Article Summaries

Chapter 2

Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development

Leo and George are identical twins. When they were born, George was a half-pound heavier than Leo, but otherwise they were so much alike that most people could not tell them apart. As they grew, friends and family used different tricks to distinguish them. If you were very observant, for instance, you might notice that George had a mole low on his left cheek, almost at the chin line. Leo also had a mole, but it was located just above his left cheekbone. Nonetheless, the boys were similar enough that they occasionally amused themselves by standing in for each other—fooling their third-grade teachers for a whole day of school or switching places with their junior prom dates. They had a shared passion for music and were gifted instrumentalists by their late teens. Yet, the boys also began to diverge more and more, both physically and psychologically. Leo’s hair was somewhat lighter than George’s by early adolescence; George was more agile on the soccer field. Leo began to excel in math and chose astronomy as his major in college. George became a theatre major and hoped for a career as a performer. Throughout their lives, George was more placid than Leo, who was more easily agitated. In early adulthood, Leo was diagnosed with schizophrenia. George suffered for his brother but never developed the disorder himself. Identical twins will help us tell the story of heredity and environment. They are called “identical” because they carry the same biological inheritance. You may assume that twins’ great similarity is due to their identical heredity—and that their differences must be somehow due to their environments. But what does that really mean? How can environments make a difference in traits such as the location of a mole or the shade of hair color? In fact, the similarities and the differences are the outcome of both heredity and environment. Neither can work alone.

The Nature–Nurture Illusion

Images like this one have been used by Gestalt psychologists to illustrate a perceptual phenomenon known as “figure-ground,” but we introduce it here because it provides a useful model for understanding the nature–nurture debate. No one would dispute that both heredity and environment influence human development, but when we focus on information about one of these contributors, the other seems to fade into the background. Evidence from both sides is compelling, and the helper may be persuaded to attend to one side of the argument to the exclusion of the other. The challenge is to guard against taking such a one-sided perspective, which allows for consideration of only half of the story. The most effective way that we know to avoid this kind of oversimplification is to understand the fundamentals of how geneenvironment interactions function. The “take away” message, as you will see, is that genes can do nothing without environmental input—and that environmental effects are shaped by genetic constraints. For helping professionals, learning about these intricate transactions makes clear that there is little value in placing “blame” for problematic outcomes (Fruzzetti, Shenk, & Hoffman, 2005). This knowledge also improves a helper’s ability to fashion therapeutic interventions that are realistic and valid for clients, and to help both clients and the general public to understand the complex interplay of heredity and environment in physical and behavioral outcomes (Dick & Rose, 2002).

Epigenesis and Coaction

Conception and Early Growth

You probably know that the inheritance of traits begins with conception, when a man’s sperm fertilizes a woman’s egg, called an ovum. Fertile women usually release an ovum from one of their ovaries into a fallopian tube during every menstrual cycle. The human ovum is a giant cell with a nucleus containing 23 chromosomes, the physical structures that are the vehicles of inheritance from the mother. The sperm, in contrast, is a tiny cell, but it too carries 23 chromosomes: the father’s contribution to inheritance. The ovum’s nucleus is surrounded by a great deal of cellular material called cytoplasm; the cytoplasm is loaded with a vast array of chemicals. During fertilization, the tiny sperm penetrates the outer membrane of the ovum and makes the long journey through the ovum’s cytoplasm to finally penetrate the nucleus, where the sperm’s outer structure disintegrates. The sperm’schromosomes become part of the nuclear material in the fertilized ovum, which is called a zygote.

The zygote contains 46 chromosomes, or more accurately, 23 pairs of chromosomes. One member of each pair comes from the mother (ovum) and one from the father (sperm). Twenty-two of these pairs are matched and are called autosomes. In autosome pairs, the two chromosomes look and function alike. The chromosomes of the 23rd pair are called sex chromosomes, because they have an important role to play in sex determination. In female zygotes, the 23rd pair consists of two matched chromosomes, called X chromosomes, but male zygotes have a mismatched pair. They have an X chromosome from their mothers but a much smaller Y chromosome from their fathers. Figure 2.2 presents two karyotypes, one from a male and one rom a female. A karyotype displays the actual chromosomes from human body cells as seen under a microscope, arranged in matching pairs and then photographed. Notice the 23rd pair is matched in the female example but not in the male example. (See Chapter 8 for a fuller description of the role of sex chromosomes in human development.) Chromosomes for a karyotype can be taken from cells anywhere in a person’s body, such as the skin, the liver, or the brain. A duplicate copy of the original set of 46 chromosomes from the zygote exists in nearly every body cell. How did they get there? The chromosomes in a zygote begin to divide within hours after conception, replicating themselves. The duplicate chromosomes pull apart, to opposite sides of the nucleus. The nucleus then divides along with the rest of the cell, producing two new cells, which are essentially identical to the original zygote. This cell division process is called mitosis (see Figure 2.3). Most importantly, mitosis produces two new cells, each of which contains a duplicate set of chromosomes. The new cells quickly divide to produce four cells, the four cells divide to become eight cells, and so on. Each of the new cells also contains some of the cytoplasm of the original fertilized egg. The cell divisions continue in quick succession, and before long there is a cluster of cells, each containing a duplicate set of the original 46 chromosomes. Over a period of about two weeks, the growing organism migrates down the mother’s fallopian tube, into the uterus, and may succeed in implantation, attaching itself to the uterine lining, which makes further growth and development possible. Now it is called an embryo. Defining Epigenesis and Coaction

If every new cell contains a duplicate set of the chromosomes from the zygote, and chromosomes are the carriers of heredity, then it would seem that every cell would develop in the same way. Yet cells differentiate during prenatal development and become specialized. They develop different structures and functions, depending on their surrounding environments. For example, cells located in the anterior portion of an embryo develop into parts of the head, whereas cells located in the embryo’s lateral portion develop into parts of the back, and so on. Apparently, in different cells, different aspects of heredity are being expressed. The lesson is clear: Something in each cell’s environment must interact with hereditary material to direct the cell’s developmental outcome, making specialization possible.

Biologists have long recognized that cell specialization must mean that hereditary mechanisms are not unilaterally in charge of development. Biologists first used the term epigenesis just to describe the emergence of specialized cells and systems of cells (like the nervous system or the digestive system) from an undifferentiated zygote. It was a term to describe the emergence of different outcomes from the same hereditary material, which all seemed rather mysterious (Francis, 2011). The term has evolved as biology has advanced. Biologists now define epigenesis more specifically as the set of processes by which factors outside of hereditary material itself can influence how hereditary material functions (Charney, 2012). These “factors” are environmental. They include the chemicals in the cytoplasm of the cell (which constitute the immediate environment surrounding the chromosomes), factors in the cells and tissues adjacent to the cell, and factors beyond the body itself, such as heat, light, and even social interaction. The epigenome is the full set of factors, from the cell to the outside world,that controls the expression of hereditary material. “The activity of the genes can be affected through the cytoplasm of the cell by events originating at any other level in the system, including the external environment” (Gottlieb, 2003, p. 7).

But, as you will see, the chemicals in the cytoplasm of the cell are themselves partly determined by the hereditary material in the chromosomes. These chemicals can move beyond a cell to influence adjacent cells and ultimately to influence behavior in the outside environment. Heredity and environment are engaged from the very beginning in an intricate dance, a process called coaction, so that neither one ever causes any outcome on its own. Gottlieb (e.g., 1992, 2003) emphasizes coaction in his epigenetic model of development, a multidimensional theory. He expands the concept of epigenesis, describing it as the emergence of structural and functional properties and competencies as a function of the coaction of hereditary and environmental factors, with these factors having reciprocal effects, “meaning they can influence each other”(Gottlieb, 1992, p. 161). Figure 2.4 gives you a flavor of such reciprocal effects. It will be familiar to you from Chapter 1. The Cell as the Scene of the Action

Understanding epigenesis starts with the cell. The chromosomes in the nucleus of the cell are made of a remarkable organic chemical called deoxyribonucleic acid or DNA. Long strands of DNA are combined with proteins called histones, wrapped and compacted to make up the chromosomes that we can see under a microscope. Chromosomes can reproduce themselves, because DNA has the extraordinary property of self-replication. Genes are functional units or sections of DNA, and they are often called “coded” sections of DNA. For each member of a pair of chromosomes, the number and location of genes are the same. So genes, like chromosomes, come in matched pairs, half from the mother (ovum) and half from the father (sperm).

You may have read reports in the popular press of genetic “breakthroughs” suggesting that scientists have identified a gene for a trait or condition, such as depression or obesity. These reports are extremely misleading. Genes provide a code that a cell is capable of “reading” and using to help construct a protein, a complex organic chemical, made up of smaller molecules called amino acids. Proteins in many forms and combinations influence physical and psychological characteristics and processes by affecting cell processes.

First, let’s consider the multistage process by which a gene’s code affects protein production. The complexity of this process can be a bit overwhelming to those of us not schooled in biochemistry, so we will only examine it closely enough to get a sense of how genes and environment coact. The DNA code is a long sequence of molecules of four bases (that is, basic chemicals, not acids): adenine, cytosine, guanine, and thymine, identified as A, C, G, and T. In a process called transcription, intertwined strands of DNA separate, and one of the strands acts as a template for the synthesis of a new, single strand of messenger ribonucleic acid or mRNA. In effect, the sequence of bases (the “code”) is replicated in the mRNA. Different sections of a gene’s code can be combined in different ways in the mRNA it produces, so that a single gene can actually result in several different forms of mRNA. In a second step, called translation, the cell “reads” the mRNA code and produces a protoprotein, a substance that with a little tweaking (e.g., folding here, snipping there) can become a protein. Here again, the cell can produce several protein variations from the same protoprotein, a process called alternative splicing (Charney, 2017). Different cell climates (combinations of chemicals) can induce different protein outcomes. One example will help here. A gene labeled the “POMC” gene is eventually translated into a protoprotein called “proopiomelanocortin” (thus the POMC abbreviation). This protein can be broken up into several different types of proteins. Cells in different parts of the body, with their different chemical workforces, do just that. In one lobe of the pituitary gland (a small gland in the brain), POMC becomes adrenocorticotropic hormone (ACTH), an important substance in the stress reaction of the body, as you will see later in this chapter. In another lobe of the pituitary gland, the cells’ chemical environments convert POMC into an opiate, called β-endorphin. In skin cells, POMC becomes a protein that promotes the production of melanin, a pigment (Francis, 2011; Mountjoy, 2015). You can see that the chemical environment of the cell affects the production of proteins at several points in the transcription and translation of coded genes. The entire transcription through translation process is referred to as gene expression. Whether or not genes will be expressed, and how often, is influenced by the environment of the cell. Most genes do not function full-time. Also, genes may be turned “on” in some cells and not in others. When a gene is on, transcription occurs and the cell manufactures the coded product or products. To understand how this works, let’s begin by noting that coded genes make up only a small portion (2% to 3%) of the DNA in a human chromosome; the rest is called “intergenic” DNA. How and when a gene’s code will be transcribed is partially regulated by sections of intergenic DNA, sometimes referred to as noncoded genes because they do not code for protein production. They function to either initiate or prevent the gene’s transcription. This process is called gene regulation. All of a person’s coded and noncoded DNA is referred to as his or her genome.

