Trajectories of Brain Maturation among Youth at Risk for Anxiety

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Abstract Anxiety occurs widely among adolescents, with one in three youth meeting criteria for an anxiety disorder before the age of 18. Although evidence-based treatments exist, rates of relapse are strikingly high and treatment does little to alter the chronic, fluctuating course of symptoms. To address these concerns and to achieve the mission of “curative therapeutics” outlined in the current NIH strategic plan, factors linked to heterogeneity in the course of anxiety must be better understood. The goal of this application is to conduct a prospective longitudinal study of youth across the full continuum of anxiety symptoms, characterizing specific neural changes that underlie the evolution of illness and impairment. Existing cross-sectional research has specified a fear circuit encompassing the amygdala (AMY) and ventromedial prefrontal cortex (vmPFC) but has overlooked the role of other potentially important systems (e.g., striatum) in contributing to anxiety. Moreover, this work has failed to address multiple key questions for the field: How does identified circuitry change over time and how does this maturation relate to the course of anxiety symptoms? How do approach and avoidant processes interact and what is the role that the maturing regulatory cortex plays in modulating these limbic- based fear systems and influencing outcomes? In this study, we examine fronto-striato-limbic system development in a community sample (n=120) of youth ages 9-13, selected to exhibit the full range of anxiety symptoms with oversampling at the more severe end of the distribution. We choose this age range in light of robust evidence that it will capture significant worsening of anxiety symptom severity. Subjects will be followed annually for three years to track trajectories of change in approach/avoidance behaviors and the corresponding regulatory circuitry as well as anxiety symptom severity and related functional outcomes. We have a particular interest in tracking divergence from age-expected increases in novelty seeking and risk-taking behavior and its covariation with symptom course. At each time-point, participants will complete risky decision-making tasks while undergoing fMRI along with self-report, behavioral, and psychophysiological measures. These methods are complemented by innovative neuroimaging models that specifically test the direction of influence among target systems, which undergo substantial change in adolescence. Findings from the proposed research will shed light on the component and interactive processes by which approach-, avoidance-, and regulatory- circuitry contribute to the persistence/remittance of anxiety. The result will be a more holistic understanding of the mechanisms underlying heterogeneity in symptom course that may be used to guide the development of targeted interventions.