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

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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.