Gene Regulation: The Heart of Coaction

What provokes the gene regulation mechanisms to get the transcription process going? Some chemicals in the cells are transcription factors; they bind with the regulatory portions of the DNA, initiating the uncoiling of the strands of DNA at the gene location. This allows mRNA production to begin. Of course, it is more complicated than that. For example, transcription factors cannot bind to the regulatory DNA unless they first bind to another chemical called a receptor. Each kind of transcription factor binds to one or only a few receptors. Some receptors are found on the surface of a cell, binding with transcription factors coming from outside the cell. Other receptors are located inside the cell.

Let’s follow the functioning of one transcription factor to illustrate how gene regulation works. Hormones, like testosterone and estrogen, are transcription factors. We’ll focus on testosterone, produced in larger quantities by males than females. Testosterone is primarily produced in the testes, and then it circulates widely through the body via the blood. Only cells in some parts of the body, such as the skin, skeletal muscles, the testes themselves, and some parts of the brain, have receptors for testosterone. In each of these locations, testosterone binds with a different receptor. As a result, testosterone turns on different genes in different parts of the body. In a skeletal muscle, it triggers protein production that affects the growth of muscle fibers; in the testes, it turns on genes that influence sperm production.

Notice the bidirectionality of the processes we have been describing. Genes in the testes must be turned on by cellular chemicals (transcription factors and receptors) to initiate testosterone production. Then testosterone acts as a transcription factor turning on several different genes in different parts of the body where testosterone-friendly receptors are also produced. The cell’s chemical makeup directs the activity of the genes, and the genes affect the chemical makeup of the cell. What makes all of this much more complex is that many influences beyond the cell moderate these bidirectional processes. For example, winning a competition tends to increase testosterone production in men, whereas losing a competition tends to decrease it. The effects of winning and losing on testosterone are found in athletes and spectators, voters in elections, even stock traders (Carre, Campbell, Lozoya, Goetz, & Welker, 2013). Coaction is everywhere.

How can factors outside of the cell, even outside the organism, influence gene regulation? Here again, the biochemistry of complex sequences of events can be daunting to follow, but let’s consider a few fundamental mechanisms at the cellular level. One epigenetic change that can affect the expression of a gene is methylation, the addition of a methyl group (an organic molecule) to DNA, either to the coded gene or to regulatory DNA. Such methylation makes transcription of the gene more difficult. Heavy methylation may even turn off a gene for good.

Methylation is persistent, and it is passed on when chromosomes duplicate during cell division, although some events can cause demethylation. That is, methyl groups may detach from DNA. In this case, gene transcription is likely to increase. Another class of epigenetic changes affects histones, the proteins that bind with DNA to make up the chromosomes. How tightly bound histones are to DNA affects how likely it is that a coded gene will be transcribed, with looser binding resulting in more transcription. A variety of biochemicals can attach to, or detach from, histones, such as methyl groups (methylation and demethylation) and acetyl groups (acetylation and deacetylation). Each of these can affect how tightly histones and DNA are bound together. Methylation causes tighter binding and reduces gene transcription; demethylation causes looser binding and more transcription. Acetylation loosens the binding, typically increasing gene transcription, and deacetylation tends to tighten the bonds again. Methylation, acetylation, and their reverse processes are common modifications of histones, but there are many others as well, each of them having some effect on the likelihood that a gene will be transcribed. In addition, other cellular components can shut down the impact of a gene, such as short sections of RNA called micro RNAs (miRNAs) that attach themselves to mRNAs and block their translation into proteins. These processes are all part of the cell’s repertoire of DNA regulation devices (see Charney, 2012; Grigorenko, Kornilov, & Naumova, 2016).

When the environment outside the organism alters gene regulation, its effects on the body must eventually influence processes like methylation inside cells, so that certain genes in these cells become either more or less active. Let’s consider one example that demonstrates the impact that the social environment can have on cellular processes in the development of rat pups. There is reason to suspect that somewhat analogous processes may occur in primates as well, including humans. Rat mothers differ in the care they give their pups, specifically, in how much licking and grooming (LG) they do. In a series of studies, Michael Meaney and his colleagues (see Kaffman & Meaney, 2007; Meaney, 2010, for summaries) discovered that variations in mothers’ care during the first postnatal week alter the development of a rat pup’s hippocampus. The hippocampus is a part of the brain with a central role to play in reactions to stress. The offspring of “high LG” mothers grow up to be more mellow—less reactive to stressful events—than the offspring of “low LG” mothers. Of course, these differences could simply indicate that the “high LG” mothers pass on to their offspring genes that influence low stress reactivity. But Meaney and colleagues were able to show that it is actually the mothers’ care that makes the difference. They did a series of cross-fostering studies: They gave the offspring of high LG mothers to low LG mothers to rear, and they gave the offspring of low LG mothers to high LG mothers to rear. Rat pups reared by high LG foster mothers grew up to be more mellow than rat pups reared by low LG foster mothers. When Meaney and others studied the biochemistry of the rats’ response to stress, they found that pups who receive extra maternal care respond to stress hormones (glucocorticoids) differently than other rats. (See later sections of this chapter for a description of the stress response in mammals, including humans.) Ordinarily, when glucocorticoids are produced, the body has been aroused for immediate action—fight or flight. But the body also launches a recovery from this arousal, reacting to reduce the further production of stress hormones. The hippocampus is the part of the brain that initiates the recovery. In rats that experience high LG as pups, just a tiny quantity of glucocorticoids is sufficient for the hippocampus to trigger a rapid reduction in the production of more stress hormones, resulting in a minimal behavioral response to stress.

Now you will see the importance of epigenesis. A mother rat’s external stimulation of her pup causes changes in the regulatory DNA of the pup’s hippocampus. One of the changes is that the affected DNA is demethylated. Because of this demethylation, regulatory DNA turns on a gene that produces a stress hormone receptor in hippocampus cells. With larger amounts of the stress hormone receptor, the hippocampus becomes more sensitive, reacting quickly to small amounts of stress hormone, which makes the rat pup recover quickly from stressful events, which makes it a mellow rat. So maternal rearing, an environmental factor, changes the activity of the rat pup’s DNA by demethylating it, which changes the pup’s brain, affecting its behavioral response to stress. This change is permanent after the first week of life. What is truly remarkable is that this cascade of changes has consequences for the next generation of rat pups. Mellow female rats (who have experienced extra mothering as pups) grow up to be mothers who give their pups extra grooming and licking. And so their pups are also mellow—for life. Researchers are exploring how human infants’ physiological responses to stress may be similarly calibrated by parental closeness and care (Gunnar & Sullivan, 2017; Tang, Reeb-Sutherland, Romeo, & McEwen, 2014; see Chapter 4). Epigenesis is one reason that identical twins can have the same genotype (type of gene or genes), but not have identical phenotypes (physical and behavioral traits). Their genotypes are exactly the same because they come from a single zygote. Usually after a zygote divides for the first time, the two new cells “stick together” and continue the cell division process, leading to a multi-celled organism. But in identical twinning, after one of the early cell divisions, one or more cells separate from the rest for unknown reasons. The detached cell or cells continue(s) the cell division process. Each of the new clusters of cells that form can develop into a complete organism, producing identical, or monozygotic twins. Yet, even though they have the same genotypes, their environments may diverge, even prenatally (e.g., Ollikainen et al., 2010). Different experiences throughout their lifetimes can affect the cellular environments of the twins, and these effects can cause differences in how, and how often, some genes are expressed. As a result, as they age twins tend to diverge more and more both physically and behaviorally (Kebir, Chaumette, & Krebs, 2018).

A large, longitudinal study of both monozygotic and dizygotic twins illustrates how variable epigenetic effects can be at the cellular level. Dizygotic twins, often called fraternal twins, are conceived when a mother releases two ova in the same menstrual cycle, and each ovum is fertilized by a separate sperm. Thus, these twins develop from two separate zygotes, and like any two siblings, they share about 50% of their genes on average. Wong, Caspi, and their colleagues (2010) studied a large number of both kinds of twins, taking cell samples when the children were 5 and 10 years old. For each child, the researchers measured the methylation of the regulatory DNA of three genes that affect brain function and behavior. You might expect a great deal of concordance (similarity between members of a pair of twins) in methylation, given that the members of each pair were exactly the same age and were growing up in the same families. Yet, the differences in the twins’ experiences were enough to lead to substantial discordance (differences between members of a pair of twins) in methylation for both monozygotic and dizygotic twins. The investigators also found that gene methylation tended to change for individual children from age 5 to age 10. These changes sometimes involved increased methylation and sometimes involved decreased methylation. Differences between twins, and changes with age within each child, could partly be a result of random processes. But much of this variation is likely to be caused by the impact that differences in life experiences have on the functioning of each child’s cells. More About Genes

What significance is there to having matched pairs of genes, one from each parent? One important effect is that it increases hereditary diversity. The genes at matching locations on a pair of chromosomes often are identical, with exactly the same code, but they can also be slightly different forms of the same gene, providing somewhat different messages to the cell. These slightly different varieties of genes at the same location or locus on the chromosome are called alleles. For example, Tom has a “widow’s peak,” a distinct point in the hairline at the center of the forehead. He inherited from one parent an allele that would usually result in a widow’s peak, but he inherited an allele that usually results in a straight hairline from the other parent. These two alleles represent Tom’s genotype for hairline shape. This example illustrates that two alleles of the same gene can have a dominant- recessive relationship, with only the first affecting the phenotype. In this case, the impact of the second gene allele is essentially overpowered by the impact of the first allele, so that the phenotype does not reflect all aspects of the genotype. Tom is a carrier of a recessive gene that could “surface” in the phenotype of one of his offspring. If a child receives two recessive alleles, one from each parent, the child will have the recessive trait. For instance, in Table 2.1, a mother and a father both have a widow’s peak. Each of the parents has one dominant gene allele for a widow’s peak and one recessive allele for a straight hairline, so they are both carriers of the straight hairline trait. On the average, three out of four children born to these parents will inherit at least one widow’s peak allele. Even if they also inherit a straight hairline allele, they are likely to have a widow’s peak. But one child out of four, on average, will inherit two straight hairline alleles, one from each parent. Without a widow’s peak allele to suppress the effects of the straight hairline allele, such a child is likely to have a straight hairline, probably much to the surprise of the parents if they were unaware that they were carriers of the straight hairline trait! Two different alleles will not necessarily have a dominant-recessive relationship. Sometimes alleles exhibit codominance, producing a blended or additive outcome. For example, Type A blood is the result of one gene allele; Type B blood is the result of a different allele. If a child inherits a Type A allele from one parent and a Type B allele from the other parent, the outcome will be a blend—Type AB blood.

