Stimulation selectively blocks subthalamic high β-cortical high γ coupling in Parkinson's disease

Subthalamic stimulation in Parkinson's disease may operate by suppressing high-beta connectivity along the hyperdirect pathway and by promoting gamma motor cortical processing. We examined how the phase of beta activity shapes the amplitude of the gamma rhythm along hyperdirect connections and how stimulation influences this coupling. Thirty-eight patients with akinetic-rigid Parkinson's disease treated with bilateral subthalamic stimulation were recruited. A high-density electroencephalogram was recorded at rest and while patients drew self-paced and traced spirals on a digital tablet at four stimulation levels. We analyzed time-resolved phase-amplitude coupling between low (13-20 Hz) and high beta (21-30 Hz) and low (31-60 Hz) and high gamma (61-100 Hz) frequency band pairs between the subthalamic nucleus and motor cortical areas. The stimulation-induced decreases in phase-amplitude coupling were correlated with real-time improvement in bradykinesia and predicted by clinical factors. Among the subthalamic beta-cortical gamma bands, the high beta-high gamma phase-amplitude coupling was the largest (p < 0.001), and decreased the most at the highest stimulation level (p < 0.001), in correlation with the improvement in bradykinesia. Its stimulation-induced decrease could be predicted in task-specific pathways consisting of the primary motor cortex and the dorsal premotor cortex; the rate of improvement in drawing speed and the active contact locations were the key predictors. Phase-amplitude coupling of the cortical beta-subthalamic gamma band pairs did not respond to stimulation. Subthalamic stimulation selectively interferes with the subthalamic high beta-driven cortical gamma block in task-specific pathways in Parkinson's disease, tracking the improvements in bradykinesia.