1 and 2

Images.com/Corbis

Learning Objectives

After completing this chapter, you should be able to:

• Give examples of several stressors and describe how the locus coeruleus and HPA axis react to these stressors. • Explain how the brain prepares the body to respond to stress, by describing changes in blood flow, breathing

rate, alertness, sleep, eating, growth, and reproduction. • Draw a diagram of the HPA axis. • Discuss how the dexamethasone suppression test can be used to diagnose depression. • Explain the difference between habituation and sensitization. • Name several disorders associated with stress. • List the symptoms of major depressive disorder and relate these to brain functions. • Give examples of reversible and irreversible psychoses. • Define schizophrenia and its positive symptoms and negative symptoms. • Discuss at least two hypotheses that have been advanced to explain schizophrenia. • Identify brain abnormalities and social and cognitive deficits associated with schizophrenia. • Compare the treatment for major depressive disorder to the treatment for bipolar disorder.

12

Disordered Behavior and Stress Syndromes

iStockphoto/Thinkstock

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CHAPTER 12Section 12.1 Defining Stress

Marcy had been married for 20 years when her husband disappeared, leaving her alone to care for their five children aged 4 to 17 years. He was finally located three years later, living in a distant state with another woman. In the interim Marcy was forced to seek public assistance before finding a job that allowed her to support her family.

Immediately after her husband left, Marcy was extremely upset. Whenever she worried about pay- ing the bills or losing her house, her heart would begin to pound, and she got “the shakes.” She had trouble sleeping and was edgy and irritable with her children. Marcy also had trouble concentrating on anything for very long. To treat these symptoms, Marcy’s physician prescribed a minor tranquil- izer for her to take.

Over the next few years, her oldest children left home to go to college or get married. As each child left, Marcy became more and more despondent. When her youngest child was diagnosed with juvenile-onset diabetes, a serious chronic illness that required that the child receive several injections of insulin daily, Marcy became so depressed that her doctor prescribed an antidepressant for her. Despite the medication, Marcy’s depression worsened. Six years to the day after her husband left her, Marcy tried to commit suicide. Her suicide note read, “There is nothing to live for,” which was far from the truth, because her youngest children were very dependent on her.

What caused Marcy’s depression? Many psychologists believe that stress causes depression. Cer- tainly Marcy had a lot of stress to deal with: being abandoned by her husband, raising five children on her own, seeing her children leave the nest one by one, treating her youngest child’s illness. But Marcy also had a serious medical problem of her own, an underactive thyroid gland, and she was menopausal. (Recall from Chapter 10 that some women experience postmenopausal depression.)

In this chapter you will learn that stress affects the brain and the body in a number of ways. Stress produces hormonal changes that alter neurotransmitter levels in the nervous system. Some of these changes can produce depression. Other hormones in addition to stress hormones can affect neurotransmitter activity, too. In Marcy’s case stress and other hormonal problems contributed to her depression. We’ll examine how stress interacts with other factors to produce depression and other disorders later in this chapter. But first let’s look at the nature of stress.

12.1 Defining Stress

Stress is a state of imbalance produced by stressors. Stressors are people, objects, places, or events that disrupt homeostasis in the nervous system (Cullinan, Herman, Helmreich, & Watson, 1995; Michelson, Licinio, & Gold, 1995; Walker & Diforio, 1997). As you learned in Chapter 11, the hypothalamus works very hard to maintain homeostasis in the nervous system and elsewhere in the body. Whenever homeostasis is challenged, the hypothalamus organizes the body’s response to the challenge. For example, when the body temperature rises drastically, the hypothalamus initi- ates changes that ultimately result in a lower body temperature. The hypothalamus also responds to the disruption of homeostasis produced by stressors.

Stressors can alter homeostasis in a variety of ways. For example, imagine the nonhomeostatic state induced when you lock yourself, while dressed in jeans and a T-shirt, out of the house on a cold day. Or imagine the disruption that occurs when you discover you’ve lost your checkbook. In the first example the stressor is primarily a physical one. In the second it is psychological. Both physical and psychological stressors disrupt homeostasis in the body, and the stress response to both types of stressors is the same, as you will learn later in this chapter.

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CHAPTER 12Section 12.1 Defining Stress

Stress is a negative experience that is accompanied by characteristic emotional, behavioral, bio- chemical, and physiological reactions (Baum, 1990). These stress reactions enable the individual to adapt to the stressor or to escape from it. In this chapter we will discuss how the body and brain respond to stressors.

Our brains have a mechanism that evaluates stimuli and determines whether the stimuli are good or bad for us and whether we can cope with a particular stimulus or control it. Those stim- uli that are judged to be stressors initiate stress responses in the nervous system (LeDoux, 1995). Consider, for example, what happens when infant humans are separated from their mothers (Photo 12.1). Separating 9-month-old human babies from their mothers causes a good deal of anxiety and emotional upset in these infants, producing psychological stress. Human babies show a physiological response (for example, an increase in certain hormones in the blood) to the psychological stress of separa- tion from their mothers (Larson, Gunnar, & Hertsgaard, 1991).

Please keep in mind that stress- ors can be very pleasant as well as unpleasant. Any stimulus that challenges the body’s homeosta- sis will produce stress. A wedding, therefore, can be as stressful as a funeral because both disrupt nor- mal functioning of the body. To help you understand this better, let’s examine how information about stressors reaches the ner- vous system and how the nervous system, in turn, responds to this information.

Stress Pathways in the Central Nervous System

Stress can be produced by environmental (external) or psychical (internal) events (psyche means “mind” in Greek). Thus, a number of pathways carrying information about stressors have been identified in the central nervous system, some that carry information from the periphery to the brain and others that originate in the brain. Because the hypothalamus organizes the body’s response to homeostatic disruptions, it is the ultimate recipient of information about stress. Axons that relay information about stressors terminate in a particular region of the hypothalamus known as the paraventricular nucleus (PVN).

Environmental stimuli excite sensory neurons in the peripheral nervous system. Information about these stimuli is sent to the brain via sensory tracts in the spinal cord and cranial nerves. The vagus nerve is especially important in conducting information about the gut and chest organs to the brain. Figure 12.1 illustrates the various pathways to the paraventricular nucleus of the hypothalamus.

David Grossman/Science Source

Photo 12.1 Separation from one’s mother causes infants a lot of anxiety and stress. If the mother is inattentive and the baby stresses often, how do you think that will affect the baby’s psychological development?

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CHAPTER 12Section 12.1 Defining Stress

Figure 12.1: Diverse inputs to the paraventricular nucleus

The paraventricular nucleus (PVN) of the hypothalamus receives input from the limbic system and cerebral cortex, from other parts of the hypothalamus, and from brain stem structures, such as the nucleus of the solitary tract, the reticular formation, the periventricular gray, the locus coeruleus, and the raphe system.

Information about stressors coming from the gut or other internal receptors is relayed via the vagus and other cranial nerves to the nucleus of the solitary tract in the medulla (Figure 12.1). For example, information about choking is sent to the nucleus of the solitary tract by way of cranial nerve IX. Thus, sensory information is sent to the nucleus of the solitary tract for process- ing. Somehow, this nucleus sorts out the stress-inducing stimuli from the other signals and sends information about these stressors to the paraventricular nucleus (Cullinan et al., 1995; Zigmond, Finlay, & Sved, 1995).

The reticular formation is responsible for arousing the nervous system in response to novel or important stimuli. The reticular formation has direct projections to the paraventricular nucleus of the hypothalamus. Recall from Chapter 6 that the periventricular gray area of the midbrain plays an important role in the response to pain. Certainly, any type of pain would function as a stressor and set in motion a response by the nervous system to deal with the pain. Pathways between these areas and the paraventricular nucleus of the hypothalamus have been identified.

The locus coeruleus, which produces almost all of the norepinephrine found in the brain, is another important brain area involved in the stress response (Zigmond et al., 1995). The locus coeruleus is sensitive to physical sensations and changes in heart rate and blood pressure (Aber- crombie & Jacobs, 1987; Aston-Jones, Chiang, & Alexinsky, 1991; Glavin et al., 1983; Maynert & Levi, 1964; Tanaka et al., 1983; Van Bockstaele, Bajic, Proudfit, & Valentino, 2001; Zigmond et al., 1995). As further evidence that the locus coeruleus is involved in initiating stress responses in the brain, a direct pathway from the locus coeruleus to the paraventricular nucleus has been identified (Bremner et al., 1996).

Bed nucleus of the striatum

(BST)

Adrenocorticotropic hormone (ACTH)

PVN B

ra in

ste m

Limbic

Cerebellum

Spinal cord

Hypothalamus

Pituitary gland

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CHAPTER 12Section 12.1 Defining Stress

The raphe system in the brainstem is the sole source of serotonin in the brain (Figure 12.2). Researchers have discovered a pathway carrying axons from the raphe system to the paraven- tricular nucleus of the hypothalamus (Akil & Morano, 1996). Therefore, stressors impacting the raphe system are believed to stimulate stress responses in the paraventricular nucleus, especially emotional stressors that activate the cerebral cortex and limbic system (Cullinan et al., 1995). Cognitive and emotional stressors stimulate these limbic system structures, which in turn excite the paraventricular nucleus (Wang, Cen, & Lu, 2001).

Figure 12.2: Serotonin pathways in the brain

Serotonin is produced by neurons in the raphe nuclei in the hindbrain and is released in all parts of the central nervous system, including the cerebral cortex, hippocampus, amygdala, basal ganglia, thalamus, hypothalamus, cerebellum, and spinal cord.

Overall, the purpose of the stress response is twofold: (1) to prepare the individual to respond to the stressor and the disequilibrium produced by the stressor and (2) to inhibit behaviors that would not be adaptive in dealing with the stressor (Michelson, Licinio, & Gold, 1995). Examples of adap- tive behaviors that enable the individual to respond effectively to the stressor include increased blood flow, increased breathing rate, increased energy availability, and increased alertness and vigilance. In contrast, functions like sleep, eating, growth, and reproduction are suppressed during the stress response. For example, disruptions in fertility, such as a cessation of menstruation, have been observed in women who are exposed to stress (Stout, Kilts, & Nemeroff, 1995).

At present, research indicates that the response to a stressor has two components: one involving the locus coeruleus and the other involving the paraventricular nucleus of the hypothalamus. Let’s examine each of these components separately.

Thalamus

To hippocampus

Cerebellum Raphe nuclei

Basal ganglia

To spinal cord

Hippocampus

Amygdala

Hypothalamus

Nucleus accumbens

Cerebral cortex

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CHAPTER 12Section 12.1 Defining Stress

The Stress Response Initiated by the Locus Coeruleus

The first component of the stress response involves the release of norepinephrine by the locus coeruleus, which increases arousal and vigilance, permitting the individual to respond effectively to the stressor (De Souza & Grigoriadis, 1995; Nestler, Alreja, & Aghajanian, 1999). Excitation of the locus coeruleus also activates the sympathetic nervous system. Recall that activation of the sympathetic nervous system causes epinephrine to be released from the adrenal gland. In turn, epinephrine has a number of effects in the nervous system, such as increased heart rate and increased respiration rate, all of which help the individual deal with stress.

The Stress Response Initiated by the Paraventricular Nucleus

The second component of the stress response begins with the stimulation of the paraven- tricular nucleus of the hypothalamus. When the paraventricular nucleus is excited, it releases corticotropic-releasing hormone (CRH). During the stress response, CRH is released by the para- ventricular nucleus of the hypothalamus and stimulates the pituitary gland to release the pituitary hormone adrenocorticotropic hormone (ACTH) (Figure 12.3). As its name implies, ACTH travels in the blood to the adrenal gland, where it activates the cortex of the adrenal gland, stimulating the synthesis and release of yet another hormone, cortisol.

Figure 12.3: The hypothalamic-pituitary-adrenal (HPA) response to stress

In response to a stressor, the paraventricular nucleus of the hypothalamus releases corticotropic-releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. In response to ACTH, the adrenal gland releases cortisol.