Gene alleles at a single gene location can heavily influence some traits, as you have seen with hairline shape and blood type. But nearly all traits are influenced by the protein products of many different gene pairs. These genes may even be located on different chromosomes. Such polygenic effects make the prediction of traits from one generation to another very difficult and suggest that any one pair of gene alleles has a very modest influence on phenotypic outcomes.

Height, skin color, and a host of other physical traits are polygenic, and most genetic influences on intelligence, personality, psychopathology, and behavior appear to be of this kind as well. One large study described 31 genes contributing to the onset of menstruation in girls, and more have been found (Tu et al., 2015). Polygenic determination on such a large scale is typical of gene influences on single traits. Do not lose sight of the importance of epigenesis in any of the gene effects we have been describing. Regulation of genes by the cellular environment, influenced by environments outside the cell, can trump dominance-recessive or codominance relationships between alleles. You will learn about some examples as we consider genetic sources of atypical development.

Atypical Development

Typical prenatal development is an amazing story of orderly and continuous progress from a single fertilized cell to a highly differentiated organism with many interconnected and efficiently functioning systems. The 9-month gestational period spans the period of the zygote (about 2 weeks), from fertilization to implantation; the period of the embryo (from about the 3rd to 8th week), when most of the body’s organ systems and structures are forming; and finally, the period of the fetus (from the 9th week until birth), when the reproductive system forms, gains in body weight occur, and the brain and nervous system continue to develop dramatically. (Figure 2.5 illustrates major developments during the periods of prenatal development.) Typical development depends on the genome to code for the products that the body needs to grow and function normally; and it depends on the environment to provide a normal range of inputs, from nutrients to social interactions, in order for gene expression to be properly timed and regulated. The principle of coaction operates at every level of the developmental drama—with genes and environment in constant communication.

What role does the gene/environment dance play in atypical development? Deviations in either the genome or the environment can push the developing organism off course. In this section you will learn about genetic and chromosomal deviations as well as environmental distortions that can alter development as early as the period of the zygote. But remember: Neither ever works alone. The effects of the genome depend on the environment and vice versa. Watch for indicators of this coaction.

The Influence of Defective Gene Alleles

Recessive, Defective Alleles

In sickle-cell anemia, the red blood cells are abnormally shaped, more like a half moon than the usual, round shape. The abnormal cells are not as efficient as normal cells in carrying oxygen to the tissues. Individuals with this disorder have breathing problems and a host of other difficulties that typically lead to organ malfunctions and, without treatment, to early death. Fortunately, modern treatments can substantially prolong life span. A recessive gene allele causes the malformed blood cells. If one normal gene allele is present, it will be dominant, and the individual will not have sickle-cell anemia. Many hereditary disorders are caused by such recessive, defective alleles, and it is estimated that most people are carriers of three to five such alleles. Yet, most of these illnesses are rare because to develop them an individual has to be unlucky enough to have both parents be carriers of the same defective allele and then to be the one in four (on average) offspring to get the recessive alleles from both parents. Table 2.2 lists some examples of these illnesses. Some recessive, defective genes are more common in certain ethnic or geographic groups than in others. The sickle-cell anemia gene, for example, is most common among people of African descent. For some of these disorders, tests are available that can identify carriers. Prospective parents who have family members with the disorder or who come from groups with a higher than average incidence of the disorder may choose to be tested to help them determine the probable risk for their own offspring. Genetic counselors help screen candidates for such testing, as well as provide information and support to prospective parents, helping them to understand genetic processes and to cope with the choices that confront them—choices about testing, childbearing, and parenting (e.g., Madlensky et al., 2017).

Dominant, Defective AllelesSome genetic disorders are caused by dominant gene alleles, so that only one defective gene need be present. Someone who has the defective gene will probably have the problem it causes, because the effects of a dominant gene allele overpower the effects of a recessive allele. Suppose that such an illness causes an early death, before puberty. Then, the defective, dominant allele that causes the illness will die with the affected individual because no offspring are produced. When these alleles occur in some future generation, it must be through mutation, a change in the chemical structure of an existing gene. Sometimes mutations occur spontaneously, and sometimes they are due to environmental influences, like exposure to radiation or toxic chemicals (Strachan & Read, 2000). For example, progeria is a fatal disorder that causes rapid aging, so that by late childhood affected individuals are dying of “old age.” Individuals with progeria usually do not survive long enough to reproduce. When the disease occurs, it is caused by a genetic mutation during the embryonic period of prenatal development, so that while it is precipitated by a genetic defect, it does not run in families.

Some disorders caused by dominant, defective alleles do not kill individuals affected by them in childhood, and thus can be passed on from one generation to another. When one parent has the disease, each child has a 50% chance of inheriting the dominant, defective gene from that parent. Some of these disorders are quite mild in their effects, such as farsightedness. Others unleash lethal effects late in life. Among the most famous is Huntington’s disease, which causes the nervous system to deteriorate, usually beginning between 30 and 40 years of age. Symptoms include uncontrolled movements and increasingly disordered psychological functioning, eventually ending in death. In recent years the gene responsible for Huntington’s disease has been identified, and a test is now available that will allow early detection, before symptoms appear. Unfortunately, there is no cure. The offspring of individuals with the disease face a difficult set of dilemmas, including whether to have the test and, if they choose to do so and find they have the gene, how to plan for the future. Again, genetic counselors may play a critical role in this process (Hines, McCarthy Veach, & LeRoy, 2010).

Often, having a dominant defective allele, or two recessive, defective alleles, seems like a bullet in the heart: If you have the defective gene or genes you will develop the associated disorder. Yet epigenetic effects can alter the course of events. The disorder may not develop if epigenetic processes prevent the transcription of defective alleles or the translation of mRNA to a protein. Consider another rodent example. A fat, diabetic yellow mouse, and a slim, healthy brown mouse can actually be identical genetically. Both mice carry a dominant “Agouti” gene allele that causes the problems of the yellow mouse. But in the brown mouse, that troublesome allele is heavily methylated. Dolinoy (2008) demonstrated that this epigenetic change can happen during fetal development if the mother mouse is fed a diet rich in folate, choline, and B12. Such a diet promotes methylation of the Agouti allele, shutting it down.

Research on the role of epigenesis in the expression of defective genes is in its infancy (Heijmans & Mill, 2012; Mazzio & Soliman, 2012). Yet it promises to help solve some medical mysteries, such as why occasionally one monozygotic twin develops a hereditary disease but the other does not, or why some people with the same genetic defect have milder forms of a disease than others (e.g., Ollikainen et al., 2010).

Such outcomes illustrate that coaction is always in play. This is true for behavioral disorders as well. For example, Caspi and his colleagues (2002) studied people with a range of variations in the “MAOA” gene. This gene provides the cell with a template for production of the MAOA enzyme, a protein that metabolizes a number of important brain chemicals called neurotransmitters, like serotonin and dopamine. (You’ll learn more about neurotransmitters later in this chapter.) Its effect is to inactivate these neurotransmitters, a normal process in neurological functioning. Apparently, while these neurotransmitters are critical to normal brain function, too much of them is a problem. Animals become extremely aggressive if the MAOA gene is deleted so that the enzyme cannot be produced. In humans, different alleles of the MAOA gene result in different amounts of MAOA enzyme production. Could alleles that cause low levels of production increase aggression and antisocial behavior in humans? Most research has suggested no such relationship. But Caspi and colleagues hypothesized that child rearing environment might affect how different gene alleles function. Specifically, they hypothesized that early abusive environments might make some MAOA alleles more likely to have negative effects on development. They studied a sample of New Zealand residents who had been followed from birth through age 26. They identified each person’s MAOA alleles and looked at four indicators of antisocial, aggressive behavior, such as convictions for violent crimes in adulthood. Finally, they looked at each person’s child-rearing history. Caspi and colleagues did find a link between gene alleles that result in low levels of MAOA enzyme production and aggression, but only when the individual carrying such an allele had experienced abuse as a child. For people with no history of abuse, variations in the MAOA gene were not related to adult aggressive behavior. This appears to be epigenesis in action. (See Ouellet-Morin et al., 2016 for related studies.)

Polygenic Influences

As with most normal characteristics, inherited disorders are usually related to more than one gene, such that some combination of defective alleles at many chromosomal sites predisposes the individual to the illness. Like all polygenic traits, these disorders run in families, but they cannot be predicted with the precision of disorders caused by genes at a single chromosomal location. Most forms of muscular dystrophy are disorders of this type. Polygenic influences have also been implicated in diabetes, clubfoot, some forms of Alzheimer’s disease, and multiple sclerosis, to name just a few. As we noted earlier, genetic effects on behavioral traits are typically polygenic. This appears to be true for most mental illnesses and behavioral disorders, such as alcoholism, schizophrenia, and clinical depression (e.g., Halldorsdottir & Binder, 2017). For example, the MAOA gene is only one of several that are associated with antisocial behavior (Ouellet-Morin et al., 2016). Genes linked to serious behavioral problems and disorders affect brain function. It will not surprise you to learn that whether and when these genes or their normal variants are expressed also depend on epigenetic modifications that are associated with a person’s experiences at different points in development, and researchers have begun to identify the biochemical processes involved (e.g., Matosin, Halldorsdottir, & Binder, 2018; Shorter & Miller, 2015).

The Influence of Chromosomal

Abnormalities

Occasionally, a zygote will form that contains too many chromosomes, or too few, or a piece of a chromosome might be missing. Problems in the production of either the ovum or the sperm typically cause these variations. Such zygotes often do not survive. When they do, the individuals usually have multiple physical or behavioral problems. The causes of chromosomal abnormalities are not well understood. Either the mother or the father could be the source, and ordinarily, the older the parent, the more likely that an ovum or sperm will contain a chromosomal abnormality. Among the most common and well known of these disorders is Down syndrome (also called trisomy 21), caused by an extra copy of chromosome number 21. The extra chromosome in this syndrome usually comes from the ovum, but about 5% of the time it comes from the sperm. Children with Down syndrome experience some degree of intellectual impairment, although educational interventions can have a big impact on the severity of cognitive deficits. In addition, these children are likely to have several distinctive characteristics, such as a flattening of facial features, poor muscle tone, small stature, and heart problems (Marchal et al., 2016). Table 2.3 provides some examples of disorders influenced by chromosomal abnormalities. Teratogenic Influences

From conception, the environment is an equal partner with genes in human development. What constitutes the earliest environment beyond the cell? It is the mother’s womb, of course, but it is also everything outside of the womb—every level of the physical and social and cultural context. For example, if a mother is stressed by marital conflict, her developing fetus is likely to be influenced by the impact that her distress has on the biochemical environment of the uterus. (For simplicity, we will use the term fetus to refer to the prenatal organism in this section, even though technically it might be a zygote or an embryo.) Even the ancient Greeks, like Hippocrates who wrote 2,500 years ago, recognized that ingestion of certain drugs, particularly during the early stages of pregnancy, could “weaken” the fetus and cause it to be misshapen. Environmental substances and agents that can harm the developing fetus are called teratogens. The name comes from the Greek and literally means “monstrosity making.”

