In 1935 the report of an experiment with a chimpanzee triggered events whose repercussions are still being felt today. Jacobsen, Wolfe, and Jackson ( 1935 ) tested some chimpanzees on a behavioral task that requires the animal to remain quiet and remember the location of food that the experimenter has placed behind a screen. One animal, Becky, displayed a violent emotional reaction whenever she made an error while performing this task. “[When] the experimenter lowered … the opaque door to exclude the animal’s view of the cups, she immediately flew into a temper tantrum, rolled on the floor, defecated, and urinated. After a few such reactions during the training period, the animal would make no further responses.” After the chimpanzee’s frontal lobes were removed, she became a model of good comportment. The chimpanzee “offered its usual friendly greeting, and eagerly ran from its living quarters to the transfer cage, and in turn went properly to the experimental cage. … If the animal made a mistake, it showed no evidence of emotional disturbance but quietly awaited the loading of the cups for the next trial” (Jacobsen, Wolfe, and Jackson, 1935 , pp. 9–10).

These findings were reported at a scientific meeting in 1935, which was attended by Egas Moniz, a Portuguese neuropsychiatrist. He heard the report by Jacobsen and his colleagues and also one by Brickner ( 1936 ), which indicated that radical removal of the frontal lobes in a human patient (performed because of a tumor) did not appear to produce intellectual impairment; therefore, people could presumably get along without their frontal lobes. These two reports suggested to Moniz that “if frontal-lobe removal … eliminates frustrational behavior, why would it not be feasible to relieve anxiety states in man by surgical means?” (Fulton, 1949 , pp. 63–64). In fact, Moniz persuaded a neurosurgeon to do so, and approximately one hundred operations were eventually performed under his supervision. (In 1949, Moniz received the Nobel Prize for the development of this procedure.)

I wrote that the repercussions of the 1935 meeting are still being felt today. Since that time, tens of thousands of people have received prefrontal lobotomies, primarily to reduce symptoms of emotional distress, and many of these people are still alive. At first, the medical community welcomed the procedure because it provided their patients with relief from emotional anguish. Only after many years were careful studies performed on the side effects of the procedure. These studies showed that although patients did perform well on standard tests of intellectual ability, they showed serious changes in personality, becoming irresponsible and childish. They also lost the ability to carry out plans, and most were unemployable. And although pathological emotional reactions were eliminated, so were normal ones. Because of these findings and because of the discovery of drugs and therapeutic methods that relieve the patients’ symptoms without producing such drastic side effects, neurosurgeons eventually abandoned the prefrontal lobotomy procedure (Valenstein, 1986 ).

I should point out that the prefrontal lobotomies that were performed under Moniz’s supervision, and by the neurosurgeons who followed, were not as drastic as the surgery performed by Jacobsen and his colleagues on Becky, the chimpanzee. In fact, no brain tissue was removed. Instead, the surgeons introduced various kinds of cutting devices into the frontal lobes and severed white matter (bundles of axons). One rather gruesome procedure did not even require an operating room; it could be performed in a physician’s office. A transorbital leucotome, shaped like an ice pick, was introduced into the brain by passing it beneath the upper eyelid until the point reached the orbital bone above the eye. The instrument was hit with a mallet, driving it through the bone into the brain. The end was then swept back and forth so that it cut through the white matter. The patient often left the office within an hour.

Many physicians objected to the “ice pick” procedure because it was done blind (that is, the surgeon could not see just where the blade of the leucotome was located) and because it produced more damage than was necessary. Also, the fact that it was so easy and left no external signs other than a pair of black eyes may have tempted its practitioners to perform it too casually. In fact, at least 2,500 patients underwent this form of surgery (Valenstein, 1986 ).

What we know today about the effects of prefrontal lobotomy—whether done transorbitally or by more conventional means—tells us that such radical surgery should never have been performed. For too long the harmful side effects were ignored. As we will see later in this chapter, neurosurgeons developed a much restricted version of this surgery to treat intractable obsessive-compulsive disorder that reduced the symptoms without producing such harmful side effects. With the development of deep brain stimulation, which does not produce irreversible damage, even these procedures are rarely performed nowadays.

Not too many years ago, the first three topics discussed in this chapter—the anxiety disorders, autism, and attention-deficit/hyperactivity disorder—would not have been covered in a book concerned with the physiology of behavior. (The importance of physiology to the fourth topic, stress, has long been recognized.) The anxiety disorders, autism, and attention-deficit/hyperactivity disorder were believed to be learned, primarily from parents who did a bad job raising their children. Although there was always at least some support for the suggestion that serious psychoses such as schizophrenia had a biological basis, other mental disorders were almost universally believed to be psychogenic in origin—that is, produced by “psychological” factors.

The tide has turned (or the pendulum has swung back, if you prefer that metaphor). Certainly, a person’s family environment, social class, economic status, and similar factors affect the likelihood that he or she will develop a mental disorder and may help or hinder recovery. But physiological factors, including inherited ones and those that adversely affect development or damage the brain, play an important role too.

Anxiety Disorders

As we saw in Chapter 16 , the affective disorders are characterized by unrealistic extremes of emotion: depression or elation (mania). The anxiety disorders are characterized by unrealistic, unfounded fear and anxiety. With a lifetime prevalence of approximately 28 percent, anxiety disorders are the most common psychiatric disorders. In addition, anxiety disorders contribute to the occurrence of depressive and substance abuse disorders (Tye et al., 2011 ). This section describes three of the anxiety disorders that appear to have biological causes: panic disorder, generalized anxiety disorder, and social anxiety disorder. Although obsessive-compulsive disorder has traditionally been classified as an anxiety disorder, it has different symptoms from the other three disorders and involves different brain regions, so it is discussed separately.

anxiety disorder A psychological disorder characterized by tension, overactivity of the autonomic nervous system, expectation of an impending disaster, and continuous vigilance for danger.

Panic Disorder, Generalized Anxiety Disorder, and Social Anxiety Disorder

DESCRIPTION

People with panic disorder suffer from episodic attacks of acute anxiety—periods of acute and unremitting terror that grip them for variable lengths of time, from a few seconds to a few hours. The prevalence of this disorder is approximately 3–5 percent (Schumacher et al., 2011 ). Women appear to be approximately twice as likely as men to suffer from panic disorder.

panic disorder A disorder characterized by episodic periods of symptoms such as shortness of breath, irregularities in heartbeat, and other autonomic symptoms, accompanied by intense fear.

Panic attacks include many physical symptoms, such as shortness of breath, clammy sweat, irregularities in heartbeat, dizziness, faintness, and feelings of unreality. The victim of a panic attack often feels that he or she is going to die and often seeks help in a hospital emergency room. Between panic attacks many people with panic disorder suffer from anticipatory anxiety —the fear that another panic attack will strike them. This anticipatory anxiety often leads to the development of a serious phobic disorder: agoraphobia (agora means “open space”). Agoraphobia can be severely disabling; some people with this disorder have stayed inside their homes for years, afraid to venture outside where they might have a panic attack in public.

anticipatory anxiety A fear of having a panic attack; may lead to the development of agoraphobia.

agoraphobia A fear of being away from home or other protected places.

The primary characteristics of generalized anxiety disorder are excessive anxiety and worry, difficulty in controlling these symptoms, and clinically significant signs of distress and disruption of their lives. The prevalence of generalized anxiety disorder is approximately 3 percent, and the incidence is approximately two times greater in women than in men.

generalized anxiety disorder A disorder characterized by excessive anxiety and worry serious enough to cause disruption of a person’s life.

Social anxiety disorder (also called social phobia) is a persistent, excessive fear of being exposed to the scrutiny of other people that leads to avoidance of social situations in which the person is called on to perform (such as speaking or performing in public). If such situations are unavoidable, the person experiences intense anxiety and distress. The prevalence of social anxiety disorder, which is equally likely in men and women, is approximately 5 percent.

social anxiety disorder A disorder characterized by excessive fear of being exposed to the scrutiny of other people that leads to avoidance of social situations in which the person is called on to perform.

POSSIBLE CAUSES

Family studies and twin studies indicate that panic disorder, generalized anxiety disorder, and social anxiety disorder all have a hereditary component (Hettema, Neale, and Kendler, 2001 ; Merikangas and Low, 2005 ). Panic attacks can be triggered in people with a history of panic disorder by a variety of treatments that activate the autonomic nervous system, such as injections of lactic acid (a by-product of muscular activity), yohimbine (an α2 adrenoreceptor antagonist), or doxapram (a drug used by anesthesiologists to increase breathing rate) or breathing air containing an elevated amount of carbon dioxide (Stein and Uhde, 1995 ). Lactic acid and carbon dioxide both increase heart rate and rate of respiration, just as exercise does; yohimbine has direct pharmacological effects on the nervous system.

Genetic investigations indicate that variations in the gene that encodes production the BDNF protein may play a role in anxiety disorders. BDNF (brain-derived neurotrophic factor) regulates neuronal survival and differentiation during development, plays a role in long-term potentiation and memory, and is associated with anxiety and depression (Yu et al., 2009 ). A particular allele of the BDNF gene (Val66Met) impairs extinction of conditioned fear memory in both humans and mice, and results in atypical activity of frontal cortex–amygdala circuitry. This allele does not normally occur in mice, but it can be inserted into their genome. Soliman et al. ( 2010 ) found that the presence of the Val66Met allele altered the circuitry of the vmPFC and impaired the extinction of a conditioned fear response in both mice and humans. In addition, the presence of this allele decreased the activity of the vmPFC during extinction.

Functional-imaging studies suggest that the amygdala and the cingulate, prefrontal, and insular cortices are involved in anxiety disorders. Fischer et al. ( 1998 ) witnessed an unexpected panic attack in a subject while her regional cerebral blood flow was being measured by a PET scanner. They observed decreased activity in the right orbitofrontal cortex and anterior cingulate cortex. Pfleiderer et al. ( 2007 ) also observed a panic attack in a subject undergoing fMRI scanning and saw increased activity in the amygdala. Phan et al. ( 2005 ) found that people with social anxiety disorder showed increases in the activation of the amygdala when they looked at pictures of faces with angry, disgusted, or fearful expressions. In addition, the activation of the amygdala was positively correlated with the severity of the people’s symptoms. Monk et al. ( 2008 ) found that adolescents with generalized anxiety disorder showed increased activation of the amygdala and decreased activation of the ventrolateral prefrontal cortex while looking at angry faces. They also found evidence that activation of the ventromedial prefrontal cortex (vmPFC) suppressed amygdala activation in healthy control subjects but not in those with anxiety disorder. (As you will recall from Chapter 11 , the vmPFC plays a critical role in extinction and inhibition of fear and anxiety.) Stein et al. ( 2007 ) found that college students with a high level of anxiety (but without a diagnosis of one of the anxiety disorders) showed increased activation of the amygdala and the insular cortex, both of which correlated positively with students’ anxiety measures.

Tye et al. ( 2011 ) found that optogenetic stimulation of the terminals of neurons of the basolateral nucleus of the amygdala that formed synapses with neurons in the central nucleus caused an immediate termination of anxious behavior of mice. Conversely, optogenetic inhibition of these same terminals induced anxious behaviors. Optogenetic methods, described in Chapter 5 , hold the promise of discovery of the neural circuits involved in the development and control of anxiety.

TREATMENT

Anxiety disorders are sometimes treated with benzodiazepines. As we just saw, increased activity of the amygdala is a common feature of the anxiety disorders. The amygdala contains a high concentration of GABAA receptors, which are the target of the benzodiazepines. Paulus et al. ( 2005 ) found that administration of a benzodiazepine (lorazepam) decreased the activation of both the amygdala and the insula of subjects looking at emotional faces. Administration of flumazenil, a benzodiazepine antagonist (having an action opposite that of the benzodiazepine tranquilizers), produces panic in patients with panic disorder but not in control subjects (Nutt et al., 1990 ).

Benzodiazepines are often used for emergency medical treatment for anxiety disorders because the therapeutic effects of these drugs have a rapid onset. However, they are less satisfactory for long-term treatment. They cause sedation, they induce tolerance and withdrawal symptoms, and they have a potential for abuse. For these reasons, researchers have been seeking other drugs to treat anxiety disorders. Benzodiazepines exert their effects by interacting with GABAA receptors via an unknown binding site. Chemicals that activate one of the known binding sites on this receptor, the neurosteroid binding site, enhance the activity of the GABAA receptor. During anxiety attacks, the synthesis of neurosteroids—and hence the activity of the GABAA receptor—is suppressed. A recently developed drug, XBD173, enhances the synthesis of neurosteroids and hence increases the activity of the GABAA receptor. Tests with human patients have shown that the drug reduces panic and does not produce sedation or withdrawal symptoms after seven days of treatment (Nothdurfter et al., 2011 ). Thus, this drug appears to be a promising candidate for treatment of anxiety disorders.

