard red, green, blue, and yellow as pure colors. It also explains complementary colors, negative aftereffects, and the impossibility of color experiences such as greenish red. (3) It predicted the discovery of three photopigments and of the excitatory/inhibitory neural connections at the ganglion cells. FIGURE 10.13 A Test for Color Blindness.

This is one of the plates from the Ishihara test for color blindness. Most people see the number 74; the person with color deficiency sees the number 21.

Color Blindness Color blindness is an intriguing curiosity; but more than that, it has played an

important role in our understanding of color perception by scuttling inadequate theories and providing the inspiration for new ones. There are very few completely color-blind people—about 1 in every 100,000. They usually have an inherited lack of cones; limited to rod vision, they see in shades of gray, they are very light sensitive, and they have poor visual acuity. More typically a person is partly color-blind, due to a defect in one of the cone systems rather than a lack of cones.

What is it like to be color-blind? There are two major types of retinal color blindness. A person who is red-green

color-blind sees these two colors but is unable to distinguish between them. We know something about what color-blind people experience by noting which colors color- blind people confuse and from studying a few rare individuals who are color-blind in only one eye. When I was trying to understand a red-green color-blind colleague’s experience of color, he explained that green grass was the same color as peanut butter! I don’t know what peanut butter looked like to him, but he assured me that he found grass and trees “very beautiful.” People in the second color-blind group do not perceive blue, so their world appears in variations of red and green. Many partly color-blind individuals are unaware that they see the world differently than the rest of us. Color vision deficiencies can be detected by having the subject match or sort colored objects or with a test like the one illustrated in Figure 10.13. Red-green color-blind individuals show a deficiency in either the red end of the

spectrum or in the green portion; this suggests that the person lacks either the appropriate cone or the photochemical. Acuity is normal in both groups, so there cannot be a lack of cones. Some are unusually sensitive to green light, and the rest are sensitive to red light; this suggests that in one case the normally red-sensitive cones are filled with green-sensitive photochemical and in the other the normally green- sensitive cones are filled with red-sensitive chemical.

Concept Check

4 Color and Color Blindness

Take a Minute to Check Your Knowledge and Understanding

Summarize the three color vision theories described here. What is the benefit of the color-opposed concentric circle receptor fields? What causes color blindness?

Form Vision Just as the auditory cortex is organized as a map of the cochlea, the visual cortex contains a map of the retina. Russell De Valois and his colleagues demonstrated this point when they presented the image in Figure 10.14a to monkeys that had been injected with radioactive 2-deoxyglucose. The animals were sacrificed and their brains placed on photographic film. Because the more active neurons absorbed more radioactive glucose, they exposed the film more darkly in the autoradiograph in Figure 10.14b; this produced an image of the stimulus that appears to be wrapped around the monkey’s occipital lobe (Tootell et al., 1982). This result tells us that, just as there is a tonotopic map of the basilar membrane in

the auditory cortex, we have a retinotopic map in the visual cortex, meaning that adjacent retinal receptors activate adjacent cells in the visual cortex. However, this does not tell us how we see images; transmitting an object’s image to the cortex like a television picture does not amount to perception of the object. Object perception is a two-stage affair. In this section we will discuss form vision, the detection of an object’s boundaries and features (such as texture); we will discuss the second component, object recognition, a bit later. The story that unfolds here is about more than perception; it provides a model for understanding how the brain processes information in general. It is also a story that begins not in the cortex but in the retina itself. Contrast Enhancement and Edge Detection Detecting an object’s boundaries is the first step in form vision. The nervous system

often exaggerates especially important sensory information; in the case of boundaries, it uses lateral inhibition to enhance the contrast in brightness that defines an object’s edge. To demonstrate this enhancement for yourself, look at the Hermann grid illusion in Figure 10.15a and the Mach band illusion in Figure 10.15b. The Hermann grid is the more dramatic of the two illusions, but the simplicity of the Mach band graphic makes it easier to explain, so we will focus on it. Each bar in the Mach band image is

consistent in brightness across its width, but it looks a bit darker on the left and a bit lighter on the right than it does in the middle. (If you don’t see a difference at the edges, you may notice that the bars seem slightly curved. This is because the illusion suggests subtle shadowing on the left side of each bar.) An illusion is not simply an error of perception, but an exaggeration of a normal perceptual process, which makes illusions very useful in studying perception.

5 Perception Tutorials FIGURE 10.14 Deoxyglucose Autoradiograph Showing Retinotopic Mapping in Visual Cortex. Monkeys were given radioactive 2-deoxyglucose and then shown the design in (a). They were sacrificed, and a section of their visual cortical tissue was placed on photographic film. The exposed film showed a pattern of activation (b) that matched the design.

SOURCE: From “Deoxyglucose Analysis of Retinotopic Organization in Primate Striate Cortex,” by R. B. H. Tootell et al.,” Science, 218, pp. 902–904. Reprinted with permission from AAAS. FIGURE 10.15 Demonstration of Lateral Inhibition. (a) In the Hermann grid illusion, lateral inhibition causes you to see small, grayish blotches at the intersections of the large squares. (b) The Mach band illusion is another example. Each band is consistent in brightness across its width, as shown in the graph of light intensity in (c). But where the bands meet, you experience a slight enhancement in brightness at the edge of the lighter band and a decrease in brightness at the edge of the darker band (e.g., at points B and C). This effect is represented graphically in (d). Exaggeration of brightness contrast at edges helps us see the boundaries of objects.

SOURCES: (a) Based on Hermann (1870). (b) From Mach Bands: Quantitative Studies on Neural Networks in the Retina (fig. 3.25, p. 107), by F. Ratcliff, 1965. San Francisco: Holden-Day. Copyright © Holden-Day Inc. Figure 10.16 will help you understand how your retinas produce the illusion. In

lateral inhibition, each neuron’s activity inhibits the activity of its neighbors and in turn its activity is inhibited by them. In this case, the inhibition is delivered by horizontal cells to nearby synapses of receptors with bipolar cells. The critical point in the illustration is at ganglion cells 7 and 8. Ganglion cell 7 is inhibited less than ganglion cells 1 to 6; this is because the receptors to its right are receiving very little stimulation and producing low levels of inhibition. This lesser inhibition of ganglion cell 7 creates a sensation of a lighter band to the left of the border, as indicated at the bottom of the illustration. Similarly, ganglion cell 8 is inhibited more than its neighbors to the right, because the receptors to its left are receiving greater stimulation and producing more inhibition. As a result, the bar appears darker to the right of the border. “

Deceptions of the senses are the truths of perception. —Johannes Purkinje

”

How do we detect objects’ boundaries? Actually, this description is more appropriate for the eye of the horseshoe crab,

where lateral inhibition was originally confirmed by electrical recording; in fact, the graph in Figure 10.15d was based on data from the horseshoe crab’s eye (Ratliff &

Hartline, 1959). The principle is the same in the mammalian eye, but each ganglion cell’s receptive field is made up of several receptors arranged in circles, like the color- coded circular fields we saw earlier (Kuffler, 1953). Light in the center of the field has the opposite effect on the ganglion cell from light in the surround. In on-center cells, light in the center increases firing, and light in the off surround reduces firing below the resting levels. Other ganglion cells have an off center and an on surround. Figure 10.17 illustrates these two types of ganglion cells. FIGURE 10.16 The Neural Basis of the Mach Band Illusion. The bar at the top represents the middle two bands from Figure 10.15b. Red arrows indicate excitation, and gray arrows indicate inhibition. All ganglion cells are activated, but ganglion cell 7 is activated most; like 1 through 6, it receives more stimulation from the brighter stimulus, but it receives less inhibition from the receptors to the right. Likewise, ganglion cell 8 receives minimal stimulation, plus it receives more inhibition from the receptors to the left than do cells 9 through 15. As a result, the light bar appears lighter at its border with the dark bar, which in turn appears darker at its border. (Cells between the receptors and ganglion cells have been omitted for simplicity. Also, you would see some gradation of contrasts, because the inhibitory connections extend farther than the adjacent cell.)

These ganglion cells are good at detecting spots of light or darkness, but their contribution to vision is as light–dark contrast detectors (Hubel, 1982). Look at the three illustrations in Figure 10.18. Light falling across the entire field will have little or no effect on the ganglion cell’s firing rate, because the excitation and inhibition cancel each other out (Figure 10.18a). Light that falls only on the off surround will suppress firing in the ganglion cell (Figure 10.18b). But the ganglion cell’s firing will be at its maximum when the stimulus falls on all of the on center and only a part of the off surround, as in Figure 10.18c. Figure 10.18d represents what happens in an off-center ganglion cell when its receptors are stimulated by an object that is darker than the background (or by a shadow). Because the dark image falls across all of the off center but only part of the on surround, the cell’s activity is high. We are so accustomed to thinking of vision in terms of light stimulation that we neglect the importance of dark stimulation. The fact is that off ganglion cells outnumber on cells

two to one in the human retina, and for good reason. When researchers analyzed photos taken in several settings ranging from the streets of Philadelphia to the plains of Africa, they found that dark-on-light contrasts were 10% to 20% more numerous than light contrasts (Ratliff, Borghuis, Kao, Sterling, & Balasubramanian, 2010). When they created a mathematical model of the ideal system for processing these scenes, it predicted the smaller and more numerous off cells found in the retina. We will see the significance of this light–dark contrast mechanism in the next section. FIGURE 10.17 Effect of Light on Center and Surround of Receptive Field. The receptive fields and ganglion cells are shown in cross section. The connecting cells between the receptors and the ganglion cells have been omitted for simplicity.

Hubel and Wiesel’s Theory Cells in the lateral geniculate nucleus have circular receptive fields just like the

ganglion cells from which they receive their input. The receptive fields of visual neurons in the cortex, however, turn out to be surprisingly different. David Hubel and Torsten Wiesel (1959) were probing the visual cortex of anesthetized cats as they projected visual stimuli on a screen in front of the cat. Their electrode was connected to an auditory amplifier so they could listen for indications of active cells. One day, they were manipulating a glass slide with a black dot on it in the projector and getting only vague and inconsistent responses when suddenly over the audio monitor the cell went off like a machine gun. After some fussing and fiddling we found out what was happening. The response had nothing to do with the black dot. As the glass slide was inserted its edge was casting onto the retina a faint but sharp shadow, a straight dark line on a light background. (Hubel, 1982, p. 517) Hubel and Wiesel then began exploring the receptive fields of these cortical cells

by projecting bars of light on the screen. They found that an actively responding cell would decrease its responding when the stimulus was moved to another location or rotated to a slightly different angle. Figure 10.19 shows the changes in response in

one cell as the orientation of the stimulus was varied. Hubel and Wiesel called these cortical cells simple cells. Simple cells respond to a line or an edge that is at a specific orientation and at a specific place on the retina. FIGURE 10.18 Effects of a Border on an On-Center and an Off-Center Ganglion Cell. The receptors shown in (a)–(c) are connected to an on-center ganglion cell, and those in (d) are connected to an off-center cell. The vertical marks on the blue bars indicate neural responses; the yellow line underneath indicates when the light was on, and the dark line indicates presence of the dark image. Notice that the greatest activity occurs in the ganglion cell when the (appropriate) stimulus falls on all of the center but less than the entire surround.

How can we explain the surprising shift in specialization in these cortical cells? Imagine several contrast-detecting circular fields arranged in a straight line, like those in Figure 10.20. (Notice that the fields overlap each other; by now you shouldn’t be surprised that receptors would share their output with multiple ganglion cells.) Then, connect the outputs of their ganglion cells to a single cell in the cortex—one of Hubel and Wiesel’s simple cells. You now have a mechanism for detecting not just spots of light–dark contrast but a contrasting edge, such as in the border of an object that is lighter or darker than its background. Fields with on centers would detect a light edge, like the one in the figure, and a series of circular fields with off centers would detect a dark edge. In other layers of the cortex, Hubel and Wiesel found complex cells, which continue

to respond when a line or an edge moves to a different location, as long as it is not too far from the original site. They explained the complex cell’s ability to continue responding in essentially the same way they explained the sensitivity of simple cells. They assumed that complex cells receive input from several simple cells that have the

same orientation sensitivity but whose fields are adjacent to each other on the retina. This arrangement is illustrated in Figure 10.21. Notice that as the edge moves horizontally, different simple cells will take over, but the same complex cell will continue responding. However, if the edge rotates to a different orientation, this complex cell will stop responding, and another complex cell specific for that orientation will take over. Connecting several simple cells to a single complex cell enables the complex cell not only to keep track of an edge as it moves but also to detect movement.

How does Hubel and Wiesel’s system work? FIGURE 10.19 Responses to Lines at Different Orientations in a Simple Cell Specialized for Vertical Lines. The vertical hatchmarks represent neural responses, and the yellow line underneath indicates when the stimulus occurred. Notice that the response was greatest when the line was closest to the cell’s “preferred” orientation (vertical) and least when the orientation was most discrepant. In the last example, the response was diminished because the stimulus failed to cover all of the cell’s field (indicated by the stimulus being off-center of the crosshair). SOURCE: From “Receptive Fields of Single Neurons in the Cat’s Striate Cortex,” by D. H. Hubel and T. N. Wiesel, 1959, Journal of Physiology, 148, pp. 574–591, Fig 3. © 1959 by The Physiology Society. Reprinted with permission from John Wiley & Sons, Inc.

The feasibility of this kind of arrangement has received support from an interesting source—artificial neural networks. Lau et al. (2002) trained a network so that its output “neurons” gave the same responses to bar-shaped stimuli as those recorded from complex cells in cats. Then they examined the hidden layer and found that those “neurons” had rearranged their connections to approximate simple cells, complete

with “on” and “off” regions in their receptive fields as well as directional sensitivity. In an earlier study, a neural network was trained to recognize curved visual objects (Lehky & Sejnowski, 1990). Its “neurons” spontaneously developed sensitivity to bars or edges of light even though they had never been exposed to such stimuli, suggesting that the Hubel-Wiesel model is a very versatile one. FIGURE 10.20 Hubel and Wiesel’s Explanation for Responses of Simple Cells. When the edge is in this position, the ganglion cell for each of the circular fields increases its firing. (The fields shown here have on centers.) The ganglion cells are connected to the same simple cell, which also increases firing, indicating that an edge has been detected. This particular arrangement would be specialized for a vertical light edge.

But so far, Hubel and Wiesel had seen only the beginnings of the intricate neural organization that makes visual perception possible. They lowered electrodes perpendicularly through a monkey’s striate cortex; as the electrode passed through simple and complex cells, the cells’ preferred width and length changed, but they had the same orientation (Hubel & Wiesel, 1974). As the researchers moved the electrode slightly to the side, the orientation shifted slightly but systematically in a clockwise or counterclockwise direction; over a distance of 0.5 mm to 1.0 mm, the orientation would progress through the complete circle. Then the process would start over again, with the input coming from an adjacent part of the retina. This sort of organization is typical of the cortex’s efficiency in processing and transmitting information. Connections mostly run up and down in columns, with much shorter lateral connections. In addition, similar functions are clustered together, increasing communication speed and reducing energy requirements. Hubel and Wiesel shared the Nobel Prize for their work in 1981. However, their

model has limitations—some would say problems. For one thing, it accounts for the

detection of boundaries, but it is questionable whether edge detection cells can also handle the surface details that give depth and character to an image. FIGURE 10.21 Hubel and Wiesel’s Explanation for Responses of Complex Cells. A complex cell receives input from several simple cells, each of which serves a group of circular fields (as in Figure 10.20). As a result, the complex cell continues to respond as the illuminated edge moves to the left or to the right. (Ganglion cells have been eliminated for simplicity.)

Spatial Frequency Theory Although some cortical cells respond best to edges (Albrecht, De Valois, & Thorell,

1980; De Valois, Thorell, & Albrecht, 1985; von der Heydt, Peterhans, & Dürsteler, 1992), other cells apparently are not so limited. Think of an edge as an abrupt or high- frequency change in brightness. The more gradual changes in brightness across the surface of an object are low-frequency changes. According to De Valois, some complex cells are “tuned” to respond to the high frequencies found in an object’s border, while others are tuned to low frequencies, for example, in the slow transition from light to shadow that gives depth to the features of a face (De Valois et al., 1985). Some cells respond better to “gratings” of alternating light and dark bars—which contain a particular combination of spatial frequencies—than they do to lines and edges. According to spatial frequency theory, visual cortical cells do a Fourier frequency analysis of the luminosity variations in a scene (see Chapter 9 to review Fourier analysis). According to this view, different visual cortical cells have a variety

of sensitivities, not just those required to detect edges (Albrecht et al., 1980; De Valois et al., 1985).

Is spatial frequency theory a better explanation? A few photographs should help you understand what we mean by spatial

frequencies, as well as the importance of low frequencies. The picture in Figure 10.22a was prepared by having a computer average the amount of light over large areas in a photograph; the result was a number of high-frequency transitions, and the image is not very meaningful. In Figure 10.22b, the computer filtered out the high frequencies, producing more gradual changes between light and dark (low frequencies). It seems paradoxical that blurring an image would make it more recognizable, but blurring eliminates the sharp boundaries. You can get the same effect from Figure 10.22a by looking at it from a distance or by squinting. In Figure 10.22c, the Spanish artist Salvadore Dali incorporated the illusion in one of his more famous paintings. A real-life example in Figure 10.23 suggests what our visual world might be like if we were limited to high frequencies or low frequencies. FIGURE 10.22 Illustration of High and Low Frequencies in a Visual Scene. (a) An image limited to abrupt changes in brightness (high spatial frequencies) is not as meaningful as (b) one that has both high- and low-frequency information. The image in (b) is the same image as (a), except that the edges have been blurred. (c) Salvadore Dali’s 1976 painting Gala Contemplating the Mediterranean Sea Which at Twenty Meters Becomes a Portrait of Abraham Lincoln. Look closely and you will see (a) rather than Dali’s wife Gala; squint your eyes and you will see (b).

SOURCES: (a) and (b) From “Masking in Visual Recognition: Effects of Two- Dimensional Filtered Noise,” by L. D. Harmon and B. Julesz, Science, 180, pp. 1194–1197. Reprinted with permission from AAAS. (c) © 2010 Salvador Dalí, Gala- Salvador Dalí Foundation/Artists Rights Society (ARS), New York. FIGURE 10.23 The Role of High and Low Frequencies in Vision. (a) The original photo; (b) the same photo with low frequencies removed; (c) the photo with high frequencies removed. Notice how high-frequency changes in contrast define borders and fine details, while low frequencies reveal distinguishing

Concept Check

characteristics through shadow and texture.

SOURCE: © Bob Garrett. So far, we have dealt only with the simplest aspects of visual perception. But we

also are able to recognize an object as an object, assign it color under varied lighting conditions, and detect its movement. Attempting to explain these capabilities will provide challenge enough for the rest of this chapter.

Take a Minute to Check Your Knowledge and Understanding

Explain how the opponent arrangement of a ganglion cell’s field enhances brightness contrast.

How did Hubel and Wiesel explain our ability to detect an edge, the orientation of an edge or a line, and an edge or a line that changed its location?

How do Hubel and Wiesel’s theory and the spatial frequency theory differ?

The Perception of Objects, Color, and Movement One of the more interesting characteristics of the visual system is how it dissects an image into its various components and analyzes them in different parts of the brain. The separation begins in the retina and increases as visual information flows through all four lobes of the brain, with locations along the way carrying out analyses of color, movement, and other features of the visual scene. Thus, we will see how visual processing is, as I mentioned earlier, both modular and hierarchical. Modular processing refers to the segregation of the various components of processing into separate locations. Hierarchical processing means that lower levels of the nervous system analyze their information and pass the results on to the next higher level for further analysis. Some neuroscientists reject the modular notion, arguing that any visual function is

instead distributed, meaning that it occurs across a relatively wide area of the brain.

One study found evidence that sensitivity to faces, for example, is scattered over a large area in the temporal lobe (Haxby et al., 2001). Research has not resolved the modular-distributed controversy, leaving researchers to quarrel over the interpretation of studies that seem to support one view or the other (J. D. Cohen & Tong, 2001). Vision may well involve a mix of modular and distributed functioning, rather like the arrangement we saw for language. With this thought in mind, we will consider what is known about the pathways and functional locations in the visual system.

What do the parvocellular and magnocellular systems do? The Two Pathways of Visual Analysis Most visual information follows two routes from the retina through the brain,

which make up the parvocellular system and the magnocellular system (Livingstone & Hubel, 1988; P. H. Schiller & Logothetis, 1990). Parvocellular ganglion cells are smaller than magnocellular cells, account for the large majority of ganglion cells, and are most numerous in the fovea. They have circular receptive fields that are small and color opponent, which suits them for the specialties of the parvocellular system, the discrimination of fine detail and color. Magnocellular ganglion cells have large circular receptive fields that are brightness opponent and respond rapidly but only briefly to stimulation. As a result, the magnocellular system is specialized for brightness contrast and for movement. FIGURE 10.24 Color Contrast and Brightness Contrast Stimulate Different Visual Systems. Image (a) has considerable brightness contrast, so it mostly stimulates the magnocellular system, giving an appearance of depth. Image (b) consists of color contrast, which provides little stimulation to the magnocellular system.

SOURCE: From “Segregation of Form, Color, Movement, and Depth: Anatomy, Physiology, and Perception,” by M. Livingstone and D. Hubel,” Science, 240, pp.

740–749. Copyright 1988, Reprinted with permission from American Association for the Advancement of Science (AAAS). We see evidence of differences in the two systems in our everyday lives. The

simplest example is that at dusk our sensitivity to light increases, but we lose our ability to see color and detail. You cannot read a newspaper under such conditions or color coordinate tomorrow’s outfit, because the high-resolution, color-sensitive parvocellular system is nearly nonfunctional. The magnocellular system’s sensitivity to movement is most obvious in your peripheral vision. Hold your arms outstretched to the side while you look straight ahead, and move your hands slowly forward while wriggling your fingers. When you just notice your fingers moving, stop. Notice that you can barely see your fingers but you are very sensitive to their movement. Figure 10.24 is a striking demonstration of another capability of the magnocellular system, depth perception. Notice that you see considerable depth in (a); this is because the bicycle differs from the background in brightness, so the image stimulates primarily the magnocellular system. The bicycle in (b) looks “flat”; the image has color contrast but little brightness contrast, so it stimulates the magnocellular system minimally. FIGURE 10.25 The Ventral “What” and Dorsal “Where” Streams of Visual Processing.

Both pathways travel to the lateral geniculate nucleus and then to the primary visual cortex, which is also known as V1. Although the two systems are highly interconnected, the parvocellular system dominates the ventral stream, which flows from the visual cortex into the temporal lobes, and the magnocellular system dominates the dorsal stream from the visual cortex to the parietal lobes (Figure 10.25). Like the two auditory pathways, the ventral stream is often referred to as involved with the what of visual processing, and the dorsal stream with the where.

Most of the research on this topic has been done with monkeys, but the two pathways have been confirmed with PET scans in humans (Ungerleider & Haxby, 1994).

What are the functions of the ventral and dorsal streams? Beyond V1, the ventral stream passes through V2 and into V4, which is mostly

concerned with color perception. It then projects to the inferior temporal cortex, which is the lower boundary of the temporal lobe; this area shows a remarkable specialization for object recognition, which we will examine shortly. Magnocellular neurons arrive in V1 in areas that are responsive to orientation,

movement, and retinal disparity (Poggio & Poggio, 1984). The dorsal stream then proceeds through V2 to V5, also known as MT because it is on the middle temporal gyrus in the monkey; neurons there have strong directional sensitivity, which contributes to the perception of movement. The dorsal stream travels then to the posterior parietal cortex, the area just behind the somatosensory cortex; its role is primarily to locate objects in space, but the behavioral implications of its functions are far more important than that simple statement suggests. Movement perception is a good example of how modular and distributed

processing work together. V5/MT and a nearby area that receives input from MT, known as MST (for medial superior temporal area), appear to be the most important areas for perceiving movement. They receive most of their input from the magnocellular pathway, including complex cells that are sensitive to movement; they also respond when the motion is only implied in a photograph of an athlete in action or a picture of a cup falling off a table (reviewed in Culham, He, Dukelow, & Verstraten, 2001). At the same time, there are many other areas that are specialized for particular kinds of movement. Viewing movement of the human body or its parts activates dorsal stream areas adjacent to V5/MT and MST, in the parietal and frontal lobes, and in the ventral stream in the temporal lobes (Vaina, Solomon, Chowdhury, Sinha, & Belliveau, 2001; Wheaton, Thompson, Syngeniotis, Abbott, & Puce, 2004). Images move across your retinas every time you move your eyes, but you don’t see

the world moving around you. (Imagine trying to read, otherwise.) This is because the activity of movement-sensitive cells in MT and MST is suppressed during eye movements (Thiele, Henning, Kubischik, & Hoffmann, 2002). These cells are sensitive to movement in a particular direction, and some of them reverse their preferred direction of movement as the head moves, which allows them to continue responding to real movement of objects. The brain’s visual movement areas are close to an area that analyzes input from the vestibular organs, which monitor body motion (Thier, Haarmeier, Chakraborty, Lindner, & Tikhonov, 2001); you are already indirectly familiar with this fact if you get motion sickness in a moving car when you read or when you watch roadside objects too closely. The functions of the ventral and dorsal streams are best illustrated by a comparison

of patients with damage in the two areas. People with damage in the temporal cortex (ventral stream) have trouble visually identifying objects, but they can walk toward or around the objects and reach for them accurately (Kosslyn, Ganis, & Thompson, 2001). People with damage to the dorsal stream have the opposite problem. They can identify objects, but they have trouble orienting their gaze to objects, reaching accurately, and shaping their hands to grasp an object using visual cues (Ungerleider & Mishkin, 1982). So the dorsal stream is also a “how” area that is important for action. From the parietal and temporal lobes, the dorsal and ventral streams both proceed

into the prefrontal cortex. One function of the prefrontal cortex is to manage this information in memory while it is being used to carry out the functions that depend on the two pathways (Courtney, Ungerleider, Keil, & Haxby, 1997; F. A. Wilson, Ó Scalaidhe, & Goldman-Rakic, 1993). As one example, we will see in Chapter 11 that the prefrontal cortex integrates information about the body and about objects around it during the planning of movements. Disorders of Visual Perception Because the visual system is somewhat modular, damage to a processing area can

impair one aspect of visual perception while all others remain normal. This kind of deficit is often called an agnosia, which means “lack of knowledge.” Because the disorders provide a special opportunity for understanding the neural basis of higher- order visual perception, we will orient our discussion of the perception of objects, color, movement, and spatial location around disorders of those abilities. Object and Face Agnosia Object agnosia is the impaired ability to recognize objects. In Chapter 3, I

described Oliver Sacks’s (1990) agnosic patient who patted parking meters on the head, thinking they were children; he was also surprised when carved knobs on furniture failed to return his friendly greeting. Dr. P. was intellectually intact; he continued to perform successfully as a professor of music, and he could carry on lively conversations on many topics. Patients with object agnosia are able to see an object, describe it in detail, and identify it by touch. But they are unable to identify an object by sight or even to recognize an object from a picture that they have just drawn from memory (Gurd & Marshall, 1992; Zeki, 1992). Object agnosia is caused by damage to the inferior temporal cortex (see Figure

10.25 again); this part of the ventral stream is where information about edges, spatial frequencies, texture, and so on is reassembled to form perceptions of objects. Cells have been located there in monkeys and humans that respond selectively to geometric figures, houses, animals, hands, faces, or body parts (Figure 10.26a; Desimone, Albright, Gross, & Bruce, 1984; Downing, Jiang, Shuman, & Kanwisher, 2001; Gross, Rocha-Miranda, & Bender, 1972; Kreiman, Koch, & Fried, 2000; Sáry, Vogels, & Orban, 1993). Some of these cells require very specific characteristics of a

stimulus, such as a face viewed in profile; others continue to respond in spite of changes in rotation, size, and color (Figure 10.26b; Miyashita, 1993; Tanaka, 1996; Vogels, 1999). The latter group of cells likely receive their input from cells with narrower sensitivities (Tanaka, 1996), like those in V1 that detect edges. The inferior temporal cortex also has a columnar organization reminiscent of what we saw in V1; a column of object-responsive cells might respond to variations on a starlike shape, for example, and a column adjacent to one that responds to a frontal view of a face is activated by a face in profile (Tanaka, 2003). “

I was having a wonderful conversation with a woman at a party, but then I went to get us some drinks. When I returned, I had forgotten what she looked like, and I was unable to find her the rest of the evening.

—A young man with prosopagnosia

” FIGURE 10.26 Stimuli Used to Produce Responses in “Hand-” and “Face-” Sensitive Cells in Monkeys. (a) The stimuli are ranked in order of increasing ability to evoke a response in a hand-sensitive cell. (b) The spikes recorded from a face-sensitive cell indicate the degree of response from the stimulus shown below.

SOURCES: (a) From “Visual Properties of Neurons in Inferotemporal Cortex of the Macaque,” by C. G. Gross et al., 1972, Journal of Neurophysiology, 35. Reprinted with permission. (b) From “Stimulus-Selective Properties of Inferior Temporal Neurons in the Macaque,” by R. Desimone et al., p. 2057. in Journal of Neuroscience, 4, 1984. Like Dr. P., many object agnosic patients also suffer from prosopagnosia, an

impaired ability to visually recognize familiar faces. The problem is not memory, because they can identify individuals by their speech or mannerisms. Nor is their visual acuity impaired; they often have no difficulty recognizing facial expressions,

gender, and age (Tranel, Damasio, & Damasio, 1988). However, they are unable to recognize the faces of friends and family members or even their own image in a mirror (Benton, 1980; A. R. Damasio, 1985). Prosopagnosia has a variety of causes, including stroke, carbon monoxide poisoning, and Alzheimer’s disease. Damage usually impairs the ability to recognize both objects and faces, but the occasional case is reported of a patient with prosopagnosia alone (Benton, 1980) or of object agnosia with spared face identification (Behrmann, Moscovitch, & Winocur, 1994). While some processing of face information goes on in the inferior temporal cortex,

recognizing individual faces requires additional structures. In humans, a part of the fusiform gyrus on the underside of the temporal lobe is so important to face recognition that it is referred to as the fusiform face area (FFA). Damage that results in prosopagnosia is usually in the right hemisphere (see Figure 10.27; Bouvier & Engel, 2006; Gauthier, Skudlarski, Gore, & Anderson, 2000; Gauthier, Tarr, Anderson, Skudlarski, & Gore, 1999), but face processing is a cooperative effort involving both sides of the brain. Facelike images produce activity in the left fusiform gyrus that strengthens as the resemblance to a face increases; about 2 seconds later, the right fusiform gyrus increases its activity only when the image is of a human face (Meng, Cherian, Singal, & Sinha, 2012). FIGURE 10.27 Location of Brain Damage in Patients With Prosopagnosia. The color of the area indicates how often damage was observed there in patients with prosopagnosia.

SOURCE: From “Behavioral Deficits and Cortical Damage Loci in Cerebral Achromatopsia,” by S. E. Bouvier and S. A. Engel, 2006, Cerebral Cortex, 16, pp. 183–191, by permission of Oxford University Press. Until recently, researchers thought the only way prosopagnosia occurred was

through brain damage. Then medical student Martina Grueter began to recognize the symptoms in her husband’s behavior and made congenital prosopagnosia the subject of her MD thesis (Grueter, 2007). An estimated 2.5% of the population has symptoms of the disorder without any history of brain damage (Kennerknecht et al., 2006); as a result, they make errors in recognizing familiar faces, and they learn new faces slowly (Grüter, Grüter, & Carbon, 2008). Afflicted individuals include noted primatologist

Jane Goodall, actor Brad Pitt, and Oliver Sacks, the neurologist who studied Dr. P. Face recognition ability has a heritability of about 39% (Zhu et al., 2010), so its deficiency in the absence of brain damage has a genetic origin. The defect, though, does not appear to be in the fusiform face area; fMRI shows that the FFA responds just as much to faces in prosopagnosics as it does in normal individuals. Instead, connections of the FFA to more anterior temporal and frontal cortex areas are diminished (Avidan & Behrmann, 2009), suggesting that face recognition is a distributed function, in spite of modularity of its components. These capabilities might be “hardwired” at birth to some extent, but they also are

amenable to learning. When researchers showed monkeys pictures of the faces of lab workers, neurons in the inferior temporal cortex increased their firing rates according to the monkeys’ familiarity with the workers (M. P. Young & Yamane, 1992). Isabel Gauthier and her colleagues (1999) trained humans to identify faces, using pictures of fictitious creatures they called “greebles” to ensure initial unfamiliarity. The fMRI scans in Figure 10.28 show that pictures of human faces activated the fusiform face area but greebles did so only after the person had learned to recognize individual creatures.

6 Face Blindness and Blindsight Prosopagnosics do respond emotionally to photographs of familiar faces they do

not recognize, as indicated by EEG evoked potentials and skin conductance response (Bauer, 1984; Renault, Signoret, Debruille, Breton, & Bolger, 1989; Tranel & Damasio, 1985). This “hidden perception” is not without precedent. Patients blinded by damage to V1 show a surprising ability to track the movement of objects and discriminate colors, all the while claiming to be guessing (Zeki, 1992). Cortically blind individuals also can identify emotions expressed in faces they do not otherwise see (Tamietto et al., 2009), and they can avoid obstacles while walking, as the video in WWW 6 shows. This ability to respond to visual stimuli that are not consciously seen is called blindsight. Imaging studies have found that blindsight depends on pathways passing through the superior colliculus directly to extrastriate areas, bypassing V1 (reviewed in de Gelder & Tamietto, 2007; Tamietto et al., 2010). A nearby area in the inferior temporal cortex has an intriguingly similar “object”

recognition function; the visual word form area (VWFA) responds to written words as a whole. Its importance in reading was demonstrated in a patient whose VWFA was disconnected from adjacent language areas by surgery intended to remove tissue that was causing epileptic seizures (Gaillard et al., 2006). Before surgery, the patient could recognize familiar words of any length in less than a second; following surgery, the time had almost doubled for three-letter words and increased by an additional 100 ms for each additional letter, indicating that he was deciphering words letter by letter. Performance in identifying faces, tools, and houses was unaffected. The VWFA is

typically underactivated in adult dyslexics during reading (McCandliss & Noble, 2003), but, consistent with what we saw in Chapter 9, the authors suggest that this is not the cause of the dyslexia but the result of phonological deficits that interfere with learning rapid word recognition. It is clear that the VWFA could not have evolved as a dedicated whole word detector, because written language is a relatively recent invention; still, it serves that function so precisely that two words evoke activity in different subareas, even when the words differ by just one letter (Glezer, Jiang, & Riesenhuber, 2009). What is intriguing about the VWFA is that, for whatever reason, the area has evolved special capabilities that suit it for learning to identify words as if they are unique visual “objects.” FIGURE 10.28 Activity in the Fusiform Face Area While Viewing Faces and “Greebles.” Viewing faces activated a part of the fusiform gyrus (indicated by the white squares) both in “greeble novices” and in “greeble experts,” who had learned to distinguish individual greebles from each other. Viewing greebles activated the area only in greeble experts. (Red indicates more activation than yellow.)

SOURCE: From “Activation of the Middle Fusiform ‘Face Area’ Increases With Expertise in Recognizing Novel Objects,” by I. Gauthier et al., Nature Neuroscience, 2, pp. 568–573. © 1999 Nature Publishing Group. Color Agnosia Let’s return to Jonathan I., whose plight was described in the beginning of the

chapter. Jonathan’s problem was color agnosia, which is the loss of the ability to perceive colors due to brain damage. But before we can discuss this disorder, we need to revisit the distinction between wavelength and color. Once as I walked past a colleague’s slightly open office door, I was astonished to see that his face was a

distinct green! Opening his door to investigate, I understood why: The light from his desk lamp was reflecting off a bright green brochure he was reading. Immediately his face appeared normal again. This ability to recognize the so-called natural color of an object in spite of the illuminating wavelength is called color constancy. If not for color constancy, objects would seem to change colors as the sun shifted its position through the day or as we went indoors into artificial light. Imagine having to survive by identifying ripe fruit if the colors kept changing.

How is color coding different from wavelength coding? When I reinterpreted my colleague’s skin color, it was not because I understood

that his face was bathed in green light; it occurred automatically as soon as my eyes took in the whole scene. Monkeys, who do not understand the principles of color vision, apparently have the same experience. When Zeki (1983) illuminated red, white, green, and blue patches with red light, each patch set off firing in V1 cells that preferred long-wavelength (red) light, regardless of its actual color; however, cells in V4 responded only when the patch’s actual color matched the cell’s color “preference.” Zeki concluded that cells in V1 are wavelength coded, while cells in V4 are color coded. Schein and Desimone (1990) suggested how V4 cells provide color constancy. They have large circular receptive fields that are color opposed; so if, for example, a green light falling on the center increases the cell’s firing rate, green light falling simultaneously in the surround reduces or eliminates the increase. In other words, the cells “subtract out” the color of any general illumination. It was my V4 cells that allowed me to see my colleague’s face as a normal pink rather than as the green that it was reflecting. We have no brain scan to tell us where Jonathan I.’s damage was located, but we

know that cortical color blindness, or cerebral achromatopsia, occurs when people have lesions between V1 and the fusiform face area (Heywood & Kentridge, 2003; Witthoft et al., 2013); this is where V4 is located, but it is unclear whether the deficiency can be attributed to V4 malfunction. Unlike Jonathan I., many patients are unaware their color vision is impaired, just as we saw in Chapter 9 with Wernicke’s aphasia. Movement Agnosia Although movement is detected by neurons in V1 and beyond, area V5/MT is the

place where that information is integrated; MT (for middle temporal area) also helps direct reaching movements and eye movements when tracking objects (Born & Badley, 2005; Whitney et al., 2007). A 43-year-old woman known in the literature as LM suffered a stroke that caused bilateral damage in the general area of MT; the result was movement agnosia, an impaired ability to detect movement (Vaina, 1998; Zihl, Cramon, & Mai, 1983). Although her vision was otherwise normal, she could distinguish between moving and stationary objects only in her peripheral view, she

had difficulty making visually guided eye and finger movements, and she had trouble detecting the movement of people if there were more than two people in the room. She was often surprised to notice that an object had changed position (Zihl et al., 1983). You might think that perceiving a change in position would be the same thing as perceiving movement, but she had no sense of the object traveling through the intermediate positions. When she poured coffee, she could not tell that the liquid was rising in the cup, so she would keep pouring until the cup overflowed! When she tried to cross a street, a car would seem far away, but then suddenly very near. Later analyses indicated that LM’s most severe impairment was in her ability to

detect radial movement (Vaina, 1998). We experience radial movement when the image of an approaching car expands outwardly, or radially. Radial movement also tells us that we are approaching an object when we walk or drive, because all the environmental objects around the central point appear to move outward; this effect provides information about our heading and is important for personal navigation. A patient with impaired perception of radial movement could not catch a ball that was thrown to him, and he frequently bumped into people in his wheelchair. Scans done while subjects perform a task involving radial movement or heading detection implicate the area MST (for medial superior temporal area, where it is located), which receives its input from MT (Peuskens, Sunaert, Dupont, Van Hecke, & Orban, 2001; Vaina). “

I knew the word “neglect” was a sort of medical term for whatever was wrong but the word bothered me because you only neglect something that is actually there, don’t you? If it’s not there, how can you neglect it?

—P. P., a neglect patient

” Neglect and the Role of Attention in Vision The posterior parietal cortex combines input from the visual, auditory, and

somatosensory areas to help the individual locate objects in space and to orient the body in the environment. Damage impairs abilities such as reaching for objects, but it also often produces neglect, in which the patient ignores visual, touch, and auditory stimulation on the side opposite the injury. The term neglect seems particularly appropriate in patients who ignore food on the left side of the plate, shave only the right side of the face, or fail to dress the left side of the body. The manifestations are largely, but not entirely, visual, and they are more likely to occur on the left side of the body, following right-hemisphere damage. (Because the symptoms affect one side of space, the term hemispatial neglect is often used.) Neglect is not due to any defect in visual processing, but rather it is due to a deficit

in attention; it illustrates the fact that to the extent attention is impaired, so is visual functioning. Two patients with this condition, caused by right parietal tumors, were asked to report whether words and pictures presented simultaneously in the left and right visual fields were the same or different. They said that the task was “silly” because there was no stimulus in the left field to compare, yet they were able to answer with a high level of accuracy (Volpe, LeDoux, & Gazzaniga, 1979). Their performance is superior to that of blindsighted individuals, which supports the contention that neglect is a deficit in attention rather than in vision. Patients’ drawings and paintings help us understand what they are experiencing.

When asked to copy drawings, they will neglect one side while completing the other side in detail, like the example in Figure 10.29. The two portraits in Figure 10.30 were painted by Anton Raderscheidt 2 and 9 months after a stroke that damaged his right parietal area. Notice that the first painting has very little detail and the left half of the image is missing. In the later painting, he was using the whole canvas, and the portrait looks more normal; but notice that the left side is still much less developed than the right, with the eyeglasses and face melting into ambiguity (Jung, 1974). FIGURE 10.29 Drawings Copied by a Left-Field Neglect Patient.

SOURCE: From Brain, Mind, and Behavior (2nd ed.; p. 300), by F. E. Bloom and A. Lazerson. © 1988 W. H. Freeman & Co. The Problem of Final Integration We have seen how the brain combines information about some aspects of an object,

but many researchers wonder where all the information about the object is brought together; how the brain combines information from different areas into a unitary whole is known as the binding problem. Imagine watching a person walking across your field of view; the person is moving, shifting orientation, and changing appearance as the lighting increases and decreases under a canopy of trees. At the same time, you are walking toward the person, but your brain copes easily with the changing size of the person’s image and the apparent movement of environmental objects toward you. It seems logical that a single center at the end of the visual pathway would combine all the information about shape, color, texture, and movement, constantly updating your perception of this image as the same person. In other words, the result would be a complete and dynamic awareness. Presumably, damage to that area would produce symptoms that are similar to blindsight but that affect all stimuli. FIGURE 10.30 Self-Portraits Demonstrating Left Visual Field Neglect. (a) A self-portrait done 2 months after the artist’s stroke, which affected the right parietal area, is incomplete, especially on the left side of the canvas. (b) One done 9 months after the stroke is more complete but still shows less attention to detail on the left side. SOURCE: © 2013 Artists Rights Society (ARS), New York/VG Bild-Kunst, Bonn.

It has been suggested that our ultimate understanding of an object occurs in a part of the superior temporal gyrus that receives input from both neural streams (Baizer, Ungerleider, & Desimone, 1991) or in the part of the parietal cortex where damage causes neglect (Driver & Mattingley, 1998). Other investigators suspect frontal areas where both streams converge. But these ideas are highly speculative, and there is no convincing evidence for a master area where all perceptual information comes together to produce awareness (Crick, 1994; Zeki, 1992). The variety of hypothesized awareness centers suggests another possibility, that visual awareness is distributed throughout the network of 32 areas of cortex concerned with vision and their 305

interconnecting pathways (Van Essen, Anderson, & Felleman, 1992). This thinking is exemplified on a small scale in the interaction between V5/MT and V1. After a stimulus occurs, activity continues back and forth between these areas for a few hundred milliseconds, and disrupting this interchange eliminates awareness of movement (reviewed in McKeefry, Gouws, Burton, & Morland, 2009).

APPLICATION

When Binding Goes Too Far Before his accident, Jonathan I. saw a “tumult” of changing colors whenever he listened to music. For other people with synesthesia, each letter may have its own characteristic color, days of the week may have personalities, visual motion might produce sounds, or words might have tastes. Synesthesia is a condition in which stimulation in one sense triggers an experience in another sense or a concept evokes an unrelated sensory experience. Over 60 varieties of synesthesia have been documented, and most synesthetes report more than one form (Brang & Ramachandran, 2011). Synesthesia was thought to be rare, based on the number of people who came forward to report these experiences, but when Julia Simner and her colleagues (2006) tested 1,700 individuals who were not self-referred, almost 5% showed some characteristics of synesthesia. A third of those were projectors, who actually experience the unrelated color or sound or taste, and the rest were associators, who have a persistent mental association between, for example, a word and a color but don’t report that they see the color. Synesthesia is a neurological phenomenon; fMRI studies show that area V4 is active when grapheme/color synesthetes view letters and numbers and when auditory word/color synesthetes listen to spoken words (see figure; Hubbard, Arman, Ramachandran, & Boynton, 2005; Nunn et al., 2002).

7 Synesthesia and Synesthetes There are two competing hypotheses as to why synesthetes “overbind”

sensory information: Either there is excess connectivity among the involved brain areas, or there is inadequate inhibition in otherwise normal pathways in the brain. Studies favor the connectivity hypothesis; a diffusion tensor imaging MRI study (suited for imaging white matter) indicated more pronounced connections in grapheme/color synesthetes in the inferior temporal, parietal, and frontal cortex—all areas involved in processing and integrating visual information (Rouw & Scholte, 2007). Synesthesia runs strongly in families, and at least four of the five chromosomal areas implicated so far contain genes for axon guidance and cortical development (Asher et al., 2009; Thomson et

Concept Check

al., 2011).

Spoken words activate left-hemisphere area V4 in a synesthete but not in a control. Why do you think this activity occurred mostly in the left hemisphere? SOURCE: From “Functional Magnetic Resonance Imaging of Synesthesia: Activation of V4/V8 by Spoken Words,” by J. A. Nunn et al., 2002, Nature Neuroscience, 5, pp. 371–375.

By all rights, synesthesia could be considered a brain disorder, but other than being a bit of a distraction, it is relatively benign and, like Jonathan I., many synesthetes enjoy their enriched sensory experience. Besides, they often have no idea they are any different from anybody else. Julian Asher, who led the genetic study described above, discovered his synesthesia only when, as a child attending a symphony concert with his parents, he remarked, “Oh, they turned the lights off so you could see the colors” (“Seeing Color,” 2000).

Actually, the brain’s task is a balancing act between combining relevant information and segregating inconsequential information, as the Application on synesthesia shows. We will spend more time examining how the brain sorts out and uses information when we talk about consciousness in the final chapter.

Take a Minute to Check Your Knowledge and Understanding

Explain why higher-order processing is required to recognize the natural color of objects; how does it work?

Draw a diagram of the brain, add lines showing the two major visual pathways, and label the various areas; for the higher-order processing areas, include their functions.

In Perspective

Very few subjects in the field of biological psychology can match the interest that researchers have bestowed on vision. As a result, we know more about the neuroanatomy and functioning of vision than any other neural system. Still, many challenges remain in the field of vision research. Researchers’ fascination with vision goes beyond the problems of vision itself. Our

understanding of the networks of neurons and structures in the visual system provides a basis for developing theories to explain other functions as well, including the integration of complex information into a singular awareness. Whatever directions future research might take, you can be sure that vision will continue to be one of the most important topics. Summary Light and the Visual Apparatus

• The human eye is adapted to the part of the electromagnetic spectrum that is reflected from objects with minimal distortion. Wavelength is related to the color of light but is not synonymous with it.

• The retina contains rods, which are specialized for brightness discrimination, and cones, which are specialized for detail vision and discrimination of colors. The cells of the retina are highly interconnected to carry out some processing at that level.

• The optic nerves project to the two hemispheres so that information from the right visual field goes to the left visual cortex, and vice versa.

Color Vision • There are three types of cones, each containing a chemical with peak sensitivity to a different segment of the electromagnetic spectrum.

• Connections of the cones to ganglion cells provide for complementary colors and for perception of yellow as a unique color.

• The most common cause of partial color blindness is the lack of one of the photochemicals.

Form Vision • Form vision begins with contrast enhancement at edges by ganglion cells with light- opponent circular fields.

• These ganglion cells contribute to cortical mechanisms that detect edges (Hubel and Wiesel’s theory) or that perform a Fourier analysis of a scene (spatial frequency theory).

The Perception of Objects, Color, and Movement • Most visual information follows two somewhat separate paths through the brain, which are part of the magnocellular and parvocellular systems.

• Structures along the way are specialized for different functions, including color, movement, object perception, and face perception.

• We do not know how or where the components of vision are combined to form the

percept of a unified object. One suggestion is that this is a distributed function. ■ Study Resources

For Further Thought • Red and green are complementary colors and blue and yellow are complementary because their receptors have opponent connections to their ganglion cells. How would you explain the fact that bluish green and reddish yellow (orange) are also complementary?

• Considering what you know about the retina, how would you need to direct your gaze to read a book or to find a very faint star?

• Explain why the visual system analyzes an object’s edges, texture, and color and then detects the object, instead of the other way around.

• Are Hubel and Wiesel’s theory and the spatial frequency theory opposed or complementary theories?

• Cones in the bird retina detect blue, green, red, and ultraviolet. Can you imagine what they might gain from detecting ultraviolet reflections from objects in their environment? Then check http://en.wikipedia.org/wiki/Bird_vision (see the section “Ultraviolet”); you might be surprised by some of the benefits!

Quiz: Testing Your Understanding 1. Summarize the trichromatic and Hurvich-Jameson theories, indicating what

facts about color vision each accounts for. 2. Compare the specialized sensitivities of simple and complex visual cortical

cells; describe the interconnections among ganglion cells, simple cells, and complex cells that account for their specializations (according to Hubel and Wiesel).

3. The visual system appears to be more or less hierarchical and modular. What does this mean? (Use examples to illustrate.)

Select the best answer: 1. The receptive field of a cell in the visual system is the part of the ____ from

which the cell receives its input. a. external world b. retina c. lateral geniculate d. cortex

2. Mixing red and green lights produces a sensation of yellow because red- sensitive and green-sensitive cones a. excite yellow/blue ganglion cells. b. have opposite effects at yellow/blue ganglion cells. c. excite red/green ganglion cells.

d. have opposite effects at red/green ganglion cells. 3. If our experience of color were entirely due to the wavelength of light

reflected from an object, we would not experience a. complementary b. the color yellow colors. c. primary colors. d. color constancy.

4. The parvocellular system is specialized for a. fine detail and movement. b. color and fine detail. c. color and movement. d. movement and brightness contrast.

5. Retinotopic map refers to a. a projection of an image on the retina by the lens. b. the upside-down projection of an image. c. the way the visual neurons connect to the cortex. d. the connections among the cells in the retina.

6. Cutting the optic nerve between the right eye and the chiasm would cause a loss of vision in a. the left visual field. b. the right visual field. c. half of each visual field. d. neither field, due to filling in.

7. People with red-green color blindness a. cannot see either red or green. b. see red and green as black. c. confuse red and green because they lack either “red” or “green” cones. d. confuse red and green because they lack one of the photopigments.

8. The enhanced apparent brightness of a light edge next to a dark edge is due to the fact that the neurons stimulated by the light edge are inhibited a. less by their “dark” neighbors. b. more by their “dark” neighbors. c. less by their “light” neighbors. d. more by their “light” neighbors.

9. The ability of complex visual cortical cells to track an edge as it changes position appears to be due to a. input from receptors with similar fields. b. input from ganglion cells with similar fields. c. input from simple cells with similar fields. d. input from other complex cells.

10. According to the spatial frequency theory of visual processing, edges are detected by a. line-detecting cells in the visual cortex. b. edge detectors located in the visual cortex. c. cells that respond to low spatial frequencies. d. cells that respond to high spatial frequencies.

11. The circles represent the receptive field of a ganglion cell; the rectangle represents light. Unlike the illustrations in this chapter, the receptive field has an off center. In which situation will the ganglion cell’s rate of firing be greatest?

12. Studies of object, color, and movement agnosias indicate that a. the visual system is unstable and malfunctions with no apparent cause. b. components of the visual image are processed separately. c. color, object identification, and movement information are integrated in

one place. d. all functions are processed in one place but the results are distributed to

other parts of the brain. 13. Movement perception is the primary function in visual area

a. V1. b. V2. c. V4. d. V5.

14. A person who has trouble identifying objects visually probably has damage in the a. temporal lobe. b. parietal lobe. c. occipital lobe. d. frontal lobe.

Answers: 1. b, 2. a, 3. d, 4. b, 5. c, 6. c, 7. d, 8. a, 9. c, 10. d, 11. b, 12. b, 13. d, 14. a.

Online Resources The following resources are available at

edge.sagepub.com/garrett4e. Select your country, click on Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. Webvision is essentially an online text covering numerous topics in vision.

Photoreceptors, a part of that site, details the structure of rods and cones with high magnification images; some animations are also available.

2. Magic Eye has a collection of 3-D stereograms and an explanation of how they work. Eye Tricks also offers Stereograms, as well as Optical Illusions; illusions are more than entertainment because they demonstrate principles of visual processing.

3. Videos show the Argus II implantable retina; the surgery to implant the Argus (not for the squeamish); an Alpha IMS recipient describing what he sees; a blind man who “sees” using BrainPort, which transmits a video image to an array of electrodes on his tongue; and Corey Haas, whose improved vision allows him to live a normal life after gene therapy.

4. Causes of Color is a well-designed site with numerous exhibits on color in the real world and sections on color vision. Colorblindness has very helpful information and illustrations, and the third page has an interactive demonstration of seven forms of color blindness. Neitzvision features color-blindness demonstrations and the research of Jay and Maureen Neitz, including a recent study in which inserting a human gene for the long-wave receptor turned dichromatic (red-green color-blind) monkeys into trichromats.

5. Sensation and Perception at Hanover College covers topics from receptive fields to illusions.

6. Faceblind is the website of prosopagnosia research centers at Dartmouth, Harvard, and University College, London. Prosopagnosia, at Wikipedia, features a rotating brain that provides a 3-D view of the fusiform face area’s location. Blindsight: Seeing Without Knowing It is a Scientific American article with a fascinating video of a man using blindsight to walk down a hallway filled with obstacles.

7. Hearing Motion is a video about motion synesthesia research, and Exactly

Like Breathing is a collection of interviews of synesthetes. Synesthesia is a Wikipedia article written by two researchers, and Neurophilosophy has an article on the genetics of synesthesia and another on tactile-emotion synesthesia.

Animations • Visual Projections to the Cortex (Figure 10.4) • Visual Detection of Edges (Figure 10.21)

Chapter Updates and Biopsychology News

For Further Reading 1. “The Case of the Colorblind Painter,” by Oliver Sacks (in Sacks’s An Anthropologist on Mars, 1995, Vintage Books), is a compelling narrative of the case of Jonathan I.

2. “Visual Object Recognition: Do We Know More Now Than We Did 20 Years Ago?” by Jessie Peissig and Michael Tarr (Annual Review of Psychology, 2007, 58, 75–96); “Mechanisms of Face Perception,” by Doris Tsao and Margaret Livingstone (Annual Review of Neuroscience, 2008, 31, 411–437); and “Perception of Human Motion,” by Randolph Blake and Maggie Shiffrar (Annual Review of Psychology, 2007, 58, 47–73), give extensive reviews of those topics.

3. The Science of Illusions, by Jacques Ninio (Cornell University Press, 2001), explains why we see illusions and how they help us understand vision. Masters of Deception: Escher, Dali & the Artists of Optical Illusion, by Al Seckel (Sterling, 2007), is a review of illusion and perception in art and literature.

4. The Astonishing Hypothesis, by Francis Crick (Scribner, 1994), is about the scientific search for consciousness; because the search focuses on visual awareness, it contains fascinating and readable information about vision.

Key Terms binding problem blindsight color agnosia color constancy complementary colors complex cell distributed dorsal stream form vision

fovea fusiform face area (FFA) hierarchical processing iodopsin lateral inhibition magnocellular system modular processing movement agnosia negative color aftereffect object agnosia opponent process theory parvocellular system photopigment prosopagnosia receptive field retina retinal disparity retinotopic map rhodopsin simple cell spatial frequency theory synesthesia trichromatic theory ventral stream visual acuity visual field visual word form area (VWFA)

C

11 The Body Senses and Movement

In this chapter you will learn • How the brain gets information about the body and the objects in contact with it • What causes pain and ways it can be relieved • How several brain structures work together to produce movement • What some of the movement disorders are and how they impair movement

The Body Senses Proprioception The Skin Senses The Vestibular Sense The Somatosensory Cortex and the Posterior Parietal Cortex Pain and Its Disorders APPLICATION: TREATING PAIN IN LIMBS THAT AREN’T THERE CONCEPT CHECK

Movement The Muscles The Spinal Cord The Brain and Movement IN THE NEWS: COORDINATING ARTIFICIAL LIMBS

Disorders of Movement IN THE NEWS: CURING PARKINSON’S IN A DISH CONCEPT CHECK

In Perspective Summary Study Resources

hristina was a healthy, active woman of 27. One day she began dropping things. Then she had trouble standing or even sitting upright; soon she was bedridden, lying motionless, speaking between shallow breaths in a faint and expressionless

voice, and with an equally expressionless face. A spinal tap indicated that she was suffering from neuritis, an inflammation of the nerves that is often caused by a viral infection. Neurological examination showed that, although she seemed paralyzed, her motor nerves were only slightly affected. She could move, but she could not control her movements or even her posture; if she failed to watch her hands, they wandered

aimlessly. She had lost all proprioception, the sense that collects information from our muscles and tendons and joints to tell us where our hands are and what movements our feet and legs are making. “

That’s what they do with frogs, isn’t it? They scoop out the centre, the spinal cord, they pith them.... That’s what I am, pithed, like a frog.

—Christina

” The neuritis did not last long, but in the meantime it had damaged her nerves, and

the damage was permanent. For a month, she was as floppy as a rag doll. But then she began to sit up, with an exaggeratedly erect posture, using only her vision for feedback. After a year of rehabilitation, she was able to leave the hospital, to walk and take public transportation and work at home as a computer programmer, all guided by vision. Christina never recovered from the damage to her nervous system, but she was able to make a remarkable compensation (Sacks, 1990). In the previous two chapters, we discussed audition and vision, sensory systems

that provide information about distant objects. Now we turn our attention to the senses that inform us about the objects in direct contact with our bodies and that tell us where our body is in space, where our limbs are in relation to our body, and what is going on inside the body. Christina’s case illustrates how important this information is for interacting physically with the world. The most important function of the body senses is to contribute to movement. In fact, the body senses are so intimately involved with our ability to move about in the world and to manipulate it that we sometimes hear the term the sensorimotor system. For that reason, we will follow our discussion of the body senses with an exploration of the topic of movement. The Body Senses We get information about our body from the somatosensory system and from the vestibular system. The somatosenses include proprioception; the skin senses, which tell us about conditions at the surface of our body; and the interoceptive system, concerned with sensations in our internal organs. The vestibular system informs the brain about body position and movement. The interoceptive system operates mostly in the background and participates less directly in behavior, so we will limit our attention to the other systems.

What is proprioception, and why is it important? Proprioception Proprioception (from the Latin proprius, “belonging to one’s self”) is the sense that

informs us about the position and movement of our limbs and body. Its sensors report

tension and length in muscles and the angle of the limbs at the joints. Proprioception is not as glamorous a sense as vision or audition, or even touch. However, without it we would have a great deal of difficulty, as Christina did, in maintaining posture, moving our limbs, and grasping objects. Ian Waterman, who is similarly afflicted, actually crumples helplessly onto the floor if someone turns the lights out (J. Cole, 1995). In other words, proprioception does more than provide information; it is critically important in the control of movement.

Why are there so many kinds of skin receptors? The Skin Senses The commonly accepted skin senses are touch, warmth, cold, and pain. However,

two studies involving mice have now found evidence that itch, until now believed to be a variant of pain, has its own receptors and neural pathway (Han et al., 2012; Mishra & Hoon, 2013), so itch will most likely be added to that list. Whatever the actual number of senses, the important point here is that each is distinct from the others, with its own receptors and separate “labeled line” pathway to the brain. To demonstrate this for yourself, move the point of a lead pencil slowly across your face. You will feel the touch of the pencil pretty continuously, but the lead will feel cold only occasionally—because touch and cold are monitored by different receptors. Although their range is limited to the surface of our body, changes there are often due to external stimulation, so the skin senses inform us about both our body and the world. (We experience these sensations deeper in the body as well, but less often and with less sensitivity.) The skin sense receptors are illustrated in the diagram of a section of skin in Figure 11.1. FIGURE 11.1 Receptors of the Skin. The different endings of the receptors account for their varied specialties, which provide the brain with the rich information it needs to interact with the world.

There are two general types of receptors. Free nerve endings are simply processes at the ends of neurons; they detect warmth, cold, and pain. All the other receptors are encapsulated receptors, which are more complex structures enclosed in a membrane; their role is to detect touch. Why are there so many receptors just for touch? Because touch is a complex sense that conveys several types of information. In the superficial layers of the skin, Meissner’s corpuscles respond with a brief burst of impulses, while Merkel’s disks give a more sustained response. Located near the surface of the skin as they are, they detect the texture and fine detail of objects. They also detect movement and come into play when you explore an object with gentle strokes of your hand or when a blind person reads Braille. Pacinian corpuscles and Ruffini endings are located in the deeper layers, where they detect stretching of the skin and contribute to our perception of the shape of grasped objects (Gardner, Martin, & Jessell, 2000). Because the density of the skin receptors varies throughout the body, so does sensitivity—as much as 10-fold in fact. The fingertips and the lips are the most sensitive, and the upper arms and calves of the legs are the least sensitive (Weinstein, 1968). The other three skin senses are detected by free nerve endings, but this statement is

a bit misleading; those nerve endings have distinctly different receptors that make the neurons stimulus specific (Basbaum, Bautista, Scherrer, & Julius, 2009). We are capable of responding to a wide range of temperatures; at least two different receptors detect different levels of warmth, and another responds to cooling of the skin. These

receptors are all members of the transient receptor potential (TRP) family of protein ion channels. Detection of pain also requires several receptors, mostly because of the variety of pain sources; these sources are categorized as thermal, chemical, and mechanical. Two TRP receptors respond to painful heat; a receptor for painful cold has not been conclusively identified, but it is clear that the coolness receptor does not account for this sensation. Chemical receptors react to a wide range of chemical irritants. Best known is the TRPV1 heat pain receptor, which also responds to capsaicin, the ingredient in chili peppers that makes spicy foods painfully hot. Ointments containing capsaicin alleviate the joint pain of arthritis, apparently because continued stimulation of the receptors depletes the neuropeptide that the neurons use to signal pain. This receptor also responds to the pain-inducing acid released in bone cancer, and a TRPV1 antagonist relieves this pain (Ghilardi et al., 2005). The TRPM8 coolness receptor produces the cool sensation of mint in toothpaste and candies, as well as the cooling effect of menthol on the skin; menthol creams are useful for treating muscle pain and skin irritations. TRPA1 receptors are responsible for the painful irritation caused by vehicle exhaust, tobacco smoke, hydrogen peroxide, and tear gas, and they account for the pungency of mustard, garlic, and wasabi, as well as the tingle you get from a carbonated drink. As we will see shortly, the body produces its own irritants when tissues are damaged; these continue to produce pain well after the stimulus is past. The receptors for mechanical pain have not been determined, which is unfortunate because persistent hypersensitivity to touch is a major problem following tissue or nerve injury.

What is the function of the vestibular sense? The Vestibular Sense In Chapter 8, you saw that the cochlea in the ear is connected to a strange-looking

appendage, the vestibular organs. The vestibular sense helps us maintain balance, and it provides information about head position and movement. The organs are the semicircular canals, the utricle, and the saccule (see Figure 11.2a). The physical arrangement of the semicircular canals makes them especially responsive to movement of the head (and body). At the base of each canal is a gelatinous (jellylike) mass called a cupula, which has a tuft of hair cells protruding into it (Figure 11.2b). During acceleration (an increase in the rate of movement), the fluid shifts in the canals and displaces the cupula; bending the hair cells in one direction depolarizes them, and bending them in the other direction hyperpolarizes them, increasing or decreasing the firing rate in the neurons. Deceleration has a similar effect. The system responds only to acceleration and stops responding when speed

stabilizes. Just as the coffee sloshes out of your cup when you start up from a traffic light and then levels off in the cup when you reach a stable speed, the fluid in the canals also returns to its normal position. Otherwise, you would continue to sense the

movement throughout an automobile trip or, worse yet, during a 500-mile per hour (805-km/hr) flight in a jetliner! The utricle and saccule monitor head position in relation to gravity. In Figure 11.2c,

you can see that the receptors (the hair cells) are covered with a gelatinous material. When the head tilts, gravity shifts the gelatinous mass and the hair cells are depolarized or hyperpolarized, depending on the direction of tilt. The hair cell receptors in the utricle are arranged in a horizontal patch, while the saccule’s receptors are on its vertical wall; together, the two organs can detect tilt in any direction.

1 Vestibular Disorders Consider what would happen without a vestibular system. Mr. MacGregor, one of

Oliver Sacks’s patients, lost his vestibular sense to the neural degeneration of Parkinson’s disease (Sacks, 1990). When he walked, his body canted to the left, tilted a full 20°. Strangely, Mr. MacGregor wasn’t aware of his tilt, even when his friends told him he was in danger of falling over. Once Sacks showed him a videotape, though, he was convinced. A retired carpenter, he put his expertise to work; 3 inches in front of his glasses he attached a miniature spirit level—a fluid-filled glass tube with a bubble in it that carpenters use to make sure their work is level with the world. By glancing at this makeshift device occasionally, he was able to walk without any slant, and after a few weeks, checking his tilt became so natural that he was no longer aware he was doing it. But the vestibular sense is not just for adjusting the body’s position. When we reach

for an object, we must know not just where the object is but the position of our body and the relation of our arm to our body; the brain combines information about the object’s spatial location with inputs from the vestibular sense and from proprioception to tell us what arm movements are required. Proprioception also triggers reflexive eye movements that keep returning our gaze to the scene as we turn our head or as our body bobs up and down when we walk; otherwise, the world would become a meaningless blur. FIGURE 11.2 The Vestibular Organs. (a) The inner ear, showing the cochlea and the vestibular organs. (b) Enlarged view of a cupula in a semicircular canal. During acceleration, the flow of endolymph displaces the cupula, triggering a neural response. (c) Receptors of the utricle and saccule. Tilting the head causes the gelatinous material to shift, stimulating the hair cells. The weight of the otoliths (calcium carbonate crystals) magnifies the shift.

SOURCES: (a) Iurato (1967). (b) Based on Goldberg and Hudspeth (2000). © 2000 McGraw-Hill. (c) Based on Martini (1988). The vestibular system sends projections to the cerebellum and the brain stem; there

is also a pathway to the cortex, an area called the parieto-insular-vestibular cortex. In Chapter 10, we observed that this is the likely location where stimulation that produces excessive eye movements causes dizziness and nausea; the same thing happens with excessive body motion, for example, during a rough boat ride or from spinning around. The Somatosensory Cortex and the Posterior Parietal Cortex The body is divided into segments called dermatomes, each served by a spinal

nerve, as Figure 11.3 shows. The divisions are not as distinct as illustrated, because each dermatome overlaps the next by one third to one half. This way, if one nerve is injured, the area will not lose all sensation. Body sense information enters the spinal cord (via spinal nerves) or the brain (via cranial nerves) and travels to the thalamus. From there the body sense neurons go to their projection area, the somatosensory cortex, located in the parietal lobes just behind the primary motor cortex and the central sulcus (Figure 11.4a). As with the auditory system, most of the neurons cross from one side of the body to the other side of the brain, so the touch of an object held in the right hand is registered mostly in the left hemisphere. Because not all neurons cross over, touching the object also stimulates the right somatosensory cortex, though

much less. FIGURE 11.3 Dermatomes of the Human Body. For sensory functions, the body is divided into segments called dermatomes, each served by a spinal or cranial nerve. The labels identify the nerve; letters indicate the part of the spinal cord where the nerve is located (cervical, thoracic, lumbar, sacral, or coccygeal), and the numbers indicate the nerve’s position within that section. Areas I, II, and III on the face are innervated by branches of the trigeminal (fifth) cranial nerve.

FIGURE 11.4 The Primary and Secondary Somatosensory Areas. (a) The primary and secondary somatosensory cortex and the posterior parietal cortex. The primary motor cortex is shown as a landmark. (b) A slice from the somatosensory cortex, showing its somatotopic organization. The size of the body parts in the figure is proportional to the area of the cortex in which they are represented. (The pictorial representation of the body on the cortex is called a homunculus.)

SOURCE: (b) Adapted from The Cerebral Cortex of Man by W. Penfield and T. Rasmussen, 1950, New York: Macmillan. © 1950 Gale, a part of Cengage Learning, Inc. Reproduced by permission. Sensory systems have a number of organizational and functional similarities; a

comparison of the somatosensory cortex with the visual cortex will illustrate this point. First, it contains a somatotopic map of the body, with adjacent body parts represented in adjacent parts of the cortex, just as the visual cortex contains a map of the retina and the auditory cortex contains a map of the cochlea (Figure 11.4b). Second, some of the cortical cells have complex receptive fields on the skin. Some of them have excitatory centers and inhibitory surrounds like those we saw in the visual system (Mountcastle & Powell, 1959). Some of them are quite large, as in Figure 11.5a, while smaller excitatory-inhibitory fields sharpen the localization of excitation and help distinguish two points touching the skin. In Figure 11.5b and c, we see that other somatosensory neurons with complex fields are feature detectors; they have sensitivities for orientation, direction of movement, shape, surface curvature, or texture (Carlson, 1981; Gardner & Kandel, 2000; S. Warren, Hämäläinen, & Gardner, 1986). Apparently, these neurons combine inputs from neurons with simpler functions, just as complex visual cells integrate the inputs of multiple simple cells

(Iwamura, Iriki, & Tanaka, 1994). One type of receptive field includes multiple fingers; the cells’ firing rate depends on how many fingers are touched, so they give an indication of the size of a held object. FIGURE 11.5 Receptive Fields in the Monkey Somatosensory System. (a) Excitatory and inhibitory areas of the receptive field of a single touch neuron in the somatosensory cortex. (b) Receptive field of a somatosensory neuron that responded most to a horizontal edge. The recordings to the right indicate the strength of the neuron’s response to edges of different orientations. (c) Receptive field of a neuron responsive to movement across the fingertip in one direction but not the other.

SOURCES: (a) From “Neural Mechanisms Subserving Cutaneous Sensibility, With Special Reference to the Role of Afferent Inhibition in Sensory Perception and Discriminiation,” by V. B. Mountcastle and T. P. S. Powell, 1959, Bulletin of the Johns Hopkins Hospital, 105, p. 224, Figure 14. © The Johns Hopkins University Press. Reprinted with permission of the Johns Hopkins University Press. (b) and (c) From “Movement-Sensitive Cutaneous Receptive Fields in the Hand Area of the Post-central Gyrus in Monkeys,” by J. Hyvärinen and A. Poranen, Journal of Physiology, 283, pp. 523–537. Copyright 1978, with permission.

How are the body senses similar to other senses? A third similarity is that somatosensory processing is hierarchical. The primary

somatosensory cortex consists of four areas, each of which contains a map of the body and plays a role in processing sensory information from the body. The thalamus sends its output to two of these subareas, which extract some information and pass the result on to the other two areas, which in turn send their output to the secondary somatosensory cortex. At this point in processing, information from the right and left sides of the body is mostly segregated.

What processing occurs at each level of the somatosensory system? The secondary somatosensory cortex receives input from the left and the right

primary somatosensory cortices, so it combines information from both sides of the body. Neurons in this area are particularly responsive to stimuli that have acquired meaning, for instance, by association with reward (Hsiao, O’Shaughnessy, & Johnson,

1993). The secondary somatosensory cortex sends connections to the part of the temporal lobe that includes the hippocampus. The hippocampus is important in learning, so these connections likely contribute to memory formation when somatosensory information is involved (Gardner & Kandel, 2000). To pick up a forkful of the apple pie on your plate, your brain must not only receive

a visual image of the pie; must also know where your arm and hand are in relation to your body, where your head is oriented in relation to your body, and where your eyes are oriented in relation to your head. That is where the posterior parietal cortex comes in. The primary somatosensory cortex projects to the posterior parietal cortex as well as to the secondary cortex. As you saw in the previous chapter, the posterior parietal cortex is an association

area that brings together the body senses, vision, and audition (K. H. Britten, 2008). See Figure 11.4 again for the location of the posterior parietal cortex in relation to the somatosensory cortex. Here, the brain determines the body’s orientation in space; the location of the limbs; and the location in space of objects detected by touch, sight, and sound. In other words, it integrates the body with the world. The posterior parietal cortex is composed of several subareas, which are responsive to different sense modalities and make different contributions to a person’s interaction with the world. Some cells combine proprioception and vision to provide information about specific postures, for example, the location and positioning of the arm and the hand (Bonda, Petrides, Frey, & Evans, 1995; Graziano, Cooke, & Taylor, 2000; Sakata, Takaoka, Kawarasaki, & Shibutani, 1973). Others contribute to reaching and grasping movements and eye movements toward targets of interest (Batista, Buneo, Snyder, & Andersen, 1999; Colby & Goldberg, 1999). The posterior parietal cortex’s function is not solely perceptual, because many of its neurons fire before and during a movement. It does not itself produce movements but passes its information on to frontal areas that do (Colby & Goldberg). A unified body image is critical to our ability to function and even to our self-

concept, so you can imagine that any disruption would have significant consequences. You saw earlier that damage to the right posterior parietal cortex can produce neglect and that some stroke patients will deny ownership of a paralyzed arm or leg. A few people with no apparent brain damage—or mental or emotional disorder, for that matter—are so convinced that a limb doesn’t belong to them that they actually ask to have it amputated; this disorder is called body integrity identity disorder, or apotemnophilia (McGeoch et al., 2009). When the limb is touched, there is no response in the superior parietal area. Skin conductance response to stimulation is doubled in that limb, though, which indicates a high level of emotional feeling about the limb. A related phenomenon incorporates the entire body into the illusion; in an out-of-body experience, the individual hallucinates seeing his or her body from another location, for example, from a position above the detached body. Causes

include traumatic damage and epilepsy affecting the junction between the parietal and temporal lobes; the experience can also be produced by electrical stimulation in that area (Blanke & Arzy, 2005). Pain and Its Disorders In Chapter 8, we learned about the emotional aspect of pain and how it motivates

our behavior. Now we need to put pain in the context of the body senses and see how it works as a sensory mechanism. In spite of our attention to pain earlier, there are still a few surprises left.

