I am psychiatrist who specializes in clinical high risk research in psychotic disorders. This proposal describes a translational research training program in patients at clinical risk for psychosis focused upon acquiring additional expertise in functional brain imaging methods, specifically in well-tolerated non-invasive imaging techniques including Arterial Spin Labeling (ASL), and Magnetic Resonance Spectroscopy (MRS), to complement ongoing Cerebral Blood Volume [CBV] studies. These studies will incorporate longitudinal study of patients at clinical risk for psychosis in a two year prospective study to identify differentially targeted brain sites in prodromal stages of disease, with a specific focus upon hippocampal dysfunction. The knowledge and new research skills gained from this study will be enhanced by advanced training in human neuroanatomy, focusing more broadly upon the neural systems most affected in schizophrenia. Differentially targeted brain sites identified with this enhanced approach will be used to test animal models of the disorder using the same functional MRI paradigm, which will provide a direct determination of how accurately a given rodent model recapitulates the known patterns observed in humans. These clinical training and research efforts will be complemented by an advanced translational research training program in the study rodent models of ventral hippocampal dysfunction. As the plausibility of putative treatment targets in these models and the effects of candidate novel treatments on hippocampal dysfunction in these models are tested using a combined fMRI/neurochemical approach, I will enhance my theoretical and practical approach to this research problem through advanced study of glutamate pharmacology and rodent modeling. The primary goal in obtaining this further training and in performing the proposed experiments is to best manipulate what we hypothesize to be key the neurochemical mechanisms underlying the emergence of hippocampal hypermetabolism in psychotic disorders, with a better tolerated, potentially more effective preventative therapeutic approach in prodromal stages of disease. As a long-term career goal, outside of the research scope of this present application, I intend to take the investigative platform described above to the clinical interface in a series of iterative proof-of-concept intervention studies in patients who are at clinical risk for psychosis. In order to prepare for this goal, during my research fellowship, I have begun to develop this coordinated brain imaging and animal models approach working with Scott Small, pioneer of high-resolution functional imaging methodology, Cheryl Corcoran, director of Columbia University s prodromal research clinic, and Holly Moore, expert in rodent models of ventral hippocampal dysfunction. I will continue to work collaboratively with this group on the proposed studies in this application. For the revised application, I have formed relationships with new mentors specifically tailored to the needs of my revised training goals. I have chosen Dr. Iris Asllani and Larry Kegeles for mentorship in ASL and MRS, respectively, two experts in these areas of brain imaging who are available to train me in acquisition and analysis of this type of imaging data here at Columbia. For enhancing my knowledge of neuroanatomy and glutamate pharmacology to the level of expert, I have chosen Dr. Suzanne Haber, Dr. Daniel Scot Zahm, and Dr. Stephen Rayport, world-experts in this area. Finally, I have chosen Dr. Lieberman as my primary mentor for this training grant, and have formed a mentorship and didactic training plan in small clinical trials design which will allow this goal to be realized over time. The optimal pharmacological strategies for this future work will be in part determined by further translational characterization of hippocampal dysfunction in humans and mouse models of disease, the first efforts of which are contained in this proposal. This longitudinal and 'full-circle'aspect of the studies described in this application constitutes my central focus and career goals for this K23 resubmission.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Wynne, Debra K
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New York State Psychiatric Institute
New York
United States
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Gilani, Ahmed I; Chohan, Muhammad O; Inan, Melis et al. (2014) Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci U S A 111:7450-5
Schobel, Scott A; Chaudhury, Nashid H; Khan, Usman A et al. (2013) Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 78:81-93
Small, Scott A; Schobel, Scott A; Buxton, Richard B et al. (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12:585-601