(continued)

Hippocampus: Glucocorticoid receptors

Pituitary: Adrenocorticotropic hormone (ATCH)

Hypothalamus (PVN): Corticotropic-releasing hormone (CRH)

Hypothalamus

Corticotropic-releasing hormone

Infundibulum

Pituitary gland

ACTH

Adrenal gland

Cortisol

Cortisol End organs: Energy usage, reproduction, metabolism, inflammatory response

Increased delivery of fuel to heart, brain, and skeletal muscle

Adrenal gland

A.

B.

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CHAPTER 12Section 12.1 Defining Stress

Figure 12.3: The hypothalamic-pituitary-adrenal (HPA) response to stress (continued)

The main function of cortisol is to increase the production and availability of blood glucose in order to provide energy to deal with the stress. Cortisol also inhibits the immune system, which explains why people often get ill when they are stressed (Akil & Morano, 1996; Michelson et al., 1995; Venkataraman, Munoz, Candido, & Witchel, 2007). In addition, cortisol affects gene tran- scription in the nuclei of cells, thus having long-term as well as immediate effects on the body. In fact, the effects of cortisol can linger long after the stressor has been removed, setting the stage for a number of physical and psychological disorders, as you will learn later in this chapter.

In summary, when the paraventricular nucleus of the hypothalamus is activated by information about a stressor, it releases CRH, which is transported to the pituitary gland. In response to CRH, the pituitary gland releases ACTH into the blood. ACTH is transported to the cortex of the adrenal gland, where it stimulates the release of cortisol. Cortisol, in turn, travels in the blood to vari- ous sites of action in the body, especially in the brain, preparing the individual to deal with the stressor. This response to stress, which is mediated by the hypothalamus, pituitary, and adrenal gland, is referred to as the HPA axis response.

The Relationship Between the Paraventricular Nucleus and the Locus Coeruleus

As you’ve just learned, there are two components of the stress response: one initiated by the paraventricular nucleus and one initiated by the locus coeruleus. You might be wondering how these two brain structures work together to enable us to respond to stress effectively, and in fact, many investigators have wondered about this, too. Research indicates that the relationship between the locus coeruleus and the paraventricular nucleus is reciprocal. That is, excitation of

Hippocampus: Glucocorticoid receptors

Pituitary: Adrenocorticotropic hormone (ATCH)

Hypothalamus (PVN): Corticotropic-releasing hormone (CRH)

Hypothalamus

Corticotropic-releasing hormone

Infundibulum

Pituitary gland

ACTH

Adrenal gland

Cortisol

Cortisol End organs: Energy usage, reproduction, metabolism, inflammatory response

Increased delivery of fuel to heart, brain, and skeletal muscle

Adrenal gland

A.

B.

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CHAPTER 12Section 12.1 Defining Stress

one structure produces excitation of the other. This relationship is characterized as a positive feedback loop (Figure 12.4).

Figure 12.4: Positive feedback loop between the locus coeruleus and the paraventricular nucleus in a rat brain

Excitation of the paraventricular nucleus (PVN) of the hypothalamus initiates excitation of the locus coeruleus. Likewise, excitation of the locus coeruleus initiates excitation of the paraventricular nucleus.

Controlling the Release of Cortisol

You’ve just learned that cortisol affects a wide range of body functions. To keep the body func- tioning optimally, the release of cortisol must be closely controlled because too much or too little of this steroid substance can cause widespread damage. In addition, cortisol must be released promptly in response to a stressor, and its release must be terminated immediately when the stressor is removed. Under normal conditions, when the stressor is removed, release of ACTH stops immediately, terminating cortisol synthesis in the adrenal gland.

Increased levels of cortisol in the blood produce inhibition of CRH and ACTH release, which ulti- mately leads to a reduction in cortisol synthesis. Dexamethasone is a form of synthetic cortisol. When dexamethasone is administered to an individual, it acts like cortisol, inhibiting the cells that release CRH and ACTH. Therefore, administration of dexamethasone is expected to suppress the release of cortisol. The dexamethasone suppression test is used to assess the ability of the HPA axis to regulate cortisol release. Cortisol release in healthy people is suppressed following the administration of dexamethasone. However, individuals with impaired regulation of the HPA axis will fail to respond appropriately to a dexamethasone challenge by decreasing cortisol release. For

Thalamus

Pituitary gland

Midbrain

Locus coeruleus

Hypothalamus

PVN (Paraventricular nucleus)

Hindbrain

+ +

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CHAPTER 12Section 12.1 Defining Stress

example, depressed people typically have impaired function of the HPA axis and show an increase in cortisol following a dexamethasone challenge.

It is important that the HPA axis and the stress response be shut down when the stressor is removed because prolonged activation of the stress response can produce a number of negative consequences. If an individual is unable to terminate or avoid the stressor, the nervous system makes neurochemical and behavioral adaptations to the stressor (Deakin, 1998). For example, chronic overexercising can have negative long-term effects on the nervous system (see the “For Further Thought” box).

For Further Thought: Effects of Excessive Exercise

Regular exercise has a number of well-documented health benefits, including improved respiration and cardiovascular health, enhanced muscular and skeletal function, and reduced risk of obesity and other chronic disorders. However, extreme physical exercise performed on a regular basis may introduce some adverse health effects (Martin, Pence, & Woods, 2009; McEwen, 1995). These adverse effects result from the increased activity of the sympathetic nervous system and the HPA axis associated with a stress response.

Chronic excessive exercise produces a stress response in the body that is accompanied by elevated levels of cortisol and, eventually, a significant increase in the size of the adrenal glands (McEwen, 1995; Szivek et al., 2013; McEwen, 2009). Recall that cortisol increases the availability of glucose in the body, which is helpful for athletes because physical exercise requires a great deal of glucose. However, cortisol also suppresses the functioning of the immune system. Investigations of immune response in men who regularly engage in extreme physical activity have revealed reduced immune function in these men. For example, a study of male swimmers on a university intercollegiate swim team showed that the level of salivary immuno- globulins (a measure of immune response) was significantly lower at

the end of the competitive swim season following several months of chronic exercise, which increased the vulnerability of these swimmers to upper respiratory infections (Tharp & Barnes, 1990).

Highly trained athletes who engage in extreme physical exertion over several years will eventually show a blunted HPA-axis response to stress. Wittert, Livesey, Espiner, and Donald (1996) examined cortisol levels in ultra-marathon runners who had been training for many years and found that blood cortisol levels were reduced in these athletes. The HPA axis adapts to the high levels of CRH released by the paraventricular nucleus during chronic physical exertion. This means that, over time, much lower levels of ACTH and cortisol are released in response to stress in these athletes. Adaptation of the pituitary gland and adrenal cortex to stress can severely limit a person’s ability to respond adequately to stress (McEwen, 2009).

Image Source/SuperStock

Photo 12.2 Athletes who engage in extreme physical exertion over several years will eventually show a blunted HPA-axis response to stress.

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CHAPTER 12Section 12.1 Defining Stress

Effect of Chronic Stress on Behavior

A chronic stressor occurs repeatedly or for prolonged periods of time. Examples of chronic stress- ors might be taking care of a terminally ill loved one or fighting in a war on another continent. Stress caused by a chronic stressor can produce persistent symptoms that interfere with normal behavior. These symptoms include habituation, sensitization, and memory impairment. You’ve probably learned about these symptoms in other psychology courses, but let’s review them here in the context of stress-related problems.

Habituation Chronic exposure to a stressor produces long-term changes in the excitation of the locus coeruleus, including habituation and sensitization (Bremner et al., 1996). Habituation involves a decrease in the release of norepinephrine in an individual who is repeatedly exposed to a given stressor (Figure 12.3). When a stressor is chronic, the individual can habituate to it. That is, the individual will fail to respond to the stressor with a stress response (Gold & McCarty, 1995). This can be a problem, especially when the person needs to respond to the stressor. For example, parents with a young child on an apnea monitor that sounds an alarm when the child stops breathing (a- means “without” and -pnea means “air” in Latin) need to respond to that alarm immediately. At first, parents respond to the alarm promptly and with a great deal of distress. But after repeated alarms, some parents fail to wake up immediately when the alarm sounds because of habituation (Zigmond et al., 1995).

Sensitization Sensitization is an enhanced response observed when a chronically stressed individual is pre- sented with a new or different stressor. Chronically stressed people, who show a sensitization response when they are confronted with a novel stressor, typically overreact to the stressor. As opposed to habituation, sensitization is an increase in responsiveness to a stressor (Charney et al., 1995). An example of this might be a person who needs to have blood drawn repeatedly for medical testing purposes, such as a person with AIDS who needs to have T-cell levels monitored. Every time a needle is inserted in this person’s arm to draw blood, the sensitized person makes a greater-than-normal stress response to the needle.

Memory Impairment Memory impairment is a critical symptom in a number of stress-related disorders. Chronic stress or exposure to a highly traumatic stressor will interfere with memory storage and working mem- ory (Bremner et al., 1996 Gold & McCarty, 1995). Some patients with stress-related disorders often show a loss of memory for events surrounding a stressful experience, and others have extremely sharp memories for a few details related to the traumatic event. These problems with long-term memory may be related to hippocampal damage resulting from chronic stress (Bremner et al., 1996; Deutch & Young, 1995; Gold & McCarty, 1995; McEwen, 1995; Horger & Roth, 1996; Sapolsky, 1996).

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CHAPTER 12Section 12.2 Disorders Associated with Stress

12.2 Disorders Associated with Stress

When people are exposed to chronic stress, dysregulation of the stress response can occur. Particularly vulnerable are those behaviors that are typically suppressed by the stress response, such as eating, sleeping, and sexual behavior. In many disorders associated with stress, eating, sleeping, or sexual behavior can be disrupted (Akil & Morano, 1996). Dysfunction of the locus coeruleus system or the HPA axis can lead to problematic behaviors such as sensitization, habituation, or memory impairment. In this section we will examine a number of stress-related dis- orders, including post-traumatic stress disorder, major depressive disorder, and fatigue disorders.

Before we examine each of the stress-related disorders individually, it must be emphasized that not everybody who experiences chronic stress develops a stress-related disorder. In fact, most of us experience a traumatic, stressful experience sometime in our lives, but only a small percent- age of us acquire post-traumatic stress disorder or depression. What makes some people more vulnerable than others to stress-related disorders? At this point, investigators are uncertain about the answer to this question. Some people may have a genetic predisposition to develop a stress- related disorder. That is, those individuals with a stress-related disorder may have inherited a genetic mutation, or an alteration in a normal gene, that causes neurons to react to stressors or stress hormones in nonadaptive ways—for example, to release too much or too little of an impor- tant enzyme, which would alter the functioning of the neurons (Duman, 1995).

Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) has only recently been recognized as a formal disorder. The third edition of the Diagnostic and Statistical Manual (DSM-III), published by the American Psy- chiatric Association, first listed PTSD as a bona fide disorder in 1980. (Table 12.1 gives the DSM-IV criteria for PTSD.) All individuals with PTSD have experienced one or more traumatic events (an extreme stressor like a car accident, rape, or exposure to acts of violence) prior to the develop- ment of the disorder. To give you a better understanding of this disorder, a Vietnam veteran with PTSD is presented in the “Case Study.” The most striking or definitive symptoms are vivid recurrent memories for certain aspects of the traumatic event and flashbacks in which the individual feels as if he or she is actually reexperiencing the traumatic event. Research on this disorder began with the study of “shell-shocked” soldiers after World War I, but intensive study of PTSD did not begin until after 1980 (Southwick, Yehuda, & Morgan, 1995).

