Remediating Emotion Deficits in PTSD: Probing and Modulating Neurocircuits

描述（由申请人提供）：这是一份K23职业发展奖申请，申请对象是Lisa M. McTeague博士，她是斯坦福大学精神病学系的临床心理学家和讲师。McTeague博士的长期职业目标是了解严重情感性疾病中情绪反应性障碍的神经基础，以确定更好地补救这些缺陷的多模式方法。K23奖将使McTeague博士能够熟练掌握以下技术：1)尖端的功能神经成像（fMRI）； 2)经颅磁刺激（TMS）作为研究完整和紊乱大脑激活的直接工具；3)将“实验医学”的原理转化为改善情绪障碍的心理社会治疗；4)利用这些新技术与她在认知行为治疗和心理生理学方面的专业知识相结合，为一系列的拨款申请提供帮助，以巩固她的独立性。这个项目的重点是创伤后应激障碍（PTSD），作为一种具有明显特征的情绪缺陷的综合征，可能容易受到外源性刺激（即经颅磁刺激）的影响，这反过来又可以用来提高传统心理治疗的效果。以创伤为重点的暴露疗法是创伤后应激障碍的一线治疗方法，但一半的患者在完成治疗后符合诊断标准。暴露的一个基本组成部分是彻底的情感投入过程——主观上和客观上——确保最终的习惯体验是最强大的。McTeague博士之前观察到慢性创伤后应激障碍的特点是防御动员的明显钝化，最主要的是在厌恶意象时的惊吓反射反应，这表明边缘（及相关网络）激活不足。为了有意义地推进这些结论并指出干预目标，麦克蒂格博士建议评估40名创伤后应激障碍患者和20名创伤暴露的健康参与者在中性和厌恶以及同样高唤起的食欲意象时的大脑激活和自主神经反应。将后者纳入研究将有助于了解PTSD是否以情感网络的核心缺陷为特征，而不是以战略回避为特征——两者都是干预计划的组成部分（目的1）。为了评估边缘和前额叶回路之间的异常、状态依赖的相互作用是否为PTSD的特征，在成像过程中，将对两个前额叶区域进行单脉冲颅磁刺激（Aim 2）。最后，将通过单次（非治疗性）rTMS刺激患者的前额叶边缘回路，以评估（潜在的正常化）对随后立即进行的意象处理的影响（目的3）。成功的完成将为McTeague博士先前对迟钝反应的观察提供更复杂的神经生物学回路理解，同时为使用经颅磁刺激增强情绪反应和调节神经回路的可行性提供必要的指导，作为创伤后应激障碍的想象暴露的序曲（计划R01应用）。

DESCRIPTION (provided by applicant): This is a K23 Career Development Award application for Lisa M. McTeague, Ph.D., a clinical psychologist and Instructor in the Department of Psychiatry at Stanford University. Dr. McTeague's long-term career goal is to understand the neural basis of emotional reactivity impairments in severe affective illness in the service of identifying multimodal approaches to better remediate these deficits. This K23 award would enable Dr. McTeague to gain proficiency in 1) cutting-edge functional neuroimaging (fMRI), 2) transcranial magnetic stimulation (TMS) as a direct tool for investigating intact and disordered brain activation, 3) translating the principles of "experimental medicine" to psychosocial treatment toward ameliorating emotional dysfunction, and 4) leveraging these new techniques in conjunction with her established expertise in cognitive- behavioral treatment and psychophysiology for a series of grant submissions to help solidify her independence. This project focuses on posttraumatic stress disorder (PTSD) as a syndrome with well-characterized emotion deficits that may be susceptible to exogenous stimulation (i.e., TMS), which could, in turn, be utilized to enhance conventional psychotherapy outcomes. Trauma-focused exposure-based therapies are the first-line treatments for PTSD but half of patients meet diagnostic criteria upon completion. A fundamental component of exposure is the process of thorough emotional engagement-both subjectively and objectively-ensuring that the ultimate experience of habituation is optimally powerful. Dr. McTeague previously observed that chronic PTSD is marked by stark blunting of defensive mobilization, foremost in startle reflex responding during aversive imagery, suggestive of deficient limbic (and associated network) activation. To meaningfully advance these conclusions and point to intervention targets, Dr. McTeague proposes to assess brain activation and autonomic responding in 40 patients with PTSD and 20 trauma-exposed healthy participants during neutral and aversive as well as equally high arousing appetitive imagery. The inclusion of the latter will inform on whether PTSD is marked by core deficiencies in emotion networks as opposed to strategic avoidance-either outcome integral to intervention planning (Aim 1). To assess whether aberrant, state-dependent, interactions between limbic and prefrontal circuitry characterize PTSD, single pulses of TMS will be administered to two prefrontal regions during imagery (Aim 2). Finally, prefrontal-limbic circuits will be excited in patients with a single (non-therapeutic) session of rTMS to assess for (potentially normalizing) effects on emotional processing in an immediately subsequent imagery session (Aim 3). Successful completion would provide a more sophisticated neurobiological circuit understanding to Dr. McTeague's prior observation of blunted responding while furnishing essential guidance on the feasibility of using TMS to enhance emotional reactivity and regulation neurocircuitry as a preamble to imaginal exposure for PTSD (planned R01 application).