The fetus is surrounded by a placenta, an organ that develops from the zygote along with the embryo; it exchanges blood products with the baby through the umbilical cord. The placenta allows nutrients and oxygen from the mother’s blood to pass into the baby’s blood and allows carbon dioxide and waste to be removed by the mother’s blood, but otherwise it usually keeps the two circulatory systems separate. Teratogens can cross the placental barrier from mother to fetus. They include some drugs and other chemicals, certain disease organisms, and radioactivity. The list of known teratogens is quite lengthy, so we have presented in Table 2.4 a summary of the main characteristics of a few of these agents. Consider, for example, alcohol. Alcohol has been called “the most prominent behavioral teratogen in the world” (Warren & Murray, 2013) because its use is common across the globe. “Behavioral” here refers to the fact that the fetus’s exposure is a result of the mother’s behavior. Conservative estimates are that 2% to 5% of babies born in the United States suffer negative effects from prenatal exposure to alcohol. Worldwide, “it is the leading cause of preventable developmental disabilities” (Hoyme et al., 2016, p. 2).

Physicians have suspected the risks of drinking during pregnancy for centuries, but only in the last few decades has there been broad recognition of those risks (Warren, 2013). Identifying teratogens is difficult, because their effects are variable and unpredictable. Maternal drinking during pregnancy can cause no harm to the fetus, or it can result in one or more of a wide range of problems, called fetal alcohol spectrum disorders (FASD). Most children on this spectrum experience some intellectual or behavioral problems. These can include specific learning disabilities, language delays, or memory problems, or more global and severe cognitive deficits, as well as difficulties with impulse control, hyperactivity, social understanding, and so on (Wilhoit, Scott, & Simecka, 2017). More severe intellectual and behavioral impairments are typically accompanied by gross structural brain anomalies. Prenatal development of the brain and the face are interrelated, so it is not surprising that alcohol exposure is also associated with facial abnormalities (del Campo & Jones, 2017). The most extreme of the disorders is fetal alcohol syndrome (FAS), which is identified by a unique facial configuration with three especially likely characteristics: small eye openings so that the eyes look widely spaced, a smooth philtrum (the ridge between the nose and upper lip), and a thin upper lip. Other likely facial variations are a flattened nasal bridge, a small nose, and unusual ear ridges. Cognitive deficits are often accompanied by a small head and sometimes recurrent seizures. Children with FAS typically show growth retardation, either pre- or postnatally, both in weight and height. Many organ systems can be affected in addition to the central nervous system; problems with the heart, kidneys, and bones are common (see Table 2.4).

Teratogens impact fetal development by modifying both intracellular and intercellular activity in the placenta and in the fetus. Teratogens may sometimes actually cause mutations in coded DNA (Bishop, Witt, & Sloane, 1997). But more often they seem to operate by making epigenetic modifications to DNA and thereby altering gene expression. For example, changes in methylation patterns (both methylation of some genes and demethylation of others) have been found in children with FASD for clusters of genes that are important for neurodevelopment and behavior (e.g., Chater-Diehl, Laufer, & Singh, 2017).

The teratogenic effects of alcohol are so variable, ranging from none at all to FAS, because a whole set of other factors moderates any teratogen’s impact. The unpredictability of teratogenic effects provides a good illustration of the multidimensionality of development. Damaging outcomes may be reduced or enhanced by the timing of prenatal exposure, the mother’s and fetus’s genomes (genetic susceptibility), the amount of exposure (dosage), and the presence or absence of other risks to the fetus.

Timing of Exposure

The likelihood and the extent of teratogenic damage depends on when in development exposure occurs (refer again to Figure 2.5). In the first few months, the structure of major organ systems is formed. Brain structures could show unusual and/or insufficient development if a fetus is exposed to a teratogen like alcohol in the first trimester. If the exposure occurs in the last trimester, obvious structural anomalies are not as likely, but brain and other organ functions are still in jeopardy, so that processes such as learning and behavior regulation, vision, and hearing are still vulnerable. Whereas “there is no safe trimester to drink alcohol” (Hoyme et al., 2016, p. 2), some teratogens seem to be harmful primarily at certain times. For example, thalidomide is a sedative introduced in the 1950s and widely prescribed to pregnant women for morning sickness. When used in the first trimester, it caused serious limb deformities (Ito, Ando, & Handa, 2011). Before thalidomide was identified as the culprit, it had affected the lives of over 10,000 children around the world.

Genetic Susceptibility

Not all fetuses are equally susceptible to a teratogen’s effects. Both the mother’s and the baby’s genes play a role in sensitivity or resistance to a teratogen. For example, FASD is slightly more prevalent among boys than girls (May et al., 2014), and there is some indication from animal studies that maternal drinking affects males’ social behavior more than females’ (e.g., Rodriguez et al., 2016). For some teratogens, such as nicotine, researchers have identified specific genes, and gene alleles, that can increase or decrease the effects of prenatal exposure (e.g., Price, Grosser, Plomin, & Jaffee, 2010). This is, of course, an illustration of coaction.

Dosage

Larger amounts of a teratogenic agent and longer periods of exposure generally have greater effects than smaller doses and shorter periods. Alcohol’s effects are dose dependent. Mothers who drink more days per week increase their babies’ chances of FAS (Gupta, Gupta, & Shirisaka, 2016). Mothers’ binge drinking seems to be especially harmful, although no “safe” dose has been found for alcohol (May et al., 2013). Note also that the effects of any amount of alcohol ingestion are always more potent for the fetus than they are for the mother. In other words, the fetus may have crossed a toxic threshold even if the mother experiences few or very mild alcohol-related effects. Consequently, the U.S. Department of Health and Human Services (2015) and the American Academy of Pediatrics (Williams & Smith, 2015) recommend that women refrain from drinking alcohol throughout a pregnancy. “No amount of alcohol intake during pregnancy can be considered safe” (Hoyme et al., 2016, p. 2).

Number of Risk Factors

As you learned in Chapter 1, risk factors are more likely to cause problems the more numerous they are. The developing organism can often correct for the impact of one risk factor, but the greater the number, the less likely it is that such a correction can be made. The negative effects of teratogens can be amplified when the fetus or infant is exposed to more than one. For example, poor maternal nutrition tends to increase the risk of FAS (Keen et al., 2010). Often, pregnant women who drink also smoke. They are also more likely to be poor, so it is fairly common that their babies have been exposed to multiple risks. The teratogenic effects of cocaine were once thought to include congenital malformations until researchers recognized that pregnant women who use cocaine frequently consume other drugs, such as alcohol, tobacco, marijuana, or heroin, and they often have poor nutrition as well. Cocaine users also tend to be poor and to experience more life stress during and after pregnancy than other women. Although prenatal cocaine exposure in the absence of other risk factors can have effects on some aspects of behavior, many of the outcomes once attributed to cocaine alone seem to result from combinations of risk factors (Terplan & Wright, 2011).

Nutritional Influences

Teratogens are problematic because they add something to the ordinary fetal environment, intruding on the developing system and driving it off course. But what happens when contextual factors that belong in the ordinary fetal environment are missing or in short supply? When food sources are lacking in protein or essential vitamins and minerals during prenatal and early postnatal development, an infant’s physical, socioemotional, and intellectual development can be compromised (e.g., Aboud & Yousafzai, 2015), and epigenetic alterations seem to be at the root of these developmental problems (Champagne, 2016).

In a classic intervention study, Rush, Stein, and Susser (1980) provided nutritional supplements to pregnant women whose socioeconomic circumstances indicated that they were likely to experience inaadequate diets. At age 1, the babies whose mothers received a protein supplement during pregnancy performed better on measures of play behavior and perceptual habituation (which is correlated with later intelligence) than those whose mothers received a high-calorie liquid or no supplement at all.

Are there longer-term behavioral consequences of inadequate prenatal nutrition? Some research does reveal enduring effects. When the fetus is unable to build adequate stores of iron, for example, the infant is likely to show signs of anemia by 4 to 6 months of age, and even if corrected, a history of anemia has been shown to affect later school performance. One large longitudinal study demonstrates the many long-term effects that famine can have on the developing fetus. During World War II, people in the western part of The Netherlands experienced a serious food shortage as a result of a food embargo imposed by Germany over the winter of 1944–45. At the end of the war, in 1945, scientists began studying the cohort of babies born to pregnant women who experienced the famine, comparing them either to siblings who were not born during the famine, or to another sample of Dutch people who were born in the same period, but who were not exposed to the famine (e.g., Lumey & van Poppel, 2013). Among the many long-term consequences of prenatal exposure to the famine are: higher rates of obesity by young adulthood; increased risk of schizophrenia and mood disorders, such as depression; more high blood pressure, coronary artery disease, and type II diabetes by age 50; and the list goes on (see Francis, 2011, for a summary). These long-term consequences appear to result from epigenetic changes at the cellular level. For example, one group of investigators found significant demethylation of a gene that codes for “insulin-like growth factor II” (IGF2) in individuals exposed to the famine very early in gestation, when methylation of this particular gene usually occurs (Heijmans et al., 2008). In another study, methylation and demethylation changes in six genes were identified. The kind of change depended on the gene, the gender of the individual, and the timing of fetal exposure to the famine (Tobi et al., 2009). It is not surprising that prenatal nutrition has such effects, given what we have learned about the effects of postnatal nutrition on children’s functioning. We have known for decades that children who experience severe protein and calorie shortages at any age may develop kwashiorkor, characterized by stunted growth, a protuberant belly, and extreme apathy (Roman, 2013). Therapeutic diets can eliminate the apathy of kwashiorkor, but cognitive impairments often persist. Some research indicates that even much less severe nutritional deficits may have impacts on children’s cognitive functioning. An intriguing study of changes in the food supplied to New York City schools provides a strong illustration (Schoenthaler, Doraz, & Wakefield, 1986). In a three-stage process, from 1978 to 1983, many food additives and foods high in sugar (sucrose) were eliminated from school meals, so that children’s consumption of “empty calories” was reduced, and, presumably, their intake of foods with a higher nutrient-to-calorie ratio increased. With each stage of this process, average achievement test scores increased in New York City schools, with improvements occurring primarily among the children who were performing worst academically.

Findings such as these suggest that children whose prenatal and postnatal environments are short on protein and other essential nutrients may not achieve the levels of behavioral functioning that they could have with adequate diets. But the long-range impact of early diet, like the effects of teratogens, is altered by the presence or absence of other risk and protective factors. Some studies have found, for example, that if children experience poor early nutrition because of extreme poverty or major events such as war, they are less likely to have cognitive impairments the more well educated their parents are (e.g., Boo, 2016). As with other risk factors, the effects of poor nutrition are lessened by other more benign influences. We note again that it is in combination that risk factors do the most harm. (See Box 2.2 for further discussion of this phenomenon.) One heartening consequence is that when we intervene to reduce one risk factor, such as malnutrition, we may actually reduce the impact of other negative influences on development as well.

