Subthalamic and nigral stimulation for freezing of gait in Parkinson's disease: Randomized pilot trial

Background Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD) with limited response to dopaminergic medication and subthalamic deep brain stimulation (STN-DBS). Substantia nigra pars reticulata (SNr) stimulation could improve FoG. Objective To analyze the effect of combined STN-SNr stimulation at different frequencies on FoG. Methods We performed a double-blind, cross-over, randomized pilot trial involving STN-DBS treated PD patients with FoG. Participants received: high-frequency (HF) STN-DBS (S), combined HF-STN and SNr stimulation (C1), and combined HF-STN and low-frequency (LF) SNr stimulation (C2), for one month each. The primary endpoint was the score change in the New-Freezing-of-Gait-Questionnaire (NFOG-Q). Secondary analyses were performed on motor complications, axial symptoms, daily living activities, psychiatric symptoms, sleep, and patient preference. Results Fifteen patients received at least one combined stimulation. No significant difference in NFOG-Q scores was found between S, C1, and C2; one-third of patients showed a clinically significant improvement (>= 8 points) with combined stimulations. Motor complications improved significantly with C1 and C2 (C1-S: 3.63.8 vs. 4.93.8, p=0.046; C2-S: 2.7 +/- 3.1 vs. 4.9 +/- 3.8, p=0.005). 80% of patients preferred the combined STN-SNr stimulation while blinded. All adverse events were manageable. Conclusions Our study did not prove a statistically significant improvement in NFOG-Q with STN-SNr stimulation; however, one-third of patients experienced a clinically meaningful FoG improvement, and the majority preferred to maintain STN-SNr stimulation. STN-SNr stimulation was both safe and effective in addressing motor complications and improving sleep quality, highlighting the importance of further exploration into the effects of combined STN-SNr stimulation. Plain Language Summary We aimed to identify novel therapeutic approaches for freezing of gait (FoG), a disabling symptom of Parkinson's disease (PD) associated with risk of falls and poor life quality. FoG affects 31 up to 87% of PD patients and can be difficult to manage with standard PD medications. FoG may remain unchanged or even worsen in patients treated with Deep Brain Stimulation (DBS). We focused on DBS-treated PD patients and stimulated simultaneously two areas of the brain: the subthalamic nucleus (STN), the typical target for treating PD motor symptoms, and the substantia nigra pars reticulata (SNr). 15 PD patients with FoG received different types of brain stimulation for one month each: STN stimulation alone and combined STN+SNr stimulation at two different stimulation frequencies. We measured improvement of FoG (using a validated questionnaire) and other PD symptoms (including motor fluctuations, anxiety and depression, and sleep quality), as well as safety and tolerability of the combined STN+SNr stimulation. Finally, we observed the patient preference for the type of stimulation provided. We found no statistically significant change of FoG scores with STN+SNr stimulation, but one-third of patients experienced a clinically meaningful reduction in FoG. STN+SNr stimulations helped improve motor fluctuations and dyskinesia. Moreover, 80% of the patients preferred the combined stimulation over the standard STN stimulation. We believe this data suggest that combined STN+SNr stimulation could be a valuable area for further research aiming to improve FoG and can be safely attempted in clinical practice in DBS-treated patients with disabling FoG.