Threat Neurocircuitry Predicts the Development of Anxiety and Depression Symptoms in a Longitudinal Study

Background: Owing to high heterogeneity and comorbidity, the shared and unique neural mechanisms underlying the development of anxiety and major depressive disorders remain unclear. Using a dimensional model describing shared versus unique symptoms associated with anxiety and depression, this study investigated how longitudinal changes in symptom dimensions relate to threat neurocircuitry. Methods: Participants were 18- to 19-year-olds (N = 279, 186 females) who completed self-report measures of anxiety and depression at baseline and at 10, 20, and 30 months. Linear slopes of symptom dimensions of general distress, fear, and anhedonia-apprehension were estimated through a trilevel factorial model. In addition, functional magnetic resonance imaging scans were obtained while participants performed Pavlovian fear conditioning tasks at baseline and 30 months, including three phases of fear acquisition, extinction, and extinction recall. Neural responses in regions of interest related to threat neural circuitry (e.g., amygdala, ventromedial prefrontal cortex, and subgenual anterior cingulate cortex) were extracted. Results: Linear mixed models used to estimate relationships between changes of symptom dimensions and neural responses revealed two major findings: 1) greater neural responses to threatening stimuli during fear acquisition at baseline were associated with a greater increase in fear symptoms during the 30-month prospective period; and 2) elevated neural responses to the extinguished stimulus during extinction recall at 30 months were negatively associated with changes in general distress, suggesting that greater increases in general distress are associated with larger deficits in extinction memory. Conclusions: These findings improve our understanding of pathophysiological pathways underlying the development of anxiety and depression, while separating symptom dimensions that are shared versus unique between the two disorders.