DBS-induced gamma entrainment as a new biomarker for motor improvement with neuromodulation

Finely tuned gamma oscillations have been recorded from the subthalamic nucleus and cortex in Parkinsons disease patients undergoing deep brain stimulation and are often associated with dyskinesia. More recently, it was shown that deep brain stimulation entrains finely tuned gamma to [1/2] of the stimulation frequency; however, the functional role of this signal is not yet fully understood. We recorded local field potentials from the subthalamic nucleus in 19 chronically implanted Parkinsons disease patients under effective dopaminergic medication and during deep brain stimulation with increasing stimulation amplitude, while they were at rest and during repetitive hand movements. We analyzed the effect of stimulation intensity on gamma band 1:2 entrainment and compared the entrained signal during rest and during repetitive movement. Spontaneous finely tuned gamma was present in eight out of 19 patients (peak frequency = 78.4 {+/-}4.3 Hz). High-frequency deep brain stimulation induced 1:2 gamma entrainment in 15 out of 19 patients. Entrainment occurred at a mean stimulation amplitude of 2.2 0.75 mA and disappeared or decreased in power during higher stimulation amplitude in three patients. In patients with spontaneous finely tuned gamma, increasing the stimulation amplitude induced a progressive frequency shift of spontaneous finely tuned gamma until it locked to 1:2 entrainment. Only five out of 15 patients with entrained gamma activity showed dyskinesia during stimulation. Further, there was a significant increase in the power of 1:2 entrained gamma activity during movement in comparison to rest. Finally, patients with entrained gamma activity had faster movements as compared to those without gamma entrainment. These findings argue for a functional relevance of the stimulation-induced 1:2 gamma entrainment in Parkinsons disease patients as a prokinetic activity that, however, is not necessarily promoting dyskinesia. Previously published electrophysiological models of entrainment fit well to our results and support our findings that stimulation-induced entrainment can be a promising real-life biomarker for closed-loop deep brain stimulation.