Structural connectivity between rostral anterior cingulate cortex and amygdala predicts first onset of depressive disorders in adolescence

Abstract Objective Adolescent-onset depressive disorders (DD) are associated with deficits in the regulation of negative affect across modalities (self-report, behavioral paradigms, and neuroimaging), which may manifest prior to first-onset DD. Whether the neurocircuitry governing emotional regulation predates DD is unclear. This study tested whether a critical pathway for emotion regulation (rostral anterior cingulate cortex (rACC)-amygdala structural connectivity) predicts first onset DD in adolescent females. Methods Diffusion tensor imaging (DTI) data were acquired on adolescent females (N=212) without a history of DD and the cohort was re-assessed for first onset DD over the next 27 months. Results 26 girls developed first onsets of DD in the 27 months after imaging. Multivariate logistic regression showed that lower weighted average fractional anisotropy of uncinate fasciculus tracts between rACC and amygdala prospectively predicted first onset of DD (adjusted odds ratio = .44, p = .005), above and beyond established risk factors including baseline depression symptom severity, history of anxiety disorders, parental history of depression, parental education, and age. Conclusions This study provides evidence for the first time showing that aberrant structural connectivity between rACC and amygdala prospectively predates first onset of DD in adolescent females. These results highlight the importance of a well-established neural circuit implicated in the regulation of negative affect as a likely etiological factor and a promising target for intervention and prevention of DD.