This revised application for a Mentored Research Scientist Development Award (K01) presents a plan for the candidate to pursue training and research in the assessment of the schizophrenia prodrome. The goals of the training and research plan are integrated around the hypothesis that attenuated negative symptoms represent a critical domain of risk for schizophrenia that is dissociable from attenuated positive symptoms at both the phenotypic and endophenotypic level. Research will utilize self-report questionnaire measures and functional magnetic resonance imaging (fMRI), with the candidate developing skills in the training program to become an independent investigator operating at the cutting edge of research in the development of schizophrenia spectrum disorders. The training plan would increase the candidate's skills in two domains necessary for state-of-the art research in subjects at risk for schizophrenia: 1) clinical assessment of psychosis and sub-psychotic states, including phenomenology, developmental issues in psychopathology, and psychometrics; and 2) functional neuroimaging assessment, including neurophysiology, neurodevelopment, and fMRI task design and statistical analysis. Additionally, the candidate will be trained in ethical issues of research involving adolescent subjects who may be at risk for severe mental illness. For each domain, there are local lead advisors who will provide regular supervision of the candidate's training and research progress, as well as consultation with and visits to leading laboratories relevant to prodromal research. The candidate will be closely supervised by the overall mentor, Dr. Barbara Cornblatt, Director of the Division of High Risk Studies at The Zucker Hillside Hospital. The research plan consists of a study integrating the two assessment domains above. Research will be conducted with adolescent subjects entering the Hillside Recognition and Prevention (RAP) Program, a federally funded study of risk for schizophrenia. Preliminary research in the RAP Program has led to a hypothesized neurodevelopmental model of the prodrome, in which cognitive deficits (such as attentional impairment) and attenuated negative symptoms (such as social isolation) precede onset of attenuated positive symptoms and psychosis. This hypothesis will be tested by administering the schizotypal personality questionnaire (SPQ) to RAP patients and treatment-seeking comparison subjects. Confirmatory factor analysis will be performed to identify positive and negative symptoms domains, which may differentiate RAP subgroups from each other and from non-RAP patients. Neurofunctional correlates of these symptom domains will be examined using both newly-developed and previously designed fMRI tasks to test the hypothesis that attenuated negative symptoms are related to dysfunction of the ventral prefrontal cortex, and attenuated positive symptoms are related to dysfunction of dorsal prefrontal cortex. This study will provide the candidate with the knowledge and research experience necessary to apply for an R01 to expand upon this research from a neurodevelopmental perspective.
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