As we saw in Chapter 16 , serotonin appears to play a role in depression. Much evidence suggests that serotonin plays a role in anxiety disorders too. Even though the symptoms of the anxiety disorders discussed in this subsection are very different from those of obsessive-compulsive disorder (described in the next subsection), specific serotonin reuptake inhibitors (SSRIs), which serve as potent serotonin agonists (such as fluoxetine), have become the first-line medications for treating all of these disorders—preferably in combination with cognitive behavior therapy (Asnis et al., 2001 ; Ressler and Mayberg, 2007 ). Figure 17.1 shows the effect of fluvoxamine, an SSRI, on the number of panic attacks in patients with panic disorder. (See Figure 17.1 . )

FIGURE 17.1 Fluvoxamine and Panic Disorder

The graph shows the effects of fluvoxamine (an SSRI) on the severity of panic disorder.

(Based on data from Asnis et al., 2001 .)

As we also saw in Chapter 16 , administration of indirect agonists of the NMDA receptor that attach to the glycine binding site have been used experimentally to successfully treat the symptoms of schizophrenia. Preliminary research suggests that the same may be true for anxiety disorder. Several studies have successfully used D-cycloserine (DCS) in conjunction with cognitive behavior therapy to treat patients with anxiety disorder. For example, studies have shown that DCS facilitates treatment of acrophobia (fear of heights), social anxiety disorder, and panic disorder. (See Figure 17.2 . )

In the treatment of anxiety disorders, cognitive behavior therapy often uses procedures that desensitize patients to the objects of situations they fear. For example, Ressler et al. ( 2004 ) used a computer program to expose their patients to a virtual glass elevator, gradually bringing them higher and higher from the ground. This procedure appears to work by extinguishing a conditioned emotional response. In fact, a study by Walker et al. ( 2002 ) found that injections of D-cycloserine facilitated the extinction of a conditioned emotional response (CER) in rats. The drug had no effect on performance of a CER unless it was administered along with extinction training. Injections of the drug by itself had no effect. Presumably, D-cycloserine exerts its therapeutic effect by augmenting the ability of cognitive behavior therapy to extinguish fear responses.

FIGURE 17.2 D-Cycloserine and Anxiety Disorders

The graphs show the effects of D-cycloserine (DCS) and placebo in conjunction with cognitive behavior therapy on the symptoms of acrophobia (fear of heights), social phobia, and panic disorder.

[Based on data from Ressler et al., 2004 (acrophobia), Guastella et al., 2010b (social phobia), and Otto et al., 2010 (panic disorder).]

Obsessive-Compulsive Disorder

DESCRIPTION

As the name implies, people with an obsessive-compulsive disorder (OCD) suffer from obsessions —thoughts that will not leave them—and compulsions —behaviors that they cannot keep from performing. Obsessions include concern or disgust with bodily secretions, dirt, germs, and the like; fear that something terrible might happen; and a need for symmetry, order, or exactness. Most compulsions fall into one of four categories: counting, checking, cleaning, and avoidance. For example, people might repeatedly check burners on the stove to see that they are off and windows and locks to be sure that they are locked. Some people will wash their hands hundreds of times a day, even if their hands become covered with painful sores. Other people meticulously clean their house or endlessly wash, dry, and fold their clothes. Some become afraid to leave home because they fear contamination and refuse to touch other members of their family. If they do accidentally become “contaminated,” they usually have lengthy purification rituals.

obsessive-compulsive disorder (OCD) A mental disorder characterized by obsessions and compulsions.

obsession An unwanted thought or idea with which a person is preoccupied.

compulsion The feeling that one is obliged to perform a behavior, even if one prefers not to do so.

Obsessions are seen in a variety of mental disorders, including schizophrenia. However, unlike schizophrenics, people with obsessive-compulsive disorder recognize that their thoughts and behaviors are senseless and desperately wish that they would go away. Compulsions often become more and more demanding until they interfere with people’s careers and daily lives.

The incidence of obsessive-compulsive disorder is 1–2 percent. Females are slightly more likely than males to have this diagnosis. OCD most commonly begins in young adulthood (Robbins et al., 1984 ). People with severe symptoms of this disorder are unlikely to marry, perhaps because of the common obsessional fear of dirt and contamination or because of the shame associated with the rituals they are compelled to perform, which causes them to avoid social contacts (Turner, Beidel, and Nathan, 1985 ).

Some investigators believe that the compulsive behaviors seen in OCD are forms of species-typical behaviors—for example, grooming, cleaning, and attention to sources of potential danger—that are released from normal control mechanisms by a brain dysfunction (Wise and Rapoport, 1988 ). Fiske and Haslam ( 1997 ) suggest that the behaviors seen in obsessive-compulsive disorder are simply pathological examples of a natural behavioral tendency to develop and practice social rituals. For example, people perform cultural rituals to mark transitions or changes in social status, to diagnose or treat illnesses, to restore relationships with deities, or to ensure the success of hunting or planting. Consider the following scenario (from Fiske and Haslam, 1997 ):

· Imagine that you are traveling in an unfamiliar country. Going out for a walk, you observe a man dressed in red, standing on a red mat in a red-painted gateway. … He utters the same prayer six times. He brings out six basins of water and meticulously arranges them in a symmetrical configuration in front of the gateway. Then he washes his hands six times in each of the six basins, using precisely the same motions each time. As he does this, he repeats the same phrase, occasionally tapping his right finger on his ear-lobe. Through your interpreter, you ask him what he is doing. He replies that there are dangerous polluting substances in the ground, … [and that] he must purify himself or something terrible will happen. He seems eager to tell you about his concerns. (p. 211)

Why is the man acting this way? Is he a priest following a sacred ritual, or does he have obsessive-compulsive disorder? Without knowing more about the spiritual rituals followed by the man’s culture, we cannot say. Fiske and Haslam compared the features of OCD and other psychological disorders in descriptions of rituals, work, or other activities in fifty-two cultures. They found that the features of OCD were found in rituals in these cultures. The features of other psychological disorders were much less common. On the whole, the evidence suggests that the symptoms of obsessive-compulsive disorder represent an exaggeration of natural human tendencies.

Zhong and Liljenquist ( 2006 ) found that even well-educated people in an industrialized country (students at Northwestern University, in the United States) apparently unknowingly consider cleansing rituals to “wash away their sins.” The investigators had the subjects recall in detail either an ethical or an unethical deed they had committed in the past. Later, they were asked to complete some word fragments by filling in letters where blanks occurred. Some word fragments could be made into words that did or did not pertain to cleansing. For example, W _ _ H, SH _ _ ER, and S _ _ P could be wash, shower, and soap, or they could be wish, shaker, and step. The subjects who had told about a misdeed were much more likely to think of cleansing-related words. And when offered a free gift—either a pencil or an antiseptic wipe—subjects who had told about a misdeed were more likely to chose the antiseptic wipe.

POSSIBLE CAUSES

Evidence indicates that obsessive-compulsive disorder is at least partly caused by hereditary factors. Several studies have found a greater concordance for obsessions and compulsions in monozygotic twins than in dizygotic twins (Hettema, Neale, and Kendler, 2001 ). Family studies have found that OCD is associated with a neurological disorder that appears during childhood (Pauls and Leckman, 1986 ; Pauls et al., 1986 ). This disorder, Tourette’s syndrome , is characterized by muscular and vocal tics: facial grimaces, squatting, pacing, twirling, barking, sniffing, coughing, grunting, or repeating specific words (especially vulgarities). Leonard et al. ( 1992a , 1992b ) found that many patients with obsessive-compulsive disorder had tics and that many patients with Tourette’s syndrome showed obsessions and compulsions. Grados et al. ( 2001 ) found a family association between OCD and tic disorders (a broad category that includes Tourette’s syndrome). Both groups of investigators believe that the two disorders are produced by the same underlying genotype. It is not clear why some people with this genotype gene develop Tourette’s syndrome and others develop obsessive-compulsive disorder.

Tourette’s syndrome A neurological disorder characterized by tics and involuntary vocalizations and sometimes by compulsive uttering of obscenities and repetition of the utterances of others.

As with schizophrenia, not all cases of OCD have a genetic origin; the disorder sometimes occurs after brain damage caused by various means, such as birth trauma, encephalitis, and head trauma (Hollander et al., 1990 ; Berthier et al., 1996 ). In particular, the symptoms appear to be associated with damage to or dysfunction of the basal ganglia, cingulate gyrus, and prefrontal cortex (Giedd et al., 1995 ; Robinson et al., 1995 ).

Tic disorders (including OCD) can be caused by a group A β-hemolytic streptococcal infection (Perlmutter et al., 1998 ; Kawikova et al., 2010 ). This infection can trigger several autoimmune diseases, in which the patient’s immune system attacks and damages certain tissues of the body, including the valves of the heart, the kidneys, and—in this case—parts of the brain. Figure 17.3 shows the parallel course of a child’s symptoms and the level of antistreptococcal DNA-B in her blood, which indicates the presence of an active infection. (See Figure 17.3 . )

FIGURE 17.3 OCD and Streptococcal Hemolytic Infection

The graph shows the parallel course of a child’s symptoms and the level of antistreptococcal DNA-B in her blood, which indicates the presence of an active infection. This relationship provides evidence that a group A β-hemolytic streptococcal infection can produce tics and the symptoms of OCD, presumably by affecting the basal ganglia.

(Based on data from Perlmutter et al., 1998 .)

The symptoms of OCD appear to be produced by damage to the basal ganglia. Bodner, Morshed, and Peterson ( 2001 ) report the case of a twenty-five-year-old man whose untreated sore throat (he lived in a religious group that prohibited antibiotics) developed into an autoimmune disease that produced obsessions and compulsions. The investigators found antibodies to type A β-hemolytic streptococcus, and MRI scans indicated abnormalities in the basal ganglia. An MRI study of thirty-four children with streptococcus-associated tics or OCD by Giedd et al. ( 2000 ) found an increase in the size of the basal ganglia that they attributed to an autoimmune inflammation of this region.

Several functional-imaging studies have found evidence of increased activity in the frontal lobes and caudate nucleus in patients with OCD. A review by Whiteside, Port, and Abramowitz ( 2004 ) found that functional-imaging studies consistently found increased activity of the caudate nucleus and the orbitofrontal cortex. Guehl et al. ( 2008 ) inserted microelectrodes into the caudate nuclei of three patients with OCD who were being evaluated for neurosurgery. They found that two of the patients, who reported the presence of obsessive thoughts during the surgery, showed increased activity in neurons in the caudate nucleus. The third patient, who did not report obsessive thoughts, showed a lower rate of neural activity.

A review by Saxena et al. ( 1998 ) described several studies that measured regional brain activity of OCD patients before and after successful treatment with drugs or cognitive behavior therapy. In general, the improvement in a patient’s symptoms was correlated with a reduction in the activity of the caudate nucleus and orbitofrontal cortex. The fact that cognitive behavior therapy and drug therapy produced similar results is especially remarkable: It indicates that very different procedures may bring about physiological changes that alleviate a serious mental disorder.

TREATMENT

As we saw in the prologue to this chapter, clinicians developed procedures that damaged the prefrontal cortex or disconnected it from other parts of the brain to treat people with emotional reactions. Some patients with severe OCD have been successfully treated with cingulotomy—surgical destruction of specific fiber bundles in the subcortical frontal lobe, including the cingulum bundle (which connects the prefrontal and cingulate cortex with the limbic cortex of the temporal lobe) and a region that contains fibers that connect the basal ganglia with the prefrontal cortex (Ballantine et al., 1987 ; Mindus, Rasmussen, and Lindquist, 1994 ). These operations have a reasonably good success rate (Dougherty et al., 2002 ). Another reasonably successful surgical procedure, capsulotomy, destroys a region of a fiber bundle (the internal capsule) that connects the caudate nucleus with the medial prefrontal cortex (Rück et al., 2008 ). Of course, brain lesions cannot be undone, so such procedures must be considered only as a last resort. As Rück and his colleagues report, some patients suffer from adverse side effects after surgery, such as problems of planning, apathy, or difficulty inhibiting socially inappropriate behavior.

In one extraordinary case a patient performed his own psychosurgery. Solyom, Turnbull, and Wilensky ( 1987 ) reported the case of a young man with a serious obsessive-compulsive disorder whose ritual hand washing and other behaviors made it impossible for him to continue his schooling or lead a normal life. Finding that his life was no longer worthwhile, he decided to end it. He placed the muzzle of a .22-caliber rifle in his mouth and pulled the trigger. The bullet entered the base of the brain and damaged the frontal lobes. He survived, and he was amazed to find that his compulsions were gone. Fortunately, the damage did not disrupt his ability to make or execute plans; he went back to school and completed his education and found employment. His IQ was unchanged. Ordinary surgery would have been less hazardous and messy, but it could hardly have been more successful.