What causes pain? Detecting Pain Pain begins when certain free nerve endings are stimulated by intense pressure or

temperature, by damage to tissue, or by various chemicals. Tissue injury also causes the injured cells to release a wide array of signaling molecules, referred to as the “inflammatory soup”; these include histamine, bradykinin, prostaglandins, and cytokines (Kidd & Urban, 2001). Some of these stimulate pain receptors, but they also produce the familiar swelling and redness of inflammation, and they enhance excitability of the pain neurons so much that the neurons respond even to touch. This effect is adaptive because it encourages guarding of the injured area, but the resulting pain can be more troublesome than the original injury. Pain information travels to the spinal cord over large, myelinated A-delta fibers and small, lightly myelinated or unmyelinated C fibers. Because A-delta fibers transmit more rapidly than C fibers, you notice a sharp pain almost immediately when you are injured, followed by a longer lasting dull pain (Basbaum & Jessell, 2000). Sharp pain makes a good danger signal and motivates you to take quick action, while dull pain hangs around for a longer time to remind you that you have been injured.

2 Pain Resources In the spinal cord, pain neurons release the neurotransmitter glutamate; as

stimulation becomes more intense, they release both glutamate and substance P, a neuropeptide that increases pain sensitivity (Cao et al., 1998). In Chapter 2, we saw that neuropeptides enhance the primary neurotransmitter’s effect at the synapse; in mice lacking substance P or its receptors, mild pain is unaffected but sensitivity to moderate and intense pain is impaired (Cao et al.). As with the other body senses, pain information passes through the thalamus to the somatosensory cortex; however, the anterior cingulate cortex and the insula carry out additional processing of the emotional implications of pain, and the prefrontal cortex is concerned with pain of longer duration. Treating Pain We saw in Chapter 2 that local anesthetics—those that are applied to or injected

into the painful area—block sodium channels in the pain neurons and reduce their ability to fire. General anesthetics, which may be injected or inhaled, render the patient unconscious. They work in the central nervous system, though their mechanism is not well understood. We know that they affect the functioning of several proteins, but we don’t know which ones are important to the anesthesia. The most frequently used drugs are aspirin, ibuprofen, and acetaminophen. Aspirin and ibuprofen block enzymes required for producing prostaglandins, so they reduce inflammation as well as pain. Acetaminophen blocks the same enzymes but weakly and with no anti-inflammatory benefit, so its major effect is probably in the central nervous system. Ameliorating pain often requires more powerful drugs, and morphine is the acknowledged gold standard, but its addictiveness and patients’ rapidly developing tolerance have spurred the development of numerous alternatives. The MDAN series of drugs, for example, target the mu opioid receptor while blocking the delta opioid receptor; these drugs are reportedly 50 times more potent than morphine, without producing either tolerance or addiction (Dietis et al., 2009). Efforts are under way on a variety of other fronts, as well. Tanezumab, an antibody

for nerve growth factor, has shown safety and effectiveness in clinical trials with chonic back pain and the inflammatory pain of arthritis (Cattaneo, 2010). An experimental drug that blocks the TRPV1 receptor produces modest reduction of bone cancer pain in mice, but much smaller doses significantly increase the effectiveness of morphine when the two are used in combination (Niiyama, Kawamata, Yamamoto, Furuse, & Namiki, 2009). There has been some preliminary success with gene therapy; patients whose pain from cancer was not relieved by 200 mg per day of morphine experienced an 80% reduction following treatment with a gene that increases endorphin production (Fink et al., 2011). The fact that pain ultimately occurs in the brain has inspired a novel approach that is also showing promise; chronic pain patients given continuous fMRI feedback of activity in their cingulate gyrus learned to reduce pain-related brain activity and their experience of pain (deCharms et al., 2005). Internal Mechanisms of Pain Relief People sometimes feel little or no pain in spite of serious injury; they may even fail

to realize they are injured until someone calls it to their attention. In the account of his search for the mouth of the Nile River, the explorer and missionary David Livingstone (1858/1971) gave an intriguing example (see Figure 11.6):

How does the brain relieve pain? Starting, and looking half round, I saw the lion just in the act of springing upon me.

I was upon a little height; he caught my shoulder as he sprang, and we both came to the ground below together. Growling horribly close to my ear, he shook me as a terrier dog does a rat. The shock produced a stupor similar to that which seems to be felt by a

mouse after the first shake of the cat. It caused a sort of dreaminess, in which there was no sense of pain nor feeling of terror, though quite conscious of all that was happening. It was like what patients partially under the influence of chloroform describe, who see all the operation, but feel not the knife. (p. 12) FIGURE 11.6 David Livingstone Attacked by a Lion. Endorphins allowed him to endure the pain of a lion’s attack.

SOURCE: Hulton Archive; Livingstone, 1858/1971. You learned in earlier chapters that the reason opiate drugs are so effective at

relieving pain is that they operate at receptors for the body’s own pain relievers. Researchers combined the words endogenous (“from within”) and morphine to come up with the name endorphins for this class of neurochemicals. Endorphins function both as neurotransmitters and as hormones, and they act at opiate receptors in many parts of the nervous system. Pain is one of the stimuli that release endorphins, but it does so only under certain conditions. Rats subjected to inescapable electric shock were highly tolerant of pain 30 minutes later; rats given an equal number of shocks that they could escape by making the correct response had only a slight increase in pain resistance (S. F. Maier, Drugan, & Grau, 1982). I am sure you can see the benefit of eliminating pain in situations of helplessness like Livingstone’s and preserving pain when it can serve as the motivation to escape. An injection of naloxone eliminates the analgesia induced by inescapable shock but not the milder analgesia that follows escapable shock; the fact that naloxone blocks opiate receptors by occupying them indicates that the analgesia of inescapable shock is endorphin based. (You may be wondering how you would determine a rat’s pain resistance, since it cannot report its pain sensation. One way is to place the rat’s tail under a heat lamp and record how long it takes the rat to flick its tail away.) Several kinds of stimulation result in endorphin release and pain reduction,

including physical stress (Colt, Wardlaw, & Frantz, 1981), acupuncture (L. R. Watkins & Mayer, 1982), and vaginal stimulation in rats (Komisaruk & Steinman, 1987) and women (Whipple & Komisaruk, 1988). Analgesia resulting from vaginal stimulation probably serves to reduce pain during birth or intercourse. Even the pain relief from

placebo, which doctors once took as evidence that the pain was not “real,” is often the result of endorphins, as revealed both by naloxone blockage of opiate receptors and by PET scans (Figure 11.7; Amanzio, Pollo, Maggi, & Benedetti, 2001; Petrovic, 2005; Petrovic, Kalso, Petersson, & Ingvar, 2002). Not all stimulation-induced pain relief comes from endorphins. For example,

naloxone does not reduce the analgesic effect of hypnosis (L. R. Watkins & Mayer, 1982), and naloxone blocks analgesia produced by acupuncture needles inserted at distant points from the pain site but not when the needles are placed near the site (L. R. Watkins & Mayer). New research indicates that the acupuncture needle causes a 24-fold increase in adenosine, which acts as a local anesthetic (N. Goldman et al., 2010). (Note, by the way, that this study’s first author is a 16-year-old girl.) FIGURE 11.7 Activation of Opiate Receptors in the Brain by a Placebo. (a) Activity in cortical and brain stem areas (in red) during opiate drug treatment for pain. (b) A similar pattern of activity occurs during placebo treatment of pain. Pain alone did not produce this result. The blue dots indicate the location of the anterior cingulate cortex, which, as you saw in Chapter 8, is involved in emotional aspects of pain.

SOURCE: From “Placebo and Opiod Analgesia—Imaging a Shared Neuronal Network,” by P. Petrovic et al., Science, 295, pp. 1737–1740, fig. 4 a and b, p. 1739. © 2004. Reprinted by permission of AAAS. The Descending Pain Inhibition Circuit During a spring break in New Orleans, I was touring one of the Civil War–era

plantation houses that the area is noted for. In a glass case was an assortment of artifacts that had been found on the plantation grounds. An odd part of the collection was a few lead rifle slugs with what were obviously deep tooth marks on them. When makeshift surgery had to be performed with only a large dose of whiskey for anesthesia, the unfortunate patient would often be given something to bite down on like a piece of leather harness or a relatively soft lead bullet. (You can probably guess the common expression that is associated with this practice.) As a toddler, when you scraped your knee you clenched your teeth and rubbed the area around the wound. And—tribute to your childhood wisdom—it really did help and got you through the pain without the benefit of either a lead bullet or whiskey. You might think that tooth clenching and rubbing simply take attention from the pain. Ronald Melzack and Patrick Wall (1965) had another idea. In their gate control theory, they hypothesized

that pressure signals arriving in the brain trigger an inhibitory message that travels back down the spinal cord, where it closes a neural “gate” in the pain pathway. Research has confirmed the general idea of their theory, and we now know that a

descending pathway in the spinal cord is one of the ways the brain uses endorphins to control pain. Pain causes the release of endorphins in the periaqueductal gray (PAG), a brain stem structure with a large number of endorphin synapses (Basbaum & Fields, 1984). As you can see in Figure 11.8, endorphin release inhibits the release of substance P, closing the pain “gate” in the spinal cord. (Note that enkephalin, the type of endorphin in the spinal cord, reduces substance P release by presynaptic inhibition, as described in Chapter 2.) Activation of the endorphin circuit apparently has multiple neural origins, including the cingulate cortex during placebo analgesia and the amygdala in the case of fear-induced analgesia (Petrovic, 2005). Brain imaging shows that placebo reduces pain through this circuit, and so does simple distraction (Petrovic, 2005; Petrovic et al., 2002; Tracey et al., 2002). Electrical stimulation of the PAG is also a very effective pain reliever, but it has the drawback of requiring brain surgery (Bittar et al., 2005). Women, unfortunately, have fewer mu opioid receptors in the PAG than men, and they receive less pain-relieving benefit from opiate drugs (Loyd, Wang, & Murphy, 2008). The PAG also contains cannabinoid receptors, which respond to endogenous cannabinoids and the active ingredient in marijuana, and they account for some forms of stimulation-induced pain relief (A. G. Hohmann et al., 2005). Pain’s Extremes: From Congenital Insensitivity to Chronic Pain Congenital insensitivity to pain is a very rare condition. This is fortunate, because

those who are afflicted not only unknowingly hurt themselves but often engage in risky and dangerous behavior that most other people avoid. One family with several afflicted members was discovered when researchers learned of a boy in northern Pakistan who entertained on the street by piercing his arms with knives; before he could be studied, he died when he celebrated his 14th birthday by jumping off a roof (Cox et al., 2006). Several genes have been identified as responsible for the different kinds of pain insensitivity. People with a mutation in the SCN9A gene have nonfunctioning versions of a particular type of sodium channel, so their pain neurons are disabled (Cox et al.). Those with a mutation in the gene for nerve growth factor (NGFB), which stimulates development of sensory nerves, have a significant loss of unmyelinated neurons and less severe loss of myelinated fibers (Einarsdottir et al., 2004). Another cause of insensitivity is illustrated in the case of a 16-year-old boy whose most significant characteristic was elevated opioid levels in his cerebrospinal fluid (Manfredi et al., 1981). FIGURE 11.8 The Descending Pain Inhibition Circuit. Endorphin release in the periaqueductal gray inhibits the release of substance P by pain neurons in the spinal cord; this reduces the pain message reaching the brain.

Chronic pain is much more common, and its victims often experience lifelong suffering. How many people are afflicted is difficult to determine, because studies include different populations and use different criteria. As a result, estimates have ranged from 10% to 55%; averages for two different criteria were 11.8% and 35.5% (International Association for the Study of Pain, 2003). Practitioners often attempt to distinguish chronic from acute pain in terms of duration, with standards varying from 1 month to 1 year. However, it makes more sense to define chronic pain as pain that persists after healing has occurred or beyond the time in which healing would be expected to occur. Whether pain becomes chronic is largely unrelated to the severity of injury. Chronic

pain patients are often clinically depressed; this could logically be attributed to the pain, but evidence indicates the depression precedes the injury in patients who exaggerate the extent and intensity of their pain (Bortsov, Platts-Mills, et al., 2013). Also, the strength of functional connectivity between the nucleus accumbens and the frontal cortex, measured shortly after back pain began, predicted with 85% accuracy

which patients would continue to suffer pain one year later (Baliki et al., 2012). Both areas are important in evaluating and dealing with stressful events, and their connection likely determines how emotionally the person reacts to pain. Several genes play a role as well. A different allele of the SCN9A sodium channel gene mentioned earlier lowers pain threshold and contributes to two types of neuropathic pain (Fischer & Waxman, 2010). Variations in the COMT gene also regulate pain sensitivity, as well as responsiveness to pain relievers, and they figure in several pain syndromes (Andersen & Skorpen, 2009). Six variations of a glucocorticoid gene were associated with increased pain intensity in patients following motor vehicle collisions, while a variant of a D2 dopamine receptor gene reduced severity (Bortsov, Smith, et al., 2013; Qadri et al., 2012). The nervous system undergoes extensive functional and structural changes during

chronic pain. The pain pathways increase their sensitivity, new connections sprout where peripheral neurons make connections in the spinal cord, and normal spinal inhibitory mechanisms are depressed (Woolf & Salter, 2000). The brain also participates in these changes. Brain stem pathways become more responsive (M. Lee, Zambreanu, Menon, & Tracey, 2008); activation increases in the prefrontal cortex, anterior cingulate cortex, and insula (Baliki et al., 2006); and the amount of somatosensory cortex devoted to the painful area expands (Flor, Braun, Elbert, & Birbaumer, 1997). There is considerable loss of gray matter, equivalent to 10 to 20 years of additional aging in chronic back pain patients (Figure 11.9; Apkarian, Sosa, Sonty, et al., 2004) and 9.5 years of additional aging per year of suffering with fibromyalgia (Kuchinad et al., 2007). Evidence of the functional disruption this causes is that chronic pain patients perform poorly, almost randomly, on the gambling test used to assess prefrontal impairment (described in Chapter 8; Apkarian, Sosa, Krauss, et al., 2004). FIGURE 11.9 Gray Matter Loss in Patients With Chronic Back Pain. Magnetic resonance imaging shows areas where patients lost more gray matter than controls in (a) the cortex and (b) the thalamus. Yellow represents greater loss.

SOURCE: From “Chronic Back Pain Is Associated With Decreased Prefrontal and Thalamic Gray Matter Density,” by Apkarian et al., Journal of Neuroscience, 24, pp. 10410–10415, fig. 2. © 2004 Society for Neuroscience. Used with permission. Phantom Pain If damage to the right parietal cortex can eliminate recognition of a paralyzed left

arm or leg, shouldn’t removing a person’s arm or leg eliminate all consciousness of the limb? Most amputees continue to experience the missing limb, not as a memory, but as vividly as if it were real (Melzack, 1992). A phantom leg seems to bend when the person sits down and then to become upright during standing; a phantom arm even feels as though it is swinging in coordination with the other arm during walking. In about 75% of amputees we see what is undeniably the strangest manifestation of

chronic pain (Kern, Busch, Rockland, Kohl, & Birklein, 2009; Richardson, Glenn, Nurmikko, & Horgan, 2006). Phantom pain, pain that is experienced in a missing limb, is not simply pain at the stump but is felt in the missing arm or leg itself. The classical explanation was that the cut ends of nerves continue to send impulses to the part of the brain that once served the missing limb. Peripheral input is a factor in some cases, but anesthetizing these nerves relieves phantom pain in no more than half of patients (Birbaumer et al., 1997; Flor, 2008), so something else must be going on.

What causes phantom pain? Following the clue that stimulating the face often produces sensations in a phantom

arm, a team of researchers in Germany used brain imaging to map face and hand somatosensory areas in upper-limb amputees (Flor et al., 1995). In patients with phantom pain, neurons from the face area appeared to have invaded the area that normally receives input from the missing hand (see Figure 11.10). The area activated by touch on the lips was shifted an average of 2.05 centimeters (cm) in the hemisphere opposite the amputation, compared with 0.43 cm for the patients without phantom pain, a fivefold difference. It is unclear how much the results were due to intrusion of foreign neurons or to activation of existing neurons. However, facial stimulation can evoke sensations in the phantom arm within 24 hours after amputation, which indicates that “unmasking” of existing but ordinarily silent inputs is at least a partial explanation (Borsook et al., 1998). We usually think of neural plasticity as adaptive, but sometimes it can lead to malfunction and, in this case, truly bizarre results. As you can imagine, treating phantom pain poses special problems, so we will give it special attention in the accompanying Application. FIGURE 11.10 Reorganization of the Somatosensory Cortex in a Phantom Pain Patient Following Arm Amputation. The symbols represent the location of sensitivity to touch of the fingers (squares) and the lips (circles); black symbols are from a patient with phantom pain and white symbols from a patient without phantom pain. By looking at the homunculus

superimposed on the left hemisphere (opposite the intact arm), you can see that the circles and the squares are in their normal locations. In the right hemisphere, opposite the amputated arm, lip sensitivity in the patient with the phantom pain (black circle) has migrated well into the area ordinarily serving finger sensitivity.

SOURCE: From “Phantom-limb Pain as a Perceptual Correlate of Cortical Reorganization Following Arm Amputation,” by H. Flor et al., 1995, Nature, 375, pp. 482-484. Copyright © 1995.

APPLICATION

Treating Pain in Limbs That Aren’t There Most treatments for phantom pain are ineffective and fail to consider the mechanisms producing the pain. Local anesthesia, surgery to sever pain pathways, and pharmacological interventions, from muscle relaxants to antidepressants, typically benefit less than 30% of patients, which is no better than results from placebo (Flor, 2008). Several studies suggest that therapies that work either prevent or reverse the cortical reorganization that occurs following amputation (Birbaumer et al., 1997). Use of a functional prosthesis (as opposed to a purely cosmetic one) prevents cortical reorganization and reduces pain occurrence (Lotze et al., 1999); newer hand prostheses that have pressure sensors in the fingers to help amputees adjust their grip to different objects should reduce phantom pain even better (Friedrich-Schiller-Universität Jena, 2010). When a prosthesis is impractical, training to discriminate frequency and location of electrical stimuli applied to the stump reverses cortical reorganization and reduces pain in 60% of patients (Flor, Denke, Schaefer, & Grüsser, 2001). Using a mirror illusion to “replace” sensations from the missing limb has

yielded some very promising results. The patient places the stump out of sight on one side of a mirror and the good limb on the other side, so the reflection of the good limb appears to replace the one that is missing (see figure). Then the patient is told to move the two limbs in unison. The first patient to use this

mirror illusion immediately felt that his missing arm was moving, and the pain disappeared temporarily. After 3 weeks of brief daily practice, he reported almost complete absence of both the pain and the phantom (Ramachandran, Rogers-Ramachandran, & Cobb, 1995). In a later study, 100% of patients using the mirror box experienced decreases in pain, compared with increases in the majority of control patients (Chan et al., 2007); another study confirmed that the pain relief is accompanied by reversal of the cortical reorganization (Flor, Diers, Christmann, & Koeppe, 2006). But how could watching the mirror image of an intact arm affect the

organization and function of the other somatosensory area? There are various possibilities, but the answer may lie in the greater responsiveness of the mirror neuron system in phantom limb patients; when they watch another person’s hand being stroked or pricked with a pin, they often report actually feeling the stimulation in their missing limb. I saw this firsthand in a colleague who had lost both legs in an accident. As we watched a construction worker walking the girders of a new building, I felt a bit of anxiety and a sympathetic tension in my legs as I imagined myself up there balancing on the narrow beams, but, to my complete surprise, my friend exclaimed, “That makes my ankles hurt!” Some investigators suggest that mirror therapy works because the reflected image triggers exaggerated activity in mirror neurons in the hemisphere that once served the missing limb (Chan et al., 2007; Ramachandran & Altschuler, 2009). According to this view, because the missing limb cannot provide contradictory feedback, the mirror neuron activity is interpreted as real touch or movement, and with continued practice the brain’s reorganization is reversed.

The mirror image of the patient’s intact leg appears to replace the missing leg. SOURCE: © Walter Morris/Medill News Service.

Concept Check Take a Minute to Check YourKnowledge and Understanding What is the contribution of each of the three classes of body senses? In what ways are the somatosensory cortex and the visual cortex organized similarly?

In what circumstances does the brain reduce pain?

Movement A popular view of the brain is that it is mostly preoccupied with higher cognitive processes, such as thinking, learning, and language. However, a surprising proportion of the brain is devoted to planning and executing movements. We are talking about more than simply moving the body from one place to another; consider the surgeon’s coordinated hand movements during a delicate operation, the control of mouth and throat muscles and diaphragm required to sing an aria, or the pass receiver’s ability to follow the trajectory of the football and arrive at the right place at the right time. Studies of the control of movement provided one of the earliest windows into the brain’s organization and functioning, and it is that facet of the research that will interest us most. Before we launch into that topic, we need some understanding of the equipment the brain has to work with. FIGURE 11.11 Muscle Fibers Innervated by a Motor Neuron.

SOURCE: © Ed Reschke/Photolibrary/Getty Images. The Muscles We have three types of muscles. The ones you are most familiar with are the

skeletal muscles, which move the body and limbs; they are also called striated muscles because of their striped appearance. Smooth muscles produce contractions in the internal organs; for example, they move food through the digestive system,

constrict blood vessels, and void the bladder. Cardiac muscles are the muscles that make up the heart. Because our focus is on movement, we will concentrate on the skeletal muscles. Anyway, in spite of differences in appearance, the muscles function similarly. Like other tissues of the body, a muscle is made up of many individual cells, or

muscle fibers. The muscle cells are controlled by motor neurons that synapse with a muscle cell at the neuromuscular junction (Figure 11.11). The number of cells served by a single axon determines the precision of movement possible. The biceps muscles have about a hundred muscle fibers per axon, but the ratio is around 3 to 1 in the eye muscles, which must make very precise movements in tracking objects (Evarts, 1979). FIGURE 11.12 Myosin and Actin Cause a Muscle to Contract. Protrusions from the myosin filament extend to the actin filament and attach, then flex, causing the actin to slide alongside the myosin; this shortens the muscle, producing a contraction. The protrusions then withdraw from the actin and repeat the process in rapid succession.

SOURCE: Adapted from Figure 10.7, Principles of Anatomy and Physiology (11 ed.), by Gerard J. Tortora and Bryan H. Derrickson, 2006, Hoboken, NJ: John Wiley & Sons. A muscle fiber is made up of myosin filaments and actin filaments. When a motor

neuron releases acetylcholine, the muscle fiber is depolarized, which opens calcium channels; the calcium influx initiates a series of actions by the myosin that contract the muscle. Small protrusions along the myosin filaments attach to the surrounding actin filaments; they then make a stroking movement that causes the actin filaments to slide along the myosin filaments, which shortens the muscle fibers. This repeats rapidly, contracting the muscle (see Figure 11.12). Skeletal muscles are anchored to bones by tendons, which are fibrous bands of

connective tissue. You can see in Figure 11.13 that by pulling against their attachments the muscles are able to operate the limbs like levers to produce movement. You can also see that limbs are equipped with two antagonistic muscles, muscles that produce opposite movements at a joint. In this case, the biceps muscle flexes the arm, and the triceps extends it. Rather than one muscle relaxing while the other does all the work, movement involves opposing contraction from both muscles.

The simultaneous contraction of antagonistic muscles creates a smoother movement, allows precise stopping, and maintains a position with minimal tremor. Standing requires the countering effects of antagonistic muscles in the legs, as well as muscles in the torso. The amount of contraction in a muscle varies from moment to moment, so the balance between two antagonistic muscles is constantly shifting, constantly correcting. If maintaining the balance between opposed pairs of muscles required conscious, voluntary activity, we would find it very difficult to hold a camera still enough to get a sharp picture or, like Christina, even to stand or sit erect. Adjustments this fast have to be controlled by reflexes at the level of the spinal cord.

What is the function of antagonistic muscles? The Spinal Cord In Chapter 3, we introduced the idea of the spinal reflex. Everyone is familiar with

the reflex that makes you quickly withdraw your hand from a hot stove. When you step on a sharp object, you reflexively withdraw your foot and simultaneously make a variety of reflexive postural adjustments to avoid losing your balance. The advantage of reflexes is that we can make the appropriate adjustments quickly, without the delay of having to figure out the right action. FIGURE 11.13 Antagonistic Muscles of the Upper Arm. When the biceps muscle contracts, it flexes the arm (left); contracting the triceps muscle extends the arm.

SOURCE: Based on Starr and Taggart (1989). FIGURE 11.14 The Patellar Tendon Reflex, an Example of a Stretch Reflex. The hammer stretches the tendon, causing a reflexive contraction of the extensor muscle and a kicking motion. This is a highly simplified representation; many more

neurons are involved.

The reflex illustrated in Figure 11.14 should also be familiar. Your doctor taps the patellar tendon, which connects the quadriceps muscle to the lower leg bone. This stretches the muscle, which is detected by muscle stretch receptors called muscle spindles and relayed to the spinal cord. There the sensory neurons synapse on motor neurons, which return to the quadriceps and cause it to contract and extend the lower leg. The function of the stretch reflex is not just to amuse your doctor. It enables a muscle to resist very quickly if the muscle is stretched by activity in its antagonistic partner; this helps, for example, to maintain an upright posture. It also allows a muscle to respond quickly to an increased external load, for example, when you are holding a stack of books in front of you and a friend unexpectedly drops another book on top of it. Golgi tendon organs, receptors that detect tension in a muscle, trigger a spinal reflex that inhibits the motor neurons and limits the contraction. This prevents muscles from contracting so much that they might be damaged. FIGURE 11.15 What Life Would Be Like Without Central Pattern Generators.

More complex patterns of motor behavior are also controlled in the spinal cord. It has been known for some time that cats whose spinal cords have been cut, eliminating control from the brain, will make rhythmic walking movements when they are suspended with their feet on a treadmill (Grillner, 1985). This behavior depends on central pattern generators (CPGs), neuronal networks that produce a rhythmic pattern of motor activity, such as those involved in walking, swimming, flying, and breathing. Central pattern generators are located in the spinal cord and in the brain. In humans, they are most obvious in infants below the age of 1 year, who also make stepping movements when held with their feet on a treadmill (Lamb & Yang, 2000). In adults, CPGs provide an important bit of automaticity to routine movements. They can be elicited in individuals with spinal cord injury to produce rhythmic stepping movements (Dimirijevic, Gerasimenko, & Pinter, 1998), and researchers are working on ways to recruit them during therapy (Boulenguez & Vinay, 2009; Dietz, 2009; Edgerton & Roy, 2009). Spinal reflexes produce quick, reliable responses, and central pattern generators provide basic routines the brain can call up when needed, freeing

the brain for more important matters (see Figure 11.15). But reflexes and central pattern generators cannot provide all our movement capabilities, so we will turn our attention to the contributions the brain makes to movement.

What do spinal reflexes and central pattern generators do? The Brain and Movement In the motor system, we again see a hierarchical organization consisting of the

forebrain, brain stem, and spinal cord. The motor cortex organizes complex acts and executes movements while modulating activity in the brain stem and spinal cord. The brain stem in turn modulates the activity of the spinal cord (Ghez & Krakauer, 2000). We will start with the cortex and give it most of our attention. The motor cortex consists of the primary motor cortex and two major secondary

motor areas, the supplementary motor area and the premotor cortex (Figure 11.16). Like the primary area, the secondary areas contain a map of the body, with greater amounts of cortex devoted to the parts of the body that produce finer movements (Figure 11.17). The sequence of processing in the motor cortex is just the opposite of what we see in the sensory areas: Planning of movement begins in the association areas, and the primary motor cortex is the final cortical motor area. Along the way, a movement is modified by inputs from the somatosensory cortex, the posterior parietal cortex, the basal ganglia, and the cerebellum. As with many other functions, the prefrontal cortex plays an executive role, so it will receive our attention first. We will be covering several brain areas and their functions in the next few pages. It would be a good idea to review the summary in Table 11.1 before reading further, so that you will have an idea of where we are going. FIGURE 11.16 The Motor Areas of the Cortex and Cerebellum. Connections between the primary motor cortex and the basal ganglia are not shown.

FIGURE 11.17 The Primary Motor Area. The homunculus shows the relative amount of cortex devoted to different parts of the body. SOURCE: Adapted from The Cerebral Cortex of Man by W. Penfield and T. Rasmussen, 1950, New York: Macmillan. © 1950 Gale, a part of Cengage Learning, Inc. Reproduced by permission.

TABLE 11.1 The Major Brain Areas of Movement and Their Functions.

The Prefrontal Cortex You already know two functions of the prefrontal cortex that suit it for its role in

movement control: First, it plans actions with regard to their consequences; second, it receives information from the ventral visual stream about object identity, which is useful in identifying targets of motor activity. As an initial step in motor planning, the prefrontal cortex integrates auditory and visual information about the world with information about the body (from the posterior parietal cortex); it then holds the information in memory while selecting the appropriate movement and its target (see Figure 11.16 again). Considering its activities, it really makes more sense to say that the role of the prefrontal cortex is not so much in planning movements as in planning for movements. These functions are typically investigated in monkeys while they perform some

variation of a delayed match-to-sample task. The monkey is presented with a visual stimulus; then, after a delay of a few seconds in which the stimulus is absent, the monkey is presented two or more stimuli and required to select the original stimulus (by reaching for it) in order to obtain a reward, such as a sip of juice. Some cells in the prefrontal cortex start firing when the first stimulus is presented and continue to fire throughout the delay, suggesting that they are “remembering” the stimulus. At response time another group of prefrontal cells starts firing before activity starts in the premotor areas; this indicates that the prefrontal cortex selects the target of behavior and the appropriate motor response (Goldman-Rakic, Bates, & Chafee, 1992; Hoshi, Shima, & Tanji, 2000; Rainer, Rao, & Miller, 1999).

What is the relationship between the primary motor area and the association areas? The Secondary Motor Areas The premotor cortex begins programming a movement by combining information

from the prefrontal cortex and the posterior parietal cortex (Krakauer & Ghez, 2000). A good example comes from a study in which monkeys were cued to reach for one of two targets, A or B, in different locations and to use the left arm on some trials and the right on others. Some premotor neurons increased their firing rate only if target A was cued, and other neurons were selective for target B. Other cells fired selectively

depending on which arm was to be used. Still other cells combined the information of the first two kinds of cells; they increased their firing only when a particular target was cued and a particular arm was to be used (Hoshi & Tanji, 2000). Two other cell types combine visual and somatosensory information to provide visual guidance of reaching and object manipulation. The first responds to visual stimuli on or near a specific part of the body, as in Figure 11.18a; another shifts the location of its visual receptive field to coincide with the location of the monkey’s hand as it moves (Figure 11.18b; Graziano, Hu, & Gross, 1997; Graziano, Yap, & Gross, 1994). FIGURE 11.18 Receptive Fields of Two Types of Premotor Neurons That Responded to Both Visual and Body Information. (a) The receptive field of a cell that responded when a visual stimulus was in the area outlined near the face. (b) The visual field of the second type of neuron when the arm was out of sight. Middle and right, the visual field as the monkey’s arm moved forward and across.

SOURCE: Adapted from Figure 1 in “Coding of Visual Space by Premotor Neurons,” by M. S. A. Graziano, G. S. Yap, and C. G. Gross, Science, 266, pp. 1054–1057. Copyright © 1994. Reprinted by permission of AAAS. A fascinating demonstration of the role these specialized cells play occurs in a

bizarre phenomenon known as the “rubber hand illusion.” The individual sits at a table with the left hand hidden from view; the experimenter strokes the hidden left hand with a brush while simultaneously stroking a rubber hand, which is in full view (Figure 11.19). After a few seconds, the sensation seems to be coming from the rubber hand, which the subject reports seems like “my hand.” A recent study used functional magnetic resonance imaging (fMRI) to determine where the illusion occurs in the brain (Ehrsson, Spence, & Passingham, 2004). The posterior parietal cortex, which combines the visual and touch information, was active whether the two hands were stroked in synchrony or in asynchrony. The premotor area, on the other hand, became active only when the stroking was simultaneous, and only after the individual began to experience the illusion; moreover, the strength of activation was related to the intensity of the illusion reported by the subject. FIGURE 11.19 The Premotor Cortex and the Rubber Hand Illusion.

(a) The hidden left hand is stroked in synchrony with the fake hand, which is in full view. (b) After a few seconds, the individual feels that the sensation is coming from the rubber hand and reports a sense of ownership of the rubber hand. Apparently, the touch field and the visual field have become coordinated in the brain (indicated by the light blue outline and the yellow circle). fMRI recording shows that the premotor cortex is active during this illusion (indicated by the red circles). SOURCE: From “Probing the Neural Basis of Body Ownership,” by M. Botvinick, Science, 305, pp. 782–783, unnumbered figure on page 782. Illustration copyright © 2004 Taina Litwak. Used with permission.

Output from the prefrontal cortex flows to the supplementary motor area, which assembles sequences of movements, such as those involved in eating or in playing the piano. In monkeys trained to produce several different sets of movement sequences, different neurons increase their firing during a delay period depending on which sequence has been cued for performance (Shima & Tanji, 2000; Tanji & Shima, 1994). An important form of movement sequencing is the coordination of movements between the two sides of the body. For example, when a monkey’s supplementary motor cortex is damaged in one hemisphere, its hands tend to duplicate each other’s actions instead of sharing the task (C. Brinkman, 1984). Humans with similar damage also have trouble carrying out tasks that require alternation of movements between the two hands (Laplane, Talairach, Meininger, Bancaud, & Orgogozo, 1977). Coordinating the actions of the limbs is one of the biggest problems to be overcome on the way to developing mechanized prostheses, as In the News explains.

Coordinating Artificial Limbs

So far, most of the success with brain-machine interfaces has been limited to movement of a single body part, such as using a robotic arm to take a drink of coffee or eat a bit of chocolate (see the video in Chapter 3’s On the Web #9). But according to neuroscientist Miguel Nicolelis at Duke University, “No device will ever work for people unless it restores bimanual behaviors.” Although scientists are getting good at implanting electrodes in the brains of paralyzed patients and decoding the signals there to operate prosthetic devices, the cells on the two

sides of the brain act differently when they’re coordinating the movements of two limbs rather than separately instructing one limb or the other. Decoding those signals is the challenge faced by Nicolelis’s team at the Duke

University Center for Neuroengineering. They chose an interesting way to do this. First, they trained a female monkey to use joysticks to control the movements of a monkey avatar on a computer screen; the monkey was rewarded when it placed the avatar’s hands on two balls and held them there. The monkey had electrodes implanted in its brain; after a year of recording from 500 neurons in both hemispheres, the researchers were confident that their interface equipment could translate the brain’s signals into the avatar’s actions. They restrained the monkey’s arms and, after a few weeks of experience, the monkey was able to control the avatar correctly 75% of the time, just by thinking. But a paralyzed human won’t be able to practice beforehand with joysticks, so the researchers had a second monkey observe the first while she performed the task. Later, he was also able to master the task without ever practicing with the joysticks. The Duke team’s goal is to improve on this technology until it can be used to

control a mechanized “exoskeleton” that will enable paralyzed individuals to walk. In an interview in 2011, Nicolelis pledged that the robotic body suit would allow a paralyzed person to kick a soccer ball during the opening ceremony of the 2014 Brazil World Cup. By the time you read this, we will know whether he was able to fulfill this lofty promise.

3 Monkey Brain Controls Avatar

The Primary Motor Cortex The primary motor cortex is responsible for the organization and execution of

voluntary movements; its cells fire most during the movement instead of prior to it (G. E. Alexander & Crutcher, 1990; Riehle & Requin, 1989). Individual motor cortex cells are not reserved for a specific movement but contribute their function to a range of related behaviors (Saper, Iverson, & Frackowiak, 2000); the primary motor cortex orchestrates the activity of these cells into a useful movement and contributes control

of the movement’s force and direction (Georgopoulos, Taira, & Lukashin, 1993; Maier, Bennett, Hepp-Reymond, & Lemon, 1993). This orchestration was particularly evident in a stimulation study by Graziano, Taylor, and Moore (2002). Instead of using the usual brief pulses of electricity, which produce only muscle twitches, they increased the duration to 1/2 second and saw complex, coordinated responses in the monkeys, such as grasping, moving the hand to the mouth, and opening the mouth. The primary motor cortex is able to put these complex movement sequences together with the aid of input from the secondary motor areas, the somatosensory cortex, and the posterior parietal area (see Figure 11.15 again) (Krakauer & Ghez, 2000). Presumably, information from the somatosensory and posterior parietal areas provides feedback needed for refining movements on the fly.

What do the basal ganglia and cerebellum add? The Basal Ganglia and Cerebellum The basal ganglia and cerebellum produce no motor acts themselves. Rather, they

modulate the activity of cortical and brain stem motor systems; in that role, they are necessary for posture and smooth movement (Ghez & Krakauer, 2000). The basal ganglia —the caudate nucleus, putamen, and globus pallidus—use information from the primary and secondary motor areas and the somatosensory cortex to integrate and smooth movements. The basal ganglia send output directly to the primary motor cortex and supplementary motor area, and to the premotor cortex via the thalamus. As you can see in Figure 11.20, these structures border the thalamus; they apparently smooth movements through both facilitating and inhibitory outputs to the thalamus (DeLong, 2000). The basal ganglia also are especially active during complex sequences of movements (Boecker et al., 1998). It appears that they are involved in learning movement sequences so the movements can be performed as a unit (Graybiel, 1998). In fact, one of the symptoms of Parkinson’s disease, which is caused by degeneration in the basal ganglia, is impaired learning, whether motor behavior is involved or not (Knowlton, Mangels, & Squire, 1996). Malfunction in the basal ganglia results in postural abnormalities and involuntary movements in Parkinson’s disease and Huntington’s disease. FIGURE 11.20 The Basal Ganglia. The basal ganglia include the caudate nucleus, putamen, and globus pallidus.

When the cerebellum receives information from the motor cortex about an intended movement, it determines the order of muscular contractions and their precise timing. It also uses information from the vestibular system to maintain posture and balance, refine movements, and control eye movements that compensate for head movements (Ghez & Thach, 2000). Once an intended movement has been modified, the cerebellum sends the information back to the primary motor cortex. We can see the contribution of the cerebellum in the deficits that occur when it is damaged. For example, we begin to shape our hand for grasping while the arm is moving toward the target, but a person with cerebellar damage reaches, pauses, and then shapes the hand. A normal individual touches the nose in what appears to be a single, smooth movement; cerebellar damage results in exaggerated, wavering corrections. The effects of cerebellar damage on coordination and accuracy in limb movements is similar to the effect of alcohol; the drunk driver who is pulled over by the police has trouble walking a straight line, standing on one foot with the eyes closed, or touching the nose with the tip of the finger. People with damage to the cerebellum are often mistakenly believed to be drunk. The cerebellum lives up to the meaning of its name, “little brain,” by applying its

expertise to a variety of tasks. It is necessary for learning motor skills (D. A. McCormick & Thompson, 1984), but it also participates in nonmotor learning (Canavan, Sprengelmeyer, Diener, & Hömberg, 1994) and in making time and speed judgments about auditory and visual stimuli (Keele & Ivry, 1990). Also, patients with cerebellar damage have difficulty shifting visual attention to another location in space (whether this involves eye movements or not), taking 0.8 to 1.2 s compared with 0.1 s for normal individuals (Townsend et al., 1999). We should think of the cerebellum in terms of its general functions rather than strictly as a motor organ.

4 Movement Disorders Disorders of Movement You might think that anything as complex as the movement system would be

subject to malfunction; if so, you would be correct. Predictably, movement disorders are devastating to their victims. We will consider as representatives of these diseases Parkinson’s disease, Huntington’s disease, myasthenia gravis, and multiple sclerosis.

What are the causes and effects of the movement disorders? Parkinson’s Disease Parkinson’s disease is characterized by motor tremors, rigidity, loss of balance and

coordination, and difficulty in moving, especially in initiating movements (Olanow & Tatton, 1999; Youdim & Riederer, 1997). Parkinson’s affects about 0.3% of the population in industrialized countries and 1% of people over the age of 60 years (Nussbaum & Ellis, 2003). The symptoms are caused by deterioration of the substantia nigra, whose neurons send dopamine-releasing axons to the striatum, which is composed of the basal ganglia’s caudate nucleus and putamen and the nucleus accumbens. In something less than 10% of cases, the disease is familial, meaning that it occurs more frequently among relatives of a person with the disease than it does in the population (Greenamyre & Hastings, 2004). If a member of a twin pair is diagnosed with Parkinson’s disease before the age of 51, the chance of an identical twin also having Parkinson’s is six times greater than it is for a fraternal twin (Tanner et al., 1999). The same study found no evidence of a genetic influence in individuals whose symptoms developed later in life; we will look at possible nongenetic causes shortly. Geneticists have located 28 chromosomal regions that are most likely related to Parkinson’s disease, and 6 of those regions contain genes whose mutations are known to cause the disease on their own (reviewed in Klein & Westenberger, 2012). These six play a number of roles in cellular functioning and protein synthesis, and at least two are associated with the presence of Lewy bodies, abnormal clumps of protein that form within neurons (see Figure 11.21). Lewy bodies are often found in Parkinson’s patients and patients with Alzheimer’s disease (Glasson et al., 2000; Spillantini et al., 1997). Lewy bodies probably contribute to the cognitive deficits and depression that often accompany Parkinson’s disease; they may represent the brain’s attempt to remove proteins that have been damaged by toxins. The patient’s complement of genes helps determine age of onset, rate of progression, and whether cognitive loss will be a part of the disease. FIGURE 11.21 Lewy Bodies in a Brain With Parkinson’s Disease. A neuron containing two stained Lewy bodies, abnormal clumps of protein.

SOURCE: From “α-Synuclein in Lewy Bodies,” by M. G. Spillantini et al., 1997, Nature 8/28/1997. Copyright © 1997. Used with permission. Several environmental influences have been implicated in Parkinson’s disease. One

cause is subtle brain injury; being knocked unconscious once increases the risk by 32%, and the risk rises by 174% for those knocked out several times. Other research points to a variety of toxins, including industrial chemicals, carbon monoxide, herbicides, and pesticides (Olanow & Tatton, 1999). Numerous studies show an association between pesticide use and Parkinson’s, but the human studies are correlational, and establishing a causal relationship has been difficult (reviewed in Moretto & Colosio, 2013). Pesticide exposure produces some of the symptoms of Parkinson’s in animals, though with very high dosages. Animal studies also suggest that some genes increase sensitivity to the toxic effects, providing another example of the interaction between hereditary and environmental effects. While firm conclusions have eluded us, a study in California’s highly agricultural Central Valley that found a tripling of risk with occupational exposure to the pesticides ziram, maneb, and paraquat (Wang et al., 2011) suggests extreme caution while we try to sort things out. FIGURE 11.22 Transplanted Embryonic Cells in the Brain of a Parkinson’s Patient. The patient died in a car accident 7 months after her surgery. (a) Her right putamen (part of the striatum) was removed and placed on a photograph of the magnetic resonance image of her brain made at the time of surgery. The red lines indicate the angle at which the needles were inserted into the brain to inject the fetal cells (right side of the brain) and as a control procedure (left side). The dark area on the putamen along the needle track is due to the staining of new dopamine cells and shows that the axons had grown 2 to 3 millimeters from the cell bodies. The image in (b) is an enlargement of the putamen.

SOURCE: From “Transplantation of Embryonic Dopamine Neurons for Severe Parkinson’s Disease,” by C. R. Freed et al., 2001, New England Journal of Medicine, 334, pp. 710–719, fig. 3a and b, p. 717. Interestingly, the risk of Parkinson’s disease is reduced as much as 80% in coffee

drinkers (G. W. Ross et al., 2000). The risk also drops by 50% in smokers (Fratiglioni & Wang, 2000), but of course no benefit of smoking outweighs its dangers. Rat studies indicate that cigarette smoke may prevent the accumulation of neurotoxins (Soto-Otero, Méndez-Alvarez, Sánchez-Sellero, Cruz-Landeira, & López-Rivadulla, 2001) and that caffeine reduces the effect of neurotoxins by blocking adenosine receptors, which we saw in Chapter 5 results in increased dopamine and acetylcholine release (J.-F. Chen et al., 2001). In heavy coffee drinkers, a variant of the glutamate receptor gene GRIN2A reduces Parkinson’s risk by 59% (Hamza et al., 2011). There has been some clinical success in treating Parkinson’s with adenosine and glutamate receptor antagonists (Gasparini, Di Paolo, & Gomez-Mancilla, 2013; Hickey & Stacy, 2012). Parkinson’s disease is typically treated by administering levodopa (L-dopa), which

is the precursor for dopamine. Dopamine will not cross the blood-brain barrier but L- dopa will, and in the brain it is converted to dopamine. Dopamine agonists can also be helpful, and even placebos increase dopamine release (de la Fuente-Fernández et al., 2001). But these treatments increase dopamine throughout the brain, which causes side effects ranging from restlessness and involuntary movements to hallucinations. Also, as more neurons die, more drug is required, increasing the side effects. While levodopa remains the standard, its side effects mean that some patients are forced to use other drugs. Unfortunately, these drugs also treat only some of the symptoms and with limited benefit. However, researchers in the United Kingdom are experimenting with a novel way of screening potential drugs (see accompanying In the News). Early attempts showed that implanted embryonic neural cells could survive in the

striatum and produce dopamine (Figure 11.22; C. R. Freed et al., 2001; Greene & Fahu, 2002). However, behavioral improvement was not clinically significant, and some of the patients developed involuntary movements, apparently due to excess dopamine. More recent work using adult neural stem cells resulted in more than 80% improvement in motor behavior ratings; the improvement held up for 3 years but had disappeared at the end of 5 years (Lévesque, Neuman, & Rezak, 2009). Clinical

application is hampered by immune reactions to stem cells and by the development of tumors at the implant site. Recent work indicates that immune response is minimal with stem cells taken from the individual (Morizane et al., 2013), and tumor development can be avoided by allowing the stem cells to mature into an early form of neural cell before implanting (Doi et al., 2012). Gene therapy has also been tried experimentally, with the intent of increasing dopamine levels or reducing excess activity in affected brain areas. Results have been mixed in the handful of clinical trials conducted at the phase 1 and phase 2 levels; so far, no procedure has reached the critical phase 3 level that could establish its effectiveness sufficiently for approval by the U.S. Food and Drug Administration (FDA) (Denyer & Douglas, 2012). In an attempt to avoid previous disappointments, the British company Oxford Biomedica has treated 15 drug-resistant patients with a combination of three genes; all patients improved in motor capability and maintained improvement for the full year of this phase 1/2 safety and dosage trial (Palfi et al., 2014). These procedures are in their infancy, and we need to remember that the first several heart transplant operations failed but they are almost routine today.

Curing Parkinson’s in a Dish A team of scientists at the Sheffield Institute for Translational Neuroscience is searching for a drug that will rescue dying cells, not just reduce the symptoms of Parkinson’s disease. To speed the process of sifting through numerous possible drugs, they tested the effects of compounds on cells obtained from patients. Five years and 2,000 drugs later, they have found one that worked. Ursodeoxycholic acid (UDCA) preserved the function of the cells’ mitochondria, which supply energy to cells. Because UDCA is already licensed for other uses, the

researchers can proceed directly to a phase 1 clinical trial to determine safety and optimum dosage.

5 Screening Parkinson’s Drugs

Frustration with therapeutic alternatives is creating something of a revival in surgical treatments, which were largely abandoned when drugs for Parkinson’s disease became available (Cosgrove & Eskandar, 1998). Strategically placed lesions in the subthalamic nucleus and the globus pallidus, both in the basal ganglia (see Figure 11.20 again), have provided some improvement for patients who have difficulty using dopaminergic drugs (Cosgrove & Eskandar). These two structures produce a rhythmic bursting activity similar to the rhythm of activity in Parkinsonian tremors, which apparently explains why destroying them reduces this symptom

(Perkel & Farries, 2000). But the surgery can damage adjacent structures, resulting in other deficits, such as weakness in a part of the body. A less drastic procedure is deep brain stimulation (DBS), electrical stimulation through implanted electrodes. Improved motor functioning, allowing levodopa reduction, has been reported for as long as 10 years (reviewed in Fasano, Daniele, & Albanese, 2012). Results are mixed with regard to cognitive deficits, which often are more disabling and resistant to treatment than the motor symptoms. DBS usually improves or eliminates impulse control problems in the 13% to 16% of patients affected, possibly due to levodopa reduction; however, some studies have reported onset of pathological gambling, hypersexuality, and compulsive eating. In addition, there is some loss of verbal fluency after DBS, and apathy increases in some patients. “

This is a scary thing.... There is a test available, but I haven’t had the guts to take it yet.

—Shana Martin, at risk for Huntington’s disease

” Huntington’s Disease Like Parkinson’s disease, Huntington’s disease is a degenerative disorder of the

motor system involving cell loss in the striatum and cortex. Years before a diagnosis, Huntington’s disease begins with jerky movements that result from impaired error correction (M. A. Smith, Brandt, & Shadmehr, 2000). Later, involuntary movements appear, first as fidgeting and then as movements of the limbs and, finally, writhing of the body and facial grimacing. Because these movements sometimes resemble a dance, Huntington’s disease is also called Huntington’s chorea, from the Greek word choreia, which means “dance.” Needless to say, the patient loses the ability to carry out daily activities. Death usually follows within 15 to 30 years after the onset of the disease. Unlike Parkinson’s disease, cognitive and emotional deficits are a universal

characteristic of Huntington’s disease. These deficits include impaired judgment, difficulty with a variety of cognitive tasks, depression, and personality changes. The motor symptoms are due to the degeneration of inhibitory GABA-releasing neurons in the striatum, while defective or degenerated neurons in the cortex probably account for the psychological symptoms (Figure 11.23; J. B. Martin, 1987; Tabrizi et al., 1999). Huntington’s disease results from a mutated form of the huntingtin gene

(Huntington’s Disease Collaborative Research Group, 1993). The loss of neurons is probably due to the accumulation of the gene’s protein, also known as huntingtin, whose function is unknown (DiFiglia et al., 1997). In normal individuals, the gene has

between 10 and 34 repetitions of the bases cytosine, adenine, and guanine (see Chapter 1). The more repeats the person has beyond 37, the earlier in life the person will succumb to the disease (R. R. Brinkman, Mezei, Theilmann, Almqvist, & Hayden, 1997). Because the gene is dominant, a person who has a parent with Huntington’s has a 50% chance of developing the disease. This is an unusual example of a human disorder resulting from a single gene. FIGURE 11.23 Loss of Brain Tissue in Huntington’s Disease. Left, a section from a normal brain; right, a section from a person with Huntington’s disease. The enlarged lateral ventricle in the diseased brain is due to loss of neurons in the caudate nuclei (arrows).

SOURCE: Courtesy of Robert E. Schmidt, Washington University. A number of drugs are used to treat the various symptoms, including

antidepressants and antipsychotics, but only one has been approved specifically for Huntington’s disease by the FDA (“FDA Approves,” 2008). It reduces the excess dopamine that causes the abnormal movements. Drugs that silence the huntingtin gene are showing promise in animals; a single injection of one of these drugs normalized movement in mice for the 9-month duration of the study and significantly reduced huntingtin protein levels for 8 weeks in monkeys (Kordasiewicz et al., 2012). Grafting of fetal striatal cells has so far produced only modest and temporary improvement (Cicchetti et al., 2009), and stem cell studies have only reached the point of demonstrating that the transplanted cells survive and mature (Maucksch, Vazey, Gordon, & Connor, 2013). Autoimmune Diseases Myasthenia gravis is a disorder of muscular weakness caused by reduced numbers

or sensitivity of acetylcholine receptors. The muscle weakness can be so extreme that the patient has to be maintained on a respirator. In fact, 25 years ago the mortality rate from myesthenia gravis was about 33%; now few patients die from the disease, thanks to improved treatment (Rowland, 2000a). The loss of receptors was demonstrated in an interesting way. The venom of the

many-banded Formosan krait, a very poisonous snake from Taiwan, paralyzes prey by binding to the acetylcholine receptor. When the venom’s toxin is labeled with radioactive iodine and applied to a sample of muscle tissue, it allows researchers to

identify and count the acetylcholine receptors. The patients turned out to have 70% to 90% fewer receptors than normal individuals (Fambrough, Drachman, & Satyamurti, 1973). Drugs that inhibit the action of acetylcholinesterase give temporary relief from the symptoms of myesthenia gravis (Figure 11.24; Rowland, Hoefer, & Aranow, 1960). Remember that acetylcholinesterase breaks down acetylcholine at the synapse; these inhibitors increase the amount of available neurotransmitter at the neuron- muscle junction. FIGURE 11.24 Effect of an Acetylcholinesterase Inhibitor on Myasthenia Gravis. (a) Patients often have drooping eyelids, as shown here. This patient also could not move his eyes to look to the side. (b) The same patient 1 min after injection of an acetylcholinesterase inhibitor. The eyes are open and able to move freely.

SOURCE: From “Mysathenic Syndromes,” by L. P. Rowland, P. F. A. Hoefer, and H. Aranow, Jr., 1960, Research Publications—Association for Research in Nervous and Mental Disease, pp. 38, pp. 547–560. Although immune system therapy has sometimes been used (Shah & Lisak, 1993),

removal of the thymus (thymectomy) has become a standard treatment for myasthenia gravis (Rowland, 2000a). The thymus is the major source of lymphocytes that produce antibodies. Improvement can take years, but thymectomy eliminates symptoms completely in almost 80% of patients and reduces them in another 13% to 17% (Ashour et al., 1995; Jaretzki et al., 1988). Multiple sclerosis is a motor disorder with many varied symptoms, caused by

deterioration of myelin (demyelination) and neuron loss in the central nervous system. In Chapter 2, you saw that demyelination causes slowing or elimination of neural impulses. Demyelination thus reduces the speed and strength of movements. Even before that happens, impulses traveling in adjacent neurons, which should arrive simultaneously, become desynchronized because of differential loss of myelin. An early sign of the disorder is impairment of functions that require synchronous bursts of neural activity, like tendon reflexes and vibratory sensation (Rowland, 2000b). As the disease progresses, unmyelinated neurons die, leaving areas of sclerosis, or hardened scar tissue (Figure 11.25). As a result, the person experiences muscular weakness, tremor, impaired coordination, urinary incontinence, and visual problems. Studies indicate that neuron loss is more important than previously thought and suggest that the loss results from a degenerative process in addition to the demyelination (DeLuca, Ebers, & Esiri, 2004; De Stefano et al., 2003).

FIGURE 11.25 The Brain of a Deceased Multiple Sclerosis Patient. The arrows indicate areas of sclerosis, or hardened scar tissue (dark areas).

SOURCE: Science Source. Like myasthenia gravis, multiple sclerosis is an autoimmune disease. Injecting

foreign myelin protein into the brains of animals produces symptoms very similar to those of multiple sclerosis (Wekerle, 1993), and T cells that are reactive to myelin proteins (see Chapter 8) have been found in the blood of multiple sclerosis patients (Allegretta, Nicklas, Sriram, & Albertini, 1990). A genome-wide study has implicated various immune system genes in multiple sclerosis (International Multiple Sclerosis Genetics Consortium, 2007), but some environmental condition may be needed to trigger the immune attack on myelin. One possibility is that the immune system has been sensitized by an earlier viral infection; for example, studies have found antibodies for Epstein-Barr virus in multiple sclerosis patients (H. J. Wagner et al., 2000), and patients more often had mumps or measles during adolescence (Hernán, Zhang, Lipworth, Olek, & Ascherio, 2001). Several drugs are available that modify immune activity in multiple sclerosis patients; they slow the progress of the disease but do not repair the harm already done. A new direction may be indicated by a potassium channel blocker, dalfampridine; it improves motor performance, particularly walking (Jeffrey, 2010), but it has the disadvantage of increasing seizure risk (“FDA Drug Safety Communication,” 2012). On the stem cell front, the FDA has approved a phase 1 safety trial using cells harvested from patients’ bone marrow; in preclinical testing, the procedure reduced brain inflammation, repaired myelin, and improved brain function (“Ground Breaking Multiple Sclerosis Stem Cell Trial,” 2013).

Concept Check Take a Minute to Check YourKnowledge and Understanding Explain how antagonistic muscles and spinal reflexes maintain posture. What contribution does each of the cortical motor areas make to movement? Make a diagram showing how you think the neurons would be interconnected to carry out the target and arm selection task described in the Hoshi & Tanji study on page 358.

What are the genetic and environmental causes of the movement disorders described here?

In Perspective Unless we have a disorder, we usually take our body senses and our capability for movement for granted. And yet just standing upright is a remarkable feat. Granted, a mechanical robot could do it easily, but only if it had a rigid body like R2D2’s. If the robot had our flexibility of movement and posture, it would have to devote a fair amount of its computer brain to making split-millisecond adjustments to avoid toppling over. Then another chunk of its computer would be required just to locate a visual object in space, to reach out smoothly and quickly for the object, and to shape its hand for grasping, deciding whether to use the whole hand or the finger and thumb and how much pressure to apply, and so on. You get the idea. Better let a human do it, because all that fancy equipment comes standard on the basic model. Now you see why so much of the brain is concerned with the sensory and motor

components of movement. It is a wonder that we have enough left over for the demands of learning, intelligence, and consciousness, but as you will see in the remaining chapters, we do. Summary The Body Senses • The body senses include proprioception, which tells us about the position and movement of our limbs and body; the skin senses, which inform us about the conditions in the periphery of our body; and the vestibular sense, which contributes information about head position and movement and helps us maintain balance.

• The skin senses—touch, warmth, cold, and pain—tell us about conditions at the body surface and about objects in contact with our body.

• The body senses are processed in a series of structures in the primary and secondary somatosensory cortex and in the posterior parietal cortex, with several similarities to visual processing. Pain processing also extends into additional areas.

• In their quest to find better ways of relieving pain, researchers have learned how the nervous system detects painful stimulation and found that the body has its own ways of relieving pain. Chronic pain presents particularly difficult challenges.

Movement

• There are three types of muscles: cardiac (heart); smooth (internal organs); and skeletal muscles, which move the body by tugging against their attachments to bones.

• Spinal reflexes produce quick responses and provide postural adjustments. Central pattern generators provide routines such as rhythmic walking movements.

• Cortical motor areas assess spatial and body information and construct movements by passing information through a succession of brain areas.

• The basal ganglia and cerebellum refine movements produced by the motor cortex. • A number of diseases attack the motor system at various points of vulnerability. Major causes that have been implicated are heredity, toxins, and autoimmune disorders. ■

Study Resources

For Further Thought • Of proprioception, the vestibular sense, pain, and the other skin senses, which do you think you could most afford to give up? Why?

• If pain is beneficial, why does the body have pain relief mechanisms? • Imagine a robot with a humanlike body. It is programmed to walk, reach, grasp, and so on. It has visual and auditory capabilities, but no body senses. What would its movement be like?

• Judging by the examples given of movement disorders, what are the points of vulnerability in the motor system?

Quiz: Testing Your Understanding 1. Explain how endorphins relieve pain, describing the receptors and the

pathway from the periaqueductal gray; include how we determine whether pain relief is endorphin based.

2. Walking barefoot, you step on a sharp rock. You reflexively withdraw your foot, plant it firmly on the ground again, and regain your posture. Describe these behaviors in terms of the sensory/pain mechanisms and reflexes involved.

3. Trace the progress of a movement through the parietal and frontal lobes, giving the names of the structures and a general idea of the processing in each.

4. Compare the symptoms, causes, and treatment options for Parkinson’s and Huntington’s diseases.

Select the best answer: 1. Proprioception gives us information about

a. conditions at the surface of our skin. b. conditions in the internal organs. c. the position and movement of our limbs and body.

d. balance and the head’s position and movement. 2. The skin senses include

a. touch, warmth, and cold. b. touch, temperature, and pain. c. touch, temperature, movement, and pain. d. touch, warmth, cold, and pain.

3. Sharp pain and dull pain are due primarily to a. different kinds of injury. b. pain neurons with different characteristics. c. the passage of time. d. the person’s attention to the pain.

4. According to Melzack and Wall, pressing the skin near a wound reduces pain by a. creating inhibition in the pain pathway. b. distracting attention from the injury. c. releasing endorphins. d. releasing histamine into the wound area.

5. Endorphins a. activate the same receptors as opiate drugs. b. occupy receptors for pain neurotransmitters. c. block reuptake of pain neurotransmitter. d. inhibit brain centers that process pain emotion.

6. Both congenital pain insensitivity and chronic pain involve a. developmental alterations of brain areas responsible for the emotion of

pain. b. alterations in the myelination of pain fibers. c. gene-mediated alterations of pain sensitivity. d. variations in the amount of substance P available.

7. Research suggests phantom pain is due to a. the patient’s anxiety over the limb loss. b. memory of the pain of injury or disease that prompted the amputation. c. activity in severed nerve endings in the stump. d. neural reorganization in the somatosensory area.

8. Without a posterior parietal cortex we would be most impaired in a. moving. b. making smooth movements. c. orienting movements to objects in space. d. awareness of spontaneously occurring movements.

9. If the nerves providing sensory feedback from the legs were cut, we would a. have to use vision to guide our leg movements.

b. have trouble standing upright. c. lose strength in our legs. d. a and b e. b and c

10. A monkey is presented a stimulus, and then must wait a few seconds before it can reach to the correct stimulus. Activity in the secondary motor area during the delay suggests that this area a. prepares for the movement. b. initiates the movement. c. executes the movement. d. all of these

11. Cells in the premotor cortex would be particularly involved when you a. remember a visual stimulus during a delay period. b. catch a fly ball. c. start to play a series of notes on the piano. d. execute a movement.

12. The primary motor cortex is most involved in a. combining sensory inputs. b. planning movements. c. preparing movements. d. executing movements.

13. The basal ganglia and the cerebellum produce a. no movements. b. movements requiring extra force. c. reflexive movements. d. sequences of movements.

14. Parkinson’s disease is characterized most by a. deterioration of the myelin sheath. b. dancelike involuntary movements. c. deterioration of dopamine-releasing neurons. d. immune system attack on acetylcholine receptors.

15. Results of removing the thymus gland suggest that myasthenia gravis is a(n) ________ disease. a. genetic b. autoimmune c. virus-caused d. degenerative

Answers: 1. c, 2. d, 3. b, 4. a, 5. a, 6. c, 7. d, 8. c, 9. d, 10. a, 11. b, 12. d, 13. a, 14. c, 15. b.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The Vestibular Disorders Association has information about vestibular

problems and provides additional resources such as newsletters, books, and videotapes.

2. The American Pain Foundation offers information for pain patients, testimonials from people suffering pain from an assortment of causes, and links to numerous other pain sites. The International Association for the Study of Pain has links to more technical resources on pain.

3. The In the News feature about monkeys learning to coordinate both hands of a computer avatar with their brains came from a ScienceNOW news article.

4. In BrainFacts.org’s Searching for Answers videos, patients and their families describe what it is like to live with Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). You can get information about a variety of movement disorders from the Neuromuscular Disease Center, National Parkinson Foundation, Huntington’s Disease Association, and National Multiple Sclerosis Society. In an interview with Katie Couric, actor Michael J. Fox talks about living with Parkinson’s disease and about his views on stem cell research

5. A University of Sheffield news release describes the groundbreaking study that screened 2,000 potential drugs for Parkinson’s disease.

Chapter Updates and Biopsychology News

For Further Reading 1. Awakenings, by Oliver Sacks (Vintage Books, 1999), describes Dr. Sacks’s

early experiments in using L-dopa to treat the symptom of parkinsonism in patients with sleeping sickness. The movie with Robin Williams was based on this book.

2. Phantoms in the Brain, by V. S. Ramachandran and Sandra Blakeslee

(Harper Perennial, 1999), called “enthralling” by the New York Times and “splendid” by Francis Crick, uses numerous (often strange) cases to explain people’s perception of their bodies.

3. Wall and Melzack’s Textbook of Pain, edited by Stephen McMahon, Martin Koltzenburg, Irene Tracey, and Dennis Turk (Saunders, 6th ed., 2013), and The Massachusetts General Hospital Handbook of Pain Management, edited by Jane Ballantyne (Lippincott Williams and Wilkins, 3rd ed., 2005) are technical references on pain and pain management.

4. Oxford Textbook of Movement Disorders, by David Burn (Oxford University Press, 2013), covers the science of movement disorders, along with their diagnosis and treatment.

Key Terms antagonistic muscles basal ganglia body integrity identity disorder cardiac muscles central pattern generator (CPG) chronic pain deep brain stimulation (DBS) dermatome endorphins familial gate control theory Golgi tendon organs Huntington’s disease levodopa (L-dopa) Lewy bodies multiple sclerosis muscle spindles myasthenia gravis out-of-body experience Parkinson’s disease periaqueductal gray (PAG) phantom pain posterior parietal cortex premotor cortex primary motor cortex primary somatosensory cortex proprioception

secondary somatosensory cortex skeletal muscles skin senses smooth muscles somatosensory cortex somatotopic map striatum substance P substantia nigra supplementary motor area vestibular sense

Part IV

Complex Behavior

Chapter 12. Learning and Memory Chapter 13. Intelligence and Cognitive Functioning Chapter 14. Psychological Disorders Chapter 15. Sleep and Consciousness

12 Learning and Memory

In this chapter you will learn • How and where memories are stored in the brain • What changes occur in the brain during learning • How aging and two major disorders impair learning

Learning as the Storage of Memories Amnesia: The Failure of Storage and Retrieval APPLICATION: THE LEGACY OF HM

Mechanisms of Consolidation and Retrieval Where Memories Are Stored Two Kinds of Learning Working Memory CONCEPT CHECK

Brain Changes in Learning Long-Term Potentiation How LTP Happens Neural Growth in Learning Consolidation Revisited Changing Our Memories APPLICATION: TOTAL RECALL IN THE NEWS: RECALLING IT NOW HELPS YOU REMEMBER IT LATER CONCEPT CHECK

Learning Deficiencies and Disorders Effects of Aging on Memory Alzheimer’s Disease IN THE NEWS: NATIONAL INSTITUTES OF HEALTH TEAMS WITH DRUG COMPANIES

Korsakoff’s Syndrome CONCEPT CHECK

In Perspective Summary Study Resources

A t the age of 7, Henry Molaison’s life was forever changed by a seemingly minorincident: He was knocked down by a bicycle and was unconscious for 5 minutes. Three years later, he began to have minor seizures, and his first major seizure

occurred on his 16th birthday. Still, Henry had a reasonably normal adolescence, taken up with high school, science club, hunting, and roller-skating, except for a 2- year furlough from school because the other boys teased him about his seizures. “

Discovering the physical basis of learning in humans and other mammals is among the greatest remaining challenges facing the neurosciences.

—Brown, Chapman,Kairiss, & Keenan, 1988

” After high school, he took a job in a factory, but eventually the seizures made it

impossible for him to work. He was averaging 10 small seizures a day and 1 major seizure per week. Because anticonvulsant medications were unable to control the seizures, Henry and his family decided on an experimental operation that held some promise. In 1953, when he was 27, a surgeon removed much of both of his temporal lobes, where the seizure activity was originating. The surgery worked, for the most part: With the help of medication, the petit mal seizures were mild enough not to be disturbing, and major seizures were reduced to about one a year. Henry returned to living with his parents. He helped with household chores, mowed the lawn, and spent his spare time doing difficult crossword puzzles. Later, he worked at a rehabilitation center, doing routine tasks like mounting cigarette lighters on cardboard displays. Henry’s intelligence was not impaired by the operation; his IQ test performance

even went up, probably because he was freed from the interference of the abnormal brain activity. However, there was one important and unexpected effect of the surgery. Although he could recall personal and public events and remember songs from his earlier life, Henry had difficulty learning and retaining new information. He could hold new information in memory for a short while, but if he were distracted or if a few minutes passed, he could no longer recall the information. When he worked at the rehabilitation center, he could not describe the work he did. He did not remember moving into a nursing home in 1980, or even what he ate for his last meal. And although he watched television news every night, he could not remember the day’s news events later or even recall the name of the president (Corkin, 1984; B. Milner, Corkin, & Teuber, 1968). Henry’s inability to form new memories was not absolute. Although he could not

find his way back to the new home his family moved to after his surgery if he was more than two or three blocks away, he was able to draw a floor plan of the house, which he had navigated many times daily (Corkin, 2002). Over the years he became

aware of his condition, and he was very insightful about it. In his own words, Every day is alone in itself, whatever enjoyment I’ve had, and whatever sorrow I’ve had.... Right now, I’m wondering. Have I done or said anything amiss? You see, at this moment everything looks clear to me, but what happened just before? That’s what worries me. It’s like waking from a dream; I just don’t remember. (B. Milner, 1970, p. 37) Over a period of 55 years, Henry would be the subject of a hundred scientific

studies that he could not remember; he was known to the world as patient HM to protect his privacy. In the next several pages, you will see why many consider HM’s surgery the most significant single event in the study of learning. Learning as the Storage of Memories Some one-celled animals “learn” surprisingly well, for example, to avoid swimming toward a light where they have received an electric shock before. I have placed the term learn in quotation marks because such simple organisms lack a nervous system; their behavior changes briefly, but if you take a lunch break during your subject’s training, when you return, you will have to start all over again. Such a temporary form of learning may help an organism avoid an unsafe area long enough for the danger to pass or linger in a place where food is more abundant. But without the ability to make a more or less permanent record, you could not learn a skill, and experience would not help shape who you are. We will introduce the topic of learning by examining the problem of storage.

How does studying amnesia help us understand memory? Amnesia: The Failure of Storage and Retrieval HM’s symptoms are referred to as anterograde amnesia, an impairment in forming

new memories. (Anterograde means “moving forward.”) This was not HM’s only memory deficit; the surgery also caused retrograde amnesia, the inability to remember events prior to impairment. His retrograde amnesia extended from the time of surgery back to about the age of 16; he had a few memories from that period, but he did not remember the end of World War II or his own graduation, and when he returned for his 35th high school reunion, he recognized none of his classmates. Better memory for earlier events than for recent ones may seem implausible, but it is typical of patients who have brain damage similar to HM’s. How far back the retrograde amnesia extends depends on how much damage there is and which specific structures are damaged. FIGURE 12.1 Temporal Lobe Structures Involved in Amnesia. (a) HM’s brain (top left) and a normal brain (below). You can see that the amygdala (A), hippocampus (H), and other structures labeled in the normal brain are partly or completely missing in HM’s brain. (b) Structures of the medial temporal lobe, which are important in learning. (The frontal lobe is to the left.)

SOURCES: (a) From “HM’s Medial Temporal Lobe Lesion: Findings From Magnetic Resonance Imaging,” by S. Corkin, D. G. Amaral, R. G. González, K. A. Johnson, and B. T. Hyman, 1997, Journal of Neurosicence, 17, pp. 3964–3979. Copyright © 1997 by the Society for Neuroscience. Used with permission. (b) Adapted with permission from “Remembrance of Things Past,” by D. L. Schacter and A. D. Wagner, Science, 285, pp. 1503–1504. Illustration: K. Sutliff. © 1999 American Association for the Advancement of Science. Reprinted with permission from AAAS. HM’s surgery damaged or destroyed the hippocampus, nearby structures that along

with the hippocampus make up the hippocampal formation, and the amygdala. Figure 12.1 shows the location of these structures; because they are on or near the inside surface of the temporal lobe, they form part of what is known as the medial temporal lobe (remember that medial means “toward the middle”). Because HM’s surgery was so extensive, it is impossible to tell which structures are responsible for the memory functions that were lost. Studies of patients with varying degrees of temporal lobe damage have helped determine which structures are involved in amnesia and, therefore, in memory. Henry died in 2008 at the age of 82, but he continues to make a contribution, as the accompanying Application explains.

APPLICATION

The Legacy of HM

SOURCE: Wikimedia Commons.

Not only did Henry Moliason devote much of his life to numerous scientific investigations, but his brain will continue to be the subject of study for many years to come (Lafee, 2009). Soon after his death, Henry’s preserved brain was in a plastic cooler strapped in a seat on a flight from Boston to San Diego; in the next seat was Jacopo Annese, director of the Brain Observatory at the University of California at San Diego. After several months of preparation, Annese and his colleagues dissected Henry’s brain into slices as thin as the width of a hair. Each slice was microscopically photographed with such resolution that the data from each slice would fill 200 DVDs. The data were then combined into a three-dimensional reconstruction of the brain, which is available online. Scientists can navigate through it to the area of their interest and then zoom in to the level of individual neurons. Ironically, the man who could not remember will never be forgotten.

1 HM and His Brain

The hippocampus consists of several substructures with different functions. The part known as CA1 provides the primary output from the hippocampus to other brain areas; damage in that part of both hippocampi results in moderate anterograde amnesia and only minimal retrograde amnesia. If the damage includes the rest of the hippocampus, anterograde amnesia is severe. Damage to the entire hippocampal formation results in retrograde amnesia extending back 15 years or more (J. J. Reed & Squire, 1998; Rempel-Clower, Zola, Squire, & Amaral, 1996; Zola-Morgan, Squire, & Amaral, 1986). More extensive retrograde impairment occurs with broader damage or deterioration, like that seen in Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, apparently because memory storage areas in the cortex are compromised (Squire & Alvarez, 1995). “

Most memories, like humans and wines, do not mature instantly. Instead they are gradually stabilized in a process referred to as consolidation.

—Yadin Dudai

” Mechanisms of Consolidation and Retrieval HM’s memory impairment consisted of two problems: consolidation of new

memories and, to a lesser extent, retrieval of older memories. Consolidation is the process in which the brain forms a more or less permanent physical representation of a memory. Retrieval is the process of accessing stored memories—in other words, the

act of remembering. When a rat presses a lever to receive a food pellet or a child is bitten by a dog or you skim through the headings in this chapter, the experience is held in memory at least for a brief time. But just like the phone number that is forgotten when you get a busy signal the first time you dial, an experience does not necessarily become a permanent memory; and if it does, the transition takes time. Until the memory is consolidated, it is particularly fragile. New memories may be disrupted just by engaging in another activity, and even older memories are vulnerable to intense experiences such as emotional trauma or electroconvulsive shock treatment (a means of inducing convulsions, usually in treating depression). Researchers divide memory into two stages, short-term memory and long-term memory. Long-term memory, at least for some kinds of learning, can be divided into two stages that have different durations and occur in different locations (see Figure 12.2), as we will see later (McGaugh, 2000). FIGURE 12.2 Stages of Consolidation. Making a memory permanent involves multiple stages and different processes.

