Personalized closed loop treatment of freezing of gait in Parkinson’s disease - Project Summary/Abstract Freezing of gait (FoG) is one of the most disabling symptoms of Parkinson’s disease (PD), affecting nearly half of all patients and up to 80% in advanced stages. FoG contributes disproportionately to falls, injuries, loss of independence, and diminished quality of life, yet existing therapies—including dopaminergic medications, and continuous deep brain stimulation—provide inconsistent or transient relief. In some cases, FoG worsens with long-term stimulation, leaving a critical unmet need for effective, durable interventions. The proposed project will evaluate Sierra, a next-generation, fully implantable, cranial-mounted deep brain stimulation (DBS) system designed for multi-site sensing and stimulation. Unlike prior devices, Sierra offers high- fidelity recordings during stimulation, detection of network biomarkers on-device, and implementation of flexible closed-loop algorithms. These features provide a unique opportunity to identify, validate, and modulate neural signatures of FoG across clinic and home environments, moving beyond empirical programming toward biomarker-driven neuromodulation. During the UG3 phase, we will establish regulatory readiness through completion of design verification and validation, and secure FDA IDE and UCSF IRB approvals for human use. In the UH3 phase, we will enroll ten PD patients with medication-refractory FoG, implanting bilateral GPi depth leads and subgaleal/epidural cortical electrodes connected to Sierra. Across three aims, we will: (1) identify and validate cortical–pallidal biomarkers of FoG in clinic and at home, (2) use advanced machine learning to map stimulation parameters that normalize these biomarkers, and (3) test closed-loop Sierra DBS in a randomized, double-blind crossover trial against optimized open-loop DBS. Outcomes will be assessed using device logs, wearable monitors, gait kinematics, and clinical ratings. If successful, this project will establish the first biomarker-guided, closed-loop neuromodulation therapy for FoG in PD. Within five years, findings will position Sierra for a Phase II multicenter trial, and longer term, for FDA Breakthrough Device designation. More broadly, this platform will advance adaptive network-based therapies for gait dysfunction and other neurological and psychiatric disorders.
