The Disordered Mind

by Eric R. Kandel

  Figure 9.2. The brain’s normal reward circuitry is disrupted by addiction.

  Other drug-induced changes in the animals’ brains bring about positive associations between the drug experience and environmental cues. Both kinds of changes help drive addiction. Thus, although an animal taking the drug will build up tolerance to the drug itself, the addiction continues because craving is triggered by cues present in the environment. Increasingly, advanced brain-imaging techniques and postmortem examinations of the brains of human addicts have confirmed that findings from animal models apply to people as well.

  Perhaps the most surprising finding to emerge from animal models is that the heritability of addiction is moderately high: roughly 50 percent. This means that the genetic risk of addiction is greater than that of type II diabetes or high blood pressure.9 The remaining 50 percent results from the interaction of environmental factors and genes. “Ultimately, the ability of environmental stimuli to influence an organism requires changes in gene expression,” says Nestler, who has explored the ways in which drug addiction alters gene expression.10 Scientists are just now developing molecular genetic techniques that will enable us to pinpoint the genes involved in addiction.

  Nestler has found several genes in the reward systems of animals that, when modified, dramatically reduce the vulnerability to addiction.11 Identifying the specific genes that confer the risk of addiction and understanding how environment interacts with those genes will guide the development of better diagnostic tests and treatments.

  The third kind of research into addiction is the epidemiological study, which tracks the incidence or prevalence of a particular addiction in a particular population over a particular period of time. Thanks to epidemiological studies, we now know that the use of certain addictive drugs increases the likelihood of using other addictive drugs.

  Denise Kandel of Columbia University has been instrumental in uncovering some of those links. She has used epidemiological studies of young people to show that smoking is a powerful first step toward cocaine or heroin addiction.12 That finding raised the question of whether young people start with nicotine because it is the first drug available, or whether nicotine does something to the brain that makes it more vulnerable to other substances and to addiction.

  Kandel, Amir Levine, and their colleagues studied this question in mice and found that exposing the animals to nicotine modifies their dopamine-receiving neurons in such a way that they respond more powerfully to cocaine. In contrast, giving the animals cocaine first has no effect on their subsequent response to nicotine.13 Thus, nicotine primes the brain for cocaine addiction.

  Society has taken great pains to discourage people from smoking, and it is quite likely that reducing the number of smokers will reduce other sorts of addictions as well.

  OTHER ADDICTIVE DISORDERS

  Some compulsive disorders—those involving eating, gambling, and sexual behavior—are very similar to drug addiction. We know that addiction is an exaggerated response to a given reward, and it is likely that the same parts of the brain activated by addictive substances are also activated by food, money, and sex. Studies that compared brain images of drug-addicted people and obese people have found similar changes in the brain. Just as addicted people often show reduced activity in parts of the reward system when taking drugs—they have become conditioned to the pleasure—so obese individuals show reduced pleasure when eating. Research has found that the reward system of obese people tends to be less responsive to dopamine and to have a lower density of dopamine receptors.

  Kyle Burger and Eric Stice at the Oregon Research Institute conducted an interesting study of adolescents’ eating habits.14 The researchers began by asking 151 teenagers of varying weights about their eating habits and food cravings. Afterward, they put the teens in a brain scanner and showed them a picture of a milkshake, followed by a few sips of the real thing. The researchers then compared the activity of the teens’ reward system to their answers to questions about their eating habits.

  The teenagers who reported eating the most ice cream showed the least activation of their reward system when consuming the milkshake. This suggests that they ate more in order to compensate for the reduced pleasure they actually got from eating. They had to consume larger quantities (and additional calories) to achieve an equivalent reward, just as someone addicted to drugs would. This finding indicates that obesity results from reward-related changes in the brain, not from gluttony or self-indulgence. Thus, an understanding of the biology of obesity is essential to stopping the stigmatizing of obese people.

  Research has shown that obesity has a social component as well: that is, it seems to spread from person to person. Nicholas Christakis of Harvard University and James Fowler of the University of California, San Diego, recently sifted through the handwritten records of 5,124 men and women from the Framingham Heart Study, an ongoing project that was begun in 1948 and that has revealed many of the risk factors associated with cardiovascular disease. The original Framingham researchers had kept careful notes not only on each participant’s family members but also on their close friends and colleagues. Because two-thirds of all Framingham adults had participated in the first phase of the study, and their children and grandchildren had participated in subsequent phases, almost the entire social network of the community had been chronicled. Christakis and Fowler constructed a detailed network of personal associations from these records, enabling them, for the first time, to see how a social network influences behavior.15

  The first variable Christakis and Fowler analyzed was obesity, and here they made a remarkable discovery: obesity seemed to spread through a social network like a virus. In fact, if one person became obese, the likelihood that a friend would follow suit increased by 171 percent. Christakis and Fowler went on to find that smoking also spreads from person to person. When a friend begins smoking, your chances of lighting up increase by 36 percent. Similar percentages apply to drinking alcohol, to happiness, and even to feelings of loneliness.