SOURCE: From “Memory—A Century of Consolidation,” by J. L. McGaugh, Science, 287, pp. 248–251. Reprinted with permission from AAAS. An animal study clearly demonstrates that the hippocampus participates in

consolidation. Rats were trained in a water maze, a tank of murky water from which they could escape quickly by learning the location of a platform submerged just under the water’s surface (Figure 12.3; Riedel et al., 1999). Then, for 7 days the rats’ hippocampi were temporarily disabled by a drug that blocks receptors for the neurotransmitter glutamate. Eleven days later—plenty of time for the drug to clear the rats’ systems—they performed poorly compared with control subjects (Riedel et al.). Researchers have been able to “watch” the consolidation happening in humans, using brain scans and event-related potentials. Presenting words or pictures activated the hippocampus and adjacent cortex; how well the material was remembered later could be predicted from how much activation occurred in those areas during stimulus presentation (Figure 12.4; Alkire, Haier, Fallon, & Cahill, 1998; Brewer, Zhao, Desmond, Glover, & Gabrieli, 1998; Fernández et al., 1999).

FIGURE 12.3 A Water Maze. The rat learns to escape the murky water by finding the platform hidden just below the surface.

FIGURE 12.4 Hippocampal Activity Related to Consolidation. The arrow is pointing to the hippocampal region. Reds and yellows indicate positive correlations of activity at the time of learning with later recall; blues indicate negative correlations.

SOURCE: From “PET Imaging of Conscious and Unconscious Memory,” by M. T. Alkire, R. J. Haier, J. H. Fallon, and S. J. Barker, 1996, Journal of Consciousness Studies, 3, pp. 448–462. Animals that were given the glutamate-blocking drug at the time of testing instead

of immediately after training also had impaired recall in the water maze, indicating that the hippocampus has a role in retrieval as well as consolidation. Researchers have used PET scans to confirm that the hippocampus also retrieves memories in humans (D. L. Schacter, Alpert, Savage, Rauch, & Albert, 1996; Squire et al., 1992). Figure 12.5 shows increased activity in the hippocampi while the research participants recalled words learned during an experiment. The involvement of the hippocampus in

retrieval seems inconsistent with HM’s ability to recall earlier memories. But the memories that patients with hippocampal damage can recall are of events that occurred at least 2 years before their brain damage. Many researchers have concluded that the hippocampal mechanism plays a time-limited role in consolidation and retrieval, a point we will examine shortly. This diminishing role of the hippocampus would explain why older memories suffer less than recent memories after hippocampal damage. FIGURE 12.5 Hippocampal Activity in the Human Brain During Retrieval. (a) As participants tried to recall visually presented words that had been poorly learned (35% recall rate), the prefrontal and visual areas, but not the hippocampi, were highly activated compared with the baseline condition. (b) However, the successful recall of well-learned words (79% recall rate) activated both hippocampal areas.

SOURCE: Reprinted with permission from “Conscious Recollection and the Human Hippocampal Formation: Evidence From Positron Emission Tomography,” by D. L. Schacter et al., Proceedings of the National Academy of Sciences, USA, 93, pp. 321– 325. Copyright 1996 National Academy of Sciences, USA. The prefrontal area is also active during learning and retrieval, and some

researchers think that it directs the search strategy required for retrieval (Buckner & Koutstaal, 1998). Indeed, the prefrontal area is active during effortful attempts at retrieval, whereas the hippocampus is activated during successful retrieval (see Figure 12.5 again; D. L. Schacter et al., 1996). We will look at the role of the frontal area again when we consider working memory and Korsakoff’s syndrome. Where Memories Are Stored The hippocampal area is not the permanent storage site for memories. If it were,

patients like HM would not remember anything that happened before their damage occurred. According to most researchers, the hippocampus stores information

temporarily in the hippocampal formation; then, over time, a more permanent memory is consolidated elsewhere in the brain. A study of mice that had learned a spatial discrimination task supported the hypothesis: Over 25 days of retention testing, metabolic activity progressively decreased in the hippocampus and increased in the cortical areas (Bontempi, Laurent-Demir, Destrade, & Jaffard, 1999).

Is there a place where memories are stored? To explore further the relationship between these two areas, Remondes and

Schuman (2004) severed the pathway that connects CA1 of the hippocampus with the cortex. The lesions did not impair the rats’ performance in a water maze during training or 24 hours (hr) later, but after 4 weeks the rats had lost their memory for the task. The results supported the hypothesis that short-term memory depends on the hippocampus but long-term memory requires the cortex and an interaction over time between the two. To pin down the window of vulnerability of the memory, the researchers lesioned two additional groups of animals at different times following training. Those lesioned 24 hr after training were impaired in recall 4 weeks later, but those whose surgery was delayed until 3 weeks after training performed as well as the controls. This progression apparently occurs over a longer period of time in humans. Christine Smith and Larry Squire (2009) used fMRI to image the brain’s activity while subjects recalled news events from the past 30 years. Activity was greatest in the hippocampus and related areas as subjects recalled recent events, with levels declining over a period of 12 years and stabilizing after that. At the same time, activity increased progressively with older memories in the prefrontal, temporal, and parietal cortex. So your brain works rather like your computer when it transfers volatile memory from RAM to the hard drive—it just takes a lot longer. In Chapter 3, you learned that when Wilder Penfield (1955) stimulated association

areas in the temporal lobes of surgery patients, he often evoked visual and auditory experiences that seemed like memories. We speculated that memories might be stored there, and more recent research has supported that idea, with memories for sounds activating auditory areas and memories for pictures evoking activity in the occipital region (see Figure 12.6; M. E. Wheeler, Petersen, & Buckner, 2000). You also saw in Chapter 9 that when we learn a new language, it is stored near Broca’s area. Naming colors (which requires memory) activates temporal lobe areas near where we perceive color; identifying pictures of tools activates the hand motor area and an area in the left temporal lobe that is also activated by motion and by action words (A. Martin, Haxby, Lalonde, Wiggs, & Ungerleider, 1995; A. Martin et al., 1996); and spatial memories appear to be stored in the parietal area and verbal memories in the left frontal lobe (F. Rösler, Heil, & Henninghausen, 1995). Thus, all memories are not stored in a single area, nor is each memory distributed throughout the brain. Rather, different memories are located in different cortical areas, apparently according to where the information

they are based on was processed. FIGURE 12.6 Functional MRI Scans of Brains During Perception and Recall. Memories of pictures and sounds evoked responses in the same general areas (arrows) as the original stimuli.

SOURCE: From “Memory’s Echo: Vivid Remembering Reactivates Sensory- Specific Cortex,” by M. E. Wheeler et al., Proceedings of the National Academy of Sciences, USA, 97, pp. 11125–11129, fig. 1c, d, e, f, p. 11127. © 2000 National Academy of Sciences, USA. An interesting example is the cells involved in place memory. Place cells, which

increase their rate of firing when the individual is in a specific location in the environment, are found in the hippocampus. Each cell has a place field (overlapping somewhat with others), and together these cells form a map of the environment. This map develops during the first few minutes of exploration; the cells’ fields are then remapped on entering a new environment, but they are restored on returning to the original location (Figure 12.7; Guzowski, Knierim, & Moser, 2004; Wilson & McNaughton, 1993). The fields are dependent on spatial cues in the environment, including visual, tactile, and even olfactory cues (Shapiro, Tanila, & Eichenbaum, 1997). Place cells do more than indicate an individual’s current location. For example, they contribute the context of location that is so important in memories of events (Smith & Mizumori, 2006). They also provide spatial memory required for planning navigation; as rats paused at choice points in a maze with which they were well experienced, cells with place fields in the alternative sections fired in sequence, as if the rats were simulating the two choices (Johnson & Redish, 2007). Functional MRI has confirmed that humans have place cells; their activity is so precise that the investigators could determine the subject’s “location” in a computer-generated virtual

environment (Hassabis et al., 2009). FIGURE 12.7 Recordings From Place Cells in a Rat in a Circular Runway. The recordings are from seven different place cells, indicated by different colors. Note that each cell responds when the rat is in a particular part of the runway. (Due to cue similarities in a circular apparatus, cells occasionally respond on the opposite side of the circle.) SOURCE: Reprinted by permission from Macmillan Publishers Ltd. From “Neural Plasticity in the Ageing Brain,” by S. N. Burke and C. A. Barnes, 2006, Nature Reviews Neuroscience, 7, pp. 30–40. Nature Publishing Group.

Two Kinds of Learning Learning researchers were in for a revelation when they discovered that HM could

readily learn some kinds of tasks (Corkin, 1984). One was mirror drawing, in which the individual uses a pencil to trace a path around a pattern, relying solely on a view of the work surface in a mirror. HM improved in mirror-drawing ability over 3 days of training, and he learned to solve the Tower of Hanoi problem (Figure 12.8). But he could not remember learning either task, and on each day of practice he denied even having seen the Tower puzzle before (N. J. Cohen, Eichenbaum, Deacedo, & Corkin, 1985; Corkin, 1984). What this means, researchers realized, is that there are two categories of memory processing. Declarative memory involves learning that results in memories of facts, people, and events that a person can vebalize or declare. For example, you can remember being in class today, where you sat, who was there, and what was discussed. Declarative memory includes a variety of subtypes, such as episodic memory (events), semantic memory (facts), autobiographical memory (information about oneself), and spatial memory (the location of the individual and of objects in space). Nondeclarative memory involves memories for behaviors; these memories result from procedural or skills learning, emotional learning, and stimulus- response conditioning. Learning mirror tracing or how to ride a bicycle or solve the Tower of Hanoi problem are examples of nondeclarative learning or, more specifically, procedural or skills learning; remembering having practiced the tasks involves declarative learning. Another way of putting it, which is admittedly a bit

oversimplified, is that declarative memory is informational, while nondeclarative memory is more concerned with the control of behavior; just as we have what and where pathways in vision and audition, we have a what and a how in memory.

What are the two kinds of learning? The main reason to distinguish between the two types of learning is that they have

different origins in the brain; studying them can tell us something about how the brain carries out its tasks. For years it looked like we were limited to studying the distinction in the rare human who had brain damage in just the right place; hippocampal lesions did not seem to affect learning in rats, so researchers thought that rats did not have an equivalent of declarative memory. But it just took selecting the right tasks. R. J. McDonald and White (1993) used an apparatus called the radial arm maze, a central platform with several arms radiating from it (Figure 12.9). Rats with damage to both hippocampi could learn the simple conditioning task of going into any lighted arm for food. But if every arm was baited with food, the rats could not remember which arms they had visited and repeatedly returned to arms where the food had already been eaten. FIGURE 12.8 The Tower of Hanoi Problem. The task is to relocate the rings in order onto another post by moving them one at a time and without ever placing a larger ring over a smaller one.

Conversely, rats with damage to the striatum could remember which arms they had visited but could not learn to enter lighted arms. Because Parkinson’s disease and Huntington’s disease damage the basal ganglia (which include the striatum), people with these disorders have trouble learning procedural tasks, such as mirror tracing or the Tower of Hanoi problem (Gabrieli, 1998). Incidentally, the term declarative seems inappropriate with rats; researchers have often preferred the term relational memory, which implies that the individual must learn relationships among cues, an idea that applies equally well to humans and animals. FIGURE 12.9 A Radial Arm Maze. The rat learns where to find food in the maze’s arms. The arms are often enclosed by walls.

SOURCE: © Hank Morgan/Science Source. You already know that the amygdala is important in emotional behavior, but it also

has a significant role in nondeclarative emotional learning. Bechara and his colleagues (1995) studied a patient with damage to both amygdalas and another with damage to both hippocampi. The researchers attempted to condition an emotional response in the patients by sounding a loud boat horn when a blue slide was presented but not when the slide was another color. The patient with amygdala damage reacted emotionally to the loud noise, indicated by increased skin conductance responses (see Chapter 8). He could also tell the researchers which slide was followed by the loud noise, but the blue slide never evoked a skin conductance increase; in other words, conditioning was absent. The patient with hippocampal damage showed an emotional response and conditioning, but he could not tell the researchers which color the loud sound was paired with. This neural distinction between declarative learning and nondeclarative emotional learning may well explain how an emotional experience can have a long- lasting effect on a person’s behavior even though the person does not remember the experience. The amygdala has an additional function that cuts across learning types. Both

positive and negative emotions enhance the memorability of any event; the amygdala strengthens even declarative memories about emotional events, apparently by increasing activity in the hippocampus. Electrical stimulation of the amygdala activates the hippocampus, and it enhances learning of a nonemotional task, such as a choice maze (McGaugh, Cahill, & Roozendaal, 1996). In humans, memory for both pleasant and aversive emotional material is related to the amount of activity in both amygdalas while viewing the material (Cahill et al., 1996; Hamann, Ely, Grafton, & Kilts, 1999). Working Memory The brain stores a tremendous amount of information, but information that is

merely stored is useless. It must be available, not just when it is being recalled into

awareness but when the brain needs it for carrying out a task. Working memory provides a temporary “register” for information while it is being used. Working memory holds a phone number you just looked up or that you recall from memory while you dial the number; it also holds information retrieved from long-term memory while it is integrated with other information for use in problem solving and decision making. Without working memory, we could not do long division, plan a chess move, or even carry on a conversation. “

The person recalls in almost photographic detail the total situation at the moment of shock, the expression of face, the words uttered, the position, garments, pattern of carpet, recalls them years after as though they were the experience of yesterday.

—G. M. Stratton, 1919

” Think of working memory as similar to the RAM in your computer. The RAM

holds information temporarily while it is being processed or used, but the information is stored elsewhere on the hard drive. But we should not take any analogy too far. Working memory has a very limited capacity (with no upgrades available), and information in working memory fades within seconds. So if you dial a new phone number and get a busy signal, you’ll probably have to look up the number again. And if you have to remember the area code, too, you’d better write it down in the first place.

Why is working memory important? The delayed match-to-sample task described in Chapter 11 provides an excellent

means of studying working memory. During the delay period, cells remain active in one or more of the association areas in the temporal and parietal lobes, depending on the nature of the stimulus (Constantinidis & Steinmetz, 1996; Fuster & Jervey, 1981; Miyashita & Chang, 1988). Cells in these areas apparently help maintain the memory of the stimulus, but they are not the location of working memory. If a distracting stimulus is introduced during the delay period, the altered firing in these locations ceases abrupty, but the animals are still able to make the correct choice (Constantinidis & Steinmetz, 1996; E. K. Miller, Erickson, & Desimone, 1996). Cells in the prefrontal cortex have several attributes that make them better candidates as working memory specialists. Not only do they increase firing during a delay, but they also maintain the increase in spite of a distracting stimulus (E. K. Miller et al., 1996). Some respond selectively to the correct stimulus (di Pellegrino & Wise, 1993; E. K. Miller et al., 1996). Others respond to the correct stimulus, but only if it is presented in a particular position in the visual field; they apparently integrate information from

Concept Check

cells that respond only to the stimulus with information from cells that respond to the location (Rao, Rainer, & Miller, 1997). Prefrontal damage impairs humans’ ability to remember a stimulus during a delay (D’Esposito & Postle, 1999). All these findings suggest that the prefrontal area plays the major role in working memory. Although the prefrontal cortex serves as a temporary memory register, its function

is apparently more than that of a neural blackboard. In Chapters 3 and 8, you learned that damage to the frontal lobes impairs a person’s ability to govern his or her behavior in several ways. Many researchers believe that the primary role of the prefrontal cortex in learning is as a central executive. That is, it manages certain kinds of behavioral strategies and decision making and coordinates activity in the brain areas involved in the perception and response functions of a task, all the while directing the neural traffic in working memory (Wickelgren, 1997).

Take a Minute to Check Your Knowledge and Understanding

What determines the symptoms and the severity of symptoms of amnesia? Describe the two kinds of learning and the related brain structures. Working memory contributes to learning and to other functions. How?

Brain Changes in Learning Learning is a form of neural plasticity that changes behavior by remodeling neural connections. Specialized neural mechanisms have evolved to make the most of this capability. We will look at them in the context of long-term potentiation. Long-Term Potentiation More than 50 years ago, Donald Hebb (1940) stated what has become known as the

Hebb rule: If an axon of a presynaptic neuron is active while the postsynaptic neuron is firing, the synapse between them will be strengthened. We saw this principle in action during the development of the nervous system, when synaptic strengthening helped determine which neurons would survive; some of that plasticity is retained in the mature individual. Researchers have long believed that in order to understand learning as a physiological process, they would have to figure out what happens at the level of the neuron and, particularly, at the synapse. Since its discovery four decades ago (T. Bliss & Lømo, 1973), long-term potentiation has been the best candidate for explaining the neural changes that occur during learning.

How do neurons change during learning? Long-term potentiation (LTP) is an increase in synaptic strength resulting from the

simultaneous activation of presynaptic neurons and postsynaptic neurons (Cooke &

Bliss, 2006). LTP is usually induced in the laboratory by stimulating the presynaptic neurons with pulses of high-frequency electricity for a few seconds (W. R. Chen et al., 1996; Dudek & Bear, 1992); temporal summation of these high-frequency stimuli ensures that the postsynaptic neurons will fire along with the presynaptic neurons. As you can see in Figure 12.10a, the postsynaptic neuron’s response to a test stimulus is much stronger following induction of LTP. What is remarkable about LTP is that it can last for hours in tissue cultures and months in laboratory animals (Cooke & Bliss). LTP has been studied mostly in the hippocampus, but it also occurs in several other areas, including the visual, auditory, and motor cortex. So LTP appears to be a characteristic of much of neural tissue, at least in the areas most likely to be involved in learning. FIGURE 12.10 LTP and LTD in the Human Brain. The graphs show excitatory postsynaptic potentials in response to a test stimulus before and after repeated stimulation. (a) 100-hertz (Hz) stimulation produced LTP. (b) 1-Hz stimulation produced LTD, which blocked the potentiation established earlier.

SOURCE: From “Long-Term Modifications of Synaptic Efficacy in the Human Inferior and Middle Temporal Cortex,” by W. R. Chen et al., Proceedings of the National Academy of Sciences, USA, 93, pp. 8011–8015. Copyright 1996 National Academy of Sciences, USA. Used with permission. Neural functioning requires weakening synapses as well as strengthening them.

Long-term depression (LTD) is a decrease in the strength of synapses that occurs when stimulation of presynaptic neurons is insufficient to activate the postsynaptic neurons (S. H. Cooke & Bliss, 2006). In the laboratory, LTD is usually produced by a low-frequency stimulus; you can see in Figure 12.10b that stimulation at 1 Hz for 15 minutes (min) blocked the potentiation that had been induced earlier; the result was a postsynaptic potential even smaller than the original. LTD is believed to be the mechanism the brain uses to modify memories and to clear old memories to make room for new information (Stickgold, Hobson, Fosse, & Fosse, 2001). Activity in presynaptic neurons also influences the sensitivity of nearby synapses.

If a weak synapse and a strong synapse on the same postsynaptic neuron are active simultaneously, the weak synapse will be potentiated; this effect is called associative

long-term potentiation (Figure 12.11). Associative LTP is usually studied in isolated brain tissue with artificially created weak and strong synapses, but it has important behavioral implications, which is why it interests us. Electric shock evokes a strong response in the lateral amygdala, where fear is registered, while an auditory stimulus produces only a minimal response there. Rogan, Stäubli, and LeDoux (1997) repeatedly paired a tone with shock to the feet of rats. As a result of this procedure, the tone alone began to evoke a significantly increased response in the amygdala, as well as an emotional “freezing” response in the rats. You may recognize this scenario as an example of classical conditioning; we could easily change the labels in Figure 12.11 from “Strong synapse” to “Electric shock” and from “Weak synapse” to “Auditory tone.” Researchers believe that associative LTP is the basis of classical conditioning, and Rogan et al.’s results support that view. LTP, LTD, and associative LTP can all be summed up in the expression “Cells that fire together wire together.” FIGURE 12.11 Associative LTP.

How LTP Happens The long trains of stimulation experimenters use to induce LTP and LTD seem very

artificial, and they are; in the brain, these changes are more likely triggered by theta EEG. Theta rhythm is EEG activity with a frequency range of 4 to 7 Hz. This rhythm is interesting because it typically occurs in the hippocampus when an animal is experiencing a novel situation, and any learning situation is somewhat novel (otherwise there would be nothing to learn). The researchers used a low-tech but effective method for producing theta in their experiment: They pinched the rats’ tails. When electrical stimulation of the hypothalamus was timed to coincide with the peaks of theta waves, LTP could be produced by just five pulses of stimulation (Hölscher, Anwyl, & Rowan, 1997). Stimulation that coincided with the trough of theta waves reversed LTP that had been induced 30 min before. Suppressing theta EEG in the hippocampus with a sedative drug eliminated rats’ ability to remember which way they turned on the previous trial in a two-choice maze (Givens & Olton, 1990). Hölscher and his colleagues believed that the theta rhythm, by responding to novel situations, might emphasize important stimuli for the brain and facilitate LTP and LTD.

LTP induction involves a cascade of events at the synapse. In most locations, the neurotransmitter involved in LTP is glutamate. Glutamate is detected by two types of receptors: the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor and the NMDA (N-methyl-d-aspartic acid) receptor. Initially, glutamate activates AMPA receptors but not NMDA receptors, because they are blocked by magnesium ions (Figure 12.12). During LTP induction, activation of the AMPA receptors by the first few pulses of stimulation partially depolarizes the membrane, which dislodges the magnesium ions. The critical NMDA receptor can then be activated, resulting in an influx of sodium and calcium ions; not only does this further depolarize the neuron, but the calcium activates CaMKII (calcium/calmodulin- dependent protein kinase Type II), an enzyme that is necessary for LTP (Lisman, Schulman, & Cline, 2002). CaMKII apparently functions as a two-way switch that changes the strength of a synapse (O’Connor, Wittenberg, & Wang, 2005).

How does the brain grow during learning? Neural Growth in Learning LTP induction is followed by gene activation, gene silencing, and synthesis of

proteins, all of which result in functional changes in synapses and the growth of new connections (Kandel, 2001; C. A. Miller & Sweatt, 2007). When the postsynaptic neuron is activated, it releases nitric oxide gas, which is a retrograde messenger, back into the synaptic cleft. The nitric oxide diffuses across the cleft to the presynaptic neuron, where it induces the neuron to release more neurotransmitter (Schuman & Madison, 1991). The nitric oxide lasts only briefly, but the increase in neurotransmitter release is long term (O’Dell, Hawkins, Kandel, & Arancio, 1991). Within 30 min after LTP, postsynaptic neurons develop increased numbers of dendritic spines, outgrowths from the dendrites that partially bridge the synaptic cleft and make the synapse more sensitive (see Figure 12.13; Engert & Bonhoeffer, 1999; Maletic-Savatic, Malinow, & Svoboda, 1999). Existing spines also enlarge or split down the middle to form two spines (Matsuzaki, Honkura, Ellis-Davies, & Kasai, 2004; Toni, Buchs, Nikonenko, Bron, & Muller, 1999). Postsynaptic strength is increased further as additional AMPA receptors are transported from the dendrites into the spines (Lisman et al., 2002; Shi et al., 1999). In addition, an increase in dopamine unmasks previously silent synapses and, 12 to 18 hours later, initiates the growth of new synapses (C. H. Bailey, Kandel, & Si, 2004). One further very important change that occurs in support of learning is the generation of new neurons in the hippocampus; though the rate of neurogenesis is relatively low, over the life span they add up to an estimated 10% to 20% of the population (Jacobs, van Praag, & Gage, 2000). These young neurons integrate into already established neural networks, where they are more likely to participate in new learning than the older neurons (Kee, Teixeira, Wang, & Frankland, 2007).

FIGURE 12.12 Participation of Glutamate Receptors in LTP. (a) Initially, glutamate activates the AMPA receptors but not the NMDA receptors, which are blocked by magnesium ions. (b) However, if the activation is strong enough to partially depolarize the postsynaptic membrane, the magnesium ions are ejected. The NMDA receptor can then be activated, allowing sodium and calcium ions to enter.

With all that growth, you might suspect that there would be some increase in the volume of the brain areas that are involved in LTP. In fact, there is evidence that this does happen. London taxi drivers, who are noted for their ability to navigate the city’s complex streets entirely from memory, spend about 2 years learning the routes before they can be licensed to operate a cab. Maguire and her colleagues (2000) used MRI to scan the brains of 16 drivers. The posterior part of their hippocampi, known to be involved in spatial navigation, was larger than in males of similar age. (Overall hippocampal volume did not change; their anterior hippocampi were smaller.) The difference was greater for cabbies who had been driving for the longest time, which we would expect if the difference was caused by experience. FIGURE 12.13 Increase in Dendritic Spines Following LTP. (a) A single synaptic spine on a dendrite (white) and a presynaptic terminal (red). (b) The same spine split into two following LTP.

SOURCE: Reprinted by permission from Macmillan Publishers Ltd. Based on “LTP Promotes Formation of Multiple Spine Synapses Between a Single Axon Terminal and a Dendrite,” by N. Toni et al., Nature, 402(6706), pp. 421–425. Nature Publishing Group. Consolidation Revisited For declarative memories, long-term memory consists of a stage that takes place in

the medial temporal lobe, followed by a transition to a more permanent form in the cortex (refer to Figure 12.2 again for the time course of these events). Some of the details of this transition were revealed in a study of mice with a defective gene for the alpha form of CaMKII (αCaMKII; Frankland, O’Brien, Ohno, Kirkwood, & Silva, 2001). Mice that are homozygous for the mutation produce no αCaMKII and they show no LTP in the hippocampus and fail to learn a task requiring the hippocampus. Mice that are heterozygous—with just one copy of the defective gene—produce more of the enzyme, but less than normal mice. Hippocampal LTP is unaffected but because the cortex normally has minimal αCaMKII to begin with, LTP no longer occurs in the cortex. As a result, learning of a hippocampal-dependent task is normal 1 to 3 days following training but severely impaired 10 days after training and beyond (Figure 12.14). Remember that the mechanisms we are considering are concerned with declarative memory; so far, there is no clear evidence that a prolonged consolidation process occurs in nondeclarative learning (Dudai, 2004).

How do the roles of the hippocampus and the cortex differ? Although αCaMKII is vital to the establishment of LTP, its maintenance during

long-term memory depends on another enzyme known as protein kinase M zeta. Inhibiting αCaMKII blocks the development of LTP but does not reverse LTP once it is established; on the other hand, chemical inhibition of protein kinase M zeta causes amnesia for an established conditioned response (Pastalkova et al., 2006). In fact, injection of the inhibitor into the insula, the cortical area involved in taste and in learning taste associations, eliminated a conditioned taste aversion in rats; the treatment was effective even when administered 25 days after training (Shema, Sacktor, & Dudai, 2007). The hippocampus has the ability to acquire learning “on the fly” while the event is

in progress, but a longer time is needed for long-term storage of declarative memories in the cortex. Many researchers now believe that the hippocampus transfers

information to the cortex during times when the hippocampus is less occupied, even during sleep (Lisman & Morris, 2001; McClelland, McNaughton, & O’Reilly, 1995). During sleep, neurons in the rats’ hippocampus and cortical areas repeat the pattern of firing that occurred during learning (Louie & Wilson, 2001; Y. Qin, McNaughton, Skaggs, & Barnes, 1997). Human EEG and PET studies showed the hippocampus repeatedly activating the cortical areas that participated in the daytime learning, and this reactivation was accompanied by significant task improvement the next morning without further practice (Figure 12.15; Maquet et al., 2000; Wierzynski, Lubenov, Gu, & Siapas, 2009). Presumably, “off-line” replay provides the cortex the opportunity to undergo LTP at the more leisurely pace it requires (Lisman & Morris, 2001). During sleep more than 100 genes increase their activity; many of those have been identified as major players in protein synthesis, synaptic modification, and memory consolidation (Cirelli, Gutierrez, & Tononi, 2004). FIGURE 12.14 Retention in Normal and αCaMKII- Deficient Mice Over Time. Mice were given three foot shocks in a conditioning chamber. Subgroups of mice were later tested for memory of the foot shocks (by observing emotional “freezing”) at one of the retention delay times. Note that in the mice heterozygous for the mutant gene, memory had begun to decay after 3 days and they failed to form permanent memory. SOURCE: Reprinted by permission from Macmillan Publishers Ltd. From “αCaMKII-Dependent Plasticity in the Cortex Is Required for Permanent Memory,” by P. W. Frankland, C. O’Brien, M. Ohno, A. Kirkwood, & A. J. Silva, 2001, Nature, 411, pp. 309–313. Figure 1. Nature Publishing Group.

FIGURE 12.15 PET Scans of Brain Activity During Sleep Following Learning. Areas previously active during learning are also more active during sleep in the trained subjects, but not in the untrained subjects.

SOURCE: Reprinted by permission from Macmillan Publishers Ltd. From “Experience-Dependent Changes in Cerebral Activation During Human REM Sleep,” by P. Maquet et al., 2000, Nature Neuroscience, 3, pp. 831–855, fig. 2, p. 833. Nature Publishing Group. Changing Our Memories As hard as the brain works to make memories “permanent,” it is still important that

these records not be inscribed in stone. Things change; the waterhole we learned was reliable over several visits is now becoming progressively more stagnant, so we must range in other directions until we find a new source of water. And sometimes erroneous learning must be corrected; the first two redheads we knew were hot tempered, and it will take meeting additional redheads to change what we have learned. A memory needs to be stable to be useful, but at the same time it must remain malleable; there are several ways the brain accomplishes this. Extinction The first is extinction. The experimenter sounds a tone just before delivering a puff

of air to your eye; after just a few trials, you blink just because you hear the tone. This doesn’t happen simply because you understand that the air blast is coming; it occurs more quickly than you can make a voluntary response. Then the experimenter sounds the tone several times without administering the puff of air. Slowly the tone loses its power to make you blink. The memory is not gone; if the experimenter repeats the puff of air, you will be back to blinking every time you hear the tone. Nor is this an example of forgetting. Rather, extinction involves new learning; one indication is that, like LTP, extinction requires activation of NMDA receptors, and blocking these receptors eliminates extinction (Santini, Muller, & Quirk, 2001). Forgetting Most memories dissipate at least somewhat over time if they are not used

frequently. We invariably regard memory loss from forgetting as a defect, but researchers are finding clues that the brain actively removes useless information to prevent the saturation of synapses with information that is not called up regularly or has not made connections with other stored memories. One way the brain cleans house apparently involves the enzyme protein phosphatase 1 (PP1), a product of the PP1 gene. To study PP1’s effect, researchers created transgenic mice (see Chapter 4) with genes for a particularly active form of PP1 inhibitor (Genoux et al., 2002). The

genes were inducible, which means that the researchers could activate them at any time. Mice were trained in a water maze, and then the genes were turned on in the transgenic animals; 6 weeks later, the control subjects’ memory for the task was completely absent, while the transgenic mice had forgotten very little. You may remember from your introductory psychology course that for most tasks, spreading out practice sessions (distributed practice) leads to better learning than massed practice. When the inhibitor genes were turned on during training, this advantage disappeared, which suggests that the reason distributed practice is superior is that PP1’s effects accumulate over massed practice trials. Another gene involved in forgetting is Drac1(V12). Its protein product, Rac, causes memory to decay after learning. Interestingly, continued training suppresses Rac, which means that additional practice has a dual benefit (Shuai et al., 2010).

APPLICATION

Total Recall Most of us would like to remember more and forget less. But a few years ago Jill Price wrote to neuropsychologist James McGaugh at the University of California, Irvine, asking for help because she couldn’t forget; she can remember what she did and what was happening in the world for practically every day of her life, and she is often tormented by bad memories (J. Marshall, 2008; E. S. Parker, Cahill, & McGaugh, 2006). Two years later two men with similar memory capabilities came forward, but unlike Price, Brad Williams and Rick Baron can keep their memories at bay (Elias, 2008; D. S. Martin, 2008). Williams uses his memory in his work as a radio news reporter; Baron is unemployed but supports himself in part by winning contests that utilize his memory for facts. The researchers are eager to understand what fuels this unusual ability, because the knowledge could help the memory impaired. Of the 33 super-memory people confirmed by McGaugh’s lab, 11 have undergone MRI scans; these revealed structural differences in nine brain areas, as well as greater white matter connections between areas (LePort et al., 2012). The interesting thing is that these individuals do no better than other people

on memorization tests; they just don’t suppress their memories once they’re formed. An indication that inadequate inhibition might be involved is that all three show signs of compulsive behavior. They are devoted collectors—years of TV guides, rare record albums, hundreds of TV show tapes—and Baron arranges all the bills in his wallet according to the city of the federal reserve bank where they were issued and how the sports teams in that city did.

Efficient memory involves a balance between remembering and forgetting. Later in

this chapter we will see how devastating memory impairment can be; the accompanying Application shows that there is another side to the coin as well. Reconsolidation Consolidation is a progressive affair extending over a relatively long period of time.

During that time, the memory is vulnerable to disruption from a number of sources, including electroconvulsive shock and drugs that interfere with protein synthesis. In recent years researchers have come to realize that each time a memory is retrieved, it must be reconsolidated, and during that time the memory becomes even more vulnerable (Dudai, 2004). For example, Nader, Schafe, and LeDoux (2000) conditioned a fear response (freezing) to a tone in mice by pairing the tone with electric shock to the feet. Anisomycin will eliminate the fear memory if it is injected shortly after learning, but injection 24 hr after training has no effect. However, as much as 2 weeks later, anisomycin eliminated the fear learning if the researchers induced retrieval of the memory by presenting the tone again (without the shock). You might very well wonder why the brain would give up protection of a consolidated memory during retrieval. Apparently, reopening a memory provides the opportunity to refine it, correct errors, and modify your emotional response to redheaded acquaintances (Lee, 2009). Reconsolidation may even have therapeutic usefulness. It can be used to eliminate a learned fear response in humans, and (as you will see in Chapter 14) could provide an effective tool for erasing fear memories in people with posttraumatic stress disorder (D. Schiller et al., 2009). Although retrieval makes a memory vulnerable, reconsolidation during the labile period apparently strengthens the memory. Rats given several brief exposures to the training apparatus during the first few days after they learned a shock avoidance task showed no forgetting when tested 55 days after training (Inda, Muravieva, & Alberini, 2011). In the News describes newfound evidence that retrieval and reconsolidation can be useful to humans as well.

Recalling It Now Helps You Remember It Later Memory practice is an important part of therapy for patients with memory impairment following severe traumatic brain injury. Shortly after patients had learned a list of word pairs, members of a retrieval group were quizzed by presenting one of the words and having the patients respond with the paired word. Two other groups restudied the words, either through massed restudy (cramming) or spaced restudy (spread over a longer time). When the patients were retested immediately after the study sessions were completed, the retrieval group

remembered three times as many word pairings as the other two groups; a week later, the retrieval group still remembered 11% of the words. The massed restudy group recalled 1.3% and the spaced restudy subjects recalled none. According to

Concept Check

the lead investigator, “If these individuals learn to incorporate this compensatory strategy into their daily routines, they can improve their memory. For example, rather than rereading an article several times, it would be more effective if they quizzed themselves periodically, eg, after each paragraph or page.”

2 Retrieval Aids Remembering

Of course, there is no way to guarantee that reconsolidation will always be adaptive; the opportunity to correct errors also allows the introduction of new errors. We have long known that memories get “reconstructed” over time, usually by blending with other memories. Reconstruction can be a progressive affair. Evidence suggests that one reason for the “recovery” of false childhood memories during therapy may be therapists’ repeated attempts to stimulate recall at successive sessions. Laboratory research has shown that people’s agreement with memories planted by the experimenter can increase over multiple interviews (E. F. Loftus, 1997). In one study, researchers using doctored photographs found that after being questioned three times, 50% of subjects were describing a childhood ride in a hot air balloon that never happened (Wade, Garry, Read, & Lindsay, 2002). More recently, Loftus and her colleagues (D. M. Bernstein, Laney, Morris, & Loftus, 2005) were able to shift their subjects’ food preferences by giving them a bogus computer analysis of their responses to a food questionnaire. For example, in a follow-up questionnaire, about 20% of the subjects agreed with the analysis that they had, in fact, been made sick by eating strawberry ice cream as children and reported that they would avoid it in the future.

3 Learning and Memory Resources

Take a Minute to Check Your Knowledge and Understanding

Make a list of the changes that occur in neurons during learning. Describe LTP, LTD, and associative LTP. Consolidated memory is both stable and vulnerable. Explain.

Learning Deficiencies and Disorders Learning may be the most complex of human functions. Not surprisingly, it is also one of the most frequently impaired. Learning can be compromised by accidents and violence that damage the structures we have been studying. But more subtle threats to

learning ability come from aging and from disorders of the brain, including Alzheimer’s disease and Korsakoff’s syndrome, which we will discuss in this section. Effects of Aging on Memory Old Man: Ah, memory. It’s the second thing to go. Young Man: So what’s first? Old Man: I forget... You may or may not find humor in this old joke, but declining memory is hardly a

laughing matter to the elderly. The older person might mislay car keys, forget appointments, or leave a pot on the stove for hours. Working memory and the ability to retrieve old memories and to make new memories may all be affected (Fahle & Daum, 1997; Small, Stern, Tang, & Mayeux, 1999). Memory loss is not just inconvenient and embarrassing; it is potentially dangerous, and it is disturbing because it suggests the possibility of brain degeneration.

Does the brain age, too? Until fairly recently, researchers believed that declining memory and cognitive

abilities were an inevitable consequence of aging. Although various kinds of cognitive deficits are typical of old age, they are not inevitable. For example, college professors in their 60s perform as well as professors in their 30s on many tests of learning and memory (Shimamura, Berry, Mangels, Rusting, & Jurica, 1995). An active lifestyle in old age has been associated with this “successful aging” (Schaie, 1994), but this fact does not necessarily tell us that staying active will stave off decline. Continued mental alertness may be the reason the person remains active, or health may be responsible for both good memory and a high activity level. However, we do know that rats reared in an enriched environment develop increased dendrites and synapses on cortical neurons (Sirevaag & Greenough, 1987). Also, we will see in Chapter 13 that cognitive skill training produces significant and enduring improvement in the elderly, which suggests that experience can affect the person’s cognitive well-being. For many years, researchers believed that deficits in the elderly were caused by a

substantial loss of neurons, especially from the cortex and the hippocampus. However, the studies that led to this conclusion were based on flawed methods of estimating cell numbers. More recent investigations have found that the number of hippocampal neurons was not diminished in aged rats, even those with memory deficits, and that neuron loss from cortical areas was relatively minor (see M. S. Albert et al., 1999, for a review). And, as we saw in Chapter 3, the number of synapses continues to increase with age in humans (Buell & Coleman, 1979). On the other hand, certain circuits in the hippocampus do lose synapses and NMDA

receptors with aging (Gazzaley, Siegel, Kordower, Mufson, & Morrison, 1996; Geinisman, de Toledo-Morrell, Morrell, Persina, & Rossi, 1992). Probably as a result of these changes, LTP is impaired in aged rats; it develops more slowly and

diminishes more rapidly (Barnes & McNaughton, 1985). The rats’ memory capabilities parallel their LTP deficits: Learning is slower, and forgetting is more rapid. There is also a decrease in metabolic activity in the entorhinal cortex, the major input and output to the hippocampus (M. J. de Leon et al., 2001). In normal elderly individuals, metabolic activity in the entorhinal cortex predicts the amount of cognitive impairment 3 years later. Another likely cause of learning deficits is myelin loss (A. R. Jensen, 1998). Without myelin, neurons conduct more slowly and interfere with each other’s activity. One subcortical area does undergo substantial neuron loss during aging, at least in

monkeys. It is the basal forebrain region (D. E. Smith, Roberts, Gage, & Tuszynski, 1999), whose acetylcholine-secreting neurons communicate with the hippocampus, amygdala, and cortex. Basal forebrain cell loss is much greater in Alzheimer’s disease, but the less pronounced degeneration that occurs in normal aging probably contributes to memory deficits as well. Some of the deficits in the elderly resemble those of patients with frontal lobe

damage (Moscovitch & Winocur, 1995). In one study, elderly individuals participated in the “gambling task” described in Chapter 8, choosing playing cards from two “safe” decks and two “risky” decks. Like patients with prefrontal brain damage, 35% of these elderly volunteers never learned to avoid the risky decks, and another 28% were slow in doing so (Denburg, Tranel, & Bechara, 2005). Deficits occur at the molecular level as well. One study, for example, examined the

brains of deceased individuals and found 17 genes in the dentate gyrus of the hippocampus that undergo changed levels of expression with aging (Pavlopoulos et al., 2013). Downregulation of one of these results in less abundant production of the protein RbAp48 in humans and mice. This protein turns out to be important for memory: Young mice engineered to produce reduced RbAp48 showed dysfunction in the dentate gyrus and performed like old mice on memory tests. Can we improve memory in the aged? Earlier, we saw the suggestion that forgetting

useless memories is adaptive; however, when useful memories are eliminated as well, forgetting becomes a deficiency. In the study described earlier, Genoux and his colleagues (2002) found that aged mice were significantly impaired on the learning task after just 1 day without practice, but performance in old mice with the enhanced PP1 inhibitor genes was still robust 4 weeks later. If we could find simple, safe ways to manipulate gene expression in humans, we could reduce many of the burdens of aging. Alzheimer’s Disease Substantial loss of memory and other cognitive abilities (usually, but not

necessarily, in the elderly) is referred to as dementia. The most common cause of dementia is Alzheimer’s disease, a disorder characterized by progressive brain deterioration and impaired memory and other mental abilities. Alzheimer’s disease

was first described by the neuroanatomist and neurologist Alois Alzheimer in 1906, after autopsying the brain of a 56-year-old patient with memory problems. Alzheimer’s is primarily a disorder of the aged, but it can strike fairly early in life. Of the nearly 5 million people in the United States with Alzheimer’s, 4.7 million are over the age of 65 (Hebert, Weuve, Scherr, & Evans, 2013). The earliest and most severe symptom is usually impaired declarative memory. Initially, the person is indistinguishable from a normally aging individual, though the symptoms may start earlier; the person has trouble remembering events from the day before, forgets names, and has trouble finding the right word in a conversation. Later, the person repeats questions and tells the same story again during a conversation. As time and the disease progress, the person eventually fails to recognize acquaintances and even family members. Alzheimer’s disease is not just a learning disorder but a disorder of the brain, so ultimately most behaviors suffer. Language, visual-spatial functioning, and reasoning are particularly affected, and there are often behavioral problems such as aggressiveness and wandering away from home. Alzheimer’s researcher Zaven Khachaturian (1997) eloquently described his mother’s decline: “The disease quietly loots the brain, nerve cell by nerve cell, like a burglar returning to the same house each night” (p. 21). Eventually, Alzheimer’s is fatal; it is the sixth leading cause of death in the United States (Murphy, Xu, & Kochanek, 2013).

4 Alzheimer’s Resources The Diseased Brain: Plaques and Tangles There are two notable characteristics of the Alzheimer’s brain, though they are not

unique to the disease. Plaques are clumps of beta amyloid (A β ), a type of protein, that cluster among axon terminals and interfere with neural transmission (Figure 12.16a). The main component is Aβ42, so called because it is 42 amino acids long; Aβ42 is particular “sticky,” so it clumps easily to form the plaques. In addition, abnormal accumulations of the protein tau form neurofibrillary tangles inside neurons; tangles are associated with the death of brain cells (Figure 12.16b). FIGURE 12.16 Neural Abnormalities in the Brain of a Person With Alzheimer’s. (a) The round clumps in the photo are plaques, which interfere with neural transmission. (b) The dark, twisted features are neurofibrillary tangles, which are associated with death of neurons.

SOURCE: (a) © Dr. M. Goedert/Science Source. (b) © SPL/Science Source. FIGURE 12.17 Alzheimer’s Brain (Left) and a Normal Brain. The illustrations show the most obvious differences, the reduced size of gyri and increased size of sulci produced by cell loss in the diseased brain.

SOURCE: Photos courtesy of Dr. Robert D. Terry.

What causes Alzheimer’s disease? Figure 12.17 shows the brain of a deceased Alzheimer’s patient and a normal brain.

Notice the decreased size of the gyri and the increased width of the sulci in the diseased brain. Internally, enlarged ventricles tell a similar story of severe neuron loss. Many of the lesions are located in the temporal lobes; because of their location, they effectively isolate the hippocampus from its inputs and outputs, which partly explains the early memory loss (B. T. Hyman, Van Horsen, Damasio, & Barnes, 1984). However, plaques and tangles also attack the frontal lobes, accounting for additional memory problems as well as attention and motor difficulties. The occipital lobes and parietal lobes may be involved as well; disrupted communication between the primary visual area and the visual association areas in the parietal and temporal lobes explains the visual deficits that plague some Alzheimer’s sufferers. While amyloid plaques have been considered the hallmark of Alzheimer’s disease,

the number of amyloid deposits is only moderately related to the degree of cognitive impairment (Selkoe, 1997), and about 25% of the elderly have plaques but suffer no dementia (Mintun et al., 2006). Over the past decade researchers have realized they need to distinguish between insoluble forms of amyloid and soluble forms (Larson &

Lesné, 2012). The soluble type of amyloids reach 70-fold higher levels in the brains of people with Alzheimer’s, compared with the brains of control subjects. In mice they have been linked to memory failure, loss of synapses, and failure of LTP in the hippocampus (Gong et al., 2003). Researchers are becoming increasingly convinced that soluble amyloids are the initiators of Alzheimer’s disease. Alzheimer’s and Heredity Heredity is an important factor in Alzheimer’s disease. The first clue to a gene

location came from a comparison of Alzheimer’s with Down syndrome (Lott, 1982). Down syndrome individuals also have plaques and tangles, and they invariably develop Alzheimer’s disease if they live to the age of 50. Because Down syndrome is caused by an extra chromosome 21, researchers zeroed in on that chromosome; there they found mutations in the amyloid precursor protein (APP) gene (Goate et al., 1991). When aged mice were genetically engineered with an APP mutation that increased plaques, both LTP and spatial learning were impaired (Chapman et al., 1999). Three additional genes that influence Alzheimer’s had been confirmed by the end of the 1990s; all of those affect amyloid production or its deposit in the brain (Selkoe, 1997). As you can see in Table 12.1, the genes fall into two classes, those associated with early-onset Alzheimer’s disease (often before the age of 60) and one found in patients with late-onset Alzheimer’s. The ε4 allele of the APOE gene is particularly interesting because it contributes to so many Alzheimer’s cases. It increases risk by three- to eightfold and is associated with plaques and tangles, but how it contributes to pathology is not well understood. Two recent studies indicate that nondemented carriers have lower cerebral blood flow (Thambisetty, Beason- Held, An, Kraut, & Resnick, 2010) and that 2- to 25-month-old children with the allele have reduced growth in temporal and parietal areas, which are affected in patients with Alzheimer’s (Dean et al., 2014). TABLE 12.1 Known Genes for Alzheimer’s Disease.

SOURCES: Marx (1998); Selkoe (1997). The four genes in the table account for just a little over half the cases of

Alzheimer’s disease, and environmental causes seem to have little effect, so there must be a number of additional genes that are difficult to detect because of their rarity or small effect. Discovery of these genes would have to await whole-genome studies with large numbers of individuals. Such studies have the advantage that they allow gene searches without the need for a preconceived target area. Prior to 2009, 11 genes

had been associated with Alzheimer’s, but in 3 years a whole-genome study of 74,000 individuals was able to add 11 additional gene locations (Lambert et al., 2013). Although the genes themselves have not been identified yet, genes near the loci are involved in amyloid and tau pathways, inflammation, immune response, cell migration, and cellular functions. Genome-wide studies have also made it possible to do broad searches for

epigenetic changes, and in the past few years the focus has been shifting in that direction; one study alone found more than 900 differently methylated genes in the brains of Alzheimer’s patients (Lunnon & Mill, 2013). If we could identify the environmental conditions that trigger these changes, then preventive measures could reduce the incidence of Alzheimer’s. Lead exposure is associated with changes in the expression of the APP gene; adding lead to the formula given to infant monkeys resulted in elevated plaques and tangles in their brains 23 years later (Bihaqi & Zawia, 2013). Until regulations were put into effect, children in the United States were exposed to lead in the water, in the air from automobile emissions, and even from eating peeling paint; in some parts of the world children lack those protections. Pesticides are also suspect, and blood levels of of a DDT metabolite have been found to be almost four times higher in patients with Alzheimer’s disease (Richardson et al., 2014). In spite of demonstrated health and environmental hazards, DDT is still used agriculturally and for malaria control in some countries. Smoking is another environmental risk factor for Alzheimer’s (Cataldo, Prochaska, & Glantz, 2010), and stress is believed to be important. The University of Southampton in England is taking monthly stress measures on people with mild cognitive impairment to see if stress contributes to the transition to Alzheimer’s (“Stress Link to Alzheimer’s...,” 2012). Treatment of Alzheimer’s Disease The annual cost of Alzheimer’s disease is estimated at $172 billion worldwide

(“Changing the Trajectory,” 2010). With an aging population, the situation is likely to worsen significantly in the future. By 2050, the population in the United States is expected to increase by 50%, while the number over the age of 85 increases sixfold (Bureau of the Census, 2001); as a result, the number of people with Alzheimer’s is projected to nearly triple (Figure 12.18; Hebert et al., 2013). Proportionate increases elsewhere will push the worldwide costs to $1 trillion a year, but a treatment that delayed the onset of Alzheimer’s by 5 years would lower that cost to $631 billion (“Changing the Trajectory”). FIGURE 12.18 Projected Increases in Alzheimer’s Disease in the United States. Note that numbers begin to escalate rapidly after 2020.

SOURCE: Based on data from Hebert et al. (2013). Five drugs are currently approved for the treatment of Alzheimer’s in the United

States, but one of those is rarely prescribed due to side effects (Patoine & Bilanow, n.d.). Three of the ones in regular use are cholinesterase inhibitors; they restore acetylcholine transmission by interfering with the enzyme that breaks down acetylcholine at the synapse. Acetylcholine-releasing neurons are significant victims of degeneration in Alzheimer’s disease, and experiments show that blocking acetylcholine activity eliminates hippocampal theta and impairs learning in rats (J. A. Deutsch, 1983) and also impairs learning in humans (Newhouse, Potter, Corwin, & Lenox, 1992). The fourth drug, memantine (marketed in the United States as Namenda), is the first approved for use in patients with moderate and severe symptoms. Some of the neuron loss in Alzheimer’s occurs when dying neurons trigger the release of the excitatory transmitter glutamate; the excess glutamate produces excitotoxicity, overstimulating NMDA receptors and killing neurons. Memantine limits the neuron’s sensitivity to glutamate, reducing further cell death. Studies indicate moderate slowing of deterioration and improvement in symptoms (“FDA Approves Memantine,” 2003; Reisberg et al., 2003). Unfortunately, these drugs provide only modest relief for the memory and behavioral symptoms of Alzheimer’s, and they are little or no help when degeneration is advanced. In their quest for more effective treatments, researchers are mounting efforts on

three major fronts: removing beta amyloid or blocking its formation, preventing tau from forming tangles, and reducing inflammation. However, no new drug has been approved by the FDA since 2003, and the disappointments continue to accumulate. The failure of two large trials of anti-amyloid antibodies, one of which was at the final phase 3 level, has some researchers now thinking that once symptoms have appeared the treatment is too late; they are shifting to pretreatment in asymptomatic individuals who are at genetic risk (Callaway, 2012). Similarly, a phase 3 trial attempting to treat inflammation with injections of immunoglobulin has come up empty-handed (Weil Cornell Medical College, 2014). However, the tangle-preventing drug LMTX is now in phase 3 clinical trials, after reducing symptom progression by 90% in phase 2 trials (TauRx Therapeutics, n.d.). Stem cell and gene therapy are obvious treatment possibilities, but work in these

areas is in its infancy. Mice genetically engineered to have Alzheimer’s performed better on a memory test a month after neural stem cells were injected into their brains (Blurton-Jones et al., 2009). However, only 6% of the stem cells turned into neurons. Instead, the stem cells secreted brain-derived neurotrophic factor, which promoted the development of new synapses. The gene therapy scene has not been very active lately, but in an interesting development, a Chinese team has demonstrated that neural stem cells can be used to deliver RNA to silence the gene responsible for the key enzyme in beta amyloid production (Liu et al., 2013). An interesting alternative approach is nutritional supplementation; one of these supplements, Souvenaid, improved memory and increased brain connectivity in phase 2 trials (Scheltens et al., 2012) and is now undergoing phase 3 testing. Finding a truly effective drug is a daunting task, which is why the National Institutes of Health is partnering with 10 drug companies in hopes of a breakthrough. (See the accompanying In the News.)

National Institutes of Health Teams With Drug Companies Drugs in development have a failure rate of 95%, which means that developing a successful drug requires about 10 years and a billion dollars. Declaring that this is a job too big for any single group, the National Institutes of Health (NIH) announced an unprecedented 5-year partnership with 10 drug companies and several nonprofit organizations to develop new treatments for Alzheimer’s disease, as well as for diabetes, lupus, and rheumatoid arthritis. The partners will put up a total of $230 million; Alzheimer’s research will get the lion’s share, $130

million, which will be used to identify new therapeutic targets and to develop biomarkers that can detect the disease early and track treatment progress.

5 NIH/Drug Partnership

Detecting Alzheimer’s Disease The aging individual dealing with memory problems typically wants to know, “Am

I getting Alzheimer’s?” No single test can diagnose Alzheimer’s, but a battery of physical, neurological, and cognitive tests can do a reasonably good job, mostly by ruling out other forms of dementia that may be more treatable, if not reversible. The physician may also order an MRI to look for atrophy in the temporal and parietal areas. For many years, patients were told that a definite diagnosis could be made only on autopsy, after examining the brain for plaques and tangles, but recent advances in PET scanning and measurement of biomarkers is changing that. Using new tracers that specifically target plaques, PET scans can identify 75% to 90% of individuals who are confirmed to have Alzheimer’s at the time of autopsy; measuring Aβ42 and

tau in the cerebrospinal fluid is equally accurate (Fraller, 2013). Biological assessment should lead to more appropriate treatment planning by differentiating better between Alzheimer’s and other dementias; in addition, it will be possible to monitor therapeutic progress, detecting changes before they translate into cognitive gains. But because current treatments only slow the progress of Alzheimer’s, researchers are interested in detecting the disease well before it is full-blown and before irreversible damage has occurred. PET scanning for amyloid predicts about one-third of individuals with mild cognitive impairment who will be diagnosed with Alzheimer’s during the next several months; among the normal elderly, 25% with high amyloid levels are diagnosed within 3 years, while those with low levels have a 98% chance of remaining cognitively stable (Gelossa & Brooks, 2012). Biomarkers found in cerebrospinal fluid and blood have shown 90% to 100% accuracy in predicting progression to Alzheimer’s over the next 5 to 6 years (DeMeyer et al., 2010; Khan & Alkon, 2010; Ray et al., 2007). A study of Roman Catholic sisters that has been going on since 1986 revealed

cognitive differences as much as five decades before some of them were diagnosed with Alzheimer’s (Riley, Snowdon, Desrosiers, & Markesbery, 2005). Autobiographical essays were available for 180 of the study participants, written when they joined the order at an average age of 22. These were scored for idea density, defined as the number of ideas expressed for every 10 words. Almost 80% of the sisters with the lowest density scores eventually developed Alzheimer’s, compared with 10% among those who scored the highest. A surprising finding was the number of participants with high density scores and no symptoms of Alzheimer’s who had neurofibrillary tangles when they were autopsied (Iacono et al., 2009; Riley et al., 2009). Also, the sisters who remained healthy were just as likely as the ones with Alzheimer’s to have one or more APOE4 alleles (Riley et al.). So what protected some of the women from Alzheimer’s? This question leads us to the reserve hypothesis. Resistance to Alzheimer’s: The Reserve Hypothesis According to the reserve hypothesis, individuals with greater cognitive or brain

capacity are able to compensate for brain changes due to aging, brain damage, or disorders such as Alzheimer’s. There is some evidence for compensation in the elderly through brain reserve, either by means of greater activation in the network involved or by recruiting other brain areas (reviewed in Stern, 2012). However, most studies have focused on cognitive reserve, by assessing experiential factors and cognitive capabilities. For example, the risk of developing dementia goes down 46% with higher educational and occupational levels and higher IQ and mental activity in earlier life. The protection, however, is temporary; the delay may last the rest of the individual’s life but, if not, decline occurs more rapidly than in other Alzheimer’s patients.

The elderly fare better if they have a history of both mental and physical activity, so they are frequently advised to stay active in order to stave off mental decline. However, choosing an active lifestyle may simply be a reflection of general fitness, rather than the cause of better cognitive health later; we should be careful about assuming cause until we have adequate experimental evidence and, so far, the results have been mixed. The most consistently positive results have been with exercise; cognitive training has not been very promising, with the possible exception of complex computer games and role-playing games. Korsakoff’s Syndrome Another form of dementia is Korsakoff’s syndrome, brain deterioration that is

almost always caused by chronic alcoholism. The deterioration results from a deficiency in the vitamin thiamine (B1), which has two causes: (1) the alcoholic consumes large quantities of calories in the form of alcohol in place of an adequate diet, and (2) the alcohol reduces absorption of thiamine in the stomach. The most pronounced symptom is anterograde amnesia, but retrograde amnesia is also severe; impairment is to declarative memory, while nondeclarative memory remains intact. The hippocampus and temporal lobes are unaffected; but the mammillary bodies (see Figures 3.20 and 8.4) and the medial part of the thalamus are reduced in size, and structural and functional abnormalities occur in the frontal lobes (Gebhardt, Naeser, & Butters, 1984; Kopelman, 1995; Squire, Amaral, & Press, 1990). A bizarre accident demonstrated that damage limited to the thalamic and mammillary areas can cause anterograde amnesia; a 22-year-old college student received a penetrating wound to the area when his roommate accidentally thrust a toy fencing foil up his left nostril, producing an amnesia that primarily affected verbal memory (Squire, Amaral, Zola- Morgan, Kritchevsky, & Press, 1989). Thiamine therapy can relieve the symptoms of Korsakoff’s syndrome somewhat if the disorder is not too advanced, but the brain damage itself is irreversible.

What are the symptoms of Korsakoff’s syndrome? Some Korsakoff’s patients show a particularly interesting characteristic in their

behavior, called confabulation; they fabricate stories and facts to make up for those missing from their memories. Non-Korsakoff amnesics also confabulate, and so do normal people occasionally when their memory is vague. However, Korsakoff patients are champions at this kind of “creative remembering,” especially during the volatile early period, when their symptoms have just heated up. We will talk about what causes confabulation shortly; in the meantime, try to refrain from assuming that it involves intentional deception. For some, confabulation becomes a way of life. Mary Frances could converse

fluently about her distant past as a college and high school English teacher and recite Shakespeare and poetry that she had written. But, robbed of the memory of more

Concept Check

recent years by Korsakoff’s disease, she constantly invented explanations for her nursing home surroundings. One time, she was just “visiting” at the home, and she watched patiently through the glass front doors for her brother who would pick her up shortly for an automobile trip to Florida. Another time, she complained that she was stranded in a strange place and needed to get back to her “post”; she had in fact been in the army in World War II as a speechwriter for General Clark. On another occasion, she thought that she was in prison—probably suggested by the memory that she had actually been a prisoner of war—and she was querying the nurse about what she had “done wrong.”

6 Korsakoff’s Resources Confabulation occurs following damage to a specific area in the frontal lobes

(Turner, Cipolotti, Yousry, & Shallice, 2008). A Korsakoff’s patient studied by Benson and his colleagues (1996) did poorly on cognitive tests that are sensitive to impairment in frontal lobe functioning, and a brain scan showed that activity levels were reduced in the frontal area as well as in the diencephalon, the lower part of the forebrain that includes the thalamus and hypothalamus. Four months later, he had ceased confabulating, and the scan of the frontal area had returned to normal; however, his amnesia and deficient diencephalic activity continued. Confabulating amnesic patients have more trouble than nonconfabulating amnesics in suppressing irrelevant information they have learned earlier (Schnider & Ptak, 1999). Consequently, Benson and colleagues (1996) suggest that confabulation is due to an inability to distinguish between current reality and earlier memories. We will take up this topic again in Chapter 15.

Take a Minute to Check Your Knowledge and Understanding

What changes occur in the brain during aging? What is the role of plaques and tangles in Alzheimer’s disease? How are Alzheimer’s disease and Korsakoff ’s syndrome similar and different?

In Perspective Learning is a form of neural plasticity. However, that simple statement ignores a variety of complex features that characterize learning. For example, different kinds of learning can be impaired selectively, as we see in patients who can learn and yet have no recollection of having learned. Our exploration of learning has been an abbreviated one, in part because a number of mysteries are waiting to be solved.

In spite of all we know about the learning process, we have little ability to enhance it. Researchers tell us that blueberries can reduce learning deficits in aging rats and that wearing a nicotine patch can improve memory, but they can do disappointingly little to help the Alzheimer’s patient. Curing learning disorders and improving normal learning ability are little more than aspirations today. But there is good reason to think the mysteries will be solved eventually, perhaps with your help. Summary Learning as the Storage of Memories • Brain damage can cause amnesia by impairing the storage of new memories (anterograde) or the retrieval of old memories (retrograde).

• The hippocampus is involved in both consolidation and retrieval. The prefrontal area may play an executive role.

• Memories are stored near the area where the information they are based on is processed.

• There are at least two kinds of learning: declarative, mediated by the hippocampus, and nondeclarative, which involves the striatum and amygdala.

• Working memory holds new information and information retrieved from storage while it is being used.

Brain Changes in Learning • LTP increases synaptic strength, and LTD reduces it. • Changes at the synapse include increases in the number and sensitivity of AMPA receptors, the amount of transmitter released, and the number of dendritic spines.

• LTP is necessary for learning; diminishing it impairs learning, and increasing it enhances learning.

• The hippocampus manages new declarative memories, but they are transferred later to the cortex.

Learning Deficiencies and Disorders • Aging usually involves some impairment of learning and memory, but in the normally aging brain, substantial loss of neurons and synapses is limited to a few areas.

• Alzheimer’s disease is a hereditary disorder that impairs learning and other brain functions, largely through the destruction of acetylcholine-producing neurons. Plaques and tangles are associated with cell death but may not be the cause. Treatment usually involves increasing acetylcholine availability, but experimental treatments take other approaches.

• Korsakoff’s syndrome is caused by a vitamin B deficiency resulting from alcoholism. Anterograde and retrograde amnesia are effects. ■

Study Resources

For Further Thought • If you were building an electronic learning and memory system for a robot, is

there anything you would change from the human design? Why or why not? • What are the learning and behavioral implications of impaired working memory?

• What implication does the experiment in which mice were injected with the antibiotic anisomycin at the time of retrieval have for your study conditions as you review material for an exam?

• Which direction of research for the treatment of Alzheimer’s do you think holds the greatest promise? Why?

Quiz: Testing Your Understanding 1. Discuss consolidation, including what it is, when and where it occurs, and its

significance in learning and memory. 2. Make the argument that LTP provides a reasonably good explanation of

learning, including some of learning’s basic phenomena. 3. Compare Alzheimer’s disease and Korsakoff’s syndrome in terms of causes,

symptoms, and brain areas affected. Select the best answer: 1. Anterograde amnesia means that the patient has trouble remembering events

that occurred a. more than a few minutes earlier. b. before the brain damage. c. since the brain damage. d. since the brain damage and for a few years before.

2. A person or animal born without the ability to consolidate would be unable to a. remember anything. b. remember for more than a few minutes. c. recall old memories that had been well learned. d. recall declarative, as opposed to nondeclarative, memories.

3. The function of the hippocampal formation is a. consolidation of new memories. b. retrieval of memories. c. as a temporary storage location. d. a and b e. a, b, and c

4. If HM’s striatum had also been damaged, he would also not have remembered a. declarative memories of childhood events. b. skills learned before his surgery. c. skills learned after his surgery. d. emotional experiences after his surgery.

e. all of the above 5. In the course of adding a long column of entries in your checkbook, you

have to carry a 6 to the next column. If you forget the number in the process, you’re having a problem with a. consolidation. b. LTP. c. retrieval. d. working memory.

6. The researcher sounds a tone and then delivers a puff of air to your eye. After several times, the tone alone causes you to blink. This behavior is probably explained by a. LTP. b. associative LTP. c. LTD. d. associative LTD.

7. LTP involves a. release of nitric oxide. b. increase in cell body size. c. increased number of NMDA receptors. d. increased sensitivity of NMDA receptors. e. all of the above

8. Without LTP a. long-term memory is impaired. b. working memory is impaired. c. old memories cannot be retrieved. d. no learning occurs.

9. The study in which the antibiotic anisomycin was injected into the brains of mice at the time of testing demonstrated that a. protein increase improves memory. b. memories are particularly vulnerable during recall. c. antibiotics can improve memory. d. once recalled, a memory takes longer to reconsolidate.

10. The aged brain is characterized by substantial ____ throughout the cortex. a. loss of neurons b. loss of synapses c. decrease in d. all of the above metabolism e. none of the above

11. The symptoms of Alzheimer’s disease are associated with a. plaques and tangles.

b. a single gene. c. environmental toxins. d. all of the above e. none of the above

12. The feature most common between Alzheimer’s disease and Korsakoff’s syndrome is the a. symptoms. b. age of onset. c. degree of hereditary involvement. d. degree of environmental contribution.

Answers: 1. c, 2. b, 3. e, 4. c, 5. d, 6. b, 7. a, 8. d, 9. b, 10. e, 11. a, 12. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The Brain Observatory’s H.M. page has information about the famous

amnesiac and the project to digitize his brain and make it available for continued scientific study. New Scientist TV describes the preparation of HM’s brain and provides a video of the slicing and staining procedure. Having trouble visualizing the hippocampus? See it in a rotating transparent brain at Wikipedia.

2. ScienceDaily was the source for the news article about the use of retrieval to strengthen memory in patients with memory impairment.

3. The professional journal Learning and Memory provides free access to published articles from the preceding year and earlier. The American Psychological Association is a good source of information on learning and memory and other topics. Many of the articles are brief updates appearing in the APA Monitor on Psychology. Just type the name of a topic in the search window.

4. The Alzheimer’s Association has information about the disease, help for

caregivers, and descriptions of research it is funding. 5. The news articles about the NIH/drug company partnership are available

from the National Institutes of Health and ScienceNOW. 6. The National Institute of Neurological Disorders and Stroke’s Wernicke-

Korsakoff Syndrome Information Page describes the disorder, treatments, and research. The Family Caregiver Alliance has a useful fact sheet on Korsakoff’s syndrome, including characteristics, prevalence, diagnosis, and treatment.

Animations Associative Long-Term Potentiation (Figure 12.11) Glutamate’s Role in Long-Term Potentiation (Figure 12.12)

Chapter Updates and Biopsychology News

For Further Reading 1. The Cognitive Neuroscience of Memory, by Howard Eichenbaum (Oxford

University Press, 2002), is an accessible textbook that assumes little background in biology or psychology. It elaborates on major topics, including synaptic changes, consolidation, and brain mechanisms involved in memory.

2. “The Machinery of Thought,” by Tim Beardsley (Scientific American, August 1997, 78–83), is about the neural basis of working memory, and “The Mind and Brain of Short-Term Memory,” by John Jonides et al. (Annual Review of Psychology, 2008, 59, 193–224), is a more recent review of that topic.

3. “New Brain Cells Go to Work,” by R. Douglas Fields (Scientific American Mind, August/September 2007, 31–35), elaborates on the possible role of neurogenesis in learning.

4. “Place Cells, Grid Cells, and the Brain’s Spatial Representation System,” by Edvard Moser, Emilio Kropff, and May-Britt Moser (Annual Review of Neuroscience, 2008, 31, 69–89), is a review of recent research on this subject.

5. “Alzheimer’s: Forestalling the Darkness,” by Gary Stix (Scientific American, June 2010, 50–57), explores the possibility of early detection and preventive treatment, while “Recent Insights Into the Molecular Genetics of Dementia,” by Rosa Rademakers and Anne Rovelet-Lecrux (Trends in Neurosciences, 2007, 32, 451–459), describes recent genetic findings.

Key Terms Alzheimer’s disease anterograde amnesia

associative long-term potentiation confabulation consolidation declarative memory dementia dendritic spines Hebb rule Korsakoff’s syndrome long-term depression (LTD) long-term potentiation (LTP) neurofibrillary tangles nondeclarative memory place cells plaques reserve hypothesis retrieval retrograde amnesia working memory

S

13 Intelligence and Cognitive Functioning

In this chapter you will learn • What some problems are in defining and measuring intelligence • Some of the neural characteristics that contribute to intelligence • The role of heredity and environment in forming intelligence • How aging, intellectual disability, autism, and attention-deficit/hyperactivity disorder affect intelligence

The Nature of Intelligence What Does “Intelligence” Mean? The Structure of Intelligence CONCEPT CHECK

The Biological Origins of Intelligence The Brain and Intelligence Specific Abilities and the Brain APPLICATION: WE AREN’T THE ONLY TOOL USERS

Heredity and Environment APPLICATION: ENHANCING INTELLIGENCE AND PERFORMANCE CONCEPT CHECK

Deficiencies and Disorders of Intelligence Effects of Aging on Intelligence Intellectual Disability Autism Spectrum Disorder APPLICATION: CHILDHOOD VACCINES AND AUTISM

Attention-Deficit/Hyperactivity Disorder IN THE NEWS: TESTING FOR ADHD CONCEPT CHECK

In Perspective Summary Study Resources

ome people are calling Cambridge’s theoretical physicist Stephen Hawking the most brilliant person living today. Following in Einstein’s footsteps, he has developed theories of the origin of the universe that are altering the way scientists

think. He lectures around the world, mixing high-powered physics with a keen sense of humor. He has achieved all this despite having Lou Gehrig’s disease (amyotrophic lateral sclerosis, or ALS), a degenerative disease that impairs voluntary movement. Confined to a wheelchair and able to make only small facial movements, he writes and speaks by moving a cursor on the screen of a computer equipped with a voice synthesizer (Figure 13.1). FIGURE 13.1 Stephen Hawking. His great intellect resides in a body that can communicate only by moving a cursor on a computer screen.

SOURCE: © Matt Dunham/Reuters/Corbis. When we consider people like Hawking, we are forced to wonder what makes one

person more intelligent than another. Is it genes, upbringing, hard work, or opportunity? And in particular, is the ultra-intelligent brain in some way different? Unfortunately, we have a problem with the presumption of who is smarter. Is Hawking more intelligent than Einstein, or has he just had the advantage of more predecessors’ accomplishments to build on? Is Marilyn vos Savant smarter than her husband because at the age of 10 she made the highest score recorded on an intelligence test (Yam, 1998) while he had trouble testing well enough to get into medical school, or is he smarter because he invented the Jarvik artificial heart? We cannot attempt to understand the biological bases of intelligence without having some appreciation of our limitations in measuring it or even defining what it is.

1 Stephen Hawking’s Website The Nature of Intelligence There are many ideas about what intelligence is, which is the first clue that we don’t have consensus about what it is. Most definitions say something to the effect that intelligence is the ability to reason, to understand, and to profit from experience. That is what we think intelligence is; the problem comes when we try to translate that

abstract definition into the behaviors that would indicate the presence of intelligence. That is what we must do in order to measure intelligence, which is the first step toward determining its biological basis. What Does “Intelligence” Mean? Understanding how we measure intelligence is important because we are in effect

defining intelligence as what that test measures. The measure of intelligence is typically expressed as the intelligence quotient (IQ). The term originated with the scoring on early intelligence tests designed for use with children. The tests produced a score in the form of a mental age, which was divided by the child’s chronological age and multiplied by 100. The tests were designed to produce a score of 100 for a child performing at the average for his or her chronological age. The scoring is completely different now, partly because the tests were extended to adults, who do not increase consistently in intellectual performance from year to year. The base score is still 100, a value that was arbitrarily selected and that is artificially preserved by occasional adjustments to compensate for any drift in performance in the population. Most people are near the average, as Figure 13.2 shows, with relatively few people at either of the extremes. For example, only 2% of the population score above 130 points or below 70 points. The first intelligence test was devised by Alfred Binet in 1905, to identify French

schoolchildren who needed special instruction (Binet & Simon, 1905). Predicting school performance is still what most intelligence tests do best, and intelligence tests have found their greatest use in the school setting. The correlation between IQ scores and school grades typically falls in the range of.40 to.60 (Kline, 1991). (If you’ve forgotten what a correlation coefficient means, see pages 112–113.) However, IQ is also related to job performance, income, and socioeconomic level and, negatively, to juvenile delinquency (Neisser et al., 1996). FIGURE 13.2 Distribution of IQ Scores in the Population.

SOURCE: From Psychology: The Adaptive Mind (2nd ed.), by J. S. Nairne, 2000, Wadsworth, a part of Cengage Learning, Inc. Reproduced by permission.

Critics believe that scores on traditional intelligence tests are closely related to academic performance and to higher socioeconomic levels mostly because the tests were designed to reflect that kind of success. According to these critics, the tests overemphasize verbal ability, education, and Western culture. A few tests are designed to be culture-free, like the Raven Progressive Matrices (Raven, 2003). These tests are mostly nonverbal, and the tasks require no experience with a particular culture. They have an obvious advantage for testing people from a very different culture or language background or with impaired understanding of language. Some researchers also believe that these tests give them a better representation of “pure” intelligence.

