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New imaging techniques have shown a dynamic wave of gray matter loss in early-onset schizophrenia. Can this pattern of destruction provide a window of opportunity to combat this disease?
Schizophrenia is a debilitating psychiatric disorder that affects 1% of Americans. Often striking without warning in the late teens or early 20s, its symptoms include visual and auditory hallucinations, psychotic outbreaks, and bizarre or disordered thinking, as well as depression and social withdrawal.
To combat schizophrenia, new antipsychotic drugs are emerging; most of these modulate dopamine and serotonin pathways in the brain. Despite the moderate success of these medications in controlling some patients' symptoms, little is known about the causes of schizophrenia and its triggers. Its peculiar age of onset is also puzzling and raises several key questions. What physical changes occur in the brain as a patient develops schizophrenia? Do these deficits spread in the brain, and can they be opposed? As the disease is partly genetic, do a patient's relatives exhibit similar brain changes? Recent advances in imaging and genetics provide exciting insight into these questions. As we will see, they may also offer powerful new strategies to assess drugs that combat schizophrenia's unrelenting symptoms.
Mapping Brain Development
Since 1992, Judith Rapoport, M.D., and her colleagues at the National Institute of Mental Health in Bethesda, Md., have scanned the brains of over 1,000 children and adolescents with high-resolution magnetic resonance imaging. What makes their study unique is the fact that these children return to the clinic to be re-scanned every two years. Many children are now receiving their fifth scan, providing a remarkable time-lapse movie as a record of how their brains have developed. The resulting brain scan treasure chest charts brain growth in unprecedented detail. Growth spurts and losses can be mapped in individual children, and the resulting patterns can be compared in health and disease (Thompson et al., 2001b, 2000).
Our recent studies of these scans, in collaboration with the NIMH group, have revealed unsuspected growth spurts in language systems before puberty (Thompson et al., 2000). The picture is surprisingly dynamic, revealing a second wave of neural development in the teen years (Giedd et al., 1999a). Paradoxically, many brain systems also lose tissue as a child develops. Parts of the basal ganglia, which control learned motor functions, lose up to 50% of their tissue in a four-year period leading up to puberty (Thompson et al., 2000); in the teen years, a gentle loss of frontal lobe gray matter begins, and this persists into adulthood (Giedd et al., 1999a, 1999b; Sowell et al., 1999).
Among those patients scanned at NIMH were 40 adolescents with early-onset schizophrenia (EOS) who were scanned repeatedly as their disorder developed. These patients had detailed cognitive and clinical evaluations; they satisfied DSM-III-R/DSM-IV criteria for diagnosis of schizophrenia before the age of 12 years (Rapoport and Inoff-Germain, 2000). Since their symptoms are continuous with the adult disorder, their brain scans and repeated neuropsychiatric tests hold key information on how schizophrenia develops during the teen-age years.
Wave of Gray Matter Loss
In recent collaborations with the NIMH team, we have aimed to develop extremely sensitive methods for mapping changes in the developing brain. The goal is to visualize where the brain is growing fastest, measure local growth rates and their statistics, and reveal where gray matter or other types of tissue are lost. By combining and comparing data from multiple subjects, we have created detailed color-coded maps to uncover where and how fast these changes occur and where the brain changes most prominently in disease (Figure).
In studying the patients with schizophrenia, we were stunned to see a spreading wave of tissue loss that began in the parietal cortices, a small region of the brain (see Figure, top row, red colors) (Thompson et al., 2001b). This deficit pattern, which we recently reported in Proceedings of the National Academy of Sciences, moved across the brain like a forest fire. It destroyed more tissue as the disease progressed (see Figure, red colors, bottom row), eventually engulfing the rest of the cortex after a period of five years. The three-dimensional maps visualize this process and are color-coded to show different degrees of change, revealing where gray matter is significantly reduced in disease.
At each scan, 12 patients with schizophrenia were compared with 12 healthy controls matched for age, gender and demographics. A measure of the local quantity of gray matter was made at each point on the cerebral cortex and changes were mapped in both patients and controls. At their first scan (an average of 1.5 years after initial diagnosis), patients showed a 10% gray matter deficit in a small region of the cortex. This deficit, observed at the age of 13 years, was initially confined to parietal brain regions involved in spatial association. After five years, this brain tissue loss swept forward into sensory and motor regions and, by the age of 18, into dorsolateral prefrontal and temporal cortices, which were not initially affected. This pattern was replicated in independent groups of male and female patients. Each showed a similar pattern of spreading deficits, reaching a 20% to 25% average loss. Overall, regions of loss corresponded with the impairments in neuromotor, auditory, visual search and frontal executive functions that characterize schizophrenia. The frontal eye fields lost tissue fastest, at about 5% per year, perhaps consistent with the eye-tracking and smooth eye pursuit deficits often reported in patients.
This dynamic wave of brain tissue loss also correlated with worsening psychotic symptoms and mirrored the progression of neurological and cognitive deficits associated with schizophrenia. Specifically, patients with fastest loss in temporal cortices had worst positive symptoms (including hallucinations and delusions, quantified by Scale for Assessment of Positive Symptoms [SAPS] scores; p<0.015, left hemisphere, p<0.004, right hemisphere). Since temporal loss rates were a good predictor of positive symptoms at follow-up, future studies in larger samples will be able to assess whether these losses link more specifically with auditory rather than visual hallucinations. Visual hallucinations may originate from multiple brain regions, perhaps in parietal or occipital, rather than temporal cortices or, if within the temporal lobe, possibly from the small inferior/posterior visual association regions, such as Brodmann area 37.
