Developmental Pathophysiology of Adverse Patterns of Substance Use in Adolescents with Anxiety

The proposed 5-year R01 study will examine maturational pathways of biomarkers (neural connectivity and stress physiology) to adverse patterns of substance use (APSU) in adolescents with anxiety symptoms to improve precision-based, targeted intervention. Anxiety remains one of the most commonly diagnosed clinical symptom domains in adolescence and is a potent precursor to and exacerbator of substance use disorder, although there is substantial heterogeneity in outcomes. As such, detection of anxiety symptoms alone provides limited information about the predictability, pathophysiology, progression, and preventability of anxiety-linked APSU. Key to understanding how anxiety symptoms increase risk for APSU may be found in a disruption of neural pathways that subserve executive cognitive modulation of threat information processing and response. We propose that local alterations in threat processing circuitry (e.g., the central extended amygdala) during anticipation or unpredictability of threat, and stress physiological dysregulation (heart rate variability and salivary cortisol) during a social stress task, underpin internalizing symptoms. However, local intra-network alterations likely do not fully explain pathways from internalizing symptoms (anxiety) to externalizing behaviors (APSU). Thus, we further propose that a breakdown in coordination between cognitive control circuity (frontoparietal and cingulo-opercular) and threat processing circuitry will be expressed in both weakened neural connectivity and poorer task performance, which will predict APSU in adolescents with anxiety symptoms at high risk for SUD. Across development, we expect these neuronal and physiological features will become even more pronounced and sex differences will become increasingly prominent. Our objective is to elucidate the role of maturational change across adolescence in neural connectivity between fronto-limbic subsystems and physiological stress responses to an acute stressor in the relationship between anxiety and APSU. We propose to chart the developmental progression of neural and stress physiological factors that confer risk for APSU in adolescents with anxiety symptoms by conducting a prospective, longitudinal study of adolescents (N=180, age 12-14), including three 12 month waves of data collection. Eligible participants will report anxiety symptoms and substance use naïvete and will be oversampled (50%) on the basis of high risk for adolescent SUD using an established cut-off on a well- established risk inventory. Graph theory will be applied to functional connectivity estimates of MRI data at rest and during cognitive control, inhibition, and threat processing tasks to test an integrative, multi-modal model with physiological, behavioral and survey measures to track trajectories of neurodevelopment. Identifying biomarkers predictive of APSU in at-risk adolescents is critical to the design of program components more precisely targeted to neural and physiological systems that support self-regulation, with potential to achieve more than the small to modest effect sizes currently produced by even our most efficacious interventions.