Aberrant Aversive Learning Signals in the Habenula in Remitted Patients With Recurrent Depression

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.

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.

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.

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.