Table 12.1: Summary of DSM-IV criteria for post-traumatic stress disorder • Has experienced traumatic event(s) that threatens the self or others

• Reexperiencing criteria (one required):

Experiencing recurrent distressing memories, dreams, or flashbacks

Experiencing intense psychological or physiological reactions to stimuli that resemble or symbolize the traumatic event (one required)

(continued)

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Table 12.1: Summary of DSM-IV criteria for post-traumatic stress disorder (continued) • Avoidance criteria (three required)

Avoidance of thoughts, feelings, or activities associated with the traumatic event

Memory loss for important aspect of the trauma

Markedly reduced interest in important activities

Feelings of detachment from others

Restricted affect or numbing

Sense of foreshortened future

• Arousal criteria (two required)

Insomnia

Irritability or angry outbursts

Impaired concentration

Constantly on guard, hypervigilant

Abnormal or exaggerated startle reaction

• Symptoms must be present for at least 1 month

• Distress or impairment must be clinically significant

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright © 2000). American Psychiatric Association.

Since 1994, when the DSM-IV’s diagnostic criteria for PTSD were published, followed the next year by the ICD-10 international diagnostic criteria that are similar to it, these definitions of the disorder have been an impetus worldwide for research. Populations as varied as disaster survi- vors, abuse victims, war veterans, and police and firefighters have been studied. Also, research on PTSD parallels the recent history of worldwide military conflict, ranging from Russia (Chech- nya and Afghanistan), to Eastern Europe, and, in the US and Western Europe, to what some now call “The Long International War on Terror” in Iraq and Afghanistan. There, the guerrilla style of warfare and the predominant use of small but powerful targeted explosive devices as weapons of choice results in many traumatic and concussive brain injuries that are comorbid with PTSD (Bryant, 2011), which has ensured that a steady stream of individuals have entered into clinics and research labs with PTSD symptoms. This has led to an increasing amount of research on the neuropsychology of the syndrome, encompassing diagnostic refinement, brain imaging, genetics, and psychotherapy.

While the essential diagnostic criteria in the new DSM-V (2013) are very similar to those in the DSM-IV, significant changes reinforce important aspects of PTSD’s definition and are directly related to recent psychobiological research (US Department of Veterans Affairs, 2012). For one thing, PTSD is now located in a DSM section on trauma and stressor-related disorders rather than being mixed in with anxiety disorders, emphasizing that PTSD is primarily related to stress rather than anxiety. For another, the criteria for the disorder have been expanded to specify four criteria for the PTSD diagnosis: intrusiveness, avoidance, negative alterations in cognitions and mood, and alterations in arousal and reactivity, indicating a heightened focus on PTSD’s cogni- tive components.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

In PTSD, the locus coeruleus remains hyperactive, causing a sensitization response to all stressors, especially those that resemble the original trau- matizing event (Bremner et al., 1996; Zigmond et al., 1995). For example, the sound of a car backfiring might make you jump a bit, but it causes an enhanced stress response in a veteran with post-traumatic stress disorder because it reminds the veteran of gun- fire during a battle or a roadside bomb exploding. Norepinephrine is released in elevated amounts throughout the nervous system in response to this harmless sound, activating the sym- pathetic nervous system.

Case Study: Post-Traumatic Stress Disorder

Doug graduated from high school in 1966 and was almost immediately drafted into the army. As soon as he finished boot camp, he was sent to Vietnam. He was installed with his platoon in a primitive camp on the edge of the jungle. The men in his camp were all extremely jumpy because mines were hidden everywhere in the jungle and fields near the camp, and nearly every day one or more exploded with a loud thud that was hair-raising. They lived a tense, lonely existence far from the comforts and distrac- tions of a city.

One night Doug awoke to the sound of gunfire. He instinctively ran from his barracks and hid in the jungle near the camp. From his hiding place, Doug could hear the screams of his fellow soldiers as they were shot. He was so frightened that he urinated in his pants as he crouched beneath some brush, listening to the rat-tat-tat of the automatic gunfire. It was dark, so he couldn’t see the attackers. But he could hear them call to each other, although he couldn’t understand their language. Doug remained very still as a few of the attackers ran through the edge of the jungle, looking for escapees. Finally, the attackers departed.

For a long time Doug hid in the brush without moving. He listened for sounds of life in the camp but heard none. Afraid that some attackers remained in the camp, he stayed in his hiding place until the sun was quite high in the sky the next morning. The sight that greeted his eyes was harrowing. Everyone in his platoon had been murdered—everyone but him. He radioed for help and was soon transported away from that place of death.

Doug was never the same after that awful night when his buddies were massacred. He returned to the United States but was unable to hold a job or stay in a relationship for long. His sleep was troubled by recurring dreams of being wakened by the sound of gunfire, and he awoke, shaking and frightened, most nights. Doug had difficulty concentrating or listening when others were talking, and he had a hard time controlling his temper, especially when he drank.

(continued)

National Geographic/SuperStock

Photo 12.3 Psychotherapy helps a patient suffering from post-traumatic stress disorder deal with traumatic memories.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Alongside the established connections with hypothalamic stress systems, an accumulating amount of brain research has revealed several areas of the brain that are related to PTSD. Hippocampal volume has been shown, in several studies over several years, to be smaller in PTSD in comparison to controls (Shin et al., 2004). More recent research has focused on the amygdala. As with hip- pocampal volume, so amygdala size is reduced in military veterans diagnosed with PTSD (Morey et al., 2011). This change in size is not related to trauma frequency, intensity, or duration, and, though longitudinal study is not presently possible for war trauma exposure, this finding sug- gests the possibility that a smaller amygdala exists prior to trauma exposure and may be a deter- mining factor in whether PTSD symptoms emerge. Other neuroanatomical studies find distinctive PTSD-related patterns of change in amygdala connections with the anterior cingulate cortex, the hippocampus, the insular cortex, and other brain regions (Liberzon & Sripada, 2008). Reduced connections between the amygdala—shown to be smaller in other studies—and cingulate cortex imply a deficit in a braking mechanism that functions normally to reduce fear vigilance and reac- tion to threats. Interaction between the stress response systems and threat reaction systems can explain the avoidance and emotional reactivity aspects of PTSD. Further, cortical changes are also present. A study of Chinese mine disaster survivors (Chen et al., 2011) utilizing advanced compu- tational techniques of MRI analysis (voxel-based morphometry) assessing cortical density indi- cates diffuse brain changes, not only in subcortical basal ganglia structures, but also across several cortical regions including the frontal, anterior, and occipital cortices. Adding cortical changes to the mix of implicated brain systems suggests a systematic interconnection between brain mecha- nisms of stress reaction, threat monitoring, memory, and cognitive appraisal that tracks the com- plex symptomatology of the disorder.

Specific genetic mechanisms related to PTSD are also beginning to be identified. A study compar- ing generations of survivors of a 1988 Armenian earthquake with controls has identified alleles of specific serotonin hydroxylase transporter genes TPH1 and TPH2 as significantly related to PTSD criteria (Goenjian et al., 2012). Another recent study (Mercer et al., 2012) examined the DNA of 204 undergraduate women after they witnessed a shooting incident on their campus and found a relationship between the SLC6A4 serotonin transporter genotype and elevated PTSD symptoms. Finally, optogenetics, a hybrid technique in which light-sensitive proteins are introduced into neu- ral tissue and activated by targeted laser light, has shown promise in locating and verifying the neural and genetic connections that imaging has revealed, and is projected as a means of further

Case Study: Post-Traumatic Stress Disorder (continued)

When he arrived back in the States, people his age were protesting the presence of American troops in Vietnam. He was invited to speak at rallies but found that he couldn’t remember anything about Vietnam. He couldn’t recall even the names of his buddies who were killed. Living on disability, Doug spent most of his time in his apartment alone. He kept the television turned off because he couldn’t bear to hear any reports about the war in Vietnam or the protests against the war.

What bothered Doug most were the flashbacks. These occurred mostly when he was drinking. Unfor- tunately, Doug had little to do but drink. He would be sitting in his living room, drinking whiskey, when all of a sudden he could hear gunshots and the sound of people running everywhere. His vision dark- ened, and he would run blindly out of the apartment, into the street, screaming. Doug could see and hear his attackers. He could feel them chasing him. Each flashback felt as vivid and real as that awful night in Vietnam. In fact, the flashbacks are as troublesome and real today, more than 40 years later, as they were when Doug first returned from Vietnam.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

establishing the interconnected neural pathways involved in PTSD and related disorders (Deis- seroth, 2012).

Treatment of Post-Traumatic Stress Disorder The current treatment for PTSD is antidepressant medication, which was originally designed to treat depression (Davidson, Kalin, Kelley, & Shelton, 2001; Buchalter, Lantz, & American Associa- tion for Geriatric Psychiatry, 2001; Marshall, Beebe, Oldham, & Zaninelli, 2001). Because excita- tion of the locus coeruleus is increased in individuals with PTSD, antidepressant drugs help relieve symptoms of the disorder by decreasing the activity of the locus coeruleus. Antidepressant medi- cations also increase serotonin and norepinephrine availability at the synapse, which improves signaling between neurons and within neurons (Duman, 1995).

Medications that are used to treat PTSD do not eliminate the memories of the traumatic event that cause the patient so much trouble. Psychotherapy is needed to help the patient deal with the traumatic memories. After antidepressant medication has subdued the overarousal caused by increased activation of the locus coeruleus, a clinical psychologist or counselor can begin work to alter the way the patient thinks and feels about the traumatic event. This therapy may focus on reducing the loss of memory for the traumatic event and discharging unacknowledged emotions about the event (Krystal et al., 1995).

A recent controversial pharmacological intervention involves therapy for PTSD specifically involv- ing abuse survivors that includes, along with ongoing behavioral and pharmacological manage- ment of the symptoms, the introduction of a pure form of MDMA (known otherwise as an illegal recreational drug, “Ecstasy”). MDMA is a psychoactive agent that can produce heightened arousal and hallucinations when taken by otherwise normal individuals (Bauernfeind et al., 2011). The procedure appears to be an analog to behavioral “flooding” techniques and, while it has received some attention, should be approached with caution as recent evaluations have shown that there are several ambiguities in the research protocols (“Leigh,” 2013).

Pharmacological and behavioral interventions remain the mainstays of therapy for PTSD. However, recent studies have also shown promise for meditation as a therapeutic intervention. Programs of guided meditation have been introduced with military personnel as predeployment inoculations against stress, with positive results including increases in working memory and attention reported (Stanley, Schaldach, Kiyonasa, & Jha, 2011). Again, the research is in early stages and should be approached with caution. However, there are reasons that support the conjecture that this form of exclusively cognitive therapy can have benefits in the disorder. As mentioned, recent diagnostic revisions have foregrounded the cognitive symptoms of the disorder, including problems with concentration and attention. In a collective review of the cognitive symptoms connected to PTSD, Aupperle and colleagues observe a constellation of neural mechanisms connecting to the dorsal prefrontal cortex, all of which relate in some way to executive function, especially attention, and which also match up well with the array of PTSD-related cortical and subcortical systems that imaging has uncovered (Aupperle, Melrose, Stein, & Paulus, 2012). It may be the case that PTSD has a large attentional component, and one conclusion of their review is that therapies specifi- cally designed to heighten attentional focus can be beneficial in forming new neural connections that can build resistance to the urgent and uncontrolled attentional and reactive demands of the PTSD-compromised nervous system. Other studies (e.g., Desbordes et al., 2012) suggest that mindfulness training and meditation can have direct effects on the amygdala, another structure implicated in PTSD.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Major Depressive Disorder

Major depressive disorder (often referred to informally as depression) is a mood disorder char- acterized by lethargy, sad affect, diminished interest in all activities, cognitive disturbances, and eating and sleeping abnormalities. Table 12.2 gives the DSM-IV criteria for major depres- sive disorder. Animal models of depression typically use chronic stress to induce symptoms of depression in the nonhuman animals under study (Leonard, 1997). These animal models have demonstrated that chronic stressors produce symptoms of depression in animals as well as alter their neurotransmitter, hormone, and immune functions.

