Identifying disease-related genetic effects is a major focus in schizophrenia research. Efforts have been multifaceted with the ultimate goal being to describe a causal path from specific genetic variants to changes in neuronal functioning to behavioral deficits to functional impairments. The schizophrenia diagnosis likely reflects a heterogeneous combination of several such causal paths, and is therefore characterized by a varying collection of phenotypes each associated with specific neurocognitive deficits reflecting the effects of a small number of gene(s). Nonspecific genetic and environmental modifiers also likely play an etiologic role. Based on this complex etiologic model, schizophrenia researchers have advocated the use of more elemental phenotypes. Notable examples include COMT and prefrontal dysfunction and nicotinic receptors and sensory gating deficits. Studies suggest that smooth pursuit eye movement (SPEM) abnormalities also mark a schizophrenia-related phenotype. However, in contrast to prefrontal and sensory gating deficits, we know little about the specific cognitive processes and associated neural substrates underlying these abnormalities. We have been focused in recent years on addressing this critical issue. Progress to date has been aided by our efforts to incorporate neurophysiological findings in human and non-human primate studies of motion perception and oculomotor functioning, which have shown that SPEM response can be parsed into component processes with distinct neuronal substrates. SPEM broadly involves: (a) the processing of retinal motion information (i.e., the movement of a target image on the retina); (b) the initiation of an oculomotor response based primarily on this retinal information; (c) the processing and integration of extraretinal motion signals generated by movement of the eyes; and (d) the maintenance of pursuit based on a combination of predictive eye movements guided by extraretinal signals and corrective eye movements guided by retinal velocity and position error signals. SPEM deficits in schizophrenia could be the result of a problem with one or more of these components. We propose to use a number of recently developed experimental techniques to characterize specific aspects of motion perception and oculomotor functionoing in 30 schizophrenia patients, 30 biological relatives who exhibit schizophrenia spectrum personality (SSP) symptoms, and 60 community subjects (30 of who exhibit SSP symptoms in the absence of family history for psychotic illness). Results will enhance the application of the SPEM phenotype in studies of schizophrenia by providing measures that reflect specific processing deficit(s). In this way, the phenotype can be used more effectively in imaging and drug probe studies to identify brain regions and receptor systems of interest. A refined phenotype is also likely to be more proximal to the effects of genes, and therefore better suited for alternative phenotype approaches in molecular genetic analyses. Finally, knowledge of the biological mechanisms underlying the SPEM phenotype will enhance studies of the functional significance of any candidate genes that are identified. The proposed project is a collaborative effort--involving clinical scientists studying schizophrenia pathophysiology and basic scientists studying motion perception and eye movements. ? ?
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