Modeling and Modulating Mechanisms of Escape, Avoidance, and Approach in the Anxiety Disorder Spectrum

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PROJECT ABSTRACT The proposed K23 Mentored Patient-Oriented Research Career Development Award launches a line of work aiming to comprehensively target mechanisms of avoidance in anxiety and other disorders; and, it provides Dr. Christopher Sege with skills necessary to becoming a leading clinical researcher. Dr. Sege’s primary clinical research career goal is to use cutting-edge translational science to improve mental health care by targeting precise disorder mechanisms. Need for this research is significant and consistent with NIMH priorities and the RDoC framework. Avoidance is a core target of anxiety and related disorder treatment, but avoidant behaviors often persist after symptom reduction and keep many from engaging in treatment at all. Novel methods to target multiple motive drivers of avoidance early in treatment are needed to improve retention and outcome especially for the 20% of individuals who do not benefit from and 40% who do not complete treatment. Basic science provides critical clues as to the multiple mechanisms of real-world avoidance that may be indirectly or inadequately addressed by current treatment techniques. Crucial goals of work proposed here is to determine how these mechanisms drive clinical behavior and support subsequent work that develops direct intervention tools. The proposed project uses direct neurostimulation (repetitive transcranial magnetic stimulation; rTMS) in concert with precise experimental methods to test how specific reactive (escape) and proactive (avoidance) coping neurocircuits can be modulated to alter downstream fear and approach-avoid decision-making. Subsequent R-level applications build on this work to determine coping profiles of treatment completers versus non-completers, and to test how profiles can be more precisely targeted to improve outcomes. A team of expert mentors (George, Liu, McTeague, Mobbs, Uhde) will use their extensive knowledge in research-based and clinical neurostimulation, advanced fMRI analysis and research methods, and creation of translational science-informed treatment adjuvants to support Dr. Sege in his development. Mentorship, hands-on research tutorials, coursework, seminars/ workshops, and international conference attendance afforded by the K23 will ensure that Dr. Sege achieves his career goals to: 1) develop expertise in cutting-edge neurostimulation for research and clinical use, 2) develop expertise in fMRI analysis and research tools for use in concert with rTMS to more precisely target ecologically-relevant avoidance behavior, and; 3) develop expertise in creating adjuvants that improve cognitive behavior therapy outcomes through application of translational science. The proposed K23 will also foster development in areas of publication, grant writing, and inter-departmental collaboration, all at an institution – the Medical University of South Carolina – which has a strong track record and commitment to early stage investigators. Proposed K23 activities will prepare Dr. Sege to become a cutting-edge clinical researcher and a leader in the development of a precision medicine of psychiatry.