  Studies of the biological and social factors underlying obesity may not only help scientists develop ways to prevent obesity, they may also provide insights into the development of drugs for other kinds of addiction. Self-control will never be easy. But perhaps we can help people with a malfunctioning reward system by making it slightly less difficult to achieve self-control.

  TREATING PEOPLE WITH AN ADDICTION

  Animal models and other studies have taught us a great deal about how to treat people with an addiction. First of all, the studies show that addiction is a chronic disease. The notion that a person can go to rehab for a month and be cured is not correct. It’s magical thinking.

  Second, addiction affects several regions of the brain, several neural circuits. This calls for a multipronged approach to treatment and raises several questions. Can an addicted person’s self-control be strengthened through behavioral therapy that helps rein in self-destructive behavior or by medication that improves the functioning of the prefrontal cortex? Can behavioral interventions or medication weaken conditioning, so that when a person sees stimuli associated with the addictive substance he or she doesn’t respond to them? Can the reward system be made to respond to natural stimuli, so that things other than drugs will motivate the addicted person?

  The most successful treatments for addiction to date are behavioral and involve regimented twelve-step programs like Alcoholics Anonymous. But most addicted people return to using drugs even after completing the best available programs. These high relapse rates reflect the long-lasting changes that take place in the brain during addiction. As we have seen, drug addiction is a form of long-term memory. The brain becomes conditioned to associate certain environmental cues with pleasure, and encountering those cues can trigger an urge to use the drug. The memory of pleasure persists long after an addicted person has stopped taking a drug; that is why maintaining treatment—even after repeated relapses—is so important.

  The goal of medications would be t
o help an addicted person forget the pleasure associated with an addictive drug and counteract the powerful biological forces that drive addiction, thereby enhancing the effectiveness of rehabilitation and psychosocial treatment. We have seen that behavioral therapies and medication both work through biological processes in the brain and that they are frequently synergistic. One of the central challenges in treating addiction is to translate our increasing knowledge of the brain’s reward circuits into new therapies.

  Unfortunately, pharmaceutical companies have devoted very little effort to developing drugs to treat addiction. One reason is their perception that they cannot recover their research costs from addicted people. Nevertheless, basic research has led to some important medications that reduce cravings.

  Nicotine-replacement drugs, for example, target the same areas of the brain as nicotine itself, but they do so in a way that helps reduce the craving for cigarettes. Methadone binds to the same receptors that are activated by heroin, but it stays on the receptor for a very long period of time, thus reducing the intensity of the emotional response. Although methadone itself is an addictive drug, addiction to methadone does not disrupt day-to-day behavior as severely as addiction to heroin does. In addition, methadone is a prescription drug that is available legally, whereas heroin is an illegal drug that must be bought on the black market, often under risky circumstances.

  Current treatments for addiction are deeply flawed, but, as we have seen, brain-imaging studies, animal models of addiction, and epidemiological studies are all contributing to an increased understanding of the changes in the brain’s reward system that underlie addiction. Many scientists are working on treatments aimed at restoring normal activity in the dopamine-producing circuits of the brain, through medication, behavioral therapy, and genetic therapy. Eventually, this research into treatment may enable us to develop ways of preventing addiction.

  LOOKING AHEAD

  The health care system has for the most part removed itself from the screening and treatment of people addicted to drugs because addiction is widely believed to be a behavior of choice—a bad behavior by a bad person. This belief stigmatizes addicted people.

  The question of exercising our will in the context of addiction is a difficult one, because drugs target the parts of our brain that control our ability to make decisions. As we have seen, addiction is a complex interplay between conscious and unconscious mental processes. It starts with a conscious decision to obtain drugs, but the drugs stimulate neurons to produce dopamine, and sometimes other chemicals, in the brain. Eventually, this unconscious activity, and the changes it causes in brain function, takes over. While an addicted person may have made the initial choice to experiment with the drug, the subsequent brain disorder diminishes his or her ability to choose freely.

  Education and science are our best means of eliminating stigma and thereby enabling individuals and society to behave in a more rational manner toward addicted people. Drug overdoses are now estimated to be the leading cause of death among Americans under the age of fifty.16 Studies have found that 40 percent of eighteen- to nineteen-year-olds in the United States have been exposed at least once to an illegal drug, and 75 percent or more have been exposed to alcohol. Some of them—approximately 10 percent—will become addicted; the others will not. Given that the risk of addiction is strongly shaped by genetics, it’s important that we approach addiction as a brain disorder, not as a moral failing, and that we provide treatment, not punishment, for people with addictions.