How meaningful are IQ scores? Claiming that true intelligence is much more than what the tests measure, these

critics often point to instances where practical intelligence or “street smarts” is greater than conventional intelligence. For example, as young Brazilian street vendors conducted their business, they were adept at performing calculations that they were unable to perform in a classroom setting (Carraher, Carraher, & Schliemman, 1985). In another study, expert racetrack gamblers used a highly complex algorithm involving seven variables to predict racetrack odds, but their performance was unrelated to their IQ; in fact, four of them had IQs in the low to mid-80s (Ceci & Liker, 1986). More recently, Robert Sternberg (2000) compared the scores that the presidential candidates George W. Bush, Al Gore, and Bill Bradley made on the verbal section of the Scholastic Aptitude Test (SAT) when they applied for college; the SAT has many items similar to those on conventional intelligence tests. Two of the candidates scored above average for college applicants but not markedly so, and one had a score that was below average. To Sternberg, their success raises questions about the narrowness of what intelligence tests measure. Sternberg (1988) argues that intelligence does not exist in the sense we usually

conceive of it but is “a cultural invention to account for the fact that some people are able to succeed in their environment better than others” (p. 71). Perhaps intelligence is, like the mind, just a convenient abstraction we invented to describe a group of processes. If so, we should not expect to find intelligence residing in a single brain location or even in a neatly defined network of brain structures. And to the extent we find processes or structures that are directly involved in intelligence, their performance may not be highly correlated with scores on traditional intelligence tests. The Structure of Intelligence Another controversy that is critical to a biological understanding of intelligence is

whether intelligence is a single capability or a collection of several independent abilities. Intelligence theorists tend to fall into one of two groups, lumpers or splitters. Lumpers claim that intelligence is a single, unitary capability, which is usually called the general factor, or simply g. General factor theorists admit that there are separate

Concept Check

abilities that vary somewhat in strength in an individual, but they place much greater weight on the underlying g factor. They point out that a person who is high in one cognitive skill is usually high in others, so they believe that a measure of g is adequate by itself to describe a person’s intellectual ability. General intelligence is sometimes assessed by the overall IQ score from a traditional intelligence test, such as the Wechsler Adult Intelligence Scale, whose 11 subtests measure more specific abilities. But many g theorists prefer to use other tests like the Raven Progressive Matrices, because they emphasize reasoning and problem solving and are relatively freer of influence from specific abilities such as verbal skills. Splitters, on the other hand, hold that intelligence is made up of several mental

abilities that are more or less independent of each other. Therefore, they are more interested in scores on the subtests of standard IQ tests or scores from tests of specific cognitive abilities. They may agree that there is a general factor, but they give more emphasis to separate abilities and to differences among them in an individual. An accurate description of a person’s intelligence would require the scores on all the subtests of these abilities. These theorists point to cases of brain damage in which one capability is impaired without affecting others and to the savant’s exceptional ability in a single area. Splitters disagree with each other, though, on how many abilities there are; a review of intelligence tests identified more than 70 different abilities that can be measured by available tests (Carroll, 1993).

Take a Minute to Check Your Knowledge and Understanding

What do IQ scores tell us, and not tell us, about a person’s capabilities? What difference does it make to our search for a biological basis for intelligence whether intelligence is a “real” entity or an invented concept?

What is the lumper–splitter controversy?

The Biological Origins of Intelligence With this background, we are now ready to explore the origins of intelligence. On the basis of our introduction, we will avoid two popular assumptions—that intelligence tests are the only way to define intelligence and that intelligence is a single entity. Instead, we will consider performance and achievement as additional indicators of intelligence, and we will first examine the evidence of a biological basis for a general factor and then consider the relationship between brain structures and individual abilities.

How are intelligent brains different?

The Brain and Intelligence Are there identifiable ways that a more intelligent brain is different from other

brains? Anyone asking this question would naturally wonder how Albert Einstein’s brain was different from other people’s. Fortunately, the famous scientist’s brain was preserved, and it has been made available from time to time to neuroscientists (Figure 13.3). In cursory examinations, it turned out to be remarkably unremarkable. In fact, at 1,230 grams (g) it was almost 200 g lighter than the average weight of the control brains (Witelson, Kigar, & Harvey, 1999). The number of neurons did not differ from normal, and studies have disagreed about whether the neurons were more densely packed or the cortex was thinner, perhaps because the samples were taken from different locations (B. Anderson & Harvey, 1996; Kigar, Witelson, Glezer, & Harvey, 1997). One study found a higher ratio of glial cells to neurons in the left parietal lobe (Diamond, Scheibel, Murphy, & Harvey, 1985). The comparison brains averaged 12 years younger than Einstein’s at the time of death, and we know that glial cells continue proliferating throughout life (T. Hines, 1998), but the number of glial cells was not elevated in Einstein’s right parietal lobe or in either frontal sample. Each of Einstein’s hemispheres was a full centimeter wider than those of control brains, due to larger parietal lobes (Witelson et al., 1999), and there were intriguing variations in some of the parietal gyri (Falk, 2009). These anomalies are interesting because the parietal lobes are involved in mathematical ability and visual-spatial processing, and Einstein reported that he performed his mathematical thinking not in words but in images. Remember, though, that in Chapter 12 we saw that London cabdrivers have enlarged posterior hippocampi, and no one has suggested that large hippocampi explain why they became cabdrivers. In fact, a later follow-up study found that drivers who qualified at the end of their training increased in hippocampal volume, but drivers who failed to qualify did not (Woollett & Maguire, 2011). Whether Einstein’s large parietal lobes or intense mathematical activity came first is uncertain (assuming they are related). FIGURE 13.3 Albert Einstein and His Brain. The brain of the genius looks just like yours; it took careful study to find differences.

SOURCES: (a) Wikimedia Commons/Ferdinand Schmutzer. (b) Sandra F. Witelson. “

The contrast between the popular estimate of my powers and achievements compared to the reality is simply grotesque.

—Albert Einstein

” “

Words and language... do not seem to play any part in my thought processes. —Albert Einstein

”

It is interesting that the strongest finding in the examination of Einstein’s brain seems to be related to a specific ability rather than to overall intelligence. British researcher John Duncan and his colleagues (2000) sought the location of general intelligence in the brains of more ordinary folk. They used tasks that required reasoning and that are known to correlate with general intelligence more than with any specific ability. Although verbal and spatial tasks had different patterns of activation, prefrontal activation was common to both tasks; the authors concluded that general intelligence may be located there. But general intelligence is likely more complex than what happens in one area of the brain. A team of researchers scanned the brains of 241 individuals with brain damage and correlated the location of their lesions with their scores on a set of intelligence subtests chosen to measure g (Gläscher et al., 2010). They found that g requires a distributed system, a network that spans the frontal, parietal, and temporal lobes (Figure 13.4). They concluded that g involves the brain’s ability to pull together different kinds of processing, such as visual-spatial processing and working memory. The ability to integrate these functions depends on the quality of connections between the areas, which is highly heritable, up to 84% in some parts of the brain (Chiang et al., 2009). FIGURE 13.4 Brain Areas Involved in General Intelligence. A view of the cortical surface (left) and subcortical areas (right) shows a g-related network extending throughout much of the brain.

SOURCE: From “Distributed Neural System for General Intelligence Revealed by Lesion Mapping,” by J. Gläscher et al., 2010, Proceedings of the National Academy of Sciences, 90, pp. 4705–4709. Brain Size Brain size itself does not determine intelligence. Elephants have much larger brains

than we do, and not many people think elephants are smarter. What is more important is the ratio of the brain’s size to body size; this ratio adjusts for the proportion of the brain needed for managing the body and tells us how much is left over for intellectual functions. As you might expect, the ratio for humans is one of the highest. Within a species, though, the answer is a bit different. Numerous magnetic

resonance imaging (MRI) studies have found correlations between brain size and measures of intelligence; a compilation of 37 studies involving 1,530 people found a modest correlation of.33 (McDaniel, 2005). Squaring the correlation coefficient tells us that about 11% of the differences among people in intelligence is related to brain size. Of course, men have larger brains than women, which we have assumed was related to men’s greater body size. However, even after adjustment for body size, men’s brains average about 118 g heavier than women’s (Ankney, 1992). Presumably, men are no smarter than women; it is actually difficult to tell, because intelligence tests were designed to avoid gender bias. But if men’s excess brain matter does not confer additional intelligence, what is its function? There are two credible hypotheses. One is that women’s brains are more efficient, because of a greater density of neurons (Witelson, Glezer, & Kigar, 1995) and a higher ratio of gray matter to white matter (Gur et al., 1999). The other hypothesis is that the male’s superior spatial intelligence requires greater brain capacity (D. Falk, Froese, Sade, & Dudek, 1999). MRI studies of fraternal and identical twins found that general intelligence was

correlated with both the volume of gray matter and the volume of white matter (Posthuma et al., 2002; Thompson, Cannon, et al., 2001). And, consistent with findings mentioned earlier, the volume of gray matter in the frontal area appears to be particularly important to general intelligence (Haier, Jung, Yeo, Head, & Alkire, 2004; Thompson, Cannon, et al.). But before we go too far in dissecting the issue of brain size, we should keep in mind that Einstein’s brain was smaller than the average female brain (Ankney, 1992). Also, how the brain matter is distributed and organized appears to be more important than size. Remember the cortical columns that we saw

back in Chapter 3? In the brains of three distinguished scientists, these were smaller and packed closer together (Casanova, Switala, Trippe, & Fitzgerald, 2007). Computer modeling has shown that smaller columns provide for better discrimination between signals during information processing. General intelligence is moderately correlated with cortical thickness in most association areas (Figure 13.5; Karama et al., 2009). So an important feature of smarter brains is that they have a larger processing area packed with more processing units. An interesting additional difference is the timing of development. In children with average intelligence, cortical thickening reaches its peak by the age of 8; in children with superior intelligence, thickening continues until age 11 or 12 before thinning to adult levels (Shaw et al., 2006). FIGURE 13.5 Areas Where Cortical Thickness is Associated With Intelligence. Notice that critical areas are distributed throughout the brain.

SOURCE: Montreal Neurological Institute. Neural Conduction Speed and Processing Speed Cognitive processes require the person to apprehend, select, and attend to

meaningful items from a welter of stimuli arriving at the sensory organs. Then the person must retrieve information from memory, relate the new information to it, and then manipulate the mental representation of the combined information. All of this takes time. In 1883, Francis Galton suggested that higher intelligence depends on greater “mental speed.” Because there were no intelligence tests then, he attempted to relate measures of intellectual achievement like course grades and occupational status to people’s reaction times, but no relationship was found. More recently, a number of researchers have shown that IQ scores do correlate with reaction time (T. E. Reed & Jensen, 1992). The relationship is not due to the fact that most intelligence tests

emphasize speed, because reaction time and IQ scores are still correlated when the IQ test is given without a time limit (A. R. Jensen, 1998). FIGURE 13.6 Relationship Between IQ Scores and Nerve Conduction Velocity. The research participants were divided into five groups according to their nerve conduction velocity. Group 1 had the lowest nerve conduction velocity and Group 5 the highest. Nerve conduction velocity was calculated by dividing the elapsed time between a stimulus and the occurrence of the evoked potential by the distance between the eyes and the back of the head.

SOURCE: Adapted from “Conduction Velocity in a Brain Nerve Pathway of Normal Adults Correlates With Intelligence Level,” by T. E. Reed and A. R. Jensen, Intelligence, 16, pp. 259–272. Copyright 1992, with permission from Elsevier Science. Apparently the reason is that IQ scores are also correlated with nerve conduction

velocity, even more than with reaction time (see Figure 13.6; McGarry-Roberts, Stelmack, & Campbell, 1992; Vernon & Mori, 1992). In addition, people who are more intelligent excel on tasks in which stimuli are presented for an extremely short interval and on tasks that require choices (A. R. Jensen, 1998). These are tasks in which processing speed is important, and, presumably, higher nerve conduction velocity contributes to the more intelligent person’s superior performance. We will see in the next section that faster nerve conduction velocity may make its contribution through improved processing efficiency. FIGURE 13.7 Greater Efficiency in the More Intelligent Brain. During an attention-demanding task, PET scans showed 20% more activity (indicated by more reds and yellows) in (a) the brain of an individual with intellectual disability than in (b) the brain of a person with above-average IQ.

SOURCE: From “Brain Size and Cerebral Glucose Metabolic Rate in Nonspecific Mental Retardation and Down Syndrome,” by R. J. Haier et al., 1995, Intelligence, 20, pp. 191–210. Processing Efficiency The prevailing view among neuroscientists is that intelligence comes down to how

well information travels throughout the brain. One of the most obvious contributors to this efficiency is myelination, which both increases conduction speed and protects against “cross-talk” between neurons. Humans have a greater proportion of white matter (myelinated processes) to gray matter than other animals, and IQ varies among individuals with the degree of myelination (Willerman, Schultz, Rutledge, & Bigler, 1994). In addition, myelination, speed of information processing, and intelligence all follow a curvilinear time path, increasing from childhood to maturity and then declining in old age. One indicator of the role of brain efficiency in intelligence is that individuals who

are higher in IQ use less brain energy. This was indicated by a lower rate of glucose metabolism during a challenging task, playing the computer game Tetris (Haier, Siegel, Tang, Abel, & Buchsbaum, 1992). And, as you can see in Figure 13.7, individuals with mild intellectual disability (IQs between 50 and 70) require 20% more neural activity to perform an attention-demanding task than do individuals with IQs of 115 or higher (Haier et al., 1995). You might think the more intelligent brain would be the more active one during a task, but remember that we are talking about efficiency. Improved technology, particularly the availability of diffusion tensor imaging, has

shifted the conversation toward brain networks and network efficiency. After reviewing 37 imaging studies related to intelligence, Rex Jung and Richard Haier (2007) proposed the Parieto-Frontal Integration Theory (P-FIT). According to their theory, information processing takes place in four stages, primarily in the parietal and frontal lobes: (1) After sensory information has been processed in secondary areas, it is passed on to (2) parietal areas, which abstract the information and integrate it, and then (3) these areas interact with frontal areas in problem solving and evaluation. (4) Finally, the anterior cingulate cortex selects the response and inhibits alternative

responses. Subsequent studies have lent support to the theory, identifying these areas as central to intelligence and the parietal cortex as the main hub (Langer et al., 2012; Li et al., 2009). In addition, the brains of more intelligent individuals were more efficient, with more numerous interconnections within clusters of neural activity and shorter paths between clusters. Specific Abilities and the Brain Brain size, speed, and efficiency can reasonably be viewed as contributors to

general intelligence; now we will consider evidence for individual components of intelligence. The statistical method called factor analysis has been useful in identifying possible components. The procedure involves giving a group of people several tests that measure cognitive abilities that might be related to intelligence; the tests may be intelligence tests, or they may be measures of more limited abilities such as verbal skills or reaction time. Then correlations are calculated among all combinations of the tests to locate “clusters” of abilities that are more closely related with each other than with the others. Performance on practically all tests of cognitive ability is somewhat related, which is consistent with the hypothesis of a general factor. However, factor analysis has also identified clusters of more specific abilities. Three capabilities have emerged frequently as major components of intelligence: linguistic, logical-mathematical, and spatial (A. R. Jensen, 1998).

Are there separate components of intelligence? Several authors have argued that each of the cognitive abilities depends on a

complex network or module in the brain that has evolved in ways that support that particular function. In other words, they believe that the brain is hardwired for functions like mathematics and language (Dehaene, 1997; Pinker, 1994). We have already seen examples of modular functions in earlier chapters. The language (linguistic) module is made up of a network of structures located mainly in the left frontal and temporal lobes. Spatial ability depends on the interaction of somatosensory and visual functions with parietal structures, mostly in the right hemisphere. FIGURE 13.8 Brain Locations Involved in Mathematical Performance. (a) Calculations from memory (such as 2 x 4) activate primarily left prefrontal cortex; estimation involves both parietal cortices. (b) Nonrote calculation involves all four areas, and activation increases with difficulty (for example, 5 − 2 versus 6 + 3 − 5).

SOURCES: (a) From “Sources of Mathematical Thinking: Behavioral and Brain- Imaging Evidence,” by S. Dehaene, E. Spelke, P. Pinel, R. Stanescu, & S. Tsivkin, 1999, Science, 284, pp. 970-973. Reprinted with permission of AAAS. (b) From “Dissociating Prefrontal and Parietal Cortex Activation During Arithmetic Processing,” by V. Menon, S. M. Rivera, C. D. White, G. H. Glover, and A. L. Reiss, 2000, NeuroImage, 12, pp. 357–365. Mathematical ability in humans depends on the prefrontal cortex and the parietal

cortex. That fact by itself makes no distinction between mathematical ability and general intelligence; most likely the distinction lies in specifics of the interconnections and how the brain is able to recruit activity in the structures. For example, subjects who performed better on tests of basic arithmetic had greater cross- connection activity between the two parietal lobes during problem solving (Park, Park, & Polk, 2012). In addition, the areas are activated selectively according to the task and progressively as difficulty increases. The left prefrontal cortex is most active when an individual performs calculations from memory, such as 2 × 4 and 2 + 4; the area is probably the storage site of arithmetic facts. Both parietal areas come into play during estimation of values (Dehaene, Spelke, Pinel, Stanescu, & Tsivkin, 1999); this makes sense, because visual-spatial representations of quantity, such as finger counting and the “number line,” are an almost universal stage in learning exact calculation. Calculation recruits both left and right prefrontal areas and both parietal cortices; activation increases further in the parietal lobes with increasing difficulty, and in the prefrontal areas as speed demands increase (Figure 13.8; Menon, Rivera, White, Glover, & Reiss, 2000). Studies of brain damage support these conclusions. Individuals with damage to the left frontal language area can arrange numbers in rank order and estimate results, but they cannot perform precise calculations; those with parietal damage are impaired in the opposite direction (Butterworth, 1999; Dehaene & Cohen, 1997). Obviously, neither of these areas is dedicated exclusively to numerical functions.

This is consistent with the suggestion in Chapter 9 that the language areas may simply

use processing strategies that make them particularly suited to the demands of the task, rather than being dedicated to language processing. However, Wynn (1998) argues that the brain has a specialized mechanism for numbers by pointing to evidence that even infants and lower primates seem to have an inborn ability for estimating quantities. The infants she studied saw two objects placed one at a time behind a screen. They acted surprised—which means that they looked for a longer time—when the screen was removed to reveal three objects or only one object instead of the expected two (Wynn, 1992). Rhesus monkeys tested in the wild responded the same way to the task (Hauser,

MacNeilage, & Ware, 1996). Monkeys can also rank order groups of objects that differ in number by touching their images on a computer monitor in the correct order (Brannon & Terrace, 1998); chimpanzees have learned to do the same with numerals (Kawai & Matsuzawa, 2000). The monkeys continued to perform at the same level of accuracy when the researchers increased the number of items presented, so the monkeys had not simply memorized the stimuli. The researchers were careful to control the spatial size of the groupings, so the monkeys could not distinguish the groups according to the space they covered. (See the accompanying Application for some thoughts on intelligence in animals.) An impartial observer would have to say that there is evidence for characteristics

that contribute to an overall intelligence and for somewhat independent capabilities as well. An either–or stance is not justified at this time; it makes sense to continue the two-pronged approach of looking for biological bases for both general intellectual ability and separate capabilities.

APPLICATION

We Aren’t the Only Tool Users Ever since people realized what surprising similarities we share with other animals, we have been fascinated with how intelligent their behavior can sometimes appear to be. Termites build great earthen mounds that are so well ventilated they stay cool under the broiling African sun. Dolphins cooperate with each other to herd schools of fish into their pod mates’ waiting mouths. Kanzi communicates with symbols, Alex mastered simple concepts (see Chapter 9), and monkeys and chimps can “count.” Especially intriguing is that after decades of denying the possibility, we

found other animals making and using tools. Chimpanzees have long been known to “fish” for termites by inserting a twig into the mound. To learn more about this behavior, naturalists in the Congo rain forest hid motion-activated cameras around termite nests and got a close look at the chimpanzees at work (Holden, 2004b). The chimps first use a puncturing stick to open a hole in the

nest. Then they follow up with a probe, a small green twig that the termites climb onto in defense of the nest, only to be slurped up by the chimp (Figure a). Congo chimps add a twist not seen elsewhere: They fray the end of the twig by pulling it between their teeth; these tools pick up 20 times as many termites as the unmodified version (Sanz, Cali, & Morgan, 2009).

2 Animals Using Tools: Videos When it comes to acquiring food, animals can show a great deal of what in

humans would pass for ingenuity and planfulness. New Caledonia crows use twigs to extract grubs from trees, and one in captivity spontaneously began shaping wire into hooks and using them to retrieve food (Weir, Chappell, & Kacelnik, 2002). Figaro, a Goffin’s cockatoo, spontaneously chewed splinters off a piece of wood and used them to retrieve objects outside his cage (Auersperg, Szabo, von Bayern, & Kacelnik, 2012). Burrowing owls spread animal dung around their burrow, but why they did it was unknown until a group of college students got curious and tackled the problem (Pain, 2005). They removed the dung from some of the burrows, and when they came back 4 days later and counted beetle shells, they found that the owls with dung around their burrows had eaten 10 times as many beetles; the owls were using the dung to lure their dinner! But the prize for planning ahead goes to Santino, a chimp in a Swedish zoo (Osvath, 2009). Santino occasionally threw stones at visitors, but zookeepers weren’t concerned because there was so little ammunition on his moat-surrounded island. Then stone throwing increased dramatically, so a caretaker watched from hiding to figure out where the stones were coming from. Each morning before the zoo opened, Santino retrieved stones from the moat and placed them in piles that were handy for launching at the visitors. He was also seen dislodging chunks of concrete from a wall, after first tapping where there were cracks and listening for the hollow sound that meant a piece was loose enough to be removed.

A Chimp Dines on Termites “Fished” From Their Mound With a Stick. SOURCE: © Corbis.

So what do these observations tell us? First, we learn that other animals are a lot smarter than we’ve given them credit for. We also understand now that some of our capabilities aren’t unique after all. But we also have a chance to discover where we are truly different. For example, watching someone retrieve an object with the hand or with a tool activates mirror neurons that are similarly located in humans and in monkeys (Peeters et al., 2009). But when a human sees the object being retrieved with a tool, an additional area is activated in the anterior parietal lobe (Figure b); no such area for tool use showed up in the monkeys, even the ones that were trained for 3 to 6 weeks to use the same tools. Perhaps—just perhaps—our brains are unique in possessing additional specialized structures or in the ability to develop them through experience.

Area Activated in Humans (Arrow) but Not in Monkeys When Viewing Retrieval of an Object With a Tool. SOURCE: From “The Representation of Tool Use in Humans and Monkeys: Common and Uniquely Human Features,” by R. Peeters et al., 2009, Journal of Neuroscience, 29, pp. 11523–11539.

Heredity and Environment We saw in Chapter 1 that intelligence is the most investigated of the genetically

influenced behaviors. Our understanding of the genetic underpinnings of intelligence hardly lives up to the amount of effort, however; this is because intelligence is so complex and poorly understood itself and because many genes are involved. In addition, environment accounts for half of the differences among us in intelligence, yet the environmental influences have themselves not been clearly identified (Plomin, 1990). FIGURE 13.9 Correlations of IQ Scores Among Relatives. Percentages indicate the degree of genetic relatedness. “Together” and “apart” refer to whether related children are raised in the same household.

SOURCE: Data from “Familial Studies of Intelligence: A Review,” by T. J. Bouchard and M. McGue, 1981, Science, 212, pp. 1055–1059. Heritability of Intelligence Figure 13.9 shows the IQ correlations among relatives, averaged from many studies

and several thousand people. You can see that IQ is more similar in people who are more closely related (T. J. Bouchard & McGue, 1981). Separating family members early in life does not eliminate the correlation; in fact, identical twins reared apart are still more similar in IQ than fraternal twins who are reared together. Interestingly, the relative influence of heredity increases with age, from 41% in childhood to 55% in adolescence and 66% in adulthood (Haworth et al., 2009). Intuition tells us that environment should progressively overtake genetic effects as siblings go their separate ways and their experiences diverge, but Gray and Thompson (2004) suggest that the genes that influence intelligence also influence the individual’s choices of environment and experience.

Which is more important, heredity or environment? FIGURE 13.10 Genetic Control of Gray Matter Volume in Identical and Fraternal Twins. Red indicates areas where the correlation between twins in gray matter was most significant; green indicates lesser correlation and blue no statistically detectable relationship. Notice the markedly greater similarity (greater abundance of red) between identical twins. (W indicates Wernicke’s area and S/M the somatosensory and motor areas.) SOURCE: Reprinted by permission from Macmillan Publishers Ltd. From “Genetic Influences on Brain Structure,” by Paul M. Thompson et al., 2001, Nature Neuroscience, 4(12), pp. 1253–1258. © 2001 Nature Publishing Group.

Not only do we know that intelligence has a heritability of around 50% (Plomin, 1990), but researchers have also documented genetic influence on several of the functions that contribute to it, including working memory, processing speed, and reaction time in making a choice (Ando, Ono, & Wright, 2001; Luciano et al., 2001; Posthuma, de Geus, & Boomsma, 2001). Most of the differences among individuals in the major structural contributors to intelligence are accounted for by genetic factors; estimated heritabilities in one twin study were 90% for brain volume, 82% for gray matter, and 88% for white matter (Baaré et al., 2001; see Figure 13.10). General intelligence has higher heritability than more specific abilities, such as verbal and spatial abilities (McClearn et al., 1997), which is an additional argument for a stronger biological basis for g (Gray & Thompson, 2004). Locating the specific genes is another matter. Two genes that have received special

interest underwent accelerated evolution following our separation from chimpanzees. The ASPM gene is a major determinant of brain size (J. Zhang, 2003), while the PACAP precursor gene plays a role in neurogenesis and neural signaling and may have contributed to the formation of human cognitive abilities (Y. Wang et al., 2005). But the search for genes has been fraught with one replication failure after another. One reason is that effect sizes for individual genes are small, on the order of around 1%, which means that unless samples are very large, the genes will be missed. On the other hand, small samples often do yield false positives that don’t hold up on further scrutiny. Recently, a large consortium of researchers has been combining genetic data with brain scanning to locate genes responsible for the structural foundations of intelligence. One of these studies has identified a genetic variant associated with brain size; its possessors scored on average 1.29 points higher on IQ tests (Stein et al., 2012). A second study identified 24 genetic variations on six genes, which were related to the structural integrity of major brain pathways; some of these were associated with intelligence, and individuals with multiple of these variants scored several points higher than others on intelligence tests (Chiang et al., 2012). Another group identified a gene linking cortical thickness to intelligence; individuals with a

particular variant had a thinner cortex in the left hemisphere and performed less well on intelligence tests (Desrivières et al., 2014). This variant, however, accounted for only 0.5% of the variation in IQ. The Genetic Controversy The conclusion that intelligence is highly heritable has not been greeted with

unquestioning acceptance. The heritability of intelligence is controversial on a variety of fronts; these controversies illustrate both the pervasive misunderstanding of genetic influence and the difficulty in resolving questions of heredity. Critics fear that inheritance of intelligence implies that intelligence is inborn and unchangeable (Weinberg, 1989). Nothing could be further from the truth, however; as Weinberg points out, genes do not fix behavior but set a range within which the person may vary. By way of illustration, height is about 90% heritable (Plomin, 1990), yet the average height has increased dramatically over the past few decades, due to improved nutrition. Similarly, IQ scores are increasing at the rate of 5 to 25 points in a generation (termed “the Flynn effect”; Flynn, 1987), so test constructors must adjust the test norms occasionally to maintain an average of 100 points. Although the environmental causes have not been identified, such rapid increases cannot be due to genetic changes. However, we know that the world is a much more stimulating, information-filled place and education has changed dramatically; and, as Flynn points out, in 1900 the median year of schooling was 6 years, compared with 13 years now, and schools taught by memorization and recitation (Flynn, te Nijenhuis, & Metzen, 2014). Some researchers argue that the correlation of IQ among relatives does not mean

that intelligence is inherited. They suggest, for example, that identical twins’ similarity in appearance and personality lead others to treat them similarly, even when they are reared apart, and this similar treatment results in similar intellectual development. Although physical features and behavior do affect how others react to a child, there is little evidence that these responses in turn influence intelligence. To test this possibility, researchers compared the IQs of twins who had been either correctly or incorrectly perceived by their parents as fraternal or identical. If similar environmental treatment accounts for IQ similarity, then the parents’ perception of their twins’ classification should be more important than the twins’ actual genetic classification. Instead, the studies showed that only the true genetic relationship influenced IQ similarity in the twins, not the parents’ perception (Scarr & Carter- Saltzman, 1982).

3 Flattening the Bell Curve In another controversy, a debate has raged since the 1930s over whether IQ

differences between ethnic groups are genetically based. The question is not whether the ethnic groups differ in IQ scores, but how much the differences are due to heredity

and to environment. Arthur Jensen (1969) has argued for 35 years that environment and socioeconomic differences are inadequate to account for the observed IQ differences among groups. He and Philippe Rushton cite studies indicating that IQ differences are consistent around the world, with East Asians averaging 106 points whether in the United States or in Asia, Whites about 100, and African Americans at 85 and sub-Saharan Africans around 70 (Rushton & Jensen, 2005). In addition, they say that differences in brain size correspond to the IQ gaps. Their position has practical as well as theoretical implications. For example, extreme hereditarians believe that intervention efforts like Head Start not only do not work but also cannot work. Other intelligence researchers countered that Jensen and Rushton ignored or

misinterpreted the most relevant data (Nisbett, 2005). For example, African Americans with more African ancestry scored as high on cognitive tests as those with mixed ancestry (Scarr, Pakstis, Katz, & Barker, 1977). Another study suggests that socioeconomic class is more important than ethnic origin; it found that IQ runs about 20 to 30 points lower in the lowest social classes than in the highest social classes (Locurto, 1991). Higher intelligence test results are not always found for Asians (Naglieri & Ronning, 2000), and their higher academic achievement is typically attributed to cultural and motivational differences (Dandy & Nettelbeck, 2002). A task force appointed by the American Psychological Association to study the intelligence debate concluded that there is not much direct evidence regarding the genetic hypothesis of IQ differences between African Americans and Whites, and what little there is does not support the hypothesis (Neisser et al., 1996). Environmental Effects Most intelligence researchers agree that intelligence is the result of the joint

contributions of genes and environment; it has even been said that intelligence is 100% hereditary and 100% environmental, because both are necessary. However, it has been more difficult than expected to identify just which environmental conditions influence intelligence, other than those that cause brain damage. We will give environmental influences more attention here than usual because intelligence is a good arena for illustrating the difficulties in sorting out heredity from environment. One problem is similar to the one we have encountered in identifying specific genes: The environmental influences are many and, for the most part, individually weak (A. R. Jensen, 1981). Even a twin study that looked at major environmental events such as severe infant and childhood illness failed to find an effect (Loehlin & Nichols, 1976). A second problem is that environmental influences are often hopelessly confounded with genetic effects. For example, family conditions such as socioeconomic level and parental education are moderately related to the offspring’s intelligence (T. J. Bouchard & Segal, 1985), but these characteristics also reflect the parents’ genetic makeup, which they pass on to their children.

The best way to demonstrate environmental influences is by environmental intervention. Although the Head Start program has produced long-term benefits in mathematics, educational attainment, and career accomplishments, the average increase of 7.42 IQ points compared with controls eventually disappears. The Abecedarian Project, which began at birth, produced IQ gains that were as strong 10 years later as those in the Head Start program after 2 years (Ramey et al., 2000). Apparently, intervention must occur at an earlier age; a new Early Head Start program now takes children from birth through age 5. Adoption has a better chance of demonstrating any environmental influences on intelligence, because it alters the entire environment for the child (Scarr & Weinberg, 1976). Adopted children’s IQs are more highly correlated with the intelligence of their biological parents than with the intelligence of their adoptive parents (Scarr & Weinberg; Turkheimer, 1991), but this does not mean that the children’s IQs do not go up or down according to the adoptive environment. When African American children were adopted from impoverished homes into middle-class homes, by the age of 6 they had increased from the 90-point average for African American children in the geographic area to 106. The beneficial effects still persisted a decade later (Scarr & Weinberg; Weinberg, Scarr, & Waldman, 1992). Does this mean there was no genetic effect at all? No; in fact, the correlation

between the children’s IQs and their biological parents’ educational levels (used in the absence of IQ scores) actually increased over the 10-year follow-up period, while correlations with their adoptive parents’ educational levels decreased (Weinberg et al., 1992). It may puzzle you how the children’s IQs could be correlated with their biological parents’ intelligence if the children’s IQs had moved into the adoptive parents’ range. Although we usually think that correlation indicates similarity within pairs of scores (e.g., a parent’s and a child’s IQs), this is not necessarily the implication; rather, it means that the scores have similar rank orders in their groups. In other words, the parent with the highest IQ has the child with the highest IQ, the parent with the second highest IQ has the child with the second highest IQ, and so on. Now move the children into a new household and raise each child’s IQ by 10 points; the parent with the highest IQ still has the child with the highest IQ and the parent with the second highest IQ... you get the point. The correlation tells us that the children’s IQs are still tied to their parents’ intelligence, as if by an elastic string that can stretch but nevertheless affects how much the IQ can change; that elastic string in this case is the influence of genes. Though it has been difficult to identify specific environmental influences that

increase intelligence, we have had some success identifying influences that have a deleterious effect. One example is prenatal exposure to pesticides. In an agricultural community in California, children whose mothers who had high levels of organophosphate pesticide residue in their blood during pregnancy averaged 7.0 IQ

points lower, compared with children of mothers with the lowest residue measures (Bouchard et al., 2011). The exposed children also scored lower on tests of working memory, processing speed, verbal comprehension, and perceptual reasoning. Similarly, children with the highest levels of prenatal exposure to chlorpyrifos scored 2.7 points lower in IQ and 5.3 points lower on a test of working memory (Raugh et al., 2011). Until it was banned for indoor use in 2001, chlorpyrifos was one of the most widely used insecticides for household pest control. FIGURE 13.11 Worldwide Relationship Between Intelligence and Infectious Disease. Although the relationship is not perfect (in which all the dots would fall on the line), you can see that high IQ scores are associated with low levels of infection and low IQ scores are associated with high levels of infection.

SOURCE: Adapted from “Parasite Prevalence and the Worldwide Distribution of Cognitive Ability,” by C. Eppig, C. L. Fincher, and R. Thornhill, 2010, Proceedings of the Royal Society B: Biological Sciences, 277(1701), pp. 3801–3808. Although childhood illness in general was not a predictor of later intelligence,

infection does seem to be important. A study in a north Manhattan, New York, community designed to identify risk factors for stroke found that people with multiple risk-associated pathogens also had lower cognitive ability (Katan et al., 2013). Researchers at the University of New Mexico concluded that the level of infectious diseases is the best predictor of national differences in intelligence (Eppig, Fincher, & Thornhill, 2010). After controlling for confounding variables, including education, climate, and economy, the correlation between national average IQ and infectious disease ranged from –0.76 to –0.82, depending on the method of estimating intelligence (Figure 13.11). The investigators believe that fighting off infections during childhood robs the body of energy needed for normal brain development. Not only might disease prevalence partly account for racial differences in intelligence, but the researchers suggest that reduction in the incidence of infectious diseases explains some of the IQ increase seen in the Flynn effect. We want to understand the antecedents of intelligence in order to enhance cognitive

functioning and prevent the disorders that diminish it. We have already seen that this is a daunting challenge in the case of Alzheimer’s, and the accompanying Application reveals that enhancing performance in normally functioning individuals is not so easy either.

APPLICATION

Enhancing Intelligence and Performance One of the consequences of living in a high-pressure world is that many people are turning to drugs of one kind or another to improve performance and compensate for the fatigue of long hours and lost sleep. Most of these drugs were designed to treat specific disorders, but they are used regularly by students in pursuit of better grades, military personnel on long missions, elderly individuals dealing with normal cognitive decline, and professionals who are either trying to climb the ladder or struggling to survive. In 2008 the journal Nature asked its readers, who are mostly academics, about their attitudes on the use of cognitive-enhancing drugs. Surprisingly, one in five of the respondents said they had used drugs to stimulate their focus, concentration, or memory (Maher, 2008). Stimulants prescribed for attention- deficit/hyperactivity disorder are popular among college students, who say the drugs improve concentration and help them learn. In a study on one college campus, 34% of students reported using these drugs without a prescription (DeSantis, Webb, & Noar, 2008). Favored drugs include modafinil, a narcolepsy drug that alleviates sleepiness, and dopamine agonists such as dextroamphetamine, which improves working memory (de Jongh, Bolt, Schermer, & Oliver, 2008). But half of the Nature poll respondents reported side effects, and these can

be severe enough to lead even patients who sorely need them to discontinue the medications (Husain & Mehta, 2011). In addition, the benefits are modest and highly variable among individuals, and the drugs can impair some types of cognitive functioning while they are enhancing others. Tweaking our intelligence by manipulating genes seems an obvious possibility, but remember that the known genes have a very small individual influence. It’s true that neuroscientists have created mutant strains of mice that were smarter at one task or another, but these mice also had their problems; one strain was overly fearful, and another solved some problems well but struggled with simpler ones (“Small, Furry... and Smart,” 2009). Faced with all the side effects, researchers have been looking for more

benign strategies. Electrical stimulation applied to the scalp causes only minor discomfort, and subjects who received stimulation over the prefrontal cortex

Concept Check

while they performed mathematical tasks learned two to five times faster than subjects given sham stimulation (Snowball et al., 2013). Blood oxygenation also was higher in the prefrontal cortex, and this was maintained 6 months later, along with a 30% superiority on a new task without stimulation. However, electrical stimulation would likely be practical only in specialized training situations. In spite of numerous failures, there have been some promising results using cognitive training to improve working memory. Elementary and middle-school children improved on a version of Raven Progressive Matrices after training on a video game that required recalling where an object appeared on the screen a few trials earlier (Jaeggi, Buschkuekhl, Jonides, & Shah, 2011), and elderly individuals who trained on a game that required steering a car on winding roads and responding to various signs along the way gained in working memory and attention and showed increased prefrontal activity (Anguera et al., 2013). Training in multiple cognitive domains produced improvement in memory, attention, and reasoning in a group of elderly Chinese (Cheng et al., 2012). Researchers have also documented brain changes with certain interventions: Working memory training increased dopamine binding (McNab et al., 2009) and functional connectivity in the frontal-parietal network (Jolles, van Buchem, Crone, & Rombouts, 2013). Similarly, adults who took 70 hours of intensive reasoning instruction in preparation for the Law School Admissions Test showed increased frontal-parietal connectivity and connectivity between parietal and striatal areas (Mackey, Singley, & Bunge, 2013). The bottom line is that there is no magic pill to increase the intelligence of

the unimpaired. The most practical road to intellectual improvement appears to be intensive practice that is guided by scientific knowledge about how intelligence works.

Take a Minute to Check Your Knowledge and Understanding

What is the likely neural basis of general intelligence and of separate components of intelligence?

You read a quote from a researcher that “intelligence is not a matter of a place in the brain, but how well the brain does its job.” Explain why someone would say this.

What are the relative contributions of heredity and environment to intelligence?

Why is it so difficult to identify the environmental influences? How can adopted children’s IQs increase into the range of their adoptive homes and yet be more highly correlated with their parents’ intelligence? (Hint: Draw a diagram, with made-up IQ scores of children from several families.)

Deficiencies and Disorders of Intelligence Intelligence is as fragile as it is complex; accordingly, the list of conditions that can impair intelligence is impressively, or depressingly, long. To give you a feel for the problems that can occur in this most revered of our assets, we will add a few thoughts to what we have already covered in Chapter 12 on aging, take a brief look at intellectual disability, then spend more time on autism in recognition of its half- century-long challenge to neuroscientists’ investigative skills, and finish with attention-deficit/hyperactivity disorder. Effects of Aging on Intelligence In Chapter 12, we discussed the most widely known cognitive disorder of aging,

Alzheimer’s disease. Here, we will limit our attention to more or less normal declines in cognitive abilities that are associated with aging. One source of normal decline is the reduced activity of numerous genes involved in long-term potentiation and memory storage due to age-related damage (T. Lu et al., 2004). Genes involved in synaptic functioning and plasticity, including those responsible for glutamate and GABA receptors and for synaptic vesicle release and recycling, are particularly affected.

How much capability is lost by the elderly? Although intelligence and cognitive abilities do typically decline with age, the

amount of loss has been overestimated. One reason is that people are often tested on rather meaningless tasks, like memorizing lists of words; older people are not necessarily motivated to perform on this kind of task. When the elderly are tested on the content of meaningful material such as television shows and conversations, the decline is moderate (Kausler, 1985). Another reason for the overestimation is that early studies were cross-sectional: People at one age were compared with different people at another age. You have already seen from Flynn’s research that more recent generations have an IQ test performance advantage over people from previous generations. When the comparison is done longitudinally—by following the same people through the aging process—the amount of loss diminishes (Schaie, 1994). Schaie followed 5,000 adults for 35 years. Perceptual speed dropped from age 25 on, and numeric ability dropped rather sharply after age 60. However, the other capabilities—inductive reasoning, spatial orientation, verbal ability, and verbal memory—increased until middle age before declining gradually to slightly lower than their levels at age 25. Apparently, performance speed is particularly vulnerable during aging, and its loss

turns out to be important. Schaie (1994) found that statistically removing the effects of speed from test scores significantly reduced elderly individuals’ performance losses. We saw earlier that working memory is especially important to intellectual capability. A study of people ranging in age from 18 to 82 showed that speed of processing accounted for all but 1% of age-related differences in working memory (Salthouse & Babcock, 1991). You know that a determinant of general intelligence is the ability to integrate

activity between brain areas. Even in healthy aging there is a loss of coordination in the default mode network, portions of the frontal, parietal, and temporal lobes that are active when the brain is at rest or focused internally rather than on the outside world; activity in the default mode network is thought to represent preparedness for action (Andrews-Hanna et al., 2007; Broyd et al., 2009). To the extent this coordination diminishes, cognitive ability does as well. Imaging reveals that the loss is due to a decline in white matter connections among the areas. In the elderly, those with better whole brain network efficiency (clustering and short path length) had higher processing speed and superior executive functions, including impulse control and decision making (Wen et al., 2011). The brain does have ways of compensating, such as the increased metabolism that

is seen in subjects with mild intellectual disability and the recruitment of frontal areas in dyslexics during reading (see Chapter 9). Studies of elderly individuals who are “aging gracefully” indicate that they are holding their own through additional neural effort (Helmuth, 2002). For example, a memory task activated only the right prefrontal cortex in young adults and in older adults who performed poorly, but older adults who performed as well as the young adults used both prefrontal areas to perform the tasks (Figure 13.12; Cabeza, Anderson, Locantore, & McIntosh, 2002). The increase in frontal activity is in proportion to decreases in other areas, which supports the idea that the shift serves a compensatory function (S. W. Davis, Dennis, Daselaar, Fleck, & Cabeza, 2008). Compensation may not be limited to frontal activity; it has also been observed in the parahippocampal area during a memory recognition task (van der Veen, Nijhuis, Tisserand, Backes, & Jolles, 2006). This less than efficient adaptation might not be the only pathway to graceful aging; elderly subjects initially coped with a task via compensation, but after just 5 hours of training on the task, they showed brain patterns like those of young subjects (Erickson et al., 2007). FIGURE 13.12 Compensatory Brain Activity in High-Performing Older Adults. A memory task activated the right prefrontal area in young and in low-performing older adults. Older adults who performed as well as the young showed activation in both prefrontal areas.

SOURCE: From “Aging Gracefully: Compensatory Brain Activity in High- Performing Older Adults,” by R. Cabeza et al., NeuroImage,17, pp. 1394–1402, fig. 2, p. 1399. © 2002 Elsevier. Some of the loss in performance is due to nonphysical causes and is reversible; for

example, older people often lack opportunity to use their skills. In one study, aged individuals were able to regain part of their lost ability through skills practice, and many of them returned to their predecline levels; they still had some advantage over controls 7 years later (Schaie, 1994). Elderly people also improved in memory test scores when their self-esteem was bolstered by presenting them with words that depict old age in positive terms such as wise, learned, and insightful (B. Levy, 1996). Loss in performance that has a physical basis may be reduced if not reversed. Diet

appears to be one factor; for example, in a study of 6,000 people over the age of 65, cognitive decline was 13% less in those who ate two or more fish meals per week,

compared with people who ate fish less than once per week (M. C. Morris, Evans, Tangney, Bienias, & Wilson, 2005). Evidence in this study and others suggested that the important factor was the overall pattern of fat intake. Vitamin supplements might also help. In elderly individuals with mild cognitive impairment, a combination of B vitamins reduced the rate of brain atrophy 50% and slowed cognitive decline, compared with subjects given a placebo (de Jager, Oulhai, Jacoby, Refsum, & Smith, 2012; Douaud et al., 2013). The B vitamins slow gray matter atrophy by reducing homocysteine, a toxic compound that is elevated in people with a diet high in animal proteins. Interestingly, the sex hormones provide some protection against the cognitive

effects of aging. In menopausal women, estrogen replacement therapy reduces the decline in verbal and visual memory as well as lowering the risk of Alzheimer’s disease (Sherwin, 2003; van Amelsvoort, Compton, & Murphy, 2001). The importance of estrogen is bolstered by the fluctuations that occur during the menstrual cycle. First, remember from Chapter 7 that women tend to be superior to men on some types of verbal tasks and that men typically outperform women on tasks requiring spatial ability. During the part of the month when estrogen is high, women perform higher on verbal tasks; then during menstruation estrogen drops and so does performance on the verbal tasks, but spatial performance improves (Kimura & Hampson, 1994; Maki, Rich, & Rosenbaum, 2002). How does estrogen produce these effects? We are not sure, but we do know that

neurons throughout the brain have estrogen receptors; estrogen levels during the menstrual cycle are correlated with cortical excitability (M. J. Smith, Keel, et al., 1999), increased glucose metabolism (Reiman, Armstrong, Matt, & Mattox, 1996), blood flow in areas involved in cognitive tasks (Dietrich et al., 2001), and responsiveness to acetylcholine, which is important in memory and cognitive functioning (O’Keane & Dinan, 1992). Finally, because untreated menopausal women are more impaired than women receiving estrogen replacement on tests of working memory, response switching, and attention, it is clear that estrogen particularly improves functioning in prefrontal areas (Keenan, Ezzat, Ginsburg, & Moore, 2001). So what about the male of the species? Men who maintain testosterone production

past the age of 50 have better preserved visual and verbal memory and visual-spatial functioning (Moffat et al., 2002). The effects of replacement therapy have been variable, owing apparently to the form of the testosterone preparation used. However, a number of studies have shown improvement in spatial, verbal, and working memory (Cherrier et al., 2005; Cherrier, Craft, & Matsumoto, 2003; Gruenewald & Matsumoto, 2003). Interestingly, testosterone improves only spatial memory; additional memory improvement requires that the testosterone be delivered in the form of dihydrotestosterone, which can be converted to estrogen in the brain by the process of aromatization (Cherrier et al., 2003, 2005). When it comes to cognitive

abilities, we could be tempted to consider estrogen a wonder drug. So losses are smaller than believed, and they differ across people and across skills.

In addition, practice, esteem enhancement, and an active lifestyle may slow cognitive decline during aging. Obviously, we cannot stereotype the older person as a person with diminished abilities.

4 Intellectual Disability Facts Intellectual Disability Intellectual impairment was previously referred to as retardation, but that term has

taken on such negative meaning in popular usage that practitioners and authorities are shifting to the term intellectual disability. Intellectual disability is a limitation in intellectual functioning (reasoning, learning, problem solving) and in adaptive behavior originating before the age of 18. The criteria are arbitrary and are based on judgments about the abilities required to get along in our complex world. In 1994, the American Psychiatric Association set the criteria as a combination of an IQ below 70 points and difficulty meeting routine needs like self-care. Looking back at Figure 13.2, you can see that 2% of the population falls in this IQ range, and a lower percentage would meet both criteria. Not only is any definition arbitrary, but it is situational and cultural as well; a person considered to have an intellectual disability in our society might fare reasonably well in a simpler environment. The situational nature is illustrated by the fact that many individuals shed the label as they move from a childhood of academic failure into adulthood and demonstrate their ability to live independent lives. Intellectual disability has historically been divided into four categories based on IQ

level. In the revised Diagnostic and Statistical Manual (DSM-V), the emphasis is on the degree of functional impairment. Intelligence testing is still used as a part of assessment, but the criterion for diagnosis is impairment in conceptual, social, and practical domains (Table 13.1; American Psychiatric Association, 2013). Intellectual disability is a developmental disorder; this means that the symptoms begin during the developmental period and are not the result of disease or brain trauma.

What causes intellectual disabilities? TABLE 13.1 Areas of Impairment Leading to a Diagnosis of Intellectual Disability.

Most individuals with mild impairment come from families of lower socioeconomic status and have at least one relative with the diagnosis (Plomin, 1989); psychologists believe their impairment is due to a combination of environmental and hereditary causes. Recently, four gene locations have been implicated in mild intellectual disability; each location accounted for only a small amount of the variation in intelligence, but their effects were cumulative (Butcher et al., 2005). About 25% of cases can be clearly attributed to one of the 200-plus physical disorders known to cause intellectual impairment (K. G. Scott & Carran, 1987). However, psychologists believe most cases of mild impairment are due to a combination of environmental and hereditary causes. Intellectual disability can be caused by diseases contracted during infancy, such as meningitis, and by prenatal exposure to viruses, such as rubella (German measles). As we saw in Chapter 5, maternal alcoholism is now the leading cause of intellectual disability. There are numerous other causes as well, and we will discuss a few of them in the following pages. FIGURE 13.13 Luke Zimmerman and Down Chromosomes. (a) Some individuals with Down syndrome are more fortunate than others. In spite of the disorder, Luke Zimmerman played a starring role in the television series The Secret Life of the American Teenager. (b) Chromosomes of a person with Down syndrome (female). The arrow points to the three 21st chromosomes.

SOURCES: (a) © Chris Wolf/Getty Images. (b) © www.nads.org, 2007. Down syndrome, usually caused by the presence of an extra 21st chromosome,

typically results in individuals with IQs in the 40 to 55 range, although some are less impaired (Figure 13.13). Its prevalence of 1 in every 700 births makes it the most common genetic cause of intellectual disability (D. L. Nelson & Gibbs, 2004). Recall that the amyloid precursor protein gene that is involved in early-onset Alzheimer’s disease is located on chromosome 21 and that it was discovered because Down syndrome individuals also develop amyloid plaques (Goate et al., 1991; Murrell, Farlow, Ghetti, & Benson, 1991). Ninety-five percent of people with Down syndrome have the entire extra chromosome, but in a few cases only an end portion is present, which is attached to another chromosome. A strain of mouse (Ts65Dn) engineered with a third copy of 55% of chromosome 21 has been a useful model for studying Down syndrome. As in people with that disorder, its glial cells secrete less of two proteins that support neuron survival. Treating pregnant Ts65Dn females with these proteins eliminates the developmental delays that would ordinarily be seen in their offspring (Toso et al., 2008). Conceivably this strategy could be used with pregnant women when amniocentesis (genetic testing of the amniotic fluid) reveals that the fetus has a third 21st chromosome. Another therapeutic possibility is postnatal correction of inadequate norepinephrine release in the hippocampus, a deficiency that is believed to contribute to learning impairment. After treatment with a drug that increased norepinephrine levels, Ts65Dn mice performed as well as normal mice (Salehi et al., 2009). However, it may be an oversimplification to focus only on the effects of chromosome 21 genes. Amniocentesis in mothers carrying fetuses with three copies of the chromosome found 5 genes on chromosome 21 that were upregulated or downregulated, but 414 genes on other chromosomes that were altered (Slonim et al., 2009). The researchers are studying the protein products of these genes to improve understanding of the mechanism of the disorder and to identify prenatal biomarkers (Cho, Smith, & Diamandis, 2010). Another frequent genetic cause of intellectual disability is fragile X syndrome,

which is due to a mutation in the fragile X mental retardation 1 gene ( FMR1 ). The FMR1 gene normally contains between 6 and 45 repetitions of the nucleotide sequence C, G, G. If the number of CGG repeats reaches 200, the gene is turned off, and no protein is made. Fragile X syndrome is the result, with IQs typically below 75. An intermediate number of CGG repeats results in reduced protein production, accompanied by a slight increase in the chance of intellectual disability. Males are affected more often, and when fragile X does occur in females, the symptoms are usually milder. In FMR1 knockout mice, unusual numbers of dendrites and immature spines indicate a failure to prune excess synapses (Bagni & Greenough, 2005). FIGURE 13.14 The Hydrocephalic Brain. (a) Normal brain. (b) Hydrocephalic brain. Notice the large lateral ventricles and the small amount of cortex around the perimeter in the hydrocephalic brain.

SOURCES: (a) © Du Cane Medical Imaging Ltd./Science Source. (b) © Mehau Kulyk/Science Source. Phenylketonuria is due to an inherited inability to metabolize the amino acid

phenylalanine; the excess phenylalanine interferes with myelination during development. Newborn infants are routinely tested for phenylalanine in the urine or blood, and intellectual disability can be prevented by avoiding foods containing phenylalanine. The artificial sweetener aspartame is a familiar example of a substance that is high in phenylalanine. Without dietary treatment, the individual is severely or profoundly disabled, with an adult IQ around 20 points. Hydrocephalus occurs when cerebrospinal fluid builds up in the cerebral ventricles;

the increased fluid volume crowds out neural tissue, usually causing intellectual disability (Figure 13.14). As we saw in Chapter 3, hydrocephalus can also be treated if caught early, by installing a shunt that prevents the accumulation of the excess cerebrospinal fluid. Also in that chapter, you learned that some individuals seem not to be harmed by the dramatic loss of cortex; in fact, half of those whose ventricles fill 95% of the cranium have IQs over 100 (Lewin, 1980).

5 Autism Facts Autism Spectrum Disorder Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders

characterized by social deficits, communication difficulties, and repetitive behaviors. In DSM-5, autism spectrum disorder includes the previous diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified, and childhood disintegrative disorder (American Psychiatric Association, 2013). For simplicity, we will refer to the disorder as autism or ASD. The prevalence of ASD was 1 in 150 children in the year 2000 (Centers for Disease Control and Prevention, 2002), and diagnoses have been on the increase ever since. By 2008 it had risen to 1 in every 88 children, and in 2012 it was 1 in 50, or 2% of children aged 6 to 17 (Blumbert et al., 2013). At least some of the increase can be attributed to improved detection, broader diagnostic criteria, and doctors’ greater willingness to use the label because of

decreasing stigmatization of autism and because the diagnosis will qualify the family for increased services and financial assistance (Rutter, 2005). Whether there has been an actual increase in the disorder is unclear. When researchers in Stafford, England, repeated a study of preschoolers done in 1998 in exactly the same area and using the same diagnostic methods, they found the incidence of autism had not changed (Chakrabarti & Fombonne, 2005). However, the position of most authorities is that we simply don’t know how much the rate has actually increased. Cognitive and Social Impairment In a recent study of cognitive abilities in children with ASD, 55% had intellectual

disability (defined as IQ < 70), and 16% had moderate to severe disability, with IQs below 50 (Charman et al., 2011). Impairment was not universal, however; 28% had average intelligence (IQs of 85 to 115), and 3% scored above 115. Autistic individuals share a common core of impairment in communication, imagination, and socialization (U. Frith, 1993). Trouble understanding verbal and nonverbal communication often makes testing difficult, raising questions about the meaningfulness of test results; in some cases nonverbal tests such as the Ravens are used or IQ is estimated from an assessment of adaptive behavior, but these do not eliminate the deficits. Difficulty with imagination shows up in an inability to pretend or to understand make-believe situations. Use of language is also very literal—“Can you pass me the salt?” is met with “Yes” with no compliance—and in some cases this literalism extends to an obsessive interest in facts, like that seen in the movie Rain Man.

What is autism like? These characteristics make it difficult to socialize with others, which is what sets

children with autism apart the most. They usually prefer to be alone and ignore people around them (Figure 13.15). Their interaction with others often is limited to requests for things they want; they otherwise treat people as objects, sometimes even walking or climbing over them. Verbalization is usually limited, and the child often repeats what others say (echolalia). FIGURE 13.15 Autistic Individuals Typically Feel Threatened by Social Interaction. Most children enjoy hiding out in a tent fashioned from sheets draped over chairs, but for this autistic child, it is a defense against social contact.

SOURCE: © Ali Jarekji/Reuters/Corbis. Some researchers believe that much of the social behavior problem is that the

person with autism lacks a theory of mind, the ability to attribute mental states to oneself and to others; in other words, the autistic person cannot infer what other people are thinking. One man with autism said that people seem to have a special sense that allows them to read other people’s thoughts (Rutter, 1983), and an observant autistic youth asked, “People talk to each other with their eyes. What is it that they are saying?” (U. Frith, 1993). In a study that measured this deficiency, children watched hand puppet Anne remove a marble from a basket where puppet Sally had placed it, and put it in a box while Sally was out of the room. On Sally’s return, children were asked where she would look for the marble. Normal 4-year-olds had no problem with this task, nor did Down syndrome children with a mental age of 5 or 6. But 80% of children with autism with an average mental age of 9 answered that Sally would look in the box (U. Frith, Morton, & Leslie, 1991). There are two hypotheses as to how we develop a theory of mind. According to the

“theory theory,” we build hypotheses over time based on our experience. Simulation theory holds that we gain insight into people’s thoughts and intentions by mentally mimicking the behavior of others. This view gets some support from studies of the mirror neurons talked about in Chapters 8 and 9. Individuals who score higher on a measure of empathy tend to have more activity in these mirror neurons (Gazzola, Aziz-Zadeh, & Keysers, 2006). Researchers have suggested that impaired mirror functions reduce the autistic person’s ability to empathize and to learn language through imitation. Children with autism engage in less contagious yawning than other children do (Senju et al., 2007), and they show neural deficiencies during mirroring tasks. For example, they can imitate others’ facial expressions, but mirror neuron activity while doing so is either delayed or nonexistent (Dapretto et al., 2005; Oberman et al., 2007). Other studies show reduced activation in the inferior frontal cortex and motor cortex, suggesting weakness in the dorsal stream connections that

provide input to those areas (Nishitani, Avikainen, & Hari, 2004; Villalobos, Mizuno, Dahl, Kemmotsu, & Müller, 2005). This interpretation was supported in a study of individuals diagnosed with Asperger syndrome, the former term for high-functioning individuals with autism. When they imitated facial expressions, transmission over the dorsal stream (occipital to superior temporal to posterior parietal to frontal) was delayed 45 to 60 milliseconds compared with normal controls (Nishitani et al., 2004). Autistic Savants and High-Functioning Autistics A savant is a person with exceptional intellectual skills, beyond the level of

“typical” genius, like Leonardo da Vinci or Albert Einstein. However, the term is more frequently used to describe individuals who have one or more remarkable skills but whose overall functioning is below normal; half of these individuals with islands of exceptional capabilities are autistic savants (Treffert & Christensen, 2006). Some can play a tune on the piano after hearing it once, another can memorize whole books, while others take cube roots of large numbers in their heads or calculate the day of the week for any date thousands of years in the past or future. A few “ordinary” individuals can perform similar feats, but the savant’s performance is typically faster, more automatic, and without insight into how it is done (A. W. Snyder & Mitchell, 1999). The savant’s exceptional capability may be limited in scope, however; some who are calendar calculators cannot even add or subtract with accuracy (Sacks, 1990).

6 Meet the Savants

7 Temple Grandin The source of the autistic savant’s enhanced ability is unknown. Dehaene (1997)

suggests that it is due to intensely concentrated practice, but more typically the skill appears without either practice or instruction, as in the case of a 3-year-old autistic girl who began drawing animated and well-proportioned horses in perfect perspective (Selfe, 1977). Allan Snyder and John Mitchell (1999) believe that these capabilities are within us all and are released when brain centers that control executive or integrative functions are compromised. This, they say, gives the savant access to speedy lower levels of processing that are unavailable to us. But, lacking the executive functions, the savants perform poorly on apparently similar tasks that require higher-order processing. The idea gains some credibility from the case of a man impaired in his left temporal and frontal areas by dementia; in spite of limited musical training, he began composing classical music, some of which was performed publicly (B. L. Miller, Boone, Cummings, Read, & Mishkin, 2000; also see Figure 13.16). The best-known savant was Kim Peek, the model used by Dustin Hoffman in his portrayal of Raymond Babbitt in Rain Man; Peek’s brain had several anomalies, particularly in the left hemisphere (Figure 13.17; Treffert & Christensen, 2006). A few

researchers have attempted to unleash savant-like capabilities by using transcranial electrical or magnetic stimulation to inhibit neural activity in the frontal-temporal area (Snyder, 2009). Most of the results have been unremarkable, but 40% of subjects receiving excitatory right-hemisphere stimulation along with inhibitory left- hemisphere stimulation were able to solve a problem that none of the control subjects could solve (Chi & Snyder, 2012). Whatever the explanation, the phenomenon adds to the argument that intellectual ability involves multiple and somewhat independent modules. FIGURE 13.16 Savant-Like Ability Following Brain Impairment. (a) The scan is from a 64-year-old woman with dementia in the left frontal- temporal area, which shows less activity than the right. (b) After the onset of her dementia, she began to do remarkable paintings like the one here.

SOURCE: From “Emergence of Artistic Talent in Frontal-Temporal Dementia,” by B. L. Miller et al., Neurology, 51, pp. 978–982. Copyright © 1998. Reprinted by permission of Wolters Kluwer. If these savants have an island of exceptional ability, autism is an island of

impairment in high-functioning individuals with ASD. As an infant, Temple Grandin would stiffen and attempt to claw her way out of her affectionate mother’s arms (Sacks, 1995). She was slow to develop language and social skills, and she would spend hours just dribbling sand through her fingers. A speech therapist unlocked her language capability, starting a slow emergence toward a normal life. Even so, she did not develop decent language skills until the age of 6 and did not engage in pretend play until she was 8. FIGURE 13.17 Kim Peek, the Original Rain Man. Kim memorized 7,600 books as well as every area code, zip code, highway, and television station in the United States, but he had an IQ of 87 and could not care for himself. He died of a heart attack in December 2009 at the age of 58.

SOURCE: © Ethan Hill/Redux. As an adult, Grandin earned a doctorate in animal science; she teaches at Colorado

State University and designs humane facilities for cattle, while lecturing all over the world on her area of expertise and on autism. Still, her theory of mind is poorly developed, and she must consciously review what she has learned to decide what others would do in a social situation. She says that she is baffled by relationships that are not centered on her work and that she feels like “an anthropologist on Mars.” Brain Anomalies in Autism Autism was long thought to be purely psychological in origin, because no specific

brain defects had been found. The problem was blamed on a lack of maternal bonding or a disastrous experience of rejection that caused the child to retreat into a world of aloneness (U. Frith, 1993). But no evidence could be found for this kind of influence; autistic children often had exemplary homes, and children with extremely negative experiences did not become autistic. The frequent association with intellectual disability and epilepsy implied that autism was a brain disorder. Later work found subtle but widespread brain anomalies, especially in the brain stem, the cerebellum, and the temporal lobes (Happé & Frith, 1996). The location of the damage varied among individuals, which suggests that there are various pathways to autism. Monitoring how brain development progresses revealed additional clues. The

brains of individuals with autism are normal or slightly reduced in size at birth but undergo dramatic growth during the first year (Redcay & Courchesne, 2005). The overgrowth occurs in frontal and temporal areas that are important for the social, emotional, and language functions that are impaired in the disorder. The excess growth ends around 3 to 5 years of age, but by then the brain has already reached normal adult size (Courchesne et al., 2007). In adulthood these areas are underactivated during tasks that would ordinarily engage them, for example, when

viewing animations that require the viewer to understand the mental state of the actor (Castelli, Frith, Happé, & Frith, 2002). In spite of comparable overall brain volumes, adult patients have more gray matter volume in parts of the prefrontal and temporal areas and less in occipital and parietal areas (Ecker et al., 2012). Some of the specific brain differences go a long way toward explaining the social

difficulties involved in autism. For one thing, there is an apparent lack of coordination (functional connectivity) between the amygdala and the ventromedial prefrontal cortex (vmPFC), which ordinarily inhibits the amygdala’s activity (Swartz, Wiggins, Carrasco, Lord, & Monk, 2013). Individuals with ASD often have difficulty looking at people’s faces, which increases difficulty with social interaction and understanding others’ emotions. As typically developing children repeatedly viewed pictures of faces, functional connectivity between the vmPFC and amygdala increased, and activity in the amygdala decreased; children with autism failed to show this habituation. There are also deficiencies in white matter tracts in the corpus callosum that connect visual and parietal areas in the two hemispheres. These were seen in 7- month-old infants who later showed symptoms of ASD, accompanied by slowness in visually tracking a moving object (Elison et al., 2013). FIGURE 13.18 Areas of Decreased White Matter in Adolescent Males With Autism. Areas of decrease are shown in dark gray. The corpus callosum (white) and the amygdalas (checkered gray) are shown for reference.

SOURCE: From “White Matter Structures in Autism: Preliminary Evidence From Diffusion Tensor Imaging,” by N. Barnea-Goraly et al., 2004, Biological Psychiatry, 55, pp. 323–326. White matter connectivity has become a major focus of autism research. In young

children with autism, the increased brain size is due largely to overgrowth of white matter; this overgrowth is followed by white matter reductions during adolescence

and adulthood, while the brains of typically developing individuals are increasing in white matter (reviewed in Just, Keller, Malave, Kana, & Varma, 2012; see Figure 3.18). As a result, there is a loss of synchronized activity among brain areas, particularly between frontal and posterior regions of the cortex. Diminished functional connectivity shows up both at rest and during tasks involving language, executive function, working memory, and social processing. Biochemical Anomalies in Autism As researchers looked for genetic links to autism, several of the genes that turned

up pointed in turn to serotonin, glutamate, GABA, and oxytocin (Freitag, Staal, Klauck, Duketis, & Waltes, 2010; Sutcliffe, 2009). Serotonin has received considerable attention because of its contribution to neural development. Prenatal serotonin activity is regulated by cortisol levels, and cortisol is increased in the mother by psychological stress, depression, Type 2 diabetes, inflammatory disorders, and obesity (Rose’Meyer, 2013). Neuroimaging studies have found diminished serotonin synthesis in children with ASD, and treatment with serotonin reuptake inhibitors, such as Prozac, decrease repetitive and obsessive behavior in some autistic individuals. The antipsychotic drug risperidone antagonizes dopamine as well as serotonin, and its stronger therapeutic track record implicates that neurotransmitter. According to an analysis of 22 previously published studies, several autism symptoms improve during treatment with risperidone (Sharma & Shaw, 2012). High levels of the excitatory transmitter glutamate have also been found in autism (Hassan et al., 2013). Treatment with glutamate antagonists alone has produced unremarkable results, but pairing the anti-Alzheimer’s drug memantine with risperidone decreased irritability more than risperidone alone (Ghanizadeh & Moghimi-Sarani, 2013). FIGURE 13.19 Reduced Response to Betrayal of Trust Following Oxytocin. Compared with subjects receiving a placebo, those who received nasally administered oxytocin responded less to betrayal of trust in an investment simulation. Areas of comparatively reduced activity (shown in yellow) were the caudate nucleus (Cau), amygdala (Amy), and midbrain (MB).

SOURCE: From “Oxytocin Shapes the Neural Circuitry of Trust and Trust Adaptation in Humans,” by T. Baumgartner et al., 2008, Neuron, 58, pp. 639–650, fig 4. In Chapter 7 we saw that oxytocin facilitates bonding and social recognition; for

that reason it is known as the “sociability molecule.” Most studies have found that

oxytocin is reduced in individuals with autism, though not in all (reviewed in Aganostou et al., 2014). Even studies using a single dose of oxytocin have reported improvements in repetitive behaviors, self-injury, empathy, social interaction, and ability to recognize mental or emotional state from photos of the eyes. Twice-daily dosing for 12 weeks via nasal spray produced social benefits that carried over 3 months after discontinuation of the drug. Results of an fMRI study indicated that oxytocin improves trust by reducing activity in fear areas in the amygdala and midbrain (Figure 13.19; Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008). The Environment and Autism Parental treatment has been ruled out as the cause of autism, but a number of other

environmental conditions have been identified as contributing factors. One’s suspicions immediately turn to environmental pollutants, such as those generated by automobile traffic, agricultural practices, and industrial activity. Two recent studies are notable for using more meaningful measures of pollution than the typical proximity to a highway or agricultural fields. Using localized estimates of traffic pollution based on Environmental Protection Agency data, traffic volume, and climatic conditions during each child’s gestational period and first year of life, researchers found that living in homes where traffic pollution was highest tripled the rate of autism (Volk, Penfold, Hertz-Picciotto, & McConnell, 2013). Recognizing that ASD occurs in geographic clusters, University of Chicago researchers used county- level data on genital malformation in male children as a surrogate for environmental exposure and found that the incidence of ASD increased 238% for every percent increase in incidence of malformations (Rzhetsky et al., 2014). Other environmental influences originate in the mother herself. Ten percent of

women who have a child with autism have immune molecules in the blood that react with proteins in the brain; this rate is four times higher than in the general population of women of childbearing age (Brimberg, Sadiq, Gregersen, & Diamond, 2013). Other researchers identified six brain proteins that anti-brain antibodies attach to; all of them are involved in neuronal development (Braunschweig et al., 2013). Maternal metabolic conditions, including obesity, diabetes, and hypertension, may also be associated with ASD; mothers of autistic children were 40% more likely to be obese and 47% more likely to have any one of these conditions (Krakowiak et al., 2012; also, see the earlier discussion of serotonin). The news is not all bad: Mothers who took folic acid during pregnancy were half as likely to bear a child who would later be diagnosed with autism (Surén et al., 2013).

APPLICATION

Childhood Vaccines and Autism

In 1998 Andrew Wakefield and several colleagues published a paper in which they linked the measles, mumps, and rubella (MMR) vaccine to autism. Years later, two reviews of all the available studies concluded that there was no credible link between autism and the MMR vaccine or the mercury-derived preservative (thimerosal) used in some vaccines (Demicheli, Jefferson, Rivetti, & Price, 2005; Immunization Safety Review Committee, 2004). In early 2010 the General Medical Council, which oversees doctors in Britain, decided that Wakefield’s study was methodologically flawed and that he had acted unethically. The Lancet, which published the study, called the report “the most appalling catalog and litany of some of the most terrible behavior in any research” and took the rare action of withdrawing the study (Park, 2010). Many parents whose children’s first signs of autism coincided with a round

of childhood vaccinations say they find these reports unconvincing. More than 5,000 families have brought suit; a U.S. federal court has denied the claims in four test cases (“Vaccine Court Finds...,” 2010), but that does not signal the end of litigation or of the controversy. In the meantime there has been a disturbing decrease in the rate of childhood immunization in several countries in spite of the health risks.

The Wakefield Paper as It Appears on the Lancet Website. SOURCE: From “Ileal-lymphoid-odular Hyperplasia, Non-specific Colitis, and Pervasive Developmental Disorder in Children,” by Wakefield et al., 1998, Lancet, 351, pp. 637–641. Retrieved from http://vaccines.procon.org/sourcefiles/ retracted-lancet-paper.pdf.

Heredity and Autism Siblings of children with autism are 25 times more likely to be diagnosed with

autism than other children (Abrahams & Geschwind, 2008); the number would be even higher, but parents tend to stop having children after the first autism diagnosis.

For the identical twin of a child with autism, the risk of autism is at least 60%. However, relatives frequently have autistic-like cognitive and social characteristics. When these symptoms are also considered, the concordance for identical twins jumps to 92%, compared with 10% for fraternal pairs (A. Bailey et al., 1995). Earlier, the presence of these milder social and cognitive deficits in the parents was interpreted as evidence that they were fostering their children’s symptoms psychologically. Now we understand that the reason is the number of autism-related genes the child has received from the two parents. As you might expect, genes that have been identified contribute to neuron

development and migration, synapse formation, and neurotransmitter activity (Freitag et al., 2010; Sutcliffe, 2008). Also as you would expect, identifying these genes has been difficult. So-called common variants—genes that occur in 5% or more of the population—have weak effects individually, requiring multiple “hits” to have an effect (Anney et al., 2012). Small effect is not the only reason identifying autism genes is difficult; often de novo mutations, which are not shared with either parent, produce cases of sporadic autism (Sanders et al., 2012). We get additional clues from studies of which genes are expressed in the autistic

brain and where. Irene Voineagu and her colleagues (2011) found 500 genes that were expressed at different levels in the frontal and temporal cortices of healthy brains, but these differences were virtually nonexistent in the brains of individuals with ASD. ASD genes are particularly expressed in superficial layers of the cortex, where they interfere with the development of connections between the layers and between the hemispheres (Parikshak et al., 2013). As you have seen before, environmental influences almost certainly exert their effect through epigenetic modification of gene expression; this fact offers a glimmer of hope in that drugs designed to reverse those modifications might be used as a treatment for autism (Siniscalco, Cirillo, Bradstreet, & Antonucci, 2013). An important factor in understanding genetic influence in autism and other

disorders is that some genes exert control over many additional genes. RORA1, a protein under the control of the RORA gene, targets more than 2,500 other genes; some of these are involved in neuron and synapse development and synaptic transmission, and at least six have been associated with ASD (Sarachana & Hu, 2013). RORA is upregulated by estrogen but downregulated by testosterone, which may contribute to the gender difference in autism. Attention-Deficit/Hyperactivity Disorder Attention-deficit/hyperactivity disorder (ADHD) develops during childhood and is

characterized by impulsiveness, inability to sustain attention, learning difficulty, and hyperactivity. Behaviorally, what we see is fidgeting and inability to sit still, difficulty organizing tasks, distractibility, forgetfulness, blurting out answers in class, and risk taking (Smalley, 1997). Diagnosticians recognize three types of ADHD; combined

inattention and hyperactivity-impulsiveness is most common, but some individuals are predominantly inattentive or predominantly hyperactive-impulsive. Although ADHD is often thought of as a learning disorder (and many ADHD children do have at least one learning disability), its effects are felt in every aspect of a person’s life. Also, ADHD is typically considered a childhood disorder, but it often persists into adulthood. ADHD is the most common childhood-onset behavioral disorder. Boys are more

than twice as likely to be diagnosed as girls, with rates of 13.2% and 5.6%, respectively. The percentage of children diagnosed with ADHD in the United States was 11% in 2011, up 41% since 2003 (Visser et al., 2014). Prescriptions for ADHD drugs increased 46% during that time (Chai et al., 2012), and in Denmark they went up a whopping 630% (Dalsgaard, Nielsen, & Simonsen, 2013). With 69% of diagnosed children taking medication (Visser et al.), some observers have raised concerns that children are being overdiagnosed and overmedicated as an easy solution to classroom behavioral problems. An objective test would be ideal, and this dream may or may not have been realized, as In the News explains. Though typically considered to be a childhood disorder, between one third and two

thirds of children with ADHD continue to show significant symptoms into adulthood (Wender, Wolf, & Wasserstein, 2001). Besides having the expected difficulties with life and work, these individuals have greatly increased rates of antisocial personality disorder, criminal behavior, and drug abuse (Biederman, 2004); in fact, 35% of people seeking treatment for cocaine abuse have a history of childhood ADHD (F. R. Levin et al., 1998). The link with drug abuse fostered concerns that treating children with stimulant drugs such as methylphenidate (Ritalin) and amphetamine was leading to addiction later in life. However, research that followed children with ADHD into adolescence and adulthood revealed that, at worst, stimulant treatment made no difference (Barkley, Fischer, Smallish, & Fletcher, 2003) and that it might even be protective against drug abuse (Figure 13.20; Wilens, Faraone, Biederman, & Gunawardene, 2003). The more positive outcome for the treated individuals could have been due to the reduction of symptoms, or it could have been the result of other factors, such as the support of parents who opted for treatment, but at least these results do not support fears that the medications act as gateway drugs.

