The overall goal of this research is to define the anatomical structures, physiological mechanisms and, whenever possible, the neurochemical substrates of surface-recorded Event Related Potentials (ERP) associated with sensory, motor and cognitive processes. ERP are the only real-time physiologic measure of brain activity available in humans and they index a wide variety of normal and deviant brain processes. We utilize unanesthetized, behaving old world monkeys (M. fascicularis), as the closest feasible model for the study of human ERPS. The timing and distribution of the epidural waveform is the starting point for the analysis. These data allow comparison with scalp-recorded ERPs in humans and form the basis for specific hypotheses regarding underlying generators. Intracranial electrophysiological studies utilize three complimentary procedures, each sensitive to a different aspect of neural activity within ensembles of neurons: 1) amplitude maxima and planes of intracortical polarity inversion are determined for all components of the field potential using a moveable 16 channel multicontact electrode, 2) the net firing level of local neurons is measured by recording multiple unit activity (MUA) for each site and for each time point in the ERP, 3) local outward and inward neural transmembrane current flows are estimated from the field potential data by one-dimensional current source density (CSD) analysis. These methods in combination provide precise temporal and spatial resolution while permitting simultaneous exploration of the entire laminar expanse of active cortex. Thus, we can evaluate patterns of neural activation in the regions of transmembrane current flow and the contribution of this activity to the surface/scalp data. The sequencing of activity across laminae and across cortical regions can also be assessed. Specific studies will include examination of the laminar distribution of activity associated with pattern stimulation within striate and extra-striate visual cortex, cerebral activity associated with trained self -initiated hand movements and the potentials related to the performance of visual and auditory discrimination tasks. A principal focus of these studies will be examining the effects of neurotransmitter manipulation on the intracortical and surface ERP. Inhibitory circuitry will be manipulated by localized injections of the GABA-A antagonist bicuculline; excitatory circuits believed to be associated with 'Hebbian' synaptic modification will be explored by using competitive and noncompetitive NMDA receptor antagonists. Within each structure electrophysiologic data will be compared to known distribution of cellular elements and the pattern of synaptic contacts as well as the distribution of specific neurotransmitters as determined by autoradiographic and immunocytochemical techniques.
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