As we saw in Chapter 15 , deep brain stimulation (DBS) has been found to be useful in treating the symptoms of Parkinson’s disease. Because OCD, like Parkinson’s disease, appears to involve abnormalities in the basal ganglia, several clinics have tried to use DBS of the basal ganglia or fiber tracts connected with them to treat this disorder. This form of therapy appears to reduce the symptoms of OCD in some patients (Abelson et al., 2005 ; Larson, 2008 ). Le Jeune et al. ( 2010 ) found that DBS of the subthalamic nucleus, which plays an integral role in the cortical–basal ganglia circuitry, reduces the symptoms of OCD. As I mentioned at the beginning of this subsection, one of the more modern forms of psychosurgery is destruction of the internal capsule. Goodman et al. ( 2010 ) found that DBS of the internal capsule reduced the symptoms of OCD in four of six patients with severe, treatment-resistant OCD. A significant benefit of DBS is that, unlike psychosurgical procedures that destroy brain tissue, it is reversible: If no benefit is obtained from the stimulation, the electrodes can be removed.

As we saw in Chapters 8 and 14 , the principal parts of the basal ganglia, the caudate nucleus and the putamen, receive information from the cerebral cortex. As this information is processed by the basal ganglia, it flows through two pathways before it passes to the thalamus and is sent back to the cortex. The direct pathway is excitatory, and the indirect pathway is inhibitory. (Refer back to Figure 8.23 . ) Saxena et al. ( 1998 ) suggest that the symptoms of OCD may be a result of overactivity of the direct pathway. They propose that one of the functions of this pathway is control of previously learned behavior sequences that have become automatic so that they can be executed rapidly. The orbitofrontal cortex, which is involved in recognizing situations that have personal significance, can activate this pathway and the behaviors that it controls. The inhibitory indirect pathway is involved in suppressing these automatic behaviors, permitting the person to switch to other, more adaptive behaviors. Thus, obsessive-compulsive behavior could be a result of an imbalance between the direct and indirect pathways.

Three drugs are regularly used to treat the symptoms of OCD: clomipramine, fluoxetine, and fluvoxamine. These effective antiobsessional drugs are specific blockers of 5-HT reuptake; thus, they are serotonergic agonists. In general, serotonin has an inhibitory effect on species-typical behaviors, which has tempted several investigators to speculate that these drugs alleviate the symptoms of obsessive-compulsive disorder by reducing the strength of innate tendencies for counting, checking, cleaning, and avoidance behaviors that may underlie this disorder. Brain regions that have been implicated in OCD, including the orbitofrontal cortex and the basal ganglia, receive input from serotonergic terminals (Lavoie and Parent, 1990 ; El Mansari and Blier, 1997 ).

The importance of serotonergic activity in inhibiting compulsive behaviors is underscored by three interesting compulsions: trichotillomania, onychophagia, and acral lick dermatitis. Trichotillomania is compulsive hair pulling. People with this disorder (almost always females) often spend hours each night pulling hairs out one by one, sometimes eating them (Rapoport, 1991 ). Onychophagia is compulsive nail biting, which in its extreme can cause severe damage to the ends of the fingers. (For those who are sufficiently agile, toenail biting is not uncommon.) Double-blind studies have shown that both of these disorders can be treated successfully by clomipramine, the drug of choice for obsessive-compulsive disorder (Leonard et al., 1992a ).

Acral lick dermatitis is a disease of dogs, not humans. Some dogs will continuously lick at a part of their body, especially their wrist or ankle (called the carpus and the hock). The licking removes the hair and often erodes away the skin as well. The disorder seems to be genetic; it is seen almost exclusively in large breeds such as Great Danes, Labrador retrievers, and German shepherds, and it runs in families. A double-blind study found that clomipramine reduces this compulsive behavior (Rapoport, Ryland, and Kriete, 1992 ). At first, when I read the term “double-blind” in the report by Rapoport and her colleagues, I was amused to think that the investigators were careful not to let the dogs learn whether they were receiving clomipramine or a placebo. Then I realized that, of course, it was the dogs’ owners who had to be kept in the dark.

We saw in the previous subsection that an NMDA receptor agonist, D-cycloserine, appears to be useful in treating the symptoms of a variety of anxiety disorders. This drug appears also to help in the treatment of the symptoms of OCD as well. A double-blind study by Wilhelm et al. (2010) found that compared with patients who received a placebo, patients who received D-cycloserine along with sessions of behavior therapy showed a greater decrease in their obsessive symptoms and retained this improvement after the sessions ended. Presumably, the drug facilitated the extinction of the maladaptive thoughts and behaviors, just as it facilitates the extinction of conditioned emotional responses in patients with anxiety disorders. (See Figure 17.4 . )

FIGURE 17.4 D-Cycloserine and OCD

The graph shows the effects of D-cycloserine and placebo in conjunction with cognitive behavior therapy on the symptoms of obsessive-compulsive behavior.

(Based on data from Wilhelm et al., 2010.)

SECTION SUMMARY: Anxiety Disorders

The anxiety disorders severely disrupt some people’s lives. People with panic disorder periodically have panic attacks, during which they experience intense symptoms of autonomic activity and often feel as if they are going to die. Frequently, panic attacks lead to the development of agoraphobia, an avoidance of being away from a safe place, such as home. Family and twin studies have shown that panic disorder is at least partly heritable, which suggests that it has biological causes.

Panic attacks can be triggered in many susceptible people by conditions that activate the autonomic nervous system, such as an caffeine, yohimbine, injection of lactate, or inhalation of air containing an elevated amount of carbon dioxide. Panic attacks can be alleviated by the administration of a benzodiazepine, and a benzodiazepine antagonist can trigger a panic attack. Nowadays, the first choice of medical treatment for panic attacks is an SSRI. In addition, the presence of a particular allele of the BDNF gene is associated with increased levels of anxiety. Functional-imaging studies suggest that the amygdala and the cingulate, prefrontal, and insular cortices are involved in anxiety disorders.

Obsessive-compulsive disorder (OCD) is characterized by obsessions—unwanted thoughts—and compulsions—uncontrollable behaviors, especially those involving cleanliness and attention to danger. Some investigators believe that these behaviors represent overactivity of species-typical behavioral tendencies.

OCD has a heritable basis and is related to Tourette’s syndrome, a neurological disorder characterized by tics and strange verbalizations. It can also be caused by brain damage at birth, encephalitis, and head injuries, especially when the basal ganglia are involved. A type A β-hemolytic streptococcus infection can stimulate an autoimmune attack—presumably on the basal ganglia—that produces the symptoms of OCD.

Functional imaging indicates that people with obsessive-compulsive disorder tend to show increased activity in the orbitofrontal cortex, cingulate cortex, and caudate nucleus. Drug treatment or behavior therapy that successfully reduces the symptoms of OCD generally reduces the activity of the orbitofrontal cortex and caudate nucleus. In severe cases of OCD that do not respond to other treatments, surgical procedures such as cingulotomy and capsulotomy may provide relief. Deep brain stimulation with implanted electrodes has been shown to be effective in some patients and, unlike cingulotomy and capsulotomy, has the benefits of being reversible. The most effective drugs are SSRIs such as clomipramine. Some investigators believe that clomipramine and related drugs alleviate the symptoms of OCD by increasing the activity of serotonergic pathways that play an inhibitory role on species-typical behaviors. Three other compulsions—hair pulling, nail biting, and (in dogs) acral lick syndrome—are also suppressed by clomipramine. In conjunction with cognitive behavior therapy, D-cycloserine, which acts as an indirect agonist at NMDA receptors, also appears to reduce the symptoms of OCD.

■ THOUGHT QUESTION

Most reasonable people would agree that a person with mental disorders cannot be blamed for his or her thoughts and behaviors. Most of us would sympathize with someone whose life is disrupted by panic attacks or obsessions and compulsions, and we would not see their plight as a failure of will power. After all, whether these disorders are caused by traumatic experiences or brain abnormalities (or both), the afflicted person has not chosen to be the way he or she is. But what about less dramatic examples: Should we blame people for their shyness or hostility or other maladaptive personality traits? If, as many psychologists believe, people’s personality characteristics are largely determined by their heredity (and thus by the structure and chemistry of their brains), what are the implications for our concepts of “blame” and “personal responsibility”?

Autistic Disorder

Description

When a baby is born, the parents normally expect to love and cherish the child and to be loved and cherished in return. Unfortunately, some infants are born with a disorder that impairs their ability to return their parents’ affection. The symptoms of autistic disorder (often simply referred to as autism) include a failure to develop normal social relations with other people, impaired development of communicative ability, and the presence of repetitive, stereotyped behavior. Most people with autistic disorder display cognitive impairments. The syndrome was named and characterized by Kanner ( 1943 ), who chose the term (auto, “self,” -ism, “condition”) to refer to the child’s apparent self-absorption.

autistic disorder A chronic disorder whose symptoms include failure to develop normal social relations with other people, impaired development of communicative ability, lack of imaginative ability, and repetitive, stereotyped movements.

According to a review by Silverman et al. ( 2010 ), the incidence of autistic disorder is 0.6–1.0 percent in the population. The disorder is four times more common in males than in females. However, if only cases of autism with mental retardation are considered, the ratio falls to 2:1, and if only cases of high-functioning autism are considered (those with average or above-average intelligence and reasonably good communicative ability), the ratio rises to approximately 7:1 (Fombonne, 2005 ). These data suggest that the social impairments are much more common in males, but the cognitive and communicative impairments are more evenly shared by males and females. At one time, clinicians believed that autism was more prevalent in families with higher socioeconomic status, but more recent studies have found that the frequency of autism is the same in all social classes. The reported incidence of autism has increased in the past two decades, but evidence indicates that the apparent increase is a result of heightened awareness of the disorder and broadening of the diagnostic criteria. By the way, studies have failed to find evidence that autism is linked to childhood immunization. In fact, the investigator who originally claimed to have obtained evidence for a linkage between immunization and autism was found guilty of dishonesty by the UK General Medical Council, and the article that first made this claim was retracted by the journal that published it, The Lancet (Dwyer, 2010 ).

Autistic disorder is one of several pervasive developmental disorders that have similar symptoms. Asperger’s syndrome, the mildest form of autistic spectrum disorder, is generally less severe than autistic disorder, and its symptoms do not include a delay in language development or the presence of important cognitive deficits. The primary symptoms of Asperger’s syndrome are deficient or absent social interactions and repetitive and stereotyped behaviors along with obsessional interest in narrow subjects. Rett’s disorder is a genetic neurological syndrome seen in girls that accompanies an arrest of normal brain development that occurs during infancy. Children with childhood disintegrative disorder show normal intellectual and social development and then, sometime between the ages of two and ten years, show a severe regression into autism.

According to the DSM-IV, a diagnosis of autistic disorder requires the presence of three categories of symptoms: impaired social interactions, absent or deficient communicative abilities, and the presence of stereotyped behaviors. Social impairments are the first symptoms to emerge. Infants with autistic disorder do not seem to care whether they are held, or they may arch their backs when picked up, as if they do not want to be held. They do not look or smile at their caregivers. If they are ill, hurt, or tired, they will not look to someone else for comfort. As they get older, they do not enter into social relationships with other children and avoid eye contact with them. In severe cases, autistic people do not even seem to recognize the existence of other people.

Frith, Morton, and Leslie ( 1991 ) suggest that some of the symptoms of autism stem from abnormalities in the brain that prevent autistic people from forming a “theory of mind.” That is, they are unable “to predict and explain the behavior of other humans in terms of their mental states” (p. 434). They cannot infer the thoughts, feelings, and intentions of other people from their emotional expressions, tone of voice, and behavior. As one autistic man complained, comparing his own social abilities with those of others, “Other people seem to have a special sense by which they can read other people’s thoughts” (Rutter, 1983 ).

The language development of people with autism is abnormal or even nonexistent. They often echo what is said to them, and they may refer to themselves as others do—in the second or third person. For example, they may say, “You want some milk?” to mean “I want some milk.” They may learn words and phrases by rote, but they fail to use them productively and creatively. Those who do acquire reasonably good language skills talk about their own preoccupations without regard for other people’s interests. They usually interpret other people’s speech literally. For example, when an autistic person is asked, “Can you pass the salt?,” he might simply say “Yes”—and not because he is trying to be funny or sarcastic.

Autistic people generally show abnormal interests and behaviors. For example, they may show stereotyped movements, such as flapping their hand back and forth or rocking back and forth. They may become obsessed with investigating objects, sniffing them, feeling their texture, or moving them back and forth. They may become attached to a particular object and insist on carrying it around with them. They may become preoccupied in lining up objects or in forming patterns with them, oblivious to everything else that is going on around them. They often insist on following precise routines and may become violently upset when they are hindered from doing so. They show no make-believe play and are not interested in stories that involve fantasy. Although most autistic people are mentally retarded, not all are; and unlike most retarded people, they may be physically adept and graceful. Some have isolated skills, such as the ability to multiply two four-digit numbers very quickly, without apparent effort.

