Cognitive and other information processing impairments are a prominent, disabling feature of schizophrenia and a strong predictor of functional outcome. Thus, understanding the pathophysiologic mechanisms underlying these deficits has become a critical focus in the development of novel therapeutics for the illness. A central hypothesis of the Center is that disturbances in GABA neurotransmission are a neurobiological substrate for these deficits by virtue of their role in generating and sustaining the synchronous oscillations in cortical networks that appear to be critical for various cognitive processes. In this project, we will investigate oscillatory disturbances in first-episode, antipsychotic-nai've individuals with schizophrenia (FEAN-S). We will also study first-episode, antipsychotic-naTve, non-schizophrenia psychotic (FEAN-NS) subjects to permit a systematic investigation of the diagnostic specificity of our findings. We will employ a multimodal imaging approach, including EEG and fMRI. EEG measures will be used to assess disturbances in gamma (30-80 Hz) and theta (4-8 Hz) oscillations, using task paradigms and examining brain regions that are effective tests of disturbances in oscillations at these two frequency bands. Closely analogous EEG tasks will be employed in monkeys in Project 4-Olson, but with measures of neural circuit functioning at a much finer physiologic resolution, thus allowing more detailed assessment of oscillatory dynamics, including their sensitivity to pharmacologic manipulations of GABA neurotransmission. Using the same task paradigms, fMRI measures will provide an index of local cortical circuit activity and thus provide critical information regarding the anatomic distribution of findings. Project-6 Mathis will provide in vivo PET measures of GABA neurotransmission in a subset of the same subjects, thus permitting inferences concerning the dependence of EEG and fMRI findings on GABA neurotransmission. Studying FEAN-S subjects will permit an evaluation of the extent to which oscillatory disturbances are a core pathophysiologic finding present early in the illness, in the absence of possible treatment effects, and will provide the basis for potential generalization of findings to the schizophrenia population at large. This project, together with other projects in the Center, could lead to a rich convergence of findings with the potential to provide biomarkers important in novel therapeutics development in schizophrenia.
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