Testing for ADHD

ADHD is diagnosed based on parent and teacher reports of the child’s behavior, along with behavioral observation by a clinician. However, these methods are not objective, leading to arguments about whether ADHD is over- or underdiagnosed. To address this concern about lack of objectivity, the Food and Drug Administration (FDA) has recently approved a new device that may help clinicians make an accurate and objective diagnosis. The Neuropsychiatric EEG-Based Assessment Aid (NEBA)

uses EEG recording to detect beta and theta frequency brain waves; the faster beta waves are seen when an individual is working on a task, and theta is associated with an inattentive, dreamy state. Studies have shown that children and adolescents with ADHD have decreased beta and increased theta. In the study that won final FDA approval, clinicians agreed on diagnoses 61% of the time, but agreement rose to 88% when information about the ratio of theta to beta EEG was included. However, one expert pointed out that the FDA has approved other objective tests

for ADHD before, but they have not become part of the standard diagnostic process. Whether the new procedure will prove sufficiently accurate in practice and gain the acceptance of parents, educators, and diagnosticians remains to be seen.

8 ADHD News and Facts

FIGURE 13.20 Relative Odds of Avoiding Substance Abuse Disorder in Individuals Receiving Stimulant Treatment for ADHD as Children, Compared With Those Not Receiving Stimulant Treatment. Individuals with ADHD who were treated with a stimulant drug as children were as much as 4.6 times as likely to be free of alcohol abuse disorder as individuals who did not receive stimulant treatment and up to 8.1 times as likely to be free of a drug abuse disorder. Values below 1 indicate that treated individuals in that study were at greater risk.

SOURCE: Based on data from Wilens et al. (2003). Neurotransmitter Anomalies in ADHD For the past 45 years, ADHD has been treated mostly with the stimulant drugs

methylphenidate and amphetamines. These drugs increase dopamine and norepinephrine activity by blocking reuptake at the synapse, so both of these transmitters have been implicated. However, most research links ADHD to reduced activity in dopamine pathways. One area with reduced activity is the prefrontal cortex (Ernst et al., 1998), and another is the striatum (K.-H. Krause, Dresel, Krause, King, & Tatsch, 2000). Functions of these structures include executive control, impulse inhibition, working memory, movement, learning, and reward; it is easy to see how their malfunction could contribute to ADHD symptoms. The significance of reward may be less immediately obvious, but several researchers believe that impaired reward contributes to impulsiveness because the allure of later rewards is too weak to overcome the temptation of immediate gratification (Castellanos & Tannock, 2002; Tripp & Wickens, 2009). Reduced brain activity and reward effects may both be due to the increased dopamine transporters found in the striatum of ADHD patients prior to drug treatment (Krause et al.). A second scan after 4 weeks of treatment with methylphenidate showed that transporter activity had decreased 29%. However, some 20% to 30% of patients do not respond to the traditional medications or cannot tolerate them (Biederman & Faraone, 2005). Two drugs sometimes used in their place, modafinil and atomoxetine, block norepinephrine reuptake, suggesting that transmitter’s role in ADHD. FIGURE 13.21 The ADHD Brain. (a) The colors indicate the relative amount of volume reduction compared with controls, with red the most, followed by yellow and green. (b) Yellow and red indicate 20% to 30% greater gray matter density compared with controls.

SOURCE: From “Cortical Abnormalities in Children and Adolescents With Attention-Deficit Hyperactivity Disorder,” by E. R. Sowell et al., Lancet, 362, figs. 2 & 3, pp. 1702–1703. © 2003 Elsevier Ltd. Brain Anomalies in ADHD Studies of ADHD patients have implicated several areas of the brain, from the

prefrontal cortex to the cerebellum (Castellanos et al., 2002; Raz, 2004), but the results have not always been in agreement. A review that combined the data from 21 studies concluded that children with ADHD have reduced volume in the cerebral hemispheres, especially the right; in the right caudate nucleus (a part of the striatum); and in parts of the cerebellum (Valera, Faraone, Murray, & Seidman, 2007). Elizabeth Sowell and her colleagues (2003) reported that the prefrontal and temporal areas are reduced in volume; they also interpreted a relative increase in gray matter in the temporal and inferior parietal areas as evidence of a reduction in white matter connections (Figure 13.21). The researchers suggested the disruption of an attention- inhibition network in that area, and Castellanos and his colleagues (2008) echoed that view after finding decreased connectivity in the default mode network. The idea is also supported by a study that required subjects to withhold a trained response on

some trials, a task that is difficult for ADHD patients (Durston et al., 2003). On these “no-go” trials, control children activated a discrete network of structures, including prefrontal, striatal, and parietal areas, whereas ADHD children inefficiently activated a much broader area that encompassed much of the brain. Heredity and ADHD To say that ADHD runs in families would be an understatement: It is five to six

times more frequent among patients’ relatives than in the rest of the population; concordances are estimated at 79% for identical twins versus 32% for fraternals, and heritability averages 75% across studies (Biederman & Faraone, 2005; Castellanos & Tannock, 2002; Smalley, 1997). Like autism, ADHD is a complex, multisymptom disorder, and different individuals display different combinations of those symptoms. So, again, we would expect involvement of several genes, each with only a small effect and difficult to identify. That has been the case. The most frequently investigated genes are involved in the dopamine, norepinephrine, and serotonin transmission systems (Banachewski, Becker, Scherag, Franke, & Coghill, 2010). In addition, whole-genome studies have implicated genes involved in cell migration, synaptic excitability, and neuronal plasticity. The picture is complicated by gene interactions; for example, researchers found that the gene LPHN3 on chromosome 4 interacts with genes on chromosome 11 to double the risk of ADHD (Jain et al., 2012). Previous research by the team had shown that LPHN3 affects brain metabolism and predicts how well the patient will respond to stimulant medications. One study found 222 copy number variations (CNVs) in ADHD patients that were not found in control subjects (Elia et al., 2010). These CNVs were located in or near genes involved in synaptic transmission, neural development, and learning and other psychological functions. A number of the CNVs are in chromosomal locations that have been identified in autism and schizophrenia (Williams et al., 2010); participation of a gene in more than one disorder should not be surprising, since different disorders share some symptoms. And remember that we are not talking about a gene for autism or a gene for ADHD or a gene for schizophrenia, but genes that regulate brain growth, receptor development, and so on. The Environment and ADHD What appears to be an environmental cause of ADHD often turns out to be an

indication of a genetic predisposition in the parents. This includes correlations of ADHD with maternal smoking and stress during pregnancy (A. Rodriguez & Bohlin, 2005); parental abuse of alcohol, stimulants, and cocaine; and parental mood and anxiety disorders (Chronis et al., 2003). Confirmed environmental influences include brain injury, stroke, and pregnancy and birth complications (Biederman & Faraone, 2005; Castellanos & Tannock, 2002), along with some toxins. Lead, for example, is a known neurotoxin; although eliminating lead in gasoline and paint has reduced levels in the environment, it is still found in children’s costume jewelry and imported

Concept Check

candies as well as in the soil and water. A recent study confirmed higher blood levels of lead in children diagnosed with ADHD, and lead levels were correlated with teacher and parent ratings of symptoms (Nigg, Nikolas, Knottnerus, Cavanagh, & Friderici, 2010). As with autism, another culprit is organophosphate pesticides; children with above

average urinary levels of a metabolite of these pesticides are twice as likely to be diagnosed with ADHD compared with children with undetectable levels (M. F. Bouchard, Bellinger, Wright, & Weisskopf, 2010). Even chemicals found in cosmetics, perfumes, and shampoo are turning out to be a problem; mothers who had higher levels of phthalates in their urine during the third trimester of pregnancy reported that their children had significantly more trouble with attention, aggression, and depression (Engel et al., 2010). How phthalates cause this result is unknown, but they may disrupt thyroid hormones that are important during brain development.

Take a Minute to Check Your Knowledge and Understanding

Make a list of the kinds of intellectual disability described and their causes. What neural and biochemical differences have been found in autistic brains?

In Perspective As important as the assessment of intelligence is in our society for determining our placement in school, our opportunity for continued education, and our employability and promotability, it is remarkable that there is still so much disagreement about what intelligence is. This lack of agreement makes it more difficult to study the brain functions that make up intelligence. Nevertheless, we have identified several features that appear to contribute to greater mental power; brain size, neural conduction speed, processing efficiency, and short-term memory are among these. Although it would be an error to overlocalize any function in the brain, we also know that some areas have a special role in important cognitive functions related to intelligence. It remains to be seen whether any particular characteristic of these areas, such as size, explains why some people have a particularly strong talent in one area, such as creative writing or mathematics. Some hope that we will eventually have objective brain measures that will tell us exactly how intelligent a person is or whether a child is autistic. When we reach that point, perhaps another dream will be realized: the ability to

diminish or even reverse some of the defects that rob the intellectually disabled, the autistic, and the aged of their capabilities. We may even be able to increase the intelligence of normal individuals. We can only hope that our capacity to make the ethical decisions required keeps pace with our ability to manipulate the human

condition. Summary The Nature of Intelligence • Intelligence is usually assessed with tests designed to measure academic ability. • Some people show strong abilities not tapped by these tests; our understanding of intelligence should be broader than what tests measure.

• Intelligence theorists are divided over their emphasis on a general factor or multiple components of intelligence.

The Biological Origins of Intelligence • Probable contributors to general intelligence are brain size, neural conduction speed, processing speed, quality of neural connections, and processing efficiency.

• The involvement of different brain areas suggests multiple components of intelligence.

• About half of the variation in intelligence among people is due to heredity. The closer the family relationship, the more correlated are the IQs. Apparently, many genes are involved; there are several leads to specific genes, but little certainty.

• Research has not supported a genetic basis for ethnic differences in intelligence. Adoption has resulted in dramatic increases in IQ above the ethnic group mean.

• Although half of the variation in intelligence is due to environment, demonstrating which environmental conditions are important has been difficult. Judging by experience with Head Start and similar programs, any particular influence must be early and intense. Adoption can have dramatic effects if the difference in environments is large.

Deficiencies and Disorders of Intelligence • Loss of intellectual functioning with age is less than previously believed and, like decreases in learning ability, it is not inevitable. Diminished speed of processing appears to be most important.

• Intellectual disability has many causes, including disease, fetal alcohol syndrome, Down syndrome, fragile X syndrome, phenylketonuria, and hydrocephalus.

• Down syndrome, caused by a third 21st chromosome, produces mild to moderate intellectual disability.

• Intellectual disability due to phenylketonuria, the inability to metabolize phenylalanine, is severe to profound.

• Hydrocephalus can usually be treated to avoid serious impairment, but there are hydrocephalic individuals with no apparent deficiencies.

• ASD is partially hereditary, with several gene locations implicated. • ASD involves abnormalities in several brain areas and possible weak connections among them. Agents like thalidomide can damage the brain and result in autism, but damage is more often developmental in origin.

• ASD may also involve anomalies in serotonin, glutamate, GABA, and oxytocin

functioning. • ADHD is a partially genetic disorder characterized by hyperactivity, impulsiveness, and impaired attention and learning. It is associated with a variety of anomalies in functioning and in dopamine, serotonin, and possibly norepinephrine transmission. Several gene locations have been implicated.

• A variety of environmental influences have been associated with autism and ADHD. These may cause brain damage, affect gene functioning, or simply contribute along with genes. Childhood vaccines and a preservative previously used in them apparently are not at fault. ■

Study Resources

For Further Thought • Environmental influences on intelligence have been hard to identify. Does this mean that we are stuck with our genetic destiny?

• Intelligence is subject to physical disorders and genetic and environmental deviations. Speculate about why intelligence is so vulnerable.

• As you look at autism and ADHD, you see several similarities in the causes. Why, for example, do you think one child exposed to organophosphate pesticides would develop ASD and another would be diagnosed with ADHD?

Quiz: Testing Your Understanding 1. Describe the uncertainties about the measurement of intelligence and how

this affects the search for biological bases of intelligence. 2. Discuss the brain characteristics that appear to contribute to general

intelligence. 3. Discuss what we know about brain and biochemical differences in autistic

individuals. Select the best answer: 1. A problem with most intelligence tests is that they

a. are not based on theory. b. are each based on a different theory. c. assess a limited group of abilities. d. try to cover too many abilities in one test.

2. Lumpers and splitters disagree on the significance of _____ in intelligence. a. heredity b. environment c. the g factor d. early education

3. It is likely that _____ is/are important to general intelligence. a. size of neurons b. processing speed

c. processing efficiency d. a, b, and c e. b and c

4. Research with adults, children, chimpanzees, and monkeys suggests that we are born with a. a mechanism for number or quantity. b. the ability to do the same things as savants. c. many times more intellectual capacity than we use. d. time-limited abilities that inevitably deteriorate with age.

5. Research suggests that, normally, environmental effect on intelligence a. is almost nonexistent. b. is significant, but difficult to identify. c. is less important than the effect of heredity. d. is more important than the effect of heredity.

6. Some claim the high correlation between identical twins’ IQs occurs because they evoke similar treatment from people. This was refuted by a study in which the correlation a. held up when the twins were reared separately. b. was unaffected by parents’ misidentification of twins as fraternal or

identical. c. was just as high in mixed-sex as in same-sex identical pairs. d. increased as the twins grew older, though they lived apart.

7. The best evidence that ethnic differences in intelligence are not genetic is that a. the various groups perform the same on culture-free tests. b. no well-done research has shown an IQ difference. c. no genes for an ethnic difference in intelligence have been found. d. adoption into a more stimulating environment reduces the difference.

8. Apparently, the most critical effect on intelligence during aging is loss of a. speed. b. motivation. c. neurons. d. synapses.

9. Sam has dramatically reduced brain tissue and enlarged ventricles, but his IQ is 105; his disorder is most likely a. hydrocephalus. b. phenylketonuria. c. Down syndrome. d. autism.

10. Most mild intellectual disability is believed to be caused by

a. an impoverished environment. b. brain damage sustained during birth. c. a combination of a large number of genes. d. a combination of environmental and hereditary causes.

11. Research with autism spectrum disorders suggests that autism involves a. a single gene. b. several genes. c. heredity alone. d. primarily environment.

12. Impaired sociability in autistic individuals may involve low levels of a. risperidone. b. serotonin. c. thalidomide. d. oxytocin.

13. ADHD is associated with reduced or impaired a. gray matter. b. intelligence. c. dopamine activity. d. theory of mind.

Answers: 1. c, 2. c, 3. e, 4. a, 5. b, 6. b, 7. d, 8. a, 9. a, 10. d, 11. b, 12. d, 13. c.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. Stephen Hawking’s website features a brief biography, information about his

professional accomplishments, and downloadable copies of public lectures. 2. At Not Exactly Rocket Science you can read about tool use in chimpanzees

and see a video of chimps making and using fishing sticks. Nature’s Tools: How Birds Use Them is an excerpt from a BBC wildlife film that shows a New Caledonia crow fishing for grubs. Also, you can see Figaro, the

cockatoo mentioned in the Application, demonstrating his inventiveness. 3. The Bell Curve Flattened, an article in the online magazine Slate, refutes

ideas about genetic racial differences in intelligence that were presented in the controversial book The Bell Curve.

4. You can get information about various kinds of intellectual disability from the The Arc, the American Association on Intellectual and Developmental Disabilities, the National Fragile X Foundation, and the National Library of Medicine’s Williams Syndrome page.

5. Sources of information on autism and autism spectrum disorders include the National Institute of Mental Health’s website Autism Spectrum Disorders, Internet Mental Health’s Autism Spectrum Disorder site, and the Autism Research Institute’s section on Treating Autism (see menu item). Mapping Connectivity has information about connectivity mapping in autism, with photos illustrating seven methods used.

6. The Wisconsin Medical Society’s Savant Syndrome 2013—Myths and Realities may dispel some of your notions about savantism and even about intelligence. Then, two videos of Kim Peek are guaranteed to impress you.

7. Temple Grandin’s Web Page features her professional work along with a brief description of her.

8. The Attention Deficit Disorder Association has high-quality articles on ADHD, and the National Institute of Mental Health explores a number of topics at its Attention Deficit Hyperactivity Disorder site. The news articles about the newly approved ADHD testing device are available from Health Day and the U.S. Food and Drug Administration.

Chapter Updates and Biopsychology News

For Further Reading 1. Possessing Genius: The Bizarre Odyssey of Einstein’s Brain, by Carolyn

Abraham (St. Martin’s, 2001), tells the story of the study of Einstein’s brain and the controversy about how it came to be removed in the first place and about its caretaker, Thomas Harvey (coauthor of all the Einstein brain studies cited here).

2. Frames of Mind, by Ulric Neisser (Basic Books, 1983), is a collection of articles on the knowns and unknowns of intelligence.

3. “Representation of Number in the Brain,” by Andreas Nieder and Stanislas Dehaene (Annual Review of Neuroscience, 2009, 32, 185–208), reviews research on the basis of number understanding in children, adults, and nonhuman primates.

4. Thinking in Pictures: My Life With Autism, by Temple Grandin (Vintage, 2010), is a perspective from the point of view of an autistic and a scientist.

Born on a Blue Day: Inside the Extraordinary Mind of an Autistic Savant, by Daniel Tammet (Free Press, 2006), chronicles his life, while his Embracing the Wide Sky: A Tour Across the Horizons of the Mind (Free Press, 2009) adds relevant scientific information.

Key Terms attention-deficit/hyperactivity disorder (ADHD) autism spectrum disorder autistic savant default mode network Down syndrome fragile X syndrome intellectual disability intelligence intelligence quotient (IQ) phenylketonuria theory of mind

14 Psychological Disorders

In this chapter you will learn • The characteristics and probable causes of schizophrenia • How heredity and environment interact to produce disorders • What the affective disorders are and their causes • The symptoms and causes of the anxiety disorders

Schizophrenia Characteristics of the Disorder Heredity Two Kinds of Schizophrenia The Dopamine Hypothesis Beyond the Dopamine Hypothesis Brain Anomalies in Schizophrenia CONCEPT CHECK

Affective Disorders Heredity The Monoamine Hypothesis of Depression Electroconvulsive Therapy Antidepressants, ECT, and Neural Plasticity APPLICATION: ELECTRICAL STIMULATION FOR DEPRESSION

Rhythms and Affective Disorders Bipolar Disorder Brain Anomalies in Affective Disorders Suicide CONCEPT CHECK

Anxiety Disorders Generalized Anxiety, Panic Disorder, and Phobia Posttraumatic Stress Disorder IN THE NEWS: VIRTUAL REALITY ISN’T JUST FOR VIDEO GAMES

Anomalies in Brain Functioning CONCEPT CHECK

Obsessive-Compulsive Disorder Brain Anomalies in Obsessive-Compulsive Disorder

I

Treating Obsessive-Compulsive Disorder Related Disorders APPLICATION: OF HERMITS AND HOARDERS CONCEPT CHECK

In Perspective Summary Study Resources

stood by my chair and waited for the students to take their places around the table, eagerly tying up the loose ends of conversations that the trek across campus hadn’t given them time to finish. As the bell in the East College tower tolled the start of the

hour and I was about to call the class to order, Ned got up from his seat and approached me. “

Canst thou not minister to a mind diseas’d Pluck from the memory a rooted sorrow Raze out the written troubles of the brain

—Shakespeare, Macbeth

” “I forgot to give the bookstore cashier her pen after I used it to write a check. Can I

take it back?” “I think she can wait until class is over,” I answered. He accepted that judgment

and returned to his seat, but he seemed restless for the remainder of the hour. As soon as class was over, he was one of the first out of the door. I couldn’t help smiling at his youthful impetuousness. The next day I understood that Ned’s behavior had a completely different origin.

Around 10 o’clock the night before, his dorm mates found him huddled on the stair landing, fending off an imaginary alien spaceship circling over his head and firing projectiles at him. He was taken to the hospital and sedated; then his parents took him back to his hometown, where he spent several months in a hospital psychiatric ward. He was diagnosed with paranoid schizophrenia. Fortunately, medication helped, and he was able to move to a home school with a comprehensive program of support and rehabilitation. Ned has now spent two thirds of his life at the home. A dozen years ago, he wrote

to me, and we have kept up a regular correspondence since; I think his primary motivation is that he remembers his brief time in college as the happiest in his life. It is not that the home is unpleasant. He is on the baseball, basketball, and golf teams; he works part time outside the home; and he has a girlfriend. Questions he asks in his letters reveal a healthy curiosity, usually provoked by something he has read or seen

on television about the brain. Once he talked candidly about his diagnosis, and about how he prefers to believe that someone slipped him a dose of LSD on that fateful night. There is no evidence that happened, but even if it did, it only precipitated, rather than caused, the decades-long debilitation that followed. In spite of his apparent good adjustment—and I see only the face that he wants to put on his situation—the preadolescent intellectual maturity of his letters and the barely legible scrawl of his handwriting suggest the havoc that schizophrenia has wreaked in his brain. Ned is unable to function outside the home’s protective environment and professional support, and he will never be able to leave. FIGURE 14.1 Psychological Disorders Impair a Person’s Ability to Cope.

SOURCE: © Sheryl Griffin/iStockphoto.com. Researchers estimate that one out of every four adults in the United States suffers

from a diagnosable mental illness, and that 46% will fall victim during their lifetime (Kessler, Berglund, et al., 2005). We aren’t really sure how many people are mentally ill, because researchers rely primarily on self-reports. When people were interviewed four times over a period of 25 years, they reported mental illnesses 2 to 12 times more often than they recalled them during the final interview (Takayanagi et al., 2014). The monetary cost in terms of treatment, benefits, and lost wages amounts to $317 billion a year in the United States (Reeves et al., 2011) and $2.5 trillion globally (Bloom et al., 2011). According to the World Health Organization (2008), mental disorders are

the leading cause of disability among people aged 15 to 44 in the United States and Canada (Figure 14.1). An obvious benefit of research is the development of improved therapeutic techniques; in addition, because the disorders involve malfunctions in neurotransmitter systems and brain structures, studying them helps researchers understand normal neural functioning as well. In this chapter we will make good use of what you have already learned about brain structure and neurotransmitter activity as we examine schizophrenia, mood disorders, and anxiety disorders, and in turn this survey will further expand your knowledge of how the brain works. Schizophrenia Schizophrenia is a disabling disorder characterized by perceptual, emotional, and intellectual deficits; loss of contact with reality; and inability to function in life. It is estimated that about 3 million Americans will develop schizophrenia during their lifetimes and that around 100,000 hospitalized patients take up 20% of the psychiatric beds in U.S. hospitals, with many more receiving outpatient care (National Institute of Mental Health, 1986; G. W. Roberts, 1990). Schizophrenia is a psychosis, which simply means that the individual has severe disturbances of reality, orientation, and thinking. Schizophrenia is the most severe of the mental illnesses, and it is particularly feared because of the bizarre behavior it produces in many of its victims. All social classes are equally vulnerable; though patients themselves “drift” to lower socioeconomic levels, when they are classified by their parents’ socioeconomic level, the classes are proportionately represented (Huber, Gross, Schüttler, & Linz, 1980). Although schizophrenia afflicts only 1% of the population (Kessler et al., 1994), its economic burden amounts to $39 billion annually in the United States, almost half the cost of all the disorders combined (Uhl & Grow, 2004). Fortunately, schizophrenia is one of the few psychological disorders that appear to be on the decline. Smaller numbers have been thought to be due to methodological flaws in studies, but a study of all people born in Finland between 1954 and 1965 found a significant decline in each successive age-group, totaling 29% for women and 33% for men (Suvisaari, Haukka, Tanskanen, & Lönnqvist, 1999).

What is schizophrenia, and what causes it?

1 Schizophrenia Characteristics of the Disorder The term schizophrenia was coined in 1911 by the Swiss psychiatrist Eugen Bleuler

(Figure 14.2) from the combination of two Greek words meaning “split mind.” Contrary to popular belief, schizophrenia has nothing to do with multiple personality; the term refers to the distortion of thought and emotion, which are “split off” from reality. The schizophrenic has some combination of several symptoms: hallucinations (internally generated perceptual experiences, such as voices telling the person what to

do); delusions (false, unfounded beliefs, such as that one is a messenger from God); paranoia, characterized by delusions of persecution; disordered thought; inappropriate emotions or lack of emotion; and social withdrawal. Note that Ned had a hallucination of a spaceship, the paranoid delusion that it was attacking him, and a possible delusion about the LSD. FIGURE 14.2 Eugen Bleuler (1857–1939). A pioneer in the field, he introduced the term schizophrenia.

SOURCE: © Bettmann/Corbis. In the past, people with schizophrenia were subdivided into diagnostic categories

based on which of these symptoms was predominant, such as paranoid or catatonic. However, patients often have overlapping symptoms and can receive multiple diagnoses, so there is little belief that these categories represent distinct disease processes. Also, as neuroscience progresses, we are realizing that two people can have the same symptom with different causes or the same brain defect with different symptoms. As a result, the National Institute of Mental Health is encouraging researchers to shift their focus from diagnostic categories to underlying neural and genetic mechanisms (Miller, 2010). As a first step in that direction, the revised Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) has eliminated these subgroups of schizophrenia as diagnostic categories. “

I’m a paranoid schizophrenic and for us life is a living hell.... Society is out to kill

me.... I tried to kill my father. I went insane and thought he ruled the world before me and caused World War Two.

—Ross David Burke in When the Music’s Over: My Journey Into Schizophrenia

” Schizophrenia afflicts men and women about equally often. Men usually show the

first symptoms during their teens or twenties, as Ned did, while the onset for women ordinarily comes about a decade later (see Figure 14.3). Acute symptoms develop suddenly and are typically more responsive to treatment; the prognosis is reasonably good in spite of brief relapses. Symptoms that develop gradually and persist for a long time with poor prognosis are called chronic. Movies have overplayed the bizarre features of schizophrenia; many patients are able to function reasonably well, especially if they are fortunate enough to be among those who respond to antipsychotic drugs. Among patients studied 20 years after their first admission, 22% were fully recovered, another 43% were improved, and the symptoms of the remaining 35% had remained the same or worsened; 56% were fully employed (Huber et al., 1980). FIGURE 14.3 Risk for Schizophrenia by Age.

SOURCE: Data from Huber et al. (1980). Doctors began to view mental illness as a medical problem in the late 1700s and

early 1800s; at that time the mentally ill were literally released from their chains and given treatment (Figure 14.4; Andreasen, 1984). By the early 20th century, it was widely assumed that schizophrenia had a physical basis. However, the search for biological causes produced little success. In the 1940s, the emphasis shifted to social causes of schizophrenia, especially in America, where Freud’s theory of psychoanalysis was in its ascendancy and biologically oriented psychiatrists were in the minority (Andreasen, 1984; Wender, Rosenthal, Kety, Schulsinger, & Welner, 1974). Until the 1960s, research techniques were not up to the task of demonstrating the validity of the physiological position. It was then that increasing knowledge of neurotransmitters, the advent of brain scanning techniques, and improved genetic studies shifted the explanation for schizophrenia back to the realm of biology and changed the perception of mental illness in general.

FIGURE 14.4 Philippe Pinel Freeing Mental Patients From Their Chains. Patients were warehoused without treatment; sometimes care consisted of throwing in fresh straw and food once a week. Pinel was convinced that they would benefit from humane treatment and in 1794 freed the mental patients of Paris from their chains. SOURCE: © Rapho Agence/Photo Researchers.

FIGURE 14.5 Concordances for Schizophrenia Among Relatives. SOURCE: From Introduction to Psychology, Gateways to Mind and Behavior (with InfoTrac), 9th edition by Coon, 2001. Reprinted with permission of Wadsworth, a division of Thomson Learning.

Heredity Schizophrenia is a familial disorder, which means that the incidence of

schizophrenia is higher among the relatives of people with schizophrenia than it is in the general population (Gottesman, McGuffin, & Farmer, 1987; Tsuang et al., 1991). Of course, this association could be due to environmental influence or to heredity; in fact, in the 1940s the genetic school and the environmental school argued for their positions from the same data (Wender et al., 1974). However, studies of twins and adoptees provided compelling evidence for a genetic influence. Twin and Adoption Studies In Figure 14.5, you can see that the shared incidence of schizophrenia increases

with the genetic closeness of the relationship and that the concordance rate for schizophrenia is three times as high in identical twins as in fraternal twins (Lenzenweger & Gottesman, 1994). In other words, identical twins of people with schizophrenia are three times as likely to be schizophrenic as the fraternal twins of patients. The heritability for schizophrenia has been estimated at between.60 and.90 (Tsuang et al., 1991). This means that 10% to 40% of the variability is due to environmental factors. Information from adoption studies gives a more impressive indication of genetic

influence; these studies show that adopting out of a schizophrenic home provides little or no protection from schizophrenia. The incidence of schizophrenia and schizophrenia-like symptoms was 28% among individuals adopted out of Danish homes in which there was one schizophrenic parent, compared with 10% in matched adoptees from presumably normal homes (Lowing, Mirsky, & Pereira, 1983). Other studies have produced similar findings. Discordance among identical twins has been used as an argument that

schizophrenia is environmentally produced. To address this issue, Gottesman and Bertelsen (1989) compared the incidence of schizophrenia in the offspring of affected and normal identical twins; they found that the offspring of the unaffected identical twins were just as likely to be schizophrenic as the offspring of the affected twins (Figure 14.6). This result would not have occurred unless the normal twins were carrying genes for schizophrenia. Discordance does raise the question, however, of whether some environmental factors determine whether the person’s schizophrenic genes will remain “silent.” FIGURE 14.6 Risk of Schizophrenia in the Offspring of Normal and Schizophrenic Twins. Offspring of the normal fraternal twin of a schizophrenic do not have an elevated risk. The offspring of the normal identical twin of a schizophrenic are as likely to become schizophrenic as the offspring of the schizophrenic identical twin.

SOURCE: Based on data from Gottesman and Bertelsen (1989). The Search for the Schizophrenia Genes Although we have known for a long time that schizophrenia is partially genetic,

identifying the genes involved has been difficult. One reason has been researchers’ inconsistency in including the spectrum disorders in their diagnosis of schizophrenia (Heston, 1970; Lowing et al., 1983). When identical twins are discordant for schizophrenia, 54% of the nonschizophrenic twins have spectrum disorders (Heston, 1970). If the spectrum disorders are due to the same genes, classifying these individuals as nonschizophrenic means that the genes will not appear to distinguish between schizophrenia and normality. A second problem is that schizophrenia apparently involves the cumulative effects of multiple genes, each of which has a small effect by itself. Evidence indicates that the number of variants contributing to schizophrenia is in the thousands (Wray & Visscher, 2010). A person’s risk of schizophrenia presumably increases with the number of these genes inherited. This view is supported by the fact that risk has been found to increase with the number of relatives who are schizophrenic and with the degree of the relatives’ disability (Heston, 1970; Kendler & Robinette, 1983). Recent genome-wide studies have identified more than 70 genes suspected of a role

in producing schizophrenia (Hosak, 2013). These genes are typically related to neurodevelopment and plasticity, immune response, and hormonal activity. Although these genes are relatively common, they have small effects and together may account for less than 5% of the variability in susceptibility. Copy number variations (CNVs) have much larger effects; for example, a deletion on chromosome 22 produces a 20- fold increase in risk. But CNVs are individually rare and make an even smaller contribution than common genes. The large majority of CNVs are inherited, but de novo mutations are more often implicated in diseases. Along with epigenetic modifications, they help account for discordance in identical twins, who otherwise have identical genomes. Epigenetic studies of schizophrenia are in their infancy; though they have produced interesting results, our knowledge is based on small

numbers of subjects and tissues taken from widely varying brain locations. According to one group of reviewers, some of the current results may be harder to interpret than early small-sample gene association studies (Dempster, Viana, Pidsley, & Mill, 2013). Schizophrenia is a very old disease (see Ray, 2014, for a review). Disorders with

psychotic-like symptoms have been reported for 4,000 years, and similar rates in disparate and long-separated societies suggest that the genes were present before humans left Africa some 100,000 years ago. So why wouldn’t genes as detrimental as those that produce schizophrenia be eliminated through evolution? One suggestion is that the genes that in combination can produce schizophrenia individually confer an evolutionary advantage. Ten or fifteen centuries ago, these individual genes might have helped individuals cope with the demands of burgeoning social culture. It has been pointed out that many gifted Nobel recipients, the likes of Albert Einstein, Bertrand Russell, and John Nash (featured in the film A Beautiful Mind), either had some schizophrenic traits or had relatives thought to have schizophrenia. The Vulnerability Model Most researchers agree that genes determine only the person’s vulnerability for the

illness; both heredity and environment are needed to explain the etiology (causes) of schizophrenia (Zubin & Spring, 1977) as well as most other disorders. According to the vulnerability model, some threshold of causal forces must be exceeded for the illness to occur; environmental challenges combine with a person’s genetic vulnerability to exceed that threshold. The environmental challenges may be external, such as bereavement, job difficulties, or divorce, or they may be internal, such as maturational changes, poor nutrition, infection, or toxic substances. There is mounting evidence that these environmental influences work in part by epigenetic means, that is, by upregulating and downregulating gene functioning (Tsankova, Renthal, Kumar, & Nestler, 2007). Vulnerability is viewed as a continuum, depending on the number of affected genes inherited. At one extreme, a small percentage of individuals will become schizophrenic under the normal physical and psychological stresses of life; at the other extreme are individuals who will not become schizophrenic under any circumstance or will do so only under the severest stress, such as the trauma of battle (Fowles, 1992).

Which type of symptoms did Ned have? Two Kinds of Schizophrenia Researchers disagree on whether schizophrenia represents one disease or many, but

most authorities do agree that the symptoms fall into two major categories: positive and negative. Positive symptoms involve the presence or exaggeration of behaviors, such as delusions, hallucinations, thought disorder, and bizarre behavior. Negative symptoms are characterized by the absence or insufficiency of normal behaviors and include lack of affect (emotion), inability to experience pleasure, lack of motivation,

poverty of speech, and impaired attention. TABLE 14.1 Positive Versus Negative Schizophrenia.

SOURCE: From “The Two-Syndrome Concept: Origins and Current Status,” T. J. Crow, 1985, Schizophrenia Bulletin, 11, pp. 471–486, with permission of Oxford University Press. Crow (1985) theorized that positive and negative symptoms are due to two different

syndromes of schizophrenia, with different causes and different outcomes. His Type I and Type II schizophrenias are described in Table 14.1. Research has supported this distinction in many respects. Positive symptoms are more often acute, and they are more likely to respond to antipsychotic drugs than are negative symptoms (Fowles, 1992). Negative symptoms tend to be chronic; these patients show poorer adjustment prior to the onset of the disease (Andreasen, Flaum, Swayze, Tyrrell, & Arndt, 1990); poorer prognosis after diagnosis (Dollfus et al., 1996); more intellectual and other cognitive deficits, suggestive of a brain disorder (Andreasen et al., 1990); and greater reduction in brain tissue (Fowles, 1992). These findings led researchers to think in terms of two more or less distinct groups of patients, a view we will modify shortly. The Dopamine Hypothesis Little could be done to treat psychotic patients until the mid-1950s, when a variety

of antipsychotic medications arrived on the scene. For the first time in history, the size of the hospitalized mental patient population went down. As is often the case in medicine, and more particularly in mental health, these new drugs had not been designed for this purpose—researchers had too little understanding of the disease to do so. Doctors tried chlorpromazine with a wide variety of mental illnesses because it calmed surgical patients, and it turned out to help those with schizophrenia as well. However, it was not clear why chlorpromazine worked, because tranquilizers have little or no usefulness in treating schizophrenia.

What neurotransmitters are involved in schizophrenia? “

What consoles me is that I am beginning to consider madness as an illness like any other, and that I accept it as such.

—Vincent van Gogh, 1889, in a letter to his brother, Theo

”

So investigators tried reverse engineering. You will remember from Chapter 5 that amphetamine overdose causes psychotic behavior indistinguishable from schizophrenia, complete with hallucinations and paranoid delusions. In time, researchers were able to determine that amphetamine produces these symptoms by increasing dopaminergic activity. This discovery eventually led to the dopamine hypothesis, that schizophrenia involves excessive dopamine activity in the brain. According to the theory, blockade of the D2 type of dopamine receptors is essential for a drug to have an antipsychotic effect, and effectiveness is directly related to the drug’s blocking potency. The theory has had considerable support; schizophrenic patients typically have higher dopamine activity in the striatum (Abi-Dargham et al., 2000), and drugs that block dopamine receptors are effective in treating the positive symptoms of schizophrenia (S. H. Snyder, Bannerjee, Yamamura, & Greenberg, 1974). In fact, the effective dosage for most antipsychotic drugs is directly proportional to their ability to block dopamine receptors (Figure 14.7; Seeman, Lee, Chau-Wong, & Wong, 1976). Beyond the Dopamine Hypothesis However, 30% to 40% of schizophrenic patients were not helped by the drugs, and

—troublesome for the dopamine theory—nonresponsive patients experienced just as much D2 receptor blockade as responders. In fact, in some of them, blockade exceeded 90%, while some responders showed remarkably low levels of receptor blocking (Kane, 1987; Pilowsky et al., 1993). Furthermore, some patients appear to have a dopamine deficiency, especially those with chronic, treatment-resistant symptoms (Grace, 1991; Heritch, 1990; Okubo et al., 1997). Another problem for the drugs was that the side effects could be intolerable.

Prolonged use of antidopamine drugs often produces tardive dyskinesia, tremors and involuntary movements caused by blocking of dopamine receptors in the basal ganglia. Seventy years ago, this effect was believed to be so inevitably linked to the therapeutic benefit that the “right” dose was the one that caused some degree of motor side effects. Thus, the drugs used to treat schizophrenia became known as neuroleptics, because the term means “to take control of the neuron” (Julien, 2008). The effect appears to be due to a compensatory increase in the sensitivity of D2 receptors in the basal ganglia. (This is a good illustration of the fact that drugs do not affect just the part of the brain we want to treat.) Since the early 1990s, we have seen the introduction of several new antipsychotic

drugs that are referred to as atypical or second-generation. One way atypical antipsychotics are different is that they target D2 receptors much less, so they produce motor problems only at much higher doses. Fortunately, avoiding motor side effects does not require a therapeutic compromise. The major atypical antipsychotics are at

least equivalent to the first-generation drugs, and some are 15% to 25% more effective; what is more, they often bring relief to patients who have been treatment resistant for years (Iqbal & van Praag, 1995; Leucht et al., 2009; Pickar, 1995; Siever et al., 1991). So, is the dopamine hypothesis just another example of a beautiful hypothesis slain by ugly facts? Not entirely; although atypical antipsychotics mostly target other receptors, those that lack at least a modest effect at D2 receptors are therapeutically ineffective (H. M. Jones & Pilowsky, 2002). So, successful therapy apparently requires D2 blockade and other effects. FIGURE 14.7 Relationship Between Receptor Blocking and Clinical Effectiveness of Schizophrenia Drugs. The horizontal axis is the average daily doses prescribed by physicians; the horizontal red lines represent typical ranges of doses used. Values on the vertical axis are amounts of the drugs required to block 50% of the dopamine receptors. SOURCE: Reprinted by permission from “Antipsychotic Drug Doses and Neuroleptic/Dopamine Receptors,” by P. Seeman et al., Nature, 261, p. 718, fig. 1. Copyright 1976 Macmillan Publishers, Ltd.

And what are these other effects? One involves serotonin. The serotonergic system is suspect largely because of the 5-HT2A receptor’s involvement in schizophrenic-like responses to hallucinogenic drugs, such as psilocybin and LSD. The number of 5- HT2A receptors is upregulated in the brains of deceased schizophrenic subjects (González-Maeso et al., 2008), and atypical antipsychotics block serotonin 5-HT2 receptors by as much as 90% (H. M. Jones & Pilowsky, 2002; Kapur, Zipursky, & Remington, 1999). But serotonin has not received nearly as much attention as

glutamate activity, which also is affected by atypical antipsychotics. The drug phencyclidine (PCP), which inhibits the NMDA (N-methyl-d-aspartic acid) subtype of glutamate receptor, mimics schizophrenia far better than amphetamine does, particularly in producing negative as well as positive symptoms (Sawa & Snyder, 2002). Glycine activates the NMDA receptor, and adding it or similar compounds to antipsychotic medications reduces both kinds of symptoms (Lisman et al., 2008). According to the glutamate theory, hypofunction of NMDA receptors results in increases in glutamate and downstream increases in dopamine, which together produce positive and negative symptoms of schizophrenia (Lisman et al.; Sendt, Giaroli, & Tracy, 2012). However, it has been difficult to develop drugs that target NMDA receptors or reduce glutamate levels, and that are both therapeutically effective and well tolerated (Sendt et al.). Those that do work produce modest results, and a couple of them are in final phase 3 clinical trials. Obviously, it would be a mistake to focus entirely on a single neurotransmitter,

considering the complex interactions among them. The glutamate theory provides some recognition of this fact, and it is showing considerable usefulness in explaining schizophrenia and some promise in guiding drug development. While we wait for the glutamate story to unfold, we have additional clues about the origins of schizophrenia from structural and functional anomalies in the brain. Brain Anomalies in Schizophrenia Malfunctions have been identified in virtually every part of the brain in people with

schizophrenia. The most consistent finding has been enlargement of the ventricles; another is hypofrontality, or reduced activity in the frontal lobes. We will examine each of these defects in turn. Brain Tissue Deficits and Ventricular Enlargement A signature characteristic of schizophrenia is a decrease in brain tissue, both gray

and white matter, with deficits reported in at least 50 different brain areas (Honea, Crow, Passingham, & Mackay, 2005). The number of sites and the variability across studies attest to the multifaceted nature of schizophrenia, but the frequency with which deficiencies are found in the frontal and temporal lobes indicates that they are particularly important. These tissue losses are accompanied by alterations in neural functioning, but not necessarily in the expected direction: Activity is decreased in the dorsolateral prefrontal cortex but increased in the orbitofrontal cortex and in a subregion of the hippocampus (Schobel et al., 2009). In fact, the hippocampal activation is so characteristic of schizophrenia that in a group of people having brief psychotic symptoms it identified those who would later be diagnosed with full-blown schizophrenia with 70% accuracy (Schobel et al.).

What brain defects have been found in schizophrenia? An indication of the tissue deficits seen in schizophrenia is ventricular enlargement;

this is because the ventricles expand to take up space normally occupied by brain cells (see Figure 14.8). Both deficiencies are usually subtle, on the order of less than a tablespoonful increase in ventricular volume (Suddath et al., 1989) and a 2% decrease in brain volume (Haijma et al., 2012), but these figures belie the functional importance of the losses. In fact, an often distinguishing feature between identical twins discordant for schizophrenia is the size of their ventricles (Suddath, Christison, Torrey, Casanova, & Weinberger, 1990). Ventricular enlargement is not specific to schizophrenia; enlarged ventricles are also associated with several other conditions, including old age, dementia (loss of cognitive abilities), Alzheimer’s disease, Huntington’s chorea (D. R. Weinberger & Wyatt, 1983), and alcoholism with dementia (D. M. Smith & Atkinson, 1995). Nor are enlarged ventricles an inherent characteristic of schizophrenia. As you can see in Figure 14.8a, several controls have enlarged ventricles, and many of the patients have ventricle sizes in the normal range. We will look more closely at the tissue deficits later when we consider their origins. Hypofrontality Earlier, we saw that prefrontal functioning can be assessed by using the gambling

task; an alternative technique is the Wisconsin Card Sorting Test, which requires individuals to change strategies in midstream, first sorting cards using one criterion but then changing to another. Many people with schizophrenia perform poorly on the test, persisting with the previous sorting strategy. Normal individuals show increased activation in the prefrontal area during the test; schizophrenic patients typically do not, in spite of normal activation in other areas (D. R. Weinberger, Berman, & Zec, 1986). Figure 14.9 shows a normal brain practically lighting up during the test, in comparison with the schizophrenic brain, especially in the frontal area called the dorsolateral prefrontal cortex. This hypofrontality apparently involves prefrontal dopamine deficiency, because administering amphetamine increases blood flow in the prefrontal cortex and improves performance on the Wisconsin Card Sorting Test (Daniel et al., 1991). Traumatic injury to the dorsolateral prefrontal cortex causes impairments similar to the symptoms of schizophrenia: flat affect, social withdrawal, reduced intelligence and problem-solving ability, diminished motivation and work capacity, and impaired attention and concentration (D. R. Weinberger et al., 1986). Because of the frontal lobes’ involvement in planning actions, recognizing the consequences of actions, and managing working memory, it is not surprising that frontal dysfunction would cause major abnormalities in thinking and behavior. FIGURE 14.8 Ventricle Size in Normals and People With Schizophrenia. In two identical twins (a) the lateral ventricles are larger in the one with schizophrenia. However, (b) shows that while this difference is true on average (indicated by the dotted lines), ventricle size is normal in several patients and increased in several controls.

SOURCES: (a) Copyright 1990 Massachusetts Medical Society. All rights reserved. (b) From “Lateral Cerebral Ventricular Enlargement in Chronic Schizophrenia,” by D. R. Weinberger et al., Archives of General Psychiatry, 36, pp. 735–739. Copyright 1979 American Medical Association. Reprinted with permission. FIGURE 14.9 Blood Flow in Normal and Schizophrenic Brains During Card Sorting Test. (a) The upper images are of the left and right hemispheres of a normal brain; the schizophrenic brain is below. Red and yellow represent greatest activation. Note especially the activity in the dorsolateral prefrontal cortex, whose location is identified in (b).

SOURCE: (a) From “Physiologic Dysfunction of Dorsolateral Prefrontal Cortex in Schizophrenia: I. Regional Cerebral Blood Flow Evidence,” by D. R. Weinberger, K. F. Berman, and R. R. Zec, 1986, Archives of General Psychiatry, 43, pp. 114–124. Neural Connections and Synchrony Recent attention has been shifting away from localized deficits and focusing

instead on disrupted coordination of neural activity across brain areas. For example, in normal controls performing a working-memory task, activity in the hippocampal formation varies together with prefrontal activity, but this coordination is absent in people with schizophrenia (Meyer-Lindberg et al., 2005). The hypofrontality seen during the Wisconsin Card Sorting Test has been attributed to disrupted communication between the hippocampus and the prefrontal cortex (Weinberger, Berman, Suddath, & Torrey, 1992). Inadequate coordination between brain areas is at least partly due to white matter reduction; white matter loss has been consistently reported in the brains of people with schizophrenia, particularly in prefrontal and

temporal areas (Begré & Koenig, 2008; Ellison-Wright & Bullmore, 2009). Diffusion tensor imaging shows that the quality of connections is compromised throughout much of the brain (Lee et al., 2013). Reduced connectivity between frontal and posterior regions of the brain correlates with positive and negative symptoms as well as performance on the Wisconsin Card Sorting Test. Brain functioning is coordinated by synchronized firing that links the activity of

neurons within a cortical area, across areas, and even between hemispheres. This synchronization is widely believed to be critical to perceptual binding and cognitive performance, and it is one of the functions that is disrupted in schizophrenia (Uhlhaas & Singer, 2010). Synchronized activity in frontal/thalamocortical circuits occurred at lower frequencies in patients (Ferrarelli et al., 2012), perhaps because the reduced white matter connections cannot support coordination at higher frequencies. Frequency reduction averaged 10 Hz in the frontal cortex; the deficit was greatest in the prefrontal area, and the frequency loss there was correlated with positive and negative symptoms. To some extent we can correlate the patterns of synchrony with the symptoms of schizophrenia; in patients with positive symptoms, for example, oscillation synchrony is enhanced within limited areas but is deficient between areas (Uhlhaas & Singer). This enhanced synchrony, which indicates hyperexcitability, is seen in the occipital area in visual hallucinators (Spencer et al., 2004) and in the left auditory cortex in auditory hallucinators (Spencer, Niznikiewicz, Nestor, Shenton, & McCarley, 2009). At the same time, auditory hallucinators fail to show normal synchrony between frontal and temporal areas while talking (Ford, Mathalon, Whitfield, Faustman, & Roth, 2002). It may surprise you to learn that hallucinations are associated with activity in the

respective sensory areas. Scans of the brains of people with schizophrenia show that language areas are active during auditory hallucinations and visual areas are active during visual hallucinations (Figure 14.10; McGuire, Shah, & Murray, 1993; McGuire et al., 1995; Silbersweig et al., 1995). Because these areas are activated in normal individuals when they are engaged in “inner speech” (talking to oneself) and imagining visual scenes, it appears that the hallucinating schizophrenic is not simply imagining voices and images but is misperceiving self-generated thoughts. FIGURE 14.10 Brain Activation During Visual and Auditory Hallucinations in a Schizophrenic.

SOURCE: From “A Functional Neuroanatomy of Hallucinations in Schizophrenia,” by D. A. Silbersweig et al., Nature, 378, pp. 176–179. Reprinted by permission of Nature, copyright 1995. One of the most documented symptoms of schizophrenia is the inability to suppress

environmental sounds. With auditory gating impaired, the intrusion of traffic noise or a distant conversation is not just annoying but can be interpreted by the person with schizophrenia as threatening. This deficit is also associated with reduced synchrony across wide areas of the brain (M. H. Hall, Taylor, Salisbury, & Levy, 2010). Atypical antipsychotics improve gating, but nicotine normalizes it (Adler et al., 2004; Kumari & Postma, 2005). Smoking declined in the United States from 42% in 1965 to about 20% in 2006, but the rate remained about 80% among people with schizophrenia (Keltner & Grant, 2006), in an apparent attempt at self-medication. Besides sensory gating, nicotine improves several negative symptoms, including impaired visual tracking of moving objects, working memory, and other cognitive abilities (Sacco, Bannon, & George, 2004; Sacco et al., 2005; Tregellas, Tanabe, Martin, & Freedman, 2005). Nicotine appears to compensate for diminished functioning of nicotinic acetylcholine receptors (S. I. Deutsch et al., 2005), increase glutamate and GABA release, and increase dopamine levels in the prefrontal cortex where it is depleted in hypofrontality (Kumari & Postma, 2005; Sata et al., 2008). Three studies have linked schizophrenia with one of the genes responsible for nicotinic receptors (De Luca, Wang, et al., 2004; De Luca, Wong, et al., 2004; S. I. Deutsch et al., 2005). Environmental Origins of the Brain and Transmitter Anomalies An obvious potential cause of brain defects would be head injury. Several studies

have reported an association between schizophrenia and brain damage that occurred within a few years prior to diagnosis (reviewed in David & Prince, 2005). However, the studies have been criticized for a number of methodological inadequacies, including reliance on patients’ and relatives’ memory of the injuries, casual diagnosis of schizophrenia, and failure to consider accident proneness and pre-injury symptoms as confounding factors (David & Prince; Nielsen, Mortensen, O’Callaghan, Mors, & Ewald, 2002). Evidence is stronger for a variety of influences at the time of birth or during the

prenatal period. These include both physical complications (Cannon, Jones, &

Murray, 2002) and emotional stresses on the mother, such as death of the father (Huttunen, 1989) and military invasion (van Os & Selten, 1998). Prenatal stress in mice results in upregulation of 5-HT2A receptors and downregulation of mGlu2 receptors, both of which are seen in the brains of schizophrenia patients (Holloway et al., 2013). One indication that birth and pregnancy complications contribute to brain deficits is that they are associated with enlarged ventricles later in life (Pearlson et al., 1989). They are a possible explanation for the difference in ventricle size between identical twins (Bracha, Torrey, Gottesman, Bigelow, & Cunniff, 1992). It is easy to see how birth complications, such as being born with the umbilical cord

around the neck, could differentiate between twins, but different experiences in the womb require some explanation. Identical twins may share the same placenta and amniotic sac or they may have their own, depending on whether the developing organism splits in two before or after the fourth day of development. Identical twins who did not share a placenta had an 11% concordance rate for schizophrenia, compared with 60% for those who shared a placenta, presumably due to the sharing of infections (J. O. Davis, Phelps, & Bracha, 1995). In spite of the importance of prenatal factors, some researchers believe that they produce schizophrenia only in individuals who are already genetically vulnerable (Schulsinger et al., 1984). The winter birth effect refers to the fact that more people who develop schizohrenia

are born during the winter and spring than during any other time of the year. The effect has been replicated in a large number of studies, some with more than 50,000 schizophrenic patients as subjects (Bradbury & Miller, 1985). The important factor in winter births is not cold weather, but the fact that infants born between January and May would have been in the second trimester of prenatal development in the fall or early winter, when there is a high incidence of infectious diseases (C. G. Watson, Kucala, Tilleskjor, & Jacobs, 1984). There is good evidence that the mother’s exposure to viral infections during the fourth through sixth months of pregnancy (second trimester) increases the risk of schizophrenia. This appears to be caused not by the virus itself but by the immune reaction that it triggers. This conclusion is supported by a markedly higher level of interleukin-1β in the spinal fluid of first- episode patients, indicating that an immune response has occurred (Figure 14.11; Söderlund et al., 2009). Because the patients were infection free at the time, the infection must have occurred earlier, possibly during the prenatal period. FIGURE 14.11 Interleukin-1β Levels in Schizophrenia Patients and Controls. Elevated levels of this protein at the time of a first schizophrenic episode indicated that strong immune reactions had occurred in the past.

SOURCE: From “Activation of Brain Interleukin-1β in Schizophrenia,” by J. Söderland et al., 2009, Molecular Psychiatry, 14, pp. 1069–1071. Copyright © 2009 Nature Publishing Group. Used with permission. FIGURE 14.12 Relationship of Schizophrenic Births to Season and Influenza Epidemics in England and Wales (1939–1960). (a) Schizophrenic birth rates by month during years of high and low influenza incidence. (b) Schizophrenic birth rate as a function of time from beginning of epidemic.

SOURCE: From “Schizophrenia Following Pre-natal Exposure to Influenza Epidemics Between 1939 and 1960,” by P. C. Sham et al., British Journal of Psychiatry, 160, pp. 461–466. Copyright 1992. Reprinted with permission of the publisher. Several illnesses have been implicated, but the effect of influenza has been

researched most frequently, and a higher incidence of schizophrenic births has been confirmed following influenza outbreaks in several countries. Figure 14.12 shows that during years of high influenza infection the birth rate of people later diagnosed with schizophrenia increases during winter and spring; also, there is a peak of such births a few months after the start of epidemics. However, these studies could not confirm that the individual mothers had actually been exposed to the influenza virus; by analyzing

the blood specimens drawn from expectant mothers, Alan Brown and his colleagues (2004) found a sevenfold increased risk for schizophrenia and spectrum disorders when influenza antibodies were present, and they estimated that influenza infection accounts for 14% of schizophrenia cases. As was the case with stress, maternal infection with the influenza virus upregulates 5-HT2A receptors and downregulates mGlu2 receptors in the frontal cortex of the offspring (Moreno et al., 2011). Injecting pregnant mice with a drug that activates the immune system produced the same result, suggesting that immune responses are responsible for the receptor alterations in schizophrenia (Holloway et al., 2013). Prenatal starvation is another pathway to schizophrenia that until recently was the

subject of controversy. The idea came about after the rate of schizophrenia doubled among the offspring of mothers who were pregnant during Hitler’s 1944 to 1945 food blockade of the Netherlands (Susser et al., 1996). However, the interpretation was questionable because the sample was small and because toxins in the tulip bulbs the women ate to survive could have been to blame. But now data from a much larger sample of adults born during the 1959 to 1961 famine in China have confirmed the association, with an increase in schizophrenia from 0.84% to 2.15% (St. Clair et al., 2005). Most of the environmental influences we have been discussing occur during

pregnancy or birth; one, however, relates to the father. There is a greater risk of schizophrenia if the father’s age at the time of conception exceeds 25, and by paternal age of 50 the risk has increased by two thirds (Miller et al., 2010). The mechanism for this effect is unknown, but chances are it is epigenetic, due either to the normal aging process or to an accumulation of external environmental insults. Epigenetic effects in general can be traced to a variety of environmental influences, including toxins, diet, starvation, drugs, and stress; they likely account for most of the environmental influences we have been talking about. The fact that obesity in the Dutch hunger winter offspring was linked to epigenetic changes (see Chapter 6) makes us suspect the same mechanism in the cases of schizophrenia in that group. This is a relatively new area of investigation, so there has been little documentation of epigenetic influences in schizophrenia. Schizophrenia as a Developmental Disease The defects in the brains of people diagnosed with schizophrenia apparently occur

early in life, some at the time of birth or before. In some cases, it appears that many neurons in the temporal and frontal lobes failed to migrate to the outer areas of the cortex during the second trimester; they are disorganized and mislocated in the deeper white layers (Figure 14.13; Akbarian, Bunney, et al., 1993; Akbarian, Viñuela, et al., 1993). The hippocampus and prefrontal cortex are 30% to 50% deficient in reelin, a protein that functions as a stop factor for migrating neurons (Fatemi, Earle, & McMenomy, 2000; Guidotti et al., 2000). These observations and the association of

schizophrenia with birth trauma and prenatal viral infection all argue for early damage to the brain or a disruption of development. FIGURE 14.13 Neural Disorganization in Schizophrenia. The neurons in the normal hippocampus have an orderly arrangement (a), but in the brain of a schizophrenic individual you can see that they have migrated in a haphazard fashion (b).

SOURCE: © Arne Scheibel, UCLA. This view is supported by behavioral data. Home movies of children who later

became schizophrenic revealed more negative facial expressions and physical awkwardness than in their healthy siblings; the movies were rated by judges who were unaware of the children’s later outcome (Walker, Lewine, & Neumann, 1996). Among New Zealanders followed from age 3 to 32, those who later developed schizophrenia had deficits in learning, attention, and problem solving during childhood, and for each year of life they fell an additional 2 to 3 months further behind other children (Reichenberg et al., 2010). FIGURE 14.14 Gray Matter Loss in Schizophrenic Adolescents. There is some loss in the brains of normal adolescents due to circuit pruning, but the rate of loss is much greater in schizophrenic adolescents. Red and pink areas represent 3% to 5% losses annually.

SOURCE: From “Mapping Adolescent Brain Change Reveals Dynamic Wave of Accelerated Gray Matter Loss in Very Early-Onset Schizophrenia,” by P. M. Thompson, PNAS, 98, pp. 11650–11655, fig. 1A, p. 11651, and fig. 5, p. 11653. © 2001 National Academy of Sciences, U.S.A. Used with permission. Gray matter deficit and ventricular enlargement are ordinarily present at the time of

patients’ diagnosis (Degreef et al., 1992). Most of the evidence indicates that the loss of brain volume occurs rapidly and dramatically in adolescence or young adulthood and then levels off (B. T. Woods, 1998). Adolescence is a particularly significant period in the development of schizophrenia. This is a time when symptoms of schizophrenia often begin to develop and a time of brain maturation, including frontal myelination and connection of temporal limbic areas (D. R. Weinberger & Lipska, 1995). Thompson, Vidal, et al. (2001) identified a group of adolescents who had been diagnosed with schizophrenia and used MRIs to track their brain development. At the age of 13, there was little departure from the normal amount of gray matter loss that occurs with circuit pruning, but over the next 5 years, loss occurred in some areas as rapidly as 5% per year (Figure 14.14). The nature of the symptoms varied as the loss progressed from parietal to temporal to frontal areas. Studies have found no evidence of dying neurons or of the inflammation that would be expected with an ongoing degenerative disease; instead, gray matter deficits have been attributed to loss of synapses (D. A. Lewis & Levitt, 2002; D. R. Weinberger, 1987). This apparent severe pruning may reflect the elimination of circuits that have already been diminished (D. A. Lewis & Levitt) by a lack of glutamate activity (Coyle, 2006); this view is supported by the fact that the diagnosis of schizophrenia preceded significant gray matter reductions in the schizophrenic adolescents.

Concept Check Take a Minute to Check YourKnowledge and Understanding What is the interplay between heredity and environment in schizophrenia? Describe the two kinds of schizophrenia. How are dopamine irregularities and brain deficits proposed to interact?

What are the affective disorders? Affective Disorders The affective disorders include depression and mania. Almost all of us occasionally experience depression, an intense feeling of sadness; we feel depressed over grades, a bad relationship, or loss of a loved one. While this reactive depression can be severe, major depression goes beyond the normal reaction to life’s challenges. In major depression, a person often feels sad to the point of hopelessness for weeks at a time; loses the ability to enjoy life, relationships, and sex; and experiences loss of energy and appetite, slowness of thought, and sleep disturbance. In some cases, the person is also agitated or restless. Stress is often a contributing factor, but major depression can occur for no apparent reason. Mania involves excess energy and confidence that often lead to grandiose schemes; decreased need for sleep, increased sexual drive, and abuse of drugs are common. Depression may appear alone as unipolar depression, or depression and mania may

occur together in bipolar disorder. In bipolar disorder, the individual alternates between periods of depression and mania; mania can occur without periods of depression, but this is rare. Bipolar patients often show psychotic symptoms such as delusions, hallucinations, paranoia, or bizarre behavior. Two quotes provide some insight into the disorders from the patients’ own perspectives (National Institute of Mental Health, 1986):

2 Depression Test Depression: I doubt completely my ability to do anything well. It seems as though my mind has slowed down and burned out to the point of being virtually useless... [I am] haunt[ed]... with the total, the desperate hopelessness of it all.... If I can’t feel, move, think, or care, then what on earth is the point? Mania: At first when I’m high, it’s tremendous... ideas are fast... like shooting stars you follow until brighter ones appear... all shyness disappears, the right words and gestures are suddenly there.... Sensuality is pervasive, the desire to seduce and be seduced is irresistible. Your marrow is infused with unbelievable feelings of ease, power, well-being, omnipotence, euphoria... you can do anything... but, somewhere this changes.

The most recent data indicate that 3 out of 10 people will suffer a mood disorder in their lifetime, most likely depression (Kessler, Petukhova, Sampson, Zaslavsky, & Wittchen, 2012). Women are two to three times more likely than men to suffer from unipolar depression during their lifetime; bipolar illness occurs equally often in both sexes (Gershon, Bunney, Leckman, Van Eerdewegh, & DeBauche, 1976; P. W. Gold, Goodwin, & Chrousos, 1988) at a rate of about 4.5% (Kessler, Merikangas, & Wang, 2007). The risk for major depression increases with age in men, whereas women experience their peak risk between the ages of 35 and 45; the period of greatest risk for bipolar disorder is in the early 20s to around the age of 30. Getting a handle on the economic burden is difficult, because it depends on what costs are included and what assumptions are made. Estimates of the annual cost for all mood disorders in the United States have varied from $24 billion to $234 billion (Dilsaver, 2009; Greenberg et al., 2003; Uhl & Grow, 2004). Heredity As with schizophrenia, there is strong evidence that affective disorders are partially

inheritable. Part of that evidence is the increased incidence of affective disorders among patients’ relatives. When one identical twin has an affective disorder, the probability that the other twin will have the illness as well is about 69%, compared with 13% in fraternal twins (Gershon et al., 1976). Lack of complete concordance in identical twins indicates that there is an environmental contribution. However, the concordance rate drops surprisingly little when identical twins are reared apart (J. Price, 1968), which may mean that the most important environmental influences occur in the prenatal period or shortly after. Genetic liability differs by gender; a Swedish twin study estimated heritability at

29% for men and 42% for women (Kendler, Gatz, Gardner, & Pedersen, 2006). These results were consistent with studies in the United States and Australia, as well as studies that identified different chromosomal locations for risk factors in men and women. In one study, seven genes were exclusive to men, nine were exclusive to women, and only three were shared between men and women (Zubenko, Hughes, Stiffler, Zubenko, & Kaplan, 2002). The sex disparity suggests one reason disorder genes can be difficult to locate in a clinical group, and it may explain the higher frequency of depression in women and the higher rate of suicide in men. Once again, the genes we are interested in are many and of small effect, requiring

much larger sample sizes than are typically employed. Researchers are more and more resorting to meta-analyses, which pool the results of many studies. One finding is that the 5-HTTLPR serotonin transporter gene has been associated with an increased vulnerability to depression, along with a 15% reduction in gray matter in the amygdala and a 25% reduction in the subgenual anterior cingulate cortex (Pezawas et al., 2005). People with the short allele show an exaggerated amygdala response to fearful facial expressions (Hariri et al., 2002), apparently due to a loss of feedback

from the cingulate cortex that would ordinarily damp amygdala activity (Pezawas et al., 2005). According to some studies, these deficiencies increase susceptibility to stress, which leads to depression (Figure 14.15; Canli et al., 2006; Caspi et al., 2003). Although a meta-analysis that pooled 56 studies produced a strong confirmation of the linkage (Barg, Burmeister, Shedden, & Sen, 2011), not all studies have confirmed it. One reason may be that studies rarely take into account gene interactions such as epistasis, the suppression of one gene’s effect by another. In this case, the VAL66MET allele of the gene for brain-derived neurotrophic factor (BDNF), a protein that encourages neuron growth and survival, protects against the effects of the 5-HTTLPR short allele on brain development (Pezawas et al., 2008). A later meta-analysis confirmed that Val66Met also reduces vulnerability to depression (Hosang, Shiles, Tansey, McGuffin, & Uher, 2014). FIGURE 14.15 The Role of Stress and the Serotonin Transporter Gene in Depression. (a) In individuals with either one or two copies of the so-called short allele, the percentage who were diagnosed at age 26 with depression increased with the number of stressful life events in the past 5 years. (b) In those with two copies of the long allele, the number of stressful events made no difference. Life events were assessed from a checklist of 14 employment, financial, housing, health, and relationship stressors.

SOURCE: From “Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene,” by A. Caspi et al., Science, 301, pp. 386–389, fig. 3, p. 389. © 2003. Reprinted by permission of AAAS. Whole-genome studies have been extremely beneficial because researchers can

explore the genome without any hypothesis or even an educated guess about what to look for. But the statistical procedure used to confirm an association must be corrected for the increased probability of a chance “hit” due to the millions of comparisons performed, which makes it even harder to find genes that have a small effect. One solution is to increase the effect size by targeting a limited group of subjects; a gene location on chromosome 3 was identified only when researchers limited their search to patients with severe depression (Breen et al., 2011). Another approach is to limit

the search to the genes known to be involved in a relevant pathway; knowledge that the immune system is dysregulated in depression led researchers to discover several candidate immune system genes (Buffalino, Hepgui, Aguglia, & Pariaante, 2013). A common characteristic of depression is disruption of the circadian (day-night)

cycle, which is controlled by a large number of genes. One study found three of those circadian genes to be associated with depression (Gouin et al., 2010), and another identified two additional genes (Soria et al., 2010); the studies used different methods, and we will have to wait for further work to find out which associations will hold up. In spite of similarities between depression and bipolar disorder, there is good

reason to believe that they are considerably independent of each other genetically (P. W. Gold et al., 1988; Moldin, Reich, & Rice, 1991). Bipolar disorder is more heritable, with estimates of 85% and 93% (Kieseppä, Partonen, Haukka, Kaprio, & Lönnqvist, 2004; McGuffin et al., 2003). Few genes have been confirmed, however, apparently again because of small sample sizes. An unusually large genome-wide study that included 9,747 patients confirmed three previously discovered genes and added two more (Mühleisen et al., 2014). The genes’ functions involve a calcium channel at the nodes of Ranvier and cellular functioning and signaling. A much larger study, with 33,332 patients, reported that some genes are shared among five disorders: bipolar disorder, major depressive disorder, schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013). Genetic sharing is one of the arguments for considering these disorders as a continuum. Whether that is appropriate or not, you should understand that all five of these disorders do have a variety of functional and structural characteristics in common. Finally, it is interesting to see that mutations have been found in bipolar patients in three genes that control circadian rhythms, none of which overlapped with the five associated with depression (McGrath et al., 2009; Soria et al., 2010). The Monoamine Hypothesis of Depression The first effective treatment for depression was discovered accidentally, and theory

again followed practice rather than the other way around. Iproniazid was introduced as a treatment for tuberculosis, but it was soon discovered that the drug produced elevation of mood (Crane, 1957) and was an effective antidepressant (Schildkraut, 1965). Iproniazid was later abandoned as an antidepressant because of its side effects, but its ability to increase activity at the monoamine receptors led researchers to the monoamine hypothesis, that depression involves reduced activity at norepinephrine and serotonin synapses. You may remember that the monoamines also include dopamine, but because dopamine agonists such as amphetamine produced inconsistent therapeutic results, researchers have limited their interest to norepinephrine and serotonin.

What is the monoamine hypothesis? All the effective antidepressant drugs increase the activity of norepinephrine or

serotonin, or both, at the synapses. They do this in different ways. Some block the destruction of excess monoamines in the terminals (monoamine oxidase inhibitors), while others block reuptake at the synapse (tricyclic antidepressants). Atypical (second-generation) antidepressants affect a single neurotransmitter; for example, Prozac (fluoxetine) is one of several selective serotonin reuptake inhibitors. These synaptic effects occur within hours, but symptom improvement takes 2 to 3 weeks. Additional evidence to support the monoamine hypothesis is that serotonin and

norepinephrine are involved in behaviors that are disturbed in affective disorders. Serotonin plays a role in mood, activity level, sleep and daily rhythms, feeding behavior, sexual activity, body temperature regulation, and cognitive function (Meltzer, 1990; Siever et al., 1991). Because the noradrenergic system is involved in responsiveness and sensitivity to the environment, reduced norepinephrine activity may contribute to the depressed individual’s slowed behavior, lack of goal-directed activity, and unresponsiveness to environmental change (Siever et al., 1991). Earlier, we saw that nicotine provides some relief from symptoms of schizophrenia.

Nonnicotine ingredients in tobacco smoke have been found to act as monoamine oxidase inhibitors. This would explain why smoking is so frequent among depressives and why they have particular difficulty giving up smoking (J. S. Fowler et al., 1996; Khalil, Davies, & Catagnoli, 2006). I mention a therapeutic effect of smoking for the second time only to illustrate again how people may self-medicate without being aware they are doing it and why some people have so much trouble quitting; if it sounds as though the benefits of smoking outweigh the cost to the smoker’s health, you should reread the section on nicotine in Chapter 5. Figure 14.16 is a dramatic demonstration of the extensive effect of smoking on monoamine oxidase inhibitor levels throughout the body. FIGURE 14.16 Monoamine Oxidase Levels in the Body of a Nonsmoker and a Smoker. PET scans were done using a radioactive tracer that binds to monoamine oxidase B. Levels were reduced 33% to 46% in smokers. Monoamine oxidase reduction can have beneficial, detrimental, or neutral effects, depending on the location and other conditions.

SOURCE: From “Low Monoamine Oxidase B Levels in Peripheral Organs of Smokers,” by J. S. Fowler et al., PNAS, 100, fig. 2, p. 11602. © 2003 National Academy of Sciences, U.S.A. Used with permission. Treatment resistance and the delay required for drugs to take effect are serious

issues, especially if the patient is suicidal; experiments with ketamine, which was developed as an anesthetic but gained infamy as a club drug, suggest that these problems might be avoidable. In a study with patients who had shown resistance to at least two antidepressant drugs, a single injection of ketamine alleviated depression in 68%, and the improvement lasted 7 days in 46% of the patients (Murrough et al., 2013). Relapse time is highly variable, though, and ketamine appears to be most valuable as a temporary treatment (aan het Rot et al., 2010). Ketamine also interests us because of its specific effect; it blocks the NMDA type of glutamate receptor, implicating glutamate function in depression as well as schizophrenia. About 30% to 50% of depressed patients fail to respond to drug therapy, a statistic made worse by the fact that the placebo response rate alone is 30% (Depression Guideline Panel, 1993). Lack of response is partly related to symptom severity; patients with mild or moderate symptoms receive little or no relief, but for patients with severe depression the benefit of medications is substantial (Fournier et al., 2010). Also, some patients are resistant to antidepressant medication. Cognitive behavioral therapy is generally about as effective as antidepressants, and when it was added to the usual treatment in resistant patients, depression scores improved by 50% or more in 46% of patients, compared with 22% in those who remained in usual care (Wiles et al., 2013). Electroconvulsive Therapy In extreme cases of treatment nonresponse or because of suicidal behaviors, an

alternative is electroconvulsive therapy. Electroconvulsive therapy (ECT) involves applying 70 to 130 volts of electricity to the head of an anesthetized patient, which

produces a seizure accompanied by convulsive contractions of the neck and limbs and lasting about a half minute to a minute (see Figure 14.17). Without the seizure activity in the brain that produces the convulsions, the treatment does not work. Within a few minutes, the patient is conscious and coherent, though perhaps a bit confused; the patient does not remember the experience. Usually ECT is administered two to three times a week for a total of 6 to 12 treatments. Electroconvulsive therapy is the most controversial of the psychiatric therapies.

