Frontoamygdalar Effective Connectivity in Youth Depression and Treatment Response

BACKGROUND: Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo.METHODS: One hundred seven young people with moderate to severe depression and 94 healthy control partici-pants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission.RESULTS: Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p = .003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (-0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r =-0.02, p = .561).CONCLUSIONS: Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depression treatments.