Prospective Determination of Neurobehavioral Risk for the Development of Emotion Disorders

 描述（由申请人提供）：焦虑症和抑郁症是常见的，昂贵的，往往难以治疗，强调需要了解的生物机制，赋予风险升高。具有神经质焦虑（NA）倾向的个体在青春期后期和成年早期特别容易受到这些使人衰弱的情绪障碍的影响。NA是一种特征样表型，在生命早期就很明显，随时间推移而稳定，可遗传，其特征是在威胁不确定、模糊或遥远的情况下持续高度焦虑。虽然NA是焦虑和抑郁症最强大的表型风险标志物之一，但仍不清楚为什么NA升高的个体更容易出现情绪障碍。我们小组和其他人最近的工作提出了一个假设，即风险升高反映了支持持续焦虑的大脑网络的活动和功能连接的改变。特别是，这项工作突出了床核的终纹（BNST）和皮质区域，如前额叶（AI）的贡献。建立在我们富有成效的跟踪记录的功能磁共振成像和生态瞬时评估（EMA）的研究，我们的目标是了解持续焦虑电路的发展，强化和复发的临床意义的内化症状，使用先进的功能磁共振成像分析技术和纵向评估的日常经验和临床症状维度的创新组合的贡献。我们将使用成熟的NA测定法对> 5，000名种族多样的18-19岁青奥尔兹进行表型分析，并招募全谱表型风险（无缺口），对风险最高的人群进行过采样（120名高，60名中等，60名低NA;一半女性）。在招募时，功能磁共振成像将用于探测涉及持续和短暂焦虑的大脑网络。使用EMA，将在0，6，24和30个月时对日常经验进行集中采样，从而对情绪，功能和病理促进行为进行前所未有的纵向评估，并首次有机会探索NA相关中间表型的现实意义。诊断、维度症状和生活压力将在0、15和30个月时通过金标准访谈技术进行评估。这些数据将使我们能够：（1）发现表型风险的神经基础并开发风险（NA）生物标志物，（2）理解BNST、AI、杏仁核和其他焦虑敏感回路对压力敏感的、临床上显著的内化症状和诊断的未来进展的贡献，以及（3）了解持续焦虑回路对日常生活中病理促进感觉和行为的出现的贡献。这些目标与NIMH战略目标和RDoC倡议密切一致。该项目将提供一个潜在的变革性机会，以确定与转诊断风险最相关的分布式神经网络和最具预测性的内化症状，告知我们对病因学的理解，并指导新的翻译模型和更精确的干预策略的开发。

 DESCRIPTION (provided by applicant): Anxiety disorders and depression are common, costly, and often difficult to treat, underscoring the need to understand the biological mechanisms that confer elevated risk. Individuals with a neurotic-anxious (NA) disposition are particularly vulnerable to these debilitating emotional disorders during late adolescence and early adulthood. NA is a trait-like phenotype that is evident early in life, stable over time, heritable, and characterized by sustained levels of heightened anxiety in contexts where threat is uncertain, ambiguous, or remote. Although NA is among the most robust phenotypic risk markers for anxiety and depression, it remains unclear why individuals with elevated NA are more likely to experience emotional disorders. Recent work by our group and others suggests the hypothesis that elevated risk reflects alterations in the activity and functional connectivity f the brain networks supporting sustained anxiety. In particular, this work highlights the contributions of the bed nucleus of the stria terminalis (BNST) and cortical regions, such as the anterior insula (AI). Building on our productive track record of fMRI and ecological momentary assessment (EMA) research, our goal is to understand the contribution of sustained-anxiety circuitry to the development, intensification, and recurrence of clinically-significant internalizig symptoms using an innovative combination of advanced fMRI analytic techniques and longitudinal assessments of daily experience and clinical symptom dimensions. We will use well-established NA assays to phenotype >5,000 racially-diverse 18-19 year olds and enroll the full spectrum of phenotypic risk (without gaps), over-sampling those at greatest risk (120 high, 60 medium, 60 low NA; half female). At enrollment, fMRI will be used to probe brain networks involved in sustained as well as transient anxiety. Using EMA, daily experience will be intensively sampled at 0, 6, 24, and 30 months, enabling an unprecedented longitudinal assessment of mood, function, and pathology-promoting behaviors and affording the first opportunity to explore the real-world significance of NA-related intermediate phenotypes. Diagnoses, dimensional symptoms, and life stress will be assessed via gold-standard interview techniques at 0, 15, and 30 months. These data would enable us to: (1) discover the neural bases of phenotypic risk and develop risk (NA) biomarkers, (2) understand the contribution of the BNST, AI, amygdala, and other anxiety- sensitive circuitry to the future progression of stress-sensitive, clinically-significant internalizing symptoms and diagnoses, and (3) understand the contribution of sustained-anxiety circuitry to the emergence of pathology- promoting feelings and behaviors in daily life. These objectives are closely aligned with the NIMH Strategic Objectives and RDoC initiative. This project would provide a potentially transformative opportunity to identify the distributed neural networks most relevant to transdiagnostic risk and most predictive of internalizing symptoms, inform our understanding of etiology, and guide the development of novel translational models and more precise intervention strategies.