Association between habenula dysfunction and motivational symptoms in unmedicated major depressive disorder

Abstract

The lateral habenula plays a central role in reward and punishment processing and has been suggested to drive the cardinal symptom of anhedonia in depression. This hypothesis is largely based on observations of habenula hypermetabolism in animal models of depression, but the activity of habenula and its relationship with clinical symptoms in patients with depression remains unclear. High-resolution functional magnetic resonance imaging (fMRI) and computational modelling were used to investigate the activity of the habenula during a probabilistic reinforcement learning task with rewarding and punishing outcomes in 21 unmedicated patients with major depression and 17 healthy participants. High-resolution anatomical scans were also acquired to assess group differences in habenula volume. Healthy individuals displayed the expected activation in the left habenula during receipt of punishment and this pattern was confirmed in the computational analysis of prediction error processing. In depressed patients, there was a trend towards attenuated left habenula activation to punishment, while greater left habenula activation was associated with more severe depressive symptoms and anhedonia. We also identified greater habenula volume in patients with depression, which was associated with anhedonic symptoms. Habenula dysfunction may contribute to abnormal response to punishment in patients with depression, and symptoms such as anhedonia.

Keywords: anhedonia; depression; fMRI; habenula; prediction error; punishment.

Fig. 1.

Behavioral task and data. (A) Example of reward-based (top) and punishment-based (bottom) trials in the probabilistic associative learning task. Two pairs of stimuli were presented to the participants: (1) the reward (AB) pair provided 80% reward feedback for A and 20% for B; (2) the punishment (CD) pair provided 80% punishment feedback for C and 20% for D. (B, C) Group-level performance over time in the reward and penalty conditions (average over the 2 blocks of 50 trials, binned every 10 trials). Dotted lines and shaded areas represent mean performance and standard error of the mean (SEM). (D, E) Comparison of learning rate parameters (α) and temperature parameters (β) from the computational model. Box plots (blue) represent the distributions of parameters for each group (median is indicated by the red vertical line, whereas the mean is denoted by the large red cross). Violin plots (shaded blue-green area) represent the smoothed distribution of the data.

Fig. 2.

Response in the left and right habenula to receipt of reward (reward > neutral) and punishment (punishment > neutral) in patients with major depressive disorder (MDD) and healthy controls (CTR). Error bars represent SEM.

Fig. 3.

Habenula responses to reward- and punishment-based prediction errors (PEs) in depressed patients and healthy controls. Error bars represent SEM.

Fig. 4.

Depressive symptoms (measured by the Hamilton Depression Rating Scale (HDRS)) and anhedonic symptoms (measured by the Temporal Experience of Pleasure Scale (TEPS), TEPS-ANT (anticipatory) and TEPS-CON (consummatory)) were associated with greater left habenula activation to the receipt of punishment vs neutral outcomes, and greater left habenula response during punishment relative to reward trials, respectively, in depressed patients.

Fig. 5.

(A) Habenula volumes in MDD and CTR. (B–D) Anhedonia (measured by TEPS, TEPS-ANT and TEPS-CON) was associated with larger normalized left habenula volume in patients. Error bars represent SEM.