Trajectories of Brain Maturation among Youth at Risk for Anxiety

摘要 焦虑在青少年中普遍存在，三分之一的年轻人符合焦虑的标准 18岁之前的精神障碍。尽管存在循证治疗，复发率惊人地高 而且，治疗对改变慢性波动的症状过程几乎没有什么作用。为了解决这些关切，并 为了实现目前NIH战略计划中概述的“治疗疗法”的使命，与以下因素相关的因素 焦虑过程中的异质性必须得到更好的理解。此应用程序的目标是进行 对青年焦虑症状的全程前瞻性纵向研究，特征为 神经变化是疾病和损伤演化的基础。现有的横断面研究表明 指定了围绕杏仁核(AMY)和腹内侧前额叶皮质(VmPFC)的恐惧回路，但 忽视了其他潜在的重要系统(如纹状体)在导致焦虑方面的作用。此外， 这项工作未能解决该领域的多个关键问题：已识别的电路如何随时间变化 这种成熟与焦虑症状的过程有什么关系？如何接近和回避 这些过程是相互作用的，成熟的调节皮质在调节这些边缘- 基于恐惧系统和影响结果？在这项研究中，我们检查了额纹边缘系统。 社区样本(n=120)9-13岁青少年的发展，被选为表现出全面的焦虑 在分布较严重的一端出现过度抽样的症状。我们根据以下因素选择这个年龄范围 有力的证据表明，它将捕捉到焦虑症状严重程度的显著恶化。主题将被跟踪 每年跟踪接近/回避行为的变化轨迹，为期三年 调节回路以及焦虑症状的严重程度和相关的功能结果。我们有一个特殊的 对跟踪年龄差异的兴趣--新奇寻求和冒险行为的预期增长及其 随病程变化而变化。在每个时间点，参与者都会完成高风险的决策任务 同时接受功能磁共振成像以及自我报告、行为和心理生理学测量。这些方法 与之相辅相成的是创新的神经成像模型，专门测试 目标系统，它在青春期经历了实质性的变化。拟议中的研究结果将 阐明方法、回避和监管的组成部分和交互过程 电路有助于焦虑的持续/缓解。其结果将是更全面地理解 病程异质性的机制可用来指导疾病的发展 有针对性的干预。

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.