Orbitofrontal Cortex Activity And Connectivity Predict Future Depression Symptoms In Adolescence

BACKGROUND: Major depressive disorder is a leading cause of disability worldwide; however, little is known about pathological mechanisms involved in its development. Research in adolescent depression has focused on reward sensitivity and striatal mechanisms implementing it. The contribution of loss sensitivity to future depression, as well as the orbitofrontal cortex (OFC) mechanisms critical for processing losses and rewards, remains unexplored. Furthermore, it is unclear whether OFC functioning interacts with familial history in predicting future depression.METHODS: In this longitudinal study, we recorded functional magnetic resonance imaging data while 229 female adolescents with or without parental history of depression completed a monetary gambling task. We examined whether OFC blood oxygen level-dependent response and functional connectivity during loss and win feedback was associated with depression symptoms concurrently and prospectively (9 months later) and whether this relationship was moderated by parental history of depression.RESULTS: Reduced OFC response during loss was associated with higher depression symptoms concurrently and prospectively, even after controlling for concurrent depression, specifically in adolescents with parental history of depression. Similarly, increased OFC-posterior insula connectivity during loss was associated with future depression symptoms, but this relationship was not moderated by parental history of depression.CONCLUSIONS: This study provides the first evidence for loss-related alterations in OFC functioning and its interaction with familial history of depression as possible mechanisms in the development of depression. While the current functional magnetic resonance imaging literature has mainly focused on reward, the current findings underscore the need to include prefrontal loss processing in existing developmental models of depression.