The Developing Brain

Now that you have a sense of the genetic and epigenetic processes at work in development, we can begin to examine behavioral change over time. We will first focus on the physical system that underlies behavior: the central nervous system and, especially, the brain. Helping professionals can better understand how their clients think, feel, and learn if they give some attention to the workings of this marvelously complex system. We will guide you through the story of prenatal and immediate postnatal brain development. Then we will examine in depth a key process mediated by the brain: the stress and adaptation system. As you will see throughout this text, stress, and individual differences in the response to stress, are at the core of what helpers must understand about human development. Early Prenatal Brain Development

When you were just a 2-week-old embryo, your very existence still unknown to your parents, cells from the embryo’s upper surface began to form a sheet that rearranged itself by turning inward and curling into a neural tube. This phenomenon, called neurulation, signaled the beginning of your central nervous system’s development. Once formed, this structure was covered over by another sheet of cells, to become your skin, and was moved inside you so that the rest of your body could develop around it. Around the 25th day of your gestational life, your neural tube began to take on a pronounced curved shape. At the top of your “C-shaped” embryonic self, three distinct bulges appeared, which eventually became your hindbrain, midbrain, and forebrain. (See Figure 2.6.)

Within the primitive neural tube, important events were occurring. Cells from the interior surface of the neural tube reproduced to form neurons, or nerve cells, that would become the building blocks of your brain. From about the 40th day, or 5th week, of gestation, your neurons began to increase at a staggering rate—one quarter of a million per minute for 9 months—to create the 100 billion neurons that make up a baby’s brain at birth. At least half would be destroyed later either because they were unnecessary or were not used. We will have more to say about this loss of neurons later.

Your neurons began to migrate outward from their place of birth rather like filaments extending from the neural tube to various sites in your still incomplete brain. Supporting cells called glial cells, stretching from the inside of the neural tube to its outside, provided a type of scaffolding for your neurons, guiding them as they ventured out on their way to their final destinations. Those neurons that developed first migrated only a short distance from your neural tube and were destined to become the hindbrain. Those that developed later traveled a little farther and ultimately formed the midbrain. Those that developed last migrated the farthest to populate the cerebral cortex of the forebrain. This development always progressed from the inside out, so that cells traveling the farthest had to migrate through several other already formed layers to reach their proper location. To build the six layers of your cortex, epigenetic processes pushed each neuron toward its ultimate address, moving through the bottom layers that had been already built up before it could get to the outside layer. (See Box 2.1 and Figures 2.7 and 2.8.) Box 2.1: The Major Structures of the Brain

Multidimensional models of mental health and psychopathology now incorporate genetics and brain processes into their conceptual frameworks. Thus, a working knowledge of the brain and its functioning should be part of a contemporary helper’s toolkit. Consumers of research also need this background to understand studies that increasingly include brain-related measures. Here we present a very short introduction to some important brain areas and describe their related functions. The complex human brain can be partitioned in various ways. One popular way identifies three main areas that track evolutionary history: hindbrain, midbrain, and forebrain. Bear in mind, however, that brain areas are highly interconnected by neural circuitry despite attempts to partition them by structure or function. In general, the more complex, higher-order cognitive functions are served by higher-level structures while lower-level structures control basic functions like respiration and circulation.

Beginning at the most ancient evolutionary level, the hindbrain structures of medulla, pons, cerebellum, and the reticular formation regulate autonomic functions that are outside our conscious control. The medulla contains nuclei that control basic survival functions, such as heart rate, blood pressure, and respiration. Damage to this area of the brain can be fatal. The pons, situated above the medulla, is involved in the regulation of the sleep–wake cycle. Individuals with sleep disturbances can sometimes have abnormal activity in this area. The medulla and the pons are also especially sensitive to an overdose of drugs or alcohol. Drug effects on these structures can cause suffocation and death. The pons transmits nerve impulses to the cerebellum, a structure that looks like a smaller version of the brain itself. The cerebellum is involved in the planning, coordination, and smoothness of complex motor activities such as hitting a tennis ball or dancing, in addition to other sensorimotor functions.

Within the core of the brainstem (medulla, pons, and midbrain) is a bundle of neural tissue called the reticular formation that runs up through the midbrain. This, together with smaller groups of neurons called nuclei, forms the reticular activating system, that part of the brain that alerts the higher structures to “pay attention” to incoming stimuli. This system also filters out the extraneous stimuli that we perceive at any point in time. For example, it is possible for workers who share an office to tune out the speech, music, or general background hum going on around them when they are involved in important telephone conversations. However, they can easily “perk up” and attend if a coworker calls their name. The midbrain also consists of several small structures (superior colliculi, inferior colliculi, and substantia nigra) that are involved in vision, hearing, and consciousness. These parts of the brain receive sensory input from the eyes and ears and are instrumental in controlling eye movement.

The forebrain is the largest part of the brain and includes the cerebrum, thalamus, hypothalamus, and limbic system structures. The thalamus is a primary way station for handling neural communication, something like “information central.” It receives information from the sensory and limbic areas and sends these messages to their appropriate destinations. For example, the thalamus projects visual information, received via the optic nerve, to the occipital lobe of the cortex (discussed later in this box). On both sides of the thalamus are structures called the basal ganglia. These structures, especially the nucleus accumbens, are involved in motivation and approach behavior.

The hypothalamus, situated below the thalamus, is a small but important area that regulates many key bodily functions, such as hunger, thirst, body temperature, and breathing rate. Lesions in areas of the hypothalamus have been found to produce eating abnormalities in animals, including obesity or starvation. It is also important in the regulation of emotional responses, including stress-related responses. The hypothalamus functions as an intermediary, translating the emotional messages received from the cortex and the amygdala into a command to the endocrine system to release stress hormones in preparation for fight or flight. We will discuss the hypothalamus in more detail in the section on the body’s stress systems.

Limbic structures (hippocampus, amygdala, septum, and cingulate cortex) are connected by a system of nerve pathways (limbic system) to the cerebral cortex. Often referred to as the “emotional brain,” the limbic system supports social and emotional functioning and works with the frontal lobes of the cortex to help us think and reason. The amygdala rapidly assesses the emotional significance of environmental events, assigns them a threat value, and conveys this information to parts of the brain that regulate neurochemical functions. The structures of the limbic system have direct connections with neurons from the olfactory bulb, which is responsible for our sense of smell. It has been noted that pheromones, a particular kind of hormonal substance secreted by animals and humans, can trigger particular reactions that affect emotional responsiveness below the level of conscious awareness. We will have more to say about the workings of the emotional brain and its ties to several emotional disorders in Chapter 4.

Other limbic structures, notably the hippocampus, are critical for learning and memory formation. The hippocampus is especially important in processing the emotional context of experience and sensitive to the effects of stress. Under prolonged stress, hippocampal neurons shrink and new neurons are not produced. The hippocampus and the amygdala are anatomically connected, and together they regulate the working of the HPA axis (described later in this chapter). In general, the amygdala activates this stress response system while the hippocampus inhibits it (McEwen & Gianaros, 2010).

The most recognizable aspect of the forebrain is the cerebrum, which comprises two thirds of the total mass. A crevice, or fissure, divides the cerebrum into two halves, like the halves of a walnut. Information is transferred between the two halves by a network of fibers comprising the corpus callosum. These halves are referred to as the left and right hemispheres. Research on hemispheric specialization (also called lateralization), pioneered by Sperry (1964), demonstrated that the left hemisphere controls functioning of the right side of the body and vice versa. Language functions such as vocabulary knowledge and speech are usually localized in the left hemisphere, and visual–spatial skills are localized on the right. Recently, this research was introduced to lay readers through a rash of popular books about left brain–right brain differences. Overall, many of these publications have distorted the facts and oversimplified the findings. Generally the hemispheres work together, sharing information via the corpus callosum and cooperating with each other in the execution of most tasks. There is no reliable evidence that underlying modes of thinking, personality traits, or cultural differences can be traced exclusively to hemispheric specialization.

Each hemisphere of the cerebral cortex can be further divided into lobes, or areas of functional specialization (see Figure 2.8). The occipital lobe, located at the back of the head, handles visual information. The temporal lobe, found on the sides of each hemisphere, is responsible for auditory processing. At the top of each hemisphere, behind a fissure called the central sulcus, is the parietal lobe. This area is responsible for the processing of somatosensory information such as touch, temperature, and pain. Finally, the frontal lobe, situated at the top front part of each hemisphere, controls voluntary muscle movements and higher-level cognitive functions.

The prefrontal cortex (PFC) is the part of the frontal lobe that occupies the front or anterior portion. This area is involved in processes like sustained attention, working memory, planning, decision making, and emotion regulation. Generally, the PFC plays a role in regulation and can moderate an overactive amygdala as well as the activity of the body’s stress response system. Another important regulatory pathway involves the anterior cingulate cortex (ACC), a structure in the middle of the brain above the corpus callosum. The ACC mediates cognition and affect.

Impaired connections between the ACC and the amygdala are related to higher levels of anxiety and neuroticism, and lower ACC volume has been found in depressed patients (Kaiser, Andrews-Hanna, Wager, & Piagalli, 2015). The size of the various brain regions and the integrity of their circuitry play a role in individuals’ cognition, affect, and behavior. Scientists have discovered that neurons sometimes need to find their destinations (for example, on the part of the cortex specialized for vision) before that part of the cortex develops. It’s a little like traveling in outer space. Or as Davis (1997) has suggested, “It’s a bit like an arrow reaching the space where the bull’s-eye will be before anyone has even set up the target” (pp. 54–55). Certain cells behave like signposts, providing the traveling neurons with way stations as they progress on their journey. Neurons may also respond to the presence of certain chemicals that guide their movements in a particular direction.

About the fourth month of your prenatal life, your brain’s basic structures were formed. Your neurons migrated in an orderly way and clustered with similar cells into distinct sections or regions in your brain, such as in the cerebral cortex or in the specific nuclei. The term nucleus here refers to a cluster of cells creating a structure, rather than to the kind of nucleus that is found in a single cell. An example is the nucleus accumbens, part of the basal ganglia in the brain’s interior.

As we have seen, one important question concerns just how specialization of cells in different regions of the brain occurs and what directs it. This issue is complex and is the subject of intense investigation (Arlotta & Vanderhaeghen, 2017). However, most available evidence supports the view that cortical differentiation is an epigenetic process, primarily influenced by the kinds of environmental inputs the cortex receives. In other words, the geography of the cortex is not rigidly built in, but responds to activity and experiences by making changes in its structural organization (LaFrenier & MacDonald, 2013). This principle was demonstrated by researchers who transplanted part of the visual cortex of an animal to its parietal lobe (O’Leary & Stanfield, 1989). The transplanted neurons began to process somatosensory rather than visual information. Studies such as these show that the brain is amazingly malleable and demonstrates great neuroplasticity, particularly during early stages of development. In time, however, most cells become specialized for their activity, and it is harder to reverse their operation even though neuroplasticity continues to exist throughout life.

