The principle goal of the proposed project is to evaluate the role of N-methyl-D-aspartate (NMDA) receptors in the generation of long-latency, processing-contingent components (PCCs) of the auditory event-related potential (AEP). As opposed to obligate components which reflect the psychoacoustic properties of presented stimuli, PCCs index attentional and cognitive processing operations. NMDA receptors uniquely mediate long-duration, """"""""conditional"""""""" depolarizations within cortex, suggesting that NMDA receptor activation may contribute selectively to PCC generation. A second goal of this project is to test the hypothesis that pharmacological antagonists of NMDA receptors can induce PCC abnormalities, including deficits in """"""""mismatch"""""""" and """"""""processing"""""""" negativity generation, that are analogous to those seen in patients with schizophrenia. The proposed project will utilize unanesthetized, behaving old world monkeys (M. fascicularis), as the closest feasible model for human AEP. The characteristic timing and epidural distribution of monkey potentials corresponding to the human mismatch and processing negativities will be determined using passive and active """"""""oddball"""""""" paradigms analogous to those employed in clinical studies. The location and extent of neural generators for identified PCCs will be determined using three dimensional mapping techniques and moveable intracranial multicontact electrodes inserted through implanted epidural guide tubes. These procedures are ideal for rapidly surveying large areas. Initial studies will focus on the posterior region of the superior temporal plane, which has been proposed as a source of both the mismatch and processing negativities. Later studies will focus also on temporal and prefrontal regions which receive auditory afferents. The laminar profile of activity will be analyzed using one-dimensional current source density (CSD) techniques which provides an index of the magnitude, location and duration of intralaminar transmembrane current flow (i.e. """"""""sources"""""""" and """"""""sinks""""""""). Concomitant recording of multiunit activity (MUA) will define the firing rate of neurons in the vicinity of the recording electrode and will permit the interpretation of current sources and sinks as indices of net excitatory and inhibitory synaptic processes. The possible contribution of NMDA receptor-mediated neurotransmission to PCCs will be assessed by systemic injection and intracortical microinfusion of competitive and noncompetitive NMDA receptor antagonists.Phencyclidine (PCP, """"""""angel dust"""""""") has been shown to induce psychotic symptoms and neuropsychological deficits similar to those observed in schizophrenia at doses at which it selectively inhibits NMDA receptor-mediated neurotransmission. The proposed studies will evaluate the possibility that dysfunction of NMDA receptor-mediated neurotransmission may also contribute to the neurophysiological dysfunction associated with schizophrenia.
| Javitt, D C; Steinschneider, M; Schroeder, C E et al. (1996) Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci U S A 93:11962-7 |
| Javitt, D C; Steinschneider, M; Schroeder, C E et al. (1994) Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation. Brain Res 667:192-200 |
| Javitt, D C; Doneshka, P; Zylberman, I et al. (1993) Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study. Biol Psychiatry 33:513-9 |
| Javitt, D C; Schroeder, C E; Steinschneider, M et al. (1992) Demonstration of mismatch negativity in the monkey. Electroencephalogr Clin Neurophysiol 83:87-90 |
