Causal evidence for prefrontal-motor coupling in reward-responsive goal-directed behavior

Interventions for major depressive disorder (MDD) using non-invasive brain stimulation often target the left lateral prefrontal cortex to reduce symptoms of anhedonia. However, the electrophysiological mechanism by which symptoms of anhedonia arise from dysfunction of the lateral prefrontal cortex is poorly understood. Furthermore, multiple constructs related to reward-processing within the positive valence systems have been found to be blunted with anhedonia. To disentangle components of the positive valence systems, human participants with an active episode of MDD performed an adaptive version of the expenditure of effort for reward task (Adaptive-EEfRT) and three constructs of reward processing were investigated: effort motivation, reward valuation, and reward-responsive goal-directed behavior. Individual-differences analysis revealed that symptoms of anhedonia were most strongly related to blunted reward-responsive goal-directed behavior. By recording electroencephalography (EEG), spectral analysis revealed that the amplitude of left prefrontal delta oscillations (2-3 Hz) increased with each reward construct; and beta oscillations decreased over the motor cortex contralateral to the hand used for effort exertion. Phase-amplitude delta-beta coupling between the left prefrontal cortex and contralateral motor cortex was significantly increased for each reward construct. When cross-frequency transcranial alternating current stimulation (tACS) was delivered to 26 females and 9 males to mimic prefrontal-motor delta-beta coupling only reward-responsive goal-directed behavior was improved relative to placebo and active-control tACS. These findings provide causal evidence that the left prefrontal cortex supports reward-responsive goal-directed behavior via cross-frequency coupling. Interventions for anhedonia that target the left prefrontal cortex might be improved by frequency-specific targeting of delta-beta coupling. Significance Statement Anhedonia remains a difficult-to-treat symptom of major depressive disorder (MDD). A better understanding of the neural correlates of anhedonia and the ability to modulate relevant neural circuits will provide an avenue for next-generation interventions. Here, patients with MDD performed a reward-based decision-making task while electroencephalography was recorded. Anhedonia severity was related to reduced reward-responsive goal-directed behavior; and reward-responsive goal-directed behavior recruited prefrontal-motor cross-frequency coupling. Non-invasive electrical stimulation was delivered targeting this activity, which successfully engaged the target and increased reward-responsive goal-directed behavior. These findings provide causal evidence that prefrontal-motor coupling supports reward-responsive goal-directed behavior in patients with MDD. The circuit described here is a novel mechanism for translating goals into action that could be targeted by future interventions for anhedonia.