Structure and Function of Neurons

The neurons in your brain are among nature’s most fantastic accomplishments. Although neurons come in various sizes and shapes, a typical neuron is composed of a cell body with a long extension, or axon, which is like a cable attached to a piece of electronic equipment. The axon itself can be quite long relative to the size of the cell’s other structures because it needs to connect or “wire” various parts of the brain, such as the visual thalamus to the visual cortex. At the end of the axon are the axon terminals, which contain tiny sacs of chemical substances called neurotransmitters. Growing out from the cell body are smaller projections, called dendrites, resembling little branches, which receive messages or transmissions from other neurons. (See Figure 2.9.) So how do brain cells “talk” to each other? Even though we speak of wiring or connecting, each neuron does not actually make physical contact with other neurons but remains separate. The points of near contact where communication occurs are called synapses. Communication is a process of sending and receiving electrochemical messages. Simply put, when a neuron responds to some excitation, or when it “fires,” an electrical impulse, or message, travels down the axon to the axon terminals. The sacs in the axon terminals containing neurotransmitters burst and release their contents into the space between the neurons called the synaptic gap. Over a hundred different neurotransmitters have been identified, and many more are likely to be. Among those that have been widely studied are serotonin, acetylcholine, glutamate, gamma-amino butyric acid (GABA), epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Some of these are more common in specific parts of the brain than in others. They are literally chemical messengers that stimulate the dendrites, cell body, or axon of a neighboring neuron to either fire (excitation) or stop firing (inhibition). For example, glutamate is an excitatory transmitter that is important for transmission in the retina of the eye; GABA is an inhibitory transmitter that is found throughout the brain. Helpers should know that psychotropic drugs, such as anti-depressants and anti-psychotics, affect synaptic transmission. They change the availability of a neurotransmitter, either increasing or decreasing it, or they mimic or block a neurotransmitter’s effects. When neurons fire, the speed of the electrical impulse is greater if the axon is wrapped in glial cells forming a white, insulating sheath that facilitates conduction. This phenomenon, called myelination, begins prenatally for neurons in the sensorimotor areas of the brain but happens later in other areas. The term white matter mainly refers to bundles of myelinated axons, while grey matter refers to bundles of cell bodies, dendrites, and unmyelinated axons.

Myelination is a key aspect of brain maturation in childhood and adolescence, but it also continues into adulthood. Generally, the more myelination there is, the more efficient brain functions are. Changes in myelination accompany some kinds of learning and experience throughout life. Researchers have found white matter density changes in specific brain areas when people learn to juggle or they practice the piano intensively. Extended social isolation of either infant or adult mice leads to myelin deterioration accompanied by behavioral dysfunctions (see Klingseisen & Lyons, 2017).

Neurons are not “wired together” randomly. Rather, they are joined via their synaptic connections into groups called circuits. Circuits are part of larger organizations of neurons, called systems, such as the visual and olfactory systems. Two main types of neurons populate these systems, projection neurons, which have axons that extend far away from the cell body, and interneurons, which branch out closer to the local area. The intricate neural fireworks described earlier are going on all the time in your brain. Perhaps as you read this chapter, you are also listening to music and drinking a cup of coffee. Or you may be distracted by thoughts of a telephone conversation that you had earlier. The neuronal circuitry in your brain is processing all these stimuli, allowing your experiences to be perceived and comprehended.

Later Prenatal Brain Development

To return to your prenatal life story, your neurons began to fire spontaneously around the fourth month of gestation. This happened despite a lack of sensory input. Even though your eyes were not completely formed, the neurons that would later process visual information began firing as though they were preparing for the work they would do in a few months’ time. By the end of the second and beginning of the third trimesters, your sense organs had developed sufficiently to respond to perceptual stimulation from outside your mother’s womb. Sounds were heard by 15 weeks. Not only did you learn to recognize the sound of your mother’s voice, but you also became familiar with the rhythms and patterns of your native language. In a classic study, DeCasper and colleagues conducted a project in which they directed pregnant women to recite a child’s nursery rhyme out loud each day from the 33rd to the 37th week of pregnancy (DeCasper, Lecaneut, Busnel, Granier-Deferre, & Maugeais, 1994). During the 38th week, the women were asked to listen to a recording of either the familiar rhyme or an unfamiliar one while their fetuses’ heart rates were being measured. The fetal heart rates dropped for the group who heard the familiar rhyme, signifying attention, but did not change for the group who heard the unfamiliar one. This result suggests that the fetus can attend to and discriminate the cadence of the rhyme. Studies such as this one should not be misinterpreted to mean that the fetus can “learn” as the term is commonly used. No one has suggested that the fetus can understand the poem. However, what this and other similar studies do indicate is an early responsivity to experience that begins to shape the contours of the brain by establishing patterns of neural or synaptic connections.

By your 25th week, you could open and close your eyes. You could see light then rather like the way you see things now when you turn toward a bright light with your eyes closed. At this point in development a fetus turns his head toward a light source, providing his visual system with light stimulation that probably promotes further brain development. Sensory experience has been found to be critical for healthy brain development after birth, and vision provides a good example of this principle. The interplay between neurons and visual experience was documented dramatically in another classic research project by Wiesel and Hubel (1965), who, in a series of experiments with kittens for which they won the Nobel Prize, showed that early visual deprivation has permanent deleterious effects. They sewed shut one of each kitten’s eyes at birth so that only one eye was exposed to visual input. Several weeks later when the eyes were reopened, the kittens were found to be permanently blinded in the eye that had been deprived of stimulation. No amount of intervention or aggressive treatment could repair the damage. The neurons needed visual stimulation to make the proper connections for sight; in the absence of stimulation, the connections were never made, and blindness resulted. The existence of a critical or sensitive period for visual development was established. This research prompted surgeons to remove infant cataracts very shortly after birth instead of waiting several years, so that permanent damage to sight could be avoided.

Sensory systems, such as the auditory and visual systems, influence each other. Their eventual development is a function of their interrelationships (Murray, Lewkowicz, Amedi, & Wallace, 2016). The integration of these systems seems to serve the baby well in making sense of his world. So, for example, when a young infant sees an object he also has some sense of how it feels. Or when a 2-year-old watches lip movements, vocal sounds are easier to decipher.

Postnatal Brain Development

After your birth, your neurons continued to reproduce at a rapid pace, finally slowing down around 12 months of age. For many years it was assumed that neurons do not reproduce after early infancy. Newer research, however, has definitively documented the growth of new neurons throughout the life span in some parts of the brain (see Lux & van Ommen, 2016). These adult neural stem cells (NSCs) are generated in two principal brain areas, the subventricular zone (SVZ) located near the ventricles and in part of the hippocampus called the dentate gyrus. SVZ neurons migrate to the olfactory bulb where they appear to maintain its functioning by generating interneurons. New hippocampal neurons appear to integrate into existing networks that involve learning and memory. The location, migration patterns, and the ways adult neural stem cells integrate with existing neural networks are subjects of intense investigation. Available research indicates that increases and decreases in hippocampal neurogenesis during adulthood depend on environmental factors, including enriching stimulation, stress, and physical activity (Charney, 2012).

Brain growth after birth is also the result of the formation of new synapses. The growth spurt in synapses reflects the vast amount of learning that typically occurred for you and for most babies in the early months of postnatal life. Some areas of your developing brain experienced periods of rapid synaptic growth after birth, such as in the visual and auditory cortices, which increased dramatically between 3 and 4 months. In contrast, the synapses in your prefrontal cortex developed more slowly and reached their maximum density around 12 months. As you will see in the following sections, infants make rapid strides in cognitive development at the end of the first year, at about the time when prefrontal synapses have reached their peak density.

The growth of these connections was the product of both internal and external factors. Certain chemical substances within your brain, such as nerve growth factor, were absorbed by the neurons and aided in the production of synapses. Your own prenatal actions, such as turning, sucking your thumb, and kicking, as well as the other sensory stimulation you experienced, such as sound, light, and pressure, all contributed to synaptic development. However, as we noted earlier, the major work of synaptogenesis, the growth of new synapses, took place after birth, when much more sensory stimulation became available. You arrived in the world with many more neurons than you would ever need. Over the next 12 years or so, through a process known as neural pruning, many neurons would die off and many synaptic connections would be selectively discarded. Some of these neurons migrated incorrectly and failed to make the proper connections, rendering them useless. Some of the synaptic connections were never established or were rarely used, so they ultimately disappeared as well. What counts most after birth is not the sheer number of neurons, but the number and strength of the interconnections. Those branching points of contact that remained to constitute your brain would be a unique reflection of your genetics and epigenetics, the conditions of your prenatal period, the nutrition you received, and your postnatal experience and environment. This rich network of connections is what makes your thinking, feeling brain, and its structure depends heavily upon what happens to you both before and after your birth.

You may be wondering how to account for the simultaneous processes of synaptogenesis and pruning, which seem to be acting at cross-purposes. What is the point of making new synaptic connections if many neurons and connections will just be culled eventually? In a classic analysis, Greenough and Black (1992) argued that synaptic overproduction occurs when it is highly likely that nature will provide the appropriate experience to structure the development of a particular system. For example, many animal species, as well as humans, go through a predictable sequence of activities designed to provide information for the brain to use in the development of vision. These include opening eyes, reaching for and grasping objects, and so on. This type of development depends upon environmental input that is experience-expectant because it is experience that is part of the evolutionary history of the organism and that occurs reliably in most situations. Hence, it is “expected.” Lack of such experience results in developmental abnormalities, as we saw in the kitten experiments performed by Wiesel and Hubel. The timing of this particular kind of experience for nervous system growth is typically very important; that is, there is a critical period for such experience-expectant development. Nature may provide for an overabundance of synapses because it then can select only those that work best, pruning out the rest.

When human infants are neglected or deprived of typical parental caregiving, the cognitive consequences can be severe. One reason may be that ordinary caregiving behaviors—repeated vocalizations, facial expressions, touch—are necessary for experience-expectant development. McLaughlin and colleagues have argued that such caregiving helps direct infant’s attention to relevant stimuli in the environment. This facilitates experience-expectant learning of basic associations between vocal sounds and situations, between actions and outcomes, and so on, that other learning depends upon (McLaughlin, Sheridan, & Nelson, 2017).