Possible Causes

When Kanner first described autism, he suggested that it was of biological origin; but not long afterward, influential clinicians argued that autism was learned. More precisely, they said, it was taught—by cold, insensitive, distant, demanding, introverted parents. Bettelheim ( 1967 ) believed that autism was similar to the apathetic, withdrawn, and hopeless behavior seen in some of the survivors of the German concentration camps of World War II. You can imagine the guilt felt by parents who were told by a mental health professional that they were to blame for their child’s pitiful condition. Some professionals saw the existence of autism as evidence for child abuse and advocated that autistic children be removed from their families and placed with foster parents.

Nowadays, researchers and mental health professionals are convinced that autism is caused by biological factors and that parents should be given help and sympathy, not blame. Careful studies have shown that the parents of autistic children are just as warm, sociable, and responsive as other parents (Cox et al., 1975 ). In addition, parents with one autistic child often raise one or more normal children. If the parents were at fault, we should expect all of their offspring to be autistic.

HERITABILITY

Evidence indicates that autism is strongly heritable. The best evidence for genetic factors comes from twin studies. These studies indicate that the concordance rate for autism in monozygotic twins is approximately 70 percent, while the rate in dizygotic twins studied so far is approximately 5 percent. The concordance rate for the more broadly defined autistic spectrum disorders (ASD), is 90 percent for monozygotic twins and 10 percent for dizygotic twins (Sebat et al., 2007 ). A study by Ozonoff et al. ( 2011 ) found that an infant with an older sibling with ASD has an 18.7 percent likelihood of developing an ASD. Having multiple older siblings with ASD increased the risk to 32.2 percent. Genetic studies indicate that autistic disorder can be caused by a wide variety of rare mutations, especially those that interfere with neural development and communication (Betancur, Sakurai, and Buxbaum, 2009 ).

BRAIN PATHOLOGY

The fact that autism is highly heritable is presumptive evidence that the disorder is a result of structural or biochemical abnormalities in the brain. In addition, a variety of medical disorders—especially those that occur during prenatal development—can produce the symptoms of autism. Evidence suggests that approximately 10 percent of all cases of autism have definable biological causes, such as rubella (German measles) during pregnancy, prenatal thalidomide, encephalitis caused by the herpes virus, and tuberous sclerosis, a genetic disorder that causes the formation of benign tumors in many organs, including the brain (DeLong, 1999 ; Rapin, 1999 ; Fombonne, 2005 ). Ploeger et al. ( 2010 ) suggest that interference with a particular stage of prenatal development can cause autism. Early organogenesis is a stage of embryonic development that occurs during days 20–40 after fertilization. During this stage, major organs are beginning to develop, and factors that interfere with normal development can cause many abnormalities, including limb deformities, malformations of the skull and face, and brain pathologies. In the 1960s, many pregnant women took thalidomide, a drug that suppressed the symptoms of morning sickness. Unfortunately, it was discovered later that this drug caused severe birth defects—including autism. Because most women knew when they had taken thalidomide, the time of drug exposure could be correlated with the development of autism in the women’s children. It turned out that the sensitive period, during which exposure to thalidomide was most likely to cause the development of autism, was twenty to thirty-six days postfertilization, which coincides with the stage of early organogenesis. Presumably, drug-induced interference with normal brain development at this time set the stage for later development of autism.

Evidence indicates significant abnormalities in the development of the brains of autistic children. Courchesne et al. ( 2005 , 2007 ) note that although the autistic brain is, on average, slightly smaller at birth, it begins to grow abnormally quickly, and by two to three years of age it is about 10 percent larger than a normal brain. Following this early spurt, the growth of the autistic brain slows down, so by adolescence it is only about 1–2 percent larger than normal.

Not all parts of the autistic brain show the same pattern of growth. The regions that appear to be most involved in the functions that are impaired in autism show the greatest growth early in life and the slowest growth between early childhood and adolescence. For example, the frontal cortex and temporal cortex of the autistic brain grow quickly during the first two years of life but then show little or no increase in size during the next four years, whereas these two regions grow by 20 percent and 17 percent, respectively, in normal brains. However, the growth pattern of “lower-order” regions of the cerebral cortex, such as the primary visual cortex and extrastriate cortex, are relatively normal in the autistic brain. The amygdala also shows an abnormal pattern of growth during development. By four years of age it is larger in autistic children. By the time of early adulthood it is the same size as the amygdala of nonautistic people but contains fewer neurons (Schumann and Amaral, 2006 ).

Autistic brains also show abnormalities in white matter. Herbert et al. ( 2004 ) found that, in the autistic brain, the volume of white matter containing short-range axons was increased but that the volume of white matter containing long-range axons that connect distant regions of the brain was not. Courchesne et al. ( 2005 , 2007 ) suggest that the production of excessive numbers of neurons early in development may cause the development of such a large number of short-range axons that the development of long-range axons is inhibited. The apparent hyperconnectivity of local regions of the cerebral cortex might possibly account for the exceptional isolated talents and skills shown by some autistics.

Researchers have employed structural- and functional-imaging methods to investigate the neural basis of the three categories of autistic symptoms. For example, Castelli et al. ( 2002 ) showed normal subjects and high-functioning people with autism or Asperger’s syndrome animations that depicted two triangles interacting in various goal-directed ways (for example, simply chasing or fighting) or in a way that suggested that one triangle was trying to trick or coax the other. For example, one normal subject described an animation in this way: “Triangles cuddling inside the house. Big wanted to persuade little to get out. He didn’t want to … cuddling again” (p. 1843). People in the autism group were able to accurately describe the goal-directed interactions of the triangles, but they had difficulty accurately describing the “intentions” of a triangle trying to trick or coax the other. In other words, they had difficulty forming a theory of mind. Functional imaging during presentation of the animations showed normal activation of early levels of the visual association cortex (the extrastriate cortex), but activation of the superior temporal sulcus (STS) and the medial prefrontal cortex was much lower in members of the autism group. (See Figure 17.5 and Simulate inferring causation on MyPsychLab.) Previous research has shown that the STS plays an important role in detection of stimuli that indicate the actions of another individual (Allison, Puce, and McCarthy, 2000 ).

The lack of interest in or understanding of other people is reflected in the response of the autistic brain to the sight of the human face. As we saw in Chapter 6 , the fusiform face area (FFA), located on a region of visual association cortex on the base of the brain, is involved in the recognition of individual faces. A functional-imaging study by Schultz ( 2005 ) found little or no activity in the fusiform face area of autistic adults looking at pictures of human faces. (See Figure 17.6 . ) Autistics are poor at recognizing facial expressions of emotion or the direction of another person’s gaze and have low rates of eye contact with other people. It seems likely that the FFA of autistics fails to respond to the sight of the human face because these people spend very little time studying other people’s faces and hence do not develop the expertise the rest of us acquire through normal interpersonal interactions. Grelotti et al. ( 2005 ) reported the case of an autistic boy who had a consuming interest in “Digimon” cartoon characters. Functional imaging showed no activation of the FFA when the boy viewed photos of faces, but photos of Digimon characters evoked strong activation of this region. This case supports the conclusion that the failure of the sight of faces to activate the FFA in people with autism is caused by a of lack of interest in faces, not by abnormalities in the FFA.

FIGURE 17.5 Theory of Mind

The graph shows relative activation of specific brain regions of autistic adults and normal control subjects viewing a “theory of mind” animation of two triangles moving interactively with implied intentions. STS = superior temporal sulcus.

(Based on data from Castelli et al., 2002 .)

FIGURE 17.6 Fusiform Face Area and Autism

The scans show activation of the fusiform face area of control subjects but not of autistic subjects while looking at pictures of human faces.

(From Schultz, R. T. International Journal of Developmental Neuroscience, 2005, 23, 125–141. Reprinted with permission.)

A study by Pelphrey et al. ( 2002 ) found that autistic people who were asked to identify the emotions shown in photographs of faces failed to look at other people’s eyes, which are informative in making judgments of emotion. This tendency undoubtedly contributes to their impairment in analyzing social information. We saw in Chapter 11 that people with damage to the amygdala also fail to look at other people’s eyes. The abnormal development of the amygdala in people with autism may be at least partly responsible for the low rates of eye contact with other people and their difficulty in assessing other people’s emotional state.

As we saw in Chapter 10 , oxytocin, a peptide that serves as a hormone and neuromodulator, facilitates pair bonding and increases trust and closeness to others. Modahl et al. (1998) reported that autistic children had lower levels of this peptide. Studies suggest that oxytocin can improve sociability of people with ASD. Guastella et al. ( 2010a ) found that administration of oxytocin increased the performance of adolescent males with ASD on a test of emotional recognition. Andari et al. ( 2010 ) found that oxytocin improved the performance of adults with high-functioning ASD on a computerized ball-toss game that required social interactions with fictitious partners.

In Chapters 8 and 11 I described the role of a circuit of mirror neurons in the perception of emotions and behavioral intentions. This circuit is activated when we see another person produce an expression of emotion or perform a goal-directed action, and feedback from this activity helps us to understand what the person feels or is trying to accomplish. In other words, the mirror neuron system may be involved in our ability to understand what people are trying to do and to empathize with their emotions.

Iacoboni and Dapretto ( 2006 ) suggest that the social deficits seen in autism may be a result of abnormal development of the mirror neuron system. In fact, a functional-imaging study by Dapretto et al. ( 2006 ) observed deficient activation in the mirror motor neuron system of autistic children, and structural MRI study by Hadjikhani et al. ( 2006 ) found that the cerebral cortex in the mirror neuron system was thinner in autistics. A study by Senju et al. ( 2007 ) even found that children with autism failed to yawn when they saw a video of other people yawning. Control subjects showed an increased rate of yawning during or immediately after seeing videos that depicted yawning but not those that depicted other kinds of mouth movements. Presumably, the mirror neuron system is involved in this type of imitation.

Baron-Cohen ( 2002 ) noted that the behavioral characteristics of people with autistic spectrum disorders appear to be exaggerations of the traits that tend to be associated with males. As we saw, the incidence of autistic spectrum disorders is four times more prevalent in males and that of Asperger’s disorder, in particular, nine times more prevalent. Baron-Cohen suggested that these disorders may be a reflection of an “extreme male brain.” For example, he noted that on average, females are better than males at inferring the thoughts or intentions of others, are more sensitive to facial expressions, are more likely to respond empathetically to the distress of others, and are more likely to share with others and take turns with them. On average, males are less likely to display these characteristics, and they are more likely to compete with their peers, to engage in rough-and-tumble play, and to establish dominance hierarchies. Males also tend to show more interest in toy vehicles, weapons, and building blocks and in pursuits such as engineering, metal-working, and computer programming and are generally better at map reading. In other words, males generally exhibit more interest in working with physical objects and logical systems than with social relations. According to Baron-Cohen, people with autistic spectrum disorders show an exaggerated pattern of masculine interests and behaviors. For example, the lack of interest in other people and an obsession with counting and lining-up objects in a row that is seen in many people with autism are seen as extreme examples of masculine traits.

We saw in Chapter 10 that sexual differentiation of the brain is largely controlled by exposure to prenatal androgens. Auyeung et al. ( 2009 ) used two tests that measure autistic traits to assess the behavior of normal children whose mothers had undergone amniocentesis (removal of a small amount of amniotic fluid during pregnancy). Auyeung and her colleagues found a significant positive correlation in both males and females between fetal testosterone levels and scores on these tests. In addition, Knickmeyer, Baron-Cohen, and Fane ( 2006 ) found that females with congenital adrenal hyperplasia, who were exposed to abnormally high levels of androgens during fetal development, had a greater number of autistic traits. Even if Baron-Cohen’s hypothesis is correct, we cannot conclude that autism is caused by prenatal exposure to excessive amounts of testosterone. An “extreme masculine brain” could be caused by genetic abnormalities that increase the sensitivity of a developing brain to androgens, and there could be (and probably are) other causes of autism that have nothing to do with masculinization of the brain.

FIGURE 17.7 Caudate Nucleus and Stereotyped Behavior in Autism

The graph shows repetitive behavior scores of people with autistic spectrum disorders as a function of the volume of the right caudate nucleus. Larger volumes are associated with higher scores.

(Adapted from Hollander et al., 2005 .)

Many investigators have noted that the presence of repetitive, stereotyped behavior and obsessive preoccupations with particular subjects resemble the symptoms of obsessive-compulsive disorder. As we saw earlier in this chapter, the symptoms of OCD appear to be related to increased activity of the caudate nucleus. Research suggests that the same may be true for the behavioral symptoms of autism. Several studies have observed increased volume of the caudate nucleus in autism (Sears et al., 1999 ; Langen et al., 2007 ). In fact, Hollander et al. ( 2005 ) found that the volume of the right caudate nucleus was positively correlated with ratings of repetitive behavior in patients with ASD. (See Figure 17.7 . )

SECTION SUMMARY: Autistic Disorder

The incidence of autistic disorder is 0.6–1.0 percent. It is characterized by poor or absent social relations and communicative abilities and the presence of repetitive, stereotyped movements. Although autistics are usually, but not always, mentally retarded, they may have a particular, isolated talent. Autistic people have difficulty predicting the behavior of other people or forming a theory of mind to explain why they are acting as they do. They tend not to pay attention to other people’s faces, as reflected in the lack of activation of the fusiform face area when they do so, and their ability to perceive emotional expressions on other people’s faces is impaired. Childhood immunization does not play a role in the development of autism.