Producing convulsions by sending a jolt of electricity through the brain sounds inhumane, and in fact the procedures used in the early days of ECT treatment often resulted in bone fractures and long-term memory deficits. Now patients are anesthetized and given muscle relaxants that eliminate injury and reduce emotional stress. The number of treatments and the voltage have both been reduced, and stimulation is delivered in brief pulses rather than continuously. Though bilateral electrode placement produces a faster response that is desirable with suicidal patients, unilateral right hemisphere placement is usually favored because it minimizes cognitive side effects, such as temporary memory impairment (Kellner, Tobias, & Wiegand, 2010). These changes have made ECT safer and, at the same time, more effective (Weiner & Krystal, 1994). Follow-up studies indicate that memory and cognitive impairment induced by ECT dissipates within a few months (Crowe, 1984; Weeks, Freeman, & Kendell, 1980) and that cognitive performance even improves over pretreatment levels as the depression lifts (Sackeim et al., 1993). Brain scans and autopsies of patients and actual cell counts in animal subjects show no evidence of brain damage following ECT (reviewed in Devanand, Dwork, Hutchinson, Bolwig, & Sackheim, 1994). FIGURE 14.17 A Patient Being Readied for Electroconvulsive Therapy.

SOURCE: James D. Wilson/Woodfin Camp & Associates. ECT is usually reserved for patients who do not respond to the medications or who

cannot take them due to extreme side effects or because of pregnancy. In a recent analysis of 13 studies that compared ECT with antidepressant drugs, 79% of patients responded to ECT, compared with 54% of patients treated with antidepressants

(Pagnin, de Queiroz, Pini, & Cassano, 2004). ECT works especially well when depression or mania is accompanied by psychosis (Depression Guideline Panel, 1993; Potter & Rudorfer, 1993), and it works rapidly, which is beneficial to suicidal patients who cannot wait for weeks while a drug takes effect (Rudorfer, Henry, & Sackeim, 1997). The disadvantage of ECT is that its benefit is often short term, but the patient can usually be maintained on drug therapy once a round of ECT has been completed. ECT is effective with depression, mania, and schizophrenia, which suggests that its

effects are complex, and research bears this out. A number of changes occur at the brain’s synapses. Like the drugs, ECT increases the sensitivity of postsynaptic serotonin receptors (Mann, Arango, & Underwood, 1990); in addition, the sensitivity of autoreceptors on the terminals of norepinephrine- and dopamine-releasing neurons is reduced, so the release of those transmitters is increased. A temporary slowing of the EEG, which is correlated with therapeutic effectiveness, suggests that ECT synchronizes neuronal firing over large areas of the brain (Ishihara & Sasa, 1999; Sackeim et al., 1996). This reduced excitability is likely due to the fact that ECT increases diminished GABA concentrations (Sanacora et al., 2003). However, as you will see in the next section, both antidepressants and ECT now appear to trigger dramatic remodeling of the depressed brain. (For information about two newer forms of electrical treatment, see the accompanying Application.) Antidepressants, ECT, and Neural Plasticity Although antidepressant drugs and ECT have been used to treat depression for

more than half a century, we are not sure how they work. Most puzzling is the delay between neurotransmitter changes and symptom relief; hypotheses that changes in receptor sensitivity account for the delay have not been successful (Yamada, Yamada, & Higuchi, 2005). A promising lead is that antidepressant drugs, lithium, and ECT all increase neuronal birth rate in the hippocampus, at least in rodents and presumably in humans as well (Figure 14.18; Inta et al., 2013; Mendez-David, Hen, Gardier, & David, 2013; Sairanen, Lucas, Ernfors, Castrén, & Castrén, 2005). While increased neurogenesis can be detected within hours of antidepressant treatment, the time required for new hippocampal neurons to migrate to their new locations and form functional connections closely matches the delay in symptom improvement (Sairanen et al., 2005).

APPLICATION

Electrical Stimulation for Depression Researchers often use an electromagnetic field (transcranial magnetic stimulation, TMS) either to disrupt or to activate brain activity in order to determine the function of that area of the brain (see the figure here and descriptions on pages 98 and 106–107). TMS is finding its way into therapies

for a variety of disorders, and one TMS device has been approved by the FDA for use with depression. Fast TMS (pulse rate above 5/second) causes neural excitation; applied over the hypoactive left dorsolateral prefrontal area daily for 4 to 6 weeks, it produces benefits comparable to those of ECT in patients with treatment-resistant severe depression (Grunhaus, Schreiber, Dolberg, Polak, & Dannon, 2003; Janicak et al., 2002; O’Reardon et al., 2007). Side effects appear to be limited to temporary scalp pain or discomfort. In a recent study, 68% of medication-resistant patients given TMS were improved 12 months later and 45% had no symptoms (Demitrack et al., 2013). Another interesting way to stimulate the brain is with electrodes implanted

on the left vagus nerve. Improvement took several months, but 70% of patients benefited (Conway et al., 2013). What was intriguing about this study was that PET scans showed brain metabolism increases before symptom improvement was seen. A more aggressive strategy is deep brain stimulation, with stimulation delivered to implanted electrodes by a pulse generator embedded under the skin. Treatment-resistant patients with electrodes implanted in the cingulate gyrus had a 75% improvement rate 3 years out; 19% were symptom free after 1 year of treatment, and this rate climbed to 50% at the end of 3 years (Kennedy et al., 2011). Whether these techniques will change the way therapy is done remains to be

seen, but they do suggest that therapists will have alternatives available for managing the treatment-resistant patient.

Transcranial Magnetic Stimulation and Deep Brain Stimulation. (a) When the electromagnetic coil is held over the scalp, it induces an electric current in the brain tissue below. (b) An X-ray showing the location of electrodes for deep brain stimulation in a depressed patient. SOURCES: (a) Courtesy of National Institute of Health. (b) Courtesy of Dr. Helen Mayberg.

After new cell development was blocked by X radiation, antidepressants no longer had an effect in mice, suggesting that neurogenesis is required for antidepressive

action (Santarelli et al., 2003). An increase in cell numbers is not the basis, however, because cell death also accelerates; some have suggested that the therapeutic effect is due to the greater plasticity of new cells (Gould & Gross, 2002). Although neurogenesis may provide this benefit, there is evidence that other factors contribute as well. When researchers used a drug instead of X radiation to block neurogenesis, antidepressant effect was not diminished (Bessa et al., 2009). The researchers found evidence of increased plasticity and synaptic enhancement, and they believed this accounted for the antidepressant effect. There is additional evidence for a plasticity hypothesis: Both antidepressants and ECT modify activity in a large number of genes, especially in the hippocampus; most of those genes contribute to neurogenesis and to various aspects of neuron survival and plasticity (Altar et al., 2004; Yamada et al., 2005). Presumably, blocking neurogenesis with a drug preserved some of the effects of the antidepressant related to synaptic remodeling. FIGURE 14.18 Increased Neurogenesis in the Hippocampus During Antidepressant Treatment. (a) Antidepressant treatment produced a 60% increase in neurogenesis, compared with administration of inert material (vehicle). (b) Brown dots are new cells (preneurons).

SOURCE: From “Requirement of Hippocampal Neurogenesis of the Behavioral Effects of Antidepressants,” by L. Santarelli et al., Science, 301, 805–809, fig. 2a and 2b, p. 806. © 2003. Reprinted with permission from AAAS. Rhythms and Affective Disorders Depressed people often have problems with their biological rhythms. The circadian

rhythm —the one that is a day in length—tends to be phase advanced in affective disorder patients; this means that the person feels sleepy early in the evening and then wakes up in the early morning hours, regardless of the previous evening’s bedtime (Dew et al., 1996). The person also enters rapid eye movement sleep earlier in the night and spends more time in this state than normal (Kupfer, 1976). As you will learn in the next chapter, rapid eye movement (REM) sleep is the stage of sleep during which dreaming occurs; the excess REM sleep is at the expense of the other stages of sleep. Unipolar depressed patients share this early onset of REM sleep with 70% of

their relatives, and relatives with reduced REM latency are three times more likely to be depressed than relatives without reduced latency (Giles, Biggs, Rush, & Roffwarg, 1988).

What are the roles of daily rhythms and seasons? Circadian Rhythms and Antidepressant Therapy Some patients who are unresponsive to medication can get relief from their

depression by readjusting their circadian rhythm. They can do this simply by staying up a half hour later each night until they reach the desired bedtime. In some patients, this treatment results in a relief from depression that lasts for months (Sack, Nurnberger, Rosenthal, Ashburn, & Wehr, 1985). Some depressed patients also benefit temporarily from sleep deprivation. This was

initially seen with REM sleep deprivation, which is accomplished by waking the person every time the EEG indicates that sleep has moved into the REM stage (Wu & Bunney, 1990). Interestingly, most antidepressant drugs also suppress REM sleep (G. W. Vogel, Buffenstein, Minter, & Hennessey, 1990). Later research showed that depressed individuals also improve following non-REM sleep deprivation (Landsness et al., 2011) or total overnight sleep deprivation (Giedke & Schwärzler, 2002). To find out why, researchers at Tufts University School of Medicine dosed mice with a drug that mimics adenosine, a compound that builds up in the brain during wakefulness and produces sleepiness. Twelve hours later the mice showed increased resistance to treatments that produce depressive-like behavior (Hines, Schmitt, Hines, Moss, & Haydon, 2013). The mice slept normally, perhaps because the drug targeted only the A1 type of adenosine receptor; a similar drug might provide humans the antidepressant benefits of sleep deprivation without the sleepiness. Seasonal Affective Disorder There is another rhythm that is important in affective disorders; some people’s

depression rises and falls with the seasons and is known as seasonal affective disorder (SAD). Most SAD patients are more depressed during the fall and winter, and then improve in the spring and summer. Others are more depressed in the summer and feel better during the winter. Members of either group may experience a mild mania-like activation called hypomania during their “good” season. While depressed, they usually sleep excessively, and they often have increased appetites, especially for carbohydrates, and gain weight. The length of day and the amount of natural light appear to be important in winter depression; symptoms improve when the patient travels farther south (or north, if the person lives in the Southern Hemisphere) even for a few days, and some report increased depression during cloudy periods in the summer or when they move to an office with fewer windows. Summer depression appears to be temperature related: traveling to a cooler climate, spending time in an air-conditioned house, and taking several cold showers a day improves the symptoms.

About 10% of all cases of affective disorder are seasonal, and 71% of SAD patients are women (Faedda et al., 1993). Although seasonal influences on affective disorder have been known for 2,000 years and documented since the mid-1850s, summer depression has received relatively little attention, so we will restrict our discussion to winter depression. FIGURE 14.19 A Woman Uses a High-Intensity Light to Treat Her Seasonal Affective Disorder.

SOURCE: Dan McCoy/Rainbow. A treatment for winter depression is phototherapy —having the patient sit in front

of high-intensity lights for a couple of hours or more a day (Figure 14.19). Patients begin to respond after 2 to 4 days of treatment with light that approximates sunlight from a window on a clear spring day; they relapse in about the same amount of time following withdrawal of treatment (Rosenthal et al., 1985). The fact that midday phototherapy is effective suggests that the increased amount of light is more important than extending the length of the shortened winter day; the observation that suicide rate is related to a locale’s amount of clear sunlight rather than the number of hours of daylight supports this conclusion (Wehr et al., 1986). Phototherapy resets the circadian rhythm (Lewy, Sack, Miller, & Hoban, 1987), so it is also helpful with circadian rhythm problems including jet lag, delayed sleep syndrome, and difficulties associated with shift work (Blehar & Rosenthal, 1989).

3 Phototherapy Lowered serotonin activity is involved in winter depression. Drugs that increase

serotonin activity alleviate the depression and reduce carbohydrate craving (O’Rourke, Wurtman, Wurtman, Chebli, & Gleason, 1989). As we saw in Chapter 5, eating carbohydrates increases brain serotonin levels. So, rather than thinking that SAD patients lack willpower when they binge on junk food and gain weight, it might be more accurate to think of them as self-medicating with carbohydrates. Bipolar Disorder The mystery of major depression is far from solved, but bipolar disorder is even

more puzzling. Bipolar patients vary greatly in their symptoms: the depressive cycle usually lasts longer than mania, but either may predominate. Some patients cycle between depression and mania regularly, whereas others are unpredictable; cycles usually vary from weeks to months in duration, while some patients switch as frequently as every 48 hours (Bunney, Murphy, Goodwin, & Borge, 1972). Stress often precipitates the transition from depression into mania, followed by a more spontaneous change back to depression; the prospect of discharge from the hospital is particularly stressful and often will precipitate the switch into mania. However, as bipolar disorder progresses, manic episodes tend to occur independently of life’s stresses (P. W. Gold et al., 1988).

4 Depression and Bipolar Support It appears that bipolar disorder involves increased sensitivity to dopamine and

either decreased sensitivity to serotonin or a more general dysregulation in the dopaminergic system (Miklowitz & Johnson, 2006). Drugs used to treat the disorder include several atypical antipsychotics, as well as carbamazepine, valproate, and lithium. Carbamazepine and valproate stabilize electrical activity in the brain and are typically used as anticonvulsants for the treatment of epilepsy. Lithium, a metal administered in the form of lithium carbonate, is the medication of choice for bipolar illness; it is most effective during the manic phase, but it also prevents further depressive episodes. Examination of lithium’s effects has not identified any critical neurotransmitters, partly because lithium affects several transmitter systems (Worley, Heller, Snyder, & Baraban, 1988). It may be that lithium stabilizes neurotransmitter and receptor systems to prevent the large swings seen in manic-depressive cycling; its dual role as an antidepressant argues for a normalizing effect rather than a directional one (Gitlin & Altshuler, 1997). Closer examination, however, has revealed a specific effect on mania; lithium and valproate indirectly inhibit protein kinase C (PKC), a family of enzymes that regulate neural excitability. The breast cancer drug tamoxifen is used to block estrogen receptors but it also inhibits PKC. In a phase 2 clinical trial, 90% of patients receiving tamoxifen with lithium were considered in remission, versus 55% receiving lithium alone (Amrollahi et al., 2011). Tamoxifen itself may not be practical as a treatment for bipolar disorder because it antagonizes estrogen activity; if the drug continues to prove effective, an alternative that targets PKC only will have to be found. Brain Anomalies in Affective Disorders As with schizophrenia, affective disorders are associated with structural

abnormalities in several brain areas. Again, a larger ventricle size suggests loss of brain tissue, but the reductions are small and are not always found (Depue & Iacono, 1989). A review of numerous studies of depression reveals volume deficits in prefrontal areas, especially the dorsolateral cortex and the anterior cingulate cortex as

well as in the hippocampus, but an increased volume in the amygdala (J. R. Davidson, Pizzagalli, Nitschke, & Putnam, 2002). Volume reduction apparently precedes depression rather than being a degenerative consequence of it; it is evident at the time of patients’ first episode, and it can even be detected in the nondepressed offspring of patients (M. C. Chen, Hamilton, & Gotlib, 2010; Peterson et al., 2009; Zou et al., 2010).

What brain irregularities are involved in affective disorders? FIGURE 14.20 Decreased Frontal Activity in Depression. Blood flow was decreased (a) in the caudate nucleus and (b) in the dorsolateral prefrontal cortex (where the arrows point). The color scale is reversed in the scan in (a); yellow and red in that image indicate decreased activity.

SOURCES: (a) From “A Functional Anatomical Study of Unipolar Depression,” by W. C. Drevets et al., Journal of Neuroscience, 12, pp. 3628–3641. © 1992 Society for Neuroscience. Used with permission. (b) From “Reduction of Prefrontal Cortex Glucose Metabolism Common to Three Types of Depression,” by L. R. Baxter et al., 1999, Archives of General Psychiatry, 46(14), pp. 243–249. These structural alterations are accompanied by changes in activity level. Not

surprisingly, total brain activity is reduced in unipolar patients (Sackeim et al., 1990) and in bipolar patients when they are depressed (Baxter et al., 1985). Activity is particularly decreased in the caudate nucleus and the dorsolateral prefrontal cortex in both groups (Figure 14.20; Baxter et al., 1985; Baxter et al., 1989; Drevets et al., 1992). What is surprising is that some areas are more active in depressed patients. In unipolar depression, blood flow is higher in the amygdala and a frontal area connected to the amygdala called the ventral prefrontal cortex (Figure 14.21). The ventral prefrontal area may also be a “depression switch,” because activation comes and goes with bouts of depression. The amygdala continues to be active between episodes and returns to normal only after the remission of symptoms. Activity in the amygdala corresponds to the trait of depression—the continuing disorder—while activation of the ventral prefrontal area indicates the state of depression, which subsides from time to time in some individuals (Drevets, 2001; Drevets et al., 1992; Drevets & Raichle, 1995).

FIGURE 14.21 Increased Activity in the Ventral Prefrontal Cortex (PFC) and Amygdala in Depression.

SOURCE: From “A Functional Anatomical Study of Unipolar Depression,” by W. C. Drevets et al., Journal of Neuroscience, 12, pp. 3628–3641. © 1992 Society for Neuroscience. Used with permission. It is also not surprising that when the bipolar patient begins a manic episode, brain

metabolism increases from its depressed level by 4% to 36% (Figure 14.22; Baxter et al., 1985). The subgenual prefrontal cortex is particularly interesting because it has been suggested as a possible “switch” controlling bipolar cycling (Figure 14.23). Its metabolic activity is reduced during both unipolar and bipolar depression, but increases during manic episodes (Drevets et al., 1997). The structure is a part of the cingulate cortex, located at the midline; it is in a good position to act as a bipolar switch, because it has extensive connections to emotion centers such as the amygdala and the lateral hypothalamus and it helps regulate neurotransmitters involved in affective disorders. Imaging studies also implicate the anterior parts of the limbic system (Strakowski, 2011). Even when bipolar subjects were asymptomatic and working on a cognitive task, activity increased in limbic and associated areas (Strakowski, Adler, Holland, Mills, & DelBello, 2004). The researchers suggested that individuals with bipolar disorder are unable to suppress emotion networks during emotionally neutral activities. FIGURE 14.22 Glucose Metabolism Increase During Mania in a Rapid-Cycling Bipolar Patient. The middle row shows the sudden increase in activity during a manic episode, just a day after the previous scan during depression. In the bottom row, the patient had returned to the depressed state. SOURCE: From “Cerebral Metabolic Rates for Glucose in Mood Disorders: Studies With Positron Emission Tomography and Fluorodeoxyglucose F18,” by L. R. Baxter et al., 1985, Archives of General Psychiatry, 42, pp. 441–447.

Both depressed and bipolar patients have anomalies in functional brain connectivity. Connectivity is reduced in the cortex, corpus callosum, and thalamus in individuals with bipolar disorder (Barysheva, Jahanshad, Foland-Ross, Altshuler, & Thompson, 2013). In depression, increased as well as decreased connectivity has been reported. For example, one study reported decreased connectivity between frontal areas and the ventral striatum, but increased connectivity between frontal areas and the dorsal striatum (Furman, Hamilton, & Gotlib, 2011). Treatment has been shown to increase deficient connectivity between some areas (Heller et al., 2013) and to decrease excess connectivity in others (Perrin et al., 2012). In both cases, the changes in connectivity were accompanied by symptom improvement. FIGURE 14.23 Activity in the Subgenual Prefrontal Cortex in Depression and Mania. (a) The dark areas (at the end of the red lines) indicate decreased activity during depression in the subgenual prefrontal cortex. (b) Comparison of groups shows that activity in the subgenual PFC is lower during depression and higher during mania, which suggests that it controls cycling between depression and mania.

SOURCES: (a) From “Subgenual Prefrontal Cortex Abnormalities in Mood Disorders,” by W. C. Drevets et al., Nature, 386, 824–827. © 1997 Macmillian

Publishing Inc. (b) From “Neurimaging and Neuropathological Studies of Depression: Implications for the Cognitive-Emotional Features of Mood Disorders,” by W. C. Drevets, Current Opinion in Neurobiology, 11, pp. 240–249, fig. 4b. © 2001 with kind permission of Elsevier. Suicide Suicide accounts for more deaths than homicide or war; it is the 13th leading cause

of death worldwide and the 4th among those aged 15 to 44 years (World Health Organization, 2002). Ninety percent of people who attempt suicide have a diagnosable psychiatric illness; mood disorder alone accounts for 60% of all completed suicides (Figure 14.24; Mann, 2003). Bipolar patients are most at risk; about 20% of people who have been hospitalized for bipolar disorder commit suicide. According to the stress-diathesis model, the suicidal individual has a predisposition, known as a diathesis, and then stress such as a worsening psychiatric condition acts as an environmental “straw that breaks the camel’s back” (Mann, 2003). FIGURE 14.24 Suicide Rates for Three Disorders in Men and Women.

SOURCE: From “Catamnestic Long-Term Study on the Course of Life and Aging of Schizophrenics,” by L. Ciompi, 1980, Schizophrenia Bulletin, 6, pp. 607–618, fig. 2, p. 610. Copyright © Oxford University Press. Used with permission. The predisposition is at least partly genetic; a study of depressed patients located

six chromosome sites that were associated with suicidal risk but independent of susceptibility for mood disorders (Zubenko et al., 2004). Psychiatric patients who attempt suicide also are more likely to have low levels of the serotonin metabolite 5- hydroxyindoleacetic acid (5-HIAA) than nonattempters, which means that their serotonin activity is particularly decreased. When a group of patients at risk for suicide was followed for 1 year, 20% of those who were below the group median in 5- HIAA level had committed suicide; none of the patients above the median had (Träskman, Åsberg, Bertilsson, & Sjöstrand, 1981). Other studies have confirmed the association between lowered serotonin and suicidality (see Figure 14.25; Mann, 2003; Roy, DeJong, & Linnoila, 1989; M. Stanley, Stanley, Traskman-Bendz, Mann, & Meyendorff, 1986). Lowered 5-HIAA is found in suicide attempters with a variety of

disorders and probably reflects impulsiveness rather than the patient’s specific psychiatric diagnosis (Mann et al., 1990; M. Stanley et al., 1986; Träskman et al., 1981); this view was supported by a later study in which impulsive suicide attempters were found to have lower 5-HIAA than either nonimpulsive attempters or controls (Spreux-Varoquaux et al., 2001). However, antidepressants can increase the risk of suicide. A variety of explanations

have been offered, including the agitation that often accompanies selective serotonin reuptake inhibitor (SSRI) use (Fergusson et al., 2005) and disappointment over slow improvement and side effects (Mann, 2003). Particular concern about the vulnerability of children and adolescents resulted in a 22% decrease in SSRI prescriptions for youths in the United States and the Netherlands; unfortunately, this turned out to be a case of throwing out the baby with the bathwater, since youthful suicides increased 14% in the United States in 1 year and 49% in the Netherlands over 2 years (Gibbons et al., 2007). Rather than reducing prescriptions wholesale, therapists need to be selective and to monitor their patients for suicidal tendencies. FIGURE 14.25 Serotonin Levels and Suicide. Serotonin level, as assessed by the metabolite 5-HIAA,was lower in depressed patients who attempted suicide than in those who did not, and even lower in those who reattempted.

SOURCE: Based on data from Roy, DeJong, and Linnoila (1989). Research has identified heritable characteristics that distinguish people at risk for

suicide from others, referred to as endophenotypes. The most reproduced personality indicators have been impulsivity and aggression (Courtet, Gottesman, Jollant, & Gould, 2011). Disadvantageous decision making, indicated by measures such as the Iowa Gambling Task, suggest a prefrontal deficiency, and this has been verified in terms of reduced neural activity and altered prefrontal serotonergic functioning. The heritability of suicidal behavior (ideation as well as attempts) has been estimated in various studies at between 38% and 55% (Brent & Melhem, 2008). Locating genes

Concept Check

that predispose a person to suicide has been difficult, in part because of confounding with so many instigators to suicide; these include mental illness, physical illness, and life disappointments. Most studies have pointed to serotonin-related genes and genes involved with brain-derived neurotrophic factor, and a few other genes have been implicated, but there has been little confirmation (Tsai, Hong, & Liou, 2011).

Take a Minute to Check Your Knowledge and Understanding

State the monoamine hypothesis; what is the evidence for it? How is affective disorder related to circadian rhythms? What brain differences are involved in the affective disorders? What are some of the factors in suicide?

Anxiety Disorders Anxiety disorders include several illnesses. The major ones—phobia, generalized anxiety, and panic disorder—have lifetime risks of about 13%, 9%, and 6.8%, respectively (Kessler et al., 2012). But their significance lies less in their prevalence than in the disruptiveness of their symptoms. The panic disorder patient or the phobic patient may be unable to venture out of the house, much less hold down a job. Generalized Anxiety, Panic Disorder, and Phobia Anxiety is often confused with fear; however, as we saw in Chapter 8, fear is a

reaction to real objects or events present in the environment, while anxiety involves anticipation of events or an inappropriate reaction to the environment. A person with generalized anxiety has a feeling of stress and unease most of the time and overreacts to stressful conditions. In panic disorder, the person has a sudden and intense attack of anxiety, with symptoms such as rapid breathing, high heart rate, and feelings of impending disaster. A person with a phobia experiences fear or stress when confronted with a particular situation—for instance, crowds, heights, enclosed spaces, open spaces, or specific objects such as dogs or snakes. Neurotransmitters Benzodiazepines were the most frequently used anxiolytic (antianxiety) drugs in

the past (Costall & Naylor, 1992) but now are considered a second line of defense because of their addiction potential. You may remember from our earlier discussion of drugs that benzodiazepines increase receptor sensitivity to the inhibitory transmitter gamma-aminobutyric acid (GABA), which is a major neurotransmitter in anxiety. A deficit in benzodiazepine receptors may be one cause of anxiety disorder. Marczynski and Urbancic (1988) injected pregnant cats with a benzodiazepine tranquilizer. When the offspring were 1 year old, they were restless and appeared anxious in novel

situations. When their brains were studied later, several areas of the brain had compensated for the tranquilizer by reducing the number of benzodiazepine receptors.

What causes anxiety disorders? Anxiety also appears to involve low activity at serotonin synapses. Antianxiety

drugs initially suppress serotonin activity, but then they apparently produce a compensatory increase. The idea that a serotonergic increase is involved in anxiety reduction is supported by the fact that antidepressants are now the drug of choice for treating anxiety. Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) is a prolonged stress reaction to a traumatic

event; it is typically characterized by recurrent thoughts and images (flashbacks), nightmares, lack of concentration, and overreactivity to environmental stimuli, such as loud noises. Because of recent news coverage, we usually associate PTSD with combat experiences, but it can be triggered by all kinds of trauma, including robbery, sexual assault, hostage situations, and automobile accidents. Men are more often exposed to such traumas, but women are almost four times as likely to develop PTSD when they do experience trauma (Fullerton et al., 2001). PTSD symptoms are resistant to traditional drug and psychotherapy treatments; an alternative approach is exposure therapy, which allows the individual to confront anxiety-provoking stimuli in the safety of the therapist’s office. Exposure therapy is essentially an extinction process, and fear memories are notoriously resistant to extinction, especially in the 30% of people who have the VAL66MET allele (which we saw is also involved in depression). We know this gene plays a causal role in fear extinction, because when it was inserted into mice they showed the same increased resistance (Soliman et al., 2010). Brain imaging of human subjects during extinction trials showed why; connections between the prefrontal cortex and the amygdala that are important in fear conditioning and extinction were hypoactive in carriers of the allele. In their search for better therapies, researchers are resorting to novel approaches;

some, for example believe that therapists could take a lesson from the phenomenon of reconsolidation that you learned about in Chapter 12. A team led by Daniela Schiller (2010) used a mild electric shock to condition an emotional reaction (measured by skin conductance response) to a blue square. A day later, the response was extinguished by repeatedly presenting the blue square alone. However, two subgroups of subjects received a “reminder” of the fear memory, one 10 minutes before extinction began and the other 6 hours before; the reminder was intended to start reconsolidation, a window of opportunity that was expected to remain open during extinction for the 10-minute group but to be closed by the time the 6-hour group’s extinction trials began. It worked: The skin conductance response was almost entirely absent in the 10-minute group but had recovered to near training levels in the two

other groups; the effect persisted for a year. Researchers hope this technique of fear erasure can be used to help relieve PTSD sufferers of their lingering fear and anxiety, but you would probably be more comfortable with the strategy that is described in the accompanying In the News.

Virtual Reality Isn’t Just for Video Games You probably think virtual reality is the coolest gamer’s device ever, but it could also be a much-needed therapeutic tool for difficult-to-treat anxiety disorders, including PTSD. A video immerses the patient in a virtual re-creation of a military patrol or a busy freeway or a darkened parking garage similar to the situation where the trauma occurred. The patient controls progress through an interactive scenario, backing off and practicing newly learned relaxation techniques when the stress gets too intense, while the therapist monitors physiological

measures of stress, such as skin conductance and finger temperature. Virtual reality is being used on an experimental basis, particularly with the

estimated 13% of U.S. combat veterans who have been diagnosed with PTSD. Preliminary results indicate an 80% improvement rate, compared with 40% for drug treatment and 44% for psychotherapy (Wiederhold, 2010). In the first study of its kind, JoAnn Difede and her colleagues at Weill Cornell Medical College combined virtual reality therapy with D-cycloserine. D-cycloserine is an antibiotic, but it has been found to increase neural plasticity and enhance learning. Patients with chronic PTSD were given either a dose of the drug or a placebo 90 minutes before each of 10 weekly virtual reality sessions that re-created the stimuli involved in their original trauma. By the sixth session, the drug/virtual reality group had begun to show faster improvement than the placebo/virtual reality group. At the end of training, remission rates were 46% for the drug group and 8% for the placebo group, and these rates increased to 69% versus 17% after 6 months.

5 Virtual Reality News SOURCES: “Posttraumatic Stress Disorder: Virtual Reality and Other Technologies Offer Hope,” Mary Ann Liebert Inc./Genetic Engineering News, February 12, 2010, ScienceDaily. Retrieved from http://www.sciencedaily.com/releases/2010/02/100211163118.htm; Cyberpsychology, Behavior, and Social Networking (2010), 13(1). Available at http://www.liebertonline.com/toc/cyber/13/1.

Anomalies in Brain Functioning For the most part, the various anxiety disorders share a commonality of functional

brain anomalies. Not surprisingly, the amygdala is hyperresponsive; the anterior cingulate cortex is hyperactive in general anxiety, panic disorder, and phobias, and the insular cortex is overly responsive in phobias and PTSD (Etkin & Wager, 2007; Morey et al., 2012; Shin & Liberzon, 2010). PTSD is distinguished by decreased activity in the medial prefrontal cortex and, according to some studies, in the hippocampus. Some structures have been reported to be smaller in anxiety disorders, particularly in PTSD. Researchers have usually assumed these variations were the result of the anxiety disorders, but we will see that this is not always the case. FIGURE 14.26 Hippocampal Volume is Reduced in Combat Veterans and Their Twins. Similar reduction in unexposed identical twins of PTSD patients suggests that hippocampal reduction is a predisposing factor.

SOURCE: From “Smaller Hippocampal Volume Predicts Pathologic Vulnerability to Psychological Trauma,” by M. W. Gilbertson et al., Nature Neuroscience, 5, pp. 1242–1247. Copyright © 2002 Nature Publishing Group. Used with permission. Whether trauma is followed by PTSD is unrelated to either the severity of the

traumatic event or the individual’s distress at the time (Harvey & Bryant, 2002; Shalev et al., 2000); the key apparently is the person’s vulnerability. Mark Gilbertson and his colleagues (2002) used magnetic resonance imaging to measure hippocampal volumes in Vietnam combat veterans and their noncombat identical twins. Those who suffered from PTSD had smaller hippocampi than PTSD-free veterans, as expected, but so did the PTSD subjects’ noncombat twins (Figure 14.26). Hippocampal reduction is often associated with childhood abuse, and Elizabeth Binder and her coworkers (2008) found that previously abused individuals were twice as likely to succumb to PTSD following traumatic events. Two mutations of the FKBP5 gene are more common among PTSD patients who were abused and apparently contribute to the vulnerability (Binder et al.). A smaller anterior cingulate cortex (ACC) may also be a vulnerability factor. After the Japanese earthquake and tsunami in 2011, researchers at Tohoku University asked 42 local residents who had previously received MRI scans to return and have their brains imaged again. Though none of the

residents had full-blown PTSD, those with the highest scores had lower gray matter volumes in the orbitofrontal cortex and in the anterior cingulate cortex (ACC), compared with control subjects (Sekiguchi et al., 2013). Reduced volume in the orbitofrontal cortex had occurred since the first scan, but the high-scoring subjects had lower ACC volume at the time of the first scan; this suggests that a smaller ACC is a vulnerability factor for PTSD. This makes sense, because the ACC is involved in the processing of fear and anxiety and in eliminating fear-related memories. FIGURE 14.27 Networks Involved in Anxiety.

SOURCE: From “Functional Network Dysfunction in Anxiety and Anxiety Disorders,” by C. Sylvester et al., 2012, Trends in Neuroscience, 35(9). With permission from Elsevier. Of course, these structures operate as part of circuits, rather than in isolation from

each other or other parts of the brain. Chad Sylvester and his colleagues (2012) at Washington University in Saint Louis have identified four networks whose faulty performance they believe contributes to anxiety (Figure 14.27). The ventral attention network orients to attention-demanding stimuli and in people with anxiety disorders contributes to excessively stimulus-driven attention. Once a response to a situation is formulated, a salience network provides error detection by comparing the intended response with appropriate responses. A mismatch would signal the need for increased executive control, the domain of the frontoparietal network. Finally, the default mode network engages in self-monitoring, future planning, and emotion regulation; underactivity in this network results in poor emotional regulation. The Anxiety Disorders and Heredity Family and twin studies indicate that the anxiety disorders are genetically

influenced, with heritabilities ranging between 20% and 47%, depending on the

Concept Check

disorder (Abramowitz et al., 2009; P. E. Arnold et al., 2004; Hettema, Neale, & Kendler, 2001). Understanding the hereditary underpinnings of anxiety is difficult because of significant genetic overlap with other disorders. More than 90% of individuals with anxiety disorders have a history of other psychiatric problems (Kaufman & Charney, 2000). The overlap with mood disorders is particularly strong; 50% to 60% of patients with major depression also have a history of one or more anxiety disorders (Kaufman & Charney), and panic disorder is found in 16% of bipolar patients (Doughty, Wells, Joyce, Olds, & Walsh, 2004). Some neural commonality between these two groups is suggested by the effectiveness of antidepressants with both mood disorders and anxiety disorders. The anxieties themselves appear to fall into three genetically related clusters, with generalized anxiety, panic, and agoraphobia (fear of crowds and open places) in one group; animal phobias and situational phobias in the second; and social phobia overlapping genetically with both groups (Hettema, Prescott, Myers, Neale, & Kendler, 2005). Genetic research has most often implicated genes responsible for serotonin

production, serotonin reuptake, and various subtypes of serotonin receptors (reviewed in P. E. Arnold et al., 2004; Rothe et al., 2004; You, Hu, Chen, & Zhang, 2005). Other leads include genes for monoamine oxidase (Tadic et al., 2003), for the adenosine receptor (P. E. Arnold et al.; Lam, Hong, & Tsai, 2005), and for cholecystokinin and its receptor (P. E. Arnold et al., 2004).

Take a Minute to Check Your Knowledge and Understanding

What neurotransmitter deviations are involved in anxiety disorders? What brain anomalies are associated with anxiety disorders? What are the environmental, physiological, and genetic contributors to PTSD?

Obsessive-Compulsive Disorder Obsessive-compulsive disorder (OCD) consists of two behaviors, obsessions and compulsions, which occur in the same person. The disorder affects about 2.6% of the population over their lifetime (Kessler et al., 2012). An obsession is a recurring thought; a person may be annoyed by a tune that mentally replays over and over or by troubling thoughts such as wishing harm to another person. Normal people have similar thoughts, but for the obsessive individual, the experience is extreme and feels completely out of control. Just as the obsessive individual is a slave to thoughts, the compulsive individual is a slave to actions. He or she is compelled to engage in ritualistic behavior (such as touching a door frame three times before passing through the door), or endless bathing and hand washing, or checking to see if appliances are

turned off and the door is locked (Rapoport, 1991).

What is obsessive-compulsive disorder, and what causes it? One psychiatrist described a patient who tired of returning home to check whether

she had turned her appliances off and solved the problem by taking her coffeemaker and iron to work with her (Begley & Biddle, 1996). The playwright and humorist David Sedaris (1998) wrote that his short walk home from school during childhood took a full hour because of his compulsion to stop every few feet and press his nose to the hood of a particular car, lick a certain mailbox, or touch a specific leaf that demanded his attention. Once home, he had to make the rounds of several rooms, kissing, touching, and rearranging various objects before he could enter his own room. About a fourth of OCD patients have a family member with OCD, suggesting a genetic involvement; boys are afflicted more often than girls, but the ratio levels off in adulthood (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989). FIGURE 14.28 Brain Structures Involved in Obsessive-Compulsive Disorder. Scans of OCD patients show that (a) activity is elevated in the caudate nucleus (a part of the basal ganglia) and in the orbital gyrus, and that (b) behavior therapy reduces this activity in the caudate nucleus.

SOURCES: (a) From “Local Cerebral Glucose Metabolic Rates in Obsessive Compulsive Disorder,” by L. R. Baxter et al., 1987, Archives of General Psychiatry, 44(14), pp. 211–218. (b) From “Systematic Changes in Cerebral Glucose Metabolic Rate After Successful Behavior Modification Treatment of Obsessive-Compulsive Disorder,” by J. M. Schwartz et al., 1996, Archives of General Psychiatry, 53(14), pp. 109–113. Brain Anomalies in Obsessive-Compulsive Disorder Imaging studies reveal increased activity in the orbitofrontal cortex, especially the

left orbital gyrus, and in the caudate nuclei (Whiteside, Port, & Abramowitz, 2004). It is unclear whether these increases cause OCD or are merely activation increases associated with symptoms of OCD, such as worry. However, both drug treatment and

behavior therapy reduce activation of the caudate nucleus and, in at least one study, the orbital gyrus as well (Figure 14.28; Porto et al., 2009; J. M. Schwartz et al., 1996; Swedo, Schapiro, et al., 1989). White matter reductions indicate that there are deficient connections between the cingulate gyrus and a circuit involving the basal ganglia, thalamus, and cortex, which apparently result in a loss of impulse control (Insel, 1992; Szeszko et al., 2005). An indication of dysfunction in this network is that orbitofrontal activity does not increase when OCD patients are required to reverse a previously correct choice; their unaffected relatives show the same deficit, suggesting that it is genetic (Chamberlain et al., 2008). OCD occurs with a number of diseases that damage the basal ganglia (H. L.

Leonard et al., 1992) which, you will remember, are involved in motor activity. There is growing evidence that the disorder can be triggered in children by a streptococcal infection that results in an autoimmune attack on the basal ganglia; vulnerability to the immune malfunction apparently is hereditary (P. D. Arnold & Richter, 2001; P. E. Arnold, Zai, & Richter, 2004). OCD has also been reported in cases of head injury (McKeon, McGuffin, & Robinson, 1984). The most famous obsessive-compulsive individual was the multimillionaire Howard Hughes (R. Fowler, 1986). Some signs of disorder during childhood and his mother’s obsessive concern with germs suggest either genetic vulnerability or environmental influence. However, symptoms of OCD did not begin until after a series of airplane crashes and automobile accidents that left him almost unrecognizable (Figure 14.29). When a business associate died, Hughes gave explicit instructions that flowers for the funeral were to be delivered by an independent messenger who would not have any contact with the florist or with Hughes’s office—even to the point of sending a bill—to prevent “backflow” of germs (Bartlett & Steele, 1979). Assistants were required to handle his papers with gloves, sometimes several pairs, and he in turn grasped them with a tissue. He instructed his assistants not to touch him, talk directly to him, or even look at him; his defense for this behavior was that everybody carries germs and he wanted to avoid germs (R. Fowler). FIGURE 14.29 Howard Hughes. Hughes was an extraordinarily successful businessman and dashing man-about- Hollywood, but he spent his later years crippled by symptoms of OCD.

SOURCE: © Bettmann/Corbis. Treating Obsessive-Compulsive Disorder Researchers believe that OCD patients are high in serotonergic activity. This was

suggested by the fact that people with OCD are inhibited in action and feel guilty about aggressive impulses; sociopaths, on the other hand, feel no guilt after committing impulsive crimes, and they have lowered serotonin activity. But the only drugs that consistently improve OCD symptoms are antidepressants that inhibit serotonin reuptake (Insel, Zohar, Benkelfat, & Murphy, 1990). So, if OCD patients do have high serotonergic activity, then reuptake inhibitors must work by causing a compensatory reduction in activity; there is some evidence that treatment does decrease the sensitivity of serotonin receptors (Insel et al., 1990), but the nature of serotonin involvement remains uncertain (Graybiel & Rauch, 2000). Patient response to serotonin reuptake inhibitors is usually only partial, and some

patients do not respond at all; a third of these benefit from antipsychotics, and an antiglutamate drug produces modest relief (Abramowitz, Taylor, & McKay, 2009), suggesting the involvement of these transmitters. For treatment-resistant patients, psychosurgery is an option. Forty-seven percent of patients went into remission following cingulotomy, which involves lesioning the ACC, and another 22% improved (Sheth et al., 2013). A less drastic procedure is deep brain stimulation (DBS), targeting the internal capsule, a bundle of fibers that connect the frontal lobe with the thalamus and other areas. A DBS device was approved by the FDA in 2009 after it produced a 40% reduction in symptoms in OCD patients (“FDA Approves Humanitarian Device Exemption,” 2009). A meta-analysis of 113 studies found associations with two serotonin genes and, in

males only, two genes involved in degradation of dopamine and serotonin (Taylor, 2013). There were trends for two dopamine-related genes and a glutamate-related gene, but these were not statistically significant. The rate of disorders in relatives of people with OCD suggests a genetic association with anxiety disorders, depression, tic disorders such as Tourette’s syndrome, and grooming disorders such as hair pulling

and skin picking (Bienvenu et al., 2012). FIGURE 14.30 Excessive Grooming and the Sapap3 Gene. The mouse lacking the Sapap3 gene (top) has groomed to the point of creating lesions on the neck and face and even damaging the eye.

SOURCE: Courtesy of Jing Lu, Jeff Welch, and Guoping Feng. Related Disorders The symptoms of OCD, particularly washing and “grooming” rituals and

preoccupation with cleanliness, suggest to some researchers that it is a disorder of “excessive grooming” (H. L. Leonard, Lenane, Swedo, Rettew, & Rapoport, 1991; Rapoport, 1991). Dogs and cats sometimes groom their fur to the point of producing bald spots and ulcers in a disorder known as acral lick syndrome. Some chimpanzees and monkeys engage in excessive self-grooming and hair pulling, and 10% of birds in captivity compulsively pull out their feathers, occasionally to the point that the bird is denuded and at risk for infection and hypothermia. Clomipramine, an antidepressant that inhibits serotonin reuptake, is effective in reducing all these behaviors (Grindlinger & Ramsay, 1991; Hartman, 1995; Rapoport, 1991). If you think that the excessive grooming idea sounds far-fetched, consider the

human behaviors of nail biting and obsessive hair pulling (trichotillomania), in which the person pulls hairs out one by one until there are visible bald spots or even complete baldness of the head, eyebrows, and eyelashes. There are several similarities between hair pulling and OCD: Both behaviors appear to be hereditary, and hair pullers have a high frequency of relatives with OCD; both symptoms also respond to serotonin reuptake inhibitors (Leonard et al., 1991; Swedo et al., 1991). However, trichotillomania and OCD sufferers appear to differ from each other in their versions of the Sapap3 gene (Bienvenu et al., 2008). The gene’s normal role is most likely a

protective one, since mice that lack the gene groom to the point of self-injury; their behavior is relieved by a serotonin reuptake inhibitor (Figure 14.30; Welch et al., 2007). Hoarders are dedicated collectors, stashing away just about anything from string to

old newspapers. People with OCD are often hoarders as well, but hoarding disorder is considered distinct from OCD. David Tolin and his colleagues (2012) placed people with hoarding disorder in an fMRI scanner and had them look at pictures of junk mail and newspapers and decide whether to keep or discard them. The subjects had brought 50 of the items from home, and another 50 were provided by the experimenters. Hoarders, people with OCD, and healthy controls all were willing to discard more than 40 of the 50 items that were not theirs. When it came to their own items, the healthy controls discarded 40 and those with OCD discarded 37, but the hoarders gave up only 29. More telling, during this part of the study the hoarders reported “not feeling right” and showed more activity than the others in the ACC, which evaluates behavior and detects errors, and in the insula, which is important to a sense of self. Apparently, giving up these possessions was threatening; this can lead to really bizarre behavior, as the accompanying Application reveals.

APPLICATION

Of Hermits and Hoarders Hoarders is a documentary series on A&E television that profiles extreme hoarders; in one segment, the home is so cluttered that the couple is forced to take meals in bed (Weiss, 2010). In each episode, clinicians and professional organizers, with the aid of friends and family, assist the hoarder in the cleanup of his or her home. The intervention is usually precipitated by a crisis, such as a threat to remove the children for health and safety reasons. Hoarding can be so extreme that it poses broader dangers as well; for example, 14 firefighters were injured when 150 of them were called to put out a fire in a New York City apartment filled with floor-to-ceiling junk (Newman, 2006). But the unquestionable all-time champion hoarders were the Collyer

brothers. They grew up in a Fifth Avenue New York mansion with their eccentric first-cousin parents; their father, a gynecologist, canoed to work at Bellevue Hospital and the family gave up their telephone, electricity, and gas to “simplify” their lives (Weiss, 2010). Homer became an attorney, and Langley graduated from Columbia in mechanical engineering and chemistry and then tried a concert piano career. After the parents died, the two brothers became reclusive hermits. Homer was confined to the home by blindness and arthritis, but Langley busied himself with nighttime treks through Harlem, dragging a cardboard box by a rope and collecting odds and ends off the

streets. On March 21, 1947, responding to a tip about an odor, police broke into the mansion through a second-story window after finding the foyer blocked by a solid wall of junk (“Collyer Brothers,” n.d.). They found Homer dead of starvation and no sign of Langley. The home was so filled with clutter that Langley had made tunnels through the debris in order to move from room to room; some of those tunnels were rigged with booby traps as a defense against intruders. Authorities began the task of removing the trash and junk from the home; 18 days after Homer’s body was discovered, Langley was found just 10 feet away, crushed under one of his own traps. Among the 130 tons removed from the home there was so little of value that an auction brought only $1,800. For the next decade, children were forced to grow up with their mothers’ admonition, “Clean up your room or you’ll end up like the Collyer brothers!” (Weiss, p. 251).

Searchers Climb Over Debris Piled Almost to the Ceiling in the Collyer Home. SOURCE: © Bettmann/CORBIS.

6 Hoarders

Another disorder associated with OCD is Tourette’s syndrome, whose victims suffer from a variety of motor and phonic (sound) tics. They twitch and grimace, throw punches at the air, cough, grunt, bark, swear, blurt out racial slurs or sexual remarks, insult passersby, echo what others say, and mimic people’s facial expressions and gestures. Both OCD and Tourette’s sufferers can manage their symptoms for short periods; for instance, Tourette’s patients are usually symptom free while driving a car, having sex, or performing surgery (yes, some of them are surgeons!). But neither OCD nor Tourette’s is a simple matter of will: Children often suppress compulsive rituals at school and “let go” at home, or they suppress tics during the day and then tic during their sleep. Neurologist Oliver Sacks (1990) graphically describes a woman on the streets of New York who was imitating other people’s expressions and gestures as

she passed them on the sidewalk:

What causes the bizarre behavior of Tourette’s? Suddenly, desperately, the old woman turned aside, into an alley-way which led off the main street. And there, with all the appearances of a woman violently sick, she expelled... all the gestures, the postures, the expressions, the demeanours, the entire behavioural repertoires, of the past forty or fifty people she had passed. (p. 123)

7 Tourette’s Syndrome Symptoms begin between the ages of 2 and 15 years and usually progress from

simple to more complex tics, with increasing compulsive or ritualistic qualities. The incidence of Tourette’s is difficult to determine; in recent studies the numbers have varied from 3 to 8 per 1,000 persons. In a survey of 64,000 children in the United States, the rate was 3 out of every 1,000, with three times as many males as females (Scahill, Bitsko, Visser, & Blumberg, 2009). Tourette’s syndrome is genetically influenced, with a concordance rate of 53% for identical twins and 8% for fraternal twins (R. A. Price et al., 1985). Tourette’s shares some genetic roots with OCD; a third of early-onset OCD patients also have Tourette’s syndrome (do Rosario-Campos et al., 2005), and 30% of adults with Tourette’s are also diagnosed with OCD (R. A. King, Leckman, Scahill, & Cohen, 1998). Recent studies have identified a mutation of the SLITRK1 gene in Tourette’s and found a mutation of the Hdc gene in a man and his eight offspring, all of whom have the disorder (Abelson et al., 2005; Ercan- Sencicek et al., 2010). The genes function in neural development and transmission, and both are highly active in brain areas involved in Tourette’s. FIGURE 14.31 Increased Dopamine Activity in the Caudate Nuclei in Tourette’s Syndrome. These two scans have not been superimposed over images of a brain; you can refer to Figure 14.28b to see where the caudate nuclei are located in the brain.

SOURCE: From “[123I] α-CIT SPECT Imaging of Striatal Dopamine Transporter Binding in Tourette’s Disorder,” by R. T. Malison et al., 1995, American Journal of Psychiatry, 152, pp. 1359–1361. Copyright © 1995 American Psychiatric Publishing. Used with permission. Tourette’s syndrome, like OCD, involves increased activity in the basal ganglia.

But unlike OCD, the most frequently prescribed drug for Tourette’s is an

Concept Check

antidopaminergic drug, haloperidol, though newer antidopamine drugs are also being used. One effect dopamine has is motor activation, and Malison and his colleagues (1995) found that dopamine activity is elevated in Tourette’s sufferers in the caudate nuclei of the basal ganglia (Figure 14.31). There has been some success treating Tourette’s with deep brain stimulation to the thalamus, which suppressed tics and produced feelings of calmness (Okun et al., 2013).

Take a Minute to Check Your Knowledge and Understanding

Describe the symptoms of OCD and the related disorders. What treatments are used with these disorders?

In Perspective The past three decades have seen enormous progress in research, and we now know a great deal about the physiological causes of disorders. We owe these breakthroughs to advances in imaging techniques and genetics research technology and to our greatly improved understanding of the physiology of synapses, not to mention the persistence of dedicated researchers. The result is that we can now describe at the biological level many disorders that previously were considered to be purely “psychological” in origin or that were only suspected of having an organic basis. In spite of these great research advances, we cannot reliably distinguish the

schizophrenic brain from a normal one or diagnose depression or an anxiety disorder from a blood test. We may be able to someday, but in the meantime, we rely for diagnosis on the behavior of the individuals. We know, at least to some extent, the physiological components of mental illness, but we do not understand the unique combination that determines who will become disordered and who will not. As long as that is true, our treatments will remain a pale hope rather than a bright promise.

8 Report of the Surgeon General We have been reminded repeatedly that genetic vulnerability is not the same thing

as fate. In most cases, the genes produce an illness only with the cooperation of the environment. This point is emphasized by the fact that psychotherapy plays an important role in treatment, enhancing and sometimes exceeding the benefit drugs can provide (see Durand & Barlow, 2006). While we search for genetic treatments of the disorders, we must remind ourselves once again that heredity is not destiny; improving the physical and psychological welfare of the population would go a long way toward preventing mental illness or reducing its severity.

Just before the dawning of this new age of research, one frustrated schizophrenia researcher concluded, “Almost everything remains to be done” (Heston, 1970, p. 254). Since then our knowledge of both the brain and its participation in the symptoms of mental illness has increased dramatically, but as you can see, much of our understanding remains tentative. The pace is quickening, and I am confident that in this second decade of the new millennium, we will be celebrating even more impressive advances than in the past. Summary Schizophrenia • Schizophrenia is characterized by some mix of symptoms such as hallucinations, delusions, thought disorder, and withdrawal.

• Twin and adoption studies indicate that heritability is.60 to.90. Genetic influences involve many small-effect genes and rarer copy number variations with stronger effects. Genes apparently determine the level of vulnerability.

• Schizophrenia is usually divided into positive and negative symptoms, possibly distinguished by excess dopamine activity versus brain deficits.

• Although there is evidence for the dopamine hypothesis, it is an incomplete explanation. The glutamate hypothesis is getting more attention because NMDA receptor antagonists produce symptoms of schizophrenia and drugs that activate NMDA receptors relieve them.

• The brain irregularities include ventricular enlargement (due to tissue deficits), hypofrontality, and impaired connections; these apparently arise from prenatal insults and impaired postnatal development, in interaction with genetic vulnerability. Reduced connectivity and impaired synchrony between areas are also involved.

• Maternal effect from illnesses such as influenza and prenatal starvation are examples of environmental influences.

Affective Disorders • The affective disorders include depression and bipolar disorder, an alternation between mania and depression.

• The affective disorders are also highly heritable, especially for women. Some genes are shared with schizophrenia, ASD, and ADHD.

• The most prominent explanation of affective disorders is the monoamine hypothesis.

• ECT is a controversial but very effective last-resort therapy that has value when medications fail and as a temporary suicide preventative.

• Both drugs and ECT increase neurogenesis and neural plasticity. • People with affective disorders often have disruptions in their circadian rhythm. Others respond to seasonal changes with winter depression or summer depression.

• Bipolar disorder is less understood than unipolar depression, even though lithium is

often a very effective treatment. Response to atypical antipsychotics suggests involvement of dopamine and, possibly, serotonin.

• A number of brain anomalies distinguish depressed people from bipolar patients and both from normal people.

• Depression, low serotonin activity, and several genes are associated with suicide risk.

Anxiety Disorders • The anxiety disorders are characterized mostly by brain hyperresponsiveness, but activity is decreased in some areas in PTSD.

• Anxiety involves low serotonin activity; GABA transmission and benzodiazepine receptor deficiency may also be involved.

• The anxiety disorders are partially hereditary, and the serotonin system is most often implicated. There is considerable overlap with mood disorders.

Obsessive-Compulsive Disorder • In OCD, activity is increased in the orbitofrontal cortex; deficient connections with the cingulate gyrus apparently reduce impulse control.

• OCD is associated with grooming disorders. • Tourette’s shares some genetic roots with OCD, but OCD appears to involve high serotonin activity, while Tourette’s is treated with dopamine antagonists. ■

Study Resources

For Further Thought • Now that we are nearing the end of the text, summarize what you know about the interaction of heredity and environment. Give examples from different chapters and include the concept of vulnerability.

• Give an overall view of what produces deviant behavior (going back to earlier chapters as well as this one). What effect does this have on your ideas about responsibility for one’s behavior?

• Behavior is vulnerable to a number of disturbances, involving both genetic and environmental influences. Consider the different ways complexity of the brain contributes to this vulnerability.

Quiz: Testing Your Understanding 1. Explain the dopamine theory of schizophrenia. What are its deficiencies?

What alternative or complementary explanations are available? 2. Describe the monoamine hypothesis of depression; include the evidence for

it and a description of the effects of the drugs and ECT used to treat depression.

3. Describe the similarities and associations among OCD, Tourette’s, and “grooming” behaviors.

Select the best answer:

1. If you were diagnosed with schizophrenia, you should prefer ____ symptoms. a. positive b. negative c. chronic d. bipolar

2. The fact that schizophrenia involves multiple genes helps explain a. vulnerability to winter viruses. b. the onset late in life. c. positive symptoms. d. different degrees of vulnerability.

3. All drugs that are effective in treating schizophrenia a. interfere with reuptake of dopamine. b. have some effect at D2 receptors. c. stimulate glutamate receptors. d. inhibit serotonin receptors.

4. Schizophrenia apparently involves a. tissue deficits. b. frontal misfunction. c. disrupted connections. d. a and b e. a, b, and c

5. One hypothesis about the timing of the onset of schizophrenia is that a. the individual is vulnerable to the effect of viruses then. b. dopamine levels decrease with age. c. adolescence is a period of brain maturation. d. there is considerable neuron death then.

6. The monoamine hypothesis states that depression results from a. reduced activity in norepinephrine and serotonin synapses. b. increased activity in norepinephrine and serotonin synapses. c. reduced activity in norepinephrine, serotonin, and dopamine synapses. d. increased activity in norepinephrine, serotonin, and dopamine synapses.

7. ECT appears to relieve depression by a. producing amnesia for depressing memories. b. the same mechanisms as antidepressant drugs. c. punishing depressive behavior. d. increasing EEG frequency.

8. A frontal area hypothesized to switch between depression and mania is the a. dorsolateral prefrontal cortex. b. caudate nucleus.

c. ventral prefrontal cortex. d. subgenual prefrontal cortex.

9. Studies indicate that risk for suicide is related to a. low norepinephrine and serotonin. b. high norepinephrine and serotonin. c. low serotonin. d. low norepinephrine.

10. The anxiety disorders are associated genetically with a. schizophrenia and depression. b. schizophrenia. c. depression. d. none of these

11. Of these, the best predictor of PTSD following trauma is a. a history of childhood abuse. b. being male. c. the severity of the trauma. d. the intensity of the reaction to the trauma.

12. OCD can be caused by a. genes. b. diseases and head injury. c. example of a family member. d. a and b e. a, b, and c

13. OCD and Tourette’s both involve compulsive rituals, probably because they involve a. increased dopamine. b. increased activity in the basal ganglia. c. a stressful home life. d. all of these

Answers: 1. a, 2. d, 3. b, 4. e, 5. c, 6. a, 7. b, 8. d, 9. c, 10. c, 11. a, 12. d, 13. b.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter. Chapter Resources • Quiz • Flashcards • Animations • Web links from the text

• Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. dmoz’s page on Schizophrenia has links to a large number of sites providing

information on the disorder. I and I, Dancing Fool, Challenge You the World to a Duel is Ian Chovil’s account of his schizophrenia, bizarre delusions, and homelessness. Coping much better on olanzapine, he now works part time educating the public about the illness.

2. PsychCentral offers an online Depression Screening Test to help a person assess his or her symptoms.

3. MD Junction and DailyStrength provide discussion groups for people affected by SAD and information about the disorder.

4. The Depression and Bipolar Support Alliance site is a place to learn about mood disorders and ongoing research and to take a mood disorders questionnaire.

5. The news article about treating PTSD with D-cycloserine and virtual reality therapy is available from Weill Cornell Medical College.

6. At Hoarders, you can watch entire episodes of the reality TV series; if you don’t have time for that, sample a few and read descriptions of the people for insights into the lives of hoarders and their families.

7. The Tourette Syndrome Association is a good resource for information on this disorder.

8. Mental Health: A Report of the Surgeon General concludes that mental health is an issue that the nation must address.

Chapter Updates and Biopsychology News

For Further Reading 1. When the Music’s Over: My Journey Into Schizophrenia, by Ross Burke

(Plume/Penguin, 1995), is the author’s account of his battle with schizophrenia, published by his therapist after Burke ended the battle with suicide.

2. An Unquiet Mind, by Kay Jamison (Knopf, 1995), tells the story of her continuing battle with bipolar disorder, which rendered her “ravingly psychotic” 3 months into her first semester as a psychology professor. With the aid of lithium, she has become an authority on mood disorders. (Kay Jamison is the writer quoted in the introduction to Chapter 1.)

3. Abnormal Psychology, by William Ray (SAGE, 2015), is a text written with a neuroscience perspective.

4. “Glutamatergic Mechanisms in Schizophrenia,” by G. Tsai and J. T. Cole (Annual Review of Pharmacology and Toxicology, 42, 165–179, 2002), reviews research that implicates the NMDA glutamate receptor in schizophrenia.

5. “All in the Mind of a Mouse,” by Carina Dennis (Nature, 438, 151–152, 2005), is an intriguing look at the creative ways researchers are using mice to study human psychological disorders.

6. “Are Bad Sleeping Habits Driving Us Mad?” by Emma Young (New Scientist, February 18, 2009, www.newscientist.com/article/mg20126962.100), describes evidence that lack of sleep can often be the cause rather than a symptom of disorders.

Key Terms acute bipolar disorder brain-derived neurotrophic factor (BDNF) chronic circadian rhythm depression dopamine hypothesis electroconvulsive therapy (ECT) glutamate theory lithium major depression mania monoamine hypothesis negative symptoms obsessive-compulsive disorder (OCD) phototherapy positive symptoms posttraumatic stress disorder (PTSD) psychosis rapid eye movement (REM) sleep schizophrenia seasonal affective disorder (SAD) tardive dyskinesia Tourette’s syndrome unipolar depression vulnerability model winter birth effect

Wisconsin Card Sorting Test

K

15 Sleep and Consciousness

In this chapter you will learn • About the rhythm of sleep and waking and its neural controls • About a shorter rhythm throughout the day, and its possible functions during sleep

• What some of the sleep disorders are and what causes them • How researchers are tackling the problem of consciousness • Some of the neural processes that contribute to consciousness

Sleep and Dreaming Circadian Rhythms Rhythms During Waking and Sleeping The Functions of REM and Non-REM Sleep Sleep and Memory Brain Structures of Sleep and Waking Sleep Disorders APPLICATION: IN THE STILL OF THE NIGHT

Sleep as a Form of Consciousness CONCEPT CHECK

The Neural Bases of Consciousness Awareness Attention The Sense of Self Network Explanations of Consciousness IN THE NEWS: CONSCIOUSNESS AND THE DYING BRAIN APPLICATION: DETERMINING CONSCIOUSNESS WHEN IT COUNTS CONCEPT CHECK

In Perspective Summary Study Resources

enneth Parks got up from the couch where he had been sleeping and drove 14 miles to his in-laws’ home. There he struggled with his father-in-law before

stabbing his mother-in-law repeatedly, killing her. He then drove to the police station, where he told the police that he thought he had “killed some people.” In court, his defense was that he was sleepwalking. Based on the testimony of sleep experts and the lack of motive—Ken had an affectionate relationship with his in-laws—the jury acquitted him of murder (Broughton et al., 1994). Were Ken’s actions possible for someone who was sleepwalking? Was he really

asleep and therefore not responsible? This case raises the question of what we mean by consciousness. Many psychologists, and especially neuroscientists, avoid the topic because they think that consciousness is inaccessible to research. This has not always been so; consciousness was a major concern of the fledgling discipline of psychology near the end of the 19th century. But the researchers’ technique of introspection was subjective: The observations were open only to the individuals doing the introspecting, who often disagreed with each other. This failing encouraged the development of behaviorism, which was based on the principle that psychology should study only the relationships between external stimuli and observable responses. Behaviorism was a necessary means of cleansing psychology of its subjective methods, but its purge discarded the subject matter along with the methodology. The interests of psychologists would not shift back to include internal experience until the emergence of the field of cognitive psychology in the 1950s and 1960s. “

Studying the brain without studying consciousness would be like studying the stomach without studying digestion.

—John R. Searle

” Many cognitive psychologists were finding it difficult to understand psychological

functions such as learning and perception without taking account of various aspects of consciousness. Still, few of them tackled the subject of consciousness itself. The problem seemed too big, there was no clear definition of consciousness, and the bias that consciousness was a problem for philosophers still lingered. Gradually, some of them began to ally themselves with philosophers, biologists, and computer experts to develop new research strategies for exploring this last frontier of psychology. The greatest inroads have been made in the study of sleep, largely because sleep is readily observable. Also, because sleep is open to study by objective techniques, it has not had the stigma among researchers that characterizes other aspects of consciousness. We will begin this last leg of our journey with the topic of sleep and dreaming. Sleep and Dreaming Each night, we slip into a mysterious state that is neither entirely conscious nor

unconscious. Sleep has intrigued humans throughout history: Metaphysically, dreaming suggested to our forebears that the soul took leave of the body at night to wander the world; practically, sleep is a period of enforced nonproductivity and vulnerability to predators and enemies. In spite of thousands of research studies, we are still unclear on the most basic

question—What is the function of sleep? The most obvious explanation is that sleep is restorative. Support for this idea comes from the observation that species with higher metabolic rates typically spend more time in sleep (Zeppelin & Rechtschaffen, 1974). A less obvious explanation is the adaptive hypothesis; according to this view, the amount of sleep an animal engages in depends on the availability of food and on safety considerations (Webb, 1974). Elephants, for instance, which must graze for many hours to meet their food needs, sleep briefly. Animals with low vulnerability to predators, such as the lion, sleep much of the time, as do animals that find safety by hiding, like bats and burrowing animals. Vulnerable animals that are too large to burrow or hide—for example, horses and cattle—sleep very little (see Figure 15.1). In a study of 39 species, the combined factors of body size and danger accounted for 80% of the variability in sleep time (Allison & Cicchetti, 1976).

1 Sleep Info An interesting new idea is that the brain cleanses itself of toxins during sleep.

Researchers at the University of Rochester in New York recently discovered a network of channels formed by glia, which transport cerebrospinal fluid (CSF) through the brain. By injecting a colored dye in the brains of mice as they slept and a dye of another color when they woke up, the researchers determined that large amounts of CSF flowed through the brain during sleep, but not during the awake state. The researchers then injected β amyloid proteins into the brains of the mice and found that the CSF cleared the proteins out of cells twice as fast during sleep (Xie et al., 2013). (Students note: This is one more argument for getting enough sleep!) FIGURE 15.1 Time Spent in Daily Sleep for Different Animals. Observations support the hypothesis that sleep is an adaptive response to feeding and safety needs.

SOURCE: Based on data from “Animal Sleep: A Review of Sleep Duration Across Phylogeny,” by S. S. Campbell and I. Tobler, 1984, Neuroscience and Biobehavioral Reviews, 8, pp. 269–300. “

Early to bed and early to rise, makes a man healthy, wealthy, and wise. —Benjamin Franklin

”

Whatever the function of sleep may be, its importance becomes apparent when we look at the effects of sleep deprivation. These effects are nowhere more evident than in shift work. Shift workers sleep less than day workers, and as a result their work performance suffers (Tepas & Carvalhais, 1990). Also, they typically fail to adjust their sleep-wake cycles adequately, because their sleep is disturbed during the day and they conform to the rest of the world’s schedule on weekends. With their work and sleep schedules at odds with their biological rhythms, shift workers find that sleep intrudes into their work and daytime arousal interferes with their sleep. Another study with mice may give us a clue why this happens. After just a few days of sleeping 3 to 5 hours a day, the mice had lost 25% of the neurons in the locus coeruleus, a part of the brain that is important for alertness (Zhang et al., 2014). In long-term sleep deprivation studies, impairment follows a rhythmic cycle—

performance declines during the night and then shows some recovery during the daytime (Horne, 1988). The persistence of this rhythm represents a safety hazard of gigantic proportions when people try to function at night. The largest number of single-vehicle traffic accidents attributed to “falling asleep at the wheel” occur around 2 a.m. (Mitler et al., 1988), and the number of work errors peaks at the same time (Broughton, 1975). In addition, the Three Mile Island nuclear plant accident took place at 4 a.m.; the Chernobyl nuclear plant meltdown began at 1:23 a.m.; the Bhopal, India, chemical plant leakage, which poisoned more than 2,000 people, began shortly after midnight; and the Exxon Valdez ran aground at 12:04 a.m., spilling 11 million

gallons of oil into fragile Alaskan waters (Alaska Oil Spill Commission, 1990; Mapes, 1990; Mitler et al., 1988). Travel across time zones also disrupts sleep and impairs performance, particularly

when you travel eastward. It is difficult to quantify the effects of jet lag, but three researchers have attempted to do so in a novel way by comparing the performance of baseball teams. When East Coast and West Coast teams played at home, their percentage of wins was nearly identical—50% and 49%, respectively. When they traveled across the continent but had time to adjust to the new time zone, they showed a typical visitor’s disadvantage, winning 45.9% of their games. Teams traveling west without time to adjust won about the same, 43.8% of their games, while teams traveling east won only 37.1% (Recht, Lew, & Schwartz, 1995). The quality of sleep is better when you extend the day’s length by traveling west, rather than shorten it as you do when you travel east. One way of looking at this effect is that it is easier to stay awake past your bedtime than it is to go to sleep when you are not sleepy. We will examine a more specific explanation when we consider circadian rhythms. Circadian Rhythms We saw in Chapter 14 that a circadian rhythm is a rhythm that is about a day in

length; the term circadian comes from the Latin circa, meaning “approximately,” and dia, meaning “day.” We operate on a 24-hour (hr) cycle, in synchrony with the solar day. We sleep once every 24 hr, and body temperature, alertness, urine production, steroid secretion, and a variety of other activities decrease during our normal sleep period and increase during our normal waking period, even when we reverse our sleep-wake schedule temporarily.

Why is the circadian rhythm important? The main biological clock that controls these rhythms in mammals is the

suprachiasmatic nucleus (SCN) of the hypothalamus. Lesioning the SCN in rats abolishes the normal 24-hr rhythms of sleep, activity, body temperature, drinking, and steroid secretion (Abe, Kroning, Greer, & Critchlow, 1979; Stephan & Nunez, 1977). The SCN is what is known as a pacemaker, because it keeps time and regulates the activity of other cells. We know that the rhythm arises in the SCN, because rhythmic activity continues in isolated SCN cells (Earnest, Liang, Ratcliff, & Cassone, 1999; Inouye & Kawamura, 1979). Lesioned animals do not stop sleeping, but instead of following the usual day-night cycle, they sleep in naps scattered throughout the 24-hr period. So the SCN controls the timing of sleep, but sleep itself is controlled by other brain structures, which we will discuss later. The SCN is shown in Figure 15.2 (you can check Figure 6.2 to see its location.). FIGURE 15.2 The Suprachiasmatic Nucleus. (a) The nuclei, indicated by the arrows, took up more radioactive 2-deoxy-glucose in the scan because the rat was injected during the “light-on” period of the day; (b)

the rat was injected during the “light-off” period.

SOURCE: Reprinted with permission from W. J. Schwartz and H. Gainer, “Suprachiasmatic Nucleus: Use of 14C-labeled Deoxyglucose Uptake as a Functional Marker,” Science, 197, 1089–1091. Copyright 1977 American Association for the Advancement of Science. The SCN is entrained to the solar day by cues called zeitgebers (“time-givers”). If

humans are kept in isolation from all time cues in an underground bunker or a cave, they usually lose their synchrony with the day-night cycle; in many studies, zeitgeber- deprived individuals “drifted” to a day that was about 25 hr long, with a progressively increasing delay in sleep onset (see Figure 15.3; Aschoff, 1984). For a long time, researchers believed that alarm clocks and the activity of others were the most important influences that entrain our activity to the 24-hr day; but research points more convincingly to light as the primary zeitgeber. The difference in light intensity between the light and dark periods is important for

entraining the day-night cycle. One group of night workers worked under bright lights and slept in complete darkness during the day (light discrepant); a second group worked under normal light and slept in the semidarkness that is typical of the day sleeper (similar light). The light-discrepant workers scored higher in performance and alertness than the similar-light workers. Their physiological measures also synchronized with the new sleep-wake cycle; for example, their body temperature dropped to its low value around 3:00 p.m., when they were asleep, but the similar- light group’s low continued to occur at 3:30 a.m. in spite of being awake and working (Czeisler et al., 1990). If you’re thinking the take-home from this study is that you should keep the lights as bright as possible when you’re awake, you would be wrong. Compared with dim light, exposure to normal room light for the 8-hr period before bedtime reduces the duration of melatonin release by 90 minutes each night (Gooley et al., 2010). Melatonin is a hormone that induces sleepiness. The typically sleep- deprived state in modern society appears to be due in part to living under bright lights and spending evenings in front of a computer.

Just how much we rely on a regular lighting schedule for entrainment was underscored in a study of four Greenpeace volunteers living in isolation during the 4- month darkness of the Antarctic winter; their sleep times and physiological measures free-ran on a roughly 25-hr interval, even though they had access to time information and social contact with each other (Kennaway & van Dorp, 1991). According to some, it is this “slow-running” clock that makes phase delays (going to sleep later) easier than phase advances (going to sleep earlier). So adjustment after westward travel is easier than after traveling east, and workers who rotate shifts sleep better and produce more if the rotation is to later shifts rather than to earlier ones (Czeisler, Moore-Ede, & Coleman, 1982). Some people seem to be relatively insensitive to the environmental cues that entrain most of us to a 24-hr day and operate on a 25-hr clock under normal circumstances; and like a clock that runs too slowly, their physical and cognitive functioning moves in and out of phase with the rest of the world, resulting in insomnia and impaired functioning. FIGURE 15.3 Sleep and Wake Periods During Isolation From Time Cues. Each dark bar indicates the timing and length of sleep during a day. During the unscheduled period (without time cues), the subject’s activity assumed a 25-hr rhythm and began to advance around the clock. When light-dark periods were scheduled, he resumed a normal sleep and activity rhythm.