For some reason not yet understood, about half of all patients with major depressive disorder have cortisol levels that are significantly higher than normal (Akil & Morano, 1996; Boyer, 2000). It may be that major depressive disorder causes disruption of the HPA axis, or it may be that dys- regulation of the HPA axis produces or maintains depression (Akil & Morano, 1996). Certainly the symptoms of increased vigilance and decreased vegetative functions like sleeping suggest that the depressed person has a hyperactive HPA axis (De Souza & Grigoriadis, 1995; Michelson et al., 1995; Stout et al., 1995).

Table 12.2: Summary of DSM-IV criteria for major depressive disorder Symptoms listed must cause distress or impair social or occupational functioning and must not be due to the effects of a drug or a medical condition. At least one of the following must be present for at least 2 weeks:

• Depressed mood most of the time • Marked loss of interest or pleasure in all activities

Four or more of the following symptoms must also be present at the same time for at least 2 weeks: • Significant weight loss when not dieting • Insomnia nearly every day • Hypersomnia nearly every day • Restlessness that is noticeable to others • Movements markedly slowed down • Fatigue or loss of energy nearly every day • Feelings of worthlessness or excessive guilt nearly every day • Unable to think, concentrate, or make decisions nearly every day • Recurrent thoughts of death, suicidal ideation with or without a specific plan, suicide attempt

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright © 2000). American Psychiatric Association.

Biological Explanations of Major Depressive Disorder Biological explanations of depression have been around since ancient times (Thase & Howland, 1995). Hippocrates, for example, taught that depression, or melancholia as it was called back then, is due to an excess of black bile in the body (melan- means “black” and -chole means “bile” in Greek). Our explanations have become more sophisticated since Hippocrates’s time, thanks to the development of chemical and imaging techniques that allow investigators to determine the activity levels of neurotransmitters, hormones, and enzymes in the brain. However, scientific investigators do not agree on the cause of major depressive disorder, and many explanations abound.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Monoamine Hypothesis of Depression Antidepressant medication selectively increases the availability of monoamines (that is, norepi- nephrine, dopamine, and serotonin) in the brain. For that reason, the monoamine hypothesis of depression is currently the most widely recognized and accepted theoretical explanation for the development of depression (Hirschfeld, 2000; Leonard, 1997; Owens, 2004). According to the monoamine hypothesis, depression occurs when the availability or activity of one or more monoamines is reduced. Antidepressant medication produces an increase in the availability of serotonin and/or norepinephrine in the brain (Gessa, 1996). For example, tricyclic antidepressant is a medication that increases norepinephrine and serotonin availability at the synapse, whereas MAO inhibitor is an antidepressant medication that inhibits the enzyme, monoamine oxidase, that breaks down monoamines, thereby increasing their availability at the synapse.

Norepinephrine Dysregulation Hypothesis Abnormalities of norepinephrine function unquestionably exist in people with major depressive disorder, and thus norepinephrine probably plays an important role in the development of depres- sion (Ressler & Nemeroff, 1999). But what can this role be? Siever and Davis (1985) have proposed a dysregulation hypothesis, which suggests that depression results from a failure in the regulation of the norepinephrine system, rather than from a deficit or excess of norepinephrine. According to their hypothesis, the firing of neurons in the locus coeruleus in depressed individuals is erratic and greatly increased, which interferes with the responsiveness of the locus coeruleus system.

Serotonin Hypothesis The serotonin hypothesis of depression was proposed in 1968, based on several lines of evidence that serotonin deficiency plays an important role in the development of major depressive disorder (Coppen, 1968). First of all, all antidepressants, including tricyclic antidepressants and MAO inhibi- tors, have been demonstrated to increase serotonin activity at the synapse. The development in the 1980s of selective serotonin reuptake inhibitors (SSRIs), which selectively increase serotonin availability at the synapse, was seen as additional support for this hypothesis.

Substance P Dysfunction Hypothesis Substance P is a neuropeptide that you learned about in Chapter 8 when we discussed pain per- ception. However, substance P appears to have receptors throughout the central nervous system, which suggests that it plays a role in a variety of neural functions in addition to the perception of pain. For example, substance P has been implicated in the development of depression (Baby, Nguyen, Raffa, & Tran, 1999). Recently, a drug that antagonizes the action of substance P has been demonstrated to effectively treat depression (Argyropoulos & Nutt, 2000; Baby et al., 1999; Hök- felt, Pernow, & Wahren, 2001; Kramer et al., 1998; Madaan & Wilson, 2009; Nutt, 1998; Rotzinger, Lovejoy, & Tan, 2010). This is the first time that a drug not directly related to monoamine function has been shown to be effective in the treatment of depression. Substance P’s role in depression is unknown, but suppression of its action can bring about an improvement in depressive symptoms.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Hypothalamus-Pituitary-Adrenal Axis Dysfunction You’ve learned already in this chapter that about half of all patients with major depression have cortisol levels that are significantly higher than normal, indicating dysregulation of the hypothalamus-pituitary-adrenal axis. This dysfunction may contribute to the abnormal neu- rotransmitter levels, particularly norepinephrine levels, observed in most depressed patients.

In Chapter 9 you learned about the control of metabolism by the thyroid gland. The hypothalamus stimulates the anterior pituitary gland to release thyroid-stimulating hormone into the blood- stream. As its name implies, thyroid-stimulating hormone stimulates the thyroid gland to release thyroid hormones, which have a number of effects in the body, including increasing metabolic rate. Deficiencies in thyroid activity, referred to as a hypothyroid condition, have been observed in some individuals with major depressive disorder.

Low levels of estrogen associated with menopause, childbirth, and the premenstrual (or late luteal) stage of the menstrual cycle have been shown to be correlated with mood disorders (Parry & Newton, 2001). In addition, estrogen has been used successfully to treat some forms of severe persistent depression (Klaiber, Broverman, Vogel, & Kobayashi, 1979). The role that estrogen plays in the development of depression is unknown at present. However, we do know that estrogen and other reproductive hormones can affect the function of all the neurotransmitters associated with depression, including norepinephrine, serotonin, and dopamine. These gonadal hormones can also alter the activity of other hormone systems, such as cortisol, thyroid, and melatonin, which regulates the biological clock. Thus, estrogen may exert its influence on moods through its effect on other hormonal or neurotransmitter systems.

Melatonin Dysfunction Sleep abnormalities are observed in many individuals with major depressive disorder (Wirz- Justice, 1995; Seifritz, 2001). Most suffer from an inability to fall asleep and an inability to stay asleep. Others complain that they feel sleepy all the time. Electroencephalographic studies of depressed patients have demonstrated that brain wave abnormalities are present in many cases of major depressive disorder, including reduced levels of slow-wave sleep and altered distribution of REM sleep throughout the night. One common feature seen in the EEG records of depressed individuals is increased REM activity, which is typically suppressed by antidepressant medication (Thase & Howland, 1995).

Anderson and Wirz-Justice (1991) have proposed that a disruption in the melatonin system, which controls circadian rhythms, is responsible for the sleep disturbances observed in depressed indi- viduals. This disruption causes a phase advancement of the circadian rhythm. The term phase advancement refers to the fact that hormonal and other physiological processes, which fluctuate throughout the day according to regular, predictable patterns in healthy individuals, appear to be shifted several hours forward in people who are depressed. For that reason, many depressed indi- viduals wake up earlier and go into REM sleep sooner during the night. In addition, the circadian rhythm for norepinephrine and cortisol release shows evidence of phase advancement in many people with major depressive disorder.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

Phase advancement explains why traveling west over several time zones often induces depression in the traveler who has a history of mood disorder. Individuals who travel west from New York to Cali- fornia find themselves in a time zone that is several hours behind their own internal clocks. The dis- ruption of the circadian rhythm caused by westward travel leads to sleep and other neurophysiologi- cal disruptions that are associated with depression. Likewise, depriv- ing a depressed person of sleep typically causes a short-term relief of depression because the sleep deprivation temporarily resets the phase-advanced circadian rhythm of the depressed individual (Wu & Bunney, 1990). The rapid return of depression following sleep recovery suggests that melatonin may play an important role in the regulation of mood.

Nearly all of the research concerned with the biology of depression that has been conducted to date, especially the human studies, is correlational in nature. Thus, we cannot impute causation from these findings. That is, we cannot infer that low levels of norepinephrine or high levels of cortisol cause depression. Rather, it may be that depression causes low levels of norepinephrine and high levels of cortisol. Because it is unethical to deliberately try to cause depression in human subjects, we may never know exactly what causes major depressive disorder.

Treatment of Major Depressive Disorder A variety of medications and procedures are used to treat major depressive disorder. The preced- ing sections described the actions of antidepressant drugs on various neurotransmitter and hor- monal systems. New classes of antidepressants are under development, including GABA agonists, CRH antagonists, and acetylcholine antagonists (Berman, Krystal, & Charney, 1996; Li, Frye, & Shelton, 2012; Rotzinger, Lovejoy, & Tan, 2010). Some of these drugs, particularly GABA agonists, have been demonstrated to be as clinically effective as traditional antidepressants (Petty, Trivedi, Fulton, & Rush, 1995). Some of the newest drugs (for example, a drug that blocks the receptors for substance P) appear to successfully treat major depressive disorder, but they don’t fit neatly into any of the explanations of depression that we’ve explored in this chapter (Kramer et al., 1998). In the future, our understanding of the mechanisms underlying depression will improve as we study the action of new medications on the nervous system.

iStockphoto/Thinkstock

Photo 12.4 Sleep disturbance is common for those suffering from a major depressive disorder.

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CHAPTER 12Section 12.2 Disorders Associated with Stress

One procedure that has been dem- onstrated to be quite successful in treating profoundly depressed patients is electroconvulsive ther- apy (ECT), in which an electric cur- rent is passed across the patient’s brain, producing a seizure (Sack- eim, Devanand, & Nobler, 1995; Szuba, O’Reardon, & Evans, 2000). This procedure has been in use since the late 1930s, although its use has declined quite a bit since the development of modern anti- depressant medications. How- ever, it is still used regularly with patients with major depressive disorder, especially with those who are severely depressed and not responding to medication.

Investigators are uncertain how electroconvulsive therapy relieves depressive symptoms in the depressed patient. One observation is that CRH levels in the cerebrospinal fluid are diminished following electroconvulsive therapy, which suggests that excess secretion of CRH in the brain maintains symptoms of depression (De Souza & Grigoriadis, 1995). Electroconvulsive therapy also alters monoamine, acetylcholine, and GABA activity in the brain. One of the negative side effects of electroconvulsive therapy is memory loss and disorientation in the patient.

Transcranial magnetic stimulation is a relatively new method of treating depression. This is a noninvasive method that involves directly stimulating neurons in the cerebral cortex (George, Wasserman, & Post, 1996; Szuba et al., 2000). Originally, transcranial magnetic stimulation was used as a research tool to map functions, like memory, movement, speech, and vision, on the cortex, much like the electrical stimulation studies that were conducted on patients undergo- ing brain surgery more than 50 years ago. However, early investigators observed a temporary elevation in mood in people tested with this procedure, and some began testing the procedure informally on depressed patients, with inconclusive results (Kirkcaldie, Pridmore, & Pascual- Leone, 1997).

More recently, investigators have applied knowledge derived from PET studies of depressed people to improve the ability of transcranial magnetic stimulation to treat depression. That is, brain-imaging studies of depressed patients have demonstrated decreased cerebral activity in the anterior regions of the brain, especially on the left side of the brain. When high-frequency repetitive transcranial magnetic stimulation is applied to the left prefrontal cortex of a depressed individual, it increases activity in that area of the brain and produces short-term relief of depres- sion. This effect has been demonstrated in well-designed studies that use a placebo control and a double-blind procedure (George et al., 1996; Figiel et al., 1998; Kirkcaldie et al., 1997). In addition, unlike electroconvulsive therapy, transcranial magnetic stimulation does not require anesthesia, does not produce seizures in patients, and appears to have minor negative side effects (Post et al., 1999). In 2009 the U.S. government (through the Food and Drug Administration) approved transcranial magnetic stimulation as a treatment for depression.

