Supplementary Material for: Simultaneous high-frequency subthalamic and ultra-low-frequency nigral deep brain stimulation improved motor symptoms and freezing of gait in Parkinson’s Disease

Introduction: Freezing of gait (FOG) in advanced Parkinson's disease (PD) remains a therapeutic challenge, with conventional subthalamic nucleus deep brain stimulation (STN-DBS) demonstrating limited efficacy. Methods: This multicenter, prospective, single-blind study investigated the effects of combined high-frequency (HF) STN stimulation and ultra-low-frequency (ULF) substantia nigra pars reticulata (SNr) stimulation in six PD patients with refractory FOG. Assessments included Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III, New Freezing of Gait Questionnaire (NFOGQ), Gait and Falls Questionnaire (GFQ) and Schwab & England Activities of Daily Living (ADL) scale. Results: Dual-target stimulation significantly outperformed STN-only stimulation in improving appendicular motor symptoms (MDS-UPDRS Part III: p = 0.04 medication-ON, p = 0.009 medication-OFF) and reducing FOG severity (NFOGQ: p = 0.02, GFQ: p=0.01 vs. STN-DBS). Postural stability remained unchanged, while ADL scores improved clinically (p = 0.04). Volume of tissue activated (VTA) analysis revealed more STN VTA connectivity in cerebrum, in contrast with more SNr VTA connectivity in cerebellum. Conclusion: These findings highlight the potential of dual-target free-frequency DBS for multimodal symptom control in PD and hopefully bring new sights in understanding mechanisms of DBS treatments in FOG.