Prospective Determination of Neurobehavioral Risk for the Development of Emotion Disorders

 描述(由申请者提供)：焦虑症和抑郁症是常见的、昂贵的，而且通常很难治疗，这强调了理解导致风险增加的生物学机制的必要性。神经质焦虑(NA)倾向的人在青春期后期和成年期早期特别容易受到这些衰弱的情绪障碍的影响。NA是一种类似特征的表型，在生命早期就很明显，随着时间的推移稳定，可遗传，在威胁不确定、模糊或遥远的环境中，其特征是持续水平的高度焦虑。尽管NA是焦虑和抑郁最明显的表型风险标记物之一，但仍不清楚为什么NA升高的人更有可能经历情绪障碍。我们团队和其他人最近的研究表明，风险增加反映了支持持续焦虑的大脑网络的活动和功能连接的变化。特别是，这项工作突出了终纹床核(BNST)和皮质区域，如前岛(AI)的贡献。基于我们在功能磁共振成像和生态瞬时评估(EMA)研究方面的卓有成效的记录，我们的目标是利用先进的功能磁共振成像分析技术与日常经验和临床症状维度的纵向评估的创新组合，了解持续焦虑回路在临床显著内在化症状的发展、强化和复发中的作用。我们将使用成熟的NA分析方法对5,000名18-19岁不同种族的人进行表型分析，并登记所有表型风险(没有差距)，过度抽样那些风险最高的人(120人高，60人中等，60人低NA；一半是女性)。在注册时，功能磁共振将被用来探测与持续性和短暂性焦虑有关的大脑网络。使用EMA，在0、6、24和30个月时将对日常体验进行密集采样，从而能够对情绪、功能和促进病理的行为进行前所未有的纵向评估，并提供第一次机会来探索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个月、15个月和30个月时通过黄金标准的面试技巧进行评估。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)生物标记物；(2)了解BNST、AI、杏仁核和其他焦虑敏感回路对未来应激敏感、临床显著的内化症状和诊断的进展的贡献；以及(3)了解持续焦虑回路对日常生活中出现的促进病理的感觉和行为的贡献。这些目标与NIMH战略目标和RDoC倡议密切相关。该项目将提供一个潜在的变革性机会，以确定与跨诊断风险最相关、最能预测内化症状的分布式神经网络，告知我们对病因学的理解，并指导新的转换模型和更精确的干预策略的发展。

 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.