Decreased reward circuit connectivity during reward anticipation in major depression

An important symptom of major depressive disorder (MDD) is the inability to experience pleasure, possibly due to a dysfunction of the reward system. Despite promising insights regarding impaired reward-related processing in MDD, circuit-level abnormalities remain largely unexplored. Furthermore, whereas studies contrasting experimental conditions from incentive tasks have revealed important information about reward processing, temporal difference modeling of reward-related prediction error (PE) signals might give a more accurate representation of the reward system. We used a monetary incentive delay task during functional MRI scanning to explore PE-related striatal and ventral tegmental area (VTA) activation in response to anticipation and delivery of monetary rewards in 24 individuals with MDD versus 24 healthy controls (HCs). Furthermore, we investigated group differences in temporal difference related connectivity with a generalized psychophysiological interaction (gPPI) analysis with the VTA, ventral striatum (VS) and dorsal striatum (DS) as seeds during reward versus neutral, both in anticipation and delivery. Relative to HCs, MDD patients displayed a trend-level (p = 0.052) decrease in temporal difference-related activation in the VS during reward anticipation and delivery combined. Moreover, gPPI analyses revealed that during reward anticipation, MDD patients exhibited decreased functional connectivity between the VS and anterior cingulate cortex / medial prefrontal cortex, anterior cingulate gyrus, angular/middle orbital gyrus, left insula, superior/middle frontal gyrus (SFG/MFG) and precuneus/superior occipital gyrus/cerebellum compared to HC. Moreover, MDD patients showed decreased functional connectivity between the VTA and left insula compared to HC during reward anticipation. Exploratory analysis separating medication free patients from patients using antidepressant revealed that these decreased functional connectivity patterns were mainly apparent in the MDD group that used antidepressants. These results suggest that MDD is characterized by alterations in reward circuit connectivity rather than isolated activation impairments. These findings represent an important extension of the existing literature since improved understanding of neural pathways underlying depression-related reward dysfunctions, may help currently unmet diagnostic and therapeutic efforts.