Persistent cognitive dysfunction is a key predictor of chronic disability and poor long-term outcome in schizophrenia. Mismatch negativity (MMN) is a short-latency event-related potential (ERP) that provides an objective index of cognitive dysfunction in schizophrenia at the level of primary auditory cortex (A1). Investigation into mechanisms underlying normal MMN generation in monkeys, therefore, provides a powerful approach for delineating potential mechanisms underlying cognitive dysfunction in schizophrenia. Old World monkeys generate MMN-like activity that closely resembles human MMN in terms of scalp distribution and deviance dependence. The overall goal of this project is to model neurophysiological and neurochemical mechanisms associated with cognitive dysfunction in schizophrenia by utilization of intracortical MMN recordings in monkey A1. For this project, monkey MMN generators are assessed using multichannel recordings from A1 coupled with focal neurochemical micromanipulation. The spatiotemporal pattern of intracortical MMN generation is analyzed using a combination of ERP, current source density, and multiunit activity measures. Phencyclidine (PCP, """"""""angel dust"""""""") induces schizophrenia-like cognitive dysfunction and psychosis by blocking NMDA receptor-mediated neurotransmission. NMDA antagonists inhibit local MMN generation in A1 without affecting generation of prior obligatory ERP components, consistent with the hypothesis that endogenous dysfunction of dysregulation of NMDA receptor-mediated neurotransmission might contribute to the pattern of cognitive dysfunction seen in schizophrenia. Deficits in MMN generation in schizophrenia are accompanied by abnormalities in long-ISI P1 and N1 generation, which may also reflect brain dysfunction at the level of sensory cortex. This study will evaluate neurophysiological and neurochemical hypotheses concerning potential etiology of early sensory processing dysfunction in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH055620-08
Application #
6830249
Study Section
Special Emphasis Panel (ZRG1-IFCN-8 (01))
Program Officer
Winsky, Lois M
Project Start
1996-12-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2006-11-30
Support Year
8
Fiscal Year
2005
Total Cost
$311,101
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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