This is an application for a FIRCA to investigate the neurophysiological basis of cognitive event-related potential (ERP) generation deficits in schizophrenia. The parent application has delineated patterns of cognitive ERP and neuropsychological dysfunction in schizophrenia in order to identify potential underlying mechanisms. In particular, the parent application has focused on abnormalities in the generation of mismatch negativity (MMN), an early cognitive component generated within primary auditory cortex, and N 1, an accompanying obligatory auditory potential. Several studies over the past 5 years have demonstrated consistent and reproducible abnormalities in MMN and N1 generation in schizophrenia. Moreover, such deficits correlate with impaired performance on tests of auditory sensory memory, indicating behavioral relevance. This study will utilize a cat model of MMN generation, developed in Hungary by the foreign collaborator (Dr. George Karmos) to evaluate the degree to which thalamic or ventral hippocampal abnormalities may give rise to the pattern of ERP dysfunction observed in schizophrenia. Both thalamus and ventral hippocampus are reported to be sites of neuropathological disturbance in schizophrenia. Furthermore, recent magnetoencephalographic studies have demonstrated schizophrenia-like ERP disturbances in a group of subjects experiencing anterior thalamic strokes. Cats will be chronically implanted with intracranial (epidural) grid electrodes overlying primary and secondary auditory regions. Auditory ERP will be obtained over several weeks prior to and following unilateral and bilateral ibotenic acid lesions of specific thalamic or ventral hippocampal targets. Significant lesion effects will be further evaluated using multichannel, linear array electrodes inserted directly into either primary or secondary auditory cortex. This study extends the aims of the parent grant by utilizing a cat model to investigate whether specific neuroanatomic lesions might underlie the pattern of neurophysiological deficit observed in schizophrenia. There is no overlap between this project and the parent application.
