Lights of Madness

HOW HORRIBLE!" screamed one voice. "Don't act stupid," warned another.' Such voices are the familiar, and un-shakable, companions of the group of schizophrenics who volunteered for a pathbreaking study. Like unwanted kibitzers at a bridge game, the voices inside the men's heads comment on their every thought and deed. But this time the voices were mouthing off in the presence of neuroscience's version of a hidden camera: the brain-imaging machine called Positron Emission Tomography (PET). Last week an international team including David Silbersweig and Emily Stern of Cornell Medical Center in New York and colleagues in London announced results of the first clinical study using PET in an unprecedented way. PET had caught six schizophrenics in the act of hallucinating, something never before captured on a brain scan. Their results, reported in the journal Nature, "pinpoint [brain] structures implicated in schizophrenia," says neuro-scientist Monte Buchsbaum of the Mount Sinai School of Medicine in New York-and may one day suggest new treatments for the devastating disease that strikes more than 2 million Americans.

Schizophrenia, from the Greek words for "split" and "mind," is marked by disordered thought, social withdrawal and hallucinations (though not the "split personality" its etymology implies). One 23-year-old man in the PET study regularly saw vivid scenes--in living color and full motion-of rolling, disembodied heads that ordered him around. To spy on what the brain was doing during such hallucinations, the researchers had six patients take turns lying in the PET scanner, where they were told to relax and close their eyes. Whenever a voice piped up, and again when it stopped, the patient pressed a button with his right thumb to alert the researchers. PET measures blood flow in various regions of the brain. Blood flow marks neuronal activity. Traditional PET scans, which require that a mental state (such as concentrating on a math puzzle) be maintained for several minutes, cannot capture such transient and involuntary events as hallucinations. With the new PET, explains Silbersweig, who with Stem invented a novel technique of analyzing PET images three years ago while at Hammersmith Hospital in London, "we can capture these ephemeral events with a high degree of sensitivity, even if they last only seconds."

Where and how the brain lights up during hallucinations offers a sort of cartography of schizophrenia, and neuroscientists are all vying to be its Magellan. In the PET study, hallucinations were marked by activity in areas deep in the brain, running from behind the forehead down toward 'the spinal cord. Normally these regions, with names like thalamus, hippocampus and striatum, are involved in generating the life of the mind, sometimes ,out of sights, sounds and memories but often out of other mental activity. They may create the often bizarre images in dreams, too, in response to little electrical tickles from deeper in the brain. The regions also integrate current and past experiences, drawing together a perception (the sight of a shadowy figure) with a memory (the last time I walked this way . . .) and a feeling (uh-oh). Based on the structures that switched on during hallucinations, it seems that at least some of the roots of schizophrenia may lie in a wiring problem deep inside the brain.

Equally striking was what did not light up in the 20-plus PET scans of each patient: the part of the brain that monitors thoughts and actions. This prefrontal lobe may act as a "reality check," says Buchs-baum, a PET-scan pioneer. "In schizophrenics the prefrontal lobe is not checking images against sensory information and memory" to determine whether they are real, imagined or hallucinated, he says. Perhaps it is this failure of the prefrontal cortex that makes schizophrenics confuse internally generated voices with, for instance, the voice of God or a CIA transmitter. "The brain," explains Silbersweig, "is creating its own reality."

The finding does not have any immediate implications for treatment, but by deepening researchers' basic understanding of the disease it may have some eventually. Buchsbaum, for instance, suggests that "this finding could indicate that the defect in schizophrenia is not just chemical"--the assumption behind the standard drug regimen. That may be why none of the five schizophrenics in the study taking medication was helped by it (the sixth patient had never been on medication). The PET results suggest that whole new treatments may be needed. If the aberrant circuits identified By the scans are a root cause of schizophrenia, it may even be possible to treat patients surgically.

This week in San Diego, at the annual meeting of the Society for Neuroscience, half a dozen researchers are offering various takes on the roots of schizophrenia. The jury is still out on whether schizophrenia is the result of a genetic defect, an injury or disease during fetal development, an obstetric complication or some combination of these. But as the cartographers close in on what has gone wrong in the disease, they may also figure out what has made things go wrong in the first place. To the schizophrenics, of course, the only thing that really matters is silencing the voices once and for all. .

Road Map of the Schizophrenic Brain

A new way of analyzing the brain images generated by PET scans allows neuroscientists to capture such involuntary, ephemeral events as the hallucinations of a schizophrenic. This scan shows a patient at the very moments he saw rolling, disembodied heads and heard them barking orders to him. The bright areas pinpoint regions of heightened neural activity--and provide a cartography of this mental illness.

'Don't Act Stupid,' Scolded the Voice

In these composite images of the brains of five schizophrenics, a PET scan identifying regions that became active when imaginary voices were heard is superimposed on an MRI showing brain structures. When the patients heard voices, networks deep within the brain lit up. These networks usually generate mental activity and integrate perceptions, emotions and memories.

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