Background: Hypersensitivity to punishment is one of the core features of major depressive disorder (MDD). Hypersensitivity to punishment has been proposed to originate from aberrant aversive learning. One of the key areas in aversive learning is the habenula. Although evidence for dysfunctional aversive learning in patients with depression is well established, whether this dysfunction and its neural correlates persist during symptomatic remission of depression remains largely unexplored. Methods: Functional magnetic resonance imaging data from 36 medication-free remitted patients with recurrent MDD and 27 healthy control participants participating in a Pavlovian classical conditioning task were assessed within a computational modeling framework to evaluate temporal difference–related activation of the habenula during aversive learning. Furthermore, generalized psychophysiological interaction analyses were performed to assess functional connectivity of the temporal difference signal with the habenula as an a priori region of interest. Results: Relative to healthy control participants, patients showed significantly increased temporal difference–related aversive learning activation in the bilateral habenula. This activation was correlated with residual symptoms in the remitted MDD group. Furthermore, patients exhibited decreased functional connectivity between the habenula and the ventral tegmental area compared with control participants. Conclusions: The increased habenula activity during aversive learning, particularly during the expectation of punishment, together with decreased functional habenula–ventral tegmental area connectivity in remitted patients with MDD, reflect hypersensitivity to and/or inability to regulate the impact of aversive environmental cues and punishment.

One of the core symptoms of major depressive disorder is anhedonia, an inability to experience pleasure. In patients with major depressive disorder, a dysfunctional reward-system may exist, with blunted temporal difference reward-related learning signals in the ventral striatum and increased temporal difference-related (dopaminergic) activation in the ventral tegmental area. Anhedonia often remains as residual symptom during remission; however, it remains largely unknown whether the abovementioned reward systems are still dysfunctional when patients are in remission. We used a Pavlovian classical conditioning functional MRI task to explore the relationship between anhedonia and the temporal difference-related response of the ventral tegmental area and ventral striatum in medication-free remitted recurrent depression patients (n = 36) versus healthy control subjects (n = 27). Computational modelling was used to obtain the expected temporal difference errors during this task. Patients, compared to healthy controls, showed significantly increased temporal difference reward learning activation in the ventral tegmental area (PFWE,SVC = 0.028). No differences were observed between groups for ventral striatum activity. A group × anhedonia interaction [t(57) = -2.29, P = 0.026] indicated that in patients, higher anhedonia was associated with lower temporal difference activation in the ventral tegmental area, while in healthy controls higher anhedonia was associated with higher ventral tegmental area activation. These findings suggest impaired reward-related learning signals in the ventral tegmental area during remission in patients with depression. This merits further investigation to identify impaired reward-related learning as an endophenotype for recurrent depression. Moreover, the inverse association between reinforcement learning and anhedonia in patients implies an additional disturbing influence of anhedonia on reward-related learning or vice versa, suggesting that the level of anhedonia should be considered in behavioural treatments.