In contrast to overproducing synapses in anticipation of later experience, some synaptic growth occurs as a direct result of exposure to more individualized kinds of environmental events. This type of neural growth is called experience-dependent. The quality of the synaptic growth “depends” upon variations in environmental opportunities. Stimulating and complex environments promote such growth in rat pups and other mammals (e.g., Kolb, Gibb, & Robinson, 2003). It seems likely that the same is true for infants and children. Imagine what might be the differences in synaptic development between children raised by parents who speak two different languages in their home and children raised by those who speak only one, for example. Experience-dependent processes do not seem to be limited to sensitive periods but can occur throughout the life span. Connections that remain active become stabilized, whereas those that are not used die out. This type of experientially responsive synaptic growth and the concomitant changes in brain structure it induces have been linked to learning and the formation of some kinds of memory. This process fine-tunes the quality of brain structure and function and individualizes the brain to produce the best person–environment fit (Bialystock, 2017).

Clearly, your early experiences played a vital role in the functional and structural development of your brain. Your experiences helped stimulate the duplication of neurons in some parts of your brain, and they prompted synaptogenesis and pruning. These processes contribute to the plasticity of brain development, which can be quite remarkable. Suppose, for example, that you had suffered an injury to your left cerebral cortex during infancy. You can see in Box 2.1 that ordinarily, the left cerebral cortex serves language functions. Yet when the left hemisphere is damaged in infancy, the right hemisphere is very likely to take over language functions. Your language acquisition might have been delayed by an early left hemisphere injury, but by 5 or 6 years of age you would most likely have caught up with other children’s language development. Adult brains also exhibit some plasticity after brain injury, but nothing as dramatic as we see in children (e.g., Gianotti, 2015; Stiles, 2001). Understanding of postnatal brain development has improved dramatically over the last few decades, spurred by modern technologies. In Table 2.5, we describe several of the approaches that are recurrently mentioned in this and later chapters.

The Developing Stress and Adaptation System

Learning about early brain development can help you to understand how development proceeds more generally. You have seen that the intricate interplay of genes and the many layers of environment, from the cell to the outside world, produces an organized brain and nervous system. That system interacts with all other bodily systems and continuously re-organizes in response to experience. Development is a life-long process of adaptation, which is adjustment to change: changing bodily needs as well as new and different opportunities and challenges from the environment. Some changes and the adaptations that we make to them are predictable and repetitious. For example, our bodies’ needs for food and rest change predictably during the course of a day, and we respond by eating and sleeping on relatively consistent schedules. But much of our experience requires adjusting to less predictable events, which can alter our brains and behavior, sometimes temporarily and sometimes more permanently. Developmental science is particularly focused on understanding the process of stress, adaptation responses to challenges, and how stress helps to produce healthy and unhealthy life trajectories.

What Is Stress?

Stress is a word that most of us use often, usually to describe what we feel when life seems challenging or frightening or uncertain. We call our feelings “stress” when it looks like we will be late for class or work, or we discover that there is not enough money to cover the rent, or we find a skin lesion that might be cancerous. Scientists and practitioners also use the term to cover lots of situations, and as a result, it can sometimes be difficult to pin down its meaning. An early researcher, Hans Selye (e.g., 1956), first used the term stress and helped launch its worldwide popularity as well as the breadth of its use. It was Selye who characterized stress as a bodily response to any change or demand (i.e., an adaptation), and a stressor as an event that initiates such a response. Stressors can be noxious or positive; the key is that they induce adaptation.

Modern researchers often make more fine-grained distinctions among types of stress. McEwen and McEwen (2016) summarize these as good stress, tolerable stress, and toxic stress. Good stress is “the efficient, acute activation and efficient turning off of the normal physiological stress response when one faces a challenge” (p. 451)—a challenge such as giving a talk or managing the drive to work through heavy traffic. Tolerable stress is a more chronic physiological response, likely to be triggered by more serious and long-lasting threats such as losing a job, but the chronic response is turned off eventually as the individual finds ways to cope, relying on a range of strengths, such as self-esteem, supportive relationships, and so on. Toxic stress is the same kind of chronic response, but it fails to “turn off”—the individual is unable to cope effectively. Determining whether an experience or event is a stressor is complicated by the fact that what is stressful is, to some degree, in the eye of the beholder. Although most people would agree that certain situations are more traumatic than others, individual differences in what people view as stressful are influenced by prior learning, memories, expectations, and perceptions about one’s ability to cope. Also, whether a potential stressor triggers a stress reaction, and the strength and duration of that reaction, depend on many contextual factors, especially social context. A person’s social standing matters; so does the presence of a loving, supportive caregiver or partner or friend (Rutter, 2016).

The concept of allostasis is helpful in understanding where stress fits into a person’s overall physical and psychological development. Allostasis refers to the regulation of many interacting bodily processes affected by stressors, from the sleep–wake cycle to blood pressure to digestion, as the individual adjusts to experiences. Allostatic load is the accumulation of the effects of multiple stressors; and allostatic overload refers to pathological changes brought on by toxic stress (McEwen & McEwen, 2016).

Some general points about allostasis are important to keep in mind. Adaptations change our brains. The physiological events involved in the stress response alter gene expression and a variety of cellular and intercellular processes. We learn and change, sometimes in ways that are positive, sometimes not. Acute, mild to moderate stressors that are typically associated with good outcomes, such as exercise or giving a speech, are often brain-enhancing. The “good stress” they generate can promote synaptic or neuron growth. When stress is chronic and/or intensely negative, brain changes can make us less resilient (more cognitively rigid), reducing the capacity to learn in the future. Dendrites are lost, synaptic and neuron growth is suppressed, and processes that promote recovery from stress can be impaired. The costs of allostatic load mount up, leading to a host of mental and physical problems (McEwen et al., 2015).

Before we consider the pathological effects of toxic stress, let’s review the typical response we call stress, or “good stress.” It involves a complicated, multilevel set of physiological reactions, governed by many parts of the brain. Because what initiates stress is affected by an individual’s cognitions and context, it is clear that cortical areas such as the prefrontal cortex play a role. Parts of the brain involved in emotional and social processing, especially the amygdala and basal ganglia, are pivotal, as are closely related areas, such as the hippocampus and hypothalamus.

The Architecture of the Stress Response

A stressor is first detected via an interconnected network of sensory areas in the cortex, thalamus, and amygdala, the brain’s specialist in threat detection (LeDoux, 2012). The amygdala is involved in virtually all fear conditioning and works to jumpstart multiple stress-related networks peripheral to the central nervous system. Two major peripheral systems subject to this central control are the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. The SNS releases important chemicals such as epinephrine (adrenaline) and norepinephrine (noradrenalin) that send a burst of energy to those organs necessary for “fight or flight” (e.g., heart, lungs) while diverting energy from less necessary systems (e.g., growth, reproduction, digestion). Adrenaline is instrumental in causing the well-known effects of arousal, such as racing heart and sweaty palms. Once the threat has passed, the parasympathetic nervous system (PSNS) counteracts the sympathetic system’s effects, down regulating its activity. The heart rate returns to base rate and ordinary bodily functions go back to normal functioning.

The HPA axis is activated when the amygdala stimulates the hypothalamus. The hypothalamus communicates the danger message to the pituitary gland by means of the chemical messenger corticotropin releasing factor (CRF). The message is read by the pituitary as a sign to release adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then makes its way to the adrenal glands, situated atop the kidneys, which receive the message to release cortisol. Cortisol is a key glucocorticoid hormone produced by humans. Glucocorticoid receptors (GRs) are located in organs and tissues throughout the body and brain. When cortisol and other glucocorticoids bind with these receptors, physiological responses to stressors are triggered. One of these, for example, is a reduction in inflammation, the body’s normal response to a disease pathogen or irritant. Another is an increase in glucose production, increasing energy levels. Cortisol in the bloodstream also travels back to the brain, forming an important feedback loop. Cortisol binds to GRs in the amygdala and the hippocampus, efficiently shutting down the acute stress response and helping the body to return to a normal state (Spencer & Deak, 2016).

Toxic Stress and Allostatic

Overload

You can see now that allostasis engages many regulatory systems, altering physiological functions temporarily as the body deals with an acute stressor. The typical “fight or flight” reaction rights itself quickly so that normal functions like digestion and fighting infection can proceed. It should not be surprising then, that chronic and intense stress can be toxic, creating allostatic load or overload with the potential to alter many physical and psychological functions, sometimes permanently. For example, cortisol secretion is part of many non–stress-related bodily processes (Spencer & Deak, 2016), and under normal circumstances, cortisol levels in the bloodstream (which can be measured in saliva samples) show a regular daily pattern of morning elevation and afternoon decline. This pattern is often disrupted in chronically stressed individuals. They might show elevated cortisol levels throughout the day or unusual daily variations (e.g., high afternoon levels). Allostatic overload also tends to make the stress response itself less efficient. It might remain activated even when a threat has ended or it may produce a blunted response to threat (Rutter, 2016). Allostatic overload also affects the immune system. Chemical messengers of the immune system, called cytokines, are produced during the immune response. These proteins can be either pro-inflammatory or anti-inflammatory in nature. Inflammation, it should be noted, is the body’s protective response to infection or injury. When appropriate, inflammation is adaptive; however, when inflammatory processes persist unremittingly, mental and physical diseases can result. During an acute stress response, as you have seen, cortisol reduces the body’s immune response. But chronic activation of the stress-response system revamps the immune system, which becomes under-responsive to cortisol so that pro-inflammatory cytokines are then under-regulated. Persistent inflammation increases the risk of health problems over time, such as cardiovascular disease, type 2 diabetes, and rheumatoid arthritis. Along with other changes associated with toxic stress, it is also linked to an increased risk of psychopathology, such as depression and schizophrenia (Danese & Baldwin, 2017).

Toxic stress may do its damage largely by fostering epigenetic alterations that modify gene expression (e.g., Provencal & Binder, 2015; Tyrka, Ridout, & Parade, 2016). For example, children who are maltreated by their caregivers are victims of toxic stress. They experience many of the short- and long-term effects of allostatic overload that we have described. In a study of low income, school-aged children, researchers found substantial differences in methylation patterns for maltreated children as compared to nonmaltreated children. Especially noteworthy is that maltreated children showed methylation differences for genes that are linked to risk for many physical and psychiatric disorders (Cicchetti, Hetzel, Rogosch, Handley, & Toth, 2016).