WILL MCINTYRE/Science Source/Getty Images

Photo 12.5 Electroconvulsive therapy has proved successful in treating profoundly depressed patients.

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CHAPTER 12Section 12.3 Psychotic Disorders

Fatigue Disorders

Fatigue disorders are characterized by lethargy, a loss of drive, and an increase in vegetative behaviors like sleeping and eating. These disorders include chronic fatigue syndrome, atypical depression, seasonal affective disorder, and fibromyalgia (Michelson et al., 1995). The major symptoms and treatments for these disorders are given in Table 12.3. In contrast to major depres- sive disorder—which, as you’ve just learned, is associated with increased levels of CRH—these fatigue disorders are associated with chronically low levels of CRH (Bradley, McKendree-Smith, & Alarcon, 2000; Cleare et al., 2001). If an individual is unable to release large amounts of CRH in response to a stressor, that individual has an impaired stress response system. Reduced CRH secretion leads to a decreased ability to respond to stress. This means that the systems that typically become activated during stress, including the HPA axis and the locus coeruleus, do not respond fully in the face of stress in a person who has a fatigue disorder. As a result, the central nervous system responses usually observed in a stress response, such as increased vigilance and attention and heightened arousal, are weak or absent in fatigue disorders.

Table 12.3: Major symptoms and treatment for representative fatigue disorders Fatigue disorder Major symptoms Treatment Chronic fatigue syndrome Lethargy, weakness, tiredness, unrefreshing

sleep, impaired memory/concentration, sore throat, tender lymph nodes in neck or armpit, muscle or joint pain, headaches, feelings of malaise following exertion. Symptoms present for >6 months

Graded exercise program; cognitive behavioral therapy; not effective: antiviral medication, SSRls, immuno- globulin (White et al., 2011)

Seasonal affective disorder In winter months: lethargy, sleeping more than normal, hyperphagia, carbohydrate craving

Light therapy (2,500 lux for 2 hours daily), SSRIs

Atypical depression Lethargy, sleeping more than normal, hyper- phagia, sensitive to rejection by others

SSRIs, MAO inhibitors

Fibromyalgia Fatigue, headaches, numbness, widespread pain in muscles and/or joints in absence of signs of inflammation

SSRIs; graded exercise program; not effective: opioids, corticosteroids (Turk, Wilson, & Cahana, 2011)

Stress has been implicated in the development of other psychological disorders, including schizo- phrenia and bipolar disorder (Walker & Diforio, 1997), as you will learn in the next section of this chapter.

12.3 Psychotic Disorders

Many people confuse the term psychotic with the term schizophrenic, or they use the terms interchangeably, believing that they mean the same thing. Actually, schizophrenia is one of many different psychotic syndromes. Psychoses are severe mental disorders in which thinking is so disturbed that the afflicted person is not well oriented for person, time, and place. A good way to test this is to ask three simple questions: “What is your name?” “What is today’s date?” “Who is the president of the United States?” A normal person would have no trouble answering these questions. A psychotic person, however, would have difficulty coming up with the correct answers.

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CHAPTER 12Section 12.3 Psychotic Disorders

Here is an example of the disordered thought processes that are characteristic of a psychosis. Below is the transcript of an interview with a young man (T) who was diagnosed as psychotic.

Dr.: Can you tell me your name?

T: Tommy.

Dr.: Okay, Tommy—?

T: Tommy, you know, like the rock opera, Tommy. The Who?

Dr.: Tommy, okay. And what is your last name?

T: It’s just Tommy.

Dr.: Uh-huh. What is your father’s last name?

T: Oh. I was created when the needle hit the record, a flash of electricity, er, energy.

Most people are aware that they have parents, and they can tell you their last name without hesitation. A psychotic person has difficulty with even the simplest questions, often choosing a ridiculous answer over an obviously correct one. Thinking is so disturbed that a person with a psy- chosis cannot distinguish between rational and irrational ideas. This lack of judgment interferes with work and social behaviors, making it difficult for those with psychotic disorders to survive on their own. Often irrational thinking in a psychotic disorder is accompanied by delusions, hallucina- tions, and inappropriate emotional responses.

In Chapter 11 we examined the biological bases of anxiety disorders. Anxious people, unlike psy- chotic individuals, are well oriented for time and place. The overwhelming symptom of people with anxiety disorders is anxiety, which may make them unhappy or cause them to behave in embarrassing ways. But anxious individuals do not generally experience hallucinations, delusions, or irrational thoughts.

For most psychotic disorders, the biological cause is well documented. These disorders are referred to as “psychotic disorders due to a general medical condition” (American Psychiat- ric Association, 1994). Another term often confused with these disorders is dementia, which involves cognitive impairment (a decline in memory, thinking, and emotional functions) and poor judgment (Bajenaru et al., 2012). Dementia and psychosis are both defined as “madness” (Gershon & Rieder, 1992). As with most psychoses, the diagnosis of dementia is usually cou- pled with a documented organic basis, such as arteriosclerosis (hardening of the arteries), malnutrition, brain tumor, or other degenerative brain disorder. We will examine dementias in Chapter 13, but they are mentioned here because they are often accompanied by psychotic symptoms. As we begin our discussion of psychotic disorders, let’s first turn to disorders that have been linked to an organic brain problem.

Reversible and Irreversible Psychoses

Not all psychoses are permanent conditions. Some people have one brief psychotic episode and then return to a normal state of mind. Other individuals have recurrent bouts of psychosis but remain functional much of the time. Most dementias, however, are irreversible because they are caused by some underlying neural problem that cannot be corrected. A person diagnosed with

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CHAPTER 12Section 12.3 Psychotic Disorders

dementia is likely to remain mentally incapacitated for life. Less than 20% of all dementia cases are reversible. Psychosis or dementia may be treatable (that is, reversible) when the cause is an infectious disease, malnutrition, or drug related (Robinson, 1997).

Infections, especially those caused by bacteria that produce powerful toxins, such as diphtheria and some forms of bacterial pneumonia, can produce toxic psychoses, with symptoms of rest- lessness, loss of orientation for time and place, hallucinations, inattention, and perceptual distor- tions. These psychotic symptoms disappear when the infection is successfully treated. Likewise, the psychotic symptoms that accompany viral encephalitis, an inflammation of the brain caused by viruses so tiny that they can pass through the filters imposed by the blood-brain barrier, are not permanent. Sometimes meningitis, an inflammation of the meninges usually caused by a bacterial infection, will result in temporary disorientation for time and place, impaired memory and confusion, and hallucinations. Advanced liver or kidney disease can also produce brain dys- function that causes psychotic symptoms.

Some brain tumors, particularly those located in the frontal, temporal, or parietal lobes or in the limbic system, will produce psychotic symptoms (Craven, 2001; Lisanby, Kohler, Swanson, & Gur, 1998; Lu & Yeh, 2001). In fact, patients with brain tumors are sometimes misdiagnosed as psy- chotic when they first come in for medical treatment, especially when their presenting symptoms are inappropriate emotional response, apathy, confusion, hallucinations, and loss of orientation for time and place. These symptoms generally subside when the tumor is removed.

Reversible psychotic symptoms can also be produced by abuse of stimulants, such as amphet- amine, cocaine, and PCP or “angel dust,” which were all discussed in Chapter 3. For example, large doses of amphetamine taken repeatedly will induce paranoid delusions similar to those observed in people with schizophrenia. This is true of amphetamine addicts and normal subjects. Studies of normal volun- teers who were administered large doses of amphetamine daily under controlled conditions revealed that 100% of the subjects developed paranoid delusions within 1 week of the start of the study (Barondes, 1993). Repeated use of cocaine will also induce suspiciousness and paranoid delusions, as well as auditory hallucinations. Abuse of PCP produces hallucinations, paranoia, disordered thought, and sometimes catatonic movement disorders that are typically seen in schizophrenia. Remember that both amphetamine and cocaine augment catecholamine activity in the brain. (You might want to refer back to Chapter 3 for their specific actions.) For abusers of these drugs, the psychotic symptoms disappear after drug use has stopped.

Seth Resnick/Science Faction/Getty Images

Photo 12.6 Reversible psychotic symptoms can also be pro- duced by abuse of stimulants such as alkaloidal cocaine (crack).

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CHAPTER 12Section 12.4 Schizophrenia

Traumatic injuries to the brain, such as cerebral concussions, contusions, and lacerations, are often followed temporarily by impaired memory, confusion, and loss of orientation for time and place. A person regaining consciousness after being knocked unconscious in an accident will frequently look around quite blankly and ask, “Where am I? What happened?” However, with severe brain injury, these psychotic symptoms may be permanent. One example of an irreversible psychotic state caused by trauma to the brain is dementia pugilistica, a disorder found in people who have suffered repeated blows to the head, such as boxers (Jordan, 2000).

12.4 Schizophrenia

Schizophrenia was first described at the beginning of the 20th century by two European psy-chiatrists, Emil Kraepelin in Germany and Eugen Bleuler in Switzerland. Impressed by the progressive intellectual deterioration of the schizophrenic patients whom he examined, Kraepelin called the disorder dementia praecox. He maintained that dementia praecox is due to deteriora- tion of the brain.

Bleuler, on the other hand, named the disorder schizophrenia because he believed that the most striking symptom of the disorder is the disorganization of associations, which leads to discon- nected thoughts, words, and emotions. He did not agree with Kraepelin that patients with schizo- phrenia get progressively worse. Bleuler observed that his schizophrenic patients sometimes functioned normally and sometimes functioned abnormally. As a result, Bleuler concluded that schizophrenia is caused by a transient physiological dysfunction in the brain and is not due to degeneration of the brain.

Today the cause of schizophrenia is still not known. In fact, some scholars wonder whether it is really one illness or a collection of related illnesses (Heinrichs, 1993). According to the DSM-IV, the criteria for a diagnosis of schizophrenia include a decline in functioning and any two of the following symptoms: delusions, hallucinations, disorganized speech or behavior, blunted mood, or apathy. However, a person is diagnosed as schizophrenic only after all other possible organic causes of psychosis are ruled out. Schizophrenia is the label people are given when their psychotic symptoms cannot be explained by drug intoxication or some other medical condition, such as a nutritional deficiency, cerebrovascular disease, Huntington’s disease, or hepatic encephalopathy.

Given the DSM-IV criteria for schizophrenia, one person diagnosed as schizophrenic may have delusions, but no hallucinations. Another may have delusions and hallucinations. Still another person diagnosed as schizophrenic may have no delusions or hallucinations but may have disorga- nized speech and social isolation instead. Do these people all have the same illness? The DSM-IV actually distinguishes among five types of schizophrenia, but research does not support these distinctions (Heinrichs, 1993).

Crow (1980) has attempted to sidestep the problem of subtypes of schizophrenia by classifying the symptoms associated with schizophrenia into two categories: positive symptoms and nega- tive symptoms. Positive symptoms are those behaviors observed in schizophrenics that most people typically do not have. That is, positive symptoms occur in addition to normal behaviors. Examples of positive symptoms include disturbed thinking, hallucinations, delusions, and move- ment disorders. In schizophrenia, thinking can be so disorganized that it resembles the cognitive deterioration of dementia. Thoughts are loosely connected, and the afflicted person will jump from one subject to the next in the same breath—for example, remarking, “Riding on the coat- tails of the law, paw, dog, number 1 dawg, that’s Jesus’s way.”

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CHAPTER 12Section 12.4 Schizophrenia

Negative symptoms represent diminished functioning. Blunted mood, poverty of speech, inabil- ity to experience pleasure, apathy, poor insight and judgment, and inattention are examples of negative symptoms. Whereas sane people exhibit a wide range of emotions, readily engage in conversation, are able to experience fun and pleasure, generally have good judgment, and show interest in their surroundings, schizophrenic people often lack these behaviors.

