Dynamic Patterns of Accelerated Gray Matter Loss are Linked with Clinical and Cognitive Change in Childhood-Onset Schizophrenia

Christine Vidal1, Judith L. Rapoport2 , Jay N. Giedd2, Jonathan Blumenthal2, Peter Gochman2, Robert Nicolson2, Arthur W. Toga1, Paul M. Thompson1
1Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine
2Child Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD

Mapping Rates of Gray Matter Loss in Schizophrenia


We recently reported the detection of striking profiles of accelerated gray matter loss in childhood-onset schizophrenia (COS [1,2]), with deficits moving in a dynamic pattern across the cerebral cortex throughout adolescence [3]. To begin to evaluate the clinical specificity and functional correlates of these findings, we developed a new mathematical method that creates detailed spatial maps linking patterns of brain change with neuropsychiatric evaluations of positive and negative symptoms.

3D maps localizing brain changes were derived from 68 high-resolution MRI scans acquired repeatedly from the same subjects over a 7-year time span [1,2]. 12 schizophrenic subjects (aged 13.9±0.8 years at first scan) and 12 healthy demographically-matched adolescents were imaged repeatedly over a 5-year time span (aged 13.5±0.7 years at initial scan). High-dimensional elastic matching of cortical patterns [4] was used to associate measures of gray matter density from homologous cortical regions across subjects and across time. Annualized 4D maps of gray matter loss rates within each subject were subsequently elastically realigned for averaging across diagnostic groups. Statistical maps were generated indicating locally the degree to which gray matter loss rates were statistically linked with positive and negative symptoms evaluated using the Scales for the Assessment of Positive and Negative Symptoms (SAPS/SANS [5]). Maps identifying these linkages were computed pointwise across the cortex and assessed statistically by permutation, using a scale-space search for distributed effects.

Rates of temporal gray matter loss were strongly correlated with SAPS total score at final scan (p<0.015, left hemisphere; p<0.004, right hemisphere; all p-values corrected). Faster loss was significantly associated with more severe positive symptoms. Faster loss rates in frontal cortex were also strongly correlated with more severe negative symptoms (total SANS score, p<0.038), consistent with the physiological hypothesis that negative symptoms of schizophrenia may depend on reduced dopaminergic activity in frontal cortices. The clinical specificity of the dynamic loss pattern was confirmed by mapping brain change in a matched similarly-medicated cohort. These 10 serially imaged subjects with psychosis not-otherwise-specified (PNOS; [2]) did not satisfy DSM-III-R criteria for schizophrenia. Controls, PNOS and COS patients lost frontal gray matter at successively increasing rates. Importantly, no temporal lobe deficits were observed in either the PNOS group or healthy controls, suggesting that the wave of disease progression into temporal cortices may be specific to schizophrenia regardless of medication, and also regardless of gender [3].

A significant, regionally-specific linkage between the deficit symptoms of schizophrenia and the progressive loss of cortical tissue suggests a disease mechanism that may only be partially opposed by neuroleptics acting on dopamine and serotonin pathways. Dynamic progression of cortical deficits in parietal, motor and supplementary motor, and temporal (including primary auditory) cortices may suggest a structural basis for the positive and negative deficit symptoms observed clinically and in studies of the functional and metabolic integrity of the cortex.

References: [1] Giedd et al. Biol. Psychiatry 46(7):892-8(1999); [2] Jacobsen & Rapoport JCPP 39(1):101-13(1998); Thompson et al.: [3]: this volume; [4]: Cerebral Cortex 11:1-16(2001); [5]. Andreasen et al. (1983).

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    Paul Thompson, Ph.D.
    Assistant Professor of Neurology
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