Aberrant aversive learning signals in the habenula in remitted patients with recurrent depression.

Abstract

Background: Hypersensitivity to punishment is one of the core features of major depressive disorder. 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 depressed patients is well established, it remains largely unexplored whether this dysfunction and its neural correlates persists during symptomatic remission of depression.

Methods: Functional MRI data from 36 medication-free remitted patients with recurrent major depressive disorder (MDD) and 27 healthy control subjects 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 controls, 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 to controls.

Conclusions: The increased habenula activity during aversive learning, particularly during the expectation of punishment, along with decreased functional habenula-ventral tegmental area connectivity in remitted MDD patients, reflect hypersensitivity to, and/or inability to regulate, the impact of aversive environmental cues and punishment.

Trial registration: NTR3768.