Motor and Cognitive Effects of Theta-burst Deep Brain Stimulation (DBS) for Parkinson Disease: Pilot-phase Results of a Double-blind Randomized Sham-controlled Trial
Xenos Mason1, Wooseong Choi5, Kevin Wu5, Jonathon Cavaleri2, Melanie Cohn6, Melissa Wilson3, Kay Jann4, Brian Lee2, Darrin Lee2
1Neurological Surgery and Neurology, 2Neurological Surgery, 3Preventative Medicine, 4Laboratory of FMRI Technology, Stevens Neuroimaging and Informatics Institute, University of Southern California Keck School of Medicine, 5University of Southern California Keck School of Medicine, 6Krembil Brain Institute, Toronto Western Hospital, University of Toronto
Objective:

Pilot-phase single-center, double-blind, randomized cross-over study of theta-burst STN-DBS for PD, assessing motor/cognitive efficacy and side effects.

Background:

Continuous high-frequency deep brain stimulation (cHF-DBS) targeting the subthalamic nucleus (STN) is an effective treatment for motor symptoms of Parkinson disease (PD). However, it may impair cognitive executive functions. We have previously shown that short-term low-frequency (5 Hz; “Theta”) STN DBS enhances verbal fluency in PD patients. “Theta-burst” is a neuromodulation paradigm that delivers high-frequency stimulation in a low-frequency (theta) burst pattern. We hypothesize that long-term theta-burst DBS will improve executive function relative to cHF-DBS, without compromising motor efficacy.

Design/Methods:

Patients with PD and optimized bilateral STN cHF-DBS underwent baseline cognitive, motor (MDS-UPDRS III/IV), and quality of life (QOL) assessments. Theta-burst DBS was programmed, normalized to total-electrical-energy-delivery (TEED) and titrated within a set amplitude range during an initial safety phase. Subjects underwent a 14-day randomized cross over period to assess medium-term efficacy, followed by a 90-day randomized cross-over period. Motor and cognitive assessments were performed at each cross-over. Functional MR-imaging was conducted to observe network-level effects of theta-burst DBS.

Results:

All comparisons are theta-burst DBS relative to cHF-DBS: In the acute/safety phase (n=8 subjects), similar motor-efficacy was achieved with lower power/TEED (mean change in MDS-UPDRS +1.1 [range -13 to +7]; mean change in power/TEED -11.2% [range -25.9% to +2.6%]). Two subjects exhibited worsening dyskinesia at equivalent power/TEED. After the 14-day crossover phase (n=3 subjects), similar motor-efficacy was maintained (mean change in MDS-UPDRS +2 [range -9 to +4]) with lower power/TEED (mean -7.1%). N-back test performance improved (mean +17.5%); verbal fluency improved in most categories (mean (n): semantic +3.33, phonetic +0.67, hippocampal-spatial +0.67, hippocampal-amygdala -1); Stroop errors were unchanged. No serious adverse events occurred.

Conclusions:

Theta-burst STN DBS can be administered safely. Theta-burst DBS may produce distinct motor and cognitive effects at equal TEED compared to cHF-DBS.

10.1212/WNL.0000000000204797