The Age Of Anxiety

Dr. Mark George admits his first impulse was to back-burner his research team's startling breakthrough. If that would mean letting other brain investigators luck into the same discovery, so be it. Those guys could have the glory--along with the grief of getting trapped in the ideological cross-fire of the war between the sexes. During the mid-'90s, George recalls, "it was almost taboo to talk about gender differences in the brain." Everyone was afraid of validating old sexual stereotypes and prejudices. George wanted only to keep on quietly doing his job at the National Institute of Mental Health, leading a pioneering effort to map the human brain at work. Through positron emission tomography (PET) scanning, a high-tech way of tracing precise areas of activity within the brain, George and his team were able to witness for the first time the hidden processes of human emotion.

The trouble arose when George began looking at the physiology of sorrow.

He asked his experimental volunteers to recall their saddest memories while he tracked the flow of blood inside their brains. The tests included both men and women, although George wasn't looking for discrepancies between them. Neither sex had much difficulty conjuring up suitably sad thoughts, and in both sexes the PET scans displayed a strong increase of circulation to parts of the limbic system, a primitive region deep within the brain. But there was a striking difference: the total area of the brain involved in the reaction was eight times larger in his women subjects than among the men. "I was quite afraid of the way the data might be interpreted in the general press," he says. The last thing he wanted was to be associated with sensational headlines about women's brains' being more "emotional" than men's.

George's boss at the NIMH urged him to publish the discovery promptly. It could be a vital piece in the puzzle of women's susceptibility to depression. The ensuing media reaction wasn't as disruptive as George had feared. Major news organizations, including NEWSWEEK, covered the story, but the press soon moved on and let the scientist get back to his lab. He continues his life's work, studying the brain's regulation of emotions. Gender differences are only a side issue for him. In most ways the brains of men and women are very much alike.

Even so, research into important differences has exploded since George's reluctant announcement in 1995. Each new finding inspires a burst of further research as scientists deepen their understanding of men's and women's brains. The explorers' basic equipment is equally new. With the state-of-the-art assistance of tools and techniques like the PET scan and functional magnetic resonance imaging (fMRI), a pathfinding generation of investigators is going where physicians since Hippocrates have barely dreamed of visiting. In some cases the discoveries have no practical value but to let women and men know themselves and each other a little better. In other cases the work has already begun rebuilding lives.

One particularly fruitful area of inquiry has been the study of stress-related ailments. Men traditionally have a higher propensity than women to act out aggressively and to abuse drugs and alcohol. Women, on the other hand, suffer disproportionately from a variety of emotional ailments, such as depression, anxiety attacks and eating disorders. Why? The question is far from academic to people struggling with such crippling problems as chronic depression. For what it's worth, approximately two out of every three depressives are female. At present the World Health Organization ranks depression as the world's fourth most devastating illness, measured in total years of healthy life stolen by death or disability. According to WHO projections, it will have climbed to second place by 2020, exceeded only by heart disease. One recent study says 17.1 percent of all Americans are likely to suffer at least one episode of major depression in their lifetime.

It's scarcely an overstatement to call the situation a public-health crisis. Medical researchers are racing to find solutions, although their progress can sometimes seem infuriatingly slow. "We are such complex and psychologically elegant creatures, it is unlikely there will ever be a 'simple' explanation for any behavioral disorder," says Dr. David Rubinow, clinical director of the NIMH in Bethesda, Md. Gradually scientists are sorting out the subtly interacting variables that lead to depression and other emotional disorders--a tangle of cultural, environmental, biological, genetic and personal factors. "We are learning that biology underlies the emotions," says Dr. Ellen Leibenluft of the NIMH. "Psychological events are biological events, with biological underpinnings." Translation: it's not all in your head.

