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

运动促进青少年恐惧消退、额边缘回路和内源性大麻素

• 批准号: 10648773
• 负责人: Hilary Marusak
• 金额: $ 76.12万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648773
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Aerobic Exercise; Affect; Age; Animal Model; Anxiety; Anxiety Disorders; Award; Behavior Therapy; Biological Markers; Brain; Clinical; Cognitive Therapy; Communication; Control Groups; Coupling; Data; Development; Disease remission; Endocannabinoids; Evidence based intervention; Evidence based treatment; Exercise; Expectancy; Extinction; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Galvanic Skin Response; Goals; Health Personnel; Hippocampus; Hour; Human; Individual; Intervention; Investigational Therapies; K-Series Research Career Programs; Learning; Life; Measures; Mental Health; Methods; Minority Groups; National Institute of Mental Health; Outcome; Pathologic; Patient Self-Report; Pharmacotherapy; Phase; Population Heterogeneity; Prefrontal Cortex; Prevention; Process; Productivity; Psychophysiology; Public Health; Randomized; Relapse; Research; Research Personnel; Resources; Risk; Risk Factors; Schools; Shapes; Societies; Stimulus; Testing; Translating; Work; Youth; anandamide; anxiety reduction; anxiety treatment; anxious; brain circuitry; circulating biomarkers; cost; diagnostic criteria; efficacious treatment; endocannabinoid signaling; endogenous cannabinoid system; ethnic minority population; exercise intensity; improved; improved outcome; innovation; learning extinction; low socioeconomic status; memory consolidation; multimodality; neurodevelopment; neuroimaging; novel; preadolescence; prevent; preventive intervention; programs; racial minority population; recruit; sedentary; standard measure; therapy outcome; treatment response

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.

焦虑影响几乎三分之一的青少年，并为两个人和 社会。尽管存在基于循证的青少年动画干预措施，但治疗反应是适中的，并且 继电器率不可接受。在低资源和种族/族裔少数民族中，结果甚至更糟 人群。最近的研究指出了与 当前针对青少年动画的循证治疗；也就是说，基于暴露的认知行为 治疗（CBT），依赖于恐惧的原则。我们的小组和其他人表明了恐惧 在生命的前二十年中，延伸和额叶电路会动态变化，并进行调制 由内源性大麻素（ECB）系统。此外，我们令人兴奋的初步数据表明，急性运动是 与年轻人的焦虑症降低和欧洲央行信号升高有关，因此是一种有希望的方法 优化青少年焦虑的有效治疗方法。但是，这些进步尚未转化为 改善了青年的治疗结果。拟议的项目将利用多模式实验 治疗方法测试急性运动是否修改了与 年轻人的病理生理学和动画治疗。将招募一百二十名青少年 焦虑风险升高的多样性人群，并随机地分为急性现代强度有氧运动 运动或久坐的控制条件，在恐惧扩展范式后立即执行（即，在 内存整合阶段）。我们的假设是急性锻炼会增强欧洲央行信号传导，这将导致 在增加恐惧延伸召回和增强的额叶激活和耦合中。并发 神经影像学，心理生理记录，自我报告的恐惧和动画以及循环生物标志物将会 允许我们在多个级别评估目标参与；具体来说，我们将测试恐惧扩展，额叶 电路和欧洲央行信号传导是锻炼对恐惧和焦虑风险影响的目标。这个项目是 理想地适合NIMH大脑奖，因为它将支持富有成效的早期阶段的发展 创新，高影响研究的研究者。拟议项目的结果将证明 相对低成本和低风险（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一起使用，以改善青年的预后。这个重要而及时的 研究是连续研究的重要第一步，最终将为有效的治疗 青少年动画，以及针对高危青年的新型预防性干预措施。这项工作也将进一步 了解在青春期大脑中如何获得和调节恐惧的方式。这些结果很高 与描述大脑机制的NIMH目标（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）并加强 鉴于我们小组与心理健康提供者和学校计划的联系，公共卫生影响（目标4）。