Impaired generation of the P300 (P3) component of the auditory event- related potential (ERP) is one of the most consistent neurophysiological abnormalities associated with schizophrenia. This study will investigate the ERP components that precede P3 in order to determine the earliest stage at which auditory information processing is impaired in schizophrenia. P3 is elicited in an auditory """"""""oddball"""""""" task by infrequently occurring stimuli (""""""""oddballs"""""""") that differ in some physical dimension from more frequent standards. In such a paradigm, generation of P3 is preceded by a sequence of negatives that index earlier information processing operations. the first ERP component, mismatch negativity (MMN), occurs with an onset latency as short as 50 msec following stimulus delivery, and indexes the automatic detection of stimulus deviance by neural structures within auditory cortex or surrounding regions of the superior temporal plane. MMN is followed by N2, which is most likely generated within auditory association cortex and may index the earliest conscious detection of stimulus deviance. When multiple categories of stimuli are presented, allocation of attentional resources to relevant compared to irrelevant stimulus categories is indexed by processing negativity (PN) which, like MMN, may occur with an onset latency as short as 50 msec. As compared to MMN, which represents the earliest cortical response to stimulus deviance and a measure of attention-independent (automatic) stimulus processing, PN represents the earliest response to stimulus relevance and a measure of attention- modulated (controlled) processing of auditory information. The present study will investigate the integrity of MMN, N2 and PN generation in schizophrenia in order to determine the integrity of early cortical processing. Abnormalities in the generation of early cognitive components of the ERP would suggest that auditory information processing is impaired even at the level of auditory cortex. A conceptual framework for these studies is provided by the PCP/NMDA model of schizophrenia. PCP (phencyclidine, """"""""angel dust"""""""") uniquely reproduces the cognitive dysfunction associated with schizophrenia at doses at which it selectively impairs neurotransmission at the N-methyl-D-aspartate (NMDA)- type excitatory amino acid receptor. the ability of PCP to reproduce the cognitive deficits associated with schizophrenia by blocking NMDA receptors suggests that endogenous impairments in NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. Preliminary studies in monkeys suggest that MMN generation is selectively inhibited by PCP-like agents, suggesting that impaired MMN generation may serve as a marker for NMDA receptor-dysfunction. Specific experiments will examine the integrity of MMN and PN generation in schizophrenia and will correlate MMN and PN amplitude, latency and topography with independent clinical and neuropsychological assessments of cognitive functioning. This project will also evaluate whether MMN or other earlier cognitive components may serve as clinically or heuristically valuable markers of NMDA receptor dysfunction in schizophrenia.
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