In addition, gray matter loss in the frontal cortices correlated with increased negative symptoms (such as lack of emotional responses and poverty of speech). This linkage was observed between total frontal loss rates and total Scale for Assessment of Negative Symptoms (SANS) scores at final scan (p<0.038). The resulting deficits are consistent with the physiological hypothesis that negative symptoms of schizophrenia may partly derive from reduced dopaminergic activity in frontal cortices. We are currently developing digital mapping methods to isolate which specific frontal deficits (e.g., dorsolateral prefrontal, orbitofrontal) link most tightly with negative symptoms.
We also wanted to address the possibility that drug treatment may have induced these patterns of gray matter loss in the patients with schizophrenia. So we also mapped 10 IQ-matched, serially imaged subjects without schizophrenia who received medication that was identical to the patients' (primarily for control of chronic mood disorders and aggressive outbursts). While the non-schizophrenic group did show some subtle but significant tissue loss, this was much less marked than for the patients with schizophrenia and was restricted to superior frontal cortices. No temporal lobe or pervasive frontal deficits were observed in the medication controls, suggesting that the wave of disease progression may be specific to schizophrenia, regardless of medication, gender or IQ.
Normal Gray Matter Pruning
A shifting pattern of deficits in these patients with schizophrenia raises interesting questions. First, tight correlations between the pattern of loss and specific symptoms could point toward the mechanisms that underlie symptoms. If the pathogenesis of schizophrenia is a dynamic, gradual process, a five-year window may be available for drugs to oppose the wave of loss. Imaging strategies will be key tools in evaluating their efficacy.
Second, just what causes this progressive wave of tissue loss? Healthy adolescents also lose gray matter in parietal regions, at a more modest rate of approximately 1% per year (Thompson et al., 2001b). The cognitive effects of this process are unclear. Future brain imaging studies will reveal whether the process of normal gray matter maturation, sometimes called pruning (Giedd et al., 1999a,b), obeys a similar shifting pattern. If so, this will clarify whether the wave of loss in schizophrenia is an alteration or acceleration of a normal developmental process. An alternative view is that it is a separate process entirely that begins in the teen-age years.
A Non-Genetic Trigger?
With the recent discovery of several candidate genes that affect individual risk for schizophrenia (e.g., Liu et al., 2002), specific genetic factors may soon be implicated in causing this deficit pattern or, at least, in increasing susceptibility to the illness. Relatives who are genetically closer to a patient with schizophrenia are more likely to develop the disorder themselves, and there is considerable interest in determining individual relatives' risk for the disease, as well as understanding its genetic transmission. Recently, we developed a technique to visualize genetic influences on brain structure (Thompson et al., 2001a, in press). This technique determines which aspects of brain structure we inherit from our parents, the aspects which are, therefore, similar among family members. This genetic brain mapping approach also links structural features that can be measured from a brain scan with behavioral traits, such as IQ, and even genetically transmitted deficits (Plomin and Kosslyn, 2001).
To examine the genetic transmission of deficits in schizophrenia, we recently measured differences in cortical gray matter between monozygotic (MZ) twins discordant for schizophrenia (Cannon et al., 2002). These twins were genetically identical, but only one twin per pair had the disorder. Since only 48% of the MZ twins of a patient ever develop schizophrenia, genes are not all-important in producing the disease. In the identical twins we examined, the member of each pair with schizophrenia showed statistically significant gray matter reductions (between 5% to 8%) in superior parietal cortices and dorsolateral prefrontal cortices and in the superior temporal gyrus of the left hemisphere. There were no significant differences between the discordant co-twins in primary somatosensory or primary motor areas. Since the MZ twins were identical genetically, the early loss of parietal cortex in the EOS patients suggests an environmental rather than a genetic origin for the disease. In the frontal and temporal regions, however, where loss occurred relatively late in the EOS patients, deficits were found to be highly heritable and were even found in healthy relatives of patients.
Schizophrenia may be triggered by a nongenetic factor, including possibly an infectious agent or virus during pre- or postnatal development. Even so, the progress of the disease appears to have a heritable component. The continued hybridization of methods from behavioral genetics and brain imaging is likely to accelerate our knowledge of the mechanism of the disease and its genetic transmission and gives us the means to block it in individual families.
A Window of Opportunity
In summary, we described the recent detection of a dynamic wave of gray matter loss in early-onset schizophrenia. This began in a brain region where deficits are not highly heritable and subsequently invaded the frontal cortex, which is at significant genetic risk for developing deficits. Intriguingly, deficits moved in a shifting pattern, enveloping increasing amounts of cortex throughout adolescence. While these deficits are severe and correlate strongly with symptom severity, their progression does not appear to be complete until at least seven years after symptom onset. This provides a window of opportunity for drug treatment to oppose the spread of the disease.
New imaging methods, including those linking brain deficits with specific risk genes, are likely to be at the forefront in discovering the triggers of schizophrenia. Imaging methods also show promise for early detection of the disease, especially in relatives who are at genetic risk. Patients may then be treated at the earliest possible opportunity, before the ravages of the disease have set in.
Cannon TD, Thompson PM, van Erp TG et al. (2002), Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci U S A 99(5):3228-3233.
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