Co-stimulating the left vmPFC compensates for apathy after levodopa withdrawal in Parkinson's patients with STN DBS

Introduction: Subthalamic nucleus deep brain stimulation (STN DBS) improves motor symptoms of Parkinson's disease (PD), but its effect on motivation is controversial. Apathy, the lack of motivation, commonly occurs in PD and is often exacerbated after surgery and its concomitant levodopa reduction. Apathy and reward processing are associated with the ventromedial prefrontal cortex (vmPFC), which standard targeting strategies avoid by targeting the dorsolateral STN. Since apathy can be a levodopa-responsive PD symptom, levodopa withdrawal could unmask apathy without sufficient stimulation of non-motor pathways, similar to the persistence of motor symptoms when motor pathways are underengaged with DBS.

Objective: Using an individualized tractography model, maximized left-sided vmPFC engagement following a DBS adjustment improved apathy in a case example. We, therefore, retrospectively investigated the moderating role of stimulation-related left-sided vmPFC connectivity and levodopa reduction on changes in apathy after STN DBS (N = 28).

Methods: We measured apathy (Starkstein Apathy Scale) and levodopa dose pre- and post-surgery. Stimulation-related connectivity was quantified using patient-specific diffusion-weighted MRI and probabilistic tractography to test the interaction with levodopa reduction.

Results: Effective DBS of the dorsolateral STN included prefrontal non-motor connections. We found a significant interaction between levodopa dose change and STN-connections to the left vmPFC. Apathy severity negatively correlated with stimulation-related connectivity to the left vmPFC in patients with greater levodopa reductions. Apathy change was unrelated to motor pathway connectivity.

Conclusion: Insufficient stimulation of the left vmPFC and associated limbic fronto-subthalamic connections combined with high levodopa reduction contributed to DBS-related apathy in PD, which may inspire novel personalized non-motor targeting strategies.