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

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.

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.

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.

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.