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Discovering Our Selves: The Science of Emotion
Executive Summary

Panel: Encountering Daily Life:
How Our Emotions Affect Us

"Schizophrenia: The Cancer of Mental Illness"

Daniel R. Weinberger, M.D., is Chief of the Clinical Brain Disorders Branch, Division of Intramural Research Programs, at the National Institute of Mental Health, National Institutes of Health.

We can learn a lot about the science of emotion by studying human conditions wherein emotions are disordered. One of these in which emotions are dramatically disordered is schizophrenia, a condition often referred to as the cancer of mental illness.

Schizophrenia is a clinical syndrome involving a number of complex abnormalities of human perception, cognition, and comportment. The word human is critical here because it is what makes schizophrenia particularly difficult to study.

Some symptoms, the so-called "positive symptoms," give this disorder its very recognizable characteristics: namely, hallucinations, delusions, and thought disorganization. Of increasing interest to scientists, however, are the so-called "negative symptoms."

These include a poverty syndrome: poverty of thought, poverty of motivation, inappropriate emotional responses and problems with affective regulation, a markedly diminished goal directedness, and a pattern of cognitive deficits.

These negative symptoms are perhaps less dramatic, but they may be a signpost to brain systems that lie at the core of the biology of the disorder. Indeed, researchers have observed that these negative symptoms are remarkably similar to a collection of behavioral and emotional features seen in human beings, and in nonhuman primates, following injury, tumors, or strokes in the frontal lobes of the brain.

Investigators long have noted that frontal lobe patients have problems of emotional blunting, inappropriate emotional responses, diminished will or motivation, an overrestriction in thinking: all characteristics that look remarkably similar, at least in kind, to some of the negative symptoms of schizophrenia. In addition, some patients with frontal lobe injury are distinctly incapable of appreciating the complexities of context in determining how they respond to stimuli, showing what may be an exaggerated form of some of the emotional inappropriateness of schizophrenia.

Even with the latest neuroimaging techniques, it is difficult to study what the brain is doing during complicated, context-dependent behavior. We can look at more easily definable context-related behaviors, however.

In one type of experiment, the subject is asked to make choices based on contextual memory--in this case, memory of an arrangement of items previously presented on a computer screen. This is a working memory test. Working memory, centered in the frontal lobes, is a kind of temporary blackboard where we hold things for a few minutes, such as an unfamiliar phone number as we get ready to make the call. Memory-guided behavior of this sort is fundamental to the complex social, psychological, and emotion-guided behaviors essential to human autonomy, interaction and adaptation.

What we have found by looking at brain activation during this test is that the left frontal lobes of normal subjects are highly activated. In patients with schizophrenia, the left frontal lobes are strikingly quiet.

It is possible that a brain faced with a behavioral demand beyond its capacity might shut down as a kind of adaptive response. It is also possible that a brain in that situation might go into overdrive in a frenzied effort to maximize what capacity it does have.

Studies with functional imaging (fMRI) show that the normal brain, when confronted with an increasing load of memory-guided behavior, recruits many different brain areas to help it perform the task. Different brain areas show different physiological patterns depending on the load characteristics.

These studies also reveal, however, that the frontal lobe does have a limit on its functional response. When the frontal lobe's capacity for making context-guided behavior is exceeded, the brains of normal people show what patients with schizophrenia show: a shutdown in the frontal lobe.

Patients with schizophrenia have a more complicated problem. Even when their capacity is not exceeded, their neural systems function less efficiently. Normal brains will dampen activity in brain regions not needed for the task at hand. In the working memory test, for example, the hippocampus, which is involved in other kinds of memory, is quiet.

Patients with schizophrenia, by contrast, show a lot of background noise and in fact overactivate the hippocampus during the working memory test. This pattern of increased noisiness is not limited to context-related behaviors but seems to be a fundamental characteristic of the organization of cortical activity in patients with schizophrenia.

Is there a population of neurons responsible for this noisiness, or is this a nonspecific characteristic of how the whole brain is wired? Studies called chemical assays have looked at particular neurochemicals and found that patients with schizophrenia are markedly deficient in something called N-acetylaspartate, normally abundant in mature nerve cells. This deficiency, moreover, is localized in the frontal lobe.

This represents just the tip of the iceberg of what we know about schizophrenia. We still have much to learn about the genetic component of this disorder and about how the medications that are currently effective actually interact with the neurochemical systems of patients with this "cancer of mental illness."

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