Negative symptoms in schizophrenia present a challenge to treatment and are associated with profound functional impairment. Characterizing the developmental trajectory of these symptoms and their relation to the emergence of schizophrenia and psychosis during adolescence and early adulthood is an essential prerequisite for early identification and clinical intervenfion. The overall goal of this Project is to probe brain circuitry that underlies the core domain of negative symptoms of diminished emotional expressivity and social drive, in informative youths at risk for psychosis and early in the course of illness. By applying deep phenotyping of clinical, neurobehavioral, physiologic and anatomic measures that complement the rodent studies (Projects II, 111) and can be integrated with cellular, molecular and genomic data (Projects IV, V), we hope to propel the field and elucidate key features of schizophrenia that require better understanding leading to new treatments. Project I will specifically contribute to elucidafing how neural responses are modulated by aversive conditioning and extinction and how these processes are impaired in affected and at risk youths. Complementary EEG and fMRI methods will help test the hypothesis that dysregulation of amgydala and its role in circuits mediating negative emofion processing contribute to schizophrenia risk, negative symptoms, and social dysfunction. The sample will include 225 youths characterized in Core A. There will be 75 participants in each group of patients with schizophrenia, clinical risk and healthy controls. They will each undergo an fMRI and an EEG experiment in a counter-balanced order. Complementary tasks that probe amygdala circuitry will be administered in the studies. The EEG procedure will include more refined gradation of timing parameters and the fMRI will provide 3-D anatomical resolution and amygdala integrity and activation measures. Basal and activation parameteres will be related to dimensional measures of negative symptomatology, social function and social learning of positive and negative value.

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Project I will integrate key dimensional clinical phenotypes with neurobehavioral measures, multi-modal neuroimaging, electrophysiology and genomics. This effort will cohere with the NIMH strategic plan for Conte Centers and for the Research Domain Criteria approach. The Project will augment current knowledge on amygdala circuitry functioning and the effects of psychosis and risk for psychosis.

National Institute of Health (NIH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1)
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University of Pennsylvania
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