My colleagues and I studied these brain scans in collaboration with the NIMH group. We developed computerized methods to pinpoint rates of brain growth and gray matter loss in individual children and teen-agers and visualized these patterns as color-coded three-dimensional maps. Combining data from multiple subjects, we compared the amount of gray matter in multiple cortical regions across subjects and across sequential scans. This analysis produced color-coded three-dimensional maps of the cortex showing loss rates and group differences, and highlighting regions where these changes link with outcome measures or symptom severity. The brain maps for patients with EOS, published in the Proceedings of the National Academy of Sciences (Thompson et al., 2001), revealed a surprisingly dynamic pattern of disease progression. At their first scan (mean age=13), patients showed a 10% gray matter deficit, which was confined to a small region of the parietal cortex involved in spatial association, compared to healthy controls. Over the five succeeding years, this brain tissue loss swept forward, like a forest fire, into frontal and temporal brain regions.
Male and female patients showed a similar, dynamically spreading pattern of deficits. The frontal eye fields lost tissue fastest (5% per year); frontal and temporal regions were spared initially, but were subsequently engulfed. By age 18, gray matter was reduced by up to 20% to 25% in some brain regions.Symptoms and Medication
The spreading deficits correlated, in some respects, with functional decline as well. Total frontal loss rates correlated with negative symptoms (total scores on the Scale for Assessing Negative Symptoms [SANS]) at final scan (p<0.038). This makes sense, as negative symptoms are thought to derive in part from reduced dopamine(Drug information on dopamine)rgic activity in frontal cortices. At an individual level, rates of temporal loss correlated strongly with Scale for Assessing Positive Symptoms (SAPS) total scores at final scan (p<0.015, left hemisphere; p<0.004, right hemisphere). Faster losses in both the superior temporal gyri and the entire temporal cortices were significantly associated with a more severe clinical profile of positive symptoms (e.g., hallucinations or delusions). While tissue loss rates were not significantly linked with the rate of change in SAPS scores from baseline (p>0.05), and SAPS scores were not linked with the amount of tissue at baseline (p>0.05), loss rates were a good predictor of positive symptoms at follow-up (i.e., the remaining symptoms that were refractory to medication).
To rule out confounding medication effects, a second medication- and IQ-matched control group was also studied, consisting of patients diagnosed with psychosis not otherwise specified. These patients exhibited only mild tissue loss, essentially confined to superior frontal cortices in a highly circumscribed pattern. Importantly, the pervasive, unrelenting spread of tissue loss was specific to schizophrenia and was not medication induced (although its rate could well be modulated by medication).
An exciting open question is how strongly different antipsychotic drugs combat this wave of loss. Clinical studies in adult patients, using MRI to assess cortical integrity, suggest that atypical drugs decelerate overall gray matter loss, while gray matter progressively declines in patients taking haloperidol(Drug information on haloperidol) alone (J. Lieberman, M.D., personal communication, 2001). In both teen-age- and adult-onset patients, these progressive losses appear to continue for a long period after diagnosis (here seven years), offering a window of opportunity for interventions. Dynamic brain maps, such as the ones shown here, may help evaluate the spatial selectivity of these medication responses when comparing different neuroleptics. Computational brain maps also make it easy to stratify cohorts into subgroups with different symptom profiles. Patterns of brain change in responders may, in the future, be compared with groups who remain refractory to treatment.Pathologic Mechanism and Specificity
A shifting pattern of deficits raises perplexing questions. Is the wave of gray matter loss an exaggeration of a "normal wave" of gray matter pruning? Or is it a separate process entirely that begins in the teen-age years? Could it be a neurodegenerative process, similar to the progressive wave of gray matter loss seen in Alzheimer's disease (Thompson et al., 2003)?
The strongest evidence against extensive neuronal loss in schizophrenia is the lack of reactive gliosis. Glial cell swelling and proliferation is the brain's natural response to neuronal cell death, and it is strikingly absent in postmortem studies. Nonetheless, in vivo proton magnetic resonance spectroscopy studies show that frontal N-acetylaspartate is reduced, and this is a good marker of neuronal integrity. Positron emission tomography also shows reduced frontal lobe glucose metabolism in both early- and adult-onset patients. Impaired cortical activation is also seen in functional MRI studies of working memory and executive function. These deficits are clearest in tasks (e.g., Wisconsin Card Sorting) that place heavy demands on frontal systems.
Rather than widespread cell loss (as in the dementias), it is more likely that neuronal shrinkage, reductions in dendritic complexity and synaptic loss, as well as vascular changes, may underlie the gray matter changes observed here in schizophrenia. An intriguing hypothesis is that schizophrenia patients may suffer an abnormal intensification of whatever regional gray matter loss occurs in healthy subjects at their specific age of onset. This idea may reconcile why deficits in EOS and adult-onset cases differ, somewhat, in their scope and severity. Predominantly frontal and temporal gray matter losses tend to be reported in adult-onset patients, while more pervasive losses are seen in early-onset studies. Frontal and temporal lobes are the last to show gray matter loss in healthy controls. These systems may be especially vulnerable if the disease begins in young adulthood, while they are being actively remodeled. Additional cortical systems may be vulnerable if the disease hits earlier, in the early teen-age years.Genetics, the Prodrome and the Future