EM inquiry

If schizophrenia is rooted in the first months of a person's life, Emory researchres ask, why do decades pass before psychotic symptoms appear?

by BRYANT FURLOW

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	Children destined to become schizophrenic
	in their teens or twenties, it has long seemed,
	share no single characteristic in their
	developmental histories.

Researchers seeking the cause of schizophrenia among its 2.2 million victims must unravel myriad, seemingly unrelated risk factors ranging from prenatal exposure to the flu to a mother’s emotional turmoil during pregnancy. Even the season of conception has been linked to schizophrenia. And there is undeniably some genetic susceptibility to the disease.

Perhaps the most perplexing problem researchers face is that of “temporal disjunction”—a span of decades between exposure to prenatal risk factors and the onset of full-blown, schizophrenic psychosis.

Unifying varied risk factors into a single, coherent theory of schizophrenia that explains the structural and chemical abnormalities in schizophrenic brains—as well as temporal disjunction—has proven so daunting a task that few researchers have even tried. But in recent years, Samuel Candler Dobbs Professor of Psychology and Neuroscience Elaine Walker and former Emory graduate student Donald Diforio ’97G-’98PhD have championed an elegantly simple theory that apparently does just that.

“Schizophrenia is an especially challenging disorder because it disrupts the basic human ability to differentiate reality from fantasy,” Walker says. Those concepts—reality and fantasy—are products of human consciousness and our ability to engage in symbolic reasoning. The inability to tell the two apart is the quintessence of schizophrenia.“Therefore, schizophrenia is probably a uniquely human disorder.”

Several researchers, including Walker, have long suspected that early developmental disruptions somehow miswire a brain in such a way that in adolescence or early adulthood reality breaks down and schizophrenia strikes.

One important indicator that this is the case is the prevalence of minor physical anomalies that are common among schizophrenia patients, such as fingerprint asymmetries between the left and right hands. Such anomalies are believed to occur when normal development—the translation of genes into body parts—is disrupted by some complication or stress.

But if schizophrenia is rooted in the first months of a person’s life, why do decades pass before psychotic symptoms appear?

Perhaps, Walker reasoned, more subtle symptoms are evident throughout childhood and have simply gone unnoticed. There was some evidence, for example, that pre-schizophrenic children are more socially withdrawn and are less successful in school than their peers. But such studies relied largely on the ability of adults to recall such things decades later, and parents trying to make sense of a child’s mental illness may exaggerate such differences in their own minds.

With a 1994 study of the childhood home movies of schizophrenia patients, Walker and her collaborators provided strong evidence that schizophrenia is indeed rooted in early brain development. Through these flickering time portals, Walker was able to compare the behavior of children destined for mental illness with their non-schizophrenic brothers and sisters.

Neurodevelopment specialists kept blind to the individual children’s eventual psychiatric status were asked to score motor skills such as coordination and to note what scientists call “neuromotor abnormalities”—unusual body postures or movement patterns. Among pre-schizophrenic children, markedly higher numbers of neuromotor abnormalities were found, such as a slightly unusual hand posture reminiscent of that seen in adults with motor disorders. The differences between the normal and the pre-schizophrenic children were transient, becoming slight by age three.

Clearly, however, the stage is set for schizophrenia years before the descent into psychosis.

Schizophrenia is something of a three-act tragedy, Walker and Diforio believe. In the first act, prenatal risk factors set the story in motion. In act two, subtle coordination and social problems generally go undetected by parents and teachers. And then, in the final act, there is a catastrophic and seemingly sudden lurch into mental illness in the late teens or early twenties.

Together with Diforio, Walker set out to understand how these acts fit together into a single, unified narrative. They knew that any theory of schizophrenia must explain not only its far-flung risk factors, but also the problem of temporal disjunction and the specific neurochemical abnormalities and anatomic anomalies typical of schizophrenic brains. Take the hippocampus, for example. A mood modulator and critical “experience integrator,” this little fold of brain is also a memory-processing center associated with those nightly hallucinations we call dreams. In schizophrenia patients, the hippocampus is atrophied and miswired.