Most patients do not show exclusively positive or negative symptoms. That is, most schizophrenic individuals will experience both types of symptoms, often at the same time. Positive and negative symptoms appear to arise from different parts of the brain, as you will learn in the next section. Any biological explanations of schizophrenia will need to address the occurrence of positive and negative symptoms in most schizophrenic patients.

Biological Explanations of Schizophrenia

Biological explanations of schizophrenia are based on four universal observations about schizo- phrenia: (1) the presence of positive and negative symptoms, which implicates disturbances in widely different parts of the brain; (2) the effective treatment of schizophrenic symptoms by drugs that reduce dopamine activity in the brain; (3) the role played by stress in the onset and worsening of schizophrenic symptoms; and (4) peak age of onset for schizophrenia, which is late adolescence or early adulthood. In addition, a number of neurotransmitter circuits appear to function abnormally in schizophrenia.

The Dopamine Hypothesis For several decades the leading biological explanation of schizophrenia, known as the dopamine hypothesis, has focused upon overactivity of particular dopamine pathways (Seeman et al., 1997). There are two lines of evidence that suggest that dopamine might play a role in schizophrenia. First of all, drugs that stimulate dopamine receptors, such as cocaine and amphetamine, can produce psychotic symptoms in normal human subjects. In addition, when dopamine agonists are administered to schizophrenic patients, their symptoms worsen. Second, drugs that counter the action of dopamine reduce or eliminate positive schizophrenic symptoms. Nearly all drugs used today to treat schizophrenia are dopamine antagonists, to some extent, and are known as neuroleptics (Davis, Kahn, Ko, & Davidson, 1991).

It is not known what produces the overactivation of dopamine pathways in schizophrenia. We do know that dopamine levels in schizophrenic individuals are not significantly higher than those in normal controls (Andreasen, 1988). Therefore, it is unlikely that excess dopamine actually pro- duces schizophrenic symptoms (Davis et al., 1991). Instead, an imbalance in dopamine activity in the brain, in which some areas of the brain are more active than normal and others are less active might explain how schizophrenia arises in the brain.

There are three major dopamine pathways in the brain. These are known as the mesolimbic, mesocortical, and nigrostriatal systems. Each pathway is composed of neurons whose cell bod- ies are in the midbrain and whose axons project to one or more areas in the forebrain. In the mesolimbic system, neurons in the midbrain release dopamine in the limbic system, including the hippocampus, amygdala, nucleus accumbens, and hypothalamus. The mesocortical pathway also begins in the midbrain, but it projects primarily to the prefrontal and other regions of the cerebral cortex. The nigrostriatal pathway projects from the substantia nigra to the basal ganglia. Put this

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CHAPTER 12Section 12.4 Schizophrenia

together with what you know about brain function: Dopamine influences emotion and motivation in the mesolimbic system, thinking and other cognitive processes in the mesocortical system, and movement in the nigrostriatal system.

Neuroleptic medications have different actions on the three dopamine systems, which suggests that not all pathways are equally active in schizophrenia. There is indeed a great deal of evidence that regional imbalances in dopamine activity occur in the brains of individuals with schizophre- nia (Davis et al., 1991; Murray, Lappin, & Di Forti, 2008; Volkow et al., 1986; Weinberger, 1987), prompting Davis and his associates to propose a modified dopamine hypothesis of schizophrenia. According to this modified hypothesis, in schizophrenia, dopamine activity in the cerebral cor- tex is decreased, whereas dopamine activity in subcortical areas of the brain is increased. That is, in schizophrenia, the mesocortical system becomes underactive, and the mesolimbic system becomes overactive (Figure 12.5). A number of investigators agree that underactivity of the pre- frontal cortex is responsible for the negative symptoms of schizophrenia and that overactivity of the mesolimbic system is responsible for the positive symptoms of schizophrenia.

Figure 12.5: Regional imbalances in dopamine (DA) activity of normal and schizophrenic states

Compared to the dopamine activity in the normal state, the mesocortical dopamine system is weakened and the mesolimbic dopamine system is overactive in the schizophrenic state.

In support of the modified dopamine hypothesis, imaging studies that measure brain activity indi- cate an imbalance in the functioning dopamine systems in schizophrenia. Using PET, Volkow and her associates (1986) measured glucose metabolism in the brains of 18 schizophrenic and 12 nor- mal subjects. They found that activity in the frontal lobes of schizophrenic subjects was decreased compared to that of normal subjects and was increased in the subcortical areas of schizophrenic patients compared to that of normal subjects.

Prefrontal cortex

Limbic sites

Prefrontal cortex

Limbic sites

Weakened

Overactive

Brain stem DA neurons Schizophrenic state

Brain stem DA neurons Normal state

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CHAPTER 12Section 12.4 Schizophrenia

Regional imbalances in dopamine activity can explain the presence of positive and negative symp- toms in schizophrenia. Overactivation of the limbic system, including the hippocampus and amyg- dala, produces hallucinations, perceptual distortions, delusions, and paranoia, as demonstrated in studies of recording from electrodes placed deep into the temporal lobes (Gloor, Olivier, Quesney, Andermann, & Horowitz, 1982; Halgren, Walter, Cherlow, & Crandell, 1978). Negative symptoms are associated with impaired function of the prefrontal cortex, particularly in the dorsolateral prefrontal cortex (Berman, Zec, & Weinberger, 1986; Stuss & Benson, 1984; Weinberger, 1987).

However convincing the evidence is in favor of the dopamine hypothesis, there is also consid- erable evidence that schizophrenia is not caused by one single neurotransmitter dysfunction (Emrich, Leweke, & Schneider, 1997; Weinberger, 1987). For example, a new class of powerful drugs used to treat schizophrenia, called atypical neuroleptics, appears to increase serotonin levels as well as block dopamine in the brain. In fact, dysfunctions in any of several neurotrans- mitter systems could produce schizophrenic symptoms. Remember that psychotic symptoms are quite complex and involve cognitive, perceptual, social, and emotional processes. This means that schizophrenia may be caused by impaired interaction between different neu- rotransmitter systems. Investigators are currently examining the possible roles of glutamate, GABA, serotonin, acetylcholine, and other peptides in schizophrenia. For example, cannabinoid neurotransmitters are associated with schizophrenic symptoms (Emrich et al., 1997; Leweke, Giuffrida, Wurster, Emrich, & Piomelli, 1999; Marsman et al., 2013; Skosnik, Spatz-Glenn, & Park, 2001).

The Diathesis-Stress Model of Schizophrenia If you take a course in abnormal psychology, you will undoubtedly learn about the diathesis-stress model of schizophrenia. This theoretical model has been used for decades to explain the develop- ment of schizophrenia. According to this model (Rosenthal, 1970), people who are predisposed to develop schizophrenia have a biological “weakness” or diathesis that makes them vulnerable to the effects of stress. Furthermore, schizophrenic individuals have an intensified response to stress, and stress worsens their symptoms. Until recently, very few investigators studied the bio- logical aspects of this model. Most research to date has focused upon the nature of the stressors associated with schizophrenia.

Earlier in this chapter, you learned that cortisol levels in the blood and urine become elevated during stress, due to activation of the hypothalamic-pituitary-adrenal axis. Although a number of cortisol abnormalities have been reported in schizophrenic individuals, these abnormalities are not sufficient to explain the onset of schizophrenic symptoms. However, schizophrenia is also associated with a pronounced dopamine response to activation of the HPA axis. It is important to remember that stress induces changes in a number of neurotransmitter systems in all people. But in schizophrenic people, stress causes the release of cortisol from the adrenal gland, which in turn produces a massive increase in dopamine activity in the mesolimbic system (Walker & Diforio, 1997).

Figure 12.6 illustrates Walker and Diforio’s diathesis-stress model. This model suggests that both biological insults and psychosocial stress can produce activation of the HPA axis and release of cortisol, which then activates the mesolimbic dopamine pathway that runs from the midbrain to the limbic system. Overactivation of the mesolimbic dopamine pathway is believed to result

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CHAPTER 12Section 12.4 Schizophrenia

in schizophrenic symptoms. This model can also explain why late adolescence or early adult- hood is the peak period for the onset of schizophrenic symptoms. Human cortisol release rises rapidly during adolescence, producing overactivation in the mesolimbic dopamine system in individuals who are vulnerable to developing schizophrenia (Bencherif, Stachowiak, Kucinski, & Lippiello, 2012).

Figure 12.6: Walker and Diforio’s neural diathesis-stress model

The release of cortisol triggered by stress can stimulate overactivity in the mesolimbic dopamine system and produce or worsen symptoms of schizophrenia.

Structural Abnormalities Associated with Schizophrenia

Modern imaging techniques allow us not only to study the binding of chemicals to brain receptors but also to visualize structural changes in the brains of schizophrenics. The finding reported most often in imaging studies concerns the size of the ventricles in schizophrenic patients. Over three dozen published papers have reported enlarged third and lateral ventricles in the brains of schizo- phrenics, as a result of CT or MRI studies. Remember that the ventricles themselves do not have a particular function, except to hold cerebrospinal fluid. An increase in the size of the ventricles generally means that the volume of surrounding brain structures is reduced.

Prenatal/perinatal insult Psychosocial stress

Hippocampal structure/function

HPA activation/ cortisol release

External factors

Neural mechanisms

Behavioral outcome

Activation of mesolimbic dopamine system

Symptom onset/exacerbation

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CHAPTER 12Section 12.4 Schizophrenia

MRI studies have revealed that the prefrontal cortex, hippocampus, and amygdala are smaller in schizophrenics than in normal subjects (Breier et al., 1992; Szeszko et al., 2002). Studies focusing on hippocampal activity have shown that there are fewer neurons available and therefore that neural processing is decreased (Freedman & Goldowitz, 2010). In addition, postmortem examina- tion of the brains of schizophrenics has revealed a number of irregularities in the neurons in the hippocampus and other periventricular limbic areas, as well as in the prefrontal cortex (Bogerts & Falkai, 1995; Bogerts, Meertz, & Schoenfeldt-Bausch, 1985; Weinberger, 1987). These abnormali- ties include decreased volume of cells, decreased number of cells, gliosis, and disarray of pyrami- dal cell orientation in the hippocampus (Jeste & Lohr, 1989; Kovelman & Scheibel, 1984).

One of the best methods to determine structural abnormalities associated with schizophrenia is to compare the brain of a schizophrenic individual with the brain of his or her nonschizophrenic, monozygotic twin. Using MRI, Suddath and his colleagues (1990) studied 15 pairs of identical twins who were discordant for schizophrenia. (Discordant means that one twin is affected by the disorder, whereas the other is not; concordant means that both twins are affected.) The hippo- campus was found to be smaller in the schizophrenic twin in 14 of the 15 pairs of twins. Also, the lateral and third ventricles were determined to be larger in 13 of 15 of the schizophrenic twins. These differences between discordant twins, however, may be due to drug treatment because the schizophrenic twin in each pair had received neuroleptic drugs to control symptoms, and the unaf- fected twin had not. In addition to MRI studies in the late twentieth century, more recent studies of twins have focused on blood-cerebral spinal fluid barrier disfunction (Johansson et al., 2012).

Another structure that appears to be disturbed in schizophrenic patients is the thalamus. Nancy Andreasen and her colleagues (1994) at the University of Iowa compared MRI scans of the brains of 47 healthy and 39 schizophrenic male subjects. Like other investigators, they found that schizo- phrenic patients had enlarged ventricles compared to the healthy volunteers. In addition, this research team discovered that the thalamus, particularly on the right side, was significantly smaller in schizophrenics and that the white matter surrounding the thalamus (that is, the axons leaving and entering the thalamus) was also smaller. Both the medial dorsal regions of the thala- mus, which sends axons to the prefrontal cortex, and the lateral thalamus, which projects to the parietal and temporal association areas, were abnormal. You learned in Chapter 4 that the main function of the thalamus is to control input to the cerebrum and other forebrain structures. It may be that abnormalities in the structure of the thalamus could interfere with the ability of the thalamus to filter out unimportant sensory input, overwhelming the schizophrenic individual with stimuli.

