Patients with schizophrenia exhibit behavioral and physiological impairments in the perception, modulation and evaluation of environmental stimuli. These information-processing deficits disrupt patients'efforts to detect, interpret and assign salience to incoming stimuli, resulting in disturbed behavioral responses. Clinically, this can result in hallucinations, ideas of reference, impaired affective expression and abnormal social interactions. Although memory deficits are among the most obvious and pervasive cognitive mpairments in schizophrenia, there is a growing body of evidence that very early elements of information processing, including perceptual integration and deviance detection, are also disrupted. Results of previous CCNMD event-related potential (ERP) studies demonstrated that: 1) deficits in early sensory processes contribute substantially to the deficits observed in later cognitive operations;2) early sensory deficits are evident in both the auditory and visual sensory systems;3) early sensory deficits are indicators of genetic vulnerability to schizophrenia. Animal and post-mortem studies suggested that genetically-mediated disturbances in glutamatergic transmission and synaptic function contribute to these ERP abnormalities. The current proposal will build upon these initial findings by further delineating the nature and etiology of deficits in early stimulus encoding and deviance detection. Patients, unaffected family members and healthy controls (80 subjects / group) will be studied using experimental protocols and analytic methods designed to assess the contributions of gamma and theta oscillations to these sensory processing disturbances. Evoked and induced gamma and theta rhythms constitute fundamental mechanisms for feature recognition and context-sensitive processing of sensory information, and are mediated by synaptic activity in the neural structures and transmitter systems implicated in schizophrenia. To determine the contribution of specific genetic vulnerability factors to these neural abnormalities, subjects will be categorized with respect to highrisk haplotypes for three genes that have been implicated in schizophrenia and that modulate pre- or postsynaptic glutamatergic neurotransmission or intracellular signaling: dysbindin (DTNBP1), neuregulin (NRG1) and RGS4. These studies will increase understanding of the brain abnormalities that underlie the cognitive impairments of schizophrenia. This, in turn, could provide the basis for developing new types of treatments.
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