Disrupted habenula function in major depression

R P Lawson,B Seymour,D L Thomas,P Dayan,S Pilling,J P Roiser,C L Nord

doi:10.1038/mp.2016.81

Abstract

The habenula is a small, evolutionarily conserved brain structure that plays a central role in aversive processing and is hypothesised to be hyperactive in depression, contributing to the generation of symptoms such as anhedonia. However, habenula responses during aversive processing have yet to be reported in individuals with major depressive disorder (MDD). Unmedicated and currently depressed MDD patients (N=25, aged 18–52 years) and healthy volunteers (N=25, aged 19–52 years) completed a passive (Pavlovian) conditioning task with appetitive (monetary gain) and aversive (monetary loss and electric shock) outcomes during high-resolution functional magnetic resonance imaging; data were analysed using computational modelling. Arterial spin labelling was used to index resting-state perfusion and high-resolution anatomical images were used to assess habenula volume. In healthy volunteers, habenula activation increased as conditioned stimuli (CSs) became more strongly associated with electric shocks. This pattern was significantly different in MDD subjects, for whom habenula activation decreased significantly with increasing association between CSs and electric shocks. Individual differences in habenula volume were negatively associated with symptoms of anhedonia across both groups. MDD subjects exhibited abnormal negative task-related (phasic) habenula responses during primary aversive conditioning. The direction of this effect is opposite to that predicted by contemporary theoretical accounts of depression based on findings in animal models. We speculate that the negative habenula responses we observed may result in the loss of the capacity to actively avoid negative cues in MDD, which could lead to excessive negative focus.

Highlights

Major depressive disorder (MDD) is associated with problems exploiting affective information to guide goal-directed behaviour.[1]Symptoms relating to motivational processing, such as anhedonia and fatigue, result in poorer treatment prognosis,[2,3] and standard treatments for depression are relatively ineffective in ameliorating them.[4]
In a recent experiment using computational modelling and high-resolution functional magnetic resonance imaging (fMRI), we demonstrated that in healthy volunteers (HVs) the habenula encodes the negative motivational value of conditioned stimuli (CSs), with greater activation elicited as the expectation of receiving a painful electric shock increases.[27]
Reaction times to respond to the fixation cross flicker were longest on the negative CS trials (main effect of CS type: F(3, 144) = 3.68, P = 0.014)

Summary

Introduction

Major depressive disorder (MDD) is associated with problems exploiting affective information to guide goal-directed behaviour.[1]. Symptoms relating to motivational processing, such as anhedonia and fatigue, result in poorer treatment prognosis,[2,3] and standard treatments for depression are relatively ineffective in ameliorating them.[4] The neurobiological mechanisms underlying motivational symptoms in depression remain poorly understood; contemporary theoretical accounts have suggested that they may be driven by hyperactivity in the habenula,[5] a small brain structure adjacent to the medial dorsal (MD) thalamus that plays a central role in negatively motivated behaviour. Single-cell recording studies in non-human primates have demonstrated that the lateral habenula (LHb) responds to aversive stimuli,[9] and that LHb stimulation profoundly inhibits VTA dopamine neuron firing.[10] when habenula activity is high, dopamine activity is suppressed

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