Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study

Abstract

Objective: Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures.

Method: A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals.

Results: Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms.

Conclusions: The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.

Figures

FIGURE 1

Diagram of Given Trial From the Reward Taska a The paradigm consists of 24 trials: 12 are reward-expectation trials, in which an arrow points upward and the possible outcomes are a win (six trials) or no change (six trials), and 12 are loss-expectation trials, in which the arrow points downward and the possible outcomes are a loss (six trials) or no change (six trials).

FIGURE 2

Association Between Reward Expectancy and Prediction Error-Related Reactivity in the Right Ventral Striatum in the First-Recruited Cohort (N=78), Second-Recruited Cohort (N=70), and the Total Sample (N=148) of Depressed Individuals and Healthy Comparison Subjects (N=31)a a RE=reward expectancy; PE=prediction error.

FIGURE 3

The Relationship Between Reward Expectancy and Prediction Error-Related Right Ventral Striatal Reactivity in Healthy Comparison (HC) Subjects and in Individuals With Low, Moderate, and High Symptoms of Anhedonia in the First-Recruited Cohort (MDD100a) and Total Sample (MDD200) of Individuals With Major Depressive Disordera a The scatter plots (A, B) show the relationship between reward expectancy and prediction error-related right ventral striatal reactivity. The bar graphs (C, D) show correlation coefficients and standard errors for HC subjects and anhedonia subgroups (defined by tertile split of anhedonia scores) within the MDD100a cohort and for HC subjects and anhedonia subgroups within the MDD200 cohort. RE=reward expectancy; PE=prediction error.

FIGURE 4

Whole-Brain Moderation Analysis Across All Participantsa a Whole-brain analysis across all participants was conducted to investigate the significant moderation effect of anhedonia at a voxel-wise level. A regression model was constructed in which prediction error was predicted on the basis of reward expectancy, Mood and Anxiety Symptom Questionnaire anhedonic depression subscale scores, and Mood and Anxiety Symptom Questionnaire anhedonic depression subscale-by-reward expectancy interaction, as well as the other covariates used for the region-of-interest analysis. This regression model (A) was fitted to each voxel. The resulting map was thresholded at a t statistic of 4.6 and a cluster size of 5, corresponding approximately to the peak/cluster family-wise-error corrected threshold (the map was thresholded at t>3.4 for display purposes). For the Mood and Anxiety Symptom Questionnaire anhedonic depression subscale-by-reward expectancy interaction effect, four clusters reflecting an increasingly positive/decreasingly negative correlation between reward expectancy and prediction error with increasing anhedonia were obtained. Two clusters were centered slightly more anteriorly with respect to the ventral striatum regions of interest, in the anterior caudate (left: peak voxel: t=5.36, df=167, p<0.05 [family-wise error] [coordinates: −16, 28, 2; 46 voxels]; right: peak voxel: t=5.60, df=167, p<0.05 [family-wise error] [coordinates: 16, 26, 0; 26 voxels]), while a small cluster was slightly more posterior, on the right (peak voxel: t=4.75, df=167, p<0.05 [family-wise error] [coordinates: 8, 12, 2; 5 voxels]). The fourth cluster was centered on the left dorsal striatum (peak voxel: t=5.63, df=167, p<0.05 [family-wise error] [coordinates: −22, 16, 8; 41 voxels; all reported coordinates are in Montreal Neurological Institute space]). There were no significant voxels for the opposite direction of the interaction. The bar graphs show correlation coefficients (and standard errors) between reward expectancy and prediction error-related reactivity (extracted from a 6-mm sphere centered at coordinates 16, 26, 0) for healthy comparison subjects and anhedonia range equivalent subgroups (defined by tertile split of anhedonia scores) in the (B) first-recruited cohort (MDD100a) and (C) second-recruited cohort (MDD100b) of depressed individuals.