Paul M. Thompson, Ph.D.
Keywords for indexing (up to 20 words): schizophrenia, MRI, brain scan, gray matter, imaging, psychosis, genetics, brain mapping, medication effects, childhood onset, development, adolescence, teenage, neuroanatomy
Schizophrenia is a debilitating psychiatric disorder that affects 1% of Americans. Often striking without warning in the late teens or early twenties, its symptoms include visual and auditory hallucinations, psychotic outbreaks, bizarre or disordered thinking, as well as depression and social withdrawal. To combat the disease, new antipsychotic drugs are emerging; most of these modulate dopamine and serotonin pathways in the brain. Despite their moderate success in controlling some patients' symptoms, little is known about the causes of schizophrenia, and what triggers the disease. 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 on these questions. As we will see, they may also offer powerful new strategies to assess drugs that combat the unrelenting symptoms of schizophrenia.
Mapping Brain Development
Since 1992, Judith Rapoport, M.D. and her colleagues at the National Institute of Mental Health in Bethesda have scanned over 1,000 children and adolescents with high-resolution brain MRIs. What makes their study unique is the fact that these children return to the clinic to be re-scanned every 2 years. Many children are now receiving their 5th scan, and have grown up in the meantime, leaving a remarkable time-lapse movie as record of how their brain has developed. The resulting treasure-chest of brain scans 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., 2000, 2001a). 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., 1999). 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 4-year period leading up to puberty (Thompson et al., 2000); in the teen years, a gentle loss of frontal lobe gray matter begins, and persists into adulthood (Sowell et al., 1999; Giedd et al., 1999a,b).
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 (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 in the teenage years.
Dynamic Wave of Gray Matter Loss
In recent collaborations with the NIMH team, we have aimed to develop extremely sensitive methods to map changes in the developing brain. The goal is to visualize where the brain is growing fastest, measuring local growth rates and their statistics, and revealing 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 (see accompanying Figure).
Mapping Brain Changes in Schizophrenia. Derived from high-resolution magnetic resonance images (MRI scans), the above images were created after repeatedly scanning 12 schizophrenia subjects over five years, and comparing them with matched 12 healthy controls, scanned at the same ages and intervals. Severe loss of gray matter is indicated by red and pink colors, while stable regions are in blue. STG denotes the superior temporal gyrus, and DLPFC denotes the dorsolateral prefrontal cortex. (Reprinted with permission from Thompson PM et al., Proceedings of the National Academy of Sciences of the USA, 98:11650-11655).
In studying the schizophrenic patients, we were stunned to see a spreading wave of tissue loss that began in a small region of the brain, the parietal cortices (see accompanying image, top row, red colors; Thompson et al., 2001a). This deficit pattern, which we recently reported in the Proceedings of the National Academy of Sciences, moved across the brain like a forest fire. It destroyed more tissue as the disease progressed (red colors, bottom row), eventually engulfing the rest of the cortex after a period of 5 years. The 3D maps visualize this process. They are color coded to show different degrees of change, revealing where gray matter is significantly reduced in disease.
At each scan, 12 schizophrenic patients were compared with 12 healthy controls matched for age, gender, and demographics. In each scan, 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, was initially confined to parietal brain regions involved in spatial association. Over the 5 succeeding 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%-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 percent 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 the disorder. Specifically, patients with fastest loss in temporal cortices had worst positive symptoms (including hallucinations and delusions, quantified by 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 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 schizophrenic patients. So we also mapped 10 IQ-matched, serially imaged non-schizophrenic subjects, who received identical medication 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 schizophrenics, 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, and also regardless of 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 towards the mechanisms that underlie these 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., 2001a). 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 schizophrenic wave of loss 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 teenage 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 schizophrenic patient 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., 2001b). This technique determines which aspects of brain structure we inherit from our parents, which are therefore similar among family members. This genetic brain mapping approach also links structure 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 are genetically identical, but only one twin per pair has 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 schizophrenic member of each pair showed statistically significant gray matter reductions (between 5-8%) 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 non-genetic factor, including possibly an infectious agent or virus during pre- or post-natal 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, its genetic transmission, and 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.
Dr. Thompson has developed several neuroimaging approaches for studying brain development and disease, and is assistant professor of neurology at the UCLA School of Medicine, in Los Angeles.
Cannon TD, Thompson PM, van Erp T et al. (2002). Cortex Mapping Reveals Regionally Specific Patterns of Genetic and Disease-Specific Gray-Matter Deficits in Twins Discordant for Schizophrenia, Proceedings of the National Academy of Sciences of the USA 99(5):3228-3233.
Giedd JN, Blumenthal J, Jeffries NO et al. (1999a). Brain development during childhood and adolescence: a longitudinal MRI study. Nature Neuroscience 2(10):861-3.
Giedd JN, Jeffries NO, Blumenthal J, Castellanos FX, Vaituzis AC, Fernandez T, Hamburger SD, Liu H, Nelson J, Bedwell J, Tran L, Lenane M, Nicolson R, Rapoport JL (1999b). Childhood-onset schizophrenia: progressive brain changes during adolescence. Biol. Psychiatry 46(7):892-8.
Liu H, Heath SC, Sobin C et al. (2002). Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proceedings of the National Academy of Sciences of the USA, March 12 2002.
Plomin R, Kosslyn SM (2001). Genes, brain and cognition. Nature Neuroscience 4(12):1153-4.
Rapoport JL, Inoff-Germain G (2000). Update on childhood-onset schizophrenia. Curr. Psychiatry Rep. 2(5):410-5.
Sowell ER, Thompson PM, Holmes CJ et al. (1999). Progression of Structural Changes in the Human Brain during the First Three Decades of Life: In Vivo Evidence for Post-Adolescent Frontal and Striatal Maturation, Nature Neuroscience 2(10):859-61.
Thompson PM, Vidal C, Giedd JN et al. (2001a). Mapping Adolescent Brain Change Reveals Dynamic Wave of Accelerated Gray Matter Loss in Very Early-Onset Schizophrenia, Proceedings of the National Academy of Sciences of the USA 98(20):11650-11655.
Thompson PM, Giedd JN, Woods RP et al. (2000). Growth Patterns in the Developing Human Brain Detected Using Continuum-Mechanical Tensor Mapping, Nature 404(6774):190-193.
Thompson PM, Cannon TD, Narr KL et al. (2001b). Genetic Influences on Brain Structure, Nature Neuroscience 4(12):1253-1258.
Thompson PM, Cannon TD, Toga AW (2002). Mapping Genetic Influences on Human Brain Structure (Review Article), Annals of Medicine [in press].
(End of article)
Paul Thompson, Ph.D.
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