Disrupted habenula function in major depression

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.

Figure 1

Conditioning task and results. (a) Exemplar trial (a detailed description is provided in the main text). (b) Explicit preference scores for win, loss, shock and neutral conditioned stimuli (CSs; maximum score of 24). (c) Reaction times to respond to fixation flickers overlaid on win, loss, shock and neutral CSs. Pale-coloured bars represent major depressive disorder (MDD) patients and bright-coloured bars represent healthy volunteers (HVs). Red and black solid lines show significant differences discussed in the text for the MDD and HV groups, respectively. Beyond the results discussed in the text, there was a significant main effect of cue type in the HVs (F(2.06, 49.66)=5.28, P=0.002) and a trend in the MDD group (F(3, 72)=2.42, P=0.073). Error bars show s.e.m. *P<0.05 and **P<0.001.

Figure 2

Habenula functional and anatomical data. (a) Location of the habenula on coronal slices of a representative subject. (b) Habenula response to the dynamically changing value of shock conditioned stimuli (CSs) is positive in healthy volunteers (HV) (bright red bar) and negative in major depressive disorder (MDD) participants (pale red bar). For the other CSs, pale-coloured bars represent MDD patients and bright-coloured bars represent HVs. These β-values represent the change in habenula response with increasing cue value. (c) The relationship between normalised average habenula volume and symptoms of anhedonia (Snaith–Hamilton Pleasure Scale (SHAPS)) in MDD participants (grey: r=−0.36, P=0.074) and HVs (black: r=−0.41, P=0.043). *P<0.07 (one tailed), **P<0.05 and ***P<0.001.

Figure 3

(a) Cerebral blood flow (CBF) values show no group difference in resting-state habenula blood flow. (b) Habenula volumes are not significantly different between the groups. Error bars represent s.e.m. HV, healthy volunteer; MDD, major depressive disorder.