SOURCE: From Introduction to Psychology, Gateways to Mind and Behavior (with InfoTrac) 9th edition, by D. Coon, 2001. Reprinted with permission of Wadsworth, a division of Thomson Learning. Why the internal clock would operate on a 25-hr cycle is unclear, especially since

animals kept in isolation typically run on a 24-hr cycle (Czeisler et al., 1999). Some believe that it has something to do with the 24.8-hr lunar cycle, which influences the tides and some biological systems (Bünning, 1973; J. E. M. Miles, Raynal, & Wilson, 1977). Czeisler and his colleagues (1999) suggested that the 25-hr cycle in isolation

studies is no more than an artifact of allowing the individuals to control the room lighting. Bright light late in the day causes the cycle to lengthen, so Czeisler kept the light at a level that was too low to influence the circadian rhythm while people lived on a 28-hr sleep-wake schedule. Under that condition, their body temperature cycle averaged 24.18 hr, which led Czeisler to conclude that the biological rhythm is approximately 24 hr long. By the way, if you think a lunar influence on sleep is hard to believe, Swiss researchers have preliminary evidence for it. Near the time of the full moon, volunteers sleeping in a windowless laboratory slept 20 minutes less, produced less melatonin, and had less non-REM sleep than at other times of the month (Cajochen et al., 2013). The SCN regulates the pineal gland’s secretion of melatonin. Melatonin is often

used to combat jet lag and to treat insomnia in shift workers and in the blind (Arendt, Skene, Middleton, Lockley, & Deacon, 1997). Light resets the biological clock by suppressing melatonin secretion (Boivin, Duffy, Kronauer, & Czeisler, 1996). Most totally blind individuals are not entrained to the 24-hr day and suffer from insomnia in spite of regular schedules of sleep, work, and social contact. These individuals do not experience a decrease in melatonin production when exposed to light; however, totally blind people without insomnia do show melatonin suppression by light, even though they are unaware of the light (Czeisler et al., 1995). Animal studies explain how some blind individuals are able to entrain to the light-

dark cycle and, thus, how the rest of us do so as well. Light information reaches the SCN by way of a direct connection from the retinas called the retinohypothalamic pathway; however, mice lacking rods and cones still show normal entrainment and cycling, so the signal must arise from some other retinal light receptors (M. S. Freedman et al., 1999; Lucas, Freedman, Muñoz, Garcia-Fernández, & Foster, 1999). Although ganglion cells ordinarily receive information about light from the receptors, about 1% of ganglion cells respond to light directly and send neurons into the retinohypothalamic pathway (Berson, Dunn, & Takao, 2002; Hannibal, Hindersson, Knudsen, Georg, & Fahrenkrug, 2002; Hattar, Liao, Takao, Berson, & Yau, 2002). These ganglion cells contain melanopsin, which has recently been confirmed as a light-sensitive substance, or photopigment (Dacey et al., 2005; Panda et al., 2005; Qiu et al., 2005); the melanopsin is located in their widely branching dendrites, which suits the cells for detecting the overall level of light, as opposed to contributing to image formation (Figure 15.4). Melanopsin is most sensitive to light of 480 nanometers, which is the wavelength of light that predominates at dusk and dawn (Foster, 2005), so the system apparently is most responsive to twilight in resetting the circadian clock. A recent study confirmed that human retinas have melanopsin in some of their ganglion cells (Dkhissi-Benyahya, Rieux, Hut, & Cooper, 2006). However, synchronizing the rhythm does not account for the rhythm itself. The

internal clock consists of a few genes and their protein products (Clayton, Kyriacou,

& Reppert, 2001; Hastings, Reddy, & Maywood, 2003; Shearman et al., 2000); the genes fall into two groups, one group that is turned on while the other is turned off. When the genes are on, their particular protein products build up. Eventually, the accumulating proteins turn their genes off, and the other set of genes is turned on. This feedback loop provides the approximately 24- or 25-hr cycle, which then must be reset each day by light. This process is not limited to neurons in the SCN; there are additional clocks, located outside the brain and controlling the activities of the body’s organs (Hastings et al., 2003). These clocks operate independently of the SCN, but the SCN entrains them to the day-night cycle. Feeding is an example of an activity that is controlled independently. According to the researchers, local clocks that affect blood pressure and heart activity explain why there is a large increase in the risk of heart attack, stroke, and sudden cardiac death after waking in the morning. The clock in the SCN does not always operate properly, as we saw in Chapter 14 with some depressed patients. FIGURE 15.4 Retinal Ganglion Cells Containing Melanopsin. The cells were labeled with a fluorescent substance that reacts to melanopsin. Notice the widespread dendrites, which contain melanopsin.

SOURCE: From “Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity,” by S. Hattar, H. W. Liao, M. Takao, D. M. Berson, and K. W. Yau, Science, 295, pp. 1065–1070. © 2002 American Association for the Advancement of Science (AAAS). Reprinted with permission from AAAS.

Rhythms During Waking and Sleeping Riding on the day-long wave of the circadian rhythm are several ultradian rhythms,

rhythms that are shorter than a day in length. Hormone production, urinary output, alertness, and other functions follow regular cycles throughout the day. For example, the dip in alertness and performance in the wee hours of the morning is mirrored by another in the early afternoon, which cannot be accounted for by postlunch sleepiness, because it also occurs in people who skip lunch (Broughton, 1975). Incidentally, this dip coincides with the time of siesta in many cultures and a rest period in nonhuman primates. The basic rest and activity cycle is a rhythm that is about 90 to 100 minutes (min) long. When people wrote down what they were thinking every 5 min for 10 hr, the contents showed that they were daydreaming on a 90-min cycle; EEG recordings verified that these were periods of decreased brain activity (Kripke & Sonnenschein, 1973).

What rhythms occur throughout the day and night? The common view of sleep is that it is a cessation of activity that occurs when the

body and brain become fatigued. Sleep, however, is an active process. This is true in two respects. First, you will soon see that sleep is a very busy time; a great deal of activity goes on in the brain. Second, sleep is not like a car running out of gas but is turned on by brain structures and later turned off by other structures.

2 Sleep Research The most important measure of sleep activity is the EEG. When a person is awake,

the EEG is a mix of alpha and beta waves. Alpha is activity whose voltage fluctuates at a frequency of 8 to 12 hertz (Hz) and moderate amplitude; beta has a frequency of 13 to 30 Hz and a lower amplitude. Beta waves, which are associated with arousal and alertness, are progressively replaced by alpha waves as the person relaxes (see Figure 15.5). It may seem strange that the amplitude of the EEG is lower during arousal. Remember that the EEG is the sum of the electrical activity of all the neurons between the two recording electrodes. When a person is cognitively aroused, neurons under the electrodes are mostly desynchronized in their firing as they carry out their separate tasks; with the neurons firing at different times, the EEG has a high frequency, but the amplitude is rather low. As the person relaxes, the neurons have less processing to do and fall into a pattern of synchronized firing. The rate is low, but the cumulative amplitude of the neurons firing at the same time is high. FIGURE 15.5 Electroencephalogram and the Stages of Sleep.

SOURCE: From Current Concepts: The Sleep Disorders, by P. Hauri, 1982, Kalamazoo, MI: Upjohn. As the person slips into the light first stage of sleep, the EEG shifts to theta waves,

with a frequency of 4 to 7 Hz (see Figure 15.5). About 10 min later, Stage 2 begins, indicated by the appearance of K complexes and sleep spindles. K complexes are sharp, large waves that occur about once a minute; sleep spindles are brief bursts of 12- to 14-Hz waves that appear to serve a gating function, preventing disruptive stimuli from reaching the cortex and waking the sleeper (Dang-Vu, McKinney, Buxton, Solet, & Ellenbogen, 2010). Stages 3 and 4 are known as slow-wave sleep and are characterized by large, slow delta waves at a frequency of 1 to 3 Hz. The person moves around in bed during this period, turning over and changing positions. Sleepwalking, bedwetting, and night terrors, disturbances that are common in children, occur during slow-wave sleep, too. Night terrors are not nightmares but involve screaming and apparent terror, which are usually forgotten in the morning; they are not a sign of a disorder unless they continue beyond childhood. After Stage 4, the sleeper moves rather quickly back through the stages in reverse order. But rather than returning to Stage 1, the sleeper enters rapid eye movement sleep. Rapid eye movement (REM) sleep is so called because the eyes dart back and forth

horizontally during this stage. The EEG returns to a pattern similar to a relaxed waking state, but the person does not wake up; in fact, the sleeper is not easily aroused by noise but does respond to meaningful sounds, such as the sleeper’s name.

It is easy to see why some researchers call this stage paradoxical sleep, because paradoxical means “contradictory.” During REM sleep, respiration rate and heart rate increase. Males experience genital erection, and vaginal secretion increases in females. In spite of these signs of arousal, the body is very still—in fact, in a state of muscular paralysis or atonia. If people sleeping in the laboratory are awakened by the researcher during REM

sleep, about 80% of the time they report dreaming. Dreams also occur during the other, non-REM sleep stages, but they are less frequent, less vivid, and less hallucinatory. Even people who say that they do not dream report dreaming when they are awakened from REM sleep; their non-REM sleep dreams are less frequent, though, and they often describe their experience as “thinking” (H. B. Lewis, Goodenough, Shapiro, & Sleser, 1966). Apparently, “nondreamers” just fail to remember their dreams in the morning; in fact, we ordinarily remember a dream only if we wake up before the short-term memory of the dream has faded (Koulack & Goodenough, 1976). A complete cycle through the stages of sleep—like the daydreaming cycle—takes about 90 min to complete. The night’s sleep is a series of repetitions of this ultradian rhythm, although the length of REM sleep periods increases and the amount of slow-wave sleep decreases through the night (Figure 15.6). FIGURE 15.6 Time Spent in Various Sleep Stages During the Night. As the night progresses, deep sleep decreases, and time in REM sleep (dark bars) increases.

What are the functions of REM and slow-wave sleep? The Functions of REM and Non-REM Sleep To find out what functions REM sleep serves, researchers deprived volunteers of

REM sleep; they did this by waking the research participants every time EEG and eye movement recordings indicated that they were entering an REM period. When this was done, the subjects showed a “push” for more REM sleep. They went into REM more frequently as the study progressed and had to be awakened more often; then, on uninterrupted recovery nights, they tended to make up the lost REM by increasing

their REM from about 20% of total sleep time to 25% or 30% (Dement, 1960). To psychoanalytically oriented theorists, these results were evidence of a psychological need for dreaming. You are probably familiar with the theory that dreams reveal the contents of the unconscious, not through their manifest content—the story the person tells on awakening—but through symbolic representations (Freud, 1900). Most neuroscientists, on the other hand, believe that dreaming is merely the by-

product of spontaneous neural activity in the brain. According to the activation- synthesis hypothesis, during REM sleep the forebrain integrates neural activity generated by the brain stem with information stored in memory (Hobson & McCarley, 1977); in other words, the brain engages in a sort of confabulation, using information from memory to impose meaning on nonsensical random input. This explanation does not imply that dream content is always insignificant; there is evidence that daytime events and concerns do influence the content of a person’s dreams (Webb & Cartwright, 1978). But neuroscientists consider dreams to be the least important aspect of REM sleep, and they note that after a century of intense effort, there is no agreed-on method of dream interpretation (Crick & Mitchison, 1995). Instead, neuroscientists argue that the pervasiveness of REM sleep among mammals and birds demands that any explanation for the function of REM sleep be a biological one. There are several proposals as to what biological needs might be met during REM sleep, but the number of hypotheses indicates that we are still unsure what benefit REM sleep confers. One hypothesis is that REM sleep promotes neural development during childhood.

Infant sleep starts with REM rather than non-REM, and the proportion of sleep devoted to REM is around 50% during infancy and decreases through childhood until it reaches an adult level during adolescence (Roffwarg, Muzio, & Dement, 1966). According to this hypothesis, excitation that spreads through the brain from the pons during REM sleep encourages differentiation, maturation, and myelination in higher brain centers, similar to the way spontaneous waves of excitation sweep across the retina during development to help organize its structure (see Chapter 3). There is some evidence from studies of the immature visual systems of newborn cats that REM sleep, and particularly these waves from the pons, regulates the rate of neural development (Shaffery, Roffwarg, Speciale, & Marks, 1999). The fact that sleep is associated with the upregulation of a number of genes involved in neural plasticity (see Chapter 12), as well as other genes that contribute to the synthesis and maintenance of myelin and cell membranes (Cirelli et al., 2004), is certainly consistent with this neurodevelopmental hypothesis. Early ideas about non-REM functions focused on rest and restoration, inspired by

studies showing that slow-wave sleep increases following exercise; after athletes competed in a 92-kilometer race, slow-wave sleep was elevated for four consecutive nights (Shapiro, Bortz, Mitchell, Bartel, & Jooste, 1981). However, this effect appears

to be due to overheating rather than fatigue. The night after people ran on treadmills, slow-wave sleep increased, at the expense of REM sleep; but if they were sprayed with water while they ran, their body temperature increased less than half as much, and there was no change in slow-wave sleep (Horne & Moore, 1985). Horne (1988) believes that slow-wave sleep is more related to the increase in the

temperature of the brain than the increase in body temperature; heating only the head and face with a hair dryer was sufficient to increase slow-wave sleep later (Horne & Harley, 1989). According to Horne (1992), slow-wave sleep promotes cerebral recovery, especially in the prefrontal cortex. Slow-wave sleep may also restore processes involved in cognitive functioning. Bonnet and Arand (1996) gave people either caffeine or a placebo before a 3.5-hr nap. The caffeine group had reduced slow- wave sleep during the nap; although they felt more vigorous and no sleepier than the placebo group, they performed less well on arithmetic and vigilance tasks during a subsequent 41-hr work period. Sleep and Memory In Chapter 12, you learned that a period of sleep following learning enhances later

performance (see Figure 15.7). REM sleep has received the most attention; the amount of REM increases during the sleep period following learning, and REM sleep deprivation after learning reduces retention (see review in Dujardin, Guerrien, & Leconte, 1990; Karni, Tanne, Rubenstein, Askenasy, & Sagi, 1994; C. Smith, 1995). How much REM sleep increases depends on how well the subject learned (Hennevin, Hars, Maho, & Bloch, 1995). Also, if training occurs over several days, REM sleep increases daily and reaches its peak in the 24-hr period before the peak in correct performance (Dujardin et al., 1990; C. Smith, 1996).

3 NOVA Video: Sleep & Memory FIGURE 15.7 Improvement in Learning Following Sleep. Participants learned a motor skill task and were retested twice at 10-hr intervals. There was no statistically significant improvement for individuals who remained awake during the interval (a, Retest 1), but performance improved following sleep (a, Retest 2, and b, Retest 1 and Retest 2).

SOURCE: Adapted from “Practice With Sleep Makes Perfect: Sleep-Dependent Motor Skill Learning,” by M. P. Walker, T. Brakefield, A. Morgan, J. A. Hobson, and R. Stickgold, 2003, Neuron, 35, pp. 205–211. FIGURE 15.8 Correlation of Slow-Wave and REM Sleep With Overnight Task Improvement. These graphs show the correlation of slow-wave sleep (SWS) and REM sleep with improvement on a visual discrimination task at the beginning of the next day’s practice. They indicate that slow-wave sleep has more effect during the first quarter of the night, while REM is important during the fourth quarter. SOURCE: Adapted with permission from Stickgold et al., “Sleep, Learning, and Dreams: Off-line Memory Reprocessing,” Science, 294, pp. 1052–1057. © 2001 American Association for the Advancement of Science. Reprinted with permission from AAAS.

Ample evidence from both animal and human studies indicates that non-REM sleep

is also important for learning (Hairston & Knight, 2004). For example, applying a 0.75-Hz oscillating current over the frontal and temporal areas during the first period of non-REM sleep increased the abundance of slow potentials and improved recall of word associations learned prior to sleep (L. Marshall, Helgadóttir, Mölle, & Born, 2006). Slow potentials are believed to increase neural plasticity. Another study indicated that consolidation is a multistep process requiring a combination of slow- wave and REM sleep. Overnight improvement on a visual discrimination task in humans was correlated with the percentage of slow-wave sleep during the first quarter of the night and the percentage of REM sleep in the last quarter of the night (see Figure 15.8; Stickgold, Whidbee, Schirmer, Patel, & Hobson, 2000). Even a 60- to 90-min nap that included both REM and slow-wave sleep produced significant improvement in performance (Mednick, Nakayama, & Stickgold, 2003). According to Ribeiro and his colleagues (2004), neuronal replay (see Chapter 12) is strongest during non-REM sleep, and during REM sleep genes involved in synaptic plasticity are upregulated. The researchers concluded from their results and others’ that memories are recalled during non-REM sleep and stored during REM sleep. Close observation of hippocampal activity after learning suggests why REM sleep

is important. Replay during REM sleep is synchronized with theta-frequency (3–7 Hz) activity occurring spontaneously in the hippocampus (Stickgold et al., 2001); in other words, the peaks of one wave coincide with the peaks of the other. After 4 to 7 days, the time during which memories become independent of the hippocampus, the replay shifts out of phase with the theta activity, with the peaks of one wave coinciding with the troughs of the other. You may remember that stimulating the hippocampus in synchrony with theta produces long-term potentiation and out-of-phase stimulation produces long-term depression. This suggests that a period of consolidation is followed by one of deleting connections—representing old memories, inaccurate connections, or both. The idea of memory deletion is consistent with Crick and Mitchison’s (1995)

reverse-learning hypothesis. They suggest that neural networks involved in memory must have a way to purge themselves occasionally of erroneous connections and that activity during REM sleep provides the opportunity to do this. Researchers studying computer neural networks found that when they added a reverse-learning process, it improved their networks’ performance (Hopfield, Feinstein, & Palmer, 1983). According to Crick and Mitchison, reverse learning makes more efficient use of our brains, allowing us to get by with fewer neurons; they point out that the only mammals so far found not to engage in REM sleep—the Echidna (a nocturnal burrower in Australia) and two species of dolphin—have unusually large brains for their body size. According to Giulio Tononi and Chiara Cirelli (2013) there is far better evidence

for synaptic pruning during sleep than for consolidation; they believe this pruning

improves the accuracy of stored information by eliminating inaccurate connections. In animals, they point to the decrease in numbers of synaptic spines and AMPA receptors during sleep, following the increases during the day. The period of non-REM sleep also sees a drop-off in the concentration of neuromodulators that strengthen synapses. Their evidence in humans is mostly circumstantial, but they do note that responsiveness to transcranial magnetic stimulation (measured by EEG) increases the longer a person is awake and then decreases after a night of sleep. Brain Structures of Sleep and Waking We have seen one of the ways sleep can be regarded as an active process: A great

deal of activity goes on in the brain during sleep. For the second aspect of this active process, we turn to the brain structures involved in turning sleep on and off. There is no single sleep center or waking center; sleep and waking depend on a variety of structures that integrate the timing of the SCN with homeostatic information about physical conditions such as fatigue, brain temperature, and time awake. The network of structures governing sleep and waking is complex, so you will want to trace its connections carefully in the accompanying illustrations. We will begin with the structures that produce sleep. Sleep Controls Sleep is homeostatic, in that a period of deprivation is followed by a lengthened

sleep period. Adenosine provides at least one of the mechanisms of sleep homeostasis. During wakefulness, adenosine accumulates in the basal forebrain area; it inhibits arousal-producing neurons there, inducing drowsiness and reducing EEG activation (Figure 15.9; Porkka-Heiskanen et al., 1997). The accumulated adenosine dissipates during the next sleep period. We saw in Chapter 5 that caffeine counteracts drowsiness by acting as an antagonist at adenosine receptors.

What brain structures are responsible for sleep and waking? Another location where adenosine increases sleep is the preoptic area of the

hypothalamus (Ticho & Radulovacki, 1991). Cells in the preoptic area are involved in several functions, including regulation of body temperature. Warming this part of the hypothalamus activates sleep-related cells, inhibits waking-related cells in the basal forebrain, and enhances slow-wave EEG (Alam, Szymusiak, & McGinty, 1995; Sherin, Shiromani, McCarley, & Saper, 1996; Szymusiak, 1995). This finding has contributed to the hypothesis that one function of slow-wave sleep is to cool the brain after waking activity. Whether that is true or not, the preoptic area no doubt accounts for the sleepiness you feel in an overheated room or when you have a fever. Neurons in a part of the preoptic area, the ventrolateral preoptic nucleus, double

their rate of firing during sleep (J. Lu et al., 2002). They induce sleep by inhibiting neurons in arousal areas: the tuberomammillary nucleus in the hypothalamus and the locus coeruleus, raphé nuclei, and pedunculopontine and laterodorsal tegmental

nuclei (PPT/LDT) in the pons (Chou et al., 2002; Saper, Chou, & Scammell, 2001; Saper, Scammell, & Lu, 2005). Different parts of the ventrolateral preoptic nucleus induce REM and non-REM sleep (Saper et al., 2005). The nucleus also receives inhibitory inputs from the structures it innervates, which helps ensure that sleep and waking mechanisms are not turned on at the same time. FIGURE 15.9 Brain Mechanisms of Sleep. Sleep is brought about primarily by suppressing activity in arousal structures (shown in green).

The pons also sends impulses downward to the magnocellular nucleus in the medulla to bring about the atonia that accompanies REM sleep. When Shouse and Siegel (1992) lesioned this nucleus in cats, the cats were no longer paralyzed during REM sleep; they seemed to be acting out their dreams (assuming that cats dream), and their movements during REM sleep often woke them up. The pons also contains adenosine receptors and is another site for the effect of your morning cup of coffee (Rainnie, Grunze, McCarley, & Greene, 1994). Waking and Arousal The arousal system consists of two major pathways (Figure 15.10; Saper et al.,

2005). The first arises from the PPT/LDT, whose acetylcholine-producing neurons are very active during waking. This pathway activates areas crucial for transmission of information to the cortex, including relay nuclei of the thalamus. It also shifts the EEG to asynchronized, high-frequency, low-amplitude activity by inhibiting nuclei in

the thalamus that ordinarily synchronize the EEG (Hobson & Pace-Schott, 2002; Saper et al., 2001). This pathway is also active when the individual shifts into each REM period. After our discussion of all the activity that goes on during sleep, it shouldn’t surprise you to find arousal mechanisms active while the brain is sleeping. FIGURE 15.10 Arousal Structures of Sleep and Waking. Several interacting structures and pathways produce waking, maintain arousal during waking, and increase arousal during REM sleep.

The second pathway activates the cortex to facilitate the processing of inputs from the thalamus. Neurons from the locus coeruleus (which release norepinephrine) and the raphé nuclei (which release serotonin) are most active during waking, relatively quiet during non-REM sleep, and almost silent during REM sleep (Figure 15.11; Khateb, Fort, Pegna, Jones, & Mühlethaler, 1995; Saper et al., 2005). Neurons from the tuberomammillary nucleus arouse the cortex by releasing histamine, and those from the basal forebrain area do so by releasing acetylcholine; neurons of the tuberomammillary nucleus and many in the basal forebrain area are active during both waking and REM sleep (Saper et al., 2005). FIGURE 15.11 Firing Rates in Brain Stem Arousal Centers During Waking and Sleep. (a) Activity in the locus coeruleus; (b) activity in the raphé nuclei. AW, alert waking; QW, quiet waking; DRO, drowsy; SWS, slow-wave sleep; pre-REM, 60 seconds before REM; post-REM, first second after REM ends.

SOURCES: (a) Copyright 1981 by the Society for Neuroscience; (b) From “Activity of Serotonin-Containing Nucleus Centralis Superior (Raphe Medianus) Neurons in Freely Moving Cats,” by M. E. Trulson et al., Experimental Brain Research, 54, 33– 44, fig. 2. © 1984. With kind permission from Springer Science and Business Media. The arousing pathway is completed by neurons in the lateral hypothalamus, which

send axons to the basal forebrain area, tuberomammillary nucleus, PPT/LDT, raphé nuclei, and locus coeruleus; during waking they release the peptide orexin to keep these arousal areas active (Figure 15.12; Saper et al., 2001, 2005). (You first saw orexin in Chapter 6, where it was described as an appetite stimulant.) Saper and his colleagues suggested that orexin stabilizes the sleep and waking system by preventing inappropriate switching into sleep. We will see in the section on sleep disorders what happens when this mechanism fails. As you can imagine, the orexin system has become a target for pharmaceuticals. Drugs that block orexin receptors have proven effective as sleep aids and are attractive for their lack of cognitive side effects, but as trials progressed questions arose about their safety. One, Almorexant, was discontinued during final phase 3 trials; approval of Suvorexant is being held up over concerns about safety at higher doses (Suvorexant, n.d.). On the other side of the coin, nasal sprays that deliver orexin have shown some promise for combating sleepiness. When intranasal orexin improved performance in monkeys on a memory task (Deadwyler, Porrino, Siegel, & Hampson, 2007), it was suggested that students would eventually use it to get through finals after pulling all-nighters. (I hope you’re imagining the researchers trying to give nasal spray to the monkeys!) At this point, it looks like it could be helpful with people suffering from narcolepsy, a sleep disorder in which a person suddenly goes from wakefulness into REM sleep. Following administration, subjects had fewer wake-to-REM sleep transitions and performed better on an attention task (Weinhold et al., 2014). FIGURE 15.12 Locations of Orexin Receptors in the Rat Brain. The receptors appear in white. Notice how widespread they are.

SOURCE: From “Mice Lacking the M3 Muscarinic Acetylcholine Receptor Are Hypophagic and Lean,” by M. Yamada et al., Nature, 410, pp. 207–212, © 2001. Used with permission. The pons is the source of PGO waves seen during REM sleep. The name refers to

the path of travel that waves of excitation take from the pons through the lateral geniculate nucleus of the thalamus to the occipital area. PGO waves are as characteristic of REM sleep as rapid eye movements are (Figure 15.13). They begin about 80 seconds before the start of an REM period and apparently are what initiate the EEG desynchrony of REM sleep (Mansari, Sakai, & Jouvet, 1989; Steriade, Paré, Bouhassira, Deschênes, & Oakson, 1989). Their arousal of the occipital area may account for the visual imagery of dreaming. FIGURE 15.13 PGO Waves, EEG Desynchrony, and Muscle Atonia. The records are of electrical activity in the lateral geniculate nucleus (LG), eye movements (EOG, electrooculogram), electroencephalogram (EEG), and muscle tension (EMG, electromyogram). Notice that PGO waves signal the beginning of EEG desynchrony, rapid eye movements, and atonia several seconds later.

SOURCE: Copyright 1989 by the Society for Neuroscience. Sleep Disorders Insomnia

Insomnia is the inability to sleep or to obtain adequate-quality sleep, to the extent that the person feels inadequately rested. Insomnia is important not only as a nuisance but also because sleep duration has important implications for health. In a study of 1.1 million men and women, sleeping less than 6 hr a night was associated with decreased life expectancy (Kripke, Garfinkel, Wingard, Klauber, & Marler, 2002). However, the surprise in the study was that sleeping more than 8.5 hr was associated with as great an increase in risk of death as sleeping less than 4.5 hr. Lack of sleep may also be a factor in the obesity epidemic. In a long-term study of sleep behavior, people who slept less than 8 hr had a higher body mass index, along with lower leptin and higher ghrelin levels (Taheri, Lin, Austin, Young, & Mignot, 2004). While the failure to get enough sleep is part of the lifestyle of industrialized

countries, many people who try to get an adequate amount of sleep complain that they have difficulty either falling asleep or staying asleep. In a survey by the National Sleep Foundation (2002), over half the respondents reported that they had trouble sleeping or woke up unrefreshed at least a few nights a week, and a third had experienced at least one symptom of insomnia every night or almost every night in the past year. Insomnia is one of the few disorders that is essentially self-diagnosed, and several studies suggest that the reported frequencies might be misleading. But although insomniacs may overestimate the time required to get to sleep and the amount of time awake through the night (Rosa & Bonnet, 2000), there are several indications that their sleep quality suffers from hyperarousal. These include excess high-frequency EEG during non-REM sleep (Perlis, Smith, Andrews, Orff, & Giles, 2001) and disturbance of the hypothalamic-pituitary-adrenal axis (see Chapter 8), with increased secretion of cortisol and adrenocorticotropic hormone during the night (Vgontzas et al., 2001).

What are the causes of sleep disorders? Insomnia can be brought on by a number of factors, such as stress, but it also

occurs frequently in people with psychological problems, especially affective disorders (Benca, Obermeyer, Thisted, & Gillin, 1992). Some loss of gray matter in the orbitofrontal cortex and the parietal cortex has been reported in insomniacs (Altena, Vrenken, Van Der Werf, van den Heuvel, & Van Someren, 2010); this could be a cause of their insomnia, or it could reflect the association with psychological disorders. Another frequent cause is the treatment of insomnia; most sleep medications are addictive, so attempts to do without medication or to reduce the dosage produce a rebound insomnia; this can happen after as little as three nights with some benzodiazepines (Kales, Scharf, Kales, & Soldatos, 1979). Insomnia can manifest itself as delayed sleep onset, nighttime waking, or early waking; a disruption of the circadian rhythm is often the culprit (M. Morris, Lack, & Dawson, 1990). FIGURE 15.14 Effects of Disrupted Circadian Rhythm on Sleep.

Ordinarily, a person falls asleep while the body temperature is decreasing and awakens as it is rising (a). If body temperature is phase delayed (b), the person has trouble falling asleep; if body temperature is phase advanced (c), the person wakes up early.

People with sleep difficulties often show a shift in their circadian rhythm; this can be the result of bad sleep habits, but it is more likely the cause. Normally, people fall asleep when their body temperature is decreasing in the evening and wake up when it is rising. But if your body temperature is still high at bedtime (phase delay), you will experience sleep-onset insomnia; if your body temperature rises too early (phase advance) you will wake up long before the alarm clock goes off (see Figure 15.14). Sleep is also more efficient if you go to bed when your body temperature is low; for example, a volunteer living in isolation from time cues averaged a 7.8-hr sleep length when he went to bed during his temperature minimum and a 14.4-hr sleep length when sleep began near his temperature peak (Czeisler, Weitzman, & Moore-Ede, 1980). Your chronotype—when your internal clock is synchronized to the 24-hr day— depends partly on your genes and partly on your environment (Roenneberg et al., 2004). People with advanced sleep phase disorder feel compelled to go to sleep around 7:30 in the evening and then wake up around 4:30 a.m. A mutation in the circadian clock gene CKIδ has been linked to the disorder (Xu et al., 2005); more recently, three mutations in another clock gene, PER2, have also been identified (Chong, Ptácˇek, & Fu, 2012). Delayed sleep phase disorder—late bedtime and rising —has been associated with the PER3 clock gene (Archer et al., 2003).

4 Sleep Disorders It is usually easier for people to delay sleep at night than to rise early, which led to

a treatment for delayed sleep syndrome that seems completely counterintuitive. The patients had a 5- to 15-year history of sleep-onset insomnia so severe that they were not even going to bed until 4:15 a.m., on average. Rather than require them to retire earlier, the researchers had the patients stay up 3 hr later each day than the day before. After about a week of this routine—for example, going to bed at 8 a.m., 11 a.m., 2 p.m., 5 p.m., 8 p.m., and 11 p.m. on successive nights—their average sleep- onset time had shifted from 4:50 a.m. to 12:20 a.m., and their average waking time had shifted from 1:00 p.m. to 7:55 a.m. All five patients were able to give up the sleeping pills they had become dependent on, and improvement was long lasting (Czeisler et al., 1981). Phototherapy is also sometimes used to reset the circadian clock. Sleepwalking Some of the sleep disorders are related to specific sleep stages. As we saw before,

bedwetting, night terrors, and sleepwalking occur during slow-wave sleep. Although sleepwalking is most frequent during childhood, about 3% to 8% of adults sleepwalk (A. Dalton, 2005). Kenneth Parks’s story in the opening vignette is not unique. The sleepwalking defense was first used in 1846 when Albert Tirrell was acquitted of the murder of his prostitute mistress and the arson of her brothel, and the plea has been successful in a few more recent instances as well (A. Dalton, 2005). Sleepwalking can be triggered by stress, alcohol, and sleep deprivation; Ken Parks’s jury was convinced that he was not responsible because he was sleep deprived due to stress over gambling debts and the loss of his job for embezzling; there was a personal and family history of sleepwalking, sleep talking, and bedwetting; and he produced a high level of slow- wave sleep during sleep monitoring (Broughton et al., 1994). Vulnerability for sleepwalking is at least sometimes genetic. Children of

sleepwalkers are 10 times more likely to sleepwalk than children without sleepwalking relatives, and people with a version of a gene that is also implicated in narcolepsy are 3.5 times as likely to sleepwalk as others (Lecendreux et al., 2003). The gene is a member of the human leukocyte antigen (HLA) family, a group of genes that target foreign cells for attack by the immune system, and the authors suspect that cells important in sleep regulation have been attacked by the individual’s immune system. A less known non-REM sleep behavior is sexsomnia, engaging in sexual behavior

while asleep. Alhough usualy the worst consequence is embarrassment, the behavior has sometimes led to criminal charges (often leading to acquittal on grounds of nonresponsibility). The prevalence of sexsomnia is uncertain, but 11% of men and 4% of women seeking treatment for sleep disorders reported engaging in sexual behavior

while asleep (American Academy of Sleep Medicine, 2010). Patients with sexsomnia didn’t differ from the other patients in fatigue, depression, smoking, or caffeine consumption, but they were twice as likely to admit using illicit drugs. Somewhere in between people who commit mayhem during sleepwalking and

those who simply wander about the house are the individuals who suffer from sleep- related eating disorder, the subject of the accompanying Application.

APPLICATION

In the Still of the Night Shirley Koecheler raids the refrigerator at night (Black & Robertson, 2010). She would like to quit because she’s gaining weight, but she isn’t aware she’s doing it until she wakes up in the morning to a crumb-filled bed and an uncomfortably full stomach. She even had her husband hide the Easter candy, but the next morning she found the wrappers from the chocolate bunnies in the wastebasket. Shirley’s 24-year-old daughter Amy is also a sleep eater and has been since she was a toddler; the difference is that she doesn’t gain weight. Anna Ryan, like Shirley, started sleep eating in adulthood; she didn’t even know about the nighttime kitchen forays that added 60 pounds to her weight in a year and a half until she went to a sleep clinic to find out why she was exhausted every morning. The victims of sleep-related eating disorder are usually women; they

ordinarily pass up the fruit and other healthy snacks for high-calorie junk food, but they have also been known to eat soap, Elmer’s glue, frozen pizza, paper, and even egg shells (Epstein, 2010). No one really knows what causes the problem, and treatment is hit-or-miss. Amy has responded well to a drug used to prevent seizures; she still sleep eats occasionally, but it’s no longer a problem. It took Anna and her doctor months of trial and error to find a combination of drugs that works, but now she sleeps through the night and is losing weight.

5 Sleep Eating Video

Narcolepsy Earlier, I said that we would see what happens when stabilization of the sleep

switch fails; the result is narcolepsy, a disorder in which individuals fall asleep suddenly during the daytime and go directly into REM sleep. Another symptom of narcolepsy is cataplexy, in which the person has a sudden experience of one component of REM sleep, atonia, and falls to the floor paralyzed but fully awake.

People with narcolepsy do not sleep more than others; rather, the boundaries are lost between sleep and waking (Nobili et al., 1996). Dogs also develop the disorder, and the study of canine narcolepsy has identified a mutated form of the gene that is responsible for the orexin receptor (see Figure 15.15; Lin et al., 1999). FIGURE 15.15 Cataplexy in a Dog. Sleep researcher William Dement holds Tucker before (a) and during (b) an attack of cataplexy. Tucker is paralyzed but awake. SOURCE: © Louie Psihoyos/Corbis.

Other researchers were studying orexin’s effect as a feeding stimulant in mice by disabling both copies of the gene responsible for producing orexin, but what they saw was more interesting than eating behavior (Chemelli et al., 1999). Occasionally, the mice would suddenly collapse, often while walking around or grooming; the mice were narcoleptic! Most narcoleptic humans (those with cataplexy) turned out to have the same deficiency as the mice; they had low or undetectable levels of orexin, due to a loss of orexin-secreting neurons in the hypothalamus (Higuchi et al., 2002; Kanbayashi et al., 2002). The neurons are destroyed by an autoimmune reaction, which in some cases can be traced to an allele of the HLA immune system gene (Hallmayer et al., 2009). Narcolepsy’s concordance of 25% to 31% in identical twins (Mignot, 1998) leaves plenty of room for environmental influence. Identifying the nongenetic causes has been difficult, but one appears to be the H1N1 influenza (swine flu) virus (Han et al., 2011; Herran-Arita et al., 2013). The onset of narcolepsy tends to be seasonal, nearly seven times more frequent shortly after winter; it also increased threefold following the 2009 H1N1 epidemic in China, and lab study has shown that the virus can trigger the immune reaction. REM Sleep Behavior Disorder An apparent opposite of cataplexy is REM sleep behavior disorder; affected

individuals are uncharacteristically physically active during REM sleep, often to the

point of injuring themselves or their bed partners. A study of 93 patients, 87% of whom were male, found that 32% had injured themselves and 64% had assaulted their spouses (E. J. Olson, Boeve, & Silber, 2000). A 67-year-old man had tied himself to his bed with a rope at night for 6 years because he had a habit of leaping out of bed and landing on furniture or against the wall. One night, he was awakened by his wife’s yelling because he was choking her; he was dreaming that he was wrestling a deer to the ground and was trying to break its neck (Schenck, Milner, Hurwitz, Bundlie, & Mahowald, 1989). REM sleep behavior disorder is often associated with a neurological disorder, such as Parkinson’s disease or a brain stem tumor (E. J. Olson et al., 2000). Lewy bodies have been found in patients’ brains, and two thirds of patients develop Parkinson’s about 10 years later (Boeve et al., 2003). These findings have contributed to the hypothesis that Parkinson’s disease is preceded by the development of Lewy bodies in the medulla, where inhibition of the magnocellular nucleus ordinarily produces atonia; the Lewy bodies then progress upward through the brain before reaching the substantia nigra years later, when the full-blown disease appears (Braak et al., 2003).

When you are asleep, are you unconscious? Sleep as a Form of Consciousness At the beginning of this discussion, I said that sleep is neither entirely conscious

nor unconscious. Francis Crick (1994), who shared a Nobel Prize for the discovery of DNA’s structure in 1962 before turning to neuroscience and the study of consciousness, believed that we are in a state of diminished consciousness during REM sleep and that we are unconscious during non-REM sleep. Certainly there are some elements of consciousness in the dream state, particularly in people who are lucid dreamers. You have probably had the occasional experience of realizing during a bad dream that it is not actually real and will end soon. That kind of experience is common for lucid dreamers—they are often aware during a dream that they are dreaming. People can be trained to become aware of their dreaming and to signal to the researcher when they are dreaming by pressing a handheld switch (Salamy, 1970). They can even learn to control the content of their dreams; they may decide before sleeping what they will dream about, or they may interact with characters in their dream (Gackenbach & Bosveld, 1989). This ability tells us that the sleeping person is not necessarily as detached from reality as we have thought. This point is further illustrated by sleepwalkers, who have driven cars; wandered the streets; brandished weapons (Schenck et al., 1989); and strangled, stabbed, and beaten people to death, all presumably during non-REM sleep. “

The world shall perish not for lack of wonders, but for lack of wonder.

Concept Check

—J. B. S. Haldane

” So it is not clear where or whether the transition from consciousness to

nonconsciousness occurs during sleep. The idea of a dividing line is blurred even further by reports that surgical patients can sometimes remember the surgical staff’s conversations while they were anesthetized, and they show some memory later for verbal material presented at the time of surgery (Andrade, 1995; Bonebakker et al., 1996). Whether you draw the line of consciousness between waking and sleeping or between REM and non-REM sleep or between sleep and coma depends more on your definition of consciousness than on any clear-cut distinctions between these conditions. Perhaps it is better to think of sleep as a different state of consciousness along a continuum of consciousness. We can then concentrate on what the differences between waking and sleeping tell

us about consciousness rather than worrying about classifications.

Take a Minute to Check Your Knowledge and Understanding

Describe the circadian and ultradian rhythms discussed here. What, according to research, are the functions of REM and slow-wave sleep? Make a table showing the brain structures involved in sleep and waking, with their functions.

Describe the sleep disorders and their causes.

The Neural Bases of Consciousness While strict behaviorists had banned consciousness as neither observable nor necessary for explaining behavior, over the last half of the 20th century, researchers began to find that various components of consciousness were necessary as they studied memory, attention, mental imagery, and emotion. Still, they carefully avoided using the word consciousness as they talked about awareness, attention, or cognition. Then, a few respected theorists began musing about consciousness in print and even suggesting that it was an appropriate subject for neuroscientists to study. Other scientists slowly began to come out of their closets, while their more cautious colleagues warned them not to allow consciousness to become a back door for the reentry of the mind or for the proverbial homunculus, the “little man” inside the head who pulls all the levers. In the words of one team of writers, “consciousness is not some entity deep inside the brain that corresponds to the ‘self,’ some kernel of awareness that runs the show” (Nash, Park, & Willwerth, 1995).

“

The explanation of consciousness is essential for explaining most of the features of our mental life because in one way or another they involve consciousness.

—John R. Searle

” So just what do we mean by consciousness? Actually, the term has a variety of

connotations. We use it to refer to a state—a person is conscious or unconscious, and we use it in the sense of conscious experience, or awareness of something. Consciousness has additional meanings for researchers, though few try to define the term; Francis Crick (1994) suggested that any attempt at definition at this point in our knowledge would be misleading and would unduly restrict thinking about the subject. While agreeing on a definition is impractical, I think most researchers would be comfortable with the following assertions about consciousness. The person is aware, at least to some extent; as a part of awareness, the person holds some things in attention, while others recede into the background. Consciousness also involves memory, at least of the short-term variety, and fully conscious humans have a sense of self, which requires long-term memory. Consciousness varies in level, with coma and deep anesthesia on one extreme, alert wakefulness on the other, and sleep in between. There are also altered states of consciousness, including hypnosis, trances, and meditative states.

6 Consciousness Resources Consciousness is a phenomenon of the brain, but most researchers agree that there

is no “consciousness center.” As we will see later, consciousness appears to result from the interaction of widely distributed brain structures. Partly because consciousness appears to be distributed among many functions, and partly because the problem is so overwhelming, researchers have opted to begin by looking at structures responsible for the components of consciousness. We will consider three of those components here—awareness, attention, and sense of self—before tackling the problem of the neural bases of consciousness in general.

How does the brain solve the “binding problem”? Awareness As an abstract concept, awareness is difficult to define and more difficult to study.

Instead, researchers have directed their attention to awareness of something. Taking this approach has helped identify brain areas as potential locations of awareness. One strategy is to monitor the brain’s activity in a scanner while flashing a series of words on a screen so briefly that they are at the threshold of detectability. If a person doesn’t

consciously notice the word, only the visual cortex is activated; as soon as the person becomes aware of the word, the lateral prefrontal cortex and posterior parietal cortex become active. These two areas and the thalamus have more interconnections with each other and the rest of the brain than any other region. These and other observations have led Daniel Bor and Ankil Seth to propose that the prefrontal parietal network is important to awareness and to consciousness in general (Bor, 2013; Bor & Seth, 2012). FIGURE 15.16 Forty-Hertz Oscillations in Neurons. Top: Recording of the combined activity of all neurons in the vicinity of the electrode. Bottom: Activity recorded at the same time from two neurons adjacent to the electrode. By visually lining up the peaks and valleys of the two tracings, you can see that the two neurons are firing in synchrony with all the others in the area. (The upper tracing appears smoother because it is the sum of the activity of many neurons and because random activity is equally often positive and negative and cancels itself out.)

SOURCE: Courtesy of Wolf Singer, Max-Planck-Institut für Hirnforschung. What happens when part of this network is damaged? There are many possibilities,

but the case of a man who often attributed one object’s color or direction of movement to another object after both parietal lobes were damaged is particularly instructive (L. J. Bernstein & Robertson, 1998). What this tells us is that brain damage impaired his ability to bind the spatial, color, and movement information together into an integrated percept. Increasingly, researchers are becoming convinced that binding involves synchronization of neural activity. Synchronized activity occurs mostly in the gamma frequency range, between 30 and 90 Hz. Early studies found that during visual stimulation, 50% to 70% of neurons in the visual area of cats fired in synchrony at an average rate of 40 Hz (Engel, König, Kreiter, & Singer, 1991; Engel, Kreiter, König, & Singer, 1991). For an illustration of 40-Hz synchrony, see Figure 15.16. In response to a moving stimulus, activity synchronized between V1, the primary visual area, and V5, the area that detects movement (Engel, Kreiter, et al., 1991). This makes sense, because studies have indicated that visual awareness requires feedback to V1 from extrastriate areas like V5 (reviewed in Tong, 2003). (You may want to refer to

Figure 10.25 for the location of V1 and V5.) FIGURE 15.17 Synchronized Activity Among Areas Involved in Learning. Numbered circles indicate the location of EEG electrodes; colored areas, from anterior to posterior, are the primary somatosensory cortex, secondary somatosensory cortex, and visual cortex. A light was paired several times with a shock to the middle finger. After that, presenting the light alone produced 40-Hz (average) EEG activity, which was synchronized between the visual cortex and the somatosensory cortex. The arrows indicate the pairs of electrodes between which synchrony was observed. Synchrony occurred (a) in the right hemisphere when shock had been applied to the left hand and (b) in the left hemisphere when shock had been applied to the right hand.

SOURCE: Adapted from “Coherence of Gamma-Band EEG Activity as a Basis for Associative Learning,” by W. H. Miltner et al., Nature, 397, pp. 434–436. © 1999 Nature Publishing. Reprinted by permission. Later investigations revealed that activity is coordinated over much wider areas.

For example, when researchers presented a light that had previously been paired with shock to the finger, activity became synchronized between the visual cortex and the finger area of the somatosensory cortex (Figure 15.17; Miltner, Braun, Arnold, Witte, & Taub, 1999). In the McIntosh et al. (1999) study described above, at the moment of awareness neural activity in the left prefrontal cortex became coordinated with activity in other parts of the brain, including the right prefrontal cortex, auditory association areas, visual cortex, and cerebellum. Another study better illustrates the integrative nature of this synchrony. Words were presented in various colors and at various locations on a screen; whether the subject became aware of the word’s color or of its location—indicated by being able to recall it later—depended on whether a frontal or temporal area was activated during the presentation. But if the individual

registered both the color and the location, additional activity occurred in a part of the parietal cortex (Uncapher, Otten, & Rugg, 2006). Gaillard and his colleagues (2009) had the opportunity to record EEG activity from

electrodes implanted in the brains of patients being evaluated for surgery to eliminate epileptic seizures; they recorded a cascade of awareness-defining events. Whether words reached awareness or not, they evoked coordinated gamma activity in the occipital area lasting about 300 milliseconds; if the words were recognized, this localized activity was followed by synchronized activity among occipital, parietal, and temporal areas. In addition, neurons in one area appeared to be triggering firing among neurons in the other areas. It is important to emphasize that much of our behavior is guided by processes that

are outside awareness. A simple example would be our constant use of proprioceptive information to sit erect, to walk, and to reach accurately for objects in our environment. You learned in previous chapters that people with impaired facial recognition (prosopagnosics) are aroused by familiar faces that they do not otherwise recognize, that people with blindsight locate objects they deny seeing, and that patients with hippocampal damage improve over time on tasks that they deny having performed before. A more esoteric example is that by relying on nonvisual photoreceptors among the ganglion cells, blind people can tell whether a light is on or off better than chance, though they report that they don’t see it (Vanderwalle et al., 2013). In one study, research participants were able to learn and use a pattern for predicting the location of a target on a computer screen, but not one of them was able to state what the pattern was—even when offered a reward of $100 for doing so. Through subtle training procedures, people have learned to associate a particular facial feature with a particular personality characteristic without being aware they had done so; in fact, when questioned, they did not believe that such a relationship existed (reviewed in Lewicki, Hill, & Czyzewska, 1992). We like to believe that our behavior is rational and guided by conscious decisions; perhaps we invent logical-sounding explanations for our behavior when we are not aware of its true origins. So what is the benefit of conscious awareness? This is actually a matter of debate, but one apparent advantage is that it enables a consistency and a planfulness in our behavior that would not be possible otherwise. Attention Separating attention and awareness is difficult, and it is even controversial whether

we can do so. However, it is instructive to think of awareness as referring to the content of consciousness and attention as a process— the act of attending, or the act of selecting among the contenders for our awareness. Attention is the brain’s means of allocating its limited resources by focusing on some neural inputs to the exclusion of others. I doubt if I need to tell you how important attention is. When you are paying attention to a fascinating book, you may not notice all the hubbub around you. Some

stimuli “grab” your attention, though; for example, the voice of a friend calling your name stands out above all the din. Also, what is attended to is easily remembered, and what escapes attention may be lost forever. The practical importance of attention is demonstrated in studies showing a fourfold increase in automobile accidents while drivers are using a mobile telephone (McEvoy et al., 2005; Redelmeier & Tibshirani, 1997). This is not due to the driver having one hand off the wheel, because the risk was just as high when the driver was using a speaker phone; clearly, the problem was attention. FIGURE 15.18 Setup for Demonstrating the Cheshire Cat Effect. Your view will alternate between your hand and your friend’s face.

Although you are aware of the importance of attention, you probably do not realize just how powerful it is. An interesting demonstration is the Cheshire cat effect, named after the cat in Alice in Wonderland, who would fade from sight until only his smile remained. Have a friend stand in front of you while you hold a mirror in your left hand so that it blocks your right eye’s view of your friend’s face but not the left eye’s (Figure 15.18). Then hold your right hand so you can see it in the mirror. (This works best if you and your friend stand in the corner of a room with blank walls on two sides.) Your hand and your friend’s face will appear to be in the same position, but your friend’s face, or part of it, will disappear. If you hold your hand steady, you will begin to see your friend’s face again, perhaps through your “transparent” hand; move your hand slightly, and the face disappears again. By experimenting, you should be able to leave your friend with only a Cheshire cat smile. Your brain continues to receive information from both your hand and your friend’s face throughout the demonstration; but because the two eyes are sending the brain conflicting information, telling it that two objects are in the same location, binocular rivalry occurs. The brain attends to one stimulus for a time and then switches to the other. Attention also switches when your hand or your friend’s head moves and demands attention.

Attention is not just a concept; it is a physiological process, and changes in attention are accompanied by changes in neural activity. When an observer attends to an object, firing synchronizes between the brain areas involved, such as prefrontal with parietal neurons or parietal neurons with visual areas, depending on the task (Buschman & Miller, 2007; Saalmann, Pigarev, & Vidyasagar, 2007). When attention shifts, for example, during binocular rivalry, activity shifts from one group of neurons in the visual cortex to another, even though the stimulus inputs do not change (Leopold & Logothetis, 1996). When research participants focused on an object’s color, PET scans showed that activity increased in visual area V4; activation shifted to the inferior temporal cortex when they attended to the object’s shape, and it changed to area V5 during attention to its movement (Chawla, Rees, & Friston, 1999; Corbetta, Miezin, Dobmeyer, Shulman, & Petersen, 1990). We know that the shifts were due to attention, because activation also increased in V4 during attention to color even when the stimuli were uncolored and in V5 during attention to movement when the stimuli were stationary (Chawla et al., 1999).

What is the neural basis of attention? So our experience of attention is a reflection of changes in brain activity. The

increases in cortical activity described above are at least partly due to the modulation of activity in the thalamus, which is the gateway for sensory information to the cortex (except for olfaction). The cortex can selectively inhibit thalamic neurons and determine which information will reach it (John, 2005). When human subjects attended to a stimulus, neural responses to that stimulus increased in the lateral geniculate nucleus of the thalamus, and responses to ignored stimuli decreased (O’Connor, Fukui, Pinsk, & Kastner, 2002). (Remember that you saw similar results in Chapter 9.) “

Neural scientists are thus beginning to address aspects of the fundamental question of consciousness by focusing on a specific, testable problem: What neural mechanisms are responsible for focusing visual attention?

—Eric R. Kandel

” Attention involves a number of structures, and imaging suggests that they are

organized into two networks: a dorsal one that allocates attention under goal-directed control and a ventral one that responds to stimulus demands (Asplund, Todd, Snyder, & Marois, 2010). However, the anterior cingulate cortex (ACC) may play an executive role (see the anterior cingulate gyrus in Figure 8.6). In individuals undergoing cingulate lesioning as a treatment for obsessive-compulsive disorder, 19%

of ACC neurons either increased or decreased their firing rate during attention- demanding cognitive tests (K. D. Davis, Hutchison, Lozano, Tasker, & Dostrovsky, 2000). (You have to admire the brave souls who were willing to submit to mental arithmetic during brain surgery!) The ACC is also active during the Stroop word-color test, in which subjects must read color names as quickly as possible (Peterson et al., 1999). This is a difficult task, because some of the words are printed in a conflicting color; the researchers believe that the ACC modulates activity in attentional pathways to focus attention on the word’s meaning and suppress attention to its color. The Sense of Self Consciousness is usually studied in relation to external reality—for example, object

recognition or object awareness; this is in keeping with psychology’s preference during much of its history for studying phenomena that are “out there,” where we can observe them objectively. But an important aspect of consciousness is what we call the self; the sense of self includes an identity—what we refer to as “I”—and the sense of agency, the attribution of an action or effect to ourselves rather than to another person or external force. “

Consciousness is a concept of your own self, something that you reconstruct moment by moment on the basis of your own body, your own autobiography and a sense of your intended future.

—Antonio Damasio

” The sense of self is shared with few other species. We have learned this by using a

cleverly simple technique developed for children. When the researcher puts a spot of rouge on a child’s nose or forehead and places the child in front of a mirror, infants younger than about 15 months reach out and touch the child in the mirror or kiss it or hit it; older children will show self-recognition and use the mirror to examine the mysterious spot on their faces (M. Lewis & Brooks-Gunn, 1979). Chimpanzees are also able, after a time, to recognize themselves in the mirror; they examine the rouge spot, and they use the mirror to investigate parts of their body they have never seen before, like their teeth and their behinds (Figure 15.19). Elephants, orangutans, porpoises, and–get this—magpies also recognize themselves, but monkeys do not (Gallup, 1983; Plotnik, de Waal, & Reiss, 2006; Prior, Schwarz, & Güntürkün, 2008; Reiss & Marino, 2001). Although monkeys learned how a mirror works and would turn to face a person whose reflection they saw in the mirror, after 17 years of continuous exposure to a mirror in their cage, they still treated their reflections like an intruder (Gallup & Povinelli, 1998). FIGURE 15.19 A Chimp Demonstrates Concept of Self.

SOURCE: Gallup and Povinelli (1998). Photos courtesy of Cognitive Evolution Group, University of Louisiana at Lafayette. Investigators have had some success in identifying neural correlates of the sense of

self. Frontal-temporal damage, for example, impairs episodic memory and may produce a detachment from the self (M. A. Wheeler, Stuss, & Tulving, 1997). The anterior cingulate cortex and the insula (Figure 15.20) are active when people recognize their own faces, identify memories as their own, or recognize descriptions of themselves (Devue et al., 2007; Farrer et al., 2003; Fink et al., 1998). Stroke or the dementia of old age can impair people’s ability to recognize their mirror image; the person may treat the “other” as a companion, as an intruder who must be driven from the home, or as a stalker who appears in automobile and shop windows (Feinberg, 2001). FIGURE 15.20 (A) The Anterior Cingulate and (b) the Insula. The insula, which is slightly visible in (a) as the outer wall of the lateral ventricle, can be seen clearly in (b) following removal of the corpus callosum and surrounding cortex.

SOURCE: (a) Courtesy of Dr. John A Beal, Heal Collection, University of Utah. (b) From “Clinical Effects of Insular Damage in Humans,” by A. Ibañez, E. Gleichgerrcht, and Facundo Manes, 2010, Brain Structure and Function, 214, pp. 397–410. Fig 1. © 2010 With kind permission from Springer Science and Business Media. Farrer and Frith and their colleagues suggest that the sense of agency is mediated

by the anterior insula and the inferior parietal area (Farrer et al., 2003; Farrer & Frith, 2002). When the subjects believed that they were controlling movements of a virtual hand or a cursor on a computer screen, activity increased in both the left and right insulas; when it became obvious that the experimenter was controlling the movement,

activity shifted to the angular gyrus (in the inferior parietal cortex), particularly on the right (Figure 15.21). In other research, activity increased in the inferior parietal cortex as the discrepancy increased between the person’s movements and feedback from the movements; Farrer and her colleagues (2007) interpret this as evidence that the angular gyrus contributes to the sense of agency by detecting discrepancies between actions and consequences. People with schizophrenia who believe their behavior is controlled by another person or agent show heightened parietal activity compared with other schizophrenia patients and controls (Spence et al., 1997). FIGURE 15.21 Brain Areas Involved in the Sense of Agency. Attributing an effect (movement of a computer cursor) to oneself activated the insula (a); attributing the movement to another person activated the angular gyrus in the inferior parietal cortex (b).

SOURCE: From “Experiencing Oneself vs. Another Person as Being the Cause of an Action: The Neural Correlates of the Experience of Agency,” by C. Farrer et al., NeuroImage, 15, pp. 596–603, fig. 2 and fig. 3, p. 598. © 2002 with permission from Elsevier, Ltd. We do not find in these studies, nor should we expect to find, a brain location for

the self; instead, what we see is scattered bits and pieces. We should regard the self as a concept, not an entity, and the sense of self as an amalgamation of several kinds of information, mediated by networks made up of many brain areas. Body image, memory, and the activity of mirror neurons are among the contributors to the sense of self; we will examine these topics and then consider two disorders of the self. Body Image Body image contributes to a sense of self because we have an identification with

our body and with its parts; it is our body, our hand, our leg. A good example of the importance of body image to the sense of self is the phantom limb phenomenon. You learned in Chapter 11 that most amputees have the illusion that their missing arm or leg is still there. The illusion occurs in 80% of amputees and may persist for the rest of the person’s life, which attests to the power of the body image. Distortions in the phantom (see Figure 15.22) sometimes add credibility to this point: One man was unable to sleep on his back because his phantom arm was bent behind him, and another had to turn sideways when walking through a door because his arm was extended to the side (Melzack, 1992). Researchers once thought that phantoms

occurred only after a person developed a learned body image, but we now know that phantoms can occur in young children and even in people born with a missing limb. Because the body image is part of the equipment we are born with, it becomes an important part of the self—even when it conflicts with reality.

Where does our sense of self come from? The “replacement” of a limb by a phantom does not prevent a feeling of loss, which

can extend to the sense of self. This point was illustrated very graphically by S. Weir Mitchell, a Civil War physician who saw numerous amputees and presented some of his observations in the fictionalized account The Case of George Dedlow (Mitchell, 1866). Mitchell’s hero, who has lost both arms and both legs in battle, says, FIGURE 15.22 Maps of a Patient’s Phantom Hand. Touching the arm above the stump produced sensations of the missing hand. The same thing happened on the face, confirming what we saw in Chapter 11, that neurons from the face have invaded the hand area in the somatosensory cortex. SOURCE: Figure 2.2 from Phantoms in the Brain by V. S. Ramachandran, MD, PhD, and Sandra Blakeslee. Copyright © 1998 by V. S. Ramachandran and Sandra Blakeslee. Reprinted by permission of HarperCollins Publishers, Inc.

I found to my horror that at times I was less conscious of myself, of my own existence, than used to be the case.... I felt like asking someone constantly if I were really George Dedlow or not. (p. 8) In Chapter 11 we saw an example of a more extensive loss in the case of Christina.

Watching a home movie of herself made before the disease had destroyed her proprioceptive sense, she exclaimed, Yes, of course, that’s me! But I can’t identify with that graceful girl any more! She’s gone, I can’t remember her, I can’t even imagine her. It’s like something’s been scooped right out of me, right at the centre. (Sacks, 1990, p. 51)

Although information about the body is processed in the somatosensory cortex, body image is a phenomenon that develops primarily in adjacent parietal areas. An example comes from earlier attempts to eliminate phantoms by surgery; lesions in the somatosensory area had no effect, but lesioning the right posterior parietal cortex did suppress the sensations (Berlucchi & Aglioti, 1997). One of the functions of the insula is the integration of internal with external information; damage to the posterior part of the insula, which is located in the inferior parietal cortex, can produce a variety of symptoms, including denial that a paralyzed limb belongs to the patient or perception of an extra limb (Berlucchi & Aglioti; Karnath & Baier, 2010). In Chapter 11, we saw that damage to the inferior parietal area can also cause the most extreme of body image illusions, the out-of-body experience (Blanke & Arzy, 2005). Memory Without long-term memory, it is doubtful there can be a self, because there is no

past and no sense of who the person is. In the words of the memory researcher James McGaugh, memory “is what makes us us” (A. Wilson, 1998). Loss of short-term memory is not as disruptive; patients like HM (described in Chapter 12) have a lifetime of information about their past and about themselves as a background for interpreting current experience, even if they do not remember events that have occurred since their brain damage. However, for Korsakoff’s and Alzheimer’s patients, memory loss extends back several years before the onset of illness, as well as after the onset. Oliver Sacks’s patient Jimmie had lost 40 years of memories to Korsakoff’s disease; restless, unable to say whether he was miserable or happy, he reported that he had not felt alive for a very long time (Sacks, 1990). Mary Frances, whom you met in Chapter 12, took another approach, explaining her

situation with one false scenario after another. Another confabulator was Mr. Thompson, who took an unauthorized day’s liberty from the hospital. At the end of the day, the cabdriver told the staff that he had never had so fascinating a passenger: “He seemed to have been everywhere, done everything, met everyone. I could hardly believe so much was possible in a single life” (Sacks, 1990, p. 110). According to Sacks, Mr. Thompson had to “make himself (and his world) up every moment” by turning everyone on the ward into characters in his make-believe world and weaving story after story as he attempted to create both a past and a present for himself. The confabulated stories amnesics tell can usually be traced back to fragments of

actual experiences. This is consistent with the hypothesis introduced in our earlier discussion, that confabulation is a failure to suppress irrelevant memories due to damage in the frontal area (Benson et al., 1996; Schnider, 2003; Schnider & Ptak, 1999). But, like Mr. Thompson, confabulators often prefer an embellished past to an ordinary one (Fotopoulou, Solms, & Turnbull, 2004); this together with the involvement of the anterior cingulate cortex (Turner et al., 2008) makes one suspect that the confabulation is also serving the self-image. The motivated nature of

confabulation suggests the importance of real or imagined memories to the person’s identity. As the movie director Luis Buñuel (1983) said as he contemplated his own failing memory, You have to begin to lose your memory, if only in bits and pieces, to realize that memory is what makes our lives. Life without memory is no life at all.... Our memory is our coherence, our reason, our feeling, even our action. Without it, we are nothing.

Self, Theory of Mind, and Mirror Neurons A sense of self requires the distinction between our self and other selves and,

arguably, some understanding of other selves. We saw in the discussion of autism that an ability to attribute mental states to others is called theory of mind and that researchers who study mirror neurons believe they are critical to our development of that comprehension. They give mirror neurons considerable credit for social understanding (Gallese & Goldman, 1998), empathy (Gazzola et al., 2006), and the ability to understand the intentions of others (Iacoboni et al., 2005). When volunteers watched a video clip, their mirror neurons responded more as a model reached for a full cup beside a plate of snacks (implying the intent to eat) than when the model reached for an empty cup beside an empty plate (implying the intent to clean up). The two scenes without the model produced no differences (Figure 15.23; Iacoboni et al., 2005). FIGURE 15.23 Different Intentions Distinguished by Mirror Neurons. The implied intention of the actor in the photo on the left is to drink; in the photo on the right, it is to clean up. Different neurons were active as research participants viewed these two scenes, suggesting that mirror neurons can distinguish among intentions.

SOURCE: From “Grasping the Intentions of Others With One’s Own Mirror Neuron System,” by M. Iacoboni, 2005, PLoS Biology, 3, pp. 529–535, fig. 1 upper right and lower right, p. 530. Used under the Creative Commons Attribution (CC BY) license. Malfunction in the mirror neuron system is one reason suggested for the autistic

individual’s failure to develop a distinction between self and others, along with empathy and theory of mind (Cascio, Foss-Feig, Burnette, Heacock, & Cosby, 2012; Williams, 2008). Children with autism spectrum disorder took twice as long as control

subjects to develop the rubber hand illusion, and the delay was correlated negatively with an empathy measure (Cascio et al.). Justin Williams and his associates suggest that the problem is not in the mirror neurons themselves, but in the regulation of their function by the anterior cingulate cortex (J. H. Williams, Whiten, Suddendorf, & Perrtt, 2001). Split Brains and Dissociative Identity Disorder: Disorders of Self Chapter 3 describes a surgical procedure that separates the two cerebral

hemispheres by cutting the corpus callosum. This surgery is used to prevent severe epileptic seizures from crossing the midline and engulfing the other side of the brain. Besides providing a unique opportunity to study the differing roles of the two hemispheres, split-brain patients also raise important questions about consciousness and the self. Gazzaniga (1970) described a patient who would sometimes find his hands behaving in direct conflict with each other—for instance, one pulling up his pants while the other tried to remove them. Once the man shook his wife violently with his left hand (controlled by the more emotional right hemisphere), while his right hand tried to restrain the left. If the person with a severed corpus callosum is asked to use the right hand to form a specified design with colored blocks, performance is poor because the left hemisphere is not very good at spatial tasks; sometimes the left hand, controlled by the more spatially capable right hemisphere, joins in to set the misplaced blocks aright and has to be restrained by the experimenter. Different researchers interpret these studies in different ways. At one extreme are

those who believe that the major or language-dominant hemisphere is the arbiter of consciousness and that the minor hemisphere functions as an automaton, a nonconscious machine. At the other extreme are the researchers who believe that each hemisphere is capable of consciousness and that severing the corpus callosum divides consciousness into two selves. Sixty years of research have prompted most theorists to take positions somewhere along the continuum between those extremes. Gazzaniga, for instance, points to the right hemisphere’s differing abilities, such as

the inability to form inferences, as evidence that the right hemisphere has only primitive consciousness (Gazzaniga, Ivry, & Mangun, 1998). He says the left hemisphere not only has language and inferential capability but also contains a module that he calls the “brain interpreter.” The role of the brain interpreter is to integrate all the cognitive processes going on simultaneously in other modules of the brain. Gazzaniga was led to this notion by observing the split-brain patient PS performing one of the research tasks. PS was presented a snow scene in the left visual field and a picture of a chicken’s foot in the right and asked to point to a picture that was related to what he had just seen. With the right hand he pointed to the picture of a chicken, and with the left he selected a picture of a shovel (see Figure 15.24). When asked to explain his choices, he (his left hemisphere) said that the chicken went with the foot and the shovel was needed to clean out the chicken shed. Unaware that the

right hemisphere had viewed a snow scene, the left hemisphere gave a reasonable but inaccurate explanation for the left hand’s choice. Although the right hemisphere has less verbal capability than the left, it can respond to simple commands; if the command “Walk” is presented to the right hemisphere, the person will get up and start to walk away. When asked where he or she is going, the patient will say something like “I’m going to get a Coke.” According to Gazzaniga, these confabulations are examples of the brain interpreter making sense of its inputs, even though it lacks complete information.

What do the disorders tell us? Perhaps researchers who view the right hemisphere’s consciousness as primitive are

confusing consciousness with the ability to verbalize the contents of consciousness. Assigning different levels of consciousness to the two hemispheres may be premature when our understanding of consciousness is itself so primitive. Research with split- brain patients tells us to avoid oversimplifying such a complex issue. FIGURE 15.24 Split-Brain Patient Engaged in the Task Described in the Text. His verbal explanation of his right hand’s selection was accurate, but his explanation of his left hand’s choice was pure confabulation.

SOURCE: Gazzaniga (2002). Based on an illustration by John W. Karpelou, BioMedical Illustrations. Another disorder of self is dissociative identity disorder (DID; formerly known as

multiple personality), which involves shifts in consciousness and behavior that appear to be distinct personalities or selves. You may be familiar with this disorder from the movie The Three Faces of Eve. Shy and reserved, Eve White would have blackouts while her alter ego, Eve Black, spent the night on the town dancing and drinking with

strange men. The puritanical Eve White would have to deal with the hangover, explain a closetful of expensive clothes she didn’t remember buying, and sometimes fend off an amorous stranger she found herself with in a bar (Lancaster, 1958; Thigpen & Cleckley, 1957). Eve, whose real name is Chris Sizemore, went on to develop 22 different personalities before she successfully integrated them into a single self (Figure 15.25; Sizemore, 1989). The causes of DID are not understood, but 90% to 95% of patients report childhood physical and/or sexual abuse (Lowenstein & Putnam, 1990; C. A. Ross et al., 1990). Most therapists believe that the individual creates alternate personalities (“alters”) as a defense against persistent emotional stress; the alters provide escape and, often, the opportunity to engage in prohibited forms of behavior (Fike, 1990; C. A. Ross et al., 1990). Although the disorder had been reported occasionally since the middle 1600s (E. L.

Bliss, 1980), reports were rare until recent times; the number of reports jumped from 500 in 1979 to 5,000 in 1985 (Braun, 1985). Since that time, prevalence in the United States has been estimated at 1% to 3% (Lowenstein, 1994). While some therapists believe that DID was underdiagnosed earlier (Fike, 1990; Lowenstein & Putnam, 1990; Putnam, 1991), critics say that the patients intentionally create the alternate personalities to provide an explanation for bizarre and troubling behavior, as a defense for criminal behavior, or at the urging of an overzealous therapist (Spanos, 1994). The case of Sybil (made famous by a book and a TV movie) is alleged to have been an elaborate hoax. According to writer Debbie Nathan (2011), it was motivated by Sybil’s need for more attention from her therapist and her therapist’s pursuit of professional recognition and a lucrative book deal. There probably are many bogus cases, but extensive documentation by therapists and inclusion of DID in the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) lend credibility to the diagnosis. FIGURE 15.25 Chris Sizemore. The story of her struggle with multiple personalities was the basis for the movie The Three Faces of Eve.

SOURCE: © AP Photo. Consistent with a history of maltreatment and trauma during the childhood of

people with DID, one study found a 19% reduction in the size of the hippocampus and a 32% reduction in the amygdala (Vermetten, Schmahl, Lindner, Loewenstein, & Bremner, 2006). From this perspective, it seems more appropriate to think of the alters not as personalities but as different ways of coping with a traumatic development. Physiological measures support this interpretation; alters respond differently in skin conductance, EEG, visual event-related potentials, and cardiovascular measures (Reinders et al., 2006). Brain scans show reduced activity in the orbitofrontal cortex, along with increases in the other frontal areas (Sar, Unal, & Ozturk, 2007) and differences in activation between alters while listening to personally relevant traumatic material (Reinders et al.). FIGURE 15.26 Hippocampal Activity During the Switch Between Multiple Personalities. The scans show inhibition of the parahippocampus and hippocampus during the switch from the primary personality to the alter (a) and increased activity in the right hippocampus during the switch back (b, c). The brain levels of these three scans are shown in (d). (The brain is viewed from below, so right and left are reversed on the page.)

SOURCE: From “Functional Magnetic Resonance Imaging of Personality Switches in a Woman With Dissociative Identity Disorder,” by G. E. Tsai et al., Harvard Review of Psychiatry, 7(15), pp. 119–122. © 1999. Reprinted by permission of Wolters Kluwer Health. Bower (1994) attempted to explain the amnesia seen in DID as an example of state-

dependent learning. In state-dependent learning, material learned in one state is difficult to recall in the other state; the altered states can be induced in the laboratory by alcohol and other drugs and even by different moods. Bower’s hypothesis is that abuse or other stresses create an altered state in which separate memories and adaptive strategies develop to the point that they form a distinct personality. Guochuan Tsai and his colleagues used functional magnetic resonance imaging to study a 33-year-old DID patient as she switched between her primary and an alter personality (Tsai, Condie, Wu, & Chang, 1999). During the switch from the primary to the alter, activity was inhibited in the hippocampus and parahippocampal area, particularly on the right side; during the switch back, the right hippocampus increased in activity (see Figure 15.26). The hippocampal activity led the researchers to suggest that learning mechanisms are involved in the disorder. Imagining a new personality did not have the same effect even though it required as much effort. Several observations are consistent with the idea that learning structures are

involved in dissociation: Childhood abuse, which is frequent in patients’ backgrounds, can produce hippocampal damage (Bremner et al., 1997); an association has been reported between identity dissociation and epileptic activity in the temporal lobes, where the hippocampi are located (Mesulam, 1981); and differences in temporal lobe activity have been found between personalities in the same individual (Saxe, Vasile, Hill, Bloomingdale, & Van der Kolk, 1992; Sheehan, Thurber, & Sewall, 2006). But speculating about how a person can develop a whole constellation of separate memories and personality characteristics points up how inadequate our understanding of learning is. We should consider dissociative identity disorder not just a challenge but an added opportunity for studying neural functioning and cognitive processes such as learning. “

One is always a long way from solving a problem until one actually has the answer. —Stephen Hawking

”

FIGURE 15.27 Map of Event-Related Potentials to Masked and Unmasked Visually Presented Words. When briefly presented words were masked by following them with nonmeaningful visual stimuli, activation was largely confined to the primary visual area (as well as

slightly delayed) and did not produce awareness. Unmasked words produced additional subsequent activity, which spread through the frontal and parietal cortex, accompanied by awareness. SOURCE: From “Cerebral Mechanisms of Word Masking and Unconscious Repetition Priming,” by S. Dehaene et al., Nature Neuroscience, 4, pp. 752–758, fig. 3, p. 755. © 2001 Macmillan Publishing. Used with permission.

Network Explanations of Consciousness Most neurobiological theories of consciousness assume that consciousness requires

a widely distributed neuronal network (Zeman, 2001). This view has arisen in part from studies that manipulate awareness of environmental stimuli by using binocular rivalry, backward masking (following a stimulus quickly with a nonmeaningful stimulus), and inattentional blindness (inserting a distracting stimulus in a visual scene). Numerous studies have shown that when stimuli become conscious, they produce widespread activity in the prefrontal and parietal cortex (Figure 15.27; reviewed in Baars, 2005; see Dehaene et al., 2001; Sergent, Baillet, & Dehaene, 2005). Similarly, when consciousness is impaired by deep sleep or by brain injury that results in a vegetative state, auditory and pain stimuli fail to evoke activity beyond the primary areas. In addition, deep sleep, coma, vegetative states, epileptic loss of consciousness, and general anesthesia are characterized by decreased metabolism in the frontal and parietal cortex, and coordinated activity among brain areas disappears.

