The long-term career goal of the primary investigator is to advance the knowledge ot schizophrenia-related functional neuropathology by establishing and directing a brain imaging laboratory. The short-term goal is to develop an expertise in the design, execution, and analysis of functional magnetic resonance imaging (fMRI) studies using a series of saccadic tasks. The realization of these goals will occur through a combination of intensive training and the completion of a systematic research plan over the course of the proposed funding period. Training in functional neuroimaging will occur within the UCSD functional neuroimaging group and during yearly 2-week training sessions at the NIMH. Training in neuroanatomy and neuropsychology will be completed within the UCSD neuroscience community. The research plan utilizes the P.I.'s existing studies on the saccadic performance of schizophrenia patients and their relatives as a foundation for generating and testing hypotheses of basal ganglia-thalamocortical circuitry dysfunction associated with schizophrenia. Schizophrenia patients perform normally on refixation saccade tasks, but demonstrate characteristic abnormalities on antisaccade and ocular motor delayed response tasks. A similar pattern of performance is observed among biological relatives of the patients, suggesting that this phenotype may be associated with the liability for developing schizophrenia. The pattern of saccadic performance is consistent with pathology of prefrontal cortex and its associated cortical and/or subcortical circuitry. This hypothesis may be tested using saccadic tasks as behavioral probes during fMRI to measure BOLD (blood oxygenation level dependent) signal change while subjects are engaged in ongoing behavioral and cognitive activity.
Three specific aims are proposed; 1) evaluate the patterns of neural activation associated with refixation saccade performance in schizophrenia and normal subjects, 2) to test hypotheses of differing patterns of frontal activation between schizophrenia and normal groups during tasks that ostensibly require prefrontally-mediated inhibition (antisaccade and delayed response tasks), and 3) to test hypotheses of prefrontal cortex dysfunction among the biological relatives of schizophrenia patients.
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