Abnormalities of smooth pursuit eye movement (SPEM) are found in 50-80% of schizophrenic patients. Based on family and twin studies, this oculomotor dysfunction is thought to be, at least partly, genetically determined and its tranmission linked with the heredity of schizophrenia. But, concordance for SPEM abnormality does not necessarily mean concordance for overt schizophrenic symptoms. It is possible that SPEM abnormality is """"""""marking"""""""" some subtle but enduring traits in a person associated with the schizophrenic illness. This application proposes to study 250 schizophrenic patients, 68 neuroleptic-free schizophrenics, and 50 normal controls to assess a variety of demographic and disease factors for their association with abnormal SPEM in these groups. Saccadic eye movements will be assessed concurrently. The factors to be measured will include age, sex, type of psychotic symptoms, premorbid history, nonlocalizing neurologic (ie. """"""""soft"""""""") signs, family history of psychotic illness, and others. Schizophrenic patients with and without tardive dyskinesia (TD) and with and without deficit (ie. enduring negative) psychotic symptoms will be targeted for assessment with eye tracking. In order to gain clinical information about the neuro-anatomic substrate for eye movements, 15 of the schizophrenic patients with, and 15 patients without TD will have a PET scan using flurodeoxyoglucose as tracer. Metabolic activity will be assessed in a range of cortical and subcortical areas with an emphasis on those CNS regions known to be involved in eye movements, eg. frontal eye fields, and basal ganglia. Glucose utilization values in these areas will be compared between good and poor """"""""trackers"""""""" and will be correlated with the magnitude of the tracking abnormality. To assess the stability of SPEM and saccadic abnormalities over time all schizophrenic patients will be tested for these movements at 6 month intervals for 4 years. Then, to test the possibility that CNS CABA-mediated transmission maybe important to SPEM or saccadic function, lumbar spinal fluid will be analyzed for GABA and for GAD activity in 68 schizophrenic patients (plus or minus TD); in these individuals eye movements will be assessed and correlations made between the CSF biochemical results and eye tracking function. Also, SPEM and saccadic function will be assessed before and during administration of a centrally active GABA mimetic in 34 patients with TD. These studies are intended to be informative about the biological and clinical determinants of abnormal ocular movements in schizophrenia.
