A new study of early-onset schizophrenia reveals that gray matter losses first occur in the parietal cortices and then spread to the temporal and frontal regions of the brain in a wave-like fashion. The findings, published in the September 25 issue of the Proceedings of the National Academy of Sciences of the USA, also indicate that the degree of frontal gray matter loss correlates with the severity of negative symptoms, whereas temporal losses are associated with positive symptoms.

The new report is not only the first to use neuroimaging “to study the timing, rates, and anatomical distribution of structural changes in the brains of adolescents with schizophrenia” but also the first study to show how the entire cerebral cortex changes in any disease over time, according to chief investigator Paul Thompson, PhD, who is an Assistant Professor of Neurology at the University of California, Los Angeles (UCLA).

Previous imaging research has identified numerous neuroanatomic abnormalities in patients with schizophrenia, but, in general, such studies “only capture how the disease looks at a particular time,” Dr. Thompson noted in an interview. “However, we repeatedly scanned adolescent subjects over approximately five years as they were developing schizophrenia. What we found is that there was a ‘wave’ of gray matter loss, which intensified and spread like a forest fire across the brain—moving from the parietal cortices to the front of the brain.”

The peak gray matter loss was more than 5% per year in the frontal eye fields, the supplementary motor and sensorimotor cortices, and the parietal and temporal cortices in both brain hemispheres, the researchers found. After nearly five years, these regions—which comprise about 60% of the gray matter—had an average loss of more than 20%. It is unclear what degree of loss, if any, occurs in the postadolescent period, though the researchers are continuing to assess the participants every two years.

The study cohort included 12 adolescents with schizophrenia (ages 13 to 15 at baseline) and 12 healthy age- and sex-matched controls. All subjects underwent magnetic resonance imaging scanning three times; the initial scans were performed about two to three years after diagnosis and the subsequent scans, on average, after an additional 2.3 and 4.6 years. The scans were used to create three-dimensional maps of gray matter loss; using image analysis software that they had developed, the researchers determined the pattern of this loss for each individual and each group.

The inclusion of a healthy control group was crucial, given that brain development—including neuronal pruning—continues to occur during adolescence. “In fact, we found that the healthy subjects lost approximately 1% of their parietal cortex gray matter per year,” Dr. Thompson said. “Perhaps this normal gray matter loss is accelerated in adolescents who go on to develop schizophrenia, or perhaps mild abnormal loss combines with other normal processes of gray matter loss to push someone over the edge into the disease.”

FRONTAL REGIONS ARE INITIALLY SPARED

The gray matter loss in schizophrenic subjects extended well beyond the parietal cortex. The first scans revealed moderate losses of 5% to 10% (relative to controls) in the supplementary and sensorimotor areas, the parietal cortex, and the frontal eye fields. “This is not surprising, because other researchers have found that patients with schizophrenia often have early mild motor problems and visual tracking difficulties,” Dr. Thompson noted. More unexpectedly, the researchers did not observe severe loss in the dorsolateral prefrontal cortex at this stage. The prefrontal regions have been widely implicated in schizophrenia, “as autopsy studies show cortical thinning here, but in our study a deficit was not evident” in the initial scan, Dr. Thompson said.

But the second and third scans did reveal substantial gray matter loss in the dorsolateral prefrontal cortex, on the order of 15% to 20%, as well as parietal losses of more than 10%. The gray matter losses progressed anteriorly into the temporal cortices (including the superior temporal gyri, where the auditory cortices are located), the supplementary motor cortices, and the frontal eye fields, all of which showed a decrease in gray matter volume of at least 10%. In general, these findings complement results from functional imaging studies, which have found decreased metabolism in many of the same areas.

When the researchers examined the relationship between neuroanatomic changes and psychotic symptoms, they found that a rapid loss of temporal gray matter was associated with increased frequency and severity of positive symptoms, whereas a rapid loss of frontal gray matter correlated with greater severity of negative symptoms. The latter finding, Dr. Thompson and colleagues noted, “is consistent with the physiological hypothesis that negative symptoms may be caused by reduced dopaminergic activity in the frontal cortices.” Conversely, “the positive symptoms, in particular auditory hallucinations, may stem from damage to the primary auditory cortex as the disease progresses.”

Given that gray matter loss is irreversible, it is not surprising that patients with the greatest loss continued to have the most severe symptoms, and tended to have them more often and for longer periods of time. “This link between gray matter loss and psychotic symptoms may help explain why one patient experiences severe psychotic symptoms, whereas another experiences mild symptoms,” Dr. Thompson said.

IS MEDICATION TO BLAME?

Because all of the subjects with schizophrenia were being treated with risperidone or clozapine, the researchers wondered if any of the gray matter changes could be attributed to medication use. Thus, they also studied an additional 10 age- and sex-matched subjects who met DSM-III-R criteria for psychosis not otherwise specified (PNOS). Eight of these subjects received doses of risperidone or clozapine similar to those in the schizophrenia group; all 10 were scanned at the same intervals as the other groups.

The outcome? “Only a small portion of the PNOS groups’ brains had gray matter loss,” Dr. Thompson said. “Consequently, we really don’t think that medication is causing these changes in the schizophrenia group. It’s certainly not having a big effect, because the PNOS group took the medication and they had very little loss.” The PNOS and schizophrenia groups did both show significantly accelerated gray matter loss in small portions of the frontal cortex, but it is unclear whether this is related to medication use, Dr. Thompson said.

Overall, the study’s findings indicate that the pathogenesis of schizophrenia is a dynamic, gradual process. “I think people have been puzzled about how schizophrenia progresses,” noted Dr. Thompson. Although the new findings do not yet provide a full answer, they constitute an important first step.

Dr. Thompson’s coauthors were Christine Vidal and Arthur Toga, PhD, both from UCLA, and Jay Giedd, MD, Peter Gochman, MA, Jonathan Blumenthal, MA, Robert Nicolson, MD, and Judith Rapoport, MD, all of the National Institute of Mental Health.

—Liz Lipton

Suggested Reading
Thompson P, Vidal C, Giedd J, et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA. 2001;98:11650-11655.

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