Remediating Emotion Deficits in PTSD: Probing and Modulating Neurocircuits

描述(由申请人提供)：这是丽莎·M·麦克蒂格博士的K23职业发展奖申请，她是斯坦福大学精神病学系的临床心理学家和讲师。麦克蒂格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。这一K23奖项将使麦克蒂格博士精通1)尖端功能神经成像(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”的原则转化为改善情绪障碍的心理社会治疗，4)利用这些新技术，结合她在认知行为治疗和心理生理学方面的成熟专业知识，为她提交一系列赠款申请，以帮助她巩固独立性。本项目的重点是创伤后应激障碍(PTSD)，这是一种具有良好特征的情绪缺陷的综合征，可能容易受到外部刺激(即TMS)的影响，这反过来可能被用来提高传统的心理治疗结果。以创伤为重点的暴露疗法是创伤后应激障碍的一线治疗，但有一半的患者在完成治疗后符合诊断标准。曝光的一个基本组成部分是彻底的情感投入过程--无论是主观上还是客观上--确保习惯化的最终体验是最有力的。麦克蒂格博士之前观察到，慢性创伤后应激障碍的特点是防御活动明显迟钝，尤其是在厌恶图像时的惊恐反射反应，这表明边缘(及相关的网络)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度唤起食欲的图像时的大脑激活和自主神经反应。后者的纳入将告知创伤后应激障碍是否以情绪网络的核心缺陷为标志，而不是战略回避--这两种结果都是干预计划(目标1)不可或缺的结果。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表现为创伤后应激障碍，将在成像过程中对两个前额叶区域进行单脉冲TMS(目标2)。最后，在接受一次(非治疗性)rTMS治疗的患者中，前额叶-边缘环路将被兴奋，以评估(潜在正常化)在随后的成像治疗中对情绪处理的影响(目标3)。成功的完成将为麦克蒂格博士先前观察到的钝化反应提供更复杂的神经生物学回路理解，同时为使用TMS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PTSD想象暴露的前奏(计划中的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).