(See In the News for a paradox that may explain the near-death experience.) According to some theorists, consciousness occurs when the functioning of

widespread networks becomes coordinated, enabling them to share and integrate information (Baars, 2005; Dehaene & Naccache, 2001; Tononi, 2005). Earlier we saw that gamma activity is proposed to be the mechanism that binds sensory information into awareness. Many theorists believe that gamma oscillations generated by a feedback loop between the thalamus and the cortex not only are the most likely means of achieving this coordination but are also necessary for consciousness (Ribary, 2005). Lesions that impair the functioning of this thalamo-cortical system produce a global loss of consciousness; damage to the intralaminar nuclei of the thalamus is particularly devastating, most likely because these nuclei are responsible for the ability of the thalamus and cortical areas to work as a system (Tononi, 2005). Recently, researchers have been focusing more specifically on the default mode

network (DMN) and its relationship to level of consciousness. Sleep deprivation, for example, is accompanied by some disruption in the DMN, and coordination between frontal and posterior brain areas is lost altogether in deep sleep (Gujar, Yoo, Hu, & Walker, 2010; Horovitz et al., 2009; Sämann et al., 2010). Activity in the DMN also corresponds to the depth of anesthesia, and during unconsciousness even transcranial magnetic stimulation cannot evoke more than localized activation (Deshpande, Kerssens, Sebel, & Hu, 2009; Ferrarelli et al., 2010). In addition, DMN activity varies with the level of consciousness in noncommunicative brain-damaged patients; locked- in syndrome patients do not differ from normal controls, but activity decreases progressively from minimally conscious to vegetative to coma patients (Vanhaudenhuyse et al., 2010). These results are consistent with Giulio Tononi’s hypothesis that consciousness depends on the brain’s ability to integrate information, an ability that is impaired by diminishing connectivity (Tononi, 2008).

Consciousness and the Dying Brain As a person approaches the moment of death, a strange experience sometimes occurs. We know this from people who have been resuscitated; in fact, 3% of people questioned in a Gallup poll said they have had a near-death experience (Choi, 2011). Most often they report a very bright light, sometimes at the end of a tunnel, and an experience of leaving the body. The person might have a sense of moving toward the light or of floating above the scene and observing those attending the “death.” Near-death experiences are often given a religious

interpretation, because of believed encounters with a deity and a sense of renewed meaning in life. Neuroscientists believe there is a biological explanation, and they point out that

most of the phenomena of near-death experiences also occur in brain disorders and

during brain stimulation. A difficulty has been accepting that the dying brain is capable of the vigorous activity implied by the intense, “realer than real” nature of the sensory experience; in fact, the brain has been assumed to be inactive during cardiac arrest. To answer this question, researchers at the University of Michigan Medical School monitored the EEG of anesthetized rats undergoing induced cardiac arrest. Surprisingly, during the first 30 seconds after arrest, all of the rats displayed a brief, widespread surge of highly synchronized brain activity similar to what is seen in an aroused brain. A nearly identical pattern occurred with rats undergoing asphyxiation. The researchers had hypothesized this would happen, but even they were surprised by the intensity and the organization of the electrical activity. According to them, this study provides the first scientific framework for explaining the near-death experience.

SOURCE: © imageegami.

7 Near Death in the News

Distribution of consciousness means that there is no center of consciousness, but some researchers believe that there must be an executive, an area that coordinates or orchestrates the activity of all the other structures. Researchers have proposed a variety of locations for this executive, including the thalamus (Crick, 1994), the anterior cingulate cortex (Posner & Rothbart, 1998), and the claustrum (Crick & Koch, 2005). However, support for such a broad role for any structure is lacking. Just as consciousness appears to be distributed, it seems that its controls might be as well. And considering the complexity of consciousness that you see in Figure 15.28, those controls are likely to be numerous. These issues are not purely academic; as the Application shows, a better understanding of consciousness is a practical necessity.

8 Talking With the Experts FIGURE 15.28 Awareness and Arousal in Normal and Impaired Consciousness.

Concept Check

SOURCE: Adapted from “The Neural Correlate of (Un)awareness: Lessons From the Vegetative State,” by S. Laureys, 2005, Trends in Cognitive Sciences, 9, pp. 556– 559.

Take a Minute to Check Your Knowledge and Understanding

What four changes in the brain accompany shifts of attention? What roles do body image and memory play in the sense of self? What controversy about consciousness have the split-brain studies produced? What physical differences have been found between alternate personalities in patients with dissociative identity disorder?

Summarize the “coordination” explanation for consciousness described here.

APPLICATION

Determining Consciousness When It Counts Brain damage relegates thousands of people to hospital beds and deprives them of the ability to interact with loved ones or to communicate their needs to caregivers. The worst of these are in a coma, unarousable and completely unresponsive to stimulation. Those who are in a vegetative state respond reflexively to stimulation and cycle through wakefulness and sleep, but they do not interact voluntarily with their environment. The minimally conscious

occasionally show some voluntary responses, such as following visual movement or crying when they hear a family member’s voice, but they are unable to communicate with any reliability. Patients with locked-in syndrome, on the other hand, are fully conscious; however, they are so paralyzed, usually due to brain stem lesions, that at best they are able to communicate only with eye movements or finger twitches. Unfortunately, physicians often rely on bedside clinical observation to

diagnose their patients, rather than neurobehavioral testing. As a result, an estimated 40% of patients classified as being in a vegetative state are actually minimally conscious (Schnakers et al., 2009). Brain scans do a much better job (see figure), but they are expensive, not every hospital has the equipment, and transfer to a facility can be stressful to the patient who has some awareness. So Jean-Rémi King and his associates (2013) have developed a bedside device that uses EEG to distinguish whether a series of beeps activates only the auditory area or a larger network, signaling some level of consciousness. In a preliminary test, it distinguished among patients who were in a vegetative state, in a minimally conscious state, or conscious; besides assessing the status of brain-damaged patients, it could be used to monitor whether patients are truly unconscious during surgery. Accurate assessment of a patient’s level of consciousness is critical not only for care decisions, such as whether pain management is appropriate, but also for guiding research to develop ways of communicating with patients and, potentially, restoring some function.

PET Scans Reveal Metabolic Activity Corresponding to Patients’ Level of Consciousness. SOURCE: From “Brain Function in Coma, Vegetative State, and Related Disorders,” by S. Laureys, A. M. Owen, and N. D. Schiff, 2004, The Lancet, 3, pp. 537–546, with permission from Elsevier.

New research indicates that it may be possible to communicate with some apparently unresponsive patients. Patients were asked to imagine playing

tennis or walking through their house while their brain activity was monitored with fMRI; five patients (all but one classified as being in a vegetative state) were able to produce distinctive activity in different regions of the brain (Monti et al., 2010). One of the patients, considered to have been in a vegetative state for 5 years, was able to answer questions correctly by thinking about one of the scenarios for “yes” and the other for “no.” Using fMRI to communicate is not very practical, so researchers are trying to adapt the task to EEG. There is also real hope that techniques now being used experimentally can

give patients back some of their capabilities. Nicholas Schiff and his colleagues (2007) implanted electrodes in the brain of a man who had been unreliably responsive for 6 years following brain injury. With electrical stimulation to the thalamus, he can now eat without tube feeding, watch movies, and communicate with gestures and phrases of up to six words. The team concluded that the thalamic stimulation compensates for lost arousal in the frontal cortex and in the anterior cingulate cortex. A less invasive approach involves the continuous injection of the dopamine receptor agonist apomorphine (Fridman et al., 2010). All patients receiving the drug improved, some within 24 hours, and seven completely recovered consciousness; all gains were sustained for at least a year, even after drug treatment was discontinued. Even simpler is the use of transcranial direct current stimulation; applied over the left dorsolateral prefrontal cortex for 20 minutes, it produced improvements lasting 2 hours in 43% of minimally conscious patients and 8% of patients in a vegetative state (Thibault, Bruno, Ledoux, Demertzi, & Laureys, 2014). For most, the changes were modest, but some were able to squeeze the researcher’s hand on command and others could communicate by nodding or making eye movements. That sounds like very little until you compare it with where they were before.

In Perspective There was a time when the topic of sleep was totally mysterious and dreaming was the province of poets and shamans. Now sleep and dreaming are both yielding to the scrutiny of neuroscience. Although we are still unclear about the functions of sleep, we are learning how various structures in the brain turn it off and on, and how our body dances not only to a daily rhythm but to another that repeats itself 16 times a day and controls our fluctuations in alertness, daydreaming, and night dreaming. Consciousness is also giving up its secrets as researchers bring modern

technologies to bear on awareness, attention, and memory. In other words, what was once a taboo topic is becoming accessible to the research strategies of science and is providing a whole new arena of opportunities to observe the brain at work.

In this final chapter, we have explored a unique field of research. The study of sleep has demonstrated neuroscience’s ability to unravel mysteries and dispel superstition. The investigation of consciousness has been more daring, taking scientists where none had gone before. That is the job of science, to push back darkness, whether by finding a treatment for depression or by explaining humanity’s most unique characteristics and capabilities. But we have traveled a road filled with questions and uncertain facts, and the words of the schizophrenia researcher that “almost everything remains to be done” still seem appropriate. If all this ambiguity has left you with a vaguely unsatisfied feeling, that is good; you may have the makings of a neuroscientist. And we have left the most exciting discoveries for you. “

[T]here is a particular problem with finding endings in science. Where do these science stories really finish? Science is truly a relay race, with each discovery handed on to the next generation.

—Richard Holmes, in The Age of Wonder

” Summary Sleep and Dreaming • Circadian rhythms are rhythms that repeat on a daily basis, affecting the timing of sleep and several bodily processes. The SCN is the most important control center but not the only one. The rhythm is primarily entrained to light.

• Several ultradian rhythms occur within the day. One involves alternating periods of arousal during waking and stages that vary in arousal during sleep.

• REM sleep is when most dreaming occurs, but it has also been implicated in neural development and learning.

• Slow-wave sleep may restore cerebral and cognitive functioning and participate in learning.

• Sleep and waking are controlled by separate networks of brain structures. • Insomnia, sleepwalking, narcolepsy, and REM sleep behavior disorder represent the effects of psychological disturbances in some cases and malfunction of the sleep- wake mechanisms in others.

• Sleep is an active period, a state of consciousness that is neither entirely conscious nor unconscious.

The Neural Bases of Consciousness • Any very specific definition of consciousness is premature, but normal consciousness includes awareness, attention, and a sense of self.

• How awareness comes about is unclear, but the thalamus apparently is involved, possibly as the coordinator of synchronous firing of neurons in involved areas,

which is hypothesized to produce binding. • Attention allocates the brain’s resources, actually shifting neural activity among neurons or brain locations.

• Body image, memory, and mirror neurons are important contributors to a sense of self.

• Split-brain surgery provides an interesting research opportunity into consciousness, which has prompted debates about each hemisphere’s contribution to consciousness and to the self.

• Dissociative identity disorder involves what appear to be distinct personalities or selves. Reports indicate that the different states include different physical and physiological characteristics.

• Consciousness appears to be distributed in networks involving numerous brain areas, perhaps coordinated by gamma activity. ■

Study Resources

For Further Thought • Animals cycle on a 24-hr schedule, either sleeping at night and being active during the day or vice versa. An alternative would be to sleep when fatigue overtakes the body, regardless of the time. What advantages can you think of for a regular schedule?

• Machines and, probably, some simpler animals function just fine without awareness. Awareness probably places a significant demand on neural resources. What adaptive benefits do you see?

• Do you think we will be able to understand consciousness at the neural level? Why or why not?

Quiz: Testing Your Understanding 1. Discuss the functions of sleep, including the REM and slow-wave stages of

sleep. 2. Discuss attention as a neural phenomenon. 3. Discuss the function of confabulation in dreaming and in the behavior of

split-brain patients and Korsakoff’s patients. Select the best answer: 1. The most important function of sleep is

a. restoration of b. restoration of the body. the brain. c. safety. d. a, b, and c e. uncertain.

2. The body’s own rhythm, when the person is isolated from light, is a. approximately 24 hr long.

b. approximately 25 hr long. c. approximately 28 hr long. d. unclear because of conflicting studies.

3. Jim is totally blind, but he follows a 24-hr day-night cycle like the rest of us and seems comfortably adapted to it. Animal studies suggest that he relies on a. a built-in rhythm in his SCN. b. nonvisual receptors in his eyes. c. clocks and social activity. d. a and b e. b and c

4. According to the activation-synthesis hypothesis, dreams are the result of a combination of random neural activity and a. external stimuli. b. wishes. c. concerns from the day d. memories.

5. Evidence that REM sleep specifically enhances consolidation is that a. REM increases after learning. b. REM deprivation interferes with learning. c. performance improves following REM sleep. d. a and b e. a, b, and c

6. An “executive” sleep and waking center is located in the a. rostral pons. b. lateral hypothalamus. c. preoptic area of the hypothalamus. d. magnocellular nucleus. e. none of the above

7. The magnocellular nucleus is responsible for a. initiating sleep. b. waking the individual. c. switching between REM and non-REM sleep. d. producing atonia during REM.

8. Cataplexy is a. sleep without an REM component. b. a waking experience of atonia. c. a more severe form of narcolepsy. d. clinically significant insomnia.

9. The binding problem is an issue because a. there is no clear dividing line between consciousness and

unconsciousness. b. we are unsure what the function of sleep is. c. there is no single place where all the components of an experience are

integrated. d. we lack agreement on what consciousness is.

10. An EEG at 40 Hz is associated with a. binding. b. dreaming. c. consolidation. d. attention.

11. The part of the brain where attention is shifted among stimuli may be the a. basal b. magnocellular forebrain. nucleus. c. thalamus. d. raphé nuclei.

12. An explanation offered for confabulation links it to damage to the a. locus coeruleus. b. temporal lobes. c. pulvinar. d. frontal areas.

13. The credibility of dissociative identity disorder is increased by a. the high frequency of its diagnosis. b. different patterns of physiological measures. c. patients’ lack of incentive to fake the symptoms. d. location of the damage in a particular brain area.

14. Evidence supporting a network theory of consciousness is a. the broader effect of a sensory stimulus during consciousness. b. that an executive for the networks has been identified. c. that there are several centers of consciousness. d. none of these

Answers: 1. e, 2. d, 3. b, 4. d, 5. e, 6. e, 7. d, 8. b, 9. c, 10. a, 11. c, 12. d, 13. b, 14. a.

Online Resources The following resources are available at edge.sagepub.com/garrett4e. Select your country, click on

Student Resources, then Chapter Resources; then select this chapter.

Chapter Resources • Quiz

• Flashcards • Animations • Web links from the text • Web resources On the Web You can access these websites from the Chapter Resources page; select this

chapter and then click on Web links from the text. (Bold items are links.) 1. The National Sleep Foundation has links to sites of sleep research and

support organizations, results of the annual poll Sleep in America, and information on sleep disorders. The National Institutes of Health’s Information About Sleep page covers a broad range of topics, with references.

2. The Sleep Well is the website of William Dement, noted sleep researcher. 3. The NOVA video Sleep features research on the role of sleep in memory. 4. The American Academy of Sleep’s Sleep Education page is a good source

for information about sleep disorders and treatments. 5. ABC News video cameras caught Amy and Anna raiding the refrigerator—

while they were asleep! 6. Online Papers on Consciousness is a directory of 7,700 articles on the topic. 7. The news item about near-death experiences appeared in ScienceDaily. 8. Charlie Rose interviews neuroscientist V. S. Ramachandran, and the website

TED presents a lecture by consciousness expert Dan Dennett. Animations Brain Mechanisms of Sleep and Arousal (Figures 15.9, 15.10) Chapter Updates and Biopsychology News

For Further Reading 1. The Sleepwatchers, by William Dement (Stanford Alumni Association,

1992), is an entertaining description of sleep research by the most widely known expert.

2. Sleep Disorders for Dummies, by Max Hirshkowitz and Patricia Smith (Wiley, 2004), is a guide for anyone who has trouble sleeping.

3. The Quest for Consciousness: A Neurobiological Approach, by Christof Koch (Roberts & Company, 2004), is the result of Koch’s collaboration with the late Francis Crick. Amazon readers gave it 4½ stars out of 5. A briefer option is Crick and Koch’s “A Framework for Consciousness” (Nature Neuroscience, 2003, 6, 119–126).

4. The Feeling of What Happens, by Antonio Damasio (Harcourt, 1999), discusses the contributions of the body and emotions to consciousness and the self. It is highly praised by professionals and very readable as well.

5. “Forty-Five Years of Split-Brain Research and Still Going Strong,” by Michael Gazzaniga (Nature Reviews Neuroscience, 2005, 6, 653–659), is a useful and extensive summary of what we have learned from the research.

6. “The Patient’s Journey: Living With Locked-In Syndrome,” by Nick Chisholm and Grant Gillett (British Medical Journal, 2005, 331, 94–97), is Nick’s account of his partial recovery from locked-in syndrome, a disorder that leaves the patient completely conscious but unresponsive, unable to vocalize, open the eyes, or signal to doctors that he or she is fully aware. The article contains useful details about the disorder and the problem of distinguishing it from a persistent vegetative state.

7. “Whose Body Is It, Anyway?” by Graham Lawton (New Scientist, March 21, 2009, 36–37), tells you how to create the illusion that you have three hands and how to get a glimpse of what an out-of-body experience is like.

Key Terms activation-synthesis hypothesis agency attention basal forebrain area brain interpreter cataplexy dissociative identity disorder (DID) insomnia melatonin narcolepsy non-REM sleep orexin PGO waves REM sleep behavior disorder slow-wave sleep ultradian rhythm

Glossary ablation Removal of brain tissue. absolute refractory period A brief period during the action potential in which the neuron cannot be fired again because the sodium channels are closed.

absorptive phase The period of a few hours following a meal during which the body relies on the nutrients arriving from the digestive system.

action potential An abrupt depolarization of the membrane that allows the neuron to communicate over long distances.

activating effects Hormonal effects on sexual development that can occur at any time in an individual’s life; their duration depends on the presence of the hormone.

activation-synthesis hypothesis The hypothesis that during REM sleep the forebrain integrates neural activity generated by the brain stem with information stored in memory; an attempt to explain dreaming.

acute Referring to symptoms that develop suddenly and are usually more responsive to treatment.

addiction A preoccupation with obtaining a drug, compulsive use of the drug in spite of adverse consequences, and a high tendency to relapse after quitting.

adequate stimulus The energy form for which a receptor is specialized. ADHD See attention-deficit/hyperactivity disorder. adoption study In heredity research, a study that reduces environmental confounding by comparing the similarity of adopted children with their biological parents and their similarity with their adoptive parents.

affective aggression Aggression that is characterized by impulsiveness and emotional arousal.

agency The sense that an action or effect is due to oneself rather than another person or external force.

aggression Behavior that is intended to harm. agonist Any substance that mimics or enhances the effect of a neurotransmitter. agonist treatment Addiction treatment that replaces the addicting drug with another drug that has a similar effect.

agouti-related protein A transmitter released by NPY/AgRP neurons in the arcuate nucleus of the hypothalamus when nutrients diminish, which stimulates feeding.

agraphia The inability to write due to brain damage. alcohol Ethanol, a drug fermented from fruits, grains, and other plant products, which

acts at many brain sites to produce euphoria, anxiety reduction, motor incoordination, and cognitive impairment.

alexia The inability to read due to brain damage. allele An alternate version of a gene. all-or-none law The principle that an action potential occurs at full strength or it does not occur at all.

Alzheimer’s disease A disorder characterized by progressive brain deterioration and impairment of memory and other mental abilities; the most common cause of dementia.

amino acids The building blocks of peptides, which in turn make up proteins. In digestion, the result of the breakdown of proteins.

amphetamine One of a group of synthetic drugs that produce euphoria and increase confidence and concentration.

amplitude The physical energy in a sound; the sound’s intensity. amygdala Limbic system structure located near the lateral ventricle in each temporal lobe that is involved with primarily negative emotions and with sexual behavior, aggression, and learning, especially in emotional situations.

analgesic Pain relieving. androgen insensitivity syndrome A form of male pseudohermaphroditism, involving insensitivity to androgen as a result of a genetic absence of androgen receptors. The person has male sex chromosomes and male internal sex organs, but external sex organs that are female or ambiguous.

androgens A class of hormones responsible for a number of male characteristics and functions.

angiotensin II A hormone that signals lowered blood volume and, thus, volemic thirst to the brain.

angular gyrus A gyrus at the border of the parietal and occipital lobes containing pathways that connect the visual area with auditory, visual, and somatosensory association areas in the temporal and parietal lobes. Damage results in alexia and agraphia.

anorexia nervosa An eating disorder in which the person restricts food intake to maintain weight at a level so low that it is threatening to health.

ANS See autonomic nervous system. antagonist Any substance that reduces the effect of a neurotransmitter. antagonist treatment A form of treatment for drug addiction using drugs that block the effects of the addicting drug.

antagonistic muscles Muscles that produce opposite movements at a joint. anterior Toward the front. anterior cingulate cortex A part of the limbic system important in attention, cognitive processing, possibly consciousness, and emotion, including the emotion of pain.

anterograde amnesia An impairment in forming new memories. antidrug vaccine A form of anti-addiction treatment using molecules that attach to the drug and stimulate the immune system to make antibodies that will break down the drug.

antisense RNA A technology that temporarily disables a targeted gene or reduces its effectiveness.

antisocial personality disorder A condition in which people behave recklessly; violate social norms; and commit antisocial acts such as fighting, stealing, using drugs, and engaging in sexual promiscuity.

anxiolytic Anxiety reducing. aphasia Language impairment caused by damage to the brain. apotemnophilia See body integrity identity disorder. arcuate nucleus A structure in the hypothalamus that monitors the body’s nutrient condition and regulates eating behavior.

area prostrema A brain area unprotected by the blood-brain barrier; blood-borne toxins entering here induce vomiting.

arousal theory The theory that people behave in ways that keep them at their preferred level of arousal.

association area Cortical areas that carry out further processing beyond what the primary projection area does, often combining information from other senses.

associative long-term potentiation Strengthening of a weak synapse when it and a strong synapse on the same postsynaptic neuron are active simultaneously.

attention The brain’s means of allocating its limited resources by focusing on some neural inputs to the exclusion of others.

attention-deficit/hyperactivity disorder (ADHD) A disorder that develops during childhood and is characterized by impulsiveness, inability to sustain attention, learning difficulty, and hyperactivity.

auditory cortex The area of cortex on the superior temporal gyrus, which is the primary projection area for auditory information.

auditory object A sound that we recognize as having an identity that is distinct from other sounds.

autism spectrum disorder A set of neurodevelopmental disorders characterized by social deficits, communication difficulties, and repetitive behaviors.

autistic savant An individual with autism with an isolated exceptional capability. autoimmune disorder A disorder in which the immune system attacks the body’s own cells.

autonomic nervous system (ANS) One of the two branches of the peripheral nervous system; composed of the sympathetic and parasympathetic nervous systems, which control smooth muscles, glands, and the heart and other organs.

autoradiography A technique for identifying brain structures involved in an activity; it

involves injecting a radioactive substance (such as 2-DG) that will be absorbed most by the more active neurons, which then will show up on an X-ray image.

autoreceptor A receptor on a neuron terminal that senses the amount of transmitter in the synaptic cleft and reduces the presynaptic neuron’s output when the level is excessive.

aversive treatment A form of addiction treatment that causes a negative reaction when the person takes the drug.

axon An extension from a neuron’s cell body that carries information to other locations.

B cell A type of immune cell that fights intruders by producing antibodies that attack a particular intruder.

barbiturate A class of drugs that act selectively on higher cortical centers, especially those involved in inhibiting behavior, so they produce talkativeness and increased social interaction. In higher doses, they act as sedatives and hypnotics. Used to treat anxiety, aid sleep, and prevent epileptic convulsions.

basal forebrain area An area just anterior to the hypothalamus that contains both sleep-related and waking-related neurons.

basal ganglia The caudate nucleus, putamen, and globus pallidus, located subcortically in the frontal lobes; they participate in motor activity by integrating and smoothing movements using information from the primary and secondary motor areas and the somatosensory cortex.

basal metabolism The amount of energy required to fuel the brain and other organs and to maintain body temperature.

basilar membrane The membrane in the cochlea that separates the cochlear canal from the tympanic canal, and on which the organ of Corti is located.

bath salts Any of a number of synthetic derivatives of the catha edulis plant, which have amphetamine-like effects.

BDNF See brain-derived neurotrophic factor. benzodiazepine A class of drugs that produce anxiety reduction, sedation, and muscle relaxation by stimulating benzodiazepine receptors on the GABAA complex, facilitating GABA binding.

binaural Involving the use of both ears. binding problem The question of how the brain combines all the information about an object into a unitary whole.

binge eating disorder An eating disorder characterized by frequent consumption of excessive amounts of food during a short interval of time and a feeling of loss of control over what and how much is eaten.

biopsychology The branch of psychology that studies the relationships between behavior and the body, particularly the brain.

bipolar disorder Depression and mania that occur together in alternation.

blindsight The ability of cortically blind individuals to respond to visual stimuli they are unaware of seeing.

blood-brain barrier The brain’s protection from toxic substances and neurotransmitters in the bloodstream; the small openings in the capillary walls prevent large molecules from passing through unless they are fat soluble or carried through by special transporters.

BMI See body mass index. body integrity identity disorder The desire, in individuals with no apparent brain damage or mental illness, to have a healthy limb amputated.

body mass index (BMI) The person’s weight in kilograms divided by the squared height in meters; an indication of the person’s deviation from the ideal weight for the person’s height.

brain-derived neurotrophic factor (BDNF) A protein that contributes to neuron growth and survival.

brain interpreter A hypothetical mechanism that integrates all the cognitive processes going on simultaneously in other modules of the brain.

Broca’s aphasia Language impairment caused by damage to Broca’s area and surrounding cortical and subcortical areas.

Broca’s area The area anterior to the precentral gyrus (motor cortex) that sends output to the facial motor area to produce speech and also provides grammatical structure to language.

BSTc See central bed nucleus of the stria terminalis. bulimia nervosa An eating disorder involving bingeing on food, followed by purging by vomiting or using laxatives.

caffeine A drug that produces arousal, increased alertness, and decreased sleepiness; the active ingredient in coffee.

CAH See congenital adrenal hyperplasia. cannabinoids A group of compounds that includes the active ingredient in marijuana (tetrahydrocannabinol) and the endogenous cannabinoid receptor ligands, anandamide and 2-arachidonyl glycerol (2-Ara-Gl). Cannabinoids act as retrograde messengers.

cardiac muscles The muscles that make up the heart. castration Removal of the gonads (testes or ovaries). cataplexy A disorder in which a person has a sudden experience of atonia similar to that seen in REM sleep; the person may fall to the floor but remains awake.

CCK See cholecystokinin. cell body The largest part of a neuron, which contains the cell’s nucleus; cytoplasm; and structures that produce proteins, convert nutrients into energy, and eliminate waste materials.

central bed nucleus of the strial terminalis (BSTc) A hypothalamic structure that is

smaller in women and has been reported to be sexually atypical in size in transsexuals.

central nervous system (CNS) The part of the nervous system made up of the brain and spinal cord.

central pattern generator A neuronal network that produces a rhythmic pattern of motor activity, such as that involved in walking, swimming, flying, or breathing.

central sulcus The groove between the precentral gyrus and the postcentral gyrus that separates the frontal lobe from the parietal lobe in each hemisphere.

cerebellum A structure in the hindbrain that contributes the order of muscular contractions and their precise timing to intended movements and helps maintain posture and balance. It is also necessary for learning motor skills and contributes to nonmotor learning and cognitive activities.

cerebral hemispheres The large, wrinkled structures that are the dorsal or superior part of the brain and that are covered by the cortex.

cerebrospinal fluid Fluid in the ventricles and spinal canal that carries material from the blood vessels to the central nervous system and transports waste materials in the other direction. It also helps cushion the brain and spinal cord.

cholecystokinin (CCK) A peptide hormone released as food passes into the duodenum. CCK acts as a signal to the brain that reduces meal size.

chronic Referring to symptoms that develop gradually and persist for a long time with poor response to treatment.

chronic pain Pain that persists after healing has occurred, or beyond the time in which healing would be expected to occur.

circadian rhythm A rhythm that is a day in length, such as the wake-sleep cycle. circuit formation The third stage of nervous system development, in which the developing neurons send processes to their target cells and form functional connections.

circuit pruning The fourth stage of nervous system development, in which neurons that are unsuccessful in finding a place on the appropriate target cell, or that arrive late, die and excess synapses are eliminated.

CNS See central nervous system. cocaine A drug extracted from the South American coca plant, which produces euphoria, decreased appetite, increased alertness, and relief from fatigue.

cochlea The snail-shaped structure where the ear’s sound-analyzing structures are located.

cochlear canal The middle canal in the cochlea; contains the organ of Corti. cocktail party effect The ability to sort out meaningful auditory messages from a complex background of sounds.

cognitive theory A theory that states that a person relies on a cognitive assessment of the stimulus situation to identify which emotion is being experienced; physiological

arousal determines the intensity of the emotional experience. coincidence detectors Neurons that fire most when they receive input from both ears at the same time; involved in sound localization.

color agnosia Loss of the ability to perceive colors due to brain damage. color constancy The ability to recognize the natural color of an object in spite of the illuminating wavelength.

compensation A response to nervous system injury, in which surviving presynaptic neurons sprout new terminals, postsynaptic neurons add more receptors, or surrounding tissue takes over functions.

complementary colors Colors that cancel each other out to produce a neutral gray or white.

complex cell A type of cell in the visual cortex that continues to respond (unlike simple cells) when a line or an edge moves to a different location.

complex sound A sound composed of more than one pure tone. computed tomography (CT) An imaging technique that produces a series of X-rays taken from different angles; these are combined by a computer into a three- dimensional image of the brain or other part of the body.

concordance rate The proportion of cases in which a pair of related individuals share a characteristic.

confabulation Fabrication of stories and facts, which are then accepted by the individual, to make up for those missing from memory.

congenital adrenal hyperplasia (CAH) A form of female pseudohermaphroditism characterized by XX chromosomes, female internal sex organs, and ambiguous external sex organs. It is caused by excess production of androgens during prenatal development.

congenital insensitivity to pain A condition present at birth in which the person is insensitive to pain.

consolidation Process in which the brain forms a permanent representation of a memory.

Coolidge effect An increase in sexual activity when the variety of sexual partners increases.

corpus callosum The largest of the groups of neurons connecting the two cerebral hemispheres.

correlation The degree to which two variables are related, such as the IQs of siblings; it is measured by the correlation coefficient, a statistic that varies between the values of 0.0 and ±1.0.

correlational study A study in which the researcher does not control an independent variable, but determines whether two variables are related to each other.

cortex The grayish 1.5- to 4-mm-thick surface of the hemispheres, composed mostly of cell bodies, where the highest-level processing occurs in the brain.

cortisol A hormone released by the adrenal glands that increases energy levels by converting proteins to glucose, increasing fat availability, and increasing metabolism. The increase is more sustained than that produced by epinephrine and norepinephrine.

cranial nerves The 12 pairs of nerves that enter and leave the underside of the brain; part of the peripheral nervous system.

CT See computed tomography. Dale’s principle The idea that a neuron is able to release only one neurotransmitter. db See diabetes gene. DBS See deep brain stimulation. deception In research, failing to tell the participants the exact purpose of the research or what will happen during the study, or actively misinforming them.

declarative memory The memory process that records memories of facts, people, and events that the person can verbalize, or declare.

deep brain stimulation (DBS) Electrical stimulation of the brain through implanted electrodes.

default mode network Portions of the frontal, parietal, and temporal lobes that are active when the brain is at rest or focused internally; its activity is thought to represent preparedness for action.

delirium tremens A reaction in some cases of withdrawal from alcohol, including hallucinations, delusions, confusion, and, in extreme cases, seizures and possible death.

dementia Substantial loss of memory and other cognitive abilities usually, but not necessarily, in the elderly.

dendrites Extensions that branch out from the neuron cell body and receive information from other neurons.

dendritic spines Outgrowths from the dendrites that partially bridge the synaptic cleft and make the synapse more sensitive.

deoxyribonucleic acid (DNA) A double-stranded chain of chemical molecules that looks like a ladder that has been twisted around itself; genes are composed of DNA.

depressant A drug that reduces central nervous system activity. depression An intense feeling of sadness. dermatome A segment of the body served by a spinal nerve. diabetes An insulin disorder in which the person produces too little insulin (Type 1), resulting in overeating with little weight gain, or the person’s brain is insensitive to insulin (Type 2), resulting in overeating with weight gain.

diabetes gene (db) A gene on chromosome 4 that produces diabetes and obesity; mice with the gene are insensitive to leptin.

DID See dissociative identity disorder. difference in intensity A binaural cue to the location of a sound coming from one side

that results from the sound shadow created by the head; most effective above 2000 to 3000 Hz.

difference in time of arrival A binaural cue to the location of a sound coming from one side due to the time the sound requires to travel the distance between the ears.

diffusion tensor imaging A variant of MRI that measures movement of water molecules to image brain pathways and quantify their quality.

dihydrotestosterone A derivative of testosterone that masculinizes the genitals of males.

dissociative identity disorder (DID) The disorder previously known as multiple personality, which involves shifts in consciousness and behavior that appear to be distinct personalities or selves.

distributed The term for any brain function that occurs across a relatively wide area of the brain.

DNA See deoxyribonucleic acid. dominant The term referring to an allele that will produce its effect regardless of which allele it is paired with in the fertilized egg.

dopamine hypothesis The hypothesis that schizophrenia involves excess dopamine activity in the brain.

dorsal Toward the back side of the body. dorsal root The branch of a spinal nerve through which neurons enter the spinal cord. dorsal stream The visual processing pathway that extends into the parietal lobes; it is especially concerned with the location of objects in space.

Down syndrome Intellectual disability characterized by IQs in the 40 to 55 range, usually caused by the presence of an extra 21st chromosome.

drive An aroused condition resulting from a departure from homeostasis, which impels the individual to take appropriate action, such as eating.

drive theory Theory based on the assumption that the body maintains a condition of homeostasis.

drug Any substance that on entering the body changes the body or its functioning. dualism The idea that the mind and the brain are separate. duodenum The initial 25 cm of the small intestine, where most digestion occurs. dyslexia An impairment of reading, which can be developmental or acquired through brain damage.

early-onset alcoholism Cloninger’s Type 2 alcoholism, which involves early onset, frequent drinking without guilt, and characteristics of antisocial personality behavior.

ECT See electroconvulsive therapy. EEG See electroencephalogram. electrical stimulation of the brain (ESB) A procedure in which animals (or humans) learn to press a lever or perform some other action to deliver mild electrical

stimulation to brain areas where the stimulation is rewarding. electroconvulsive therapy (ECT) The application of 70 to 130 volts of electricity to the head of a lightly anesthetized patient, which produces a seizure and convulsions; a treatment for major depression.

electroencephalogram (EEG) A measure of brain activity recorded from two electrodes on the scalp over the area of interest, which are connected to an electronic amplifier; it detects the combined electrical activity of all the neurons between the two electrodes.

electron microscope A magnification system that passes a beam of electrons through a thin slice of tissue onto a photographic film, forming an image magnified up to 250,000 times. The scanning electron microscope has less magnification but produces three-dimensional images.

electrostatic pressure The force by which like-charged ions are repelled by each other and opposite-charged ions are attracted to each other.

embryo An organism in the early prenatal period; in humans, during the first 8 weeks. emotion A state of feelings accompanied by an increase or a decrease in physiological activity and, possibly, characteristic facial expression and behavior.

empiricism The procedure of obtaining information through observation. endogenous Generated within the body; usually used to refer to natural ligands for neurotransmitter receptors.

endorphins Substances produced in the body that function both as neurotransmitters and as hormones and act on opioid receptors in many parts of the nervous system.

epigenetic Referring to inheritable characteristics resulting from modifications in gene expression.

EPSP See excitatory postsynaptic potential. equipotentiality The idea that the brain functions as a whole; opposite of localization. ESB See electrical stimulation of the brain. estrogen A class of hormones responsible for a number of female characteristics and functions, produced by the ovaries in women and, to a lesser extent, by the adrenal glands in males and females.

estrus A period when a nonhuman female animal is ovulating and sex hormone levels are high.

euphoria A sense of happiness or ecstasy; many abused drugs produce euphoria. event-related potential An EEG technique for measuring the brain’s responses to brief stimulation; it involves presenting a stimulus repeatedly and averaging the EEG over all the presentations to cancel out random activity, leaving the electrical activity associated with the stimulus.

excitatory postsynaptic potential (EPSP) A hypopolarization of the dendrites and cell body, which makes the neuron more likely to fire.

experiment A study in which the researcher manipulates an independent variable and

observes its effect on one or more dependent variables. expression The translation of a gene’s encoded information into the production of proteins, determining the gene’s functioning.

fabrication In research, the faking of data or results. familial Term referring to a characteristic that occurs more frequently among relatives of a person with the characteristic than it does in the population.

family study A study of how strongly a characteristic is shared among relatives. FAS See fetal alcohol syndrome. fasting phase The period following the absorptive phase, when the glucose level in the blood drops and the body must rely on its energy stores.

fatty acids Breakdown product of fat, which supplies the muscles and organs of the body (except for the brain).

fetal alcohol syndrome (FAS) A condition caused by the mother’s use of alcohol during the third trimester of pregnancy; neurons fail to migrate properly, often resulting in intellectual disability. FAS is the leading cause of intellectual disability in the Western world.

fetus An organism after the initial prenatal period; in humans, after the first 8 weeks. FFA See fusiform face area. fissure A groove between gyri of the cerebral hemispheres that is larger and deeper than a sulcus.

fMRI See functional magnetic resonance imaging. force of diffusion The force that moves ions from an area of greater concentration to an area where they are less concentrated.

form vision The detection of an object’s boundaries and features, such as texture. 46 XX difference in sexual development A variation in sexual development of an individual with XX chromosomes resulting in some degree of masculinization of the external genitals.

46 XY difference in sexual development A variation in sexual development of an individual with XY chromosomes resulting in partial or complete feminization of the external genitals.

fovea A 1.5-mm-wide area in the middle of the retina in which cones are most concentrated and visual acuity and color discrimination are greatest.

fragile X syndrome A form of intellectual disability caused by excessive CGG repeats in the FMR1 gene; IQ is typically below 75.

frequency A characteristic of sound; the number of cycles or waves of alternating compression and decompression of the vibrating medium that occur in a second.

frequency-place theory The theory that frequency following accounts for the discrimination of frequencies up to about 200 Hz, and higher frequencies are represented by the place of greatest activity on the basilar membrane.

frequency theory Any one of a number of theories of auditory frequency analysis that

state that the frequency of a sound is represented in the firing rate of each neuron or a group of neurons.

frontal lobe The area of each cerebral hemisphere anterior to the central sulcus and superior to the lateral fissure.

functional magnetic resonance imaging (fMRI) A brain-imaging procedure that measures brain activation by detecting the increase in oxygen levels in active neural structures.

fusiform face area (FFA) A part of the inferior temporal lobe important in face identification. See prosopagnosia.

ganglion A group of cell bodies in the peripheral nervous system. gate control theory The idea that pressure signals arriving in the brain trigger an inhibitory message that travels back down the spinal cord, where it closes a neural “gate” in the pain pathway.

gender The behavioral characteristics associated with being male or female. gender identity The sex a person identifies as being. gender nonconformity Sex-atypical mannerisms and dress, a tendency to engage in activities usually preferred by the other sex, and an atypical preference for other- sex playmates and companions while growing up.

gender role A set of behaviors society considers appropriate for members of the same sex.

gene The biological unit that directs cellular processes and transmits inherited characteristics.

gene therapy Treatment of a disorder by gene manipulation. gene transfer Insertion of a gene from another organism into a recipient’s cells, usually within a virus.

genetic engineering Manipulation of an organism’s genes or their functioning. genome The entire collection of genes in a species’ chromosomes. genotype The combination of genes an individual has. ghrelin A hormone released by the stomach during fasting, which initiates eating. glial cell A nonneural cell that provides a number of supporting functions to neurons, including myelination.

glucagon A hormone released by the pancreas that stimulates the liver to transform stored glycogen back into glucose during the fasting phase.

glucose One of the sugars; the body’s main source of energy, reserved for the nervous system during the fasting phase; a major signal for hunger and satiation.

glutamate theory The theory that NMDA receptor hypofunction results in glutamate and dopamine increases that produce positive and negative symptoms of schizophrenia.

glycerol A breakdown product of fats, which is converted to glucose for the brain during the fasting period.

glycogen The form in which glucose is stored in the liver and muscles during the absorptive phase; converted back to glucose for the brain during the fasting phase.

Golgi stain A staining method that randomly stains about 5% of neurons, which makes them stand out individually.

Golgi tendon organs Receptors that detect tension in a muscle. gonads The primary reproductive organs, the testes in the male or the ovaries in the female.

graded potential A voltage change in a neuron that varies with the strength of the stimulus that initiated it.

growth cone A formation at the tip of a migrating neuron that samples the environment for directional cues.

gyrus A ridge in the cerebral cortex; the area between two sulci. Hebb rule Principle stating that if an axon of a presynaptic neuron is active while the postsynaptic neuron is firing, the synapse between them will be strengthened.

heritability The percentage of the variation among individuals in a characteristic that can be attributed to heredity.

heroin A major drug of addiction synthesized from morphine. heterozygous Having a pair of alleles for a specific characteristic that are different from each other.

hierarchical processing A type of processing in which lower levels of the nervous system analyze their information and pass the results on to the next higher level for further analysis.

homeostasis A condition in which any particular body system is in balance or equilibrium.

homozygous Having a pair of alleles for a specific characteristic that are identical with each other.

Human Connectome Project A large-scale cooperative effort to map the circuits in the human brain.

Human Genome Project An international project with the goal of mapping the location of all the genes on the human chromosomes and determining the base sequences of the genes.

Huntington’s disease A degenerative disorder of the motor system involving cell loss in the striatum and cortex.

hydrocephalus A disorder in which cerebrospinal fluid fails to circulate and builds up in the cerebral ventricles, crowding out neural tissue and usually causing intellectual disability.

hyperpolarization An increase in the polarization of a neuron membrane, which is inhibitory and makes an action potential less likely to occur.

hypnotic Sleep inducing. hypocretin See orexin.

hypopolarization A decrease in the polarization of a neuron membrane, which is excitatory and makes an action potential more likely to occur.

hypothalamus A subcortical structure in the forebrain just below the thalamus that plays a major role in controlling emotion and motivated behaviors such as eating, drinking, and sexual activity.

hypothalamus-pituitary-adrenal axis A group of structures that helps the body cope with stress.

hypovolemic thirst A fluid deficit that occurs when the blood volume drops due to a loss of extracellular water.

immune system The cells and cell products that kill infected and malignant cells and protect the body against foreign substances, including bacteria and viruses.

immunocytochemistry A procedure for labeling cellular components such as receptors, neurotransmitters, or enzymes, using a dye attached to an antibody designed to attach the component.

in situ hybridization A procedure for locating gene activity, which involves constructing strands of complementary DNA that will dock with strands of messenger RNA. The complementary DNA is radioactive, so autoradiography can be used to locate the gene activity.

INAH 3 See third interstitial nucleus of the anterior hypothalamus. incentive theory A theory that recognizes that people are motivated by external stimuli (incentives), not just internal needs.

inferior Below another structure. inferior colliculi Part of the tectum in the brain stem that is involved in auditory functions such as locating the direction of sounds.

inferior temporal cortex An area in the lower part of the temporal lobe that plays a major role in the visual identification of objects.

informed consent Voluntary agreement to participate in a study after receiving full information about any risks, discomfort, or other adverse effects that might occur.

inhibitory postsynaptic potential (IPSP) A hyperpolarization of the dendrites and cell body, which makes a neuron less likely to fire.

inner hair cells A single row of about 3,500 hair cells located on the basilar membrane toward the inside of the cochlea’s coil; they produce most, if not all, of the auditory signal.

insomnia The inability to sleep or to obtain quality sleep, to the extent that the person feels inadequately rested.

instinct A complex behavior that is automatic and unlearned and occurs in all the members of a species.

insulin A hormone secreted by the pancreas that enables entry of glucose into cells (not including the nervous system) during the absorptive phase and facilitates storage of excess nutrients.

intellectual disability Limitation in intellectual functioning (reasoning, learning, problem solving) and in adaptive behavior originating before the age of 18.

intelligence The capacity for learning, reasoning, and understanding. intelligence quotient (IQ) The measure typically used for intelligence. intensity The physical energy in a sound; the sound’s amplitude. interneuron A neuron that has a short axon or no axon at all and connects one neuron to another in the same part of the central nervous system.

iodopsin The photopigment in cones. ion An atom that is charged because it has lost or gained one or more electrons. ionotropic receptor A receptor on a neuron membrane that opens ion channels directly and immediately to produce quick reactions.

IPSP See inhibitory postsynaptic potential. IQ See intelligence quotient. James-Lange theory The idea that physiological arousal precedes and is the cause of an emotional experience and the pattern of arousal identifies the emotion.

knockout Genetic engineering technique in which a nonfunctioning gene mutation is inserted during the embryonic stage.

Korsakoff’s syndrome A form of dementia in which brain deterioration is almost always caused by chronic alcoholism.

L -dopa See levodopa. language acquisition device A part of the brain hypothesized to be dedicated to learning and controlling language.

late-onset alcoholism Cloninger’s Type 1 alcoholism, involving late onset, long periods of abstinence with binges, guilt over drinking, and cautious and emotionally dependent personality.

lateral Toward the side. lateral fissure The fissure that separates the temporal lobe from the frontal and parietal lobes.

lateral hypothalamus A nucleus of the hypothalamus with roles in feeding and metabolism, aggression, and waking arousal.

lateral inhibition A method of enhancing neural information in which each neuron’s activity inhibits the activity of its neighbors, and in turn its activity is inhibited by them.

learned taste aversion Learned avoidance of a food (based on its taste) eaten prior to becoming ill.

learned taste preference Preference for a food containing a needed nutrient (identified by the food’s taste), learned, presumably, because the nutrient makes the individual feel better.

leptin A hormone secreted by fat cells, which is proportional to the percentage of body fat and which signals fat level to the brain.

lesion Damage to neural tissue. This can be brought about surgically for research or therapeutic reasons, or it can result from trauma, disease, or developmental error.

leukocytes White blood cells, which include macrophages, T cells, and B cells; part of the immune system.

levodopa (L-dopa) The precursor for dopamine; used to treat Parkinson’s disease. Lewy bodies Abnormal clumps of protein that form within neurons, found in some patients with Parkinson’s disease and Alzheimer’s disease.

limbic system A group of forebrain structures arranged around the upper brain stem that have roles in emotion, motivated behavior, and learning.

lithium A metal administered in the form of lithium carbonate; the medication of choice for bipolar illness.

lobotomy A surgical procedure that disconnects the prefrontal areas from the rest of the brain; it reduces emotionality and pain, but leaves the person emotionally blunted, distractible, and childlike in behavior.

localization The idea that specific parts of the brain carry out specific functions. long-term depression (LTD) Weakening of a synapse when stimulation of presynaptic neurons is insufficient to activate the postsynaptic neurons.

long-term potentiation (LTP) An increase in synaptic strength that occurs when presynaptic neurons and postsynaptic neurons are active simultaneously.

longitudinal fissure The large fissure that runs the length of the brain, separating the two cerebral hemispheres.

loudness The term for our experience of sound intensity. LTD See long-term depression. LTP See long-term potentiation. macrophage A type of leukocyte that ingests intruders. magnetic resonance imaging (MRI) An imaging technique that involves measuring the radiofrequency waves emitted by hydrogen atoms when they are subjected to a strong magnetic field. Because different structures have different concentrations of hydrogen atoms, the waves can be used to form a detailed image of the brain.

magnocellular system A division of the visual system, extending from the retina through the visual association areas, that is specialized for brightness contrast and movement.

major depression A disorder involving feelings of sadness to the point of hopelessness for weeks at a time, along with slowness of thought, sleep disturbance, and loss of energy and appetite and the ability to enjoy life; in some cases the person is also agitated or restless.

major histocompatibility complex (MHC) A group of genes that contribute to the functioning of the immune system.

mania A disorder involving excess energy and confidence that often leads to grandiose schemes, decreased need for sleep, increased sexual drive, and, often,

abuse of drugs. marijuana The dried and crushed leaves and flowers of the Indian hemp plant Cannabis sativa.

materialistic monism The view that the body and the mind and everything else are physical.

medial Toward the middle. medial amygdala Part of the amygdala that apparently responds to sexually exciting stimuli. In both male and female rats, it is active during copulation, and it causes the release of dopamine in the MPOA.

medial forebrain bundle A part of the mesolimbocortical dopamine system and a potent reward area.

medial preoptic area (MPOA) A part of the preoptic area of the hypothalamus that appears to be important for sexual performance, but not sexual motivation, in male and female rats.

median preoptic nucleus A nucleus of the hypothalamus that initiates drinking in response to osmotic and volumetric deficits.

medulla The lower part of the hindbrain; its nuclei are involved with control of essential life processes such as cardiovascular activity and respiration.

melatonin A hormone secreted by the pineal gland that induces sleepiness. meninges A three-layered membrane that encloses and protects the brain. mesolimbocortical dopamine system A pathway including the ventral tegmental area, medial forebrain bundle, nucleus accumbens, and projections into prefrontal areas. The pathway is important in reward effects from drugs, electrical stimulation of the brain (ESB), and activities such as eating and sex.

messenger ribonucleic acid (RNA) A copy of one strand of DNA that moves out of the nucleus to direct protein construction.

metabotropic receptor A receptor on a neuron membrane that opens ion channels slowly through a metabolic process and produces long-lasting effects.

methadone A synthetic opioid used as an agonist treatment for opiate addiction. MHC See major histocompatibility complex. microglia Glial cells that provide immune protection in the central nervous system by acting as macrophages.

midbrain The middle part of the brain, consisting of the tectum (roof) on the dorsal side and the tegmentum on the ventral side.

migrate In brain development, movement of newly formed neurons from the ventricular zone to their final destination.

mind-brain problem The issue of what the mind is and its relationship to the brain. mirror neurons Neurons that respond when engaging in an act and while observing the same act in others.

model A proposed mechanism for how something works.

modular processing The segregation of the various components of processing in the brain into separate locations.

monism The idea that the mind and the body consist of the same substance. monoamine hypothesis The hypothesis that depression involves reduced activity at norepinephrine and serotonin synapses.

motivation The set of factors that initiate, sustain, and direct behavior. motor cortex The area in the frontal lobes that controls voluntary (nonreflexive) body movements; the primary motor cortex is on the precentral gyrus.

motor neuron A neuron that carries commands to the muscles and organs. movement agnosia Impaired ability to perceive movement. MPOA See medial preoptic area. MRI See magnetic resonance imaging. Müllerian ducts Early structures that in the female develop into the uterus, fallopian tubes, and inner vagina.

Müllerian inhibiting hormone A hormone released in the male that causes the Müllerian ducts to degenerate.

multiple sclerosis A motor disorder caused by the deterioration of myelin (demyelination) and neuron loss in the central nervous system.

muscle spindles Receptors that detect stretching in muscles. myasthenia gravis A disorder of muscular weakness caused by reduced numbers or sensitivity of acetylcholine receptors.

myelin A fatty tissue that wraps around an axon to insulate it from the surrounding fluid and from other neurons.

myelin stain A staining method that stains myelin, thus identifying neural pathways. narcolepsy A disorder in which individuals fall asleep suddenly during the daytime and go directly into REM sleep.

natural killer cell A type of immune cell that attacks and destroys certain kinds of cancer cells and cells infected with viruses.

natural selection The principle that those whose genes endow them with greater speed, intelligence, or health are more likely to survive and transmit their genes to more offspring.

nature versus nurture The issue of the relative importance of heredity and environment.

negative color aftereffect The experience of a color’s complement following stimulation by the color.

negative symptoms Symptoms of schizophrenia characterized by the absence or insufficiency of normal behaviors, including lack of affect (emotion), inability to experience pleasure, lack of motivation, poverty of speech, and impaired attention.

neglect A disorder in which the person ignores objects, people, and activity on the side opposite the brain damage.

nerve A bundle of axons running together in the peripheral nervous system. neural network A group of neurons that function together to carry out a process. neurofibrillary tangles Abnormal accumulations of the protein tau that develop inside neurons and are associated with the death of brain cells in people with Alzheimer’s disease and Down syndrome.

neurogenesis The birth of new neurons. neuron A specialized cell that conveys sensory information into the brain, carries out the operations involved in thought and feeling and action, or transmits commands out into the body to control muscles and organs; a single neural cell, in contrast to a nerve.

neuropeptide Y (NPY) A transmitter released by NPY/AgRP neurons in the arcuate nucleus of the hypothalamus when nutrient levels diminish; it is a powerful stimulant for eating and conserves energy.

neuroscience The multidisciplinary study of the nervous system and its role in behavior.

neurotoxin A neuron poison; substance that impairs the functioning of a neuron. neurotransmitter A chemical substance that a neuron releases to carry a message across the synapse to the next neuron or to a muscle or an organ.

neurotrophins Chemicals that enhance development and survival in neurons. nicotine The primary psychoactive and addictive ingredient in tobacco. Nissl stain A staining method that stains cell bodies. node of Ranvier A gap in the myelin sheath covering an axon. nondeclarative memory Nonstatable memories that result from procedural or skills learning, emotional learning, and simple conditioning.

nondecremental A property of the action potential, which travels through the neuron without any decrease in size.

non-REM sleep The periods of sleep that are not rapid eye movement sleep. NPY See neuropeptide Y. NST See nucleus of the solitary tract. nucleus (1) The part of every cell that contains the chromosomes and governs activity in the cell. (2) A group of neuron cell bodies in the central nervous system.

nucleus accumbens A forebrain structure that is part of the mesolimbocortical dopamine system and a potent center for reward.

nucleus of the solitary tract (NST) A part of the medulla that monitors several signals involved in the regulation of eating.

obesity gene (ob) A gene on chromosome 6 that causes obesity; in mice it results in an inability to produce leptin.

object agnosia Impairment of the ability to recognize objects visually. obsessive-compulsive disorder (OCD) A disorder consisting of obsessions (recurring thoughts) and compulsions (repetitive, ritualistic acts the person feels compelled to

perform). occipital lobe The most posterior part of each cerebral hemisphere, and the location of the visual cortex.

OCD See obsessive-compulsive disorder. oligodendrocyte A type of glial cell that forms the myelin covering of neurons in the brain and spinal cord.

opiate Any drug derived from the opium poppy. The term is also used to refer to effects at opiate receptors, including those by endorphins.

opponent process theory A color vision theory that attempts to explain color vision in terms of opposing neural processes.

optogenetics Control of neurons by creating light-responsive ion channels in the cell membrane.

orexin A neuropeptide released by lateral hypothalamic neurons that increases feeding and arousal; also known as hypocretin.

organ of Corti The sound-analyzing structure on the basilar membrane of the cochlea; it consists of four rows of hair cells, their supporting cells, and the tectorial membrane.

organizing effects Hormonal effects of sexual development that occur during the prenatal period and shortly after birth and are permanent.

organum vasculosum lamina terminalis (OVLT) A structure bordering the third ventricle that monitors fluid content in the cells and contributes to the control of osmotic thirst.

osmotic thirst Thirst that occurs when the fluid content is low inside the body’s cells. ossicles Tiny bones in the middle ear that operate in lever fashion to transfer vibration from the tympanic membrane to the cochlea; they also produce a slight amplification of the sound.

out-of-body experience A phenomenon, usually resulting from brain damage or epilepsy, in which the person hallucinates seeing his or her detached body from another location.

outer hair cells Three rows of about 12,000 cells located on the basilar membrane toward the outside of the cochlea’s coil; they amplify the cochlea’s output and sharpen frequency tuning, possibly by adjusting the tension of the tectorial membrane.

ovaries The female gonads, where the ova develop. OVLT See organum vasculosum lamina terminalis. oxytocin A neuropeptide hormone and neurotransmitter involved in lactation and orgasm; dubbed the “sociability molecule” because it affects social behavior and bonding.

PAG See periaqueductal gray. parasympathetic nervous system The branch of the autonomic nervous system that

slows the activity of most organs to conserve energy and activates digestion to renew energy.

paraventricular nucleus (PVN) A structure in the hypothalamus that monitors several signals involved in the regulation of eating, including input from the NST; it helps regulate metabolic processes.

parietal lobe The part of each cerebral hemisphere located above the lateral fissure and between the central sulcus and the occipital lobe; it contains the somatosensory cortex and visual association areas.

Parkinson’s disease A movement disorder characterized by motor tremors, rigidity, loss of balance and coordination, and difficulty in moving, especially in initiating movements; it is caused by deterioration of the substantia nigra.

parvocellular system A division of the visual system, extending from the retina through the visual association areas, that is specialized for fine detail and color.

peptide YY 3-36 An appetite-suppressing peptide hormone released in the intestines in response to food.

perception The interpretation of sensory information. periaqueductal gray (PAG) A brain-stem structure with a large number of endorphin synapses; stimulation reduces pain transmission at the spinal cord level. The PAG also produces symptoms of drug withdrawal.

peripheral nervous system (PNS) The part of the nervous system made up of the cranial nerves and spinal nerves.

PET See positron emission tomography. PGO waves Waves of excitation that flow from the pons through the lateral geniculate nucleus of the thalamus to the occipital area and appear to initiate the EEG desynchrony of REM sleep.

phantom pain Pain that seems to be in a missing limb. phase difference A binaural cue to the location of a sound coming from one side; at frequencies below 1500 Hz, the sound will be in a different phase of the wave at each ear.

phenotype In heredity, the characteristic of the individual. phenylketonuria An inherited form of intellectual disability in which the body fails to metabolize the amino acid phenylalanine, which interferes with myelination during development.

pheromones Airborne chemicals released by an animal that have physiological or behavioral effects on another animal of the same species.

phonological hypothesis The hypothesis that the fundamental problem in dyslexia is impaired phoneme processing.

photopigment A light-sensitive chemical in the visual receptors that initiates the neural response.

phototherapy A treatment for winter depression involving the use of high-intensity

lights for a period of time each day. phrenology The theory in the early 1900s that “faculties” of emotion and intellect were located in precise areas of the brain and could be assessed by feeling bumps on the skull.

pineal gland A gland located just posterior to the thalamus that secretes sleep-inducing melatonin; it controls seasonal cycles in nonhuman animals and participates with other structures in controlling daily rhythms in humans.

pinna The ear flap on each side of the head; the outer ear. pitch The experience of the frequency of a sound. place cells Cells in the hippocampus that increase their firing rate when the individual is in a specific location in the environment.

place theory A theory that states that the frequency of a sound is identified by the location of maximal vibration on the basilar membrane and which neurons are firing most.

plagiarism The theft of another’s work or ideas. planum temporale The area in each temporal lobe that is the location in the left hemisphere of Wernicke’s area and that is larger on the left in most people.

plaques Clumps of amyloid, a type of protein, that cluster among axon terminals and interfere with neural transmission in the brains of people with Alzheimer’s disease and Down syndrome.

plasticity The ability to be modified; a characteristic of the nervous system. PNS See peripheral nervous system. polarization A difference in electrical charge between the inside and outside of a neuron.

polygenic Determined by several genes rather than a single gene. pons A part of the brain stem that contains centers related to sleep and arousal. positive symptoms Symptoms of schizophrenia that involve the presence or exaggeration of behaviors, such as delusions, hallucinations, thought disorder, and bizarre behavior.

positron emission tomography (PET) An imaging technique that reveals function. It involves injecting a radioactive substance into the bloodstream, which is taken up by parts of the brain according to how active they are; the scanner makes an image that is color coded to show the relative amounts of activity.

posterior Toward the rear. posterior parietal cortex An association area that brings together the body senses, vision, and audition. It determines the body’s orientation in space, the location of the limbs, and the location in space of objects detected by touch, sight, and sound.

postsynaptic A term referring to a neuron that receives transmission from another neuron.

posttraumatic stress disorder (PTSD) A prolonged stress reaction to a traumatic event;

it is typically characterized by recurrent thoughts and images (flashbacks), nightmares, lack of concentration, and overreactivity to environmental stimuli, such as loud noises.

precentral gyrus The gyrus anterior to, and extending the length of, the central sulcus; it is the location of the primary motor cortex.

predatory aggression Aggression in which an animal attacks and kills its prey or a human engages in a premeditated, unprovoked, and similarly relatively emotionless attack.

prefrontal cortex The most anterior cortex of the frontal lobes; it is involved in working memory, planning and organization of behavior, and regulation of behavior in response to its consequences. It also integrates information about the body with sensory information from the world to select and plan movements.

premotor cortex An area anterior to the primary motor cortex that combines information from the prefrontal cortex and the posterior parietal cortex and begins the programming of a movement.

preoptic area A structure in the hypothalamus that contains warmth-sensitive cells and cold-sensitive cells and participates in the control of body temperature. See medial preoptic area regarding regulation of sexual behavior.

presynaptic A term referring to a neuron that transmits to another neuron. presynaptic excitation Increased release of neurotransmitter from a neuron’s terminal as the result of another neuron’s release of neurotransmitter onto the terminal (an axoaxonic synapse).

presynaptic inhibition Decreased release of neurotransmitter from a neuron’s terminal as the result of another neuron’s release of neurotransmitter onto the terminal (an axoaxonic synapse).

primary motor cortex The area on the precentral gyrus responsible for the execution of voluntary movements.

primary somatosensory cortex The first stage in the cortical-level processing of somatosensory information, which is processed through the four subareas of the primary somatosensory cortex and then passed on to the secondary somatosensory cortex.

proliferation The first stage of nervous system development, in which cells that will become neurons multiply at the rate of 250,000 new cells every minute.

proprioception The sense that informs us about the position and movement of the parts of the body.

prosody The use of intonation, emphasis, and rhythm to convey meaning in speech. prosopagnosia The inability to visually recognize familiar faces. pseudohermaphrodite An individual who has ambiguous internal and external sexual organs, but whose gonads are consistent with his or her chromosomes.

psychedelic drug Any compound that causes perceptual distortions in the user.

psychoactive drug Any drug that has psychological effects, such as anxiety relief or hallucinations.

psychosis A severe mental disturbance of reality, thought, and orientation. psychosurgery The use of surgical intervention to treat cognitive and emotional disorders.

PTSD See posttraumatic stress disorder. pure tone A sound consisting of a single frequency. PVN See paraventricular nucleus. PYY See peptide YY3-36. radial glial cells Specialized glial cells that provide a scaffold for migrating neurons to climb to their destination.

rapid eye movement (REM) sleep The stage of sleep during which most dreaming occurs; research indicates that it is also a time of memory consolidation during which neural activity from the day is replayed.

rate law A principle that intensity of a stimulus is represented in an axon by the frequency of action potentials.

receptive field In vision, the area of the retina from which a cell in the visual system receives its input.

receptor A cell, often a specialized neuron, that is suited by its structure and function to respond to a particular form of energy, such as sound.

recessive The term referring to an allele that will have an influence only when it is paired with the same recessive allele on the other chromosome.

reflex A simple, automatic movement in response to a sensory stimulus. regeneration The growth of severed axons; in mammals, it is limited to the peripheral nervous system.

relative refractory period The period during which a neuron can be fired again following an action potential, but only by an above-threshold stimulus.

REM See rapid eye movement sleep. REM sleep behavior disorder A sleep disorder in which the person is physically active during REM sleep.

reorganization A shift in neural connections that changes the function of an area of the brain.

reserve hypothesis The hypothesis that individuals with greater cognitive or brain capacity are able to compensate for brain changes due to aging, brain damage, or disorders such as Alzheimer’s.

resting potential The difference in charge between the inside and outside of the membrane of a neuron at rest.

reticular formation A collection of more than 90 nuclei running through the middle of the hindbrain and the midbrain with roles in sleep and arousal, attention, reflexes, and muscle tone.

retina The structure at the rear of the eye, which is made up of light-sensitive receptor cells and the neural cells that are connected to them.

retinal disparity A discrepancy in the location of an object’s image on the two retinas; a cue to the distance of a focused object.

retinotopic map A map of the retina in the visual cortex, which results from adjacent receptors in the retina activating adjacent cells in the visual cortex.

retrieval The process of accessing stored memories. retrograde amnesia The inability to remember events prior to impairment. reuptake The process by which a neurotransmitter is taken back into the presynaptic terminals by transporters.

reward The positive effect on a user from a drug, electrical stimulation of the brain (ESB), sex, food, warmth, and so on.

rhodopsin The photopigment in rods. SAD See seasonal affective disorder. saltatory conduction Conduction in the axon in which action potentials jump from one node of Ranvier to the next.

satiety Satisfaction of appetite. schizophrenia A disabling disorder characterized by perceptual, emotional, and intellectual deficits, loss of contact with reality, and an inability to function in life.

Schwann cell A type of glial cell that forms the myelin covering on neurons outside the brain and spinal cord.

SCN See suprachiasmatic nucleus. SCR See skin conductance response. SDN See sexually dimorphic nucleus. seasonal affective disorder (SAD) Depression that is seasonal, being more pronounced in the summer in some people and in the winter in others.

secondary somatosensory cortex The part of the somatosensory cortex that receives information from the primary somatosensory cortex, from both sides of the body.

sedative A calming effect of a drug. sensation The acquisition of sensory information. sensory neuron A neuron that carries information from the body and from the outside world into the central nervous system.

sensory-specific satiety Decreased attractiveness of a food as the person or animal eats more of it.

set point A value in a control system that is the system’s point of equilibrium or homeostasis; departures from this value initiate actions to restore the set-point condition.

sex The term for the biological characteristics that divide humans and other animals into the categories of male and female.

sexually dimorphic nucleus (SDN) A part of the MPOA important to male sexual

behavior. It is larger in male rats, and their level of sexual activity depends on SDN size.

SFO See subfornical organ. simple cell A cell in the visual cortex that responds to a line or an edge that is at a specific orientation and a specific place on the retina.

skeletal muscles The muscles that move the body and limbs. skin conductance response (SCR) A measure of sweat gland activation and thus sympathetic nervous system activity.

skin senses Touch, warmth, cold, and pain (and, possibly, itch); the senses that arise from receptors in the skin.

slow-wave sleep Stages 3 and 4 of sleep, characterized by delta EEG and increased body activity; it appears to be a period of brain recuperation and may play a role in consolidation of declarative memory.

smooth muscles Muscles that control the internal organs other than the heart. sodium-potassium pump Large protein molecules that move sodium ions through the neuron membrane to the outside and potassium ions back inside, helping to maintain the resting potential.

somatic nervous system The division of the peripheral nervous system that carries sensory information into the central nervous system (CNS) and motor commands from the CNS to the skeletal muscles.

somatosensory cortex The area in the parietal lobes that processes the skin senses and the senses that inform us about body position and movement, or proprioception; the primary somatosensory cortex is on the postcentral gyrus.

somatotopic map The form of topographic organization in the motor cortex and somatosensory cortex, such that adjacent body parts are represented in adjacent areas of the cortex.

spatial frequency theory The theory that visual cortical cells do a Fourier frequency analysis of the luminosity variations in a scene.

spatial summation The process of combining potentials that occur simultaneously at different locations on the dendrites and cell body.

spinal cord A part of the central nervous system; the spinal nerves, which communicate with the body below the head, enter and leave the spinal cord.

spinal nerves The peripheral nerves that enter and leave the spinal cord at each vertebra and communicate with the body below the head.

stem cells Undifferentiated cells that can develop into specialized cells such as neurons, muscle, or blood.

stereotaxic instrument A device used for the precise positioning in the brain of an electrode or other device, such as a cannula.

stimulant A drug that activates the nervous system to produce arousal, increased alertness, and elevated mood.

stress A condition in the environment that makes unusual demands on the organism, such as threat, failure, or bereavement; the individual’s negative response to a stressful situation.

striatum The caudate nucleus and putamen, both of the basal ganglia, and the nucleus accumbens.

stroke A medical condition caused by a loss of blood flow in the brain (also known as cerebrovascular accident).

subfornical organ (SFO) One of the structures bordering the third ventricle that increases drinking when stimulated by angiotensin II.

substance P A neuropeptide involved in pain signaling. substantia nigra The nucleus that sends dopamine-releasing neurons to the striatum and that deteriorates in Parkinson’s disease.

sudden cardiac death Death occurring when stress causes excessive sympathetic activity that sends the heart into fibrillation, contracting so rapidly that little or no blood is pumped.

sulcus The groove or space between two gyri. superior Above another structure. superior colliculi Part of the tectum in the brain stem that is involved in visual functions such as guiding eye movements and fixation of gaze.

supplementary motor area The prefrontal area that assembles sequences of movements, such as those involved in eating or playing the piano, prior to execution by the primary motor cortex.

suprachiasmatic nucleus (SCN) A structure in the hypothalamus that (1) was found to be larger in gay men than in heterosexual men, (2) regulates the reproductive cycle in female rats, and (3) is the main biological clock, controlling several activities of the circadian rhythm.

sympathetic ganglion chain The structure running along each side of the spine through which most sympathetic neurons pass (and many synapse) on their way to and from the body’s organs.

sympathetic nervous system The branch of the autonomic nervous system that activates the body in ways that help it cope with demands, such as emotional stress and physical emergencies.

synapse The connection between two neurons. synaptic cleft The small gap between a presynaptic neuron and a postsynaptic neuron. synesthesia A condition in which stimulation in one sense triggers an experience in another sense, or a concept evokes an unrelated sensory experience.

T cell A type of leukocyte that attacks specific invaders. tardive dyskinesia Tremors and involuntary movements caused by blocking of dopamine receptors in the basal ganglia due to prolonged use of antidopamine drugs.

TBI See traumatic brain injury. tectorial membrane A shelflike membrane overlying the hair cells and the basilar membrane in the cochlea.

telephone theory A theory of auditory frequency analysis, which stated that the auditory neurons transmit the actual sound frequencies to the cortex.

temporal lobe The part of each cerebral hemisphere ventral to the lateral fissure; it contains the auditory cortex, visual and auditory association areas, and Wernicke’s area.

temporal summation The process of combining potentials that arrive a short time apart on a neuron’s dendrites and cell body.

terminal A swelling on the branches at the end of a neuron that contains neurotransmitters; also called an end bulb.

testes The male gonads that produce sperm. testosterone The major sex hormone in males; a member of the class of androgens. thalamus A forebrain structure lying just below the lateral ventricles, which receives information from all sensory systems except olfaction and relays it to the respective cortical projection areas. It has additional roles in movement, memory, and consciousness.

theory A system of statements that integrate and interpret diverse observations in an attempt to explain some phenomenon.

theory of mind The ability to attribute mental states to oneself and to others. third interstitial nucleus of the anterior hypothalamus (INAH 3) A nucleus found to be half as large in gay men and heterosexual women as in heterosexual men, and similar in size in women and male-to-female transsexuals.

TMS See transcranial magnetic stimulation. tolerance After repeated drug use, the individual becomes less responsive and requires increasing amounts of a drug to produce the same results.

tonotopic map The form of topographic organization in the auditory cortex, such that each successive area responds to successively higher frequencies.

topographical organization Neurons from adjacent receptor locations project to adjacent cells in the cortex.

Tourette’s syndrome A disorder characterized by motor and phonic (sound) tics. tract A bundle of axons in the central nervous system. transcranial magnetic stimulation A noninvasive stimulation technique that uses a magnetic coil to induce a voltage in brain tissue.

transsexual An individual who believes he or she has been born into the wrong sex; the person may dress and live as the other sex and may undergo surgery for sex resassignment.

traumatic brain injury (TBI) An injury caused by an external mechanical force such as a blow to the head, sudden acceleration or deceleration, or penetration.

trichromatic theory The theory that three color processes account for all the colors we are able to distinguish.

twin study In heredity research, a study that assesses how similar twins are in some characteristic; their similarity is then compared with that of nontwin siblings, or the similarity between identical twins is compared with the similarity between fraternal twins.

tympanic membrane The eardrum, a very thin membrane stretched across the end of the auditory canal; its vibration transmits sound energy to the ossicles.

ultradian rhythm A rhythm with a length of less than a day, including the sleep stages and the basic rest and activity cycle during the day.

unipolar depression Depression without mania. ventral Toward the stomach side. ventral root The branch of each spinal nerve through which the motor neurons exit. ventral stream The visual processing pathway that extends into the temporal lobes; it is especially concerned with the identification of objects.

ventral tegmental area A part of the mesolimbocortical dopamine system, which sends neurons to the nucleus accumbens and is a potent reward area.

ventricles Cavities in the brain filled with cerebrospinal fluid. ventromedial hypothalamus An area in the hypothalamus important for sexual receptivity and copulation in female rats. It is also involved in eating behavior, and destruction in rats produces extreme obesity.

vesicle A membrane-enclosed container that stores neurotransmitter in the neuron terminal.

vestibular sense The sense that helps us maintain balance and that provides information about head position and movement; the receptors are located in the vestibular organs.

visual acuity The ability to distinguish visual details. visual cortex The cortex in each occipital lobe where visual information is processed. visual field The part of the environment that is being registered on the retina. visual word form area (VWFA) An area in the human inferior temporal lobe involved in reading words as a whole.

VNO See vomeronasal organ. volley theory Theory of auditory frequency analysis that states that groups of neurons follow the frequency of a sound when the frequency exceeds the firing rate capability of a single neuron.

voltage The difference in electrical charge between two points. vomeronasal organ (VNO) A cluster of receptors in the nasal cavity that detect pheromones.

vulnerability The idea that genes produce susceptibility to a disorder and that environmental challenges may combine with a person’s biological susceptibility to

exceed the threshold required to produce the disorder. vulnerability model The idea that environmental challenges combine with a person’s genetic vulnerability for a disease to exceed the threshold for the disease.

VWFA See visual word form area. Wernicke’s aphasia Language impairment resulting from damage to Wernicke’s area; the person has difficulty understanding and producing spoken and written language.

Wernicke’s area The area just posterior to the auditory cortex (in the left hemisphere in most people) that interprets spoken and written language input and generates spoken and written language.

winter birth effect The tendency for more schizophrenics to be born during the winter and spring months than at any other time of the year.

Wisconsin Card Sorting Test A test of prefrontal functioning that requires the individual to sort cards using one criterion and then change to another criterion.

withdrawal A negative reaction that occurs when drug use is stopped. Wolffian ducts The early structures that in the male develop into the seminal vesicles and the vas deferens.

working memory A memory function that provides a temporary “register” for information while it is being used.

X-linked In heredity, a condition in which a gene on the X chromosome is not paired with a gene on the shorter Y chromosome, so that a single recessive gene is adequate to produce a characteristic.

zygote A fertilized egg.

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