Dataset Information

Machine Learning Identifies Large-Scale Reward-Related Activity Modulated by Dopaminergic Enhancement in Major Depression.

ABSTRACT:

Background

Theoretical models have emphasized systems-level abnormalities in major depressive disorder (MDD). For unbiased yet rigorous evaluations of pathophysiological mechanisms underlying MDD, it is critically important to develop data-driven approaches that harness whole-brain data to classify MDD and evaluate possible normalizing effects of targeted interventions. Here, using an experimental therapeutics approach coupled with machine learning, we investigated the effect of a pharmacological challenge aiming to enhance dopaminergic signaling on whole-brain response to reward-related stimuli in MDD.

Methods

Using a double-blind, placebo-controlled design, we analyzed functional magnetic resonance imaging data from 31 unmedicated MDD participants receiving a single dose of 50 mg amisulpride (MDD_Amisulpride), 26 MDD participants receiving placebo (MDD_Placebo), and 28 healthy control subjects receiving placebo (HC_Placebo) recruited through two independent studies. An importance-guided machine learning technique for model selection was used on whole-brain functional magnetic resonance imaging data probing reward anticipation and consumption to identify features linked to MDD (MDD_Placebo vs. HC_Placebo) and dopaminergic enhancement (MDD_Amisulpride vs. MDD_Placebo).

Results

Highly predictive classification models emerged that distinguished MDD_Placebo from HC_Placebo (area under the curve = 0.87) and MDD_Placebo from MDD_Amisulpride (area under the curve = 0.89). Although reward-related striatal activation and connectivity were among the most predictive features, the best truncated models based on whole-brain features were significantly better relative to models trained using striatal features only.

Conclusions

Results indicate that in MDD, enhanced dopaminergic signaling restores abnormal activation and connectivity in a widespread network of regions. These findings provide new insights into the pathophysiology of MDD and pharmacological mechanism of antidepressants at the system level in addressing reward processing deficits among depressed individuals.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7010544 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveMajor depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals.MethodIn a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D2/D3 receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride.ResultsDepressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo.ConclusionsAcute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration.