CSR&D Research Career Scientist Award Application

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Schizophrenia spectrum disorders and suicidal behavior are major public health problems affecting Veterans. Each year, the VA provides care to approximately 100,000 schizophrenia patients, accounting for nearly 12% of the VA’s total healthcare costs. At the same time, recent studies indicate that Veterans exhibit higher suicide risk compared with the general U.S. population. The PI’s ongoing clinical cognitive neuroscience research at the VA uses neuroimaging and psychophysiological approaches and primarily focuses on these two areas: elucidating the neurobiology of schizophrenia and suicidal behavior. Identification of promising new targets for intervention in schizophrenia and suicide prevention are critically important goals of the VA. The PI’s track record of federal funding and peer-reviewed publications in these two areas has helped advance the field. The PI’s new VA CSR&D Merit Award aims to identify the neural correlates and psychophysiology of normal emotional reactivity and regulation in healthy control Veterans and pathological severity of emotion dysregulation in Veterans with major depressive disorder (MDD) at low (non-suicidal psychiatric controls) and high-risk (suicidal ideators and suicide attempters) for suicide. Participants receive baseline functional MRI scans and a psychophysiological paradigm that provides a reliable, non-verbal, low-cost measure of emotion processing (i.e. affective startle modulation). The psychophysiology session is repeated at a 6-month follow-up; clinical symptom assessments are done at baseline, 6-, and 12-month follow-up. Understanding brain circuitry anomalies underlying dysregulated emotional expression and psychological mediators that give rise to and predict suicidal behavior and distinguish between ideators and attempters has clear public health importance. This newly-funded VA Merit study promises to help uncover the mechanisms by which biological and psychological factors give rise to suicidal behavior and may aid in prospectively identifying Veterans at greatest risk for suicide. The goal of the PI’s current schizophrenia-spectrum research (funded by her previous VA CSR&D Merit Award) is to begin to translate pre-clinical scientific research in schizophrenia into the clinical arena. In order to identify promising new targets for intervention in schizophrenia, a better understanding of its pathological circuitry and underlying genetic susceptibilities is required. Her work uses diffusion tensor imaging (DTI) and structural MRI to characterize white matter abnormalities in frontal-temporal regions. DTI fiber tractography allows quantification of the integrity of white matter connectivity in the brain. Various susceptibility genes are implicated in white matter abnormalities and schizophrenia (e.g., NRG1 and ERBB4). Together with her multidisciplinary VA-Icahn School of Medicine at Mount Sinai (ISMMS) colleagues who bring expertise in genetics, the PI’s work investigates a model of white matter disorganization in schizophrenia. Data are currently being analyzed and published from her recent VA Merit study of 60 individuals with schizotypal personality disorder (SPD) and 60 healthy controls who received MRI and were genotyped. This work evaluates white matter organization and examines the relationship between white matter connectivity (fractional anisotropy and tractography DTI measures), white matter volume (structural MRI), allelic variation in two underlying susceptibility genes (NRG1 and ERBB4), and cognitive impairment/deficit symptoms across the spectrum. SPD participants are studied as our choice of phenotype as they represent a form of schizophrenia without the confounding artifacts of chronic antipsychotic treatment, long-term psychosis, and hospitalization. Impact: This Research Career Scientist Award will allow the PI to augment her highly collaborative VA research and mentoring of promising VA MIRECC fellows and clinician-scientists. The PI’s current VA Merit is the first study at the JJPVAMC to conduct research 3T MRI scans. The PI’s goal is to further expand her MRI research program in schizophrenia and suicidal behavior at the JJPVAMC.