Theta Burst Subthalamic Nucleus Stimulation for Parkinson Disease: Motor, Cognitive, and Functional Connectivity Outcomes in a Pilot-phase Study

Introduction: While deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson disease (PD) motor symptoms, it has a potential for cognitive/executive dysfunction. Theta-burst stimulation (TBS) is a DBS paradigm wherein bursts of stimulation at gamma frequency are applied in theta frequency pattern. We previously demonstrated that short-term STN theta DBS improves verbal fluency in PD patients. We hypothesize that chronic TBS will improve executive function and cognitive network functional connectivity while maintaining the motor benefits of continuous high-frequency (cHF) DBS.

Methods: In a pilot-phase single-center, prospective, double-blind, randomized cross-over study, patients with bilateral STN DBS for PD will undergo baseline cognitive testing, motor assessment (MDS-UPDRS III/IV), and quality of life (QOL) assessments. TBS will be established with normalized total-electrical-energy-delivery (TEED). Subjects will undergo a 14-day randomized cross over period to assess medium-term efficacy, followed by a 90-day randomized cross-over period to assess long-term efficacy. At each cross-over (7, 14, 104, 194 days), subjects will undergo repeat assessment. Functional MR-imaging will be conducted in eligible subjects to observe network-level effects of TBS.

Results: Two subjects completed the 14-day randomized cross over phase. In these two subjects, power/TEED was comparable in TBS compared to cHF-DBS (-0.3 µJ mean difference). In both patients, they exhibited greater verbal fluency with TBS compared to cHF-DBS. However, both subjects exhibited worsening dyskinesia with variable changes in UPDRS-III scores (+15 and -4). In a separate group of two patients, resting state fMRI with stimulation on showed that connectivity in the frontal-parietal and default mode networks increased, while connectivity in the somatomotor network decreased with TBS relative to cHF-DBS.

Conclusion : Theta-burst STN DBS may improve verbal fluency and connectivity in cognitive networks. Theta-burst DBS may produce distinct motor effects at equal TEED compared to cHF-DBS. Motor and cognitive assessments in patients undergoing theta-burst DBS are feasible.