Abnormalities of eye movement control and spatial cognition are well-established deficits in schizophrenia. However, the regional disturbances in brain function causing these deficits are not yet known. This application proposes a series of integrated behavioral and fMRI studies designed to identify causes of pursuit eye movement and spatial working memory deficits in schizophrenia. We will determine whether there are intrinsic functional disturbances in extrastriate regions that process visual motion information (Area MT) using both optic flow and motion aftereffect paradigms. We will parametrically manipulate attentional enhancements during pursuit tracking to clarify the causes of what appears to be a reduced influence of extra retinal signals on the control of pursuit eye movements in schizophrenia. We will use an oculomotor delayed response (ODR) task to study spatial working memory impairments in schizophrenia. We will parametrically manipulate the rate of """"""""distractor"""""""" information presented during the delay period of this prototypic spatial working memory task in order to model changes in dorsal brain regions of interest across a range of processing load conditions. Fifty schizophrenic patients will be recruited, 25 first episode antipsychotic-naive patients and 25 unmedicated chronic patients. In addition to matched healthy subjects, 50 patients with non-bipolar depression will be recruited as a clinical comparison group. Depressed patients are of interest because our group and others have demonstrated relevant disturbances of eye movement control and spatial cognition in this disorder. Subjects will be restudied after 3 months, during which all patients will receive controlled treatment, in order to assess the extent of normalization of brain function associated with treatment and clinical recovery. The results of these studies will clarify the neurobiological basis of one of the most robust and promising biological markers of risk for schizophrenia, and of working memory disturbances known to be a prominent component of the neuropsychological profile of the disorder. Findings will also clarify the diagnostic specificity of regional brain disturbances causing these abnormalities, and the impact of known effective treatments upon them.
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