The Dorsolateral Prefrontal Cortex Today it is clear that schizophrenia is a disease of the brain, in which certain areas of the brain become damaged early in life, perhaps prenatally in some cases. However, onset of the illness does not occur until brain maturation is nearly complete, usually in late adolescence (Olney & Farber, 1995; Walker & Diforio, 1997; Weinberger, 1987). One of the last brain areas to mature is the dorsolateral prefrontal cortex, which reaches functional maturity in early adulthood. Because this area of the brain matures in late adolescence, prenatal damage to this area of the brain would not be evident during childhood. The social and cognitive deficits (the negative symptoms of schizophrenia) associated with damage to the dorsolateral prefrontal cortex would not be appar- ent until after this area has fully developed (Figure 12.7).

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CHAPTER 12Section 12.4 Schizophrenia

Figure 12.7: Areas of the dorsolateral prefrontal cortex that have been linked to deficits observed in schizophrenia

Once this area of the brain is completely developed, which occurs during late adolescence, social and behavioral deficits become apparent.

Hallucinations Hallucinations are among the most commonly reported positive symptoms of schizophrenia. These hallucinations are abnormal perceptual experiences that occur in the absence of external stimuli. This means that hallucinations most likely arise from abnormal brain activity. Using PET

imaging, a team of investigators from London and New York has examined the brain areas activated during audi- tory and visual hallucinations (Silber- sweig et al., 1995). As you might expect, activation of the auditory- linguistic association cortex in the temporal lobe did occur in all sub- jects experiencing auditory hallucina- tions. Likewise, visual hallucinations were associated with activation of the visual association cortex. This activation in the association areas of the cortex rather than in the primary sensory cortex makes sense given the internally generated nature of the hallucinations. Also activated during both visual and auditory hallucina- tions were subcortical structures

Impairment in Wisconsin Card

Sorting Test

Smooth pursuit eye movement (area 8)

Temporal lobe

Parietal lobe

Oculomotor/manual delayed-response (area 46)

Frontal lobe

Tim Beddow/Science Source

Photo 12.7 Brain areas with significantly increased activity dur- ing visual and auditory hallucinations are highlighted in yellow.

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CHAPTER 12Section 12.4 Schizophrenia

located deep within the brain, including the thalamus and hippocampus. The relative absence of activation in the prefrontal cortex in the brains of hallucinating schizophrenic patients is consistent with our earlier discussion of reduced activity in the mesocortical pathway.

Genetic Bases of Schizophrenia

Schizophrenia appears to run in some families, fueling speculation that there might be a genetic basis for schizophrenia. Certainly, the data suggest the existence of a genetic basis, but the inheri- tance pattern of schizophrenia does not follow simple Mendelian genetics, which emphasizes the presence of dominant and recessive genes (Emrich et al., 1997). Let’s take a look at the inheritance data for schizophrenia and some of the proposed genetic explanations.

All published reports agree that a schizophrenic individual is more likely to have a blood rela- tive who is also schizophrenic than a nonschizophrenic individual is. The likelihood of develop- ing schizophrenia is highest if one has a monozygotic twin who is also schizophrenic. Likewise, the likelihood is quite high in those who have two schizophrenic parents. On the other hand, 90% of the people who develop schizophrenia have no close relatives with schizophrenia (McGue & Gottesman, 1989; Straube & Oades, 1992). What does this tell us about the inheritance of schizophrenia?

According to classical Mendelian rules, if schizophrenia were carried by a dominant gene, the concordance rate in monozygotic twins would be expected to be 100%, and the rate in dizygotic twins would approach 50%. In reality, the concordance rate for monozygotic twins is 44% and that for dizygotic twins only 12% (McGue & Gottesman, 1989). Obviously, we must discard Mendelian genetics as an explanation for the incidence of schizophrenia. But there must be some influence of genetic inheritance because schizophrenia is more likely to occur in monozygotic twins, who share identical genes, than in dizygotic twins, who share approximately 50% of their genes. In addition, adopted children who have schizophrenic biological parents but are raised by healthy adoptive parents are more likely to become schizophrenic than are adopted children with healthy biological parents. Again, the influence of heredity is obvious.

The model that has found the most acceptance is a multifactorial model. According to this model, a combination of genetic and environmental factors produces schizophrenia. This model assumes that more than one gene is involved, but it also emphasizes the role of the environment, including prenatal influences, brain development, and psychosocial factors. That is, according to this model, schizophrenia develops in those who have the appropriate genetic background and certain envi- ronmental exposures that make them susceptible to the illness. Molecular geneticists who study the inheritance of schizophrenia have been searching for a gene locus on chromosomes 5, 6, 9, 19, 20, and 22. The locus on chromosome 5 is particularly interesting because it is near the locus that controls metabolism of cortisol, which is important in stress reactions (Fanous et al., 2007; Straube & Oades, 1992; Zaharieva et al., 2008).

Support for the multifactorial model of schizophrenia comes from studies of monozygotic twins. Some pairs of monozygotic twins are monochorionic, which means that they shared the same placenta, whereas other pairs are dichorionic, which means that each twin had his or her own pla- centa. Identical twins who shared the same placenta have a concordance rate of 60% for schizo- phrenia. In contrast, identical twins who are dichorionic have a concordance rate of only 10.7%

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CHAPTER 12Section 12.5 Mood Disorders

(Davis, Phelps, & Bracha, 1995). Thus, monochorionic monozygotic twins are much more likely to both be schizophrenic than are dichorionic monozygotic twins. This finding suggests that environ- mental factors also play a role in the development of schizophrenia. Monochorionic/monozygotic twins share the same blood circulation and are more likely to share infections than are dichorionic monozygotic twins. For this reason, a number of investigators have proposed that a prenatal viral infection, together with a genetic predisposition, can contribute to the development of schizo- phrenia later in life (Brown, 2011; Davis et al., 1995; Squires, 1997).

In summary, there appear to be a large number of biochemical, structural, and functional abnor- malities associated with schizophrenia. Dopamine overactivity and disturbed cannabinoid sys- tems have been implicated in this illness. Structural changes involving the prefrontal cortex, the thalamus, the hippocampus, and other limbic structures have been associated with schizophrenic symptoms. However, at the present time, it is unclear whether any of these abnormalities actually cause schizophrenia or whether they are the result of having schizophrenia. Some of these abnor- malities might even be produced by the medication that is administered to control schizophrenic symptoms, for example, problems with motor coordination. It may be, as Heinrichs (1993) has pointed out, that we will never find a unitary cause for schizophrenia because schizophrenia as we know it today may not be one single illness. Instead, schizophrenia may actually be many illnesses, which means that there will be different causes for each subtype of this devastating disorder.

12.5 Mood Disorders

Mood disorders are characterized by states of extreme moods in which the affected individual experiences severe depression or wild elation (mania). There are two categories of mood disorders, depressive disorders (in which the individual has one or more episodes of depression) and bipolar disorders (in which the individual experiences mood swings from severe depression to mania to depression, often with a return to normal mood in between). Earlier in this chapter, you learned about a number of depressive disorders that are associated with stress, including major depressive disorder. In this section we will examine the biological bases of bipolar disorder.

Bipolar Disorder

Bipolar disorder, or manic-depressive disorder as it is sometimes called, can present with psy- chotic symptoms and thus is discussed in this chapter with other psychotic disorders. Persons with bipolar disorder can show symptoms of depression at times and symptoms of mania, or high excitability, at other times. When in a manic state, persons with bipolar disorder will experience generally elevated mood and self-esteem, feeling that their abilities and/or beliefs are superior to those of others. They also have high levels of energy, don’t seem to require much sleep, and can have irrational thinking that is accompanied by poor judgment, delusions, and hallucinations. PET images of the brain of an individual with bipolar disorder indicate that the metabolic activity of the brain is increased on days of the manic phase and is decreased on days of the depressed phase.

A number of alterations in neurotransmitter and hormone functions have been associated with bipolar disorder. For example, earlier in this chapter you learned that major depressive disorder is associated with higher-than-normal levels of cortisol. The same is true of bipolar disorder, which indicates that regulation of the HPA axis may be disrupted in this disorder. Abnormalities of the

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CHAPTER 12Section 12.6 Chapter Summary

thyroid system have also been reported in patients with bipolar disorder (Nathan, Musselman, Schatzberg, & Nemeroff, 1995).

Abnormalities in serotonin, norepinephrine, and dopamine have been implicated in the cause of bipolar disorder. Serotonin activity is reduced in bipolar disorder, whereas norepinephrine activity is increased (Alda, 2004; Matthews & Harrison, 2012). This pattern differs from that observed in patients with major depressive disorder, who have depressed levels of serotonin and norepineph- rine activity. Increased dopamine levels have been observed in patients with psychotic mania and psychotic depression (Thase & Howland, 1995). In addition, bipolar disorder appears to be an inheritable condition and has been associated with genes on chromosomes 4, 18, and 21, as well as the X chromosome (Alsabban, Rivera, & McGuffin, 2011; Asherson et al., 1998; Berrettini et al., 1998; Curtis, Lebow, Lake, Katsanis, & Iacono, 1999; Kennedy, Basile, & Macciardi, 1998; Van Broeckhoven & Verheyen, 1999).

Treatment of Bipolar Disorder Treatment of bipolar disorder has centered on relieving the manic or depressive symptoms and providing prophylactic or preventive therapy (Mitchell & Malhi, 2002). Lithium is used to treat manic symptoms. It also works as a prophylactic treatment, stabilizing mood and preventing the individual with bipolar disorder from cycling into a manic or depressive phase. A number of other medications are sometimes prescribed, in conjunction with lithium or alone, for patients with bipolar disorder. For example, antidepressants may be prescribed for bipolar individuals experi- encing severe depressive symptoms. Antipsychotic agents may also be given to those individuals with symptoms of psychotic depression or mania, such as delusions or hallucinations. Atypical antipsychotic medications appear to be more effective and safer to use with lithium than are tradi- tional antipsychotics (Ghaemi & Goodwin, 1999). Anticonvulsant drugs, which are primarily used to treat seizure disorders, have also been found to be effective in the treatment of some individu- als with bipolar disorder (Schaffer, Schaffer, & Caretto, 1999).

12.6 Chapter Summary Defining Stress

• Stressors are people, objects, places, or events that disrupt homeostasis in the nervous system. Stress is a state of imbalance produced by a stressor.

• Information about stressors reaches the paraventricular nucleus of the hypothalamus by way of the nucleus of the solitary tract (which relays information from the gut and other internal receptors), the reticular formation, the periventricular gray areas (which process information about pain), the locus coeruleus, the raphe system, and the limbic system.

• When homeostasis is disrupted, the paraventricular nucleus of the hypothalamus organizes the body’s response.

The Response to Stress • The stress response has two purposes: (1) to prepare the person to respond to the stressor

(with increased blood flow, breathing rate, and alertness) and (2) to inhibit behaviors that interfere with dealing with the stressor (suppress sleep, eating, growth, and reproduction).

• The locus coeruleus responds to acute stress by activating the sympathetic nervous sys- tem, which stimulates the release of norepinephrine and epinephrine.

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CHAPTER 12Section 12.6 Chapter Summary

• The paraventricular nucleus responds to acute stress by releasing corticotropic-releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland.

• In response to ACTH, the cortex of the adrenal gland secretes cortisol. The main function of cortisol is to increase the availability of blood glucose to provide energy to deal with stress.

• The hypothalamic-pituitary-adrenal (HPA) axis involves the hypothalamus, the pituitary gland, and the adrenal gland.

• The relationship between the paraventricular nucleus and the locus coeruleus is charac- terized as a positive feedback loop because CRH released by the paraventricular nucleus increases activity of the locus coeruleus and norepinephrine from the locus coeruleus activates the paraventricular nucleus.

• The release of cortisol is tightly controlled. In the dexamethasone suppression test, admin- istration of dexamethasone suppresses the release of cortisol in healthy individuals but increases cortisol levels in depressed people.

