Causal role of delta-beta coupling for goal-directed behavior in anhedonia

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PROPOSAL SUMMARY/ABSTRACT Anhedonia – the inability to seek-out and experience pleasure – is a common symptom in depression that predicts treatment resistance and is sometimes exacerbated by first-line antidepressants. Anhedonia falls within the “Positive Valence System” of the Research Domain Criteria framework that comprises two primary components: “liking” and “wanting.” The “liking,” or consummatory, component reflects the evaluation of rewards reliant on the medial prefrontal cortex and ventral striatum. The “wanting,” or anticipatory, component modulates the degree to which effort is expended in goal-directed behavior reliant on the lateral prefrontal cortex and dorsal striatum. Previous research found decreased neural activity in both of these neural circuits in depressed patients with anhedonia but has not causally investigated the role of these neural circuits, or their temporal dynamics, in different components of reward-based decision-making. The preliminary data found decreased goal-directed behavior in depressed patients with anhedonia and reduced cross-frequency coupling between the phase of delta oscillations (2-4 Hz) in lateral prefrontal cortex and task-modulated beta oscillations (15-30 Hz) (delta-beta coupling). The objective of this research plan is to dissect the causal role of frontal-striatal circuity in different components of reward-based decision-making and their impairment in anhedonia. The central hypothesis is that anhedonia arises from decreased goal-directed behavior and disruption of delta-beta coupling in lateral prefrontal cortex and dorsal striatum. The rationale is that spatially and temporally-targeted non-invasive brain stimulation during performance of a reward-based decision-making task will provide causal evidence for which network dynamics are impaired in anhedonia. Accordingly, the three specific aims are (1) Causally dissociate the neural circuits that implement goal-directed behavior and reward-evaluation in decision-making, (2) Increase goal- directed behavior in depressed patients with anhedonia using network-targeted non-invasive brain stimulation, and (3) Investigate target engagement of delta-beta coupling in a potential treatment paradigm with network- targeted stimulation in a randomized clinical trial for depressed patients with symptoms of anhedonia. This proposal is significant because it will causally evaluate mechanistic models of the networks and cognitive processes that are disrupted in anhedonia. The work is innovative because it uses concurrent neurophysiology and neurostimulation, integrates high-resolution spatial and temporal investigation tools, and utilizes individualized stimulation parameters such as subcortical-targeting with functional-connectivity and task-specific frequency targeting. The positive impact of this proposal is a refined definition of anhedonia based in biological mechanism that may have transdiagnostic relevance for other psychiatric illnesses such as schizophrenia and substance use disorder. The implication of this proposal is that the knowledge gained can be directly used for the development of novel interventions using precision medicine.