What emerged after reviewing the medical literature was a tale of stress plaguing the schizophrenic brain from just after conception to the adolescent fall into psychosis and delusion. The centerpiece of this theory is a stress hormone called cortisol.

“For the most part,” Walker and Diforio told colleagues, “the behavioral and biological aspects of stress response in schizophrenia have been studied separately.” But cortisol is the expression of both social and biological stress. And that may be key to uniting risk factors and symptoms into a single theory of schizophrenia.

Stress—be it emotional or physical—causes cortisol levels to jump. It’s an important part of our body’s stress response—putting us on alert, getting energy stores ready for an assault by a predator or parasite. But in high doses, it becomes toxic, destroying neurons. In lab animals, such increases in stress hormones result in the same atrophy of the hippocampus seen in schizophrenia patients. As it turns out, all of those seemingly unrelated prenatal risk factors—malnutrition, flu, maternal emotional turmoil—also cause the body to increase cortisol production. Research with animals also has shown that when stress hormones are elevated during pregnancy, the offspring show abnormalities in the hippocampus. (British endocrinologists unaware of Walker and Diforio’s theory have recently reported that in men, at least, the body produces significantly more cortisol in winter months. If this is true of women as well, it could explain the excess of schizophrenic births in the spring.)

What’s more, the brain circuitry for controlling stress reactions—think of it as an emotional thermostat—is set differently in pre-schizophrenic children. This might explain why parents and teachers recall schizophrenia patients being more emotionally reactive as children than their peers.

“We know that stress can have a significant physical and psychological impact on people,” says Walker. “But there are individual differences in how people react to stress. Some people show a dramatic response to relatively common stressors. Others are more resilient. We think that part of the vulnerability to schizophrenia is a heightened sensitivity to stress.”

During puberty, cortisol production naturally increases. Because people at risk for schizophrenia started with higher levels of stress hormones and an overly reactive stress thermostat, by the time they reach adolescence, their cortisol levels may be chronically high. This, Walker and Diforio believe, explains the temporal disjunction that has long puzzled researchers. With the cortisol spike associated with adolescence, the brain’s early miswiring is catastrophically revealed.

“In vulnerable individuals,” Walker says, “the release of stress hormones may trigger changes in the neurotransmitter systems that are involved in schizophrenia.”

Brains long teetering on the edge of psychosis, in other words, are pushed over the edge by adolescent spikes in stress hormone production. Indeed, studies suggest a link between the amount of cortisol released and the amount of dopamine, a chemical messenger that affects brain processes that control movement, emotional response, and ability to experience pleasure and pain, and which has been linked to schizophrenia. In the emerging, convoluted map of schizophrenia, it seems, all roads point to stress.

As more is learned about schizophrenia, doctors will be better able to help pregnant women minimize the risk that their offspring will become victims. If Walker and Diforio’s theory is correct, prevention should be possible on several fronts.

“One of the most obvious,” says Walker, “is the prevention of complications of pregnancy. Minimizing the exposure of pregnant women to infectious agents and psychological stress, and optimizing their nutritional status, may make a significant contribution.”

And if elevated cortisol levels really do contribute to the onset of psychosis after puberty, she cautiously notes, psychiatrists may have a second chance to save patients from crippling mental illness.

“Adolescence may be another point of entry for prevention,” she says. “However, we need to know more about the biological changes that occur at this time.”

Currently, available medications for schizophrenia patients are designed to control dopamine activity in the brain. Many of these drugs have long-term side-effects, such as tremors and uncontrolled grimacing. Might researchers building on Walker and Diforio’s ideas develop medications for moderating emotional reactivity or for lowering cortisol levels in adolescents at risk for schizophrenia?

Walker has been thinking along those lines herself—and she’s hopeful.

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Bryant Furlow is a California free-lance writer and a contributor to New Scientist magazine.