Exercise facilitation of adolescent fear extinction, frontolimbic circuitry, and endocannabinoids

焦虑症影响着近三分之一的青少年，给个人和家庭都带来沉重负担。 社会。尽管存在针对青少年焦虑的循证干预措施，但治疗效果有限且 复发率高得令人无法接受。资源匮乏和少数种族/族裔的结果更糟 人口。最近的研究已经确定了与神经发育相关的目标 当前青少年焦虑症的循证治疗方法；即基于暴露的认知行为 疗法（CBT），它依赖于消除恐惧的原理。我们的团队和其他人已经表明，恐惧 消退和额边缘电路在生命的前二十年动态变化，并受到调节 由内源性大麻素（ECB）系统产生。此外，我们令人兴奋的初步数据表明，剧烈运动是 与青少年焦虑程度降低和 eCB 信号升高相关，因此是一种很有前途的方法 优化青少年焦虑的有效治疗方法。然而，这些进步尚未转化为 改善青少年的治疗结果。拟议的项目将利用多模式实验 治疗方法来测试急性运动是否改变与相关的假设目标 青年焦虑的病理生理学和治疗。将从中招募一百二十名青少年 焦虑风险较高的不同人群被随机分为急性中等强度有氧运动 运动或久坐控制条件，在恐惧消退范式之后立即进行（即，在 记忆巩固阶段）。我们的假设是剧烈运动会增强 eCB 信号传导，从而导致 增加恐惧消退回忆并增强额边缘激活和耦合。并发 神经影像学、心理生理学记录、自我报告的恐惧和焦虑以及循环生物标志物将 允许我们在多个层面评估目标参与度；具体来说，我们将测试恐惧消退、额边缘 电路和 eCB 信号传导作为运动对恐惧消退和焦虑风险影响的目标。这个项目是 非常适合获得 NIMH BRAINS 奖，因为它将支持富有成效的早期阶段的开发 创新、高影响力研究的研究员。拟议项目的结果将表明 相对较低的成本和较低的风险（例如与药物治疗相比）行为干预可能是 单独使用或与当前治疗结合使用可改善青少年的治疗结果。这一重大而及时的 这项研究是一系列研究中至关重要的第一步，最终将带来有效的治疗方法 青少年焦虑，以及针对高危青少年的新型预防干预措施。这项工作也将进一步推动我们 了解青少年大脑中恐惧是如何获得和调节的。这些结果是高度 与 NIMH 描绘大脑机制（目标 1）、了解风险因素和 疾病和治疗反应的生物标志物（目标 2）、改善预防（目标 3）以及加强 鉴于我们小组与心理健康提供者和学校项目的联系，公共健康影响（目标 4）。

Anxiety affects nearly one in three adolescents and contributes to substantial burden on both individuals and society. Although evidence-based interventions for adolescent anxiety exist, treatment response is modest and relapse rates are unacceptably high. Outcomes are even worse among low resource and racial/ethnic minority populations. Recent studies have pinpointed neurodevelopmentally-informed targets that are relevant to current evidence-based treatments for adolescent anxiety; namely, exposure-based cognitive behavioral therapy (CBT), which relies on principles of fear extinction. Our group and others have shown that fear extinction and frontolimbic circuitry change dynamically across the first two decades of life, and is modulated by the endocannabinoid (eCB) system. Further, our exciting preliminary data show that acute exercise is associated with lower anxiety and elevated eCB signaling in youth, and is therefore a promising approach for optimizing efficacious treatments for adolescent anxiety. However, these advances have not yet translated to improved therapeutic outcomes for youth. The proposed project will leverage a multi-modal experimental therapeutics approach to test whether acute exercise modifies hypothesized targets that are relevant for the pathophysiology and treatment of anxiety in youth. One hundred and twenty adolescents will be recruited from a diverse population at elevated risk of anxiety and randomized into either an acute moderate-intensity aerobic exercise or sedentary control condition, performed immediately after a fear extinction paradigm (i.e., during the memory consolidation phase). Our hypothesis is that acute exercise will boost eCB signaling, which will result in increased fear extinction recall and enhanced frontolimbic activation and coupling. Concurrent neuroimaging, psychophysiological recordings, self-reported fear and anxiety, and circulating biomarkers will allow us to evaluate target engagement at several levels; specifically, we will test fear extinction, frontolimbic circuitry, and eCB signaling as targets for exercise’s effects on fear extinction and anxiety risk. This project is ideally suited for the NIMH BRAINS award because it will support the development of a productive early-stage investigator in innovative, high-impact research. Results of the proposed project will demonstrate that a relatively low cost and low risk (compared to pharmacotherapy, for example) behavioral intervention may be used alone or in conjunction with current treatments to improve outcomes for youth. This significant and timely study is an essential first step in a continuum of research that will ultimately lead to efficacious treatments for adolescent anxiety, and novel preventive interventions for at-risk youth. This work will also further our understanding of how fear is acquired and regulated in the adolescent brain. These outcomes are highly aligned with the NIMH goals of delineating brain mechanisms (Goal 1), understanding risk factors and biomarkers of illness and treatment response (Goal 2), improving prevention (Goal 3), and strengthening the public health impact (Goal 4), given our group’s ties to mental health providers and school programs.