Neuroimaging Studies of Neurophysiological Phenotypes in Schizophrenia

Objective: The proposed protocol aims to combine functional magnetic resonance imaging (fMRI) and SPEM eyetracking measures to study 1) the neural circuit controlling the psychophysical, cognitive, and oculomotor aspects of eyetracking; 2) the underlying neural mechanism of schizophrenia-related eyetracking impairments; and 3) the degree to which pursuit-related imaging changes aggregate in families. The human eye movement system is complex. It is likely that only components of the system, rather than the whole system, are involved in the pathology of schizophrenia. Study Population: Three groups of subjects will be tested: schizophrenic patients (approximately n=60), full siblings of patients (approximately n=60), and healthy controls without family history of psychosis (approximately n=60). To reach this goal of 60 per group we expect to enroll 225 subjects. Design: Experiments in this protocol employ fMRI in combination with psychophysical and oculomotor paradigms to dissect the neural correlates of the neurophysiological components controlling pursuit eye movement. A high-resolution in-magnet eyetracking system will be used during imaging. Using this imaging technology we will be able to associate behavioral performance with specific brain regions. Outcome Measures: Combining fMRI and visual neuroscience techniques, this protocol will study the functional neuroanatomic underpinnings of smooth pursuit eye movement (SPEM) deficits in schizophrenia. We aim to establish a pathophysiological model of the illness based on the SPEM paradigm. Such a disease model may provide safe in vivo examination of the effects of pharmacological interventions, comorbidity, and functionality relating to schizophrenia. For example, patients with schizophrenia have high comorbidity of nicotine use. High incidence of substance abuse in schizophrenia suggests that the two conditions may share some common pathophysiology. Excessive nicotine use in schizophrenia is increasingly viewed as a form of self-medication by patients to correct underlying pathophysiological changes caused by the illness. We have found that nicotine can transiently improve smooth pursuit eye movement deficits in patients. We are currently examining the nicotinic effect on the learning components of smooth pursuit eye movement in schizophrenic patients using fMRI. This is an example on how carefully validated behavioral/imaging paradigm can be used as a pathophysiological model in aiding the study of complex brain illness including schizophrenia and substance abuse. Clearly, this research direction also requires a parallel research effort that aims at in-depth understanding of the foundational neural mechanism of the smooth pursuit eye movement itself.