  10

  SEXUAL DIFFERENTIATION OF THE BRAIN AND GENDER IDENTITY

  Most of us have a strong sense of gender identity—of being a boy or a girl—early in life. Consequently, we grow up behaving in ways that are more or less typical of other boys or girls in our society. Usually, our gender identity conforms to our anatomical sex, our genitals and reproductive organs, but not always. We may have a male body but feel like a girl or a woman, or have a female body but feel like a boy or a man. This variance is possible because our sex and our gender identity are determined separately, at different times in the course of development.

  Gender identity is our sense of where we belong on the continuum of sexuality, of being a man, a woman, or neither, or both. It encompasses our biological development, our feelings, and our behavior. So while gender identity may vary widely among individuals, it is a function of the normal sexual differentiation of the brain. It is because we can learn so much about ourselves from the study of gender identity that I digress from consideration of brain disorders to include this chapter on sexual differentiation of the brain.

  For people whose gender identity is at odds with their anatomical sex—that is, for people who are transgender—the feeling of being in the wrong body begins in childhood and may intensify in adolescence and adulthood. The tension between their outward appearance—which creates a constellation of social expectations regarding behavior—and their inner feelings causes confusion and distress and may make interactions with others difficult. As a result, transgender people may experience anxiety, depression, or other disorders. Moreover, transgender people often face severe discrimination and physical danger.

  Gender identity is not the same thing as sexual orientation, a person’s romantic attraction to the opposite sex, the same sex, or both sexes. At present, we know too little about the biology of sexual orientation to discuss it here.

  Where does our sense of gender identity come from? Is it determined before birth, or is it a social construct? In this chapter we first consider sexual differentiation, the genetic, hormonal, and structural changes that take place during development and that determine our anatomical sex. Next, we look at gender-specific behavior. We explore what differences between male and female behavior tell us about physical differences between the male and female brain. We then learn about genes that can cause gender identity and anatomical sex to diverge. Together, these findings are beginning to give us a much more nuanced picture of human gender identity and how it is influenced by the brain.

  We learn from a gifted scientist how he felt growing up as a boy in a girl’s body and later transitioning from a woman to a man. Finally, we look at some of the questions surrounding how best to support children and adolescents whose gender identity is different from their sex at birth.

  ANATOMICAL SEX

  The word “sex” is used in three ways to describe the biological differences between men and women. Anatomical sex, as we have seen, refers to overt differences, including differences in the external genitalia and other sexual characteristics, such as distribution of body hair. Gonadal sex refers to the presence of male or female gonads, the testes or ovaries. Chromosomal sex refers to the distribution of the sex chromosomes between women and men.

  Our DNA is distributed into twenty-three pairs of chromosomes (fig. 10.1). Each pair is made up of one chromosome from our mother and one from our father. The chromosomes in any given pair between 1 and 22 have a similar, but not identical, DNA sequence.

  The two chromosomes in the twenty-third pair—the X and Y chromosomes—are very different from each other. These are the chromosomes that determine our anatomical sex. The X chromosome, the female chromosome, is roughly the same size as the other forty-four chromosomes; the Y chromosome, the male chromosome, is considerably smaller. Women have two copies of the X chromosome, so they are genetically XX; men have one copy of X and one of Y, so they are genetically XY.

  Figure 10.1. The human genome is made up of twenty-three pairs of chromosomes; the twenty-third pair determines anatomical sex.

  How does the Y chromosome produce a boy? Initially, every embryo has an undifferentiated gonadal precursor called the genital ridge. Around the sixth or seventh week of gestation, a gene on the Y chromosome called SRY (sex-determining region Y) initiates the process of becoming male by directing the undifferentiated genital ridge to develop into the testis (figs. 10.2 and 10.3). Once the testis has developed, the embryo’s sexual fate is sealed further by the action
of the hormones released by the testes, such as testosterone. By about the eighth week of gestation, the testes of the male fetus release almost as much testosterone as those of a boy at puberty or an adult man. That massive release of testosterone is responsible for almost every aspect of being male, including body form and brain characteristics.

  At about six weeks of gestation, an embryo with two X genes begins the process of female sexual development: ovaries develop, and the sexual differentiation of the body and aspects of brain development follow the female pathway (figs. 10.2 and 10.3). The embryo does not require a massive release of hormones from the ovaries in order to become female.

  GENDER-SPECIFIC BEHAVIOR

  Male and female animals display clear differences in their sexual and social behaviors. Indeed, in every species, including our own, each individual exhibits a set of behaviors that is typical of its sex: biological males behave in a manner that is typical of males, and biological females behave in a manner that is typical of females.

  Gender-specific behaviors, particularly sexual and aggressive behaviors, are remarkably similar across species, which indicates that such behaviors have been carefully conserved over the course of evolution. This suggests, in turn, that the neural circuits driving the behaviors are also very similar and highly conserved. The signals that trigger gender-specific behaviors, however, are usually specific to a given species.

  Figure 10.2. The differentiation of an embryo into male or female occurs in the sixth or seventh week of gestation.