Schizophrenia is a highly debilitating disease of great public health importance. This illness typically begins in adolescence, tends to be lifelong, and is one of the leading causes of disability worldwide. While the pathophysiological basis of this illness is still poorly understood, accumulating evidence suggests structural and functional brain abnormalities in the early course of schizophrenia. The view that these abnormalities are related to abnormal brain development is gaining ground; this model suggests that the observed brain abnormalities may be present before illness onset in individuals genetically predisposed to this disorder. Preliminary and ongoing work by this investigator in this little studied area has shown that child and adolescent relatives of schizophrenia patients have evidence of attentional, neurological and executive function deficits, and impaired structural and molecular integrity of the heteromodal association cortex (HAC) and subcortical brain structures; these impairments appear to progressively evolve during adolescence. These observed deficits also appear to predict schizotypy and other measures of behavioral pathology. The central hypotheses of the proposed study are that progressive neurodevelopmental dysmaturation of the HA C and subcortical brain regions underlies the vulnerability to schizophrenia, and may predict schizophrenia spectrum psychopathology (SSP). In the proposed study the investigator will seek to prospectively characterize the nature and longitudinal course of these observations in high-risk non-psychotic adolescent offspring of schizophrenia patients (HR, n=150) and matched and temporally """"""""yoked"""""""" healthy control (HC, n=100) subjects. All the subjects will be evaluated with neurobehavioral (neuropsychological and eye movement studies) and neuroimaging (magnetic resonance imaging and multi-voxel proton and phosphorus magnetic resonance spectroscopy) studies. Subjects will be followed up annually for three years to seek evidence of progressive brain dysmaturation and its relation to the emergence of SSP. These studies will establish a cohort of high-risk subjects for further follow-up studies of developmental vulnerability to schizophrenia.
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