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.

焦虑影响近三分之一的青少年，并对个人和家庭造成巨大负担。 社会虽然存在针对青少年焦虑症的循证干预措施，但治疗反应温和， 复发率高得令人无法接受。在低资源和种族/少数民族中，结果甚至更糟 人口。最近的研究已经确定了神经发育相关的目标， 目前对青少年焦虑的循证治疗;即，基于确定性的认知行为 CBT疗法（CBT），它依赖于恐惧消退的原则。我们的团队和其他人已经证明了恐惧 在生命的前二十年，灭绝和额缘电路动态变化， endocannabinoid（eCB）系统。此外，我们令人兴奋的初步数据表明，急性运动是 与年轻人的焦虑降低和eCB信号升高相关，因此是一种有前途的方法， 优化青少年焦虑的有效治疗方法。然而，这些进展尚未转化为 改善青少年的治疗效果。拟议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了与运动相关的假设目标。 青年焦虑症的病理生理学和治疗。将招募120名青少年， 焦虑风险升高的多样化人群，随机分为急性中等强度有氧运动组和 运动或久坐不动的控制条件，在恐惧消退范例之后立即进行（即，期间 记忆巩固阶段）。我们的假设是，剧烈运动会增强eCB信号，这将导致 恐惧消退回忆增加，额边缘激活和耦合增强。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 允许我们在几个级别上评估目标的参与;具体来说，我们将测试恐惧消退，额边缘 电路和eCB信号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NIMH的大脑奖，因为它将支持一个富有成效的早期阶段的发展 研究人员在创新，高影响力的研究。拟议项目的结果将表明， 相对低成本和低风险（例如，与药物治疗相比）的行为干预可能是 单独使用或与目前的治疗方法结合使用，以改善青年的预后。这一重大而及时的 研究是一系列研究中必不可少的第一步，这些研究最终将导致有效的治疗方法， 青少年焦虑症，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促进我们的 了解恐惧是如何在青少年大脑中获得和调节的。这些成果高度 符合NIMH的目标，即描绘大脑机制（目标1），了解风险因素， 疾病和治疗反应的生物标志物（目标2），改善预防（目标3），加强 公共卫生影响（目标4），考虑到我们集团与心理健康提供者和学校计划的联系。