Also it's not "just hormones." There's no doubt that estrogen and progesterone occupy pivotal roles in many mood and anxiety disorders--and in the routine metabolic functions of every healthy individual, male or female. Scientists have yet to sort out all the different vital tasks those ubiquitous substances perform, from the regulation of reproductive cycles to the imprinting and evoking of particular emotional responses in the brain. And the puzzle is made more complicated by the fact that different women react quite differently to identical amounts of the same hormone. "Some women's mood states appear to be affected by levels of hormones," says Leibenluft. "But in many women they are not. The question is not 'Do women's moods respond to [estrogen and progesterone]?' The question is 'Which women do the hormones affect, and why?' "

It's a short word and a huge question. Many patients appear to suffer from deficiencies or abnormalities in their neurotransmitters (the chemical messengers by which nerve cells communicate), especially the vasoconstrictor known as serotonin. And in the treatment of most mood and anxiety disorders, some of the most effective drugs belong to the pharmaceutical category of "selective serotonin reuptake inhibitors" (SSRIs), such as Prozac. The precise relationship between hormones, moods and neurotransmitters is at the cutting edge of brain research these days. Scientists at McGill University recently announced a particularly provocative discovery. According to their research, serotonin production is 53 percent higher in men's brains than in women's--one of the biggest gender divergences ever found in human brains. Doctors don't yet know what role serotonin plays in the regulation of emotions. The male's reserves of neurotransmitters may give extra emotional protection--but why should women be shortchanged? It's anybody's guess. These are exciting times for neurophysiologists--and even more so for victims of an array of crippling mood and anxiety disorders.

CLASSIC DEPRESSION: Researchers can actually see the shadow of the monster. It's visible on the PET scans of depression sufferers: a chilly blue blob of reduced blood flow on the left prefrontal lobe, along with apparent metabolic abnormalities in the anterior paralimbic regions. Those areas are established centers of emotional response. "It's very exciting," says Dr. Darren Daugherty, a psychiatrist and researcher at Boston's Massachusetts General Hospital. "We've learned which areas aren't working right--and it makes perfect sense that they don't." Neuropharmacologists have even felt the thrill of watching the shadows lift. As SSRI treatment takes effect in the patient's brain, blood flow in the affected areas rises to levels seen in healthy brains.

The transformation can be still more dramatic from the patient's point of view. The symptoms of major depression are devastating, including a prolonged loss of joy in most activities, exaggerated guilt, fatigue, inability to concentrate and recurrent thoughts of death or suicide. "It took everything I had just to get through the day," recalls Linda Cook, 51, a Boston nurse and mother who has battled episodes of severe depression since she was 22. She began taking Prozac 10 years ago. "It was a miracle drug for me," she says. "I just feel so much more like a human being."

Hard questions remain--but answers may be coming. "Nobody has been able to identify a specific genetic or physiological dysfunction that turns depression on and off," says Jerrold Rosenbaum, executive director of the Mood and Anxiety Disorder Institute at the University of Massachusetts Hospital. "That's about 10 years away." As dazzling as the SSRIs can be, talk therapy continues to be an effective treatment for depression. For longtime sufferers like Cook, the growth of medical knowledge has itself been a source of real comfort. She used to think her illness was a personal failure. "I felt I should be able to control it, so I was ashamed," she says. "When I realized this is something I didn't have control over--that it's purely physical--it was a great relief. I could change my attitude toward myself and found that I liked myself a whole lot better."

ANXIETY DISORDERS: Fear is healthy. The trick is to keep it from running wild. According to the NIMH, anxiety disorders are the most common of all mental illnesses. The condition's generalized form is characterized by chronic worry and tension, often without apparent provocation, lasting six months or more. Physical symptoms can include headaches, nausea and frequent urination. Another form of anxiety disorder, panic attacks, strikes between 3 million and 6 million Americans annually, two thirds of them women. With no warning the patient suddenly and repeatedly experiences an overwhelming sense of terror. "You try to stand up but you physically can't move," says Louise Ross, 52, a fund-raising consultant who had her first panic attack three years ago. "It's very scary."

SSRIs can help. Meanwhile scientists are searching for the areas of brain circuitry that set off full-blown illness. "We've studied a variety of anxiety disorders," says Dr. Scott Rauch, an associate professor of psychiatry at Harvard Medical School. "There is a common network: the anterior paralimbic system. It seems to be activated across the anxiety disorders and across a variety of intense normal emotional states."

