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.
A key challenge for psychiatry and clinical psychology is to discover, understand, and ultimately to treat the root causes of the most common and costly mental disorders. The proposed study will harness an innovative combination of state-of-the-art brain imaging techniques and longitudinal measures of symptom progression, function, and real-world experience to identify the neural and behavioral pathways that contribute to the development and recurrence of anxiety disorders and depression-mental illnesses that are highly prevalent and often difficult to treat. This work is a critical step toward the development f new, neurobiologically- grounded strategies for preventing or treating these debilitating emotional disorders.
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