In the past, clinicians blamed parents for autism, but now it is generally accepted as a disorder with biological roots. Genetic studies have shown that autism is highly heritable but that many different genes are responsible for its development. Autism can also be caused by events that interfere with prenatal development, such as prenatal thalidomide or maternal infection with rubella. MRI studies indicate that the brains of babies who become autistic show abnormally rapid growth until two to three years of age and then grow more slowly than the brains of unaffected children. The amygdala follows a similar pattern of development. Regions of the brain involved in higher-order processes such as communicative functions and interpretation of social stimuli develop more quickly in the autistic brain but then fail to continue to develop normally.

Some characteristics of autism can be seen as exaggerations of behaviors more often seen in males, which has led to the “extreme male brain” hypothesis.

■ THOUGHT QUESTION

Have you heard about research that suggests that childhood immunizations are associated with the development of autism? Have you heard (before reading this chapter) that the publication that reported this research and its principal author have been discredited? Why do you think that many parents are still fearful about having their children immunized?

Attention-Deficit/Hyperactivity Disorder

Some children have difficulty concentrating, remaining still, and working on a task. At one time or other, most children exhibit these characteristics. But children with attention-deficit/hyperactivity disorder (ADHD) display these symptoms so often that they interfere with the children’s ability to learn.

attention-deficit/hyperactivity disorder (ADHD) A disorder characterized by uninhibited responses, lack of sustained attention, and hyperactivity; first shows itself in childhood.

Description

ADHD is the most common behavior disorder that shows itself in childhood. It is usually first discovered in the classroom, where children are expected to sit quietly and pay attention to the teacher or work steadily on a project. Some children’s inability to meet these expectations then becomes evident. They have difficulty withholding a response, act without reflecting, often show reckless and impetuous behavior, and let interfering activities intrude into ongoing tasks.

According to the DSM-IV, the diagnosis of ADHD requires the presence of six or more of nine symptoms of inattention and six or more of nine symptoms of hyperactivity and impulsivity that have persisted for at least six months. Symptoms of inattention include such things as “often had difficulty sustaining attention in tasks of play activities” or “is often easily distracted by extraneous stimuli,” and symptoms of hyperactivity and impulsivity include such things as “often runs about or climbs excessively in situations in which it is inappropriate” or “often interrupts or intrudes on others (e.g., butts into conversations or games)” (American Psychiatric Association, 1994 , pp. 64–65).

ADHD can be very disruptive of a child’s education and that of other children in the same classroom. It is seen in 4–5 percent of grade school children. Boys are about ten times more likely than girls to receive a diagnosis of ADHD, but in adulthood the ratio is approximately 2 to 1, which suggests that many girls with this disorder fail to be diagnosed. Because the symptoms can vary—some children’s symptoms are primarily those of inattention, some are those of hyperactivity, and some show mixed symptoms—most investigators believe that this disorder has more than one cause. Diagnosis is often difficult because the symptoms are not well defined. ADHD is often associated with aggression, conduct disorder, learning disabilities, depression, anxiety, and low self-esteem. Approximately 60 percent of children with ADHD continue to display symptoms of this disorder into adulthood, at which time a disproportionate number develop antisocial personality disorder and substance abuse disorder (Ernst et al., 1998 ). Adults with ADHD are also more likely to show cognitive impairments and lower occupational attainment than would be predicted by their education (Seidman et al., 1998 ). The most common treatment for ADHD is administration of methylphenidate (Ritalin), a drug that inhibits the reuptake of dopamine. Amphetamine, another dopamine agonist, also reduces the symptoms of ADHD, but this drug is used much less often.

Possible Causes

There is strong evidence from both family studies and twin studies that hereditary factors play an important role in determining a person’s likelihood of developing ADHD. The estimated heritability of ADHD is high, ranging from 75 to 91 percent (Thapar, O’Donovan, and Owen, 2005 ).

According to Sagvolden and his colleagues (Sagvolden and Sergeant, 1998 ; Sagvolden et al., 2005 ), the impulsive and hyperactive behaviors that are seen in children with ADHD are the result of a delay of reinforcement gradient that is steeper than normal. As we saw in Chapter 13 , the occurrence of an appetitive stimulus can reinforce the behavior that just preceded it. For example, a piece of food can reinforce the lever press that a rat just made, and a smile can reinforce a person’s attempts at conversation. Reinforcing stimuli are most effective if they immediately follow a behavior: The longer the delay, the less effective the reinforcement. Sagvolden and Sergeant suggest that deficiencies in dopaminergic transmission in the brains of people with ADHD increase the steepness of their delay of reinforcement gradient, which means that immediate reinforcement is even more effective in these children, but even slightly delayed reinforcement loses its potency. (See Figure 17.8 . )

FIGURE 17.8 Hypothetical Delay of Reinforcement Gradients in ADHD

The graph illustrates different delay of reinforcement gradients as a function of time. Sagvolden and Sergeant ( 1998 ) hypothesize that a steeper gradient is responsible for the impulsive behavior of children with ADHD.

Why would a steeper delay of reinforcement gradient produce the symptoms of ADHD? According to Sagvolden and his colleagues, for people with a steep gradient, reinforcement with a short delay will be even more effective, thus producing overactivity. On the other hand, these people will be less likely to engage in behaviors that are followed by delayed reinforcement, as many of our behaviors (especially classroom activities) are. In support of this hypothesis, Sagvolden et al. ( 1998 ) trained normal boys and boys with ADHD on an instrumental conditioning task. When a signal was present, responses would be reinforced every 30 seconds with coins or trinkets. When the signal was not present, responses were never reinforced. The normal boys learned to respond only when the signal was present. When the signal was off, they waited patiently until it came on again. In contrast, the boys with ADHD showed impulsive behavior—intermittent bursts of rapid responses whether the signal was present or not. According to the investigators, this pattern of responding was what would be expected by a steep delay of reinforcement gradient.

The symptoms of ADHD resemble those produced by damage to the prefrontal cortex: distractibility, forgetfulness, impulsivity, poor planning, and hyperactivity (Aron, Robbins, and Poldrack, 2004 ). As we saw in Chapter 13 , the prefrontal cortex plays a critical role in short-term memory. We use short-term memory to remember what we have just perceived, to remember information that we have just recalled from long-term memory, and to process (“work on”) all of this information. For this reason, short-term memory is often referred to as working memory. The prefrontal cortex uses working memory to guide thoughts and behavior, regulate attention, monitor the effects of our actions, and organize plans for future actions (Arnsten, 2009 ). Damage or abnormalities in the neural circuits that perform these functions give rise to the symptoms of ADHD.

As we saw in Chapter 16 , the fact that dopamine antagonists were discovered to reduce the positive symptoms of schizophrenia suggested the hypothesis that schizophrenia is caused by overactivity of dopaminergic transmission. Similarly, the fact that methylphenidate, a dopamine agonist, alleviates the symptoms of ADHD has suggested the hypothesis that this disorder is caused by underactivity of dopaminergic transmission. As we saw in Chapter 13 , normal functioning of the prefrontal cortex is impaired by low levels of dopamine receptor stimulation in this region, so the suggestion that abnormalities in dopaminergic transmission play a role in ADHD seem reasonable.

Berridge et al. ( 2006 ) administered methylphenidate to rats and established a moderate dose that improved their performance on tasks that required attention and working memory—tasks that involve the participation of the prefrontal cortex. They used microdialysis to measure the release of dopamine and norepinephrine and found that the drug increased the levels of both of these neurotransmitters in the prefrontal cortex but not in other brain regions. A follow-up study by Devilbiss and Berridge ( 2008 ) found that a moderate dose of methylphenidate increased the responsiveness of neurons in the prefrontal cortex. A high dose of methylphenidate profoundly suppressed neural activity.

FIGURE 17.9 An Inverted U Curve

The graph illustrates an inverted U-curve function, in which low and high values of the variable on the horizontal axis are associated with low values of the variable on the vertical axis and moderate values are associated with high values. Presumably, the relationship between brain dopamine levels and the symptoms of ADHD follow a function like this one.

Many studies have shown that the effect of dopamine levels in the prefrontal cortex on the functions of this region follow an inverted U-shaped curve. (See Figure 17.9 . ) Graphs of many behavioral functions have an inverted U shape. For example, moderate levels of motivation increase performance on most tasks, but very low levels fail to induce a person to perform, and very high levels tend to make people nervous and interfere with their performance. The dose-response curve for the effects of methylphenidate also follow an inverted U-shaped function, which is why Berridge and his colleagues tested different doses of the drug to find a dose that optimized the animals’ performance. Clinicians have found the same to be true for the treatment of ADHD: Doses that are too low are ineffective, and doses that are too high produce increases in activity level that disrupt children’s attention and cognition.

Good evidence that the levels of dopamine in the human prefrontal cortex have effects on behavior comes from studies of people with two different variants of the gene for an enzyme that affects dopamine levels in the brain. COMT (catechol-O-methyltransferase) is an enzyme that breaks down catecholamines (including dopamine and norepinephrine) in the extracellularfluid. Although reuptake is the primary means of removing catecholamines from the synapse, COMT also plays a role in deactivating these neurotransmitters after they are released. Mattay et al. ( 2003 ) noted that the clinical effects of amphetamine (which are similar to those of methylphenidate) are variable. In some people, amphetamine increases positive mood and facilitates performance on cognitive tasks, but in other people it has the opposite effect. Mattay et al. tested the effect of amphetamine on tasks that made demands on working memory in people with two different variants of the COMT gene. They found that people with the val-valvariant, who have lower brain levels of catecholamines, performed better when they were given low doses of amphetamine. In contrast, administration of amphetamine to people with the met-met variant, who have higher brain levels of catecholamines, actually impaired their performance. Presumably, the first group was pushed up the U-shaped curve, and the second group, already around the top of the curve, was pushed down the other side. (See Figure 17.10 . )

FIGURE 17.10 Interactions Between Amphetamine and COMT Alleles on Working Memory

The graph shows the differential effects of amphetamine on the performance on a working memory task of people with two different variants of the gene for the COMT enzyme. The performance of people with the val-val variant was enhanced by amphetamine, and the performance of people with the met-met variant was reduced.

(Based on data from Mattay et al., 2003 .)

I mentioned a few paragraphs ago that Berridge et al. ( 2006 ) found that methylphenidate increased the level of both dopamine and norepinephrine in the prefrontal cortex. It appears that both of these effects improve the symptoms of ADHD. Drugs that block α2 receptors (one of the families of receptors that respond to norepinephrine) impair performance of monkeys on working-memory tasks and produce the symptoms of ADHD. Conversely, that stimulate these receptors improve performance (Arnsten and Li, 2005 ). Evidence suggests that optimal levels of both dopamine and norepinephrine in the prefrontal cortex facilitate the functions of this region, and the effects of methylphenidate on both of these neurotransmitters is responsible for the drug’s therapeutic effects.

We saw in the previous section that the brains of children with autism develop differently from those of unaffected children. A study by Shaw et al. ( 2007 ) found differences in the development of the brains of children with ADHD as well. The investigators found that cortical growth was delayed in children with ADHD. In fact, the cortical thickness of the brains of children with ADHD at age 10.5 years was about the same as that of the brains of unaffected children at 7.5 years. Ultimately, the growth of the brains of the children with ADHD caught up with those of unaffected children.

Most investigators believe that ADHD is caused by abnormalities in a network of brain regions that involves the striatum (caudate nucleus and putamen) as well as the prefrontal cortex, which has reciprocal connections with the striatum. Functional-imaging studies lend support to this hypothesis. Studies have reported decreased activation of the caudate nucleus (Rubia et al., 1999 ; Durston et al., 2003 ; Vaidya et al., 2005 ) or medial prefrontal cortex (Rubia et al., 1999 ; Tamm et al., 2004 ) while subjects with ADHD were performing tasks that required careful attention and the ability to inhibit a response. Given the importance of dopaminergic innervation of both regions, abnormalities in dopaminergic transmission may be responsible for the alterations in brain functions.

SECTION SUMMARY: Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder is the most common behavior disorder that first appears in childhood. Children with ADHD show symptoms of inattention, hyperactivity, and impulsivity. The most common medical treatment is methylphenidate, a dopamine agonist.

Family and twin studies indicate a heritable component in this disorder. Evidence suggests that a steeper delay of reinforcement gradient may account for impulsiveness and hyperactivity. Molecular genetic studies have found an association between ADHD and different alleles for COMT, an enzyme that deactivates monoamines.

Growth of the brains of children with ADHD follows that of the brains of unaffected children, but the rate of growth is slower. Most investigators believe that ADHD is caused by abnormalities in a network of brain regions that involves the striatum and the prefrontal cortex. Functional-imaging studies have shown hypoactivation of these structures in the brains of people with ADHD while they are performing tasks that require careful attention and the ability to inhibit a response.