The impact of stressors on the development of the stress response and all of the systems involved in that response begins in utero. In the prenatal period, stress experienced by the mother has teratogenic effects on the developing fetus. Maternal stress increases the risk of a wide range of negative outcomes, from miscarriage to low birth weight to postnatal neural and behavioral dysregulation, such as learning problems and increased anxiety levels. When glucocorticoids such as cortisol are present at typical, daily levels during pregnancy, they play a positive role in the development of a fetus’s organs and tissues, especially in the third trimester. But human and animal studies have shown that when a fetus is overexposed prenatally to a mother’s stress hormones, brain development can be altered, especially in the HPA axis (Provencal & Binder, 2015). Even mild prenatal maternal stress in later pregnancy has been shown in animal studies to increase DNA methylation levels in the frontal cortex and hippocampus; heavy doses of maternal stress dramatically decrease methylation in the same areas. In either case, epigenetic changes are induced in brain areas that are key to normal stress reactivity and to many cognitive functions as well (Bock, Wainstock, Braun, & Segal, 2015). In humans and other mammals, the HPA axis is relatively immature at birth, and the environment can play a major role in its further development. You saw earlier in this chapter that early maternal caregiving can alter the reactivity of a rat pup’s stress response for life. Rat pups who get lots of maternal licking and grooming produce more of the critical receptors in the hippocampus that bind with glucocorticoids, ending acute stress responses quickly. These pups mature into mellow adults (Meaney, 2010). With human babies, researchers have found that more sensitive maternal caregiving in infancy is linked to lower cortisol levels during and after exposure to stressors over the first three years of life (Laurent, Harold, Leve, Shelton & van Goozen, 2016). This suggests that just as in rats, the care babies receive early in life can alter the architecture of their stress response. In Box 2.2 and in the Applications section of this chapter, you will learn more about the long-term consequences of prenatal exposure to stressors and of chronic stress early in life. You will also learn how helpers might intervene to mitigate those consequences. Box 2.2: Do Numbers Matter? Early Adverse Experiences Add Up

No doubt about it, early experience matters. In this chapter, we describe some of the processes that explain how adverse experiences exert harm. This knowledge raises serious concerns for practitioners. Which experiences pose risks for children’s development? Is there a tolerable level of stress for children? Are there certain times during development when risks exert maximal influence? At first glance, these questions seem impossible to answer. Each individual possesses a unique blend of strengths and vulnerabilities, making exact prediction unlikely. Nonetheless, some large-scale epidemiological investigations of this question could provide useful guidance for clinicians and public health experts.

Several longitudinal investigations have looked at numbers of stressful experiences in children’s lives and their subsequent relationship to health or adversity. A western Australian study (Robinson et al., 2011) followed a group of 2,868 pregnant women from 16 weeks gestation (updated at 34 weeks gestation) until their children were adolescents. During their pregnancies, mothers were asked about the number and types of stressors they experienced. Stressors included financial difficulties, job loss, deaths of relatives, residential moves, marital difficulties, separation, or divorce. The researchers controlled for maternal SES, age, ethnic status, smoking, drinking, education, and history of emotional problems. Child variables, including gestational age, birth weight, and histories of breastfeeding, were also controlled. Assessments of children’s physical, emotional, and behavioral functions were made at ages 1, 2, 3, 5, 8, 10, and 14.

Results showed that offspring of mothers who reported zero to two stressors during pregnancy did not differ significantly on measures of internalizing problems (e.g., depression, low self-esteem) and externalizing problems (e.g., acting out, aggressive, disruptive behaviors). However, children whose mothers experienced three or more stressful events during their pregnancies exhibited significantly higher levels of internalizing and externalizing problems at every assessment period across the prospective study compared to the group with fewer stressors. Externalizing problems were more pronounced in children whose mothers experienced four events compared to children of mothers reporting no stress. If mothers experienced five or more events, higher rates of child internalizing disorders were observed even after controlling for many other possible contributions to depression and anxiety. Maternal stressors experienced at 16 weeks gestation were more strongly related to later problems than those experienced at 34 weeks. Overall, the results of this study support a dose-response relationship between numbers of prenatal stressors and later maladaptive outcomes. This means that lower levels of stressors predicted lower symptom levels. Symptoms increased with each additional stressor exposure in a stepwise fashion. It’s important to keep in mind, however, that the nature of some stressors (e.g., low SES, financial difficulty) can exert an ongoing influence on development in addition to having prenatal impact. Conditions of low SES can provide a context for ongoing development in which adverse consequences accumulate (Duncan & Brooks-Gunn, 1997).

Researchers from a large California health consortium took a similar epidemiological approach to the study of the effect of early life stress on subsequent illness. Chronic diseases like cancer, heart disease, and diabetes account for 70% of deaths in the United States (Centers for Disease Control [CDC], 2012). To a large degree, these diseases are related to unhealthy behaviors like smoking, overeating, drinking, lack of exercise, and so on. Because such behaviors are modifiable, efforts to understand the factors underlying unhealthy behaviors can improve public health, reduce mortality, and potentially decrease national health expenditures. Two waves of patient data from San Diego’s Kaiser Permanente Medical System were collected for the Adverse Childhood Experiences (ACE) study (Felitti et al., 1998). Respondents (N = 17,421) reported their early experiences of adversity in the following 10 categories: emotional abuse, physical abuse, sexual abuse, physical neglect, emotional neglect, substance abuse in the home, mental illness of parent or household member, domestic violence, incarceration of a household member, parental divorce or separation. Close to two thirds of the sample reported having experienced at least one of these adverse childhood experiences (see Figure 2.10). Over 20% reported three or more ACEs, and rates of comorbidity were high. The most common adverse experience was substance abuse in the home. Findings showed a similar pattern to that observed in the Australian study. Mental and physical health consequences in adulthood increased in a stepwise fashion proportional to the number of early adverse experiences (Anda et al., 2006). To date, over 60 studies have supported the initial finding that early life experience of adversity confers risk. The higher the dose of early adversity, the greater the risk. Adversity’s effects manifest in the following areas: alcoholism and alcohol abuse, behavioral problems and developmental delays in children, chronic obstructive pulmonary disease, depression, fetal death, financial stress, health-related quality of life, illicit drug use, ischemic heart disease, liver disease, obesity, poor work performance, risk for intimate partner violence, schizophrenia in males, multiple sexual partners, sexually transmitted diseases, smoking, suicide attempts, unintended pregnancies, early initiation of smoking and/or sexual activity, adolescent pregnancy, risk for sexual violence, use of prescription psychotropic medication, poor academic achievement and premature mortality (The Adverse Childhood Experience CDC website: www.cdc.gov/violenceprevention/acestudy/journal.html; Larkin, Shields, & Anda, 2012; Vallejos, Cesoni, Farinola, Bertone, & Prokopez, 2016). Studies suggest that early adverse experiences contribute to the etiology of later illness by altering allostatic regulation and interfering with brain, immune, and endocrine system development (Danese & McEwen, 2012). If this is what is actually happening, you should expect that the effect would be present regardless of changing social attitudes about reporting mental illness, medication use, and so on. In other words, the biologically based changes attendant upon adversity would be fundamental. Analyses of ACEs in four patient cohorts from 1900 to 1978 provided supportive results (Dube, Felitti, Dong, Giles, & Anda, 2003). The strength of the dose-response association between ACEs and health outcomes was observed within each successive cohort, even though the prevalence of risk behaviors varied across decades. For example, changes in attitudes about smoking and variations in smoking behavior have occurred over the 78 years included in this analysis. Nevertheless, the relationship between ACE and smoking remained consistent. This evidence suggests that early adverse experiences contribute to multiple health problems by means of “inherent biological effects of traumatic stressors (ACEs) on the developing nervous systems of children” (Dube et al., 2003, p. 274).

The impact of ACE research has been profound because it connects some dots between the rich literature on early childhood maltreatment and that of adult health and productivity. Many states have begun to add ACE questions to their own assessments of statewide behavioral health (e.g., Austin & Herrick, 2014). However, the original work from Kaiser Permanente involved primarily White participants with college experience and health insurance. Recognition of racial disparities in both health and health care have prompted researchers to expand the list of conventional adversity categories to include experiences that may be more frequently observed in diverse groups. Since poverty has such a powerful impact on development (Evans & Kim, 2013), and because low SES children tend to report higher numbers of ACEs (Slopen et al., 2016), its inclusion in the list could improve ability to track outcomes and predict the needs of poor children as they age. In addition, factors outside the home such as community violence and racism have research support that indicates long-term adverse effects.

Using a racially and socioeconomically diverse sample in Philadelphia, Cronholm and his colleagues (2015) tested a “second-generation” measure of ACEs. This measure included the conventional categories but added five additional questions related to witnessing violence in one’s community, having a history of foster care, being bullied, experiencing racism, and living in an unsafe neighborhood. Survey results from a group of 1,784 predominantly African American respondents indicated higher incidences of conventional ACEs except for sexual abuse, physical neglect, and emotional neglect, which were more frequently reported in the original California sample. Notably, 50% of the Philadelphia sample experienced 1 to 2 expanded ACEs and 13% experienced 3 or more. Approximately one third reported no experience with expanded ACEs. As you might imagine, there was some overlap between conventional and expanded categories. Almost half of the Philadelphia sample had experienced both categories of early adverse events. About 14% experienced adversities only included in the expanded list. If not for these additional categories, researchers would have missed specific kinds of adversity faced by this lower income, urban group.

If we are to fully understand the developmental pathways to health and disease for everyone, it is crucial to understand the vulnerability profiles and specific stress exposure that may be related to culture, race, gender, disability, and socioeconomic status. This epidemiological approach provides a good example of early steps in the process of translational research. As the process moves forward, programs and policies can be developed, tested, and implemented to target common and specific risks, ultimately improving quality of life and reducing disease burden for all. With such clear evidence of risk factors and such potential for remediation, prevention and intervention may never have been more important than they are now. Case Study

Jennifer and Jianshe Li have been married for 10 years. Jennifer is a White, 37-year-old woman who is an associate in a law firm in a medium-sized, Midwestern city. Her husband, Jianshe, a 36-year-old Chinese American man, is a software developer employed by a large locally based company. The couple met while they were in graduate school and married shortly thereafter. They have no children. They own a home in one of the newly developed suburban areas just outside the city. Jennifer was adopted as an infant and maintains close ties with her adoptive parents. She is their only child. There has been no contact between Jennifer and her biological parents, and she has never attempted to learn their names or find out where they live. Jianshe’s parents, two brothers, and one sister live on the U.S. West Coast, and all the family members try to get together for visits several times a year. Jennifer and Jianshe are active in a few local community organizations. They enjoy the company of many friends and often spend what leisure time they have hiking and camping.

The Lis have been unsuccessful in conceiving a child even though they have tried for the past four years. Both husband and wife have undergone testing. Jennifer has had infertility treatment for the past three years but without success. The treatments have been lengthy, expensive, and emotionally stressful. Approximately a year ago, Jennifer began to experience some mild symptoms of dizziness and dimmed vision. At first, she disregarded the symptoms, attributing them to overwork. However, they persisted for several weeks, and she consulted her physician. He thought that they might be a side effect of the medication she had been taking to increase fertility. Jennifer’s treatment protocol was changed, and shortly afterward, much to the couple’s delight, Jennifer became pregnant. Unfortunately, the symptoms she had experienced earlier began to worsen, and she noticed some mild tremors in her arms and legs as well. Jennifer’s physician referred her to a specialist, who tentatively diagnosed a progressive disease of the central nervous system that has a suspected genetic link and is marked by an unpredictable course. The Lis were devastated by the news. They were very concerned about the risks of the pregnancy to Jennifer’s health. They also worried about the possible transmission of the disease to the new baby whom they had wanted for such a long time. In great distress, they sought counseling to help them deal with some of these concerns.