The influence of aerobic exercise on consolidation of fear extinction learning in PTSD

项目总结 以暴露为基础的心理疗法(例如，长期暴露)是对以下疾病最好的支持治疗之一 创伤后应激障碍(PTSD)，但这些一线治疗的缓解率通常只有50%- 60%。这些疗法旨在通过实现治疗安全学习来减少对创伤提醒的焦虑， 这被认为是通过恐惧消退学习的机制起作用的。因此，恐惧的消亡 范例被广泛用作暴露疗法的实验室模型，在这一概念下，治疗 在实验室中加强灭绝学习和回忆可能是提高脑力衰竭疗效的有希望的候选者 基于暴露的疗法。我们最近的临床先导研究的结果(不含成像组件) 提供的初步证据表明，中等强度的有氧运动可以促进巩固恐惧 消退记忆和增强消退回忆的认知指数--一种效应是由 运动引起的脱氧核糖核酸(AEA；一种主要的内源性大麻素)的增加。因此，这个K01项目涉及到 一项随机对照的fMRI实验室研究：1)测试不同剂量的有氧运动(轻度、 中强度和高强度)在消退训练后进行，可改善认知、生理和神经 包括对消亡记忆编码多变量模式的增强检索的消退回忆指数 (24小时后测试)，以及2)通过确定剂量-反应关系进一步探讨AEA的作用 有氧运动强度和外周AEA浓度之间的关系(以及运动是否导致 AEA的增加调节了上述关系)在创伤暴露的男性和女性中 无创伤后应激障碍者(N=120)。PI将接受培训和指导，包括：1)计算方面的培训 神经科学理论和统计技术(例如，多变量成像分析和计算 建模以分析心理生理学和神经成像数据)，2)临床暴露和临床专业知识 创伤后应激障碍和焦虑症的模型和神经回路，3)在临床试验中获得专业知识，以便能够 作为独立的调查者设计、实施和分析药理学和非药理学随机对照试验， 以及4)专业和职业发展活动，以促进多学科研究合作。这个 拟议的培训和研究将在德克萨斯大学奥斯汀分校进行，包括国内和 与顶尖研究人员的国际合作，所有这些都建立了广泛的NIH研究 涵盖多个领域，例如：计算神经科学、精神病学、临床心理学、 生物统计学和药理学。归根结底，从PI获得的指导和培训经验 导师团队，以及从K01奖中获得的结果，将成为PI成为 能够在创伤后应激障碍和临床上进行有影响力的心理健康研究的独立调查者 利用多学科的视角和不断进步的先进方法 精神病学和计算神经科学领域。

PROJECT SUMMARY Exposure-based psychotherapies (e.g., prolonged exposure) are among the best supported treatments for posttraumatic stress disorder (PTSD), yet remission rates for these front-line treatments are typically only 50- 60%. These therapies aim to reduce anxiety towards trauma reminders by enabling therapeutic safety learning, which is hypothesized to work via the mechanisms of fear extinction learning. As such, fear extinction paradigms are widely used as laboratory models of exposure therapy, under the notion that treatments that enhance extinction learning and recall in the lab may be promising candidates for improving the efficacy of exposure-based therapies. Results from our recent clinical pilot studies (without an imaging component) provided preliminary evidence suggesting moderate-intensity aerobic exercise can boost consolidation of fear extinction memories and enhance cognitive indices of extinction recall – an effect that was mediated by exercise-induced increases in anandamide (AEA; a primary endocannabinoid). Thus, this K01 project involves a randomized controlled fMRI laboratory study to: 1) test whether different doses of aerobic exercise (light-, moderate-, and high-intensity) delivered after extinction training improves cognitive, physiological, and neural indices of extinction recall including enhanced retrieval of multivariate patterns of extinction memory encoding (when tested 24hrs later), and 2) further probe the role of AEA by determining dose-response relationships between aerobic exercise intensities and peripheral AEA concentrations (and whether the exercise-induced increases in AEA mediate the aforementioned relationships) in trauma-exposed men and women with and without PTSD (N=120). The PI will receive training and mentorship including: 1) training in computational neuroscience theory and statistical techniques (e.g., multivariate imaging analyses and computational modeling to analyze psychophysiological and neuroimaging data), 2) clinical exposure and expertise in clinical models and neurocircuitry of PTSD and anxiety disorders, 3) gaining expertise in clinical trials to be able to design, conduct, and analyze pharmacological and non-pharmacological RCTs as an independent investigator, and 4) professional and career development activities to foster multi-disciplinary research collaborations. The proposed training and research will occur at The University of Texas at Austin and includes domestic and international collaborations with top-notch researchers, all of which have established extensive NIH research portfolios spanning several fields such as: computational neuroscience, psychiatry, clinical psychology, biostatistics, and pharmacology. Ultimately, the guidance and training experiences gained from the PI’s mentorship team, and the results obtained from this K01 award, will serve as a scaffolding for the PI to become an independent investigator capable of conducting impactful mental health research in PTSD and clinical anxiety populations by utilizing a multidisciplinary lens and advanced methodologies from the ever-advancing fields of psychiatry and computational neuroscience.