• When an individual has successfully coped with a stressor, activation of the HPA axis and the locus coeruleus is terminated.

The Effect of Chronic Stress on Behavior • A chronic stressor occurs repeatedly or for prolonged periods of time. • Chronic stress affects the locus coeruleus–norepinephrine system, the HPA axis, the hip-

pocampus and prefrontal cortex, and behavior. • Habituation and sensitization are observed when an individual is exposed to chronic stress.

Habituation involves a decrease in the release of norepinephrine from the locus coeruleus in response to a chronic stressor. Sensitization involves an increase in the release of nor- epinephrine in response to a chronic stressor.

• Chronic stress can produce permanent changes in the HPA axis, impairing the control of cortisol release. In response to a chronic stressor, levels of glucocorticoids are persistently elevated, which has devastating effects on the brain and immune system.

• Chronic stress also affects brain structures such as the hippocampus, impairing learning and memory.

• Abnormal behaviors are associated with chronic or traumatic stress, including habitua- tion (failure of response to the stressor), sensitization (increase in responsiveness to a stressor), and memory impairment (disruption in encoding and retrieval of information associated with the chronic or traumatic stressor).

Disorders Associated with Stress • Dysregulation of the stress response can produce a number of disorders, including post-

traumatic stress disorder, major depressive disorder, and fatigue disorders. • In post-traumatic stress disorder, individuals have experienced one or more traumatic

events. The most definitive symptoms of post-traumatic stress disorder are vivid recur- rent memories for the traumatic event and flashbacks in which the person feels as if he or she is actually reexperiencing the traumatic event.

• The current treatment for post-traumatic stress disorder is antidepressant medication. • Major depressive disorder is a mood disorder characterized by a lack of energy, sad affect,

diminished interest in activities, and eating, sleeping, and cognitive disturbances. • About half of all people with major depressive disorder have excessively high cortisol levels,

indicating HPA dysfunction.

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CHAPTER 12Section 12.6 Chapter Summary

• A number of biological explanations of major depressive disorders have also been pro- posed. The most widely accepted explanation for the development of depression is the monoamine hypothesis, which is based on the observation that drugs that increase the availability of serotonin, norepinephrine, and dopamine relieve symptoms of depression.

• Hormonal abnormalities associated with major depressive disorder include higher-than- normal levels of cortisol, deficiencies in thyroid activity, low levels of estrogen (associated with menopause, childbirth, and the premenstrual phase of the menstrual cycle), and melatonin dysfunction associated with sleep abnormalities and phase advancement of the circadian rhythm.

• Treatment for major depressive disorder includes SSRIs, MAO inhibitors, and tricyclic anti- depressants, as well as electroconvulsive therapy and transcranial magnetic stimulation.

• Fatigue disorders are characterized by lethargy, a loss of drive, and an increase in veg- etative behaviors. These disorders include chronic fatigue syndrome, seasonal affective disorder, and fibromyalgia.

Psychoses • Psychoses are severe mental disorders in which thinking is disturbed and the affected indi-

vidual is not well oriented for person, time, and place. Dementia is a disorder that involves cognitive impairment and poor judgment.

• Schizophrenia is one of many different psychotic disorders. Other psychotic syndromes can be produced by infections, toxins, malnutrition, brain tumors, stimulant drugs, and traumatic injuries to the brain.

• Toxic psychoses are reversible psychoses produced by bacterial infections, which induce symptoms of restlessness, loss of orientation for time and place, hallucinations, inatten- tion, and perceptual distortions.

• Reversible psychoses are also produced by viral encephalitis (a brain inflammation caused by a virus) and meningitis (an inflammation of the meninges caused by an infection).

• Abuse of stimulants such as amphetamine, cocaine, and PCP can also produce reversible psychoses.

• An irreversible psychotic state called dementia pugilistica is observed in some boxers who have suffered repeated blows to the head.

Schizophrenia • The symptoms associated with schizophrenia can be classified into two categories: posi-

tive symptoms (behaviors observed in addition to normal behaviors, such as hallucina- tions, disturbed thinking, or delusions); or negative symptoms (diminished functioning, such as blunted mood, apathy, or poor judgment).

• Although the cause of schizophrenia is not known, a number of hypotheses have been advanced to explain the development of the disorder, including the dopamine hypothesis and the diathesis-stress model.

• Of these, the dopamine hypothesis, which emphasizes an imbalance in dopamine activ- ity in the brain, has received the most widespread attention. The dopamine hypothesis of schizophrenia is based on the observation that drugs used to treat schizophrenia are dopamine antagonists called neuroleptics.

• According to the modified dopamine hypothesis of schizophrenia, dopamine activity is diminished in the prefrontal cortex and is increased in the subcortical brain regions.

• The diasthesis-stress model of schizophrenia proposes that stress causes the release of cortisol from the adrenal cortex, which produces a massive increase in dopamine in the mesolimbic dopamine system of schizophrenic individuals.

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CHAPTER 12Web Links

• Imaging studies have revealed a number of structural abnormalities associated with schizophrenia, including enlarged ventricles and reductions in the size of the hippocam- pus, prefrontal cortex, and thalamus.

• The social and cognitive deficits of schizophrenia have been associated with damage to the dorsolateral prefrontal cortex, which is one of the last brain areas to mature.

• Investigators are studying a number of chromosomes for a possible gene locus for schizo- phrenia, although most researchers in the field believe that environmental factors such as prenatal exposure to a virus can also contribute to the development of schizophrenia.

• The genetic model that has found the most acceptance in explaining the inheritance of schizophrenia is the multifactorial model, which proposes that a combination of genetic and environmental factors produce schizophrenia.

Mood Disorders • Bipolar disorder is characterized by the presence of depressed symptoms for a period of

time and symptoms of mania (high excitability, elevated mood, and self-esteem) at other times. Bipolar disorder can present with psychotic symptoms, and treatment for this dis- order can include drugs to control manic, depressive, and/or psychotic symptoms.

• Abnormalities of serotonin, norepinephrine, and dopamine are associated with bipolar disorder.

• Treatment for bipolar disorder includes lithium, antidepressant medication, antipsychotic medication, and anticonvulsant medication.

Questions for Thought

1. Can you remember a time when you became ill after experiencing stress? 2. Which system is more important in dealing with stress: the locus coeruleus-norepinephrine

system or the HPA axis? 3. How can stress contribute to depression? 4. Can early childhood experiences affect future brain function? 5. What is the evidence that supports a multifactorial explanation for schizophrenia? 6. Why are schizophrenia and bipolar disorder often hard to differentiate? 7. How do hallucinations occur? 8. Describe the various pathways by which information about stressors reaches the para-

ventricular nucleus of the hypothalamus. 9. Describe the stress response initiated by the paraventricular nucleus.

10. Which brain systems are disturbed in post-traumatic stress disorder? 11. Identify the numerous hypotheses that have been proposed to explain schizophrenia. 12. What neurotransmitters and hormones have been implicated in the development of

major depressive disorder? 13. Compare the treatments for depression, schizophrenia, and bipolar disorder.

Web Links

The Brain and Behavior Research Foundation’s website is an excellent resource for information on many behavioral, psychological, and mood disorders, including post-traumatic stress disorder (PTSD), depression, schizophrenia, bipolar disorder, and many others. http://bbrfoundation.org/

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CHAPTER 12Key Terms

adrenocorticotropic hormone (ACTH) A hormone released by the paraventricular nucleus that stimulates the adrenal cortex to produce cortisol.

bipolar disorder A mood disorder in which the affected individual will show symptoms of depression at some times and symptoms of mania at others.

chronic stressor A stressor that occurs repeat- edly or for prolonged periods of time.

corticotropic-releasing hormone (CRH) A hormone released by the paraventricular nucleus that stimulates the release of ACTH from the anterior pituitary gland.

cortisol A steroid hormone derived from the cortex of the adrenal gland in humans.

dementia A disorder that involves an impair- ment of memory, thinking, and emotional function.

dementia pugilistica An irreversible psychotic state caused by brain trauma that results from repeated blows to the head.

dexamethasone A form of synthetic cortisol that inhibits the release of CRH and ACTH.

dexamethasone suppression test A test that assesses the ability of the HPA axis to regulate cortisol release, which can be used to diagnose depression.

diathesis-stress model of schizophrenia A theory on the development of schizophrenia that proposes that stress causes the release of cortisol from the adrenal cortex, which pro- duces a massive increase in dopamine in the mesolimbic dopamine system of schizophrenic individuals.

dichorionic Describes twins who each had his or her own placenta in the womb.

discordant Describes a scenario in which one twin is affected by a disorder but the other is not.

dopamine hypothesis A hypothesis advanced to explain the development of schizophrenia; it emphasizes an imbalance in dopamine activ- ity in the brain and is based on the observa- tion that drugs used to treat schizophrenia are dopamine antagonists called neuroleptics.

electroconvulsive therapy (ECT) A procedure, used to treat profoundly depressed patients, in which a high-voltage electrical current is passed through the patient’s brain, producing a seizure.

fatigue disorders A cluster of disorders characterized by lethargy, loss of drive, and an increase in vegetative disorders such as sleep- ing and eating.

habituation A decrease in the response of the nervous system to a repeated stimulus, such as a chronic stressor.

HPA axis The connection between the hypo- thalamus, pituitary gland, and adrenal gland.

hypothyroid condition A deficiency in thyroid activity.

major depressive disorder A mood disorder characterized by lethargy, sad affect, dimin- ished interest in all activities, cognitive distur- bances, and eating and sleeping abnormalities.

MAO inhibitor An antidepressant medication that inhibits the enzyme that breaks down monoamines, thereby increasing their avail- ability at the synapse.

The US Department of Veterans Affairs’ National Center for Post-Traumatic Stress Disorder (PTSD) offers numerous resources for those suffering from PTSD. http://www.ptsd.va.gov/

For information on the causes of chronic stress and tips for managing multiple kinds of stress, visit the website for the Centers for Disease Control and Prevention (CDC). http://www.cdc.gov/

Key Terms

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CHAPTER 12Key Terms

memory impairment A symptom associated with a number of disorders, including stress- related disorders, in which memory storage or retrieval is disrupted.

monoamine hypothesis of depression A theoretical explanation for the development of depression; it states that depression occurs when the availability or activity of one or more monoamines is reduced.

monochorionic Describes twins who shared the same placenta in the womb.

mood disorders Disorders that are charac- terized by states of extreme moods in which the affected individual experiences severe depression or mania; there are two categories of mood disorders, depressive disorders and bipolar disorders.

negative symptoms Those behaviors observed in schizophrenic individuals who demonstrate diminished functioning.

neuroleptics Dopamine antagonists used to treat schizophrenia.

paraventricular nucleus (PVN) A nucleus of neurons in the hypothalamus that organizes behavior, including eating, to respond to changes in internal body states.

phase advancement The shift of hormonal and other physiological functions several hours forward in time.

positive symptoms Those behaviors, such as hallucinations and delusions, observed in indi- viduals with schizophrenia that most people typically do not exhibit.

post-traumatic stress disorder (PTSD) A disorder caused by exposure to one or more traumatic events that is characterized by recurrent distressing memories of the event and feeling as if the traumatic event were recurring.

psychoses Severe mental disorders in which thinking is disturbed and the affected individ- ual is not well oriented for person, time, and place.

schizophrenia A psychotic disorder of unknown origin that is characterized by the disorganization of associations, producing dis- connected thoughts, words, and emotions.

sensitization An enhanced response observed when a chronically stressed individual is pre- sented with a new or different stressor.

stress A negative experience accompanied by characteristic emotional, behavioral, biochemi- cal, and physiological responses.

stressors Individuals, objects, places, or events that disrupt homeostasis in the nervous system.

toxic psychoses Psychotic disorders caused by bacteria that produce powerful toxins.

tricyclic antidepressant A medication that increases norepinephrine and serotonin avail- ability at the synapse.

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