Trajectories of Brain Maturation among Youth at Risk for Anxiety

摘要 焦虑在青少年中广泛存在，三分之一的青少年符合焦虑标准 18 岁之前患有疾病。尽管存在基于证据的治疗方法，但复发率却惊人地高 治疗对于改变慢性、波动性的症状进程几乎没有作用。为了解决这些问题并 为了实现当前 NIH 战略计划中概述的“治愈性治疗”使命，与以下因素相关的因素 必须更好地理解焦虑过程中的异质性。该应用程序的目标是进行 对青少年整个焦虑症状连续性的前瞻性纵向研究，描述特定的特征 疾病和损伤演变过程中的神经变化。现有的横断面研究已 指定了一个包含杏仁核（AMY）和腹内侧前额叶皮层（vmPFC）的恐惧回路，但 忽视了其他潜在重要系统（例如纹状体）在导致焦虑方面的作用。而且， 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何关系？如何接近和回避 过程相互作用，成熟的调节皮层在调节这些边缘系统中发挥什么作用？ 基于恐惧系统并影响结果？在这项研究中，我们检查额-纹状体-边缘系统 9-13 岁青少年的社区样本（n=120）的发展，被选择表现出全方位的焦虑 在分布更严重的一端出现过采样的症状。我们选择这个年龄段的考虑因素是 强有力的证据表明它将捕获焦虑症状严重程度的显着恶化。主题将被关注 三年内每年跟踪接近/回避行为的变化轨迹以及相应的 调节回路以及焦虑症状的严重程度和相关的功能结果。我们有一个特别的 有兴趣追踪与年龄预期增长的好奇心和冒险行为的差异及其 与症状过程的协变。在每个时间点，参与者将完成有风险的决策任务 同时接受功能磁共振成像以及自我报告、行为和心理生理测量。这些方法 创新的神经影像模型对这些模型进行了补充，这些模型专门测试了之间的影响方向 目标系统在青春期发生重大变化。拟议研究的结果将 阐明了接近、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。结果将是更全面地了解 症状过程中异质性的潜在机制可用于指导疾病的发展 有针对性的干预措施。

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.