Doctors have made particular progress on the neurological riddles of panic attacks. Dr. Jeremy Coplan, a researcher at Columbia University Medical College, says panic sufferers appear to experience false alarms of smothering, deep in the part of the brain that controls breathing. "When people hyperventilate with panic disorder, they reduce their blood flow to the brain," says Coplan. "The brain interprets this aberrant reduction of blood flow as a sign of suffocation." The sufferer is effectively drowning in fear. Ross has been taking Zoloft, one of the SSRI family, for two years. "It's the answer to my prayers," she says.

SEASONAL AFFECTIVE DISORDER: An emotional illness doesn't have to be fully explained before it can be effectively treated. Researchers suspect seasonal affective disorder (SAD) may be set off by the delayed sunrises and short daylight hours of winter. Perhaps the lack of natural light upsets the patient's daily biological rhythms and delays the secretion of melatonin, a hormone linked to the sleep-wake cycle. Researchers say four out of five SAD patients are women in their reproductive years. Women over 55 tend to have about the same incidence as men. The disorder's prevalence among menstruating women would seem to implicate a familiar culprit. "It's got to have something to do with the female hormones," says Dr. Alfred Lewy, one of the pioneers of SAD research--but even he is not sure why women are more susceptible. The disorder's biological underpinnings remain a mystery.

Sufferers exhibit "atypical" symptoms of depression: overeating, oversleeping, a lack of energy and a loss of concentration. Lewy prescribes light--lots of it. His patients receive daily megadoses of light, preferably first thing every morning, bathing their eyes in the glow of special fluorescent lamps 20 times brighter than standard indoor illumination. Lewy's treatment is usually just what the doctor ordered--most patients start feeling better within a couple of days. The one thing he knows for sure is that SAD is a legitimate illness. "It's not a case of disliking rainy days," he says. "This is a real psychological disorder."

ANOREXIA AND BULIMIA: More than nine out of 10 victims of eating disorders are adolescent and young women. Detection is difficult. By the time anorexics see a doctor, they are likely to have become severely ill, often suffering from malnutrition or outright starvation. Sufferers tend to be at least 15 percent below their appropriate body weight--and at the same time to think of themselves as overweight. In severe cases the brain begins to shrink from starvation and become "watery." Some of the changes may be permanent. Bulimia can be even more elusive; sufferers may be at or above normal weight. Yet in extreme cases, bulimia can result in heart failure.

Anorexia and bulimia used to be regarded as medical rarities. Since the 1970s, however, the problem has spread to epidemic levels. Doctors still can't say precisely what triggers the sickness. Apparently it requires a little of everything, from genetics to particular personality traits to pop culture's idealization of thinness. "Eating disorders are multifactorial," says Diana Mickley, who in 1982 established the Wilkins Center for Eating Disorders in Greenwich, Conn. In susceptible individuals, dieting beyond a certain point can apparently set off a cascade of metabolic disruptions, including reduced serotonin levels. Many patients suffer from severe disturbances of the neuroendocrine system, which regulates a wide range of functions, including sex drive and reproductive cycles, appetite and digestion, emotions, memory and the workings of the heart and kidneys.

If a magic bullet exists, no one has found it. Doctors have to treat eating disorders symptom by symptom--with special priority on restoring the patient's weight to normal range. The hope is that a concerted education campaign in the public schools will stop the epidemic.

Beyond the challenge of conquering emotional illnesses, brain investigators are facing vast new territories to chart. "We have entered a whole new era with the new technology," says Dr. Sally Shaywitz, codirector of the Yale Center for the Study of Learning and Attention. She and other scientists at the center have been finding ways in which healthy men and women use their brains differently in such basic tasks as reading. Where men tend to use only the left side of their brains, many women use both--although the choice appears to have little effect on speed or accuracy. "They took two different routes to get the same results," says Shaywitz. She predicts the discovery of many other gender differences in the brain--and many other areas of convergence. There's no telling where such discoveries might ultimately lead. What's important is that the journey will be a fascinating one.

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