Stress Disorders

Aversive stimuli can harm people’s health. Many of these harmful effects are produced not by the stimuli themselves but by our reactions to them. Walter Cannon, the physiologist who criticized the James-Lange theory described in Chapter 11 , introduced the term stress to refer to the physiological reaction caused by the perception of aversive or threatening situations.

stress A general, imprecise term that can refer either to a stress response or to a situation that elicits a stress response.

The word stress was borrowed from engineering, in which it refers to the action of physical forces of mechanical structures. The word can be a noun or a verb; and the noun can refer to situations or the individual’s response to them. When we say that someone was subjected to stress, we really mean that someone was exposed to a situation that elicited a particular reaction in that person: a stress response .

The physiological responses that accompany the negative emotions prepare us to threaten rivals or fight them or to run away from dangerous situations. Walter Cannon introduced the phrase fight-or-flight response to refer to the physiological reactions that prepare us for the strenuous efforts required by fighting or running away. Normally, once we have bluffed or fought with an adversary or run away from a dangerous situation, the threat is over, and our physiological condition can return to normal. The fact that the physiological responses may have adverse long-term effects on our health is unimportant as long as the responses are brief. But sometimes, the threatening situations are continuous rather than episodic, producing a more or less continuous stress response. And as we will see in the section on posttraumatic stress disorder, sometimes threatening situations are so severe that they trigger responses that can last for months or years.

stress response A physiological reaction caused by the perception of aversive or threatening situations.

fight-or-flight response A species-typical response preparatory to fighting or fleeing; thought to be responsible for some of the deleterious effects of stressful situations on health.

Physiology of the Stress Response

As we saw in Chapter 11 , emotions consist of behavioral, autonomic, and endocrine responses. The latter two components, the autonomic and endocrine responses, are the ones that can have adverse effects on health. (Well, I guess the behavioral components can, too, if a person rashly gets into a fight with someone who is much bigger and stronger.) Because threatening situations generally call for vigorous activity, the autonomic and endocrine responses that accompany them are catabolic; that is, they help to mobilize the body’s energy resources. The sympathetic branch of the autonomic nervous system is active, and the adrenal glands secrete epinephrine, norepinephrine, and steroid stress hormones. Because the effects of sympathetic activity are similar to those of the adrenal hormones, I will limit my discussion to the hormonal responses.

Epinephrine affects glucose metabolism, causing the nutrients stored in muscles to become available to provide energy for strenuous exercise. Along with norepinephrine, the hormone also increases blood flow to the muscles by increasing the output of the heart. In doing so, it also increases blood pressure, which, over the long term, contributes to cardiovascular disease.

Besides serving as a stress hormone, norepinephrine is (as you know) secreted in the brain as a neurotransmitter. Some of the behavioral and physiological responses produced by aversive stimuli appear to be mediated by noradrenergic neurons. For example, microdialysis studies have found that stressful situations increase the release of norepinephrine in the hypothalamus, frontal cortex, and lateral basal forebrain (Yokoo et al., 1990 ; Cenci et al., 1992 ). Montero, Fuentes, and Fernandez-Tome ( 1990 ) found that destruction of the noradrenergic axons that ascend from the brain stem to the forebrain prevented the rise in blood pressure that is normally produced by social isolation stress. The stress-induced release of norepinephrine in the brain is controlled by a pathway from the central nucleus of the amygdala to the locus coeruleus, the nucleus of the brain stem that contains norepinephrine-secreting neurons (Van Bockstaele et al., 2001 ).

The other stress-related hormone is cortisol, a steroid secreted by the adrenal cortex. Cortisol is called a glucocorticoid because it has profound effects on glucose metabolism. In addition, glucocorticoids help to break down protein and convert it to glucose, help to make fats available for energy, increase blood flow, and stimulate behavioral responsiveness, presumably by affecting the brain. They decrease the sensitivity of the gonads to luteinizing hormone (LH), which suppresses the secretion of the sex steroid hormones. In fact, Singer and Zumoff (1992) found that the blood level of testosterone in male hospital residents (doctors, not patients) was severely depressed, presumably because of the stressful work schedule they were obliged to follow. Glucocorticoids have other physiological effects, too, some of which are only poorly understood. Almost every cell in the body contains glucocorticoid receptors, which means that few of them are unaffected by these hormones.

glucocorticoid One of a group of hormones of the adrenal cortex that are important in protein and carbohydrate metabolism, secreted especially in times of stress.

The secretion of glucocorticoids is controlled by neurons in the paraventricular nucleus of the hypothalamus (PVN), whose axons terminate in the median eminence, where the hypothalamic capillaries of the portal blood supply to the anterior pituitary gland are located. (The pituitary portal blood supply was described in Chapter 3 .) The neurons of the PVN secrete a peptide called corticotropin-releasing hormone (CRH) , which stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH) . ACTH enters the general circulation and stimulates the adrenal cortex to secrete glucocorticoids. (See Figure 17.11 . )

corticotropin-releasing hormone (CRH) A hypothalamic hormone that stimulates the anterior pituitary gland to secrete ACTH (adrenocorticotropic hormone).

adrenocorticotropic hormone (ACTH) A hormone released by the anterior pituitary gland in response to CRH; stimulates the adrenal cortex to produce glucocorticoids.

CRH (also called CRF, or corticotropin-releasing factor) is also secreted within the brain, where it serves as a neuromodulator/neurotransmitter, especially in regions of the limbic system that are involved in emotional responses, such as the periaqueductal gray matter, the locus coeruleus, and the central nucleus of the amygdala. The behavioral effects produced by an injection of CRH into the brain are similar to those produced by aversive situations; thus, some elements of the stress response appear to be produced by the release of CRH by neurons in the brain. For example, intracerebroventricular injection of CRH decreases the amount of time a rat spends in the center of a large open chamber (Britton et al., 1982 ), enhances the acquisition of a classically conditioned fear response (Cole and Koob, 1988 ), and increases the startle response elicited by a sudden loud noise (Swerdlow et al., 1986 ). On the other hand, intracerebroventricular injection of a CRH antagonist reduces the anxiety caused by a variety of stressful situations (Kalin, Sherman, and Takahaski, 1988 ; Heinrichs et al., 1994 ; Skutella et al., 1994 ).

FIGURE 17.11 Control of Secretion of Stress Hormones

The diagram illustrates control of the secretion of glucocorticoids by the adrenal cortex and of catecholamines by the adrenal medulla.

The secretion of glucocorticoids does more than help an animal react to a stressful situation: It helps the animal to survive. If a rat’s adrenal glands are removed, the rat becomes much more susceptible to the effects of stress. In fact, a stressful situation that a normal rat would take in its stride might kill one whose adrenal glands have been removed. And physicians know that if an adrenalectomized person is subjected to stressors, he or she must be given additional amounts of glucocorticoid (Tyrell and Baxter, 1981 ).

Health Effects of Long-Term Stress

Many studies of people who have been subjected to stressful situations have found evidence of ill health. For example, survivors of concentration camps, who were obviously subjected to long-term stress, have had generally poorer health later in life than other people of the same age (Cohen, 1953 ). Drivers of subway trains that injure or kill people are more likely to suffer from illnesses several months later (Theorell et al., 1992 ). Air traffic controllers, especially those who work at busy airports where the danger of collisions is greatest, show a greater incidence of high blood pressure, which gets worse as they grow older (Cobb and Rose, 1973 ). (See Figure 17.12 . ) They also are more likely to suffer from ulcers or diabetes.

FIGURE 17.12 Stress and Hypertension

The graph shows the incidence of hypertension in various age groups of air traffic controllers at high-stress and low-stress airports.

(Based on data from Cobb and Rose, 1973 .)

A pioneer in the study of stress, Hans Selye suggested that most of the harmful effects of stress were produced by the prolonged secretion of glucocorticoids (Selye, 1976 ). Although the short-term effects of glucocorticoids are essential, the long-term effects are damaging. These effects include increased blood pressure, damage to muscle tissue, steroid diabetes, infertility, inhibition of growth, inhibition of the inflammatory responses, and suppression of the immune system. High blood pressure can lead to heart attacks and stroke. Inhibition of growth in children who are subjected to prolonged stress prevents them from attaining their full height. Inhibition of the inflammatory response makes it more difficult for the body to heal itself after an injury, and suppression of the immune system makes an individual vulnerable to infections. Long-term administration of steroids to treat inflammatory diseases often produces cognitive deficits and can even lead to steroid psychosis, whose symptoms include profound distractibility, anxiety, insomnia, depression, hallucinations, and delusions (Lewis and Smith, 1983 ; de Kloet, Joëls, and Holsboer, 2005 ).

FIGURE 17.13 Stress and Healing of Wounds

The graph shows the percentage of caregivers and control subjects whose wounds had healed as a function of time after the biopsy was performed.

(Based on data from Kiecolt-Glaser et al., 1995 .)

The adverse effects of stress on healing were demonstrated in a study by Kiecolt-Glaser et al. ( 1995 ), who performed punch biopsy wounds in the subjects’ forearms, a harmless procedure that is used often in medical research. The subjects were people who were providing long-term care for relatives with Alzheimer’s disease—a situation that is known to cause stress—and control subjects of the same approximate age and family income. The investigators found that healing of the wounds took significantly longer in the caregivers (48.7 days versus 39.3 days). (See Figure 17.13 . ) A subsequent study (Kiecolt-Glaser et al., 2005) found that the wounds of couples who displayed high levels of hostile behavior healed more slowly than those of couples with more friendly interactions.

Effects of Stress on the Brain

Sapolsky and his colleagues have investigated one rather serious long-term effect of stress: brain damage. As you learned in Chapter 14 , the hippocampal formation plays a crucial role in learning and memory, and evidence suggests that one of the causes of memory loss that occurs with aging is degeneration of this brain structure. Research with animals has shown that long-term exposure to glucocorticoids destroys neurons located in field CA1 of the hippocampal formation. The hormone appears to destroy the neurons by decreasing the entry of glucose and decreasing the reuptake of glutamate (Sapolsky, 1992 , 1995 ; McEwen and Sapolsky, 1995 ). Both of these effects make neurons more susceptible to potentially harmful events, such as decreased blood flow, which often occurs as a result of the aging process. The increased amounts of extracellular glutamate permit calcium to enter through NMDA receptors. (You will recall that the entry of excessive amounts of calcium can kill neurons.) Perhaps, then, the stressors to which people are subjected throughout their lives increase the likelihood of memory problems as they grow older. In fact, Lupien et al. ( 1996 ) found that elderly people with elevated blood levels of glucocorticoids learned a maze more slowly than did those with normal levels.

Prenatal stress can cause long-lasting malfunctions in learning and memory by interfering with normal development of the hippocampus. Son et al. ( 2006 ) subjected pregnant mice to stress caused by periodic restraint in a small chamber. They found that this treatment interfered with the establishment of hippocampal long-term potentiation in the offspring of the stressed females, along with impairments in a spatial learning task that requires the participation of the hippocampus.

Brunson et al. ( 2005 ) confirmed that stress early in life can cause the deterioration of normal hippocampal functions later in life. During the first week after delivery the investigators placed female rats and their newborn pups in cages with hard floors and only a small amount of nesting material. When the animals were tested at 4–5 months of age, their behavior was normal. However, when they were tested at 12 months of age, the investigators observed impaired performance in the Morris water maze and deficient development of long-term potentiation in the hippocampus. They also found dendritic atrophy in the hippocampus, which might have accounted for the impaired spatial learning and synaptic plasticity.

Even brief exposure to stress can have adverse effects on normal brain functioning. Diamond and his colleagues (Diamond et al., 1999 ; Mesches et al., 1999 ) placed rats individually in a Plexiglas box and then placed the box in a cage with a cat for 75 minutes. Although the cat could not harm the rats, the cat’s presence (and odor) clearly alarmed the rats and elicited a stress response; the stressed rats’ blood glucocorticoid increased to approximately five times its normal level. The investigators found that this short-term stress affected the functioning of the animals’ hippocampus. The stressed rats’ ability to learn a spatial task was impaired, and primed-burst potentiation (a form of long-term potentiation) was impaired in hippocampal slices taken from stressed rats. (See Figure 17.14 . ) A study by Thomas, Hotsenpiller, and Peterson ( 2007 ) found that acute stress diminished the long-term survival of hippocampal neurons produced by the process of neurogenesis. As we saw in Chapter 16 , impaired hippocampal neurogenesis appears to play a role in the development of depression.

Salm et al. ( 2004 ) found that mild prenatal stress can affect brain development and produce changes that last the animal’s lifetime. Once a day during the last week of gestation, they removed pregnant rats from their cage and gave them an injection of a small amount of sterile saline—a procedure that lasted less than five minutes. This mild stress altered the development of their amygdalas. The investigators found that the volume of the lateral nucleus of the amygdala, measured in adulthood, was increased by approximately 30 percent in the animals that sustained mild prenatal stress. (See Figure 17.15 . ) As previous experiments have shown, prenatal stress increases fearfulness in a novel environment (Ward et al., 2000 ). Presumably, the increased size of the lateral nucleus contributes to this fearfulness.

