Event-related potentials (ERPs) provide millisecond temporal resolution of neural activity underlying cognitive processing. Research utilizing implanted electrodes in behaving humans, animal models, neural modeling of intracranial sources and study of neurological patients with focal damage in neocortical or limbic regions has provided converging information on the intracranial generators of ERPs. Thus, ERPs constitute a physiological method for measurement of cognitive activity with high temporal and spatial resolution. Study of patients with focal brain damage has shown that the P300 response, initially proposed to be a unitary phenomenon, has multiple modality independent generators in cortex in prefrontal regions, temporal-parietal junction and hippocampal formation. Patient research utilizing combined behavioral and electrophysiological techniques may provide additional information on the cognitive basis of different ERP components since specific ERP amplitude reductions can be lined to defined behavioral deficits. Theories of the cognitive basis of P300 have centered around attention and memory although no consensus has emerged. The N400 response has been linked to linguistic processing and access to the long-term memory store. Less information on neural sources is available although intracranial recording has reported N400-like activity in entorhinal cortex. Recent data collected in our laboratory in neurological patients with focal areas of brain damage suggest that the P300 and N400 responses may index neural activity generated in neocortical and limbic regions during early attention and working memory processes. In the current proposal we will study groups of patients with MRI defined damage in subregions of either prefrontal or posterior association cortex or in mesial temporal areas including hippocampus and adjacent entorhinal cortex. Combined ERP and behavioral methods will be employed to test cognitive theories of P300 and N400 generation. This approach may also provide further insight into the neural regions responsible for generation of the P300 and N400.

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