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

项目摘要 拟议的K23指导以患者为导向的研究职业发展奖推出了一系列工作 旨在全面靶向机制，避免焦虑和其他疾病; 克里斯托弗·西格具备成为领先的临床研究人员所需的技能。Sege医生的主要临床 研究生涯的目标是利用尖端的转化科学，以改善精神卫生保健的目标， 精确的无序机制这项研究的需要是显着的，并与NIMH的优先事项和 RDoC框架。回避是焦虑和相关障碍治疗的核心目标，但回避行为 通常在症状减轻后仍持续存在，并使许多人根本不参与治疗。新方法， 需要在治疗早期针对回避多个动机驱动因素，以改善保留和结果 特别是对于20%没有从治疗中受益的人和40%没有完成治疗的人。基本 科学提供了重要的线索，以了解现实世界中回避的多种机制，这些机制可能是间接的， 目前的治疗技术还没有完全解决。这里提出的工作的关键目标是确定 这些机制如何驱动临床行为并支持开发直接干预的后续工作 工具.拟议的项目使用直接神经刺激（重复经颅磁刺激; rTMS）， 与精确的实验方法相结合，以测试特定的反应性（逃避）和主动性（回避） 应对神经回路可以被调节，以改变下游的恐惧和接近-避免决策。 随后的R级应用程序建立在这项工作的基础上，以确定治疗完成者的应对概况， 非完成者，并测试如何更精确地定位概况以改善结果。一队 专家导师（乔治，刘，麦克蒂格，莫布斯，乌德）将利用他们的广泛知识，在研究为基础的 和临床神经刺激，先进的功能磁共振成像分析和研究方法，并创造翻译 科学知情的治疗辅助剂，以支持Sege博士的发展。导师制，实践研究 K23提供的教程、课程、研讨会/讲习班和国际会议出席将 确保Sege博士实现其职业目标：1）发展尖端神经刺激方面的专业知识， 研究和临床使用，2）发展功能磁共振成像分析和研究工具的专业知识， rTMS更精确地针对生态相关的回避行为，和; 3）发展专业知识， 通过应用转化科学改善认知行为治疗结果的佐剂。的 拟议的K23还将促进出版、赠款撰写和跨部门领域的发展。 合作，都在一个机构--南卡罗来纳州医科大学--有着良好的记录 和对早期调查人员的承诺。拟议的K23活动将使Sege博士成为一名 尖端的临床研究人员和精神病学精确医学发展的领导者。

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.