FIGURE 17.14 Acute Stress, Glucocorticoid Level, Synaptic Plasticity, and Learning

The graphs show the effects of acute stress caused by exposing a rat to the sight and smell of a cat. The stress raised the glucocorticoid level (corticosterone, in the case of a rat), impaired the development of primed-burst potentiation (PBP, a form of long-term potentiation) in slices taken from these animals, and interfered with learning of a spatial task that requires the hippocampus.

(Based on data from Diamond et al., 1999 .)

A study by Fenoglio, Chen, and Baram ( 2006 ) found that experiences that occur during early life can reduce reactivity to stressful situations in adulthood. Fenoglio and her colleagues removed rat pups from their cage, handled them for fifteen minutes, and then returned them to their cage. Their mother immediately began licking and grooming the pups. This nurturing behavior activated several regions of the pups’ brains, including the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus, the location of neurons that secrete CRH. The result of this treatment was to reduce the production of CRH in response to stressful stimuli, which conferred a lifelong attenuation of the hormonal stress response.

At least some of the effects of prenatal stress on the fetus appear to be mediated by the secretion of glucocorticoids. Barbazanges et al. ( 1996 ) subjected pregnant female rats to stress and later observed the effects of this treatment on their offspring once they grew up. They found that the prenatally stressed rats showed a prolonged secretion of glucocorticoids when they were subjected to restraint stress. However, if the mothers’ adrenal glands had been removed so that glucocorticoid levels could not increase during the stressful situation, their offspring reacted normally in adulthood. (The experimenters gave the adrenalectomized mothers controlled amounts of glucocorticoids to maintain them in good health.) (See Figure 17.16 . )

FIGURE 17.15 Prenatal Stress and the Amygdala

The graph shows volumes of nuclei of the amygdala in control rats and rats that had been subjected to prenatal stress.

(Based on data from Salm et al., 2004 .)

Uno et al. ( 1989 ) found that if long-term stress is intense enough, it can even cause severe brain damage in young primates. The investigators studied a colony of vervet monkeys housed in a primate center in Kenya. They found that some monkeys died, apparently from stress. Vervet monkeys have a hierarchical society, and monkeys near the bottom of the hierarchy are picked on by the others; thus, they are almost continuously subjected to stress. (Ours is not the only species with social structures that cause a stress reaction in some of its members.) The deceased monkeys had gastric ulcers and enlarged adrenal glands, which are signs of chronic stress. And as Figure 17.17 shows, neurons in the CA1 field of the hippocampal formation were completely destroyed. (See Figure 17.17 . ) Severe stress appears to cause brain damage in humans as well; Jensen, Genefke, and Hyldebrandt ( 1982 ) found evidence of brain degeneration in CT scans of people who had been subjected to torture. More mild forms of stress early in life also appear to affect brain development. van Harmelen et al. ( 2010 ) found that episodes of emotional maltreatment during childhood was associated with an average 7.2 percent reduction in the volume of the dorsomedial prefrontal cortex. (See Figure 17.18 . )

FIGURE 17.16 Prenatal Stress and Glucocorticoids in Adulthood

The graph shows the effects of prenatal stress and glucocorticoid level on the stress response of adult rats. Adrenalectomy of the mother before she was subjected to stress prevented the development of an elevated stress response in the offspring during adulthood.

(Based on data from Barbazanges et al., 1996 .)

Several studies have confirmed that the stress of chronic pain has adverse effects on the brain and on cognitive behavior. Apkarian et al. ( 2004b ) found that each year of severe chronic back pain resulted in the loss of 1.3 cm3 of gray matter in the cerebral cortex, with the greatest reductions seen in the dorsolateral prefrontal cortex. In addition, Apkarian et al. ( 2004a ) found that chronic back pain led to poor performance on a task that has been shown to be affected by prefrontal lesions.

FIGURE 17.17 Brain Damage Caused by Stress

The photomicrographs show sections through the hippocampus. (a) A normal monkey. (b) A monkey of low social status subjected to stress. Compare the regions between the arrowheads, which are normally filled with large pyramidal cells.

(Based on data from Hollander et al., 2005 .)

FIGURE 17.18 Early Stress and the Prefrontal Cortex

The scans show the region of the dorsolateral prefrontal cortex that showed a 7.2 percent reduction in volume in adults who were subjected to emotional maltreatment during childhood.

(From van Harmelen, A. L., van Tol, M. J., van der Wee, N. J., et al. Biological Psychiatry, 2010, 68, 832–838. Reprinted by permission.)

Posttraumatic Stress Disorder

The aftermath of tragic and traumatic events such as those that accompany wars, violence, and natural disasters often includes psychological symptoms that persist long after the stressful events are over. According to the DSM IV, posttraumatic stress disorder (PTSD) is caused by a situation in which a person “experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others” that provoked a response that “involved intense fear, helplessness, or horror.” The likelihood of developing PTSD is increased if the traumatic event involved danger or violence from other people, such as assault, rape, or wartime experiences (Yehuda and LeDoux, 2007 ). The symptoms produced by such exposure include recurrent dreams or recollections of the event, feelings that the traumatic event is recurring (“flashback” episodes), and intense psychological distress. These dreams, recollections, or flashback episodes can lead the person to avoid thinking about the traumatic event, which often results in diminished interest in social activities, feelings of detachment from others, suppressed emotional feelings, and a sense that the future is bleak and empty. Particular psychological symptoms include difficulty falling or staying asleep, irritability, outbursts of anger, difficulty in concentrating, and heightened reactions to sudden noises or movements. As this description indicates, people with PTSD have impaired mental health functioning. They also tend to have generally poor physical health (Zayfert et al., 2002 ). Although men are exposed to traumatic events more often than women are, women are more likely to develop PTSD after being exposed to such events (Fullerton et al., 2001 ).

posttraumatic stress disorder (PTSD) A psychological disorder caused by exposure to a situation of extreme danger and stress; symptoms include recurrent dreams or recollections; can interfere with social activities and cause a feeling of hopelessness.

Evidence from twin studies suggest that genetic factors play a role in a person’s susceptibility to develop PTSD. In fact, genetic factors influence not only the likelihood of developing PTSD after being exposed to traumatic events but also the likelihood that the person will be involved in such an event (Stein et al., 2002 ). For example, people with a genetic predisposition toward irritability and anger are more likely to be assaulted, and those with a predisposition toward risky behavior are more likely to be involved in accidents. In a review of the Vietnam Era Twin Registry, Koenen et al. ( 2002 ) reported that the following demographic and personality factors predict an increased risk for being exposed to traumatic events: military service in Southeast Asia during the Vietnam war, a preexisting conduct disorder or substance dependence, and a family history of mood disorders. The following factors predict the risk of developing PTSD after exposure: earlier age at the time of the traumatic event; exposure to more than one traumatic event; a father with a depressive disorder; a low educational level; poor social support; and a preexisting conduct disorder, panic disorder, generalized anxiety disorder, or depressive disorder.

Although many people are exposed to potentially traumatic event during their lives, most of them recover rapidly and do not develop PTSD (Kessler et al., 1995 ). For example, Rothbaum and Davis ( 2003 ) reported that two weeks after having been raped, 92 percent of the victims showed symptoms that met the criteria for PTSD. However, within thirty days, the symptoms in most of the victims had subsided. Twin studies have shown that the overlap between PTSD and panic disorder, generalized anxiety disorder, and depressive disorder is at least partly a result of shared genetic factors (Nugent, Amstadter, and Koenen, 2008 ). Presumably, these genetic factors make some people more sensitive to the effects of stress.

A few studies have identified specific genes as possible risk factors for developing PTSD. These genes include those responsible for the production of dopamine D2 receptors, dopamine transporters, and 5-HT transporters (Nugent, Amstadter, and Koenen, 2008 ). The risk for PTSD appears to depend on both genetic and environmental factors. and Kolassa et al. ( 2010 ) studied 424 survivors of the genocide in the Rwanda. They found that the likelihood of developing PTSD increased with the number of traumatic events the person had experienced. (See Figure 17.19 . ) They also found that people with a particular allele of the gene responsible for the production of COMT, the enzyme that destroys catecholamines present in the interstitial fluid, were more likely to develop PTSD. This allele (the Val158Met polymorphism) is associated with slower destruction of catecholamines, which supports the conclusion from other research that these neurotransmitters are associated with the deleterious effects of stress.

FIGURE 17.19 Prevalence of PTSD and Traumatic Events

This graph shows the prevalence of PTSD in survivors of the Rwanda genocide as a function of the number of traumatic events they had suffered.

(Based on data from Kolassa et al., 2010 .)

As we saw in the previous subsection, studies with laboratory animals have shown that prolonged exposure to stress can cause brain abnormalities, particularly in the hippocampus and amygdala. At least two MRI studies have found evidence of hippocampal damage in veterans with combat-related posttraumatic stress disorder (Bremner et al., 1995 ; Gurvits et al., 1996 ). In the study by Gurvits et al., the volume of the hippocampal formation was reduced by over 20 percent, and the loss was proportional to the amount of combat exposure the veteran had experienced. Lindauer et al. ( 2005 ) found that police officers with PTSD had a smaller hippocampus than those who had also been exposed to trauma but had not developed the disorder.

An intriguing study by Gilbertson et al. ( 2002 ) suggests that at least part of the reduction in hippocampal volume seen in people with PTSD may predate the exposure to stress. In other words, a smaller hippocampus may be a predisposing factor in the acquisition of PTSD. Gilbertson and his colleagues studied forty pairs of monozygotic twins in which only one member went to Vietnam and experienced combat. Almost half of the men who experienced combat developed PTSD. As expected, the hippocampal volumes of these men were smaller than those of the men who did not develop PTSD after their combat experience. In addition, a smaller hippocampus was associated with more severe PTSD. The interesting fact is that the twin brothers of the PTSD patients who stayed home also showed smaller-than-average hippocampal volumes. Given that monozygotic twins are genetically identical and usually have very similar brains, this finding suggests that a person with a small hippocampus is more likely to develop PTSD after exposure to psychological trauma. (See Figure 17.20 . )

What role might the hippocampus play in a person’s susceptibility to developing PTSD? One possibility is that the hippocampus, which plays a role in contextual learning, participates in recognition of the context in which a traumatic event occurs. The hippocampus then aids in distinguishing safe from dangerous contexts (Yehuda and LeDoux, 2007 ). Consider a person who has been attacked by another person. The sight of other people who even slightly resemble the attacker or situations that even slightly resemble the one in which the attack occurred might then activate the amygdala and trigger an emotional response. However, a normally functioning hippocampus would detect the difference between the present context and the one associated with the attack and inhibit the activity of the amygdala.

I mentioned a few paragraphs ago that most people who are exposed to a potentially traumatic event manage to suppress their emotional reaction. What brain mechanisms suppress the emotional reaction and enable a person to recover? As we saw in Chapters 11 and 16 , the prefrontal cortex can exert an inhibitory effect on the amygdala and suppress emotional reactions. For example, the medial prefrontal cortex plays an essential role in the extinction of conditioned emotional responses. In fact, Milad, Vidal-Gonzalez, and Quirk (2005) found that the medial prefrontal cortex was thicker in people who showed rapid extinction of a conditioned emotional response. And as we also saw earlier, van Harmelen et al. ( 2010 ) found a reduction in the volume of the ventromedial prefrontal cortex in adults who had sustained emotional maltreatment during childhood.

FIGURE 17.20 Hippocampal Volumes of Pairs of Monozygotic Twins

The graph shows that the size of the hippocampus of twins not exposed to combat was similar to the size of their combat-exposed co-twins whether or not the co-twins had PTSD. These results suggest that hippocampal size is a genetically determined trait that predates the exposure to combat.

(Based on data from Gilbertson et al., 2002 .)

Several studies have found evidence that the amygdala is responsible for emotional reactions in people with PTSD and that the prefrontal cortex plays a role in these reactions in people without PTSD by inhibiting the activity of the amygdala (Rauch, Shin, and Phelps, 2006 ). For example, a functional-imaging study by Shin et al. ( 2005 ) found that, when shown pictures of faces with fearful expressions, people with PTSD show greater activation of the amygdala and smaller activation of the prefrontal cortex than did people without PTSD. In fact, the symptoms of the people with PTSD were positively correlated with the activation of the amygdala and negatively correlated with the activation of the medial prefrontal cortex. (See Figure 17.21 . )

The most common treatments for PTSD are cognitive behavior therapy, group therapy, and SNRIs. Boggio et al. ( 2010 ) report on the results of a clinical trial of transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex on thirty patients with PTSD. They found that ten sessions of stimulation of the left or right dlPFC significantly reduced the symptoms of PTSD and that the beneficial effects was still seen three months later. (See Figure 17.22 . )

FIGURE 17.21 Amygdala and Medial Prefrontal Cortex Activation in PTSD

The graph shows the activation of the amygdala and medial prefrontal cortex in response to the sight of happy or fearful faces in control subjects and subjects with PTSD.

