Gamma entrainment induced by DBS as a biomarker for motor improvement with neuromodulation.

Mathiopoulou V, Habets J, Feldmann LK, Busch JL, Roediger J, Behnke JK, Schneider GH, Faust K, Kühn AA.

 

Nat Commun. 2025; 16(1): 2956.
doi: 10.1038/s41467-025-58132-7. PMID: 40140380; PMCID: PMC11947250.
Download summary: ReTune PoY 2025

 

Finely tuned gamma (FTG) oscillations in the subthala­mic nucleus (STN) and cortex have been implicated in the development of dyskinesia in Parkinson’s disease (PD) patients. While FTG is frequently observed in these in­dividuals, its precise functional significance has remained elusive. Recent research has shed light on a potential mecha­nism by which DBS interacts with these oscillations. Specifi­cally, it has been demonstrated that DBS can entrain gamma activity at a subharmonic frequency—1:2 of the stimulation frequency—suggesting a structured neural response to sti­mulation rather than random activation. Despite this, the role of such entrained gamma rhythms in motor behavior or sym­ptom modulation remains not fully understood.

To investigate this further, local field potentials (LFPs) were recorded from the STN in a cohort of 19 PD patients who had been chronically implanted with DBS electrodes. All recor­dings were performed while patients were on dopaminergic medication and included periods of rest, on/off DBS, and re­petitive voluntary movements. The results showed that high-frequency DBS elicited 1:2 gamma entrainment in 15 out of the 19 patients. Spontaneous FTG, independent of stimula­tion, was observed in 8 patients. Notably, in 5 of these pati­ents, the presence or enhancement of FTG coincided with the emergence or worsening of dyskinesias during DBS-induced entrainment, suggesting a complex interplay between stimu­lation, gamma activity, and involuntary motor symptoms.

Moreover, a significant increase in the power of entrained 1:2 gamma oscillations was observed during movement tasks compared to resting conditions. Patients who exhibited this entrainment also demonstrated faster movement speeds than those who did not, indicating a potential prokinetic role of this neural signature. Importantly, while entrained FTG may sometimes co-occur with dyskinesia, its presence does not appear to be inherently pathological. Instead, it may represent a physiologically meaningful pattern that supports improved motor performance.

These findings support the hypothesis that DBS-induced 1:2 gamma entrainment serves a functional role in enhancing motor activity in PD patients, rather than merely being a by­product of pathological processes. This entrainment could, therefore, serve as a valuable neurophysiological marker for optimizing stimulation parameters. In the context of closed-loop DBS systems, monitoring entrained gamma power could help in real-time adjustment of stimulation amplitude, potenti­ally improving therapeutic outcomes while minimizing adver­se effects such as dyskinesia.

Varvara Mathiopoulou

Varvara Mathiopoulou is a Doctoral Student in the Movement Disorders and Neuromodulation Unit at Charité – Universitätsmedizin Berlin. She has been working on chronic recordings of local field potentials from the STN in PD patients, with a focus on beta and gamma band activity as biomarkers for closed-loop DBS.

Prof. Andrea Kühn

Andrea Kühn is the director of the Movement Disorders and Neuromo­dulation Unit at Charité Berlin and the ReTune Spokesperson. Her research on basal ganglia electrophysiology has majorly contributed to the understan­ding of the pathophysiology of move­ment disorders and the mechanisms of action of DBS.