Effects of Accelerated rTMS On Motor and Cognitive Function in Parkinson's Disease

Background and Rationale: Parkinson's disease (PD) affects approximately 1-2% of adults over age 60 and is characterized by progressive motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Cognitive impairment is also common, with approximately 50% of people with PD experiencing mild cognitive impairment and cumulative dementia prevalence reaching up to 80% over the disease course. Current pharmacological treatments provide symptomatic motor benefit but are limited by declining efficacy over time, motor fluctuations, dyskinesias, and other side effects. No disease-modifying therapy is currently available. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that modulates neural circuits through targeted electromagnetic stimulation. Multiple meta-analyses have demonstrated that rTMS significantly improves motor symptoms in PD, with pooled effect sizes (standardized mean difference) ranging from 0.46 to 0.64. High-frequency rTMS targeting the primary motor cortex (M1) produces the largest motor effect sizes (SMD 0.77-0.79). However, most existing studies have used conventional protocols requiring daily sessions over several weeks, which may limit accessibility and adherence. Additionally, prior studies have relied primarily on global motor assessments and have not systematically characterized the relationship between motor and cognitive changes following rTMS over extended follow-up periods. Study Design: This is a single-center, open-label, prospective pilot study conducted at the San Francisco Neurology and Sleep Center. The study consists of three phases: a screening phase (up to 14 days), an open-label treatment phase (approximately 21 days), and a follow-up phase (90 days). Total participation duration is up to 139 days. Treatment Protocol: Participants receive 6 sessions of high-frequency rTMS using the EXOMIND™ device (BTL-699-2), administered twice weekly over approximately 3 weeks. Each session delivers stimulation at 10-20 Hz frequency and 90-110% of resting motor threshold (RMT) intensity, with 3,000-6,000 total pulses per session. The target site is the primary motor cortex (M1) bilaterally, localized using the standard motor threshold determination procedure by identifying the scalp position that produces consistent contraction of the contralateral hand muscles. All sessions are conducted on-site with medical staff support. Assessment Schedule: Baseline assessments are completed during screening (Day -14 to Day -1) and include motor evaluations, cognitive testing, mood and quality of life questionnaires, vital signs, medical history, TMS safety screening, and calculation of Levodopa Equivalent Daily Dose (LEDD). A Creyos cognitive battery training session is administered at screening to familiarize participants with test procedures and reduce learning effects. Post-treatment assessments are conducted at three time points: the last treatment session (approximately Day 21), 1-month follow-up (Day 51 ± 7 days), and 3-month follow-up (Day 111 ± 7 days). At each post-treatment time point, the full battery of motor, cognitive, mood, and quality of life assessments is repeated along with vital signs, adverse event assessment, and concomitant medication review. The cognitive assessment approach uniquely combines the Montreal Cognitive Assessment (MoCA) for global cognitive screening with the Creyos cognitive battery for domain-specific evaluation across six domains: visual spatial working memory, episodic memory, deductive reasoning, mental rotation, verbal short-term memory, and attention. This multi-domain approach is designed to identify which specific cognitive functions may be most responsive to motor cortex rTMS. Safety Monitoring: Adverse events are monitored at each treatment