(Based on data from Shin et al., 2005 .)

Psychoneuroimmunology

As we have seen, long-term stress can be harmful to one’s health and can even result in brain damage. The most important cause of these effects is elevated levels of glucocorticoids, but the high blood pressure caused by epinephrine and norepinephrine also plays a contributing role. In addition, the stress response can impair the functions of the immune system, which protects us from assault from viruses, microbes, fungi, and other types of parasites. Study of the interactions between the immune system and behavior (mediated by the nervous system, of course) is called psychoneuroimmunology . Some research in this field is described in the following subsection.

psychoneuroimmunology The branch of neuroscience involved with interactions among environmental stimuli, the nervous system, and the immune system.

FIGURE 17.22 Transcranial Magnetic Stimulation and PTSD

The graph shows the effects of TMS of the dorsolateral prefrontal cortex on symptoms of PTSD.

(Based on data from Boggio et al., 2010 .)

THE IMMUNE SYSTEM

The immune system is one of the most complex systems of the body. Its function is to protect us from infection; and because infectious organisms have developed devious tricks through the process of evolution, our immune system has evolved devious tricks of its own. The description I provide here is abbreviated and simplified, but it presents some of the important elements of the system.

The immune system derives from white blood cells that develop in the bone marrow and in the thymus gland. Some of the cells roam through the blood or lymphatic system; others reside permanently in one place. Two types of specific immune reaction occur when the body is invaded by foreign organisms, including bacteria, fungi, and viruses: chemically mediated and cell-mediated. Chemically mediated immune reactions involve antibodies. Infectious microorganisms have unique proteins on their surfaces, called antigens . These proteins serve as the invaders’ calling cards, identifying them to the immune system. Through exposure to the microorganisms, the immune system learns to recognize these proteins. (I will not try to explain the mechanism by which this learning takes place.) The result of this learning is the development of special lines of cells that produce specific antibodies —proteins that recognize antigens and help to kill the invading microorganism.

antigen A protein present on a microorganism that permits the immune system to recognize the microorganism as an invader.

antibody A protein produced by a cell of the immune system that recognizes antigens present on invading microorganisms.

One type of antibody is released into the circulation by B-lymphocytes , which receive their name from the fact that they develop in bone marrow. These antibodies, called immunoglobulins , are chains of protein. Each type of immunoglobulin (there are five of them) is identical except for one end, which contains a unique receptor. A particular receptor binds with a particular antigen, just as a molecule of a hormone or neurotransmitter binds with its receptor. When the appropriate line of B-lymphocytes detects the presence of an invading bacterium, the cells release their antibodies, which bind with the antigens present on the surface of the invading microorganisms. The antigens either kill the invaders directly or attract other white blood cells, which then destroy them. (See Figure 17.23a . )

B-lymphocyte A white blood cell that originates in the bone marrow; part of the immune system.

immunoglobulin An antibody released by B-lymphocytes that bind with antigens and help to destroy invading microorganisms.

FIGURE 17.23 Immune Reactions

(a) Chemically mediated reaction. The B-lymphocyte detects an antigen on a bacterium and releases a specific immunoglobulin. (b) Cell-mediated reaction. The T-lymphocyte detects an antigen on a bacterium and kills it directly or releases a chemical that attracts other white blood cells.

The other type of defense by the immune system, cell-mediated immune reactions, is produced by T-lymphocytes , which originally develop in the thymus gland. These cells also produce antibodies, but the antibodies remain attached to the outside of their membrane. T-lymphocytes primarily defend the body against fungi, viruses, and multicellular parasites. When antigens bind with their surface antibodies, the cells either directly kill the invaders or signal other white blood cells to come and kill them. (See Figure 17.23b . )

T-lymphocyte A white blood cell that originates in the thymus gland; part of the immune system.

The reactions illustrated in Figure 17.23 are much simplified; actually, both chemically mediated and cell-mediated immune reactions involve several different types of cells. The communication between these cells is accomplished by cytokines , chemicals that stimulate cell division. The cytokines that are released by certain white blood cells when an invading microorganism is detected (principally interleukin-1 and interleukin-2) cause other white blood cells to proliferate and direct an attack against the invader. The primary way in which glucocorticoids suppress specific immune responses is by interfering with the messages conveyed by the cytokines (Sapolsky, 1992 ).

cytokine A category of chemicals released by certain white blood cells when they detect the presence of an invading microorganism; causes other white blood cells to proliferate and mount an attack against the invader.

NEURAL CONTROL OF THE IMMUNE SYSTEM

As we will see in the next subsection, the stress response can increase the likelihood of infectious diseases. What is the physiological explanation for these effects? One answer, probably the most important one, is that stress increases the secretion of glucocorticoids, and as we saw, these hormones directly suppress the activity of the immune system.

A direct relationship between stress and the immune system was demonstrated by Kiecolt-Glaser et al. ( 1987 ). Using several different laboratory tests, these investigators found that caregivers of family members with Alzheimer’s disease, who certainly underwent considerable stress, showed weaker immune systems. One measure of the quality of a person’s immune response is measurement of antibodies produced in response to a vaccination. Glaser et al. ( 2000 ) found that people taking care of spouses with Alzheimer’s disease maintained lower levels of IgG antibodies after receiving a pneumococcal bacterial vaccine. (See Figure 17.24 . ) Bereavement, another source of stress, also suppresses the immune system. Schleifer et al. ( 1983 ) tested the husbands of women with breast cancer and found that their immune response was lower after their wives died. Knapp et al. ( 1992 ) even found that when healthy subjects imagined themselves reliving unpleasant emotional experiences, the immune response measured in samples of their blood was decreased.

Several studies indicate that the suppression of the immune response by stress is largely (but not entirely) mediated by glucocorticoids (Keller et al., 1983 ). Because the secretion of glucocorticoids is controlled by the brain (through its secretion of CRH), the brain is obviously responsible for the suppressing effect of these hormones on the immune system. Neurons in the central nucleus of the amygdala send axons to CRH-secreting neurons in the paraventricular nucleus of the hypothalamus; thus, we can reasonably expect that the mechanism that is responsible for negative emotional responses is also responsible for the stress response and the immuno-suppression that accompanies it.

FIGURE 17.24 Effect of Stress on Immune Function

The graph shows levels of antibodies produced in response to a pneumococcal bacterial vaccine in the blood of controls and former and current caregivers of spouses with Alzheimer’s disease.

(Based on data from Glaser, R., Sheridan, J., Malarkey, W. B., MacCallum, R. C., and Kiecolt-Glaser, J. K. Psychosomatic Medicine, 2000, 62, 804–807.)

STRESS AND INFECTIOUS DISEASES

Often when a married person dies, his or her spouse dies soon afterward, frequently of an infection. In fact, a wide variety of stress-producing events in a person’s life can increase the susceptibility to illness. For example, Glaser et al. ( 1987 ) found that medical students were more likely to contract acute infections and to show evidence of suppression of the immune system during the time that final examinations were given.

Stone, Reed, and Neale ( 1987 ) attempted to determine whether stressful events in people’s daily lives might predispose them to upper respiratory infection. If a person is exposed to a microorganism that might cause such a disease, the symptoms do not occur for several days; that is, there is an incubation period between exposure and signs of the actual illness. Thus, the authors reasoned that if stressful events suppressed the immune system, one might expect to see a higher likelihood of respiratory infections several days after such stress. To test their hypothesis, they asked volunteers to keep a daily record of desirable and undesirable events in their lives over a twelve-week period. The volunteers also kept a daily record of any discomfort or symptoms of illness.

The results were as predicted: During the three- to five-day period just before showing symptoms of an upper respiratory infection, people experienced an increased number of undesirable events and a decreased number of desirable events in their lives. (See Figure 17.25 . )

FIGURE 17.25 Role of Desirable and Undesirable Events on Susceptibility to Upper Respiratory Infections

The graph shows mean percentage change in frequency of undesirable and desirable events during the ten-day period preceding the onset of symptoms of upper respiratory infections.

(Based on data from Stone et al., 1987 .)

FIGURE 17.26 Colds and Psychological Stress

The graph shows the percentage of subjects with colds as a function of an index of psychological stress.

(Based on data from Cohen et al., 1991 .)

Stone et al. ( 1987 ) suggest that the effect is caused by decreased production of a particular immunoglobulin that is present in the secretions of mucous membranes, including those in the nose, mouth, throat, and lungs. This immunoglobulin, IgA, serves as the first defense against infectious microorganisms that enter the nose or mouth. They found that IgA is associated with mood; when a subject is unhappy or depressed, IgA levels are lower than normal. The results suggest that the stress caused by undesirable events may, by suppressing the production of IgA, lead to a rise in the likelihood of upper respiratory infections.

The results of the study by Stone and his colleagues were confirmed by an experiment by Cohen, Tyrrell, and Smith ( 1991 ). The investigators found that subjects who were given nasal drops containing cold viruses were much more likely to develop colds if they reported stressful experiences during the past year and if they said they felt threatened, out of control, or overwhelmed by events. (See Figure 17.26 on page 611 .)

SECTION SUMMARY: Stress Disorders

People’s emotional reactions to aversive stimuli can harm their health. The stress response, which Cannon called the fight-or-flight response, is useful as a short-term response to threatening stimuli but is harmful in the long term. This response includes increased activity of the sympathetic branch of the autonomic nervous system and increased secretion of hormones by the adrenal gland: epinephrine, norepinephrine, and glucocorticoids. Corticotropin-releasing hormone, which stimulates the secretion of ACTH by the anterior pituitary gland, is also secreted in the brain, where it elicits some of the emotional responses to stressful situations.

Although increased levels of epinephrine and norepinephrine can raise blood pressure, most of the harm to health comes from glucocorticoids. Prolonged exposure to high levels of these hormones can increase blood pressure, damage muscle tissue, lead to infertility, inhibit growth, inhibit the inflammatory response, and suppress the immune system. It can also damage the hippocampus. Acute stress can also impair hippocampal functioning. Exposure to stress during prenatal or early postnatal life can affect brain development and behavior such as impaired functions of the hippocampus and increased size of the amygdala. Stress also decreases the survival rate of hippocampal neurons produced by adult neurogenesis. These changes appear to predispose animals to react more to stressful situations. In humans the stress of chronic pain can cause loss of cerebral gray matter, especially in the prefrontal cortex, with accompanying deficits in behaviors that involve the prefrontal cortex.

Exposure to extreme stress can also have long-lasting effects; it can lead to the development of posttraumatic stress disorder. This disorder is associated with memory deficits, poorer health, and a decrease in the size of the hippocampus. Twin studies indicate a hereditary component to susceptibility to PTSD. Predisposing factors appear to involve decreased hippocampal volume and differences in the genes for D2 receptors, dopamine transporters, and 5-HT transporters. The prefrontal cortex of people who are resistant to the development of PTSD following severe stress appears to inhibit the amygdala. The prefrontal cortex appears to be hypoactive in people with PTSD. Transcranial magnetic stimulation of the dorsolateral prefrontal cortex appears to reduce the symptoms of PTSD.

Psychoneuroimmunology is a field of study that investigates interactions between behavior and the immune system, mediated by the nervous system. The immune system consists of several types of white blood cells that produce both nonspecific and specific responses to invading microorganisms. The nonspecific responses include the inflammatory response, the antiviral effect of interferon, and the action of natural killer cells against viruses and cancer cells. The specific responses include chemically mediated and cell-mediated responses. Chemically mediated responses are carried out by B-lymphocytes, which release antibodies that bind with the antigens on microorganisms and kill them directly or target them for attack by other white blood cells. Cell-mediated responses are carried out by T-lymphocytes, whose antibodies remain attached to their membranes.

A wide variety of stressful situations have been shown to increase people’s susceptibility to infectious diseases. The most important mechanism by which stress impairs immune function is the increased blood levels of glucocorticoids. The neural input to the bone marrow, lymph nodes, and thymus gland may also play a role; and the endogenous opioids appear to suppress the activity of natural killer cells.

■ THOUGHT QUESTION

Researchers are puzzled by the fact that glucocorticoids suppress the immune system. Can you think of any potential benefits that come from the fact that our immune system is suppressed during times of danger and stress?

Review Questions

Study and Review on MyPsychLab

Describe the symptoms and possible causes of panic disorder.

Describe the symptoms and possible causes of obsessive-compulsive disorder.

Describe the symptoms and possible causes of autistic disorder.

Describe the symptoms and possible causes of attention-deficit/hyperactivity disorder.

Describe the physiological responses to stress and their effects on health.

Discuss posttraumatic stress disorder.

Discuss psychoneuroimmunology and the interactions between the immune system and stress.

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■ EMOTION AND STRESS

Dysregulation of the neural circuits involved in emotion and stress may underlie some psychopathologies, including anxiety disorders and stress disorders. The Emotion and Stress module of the virtual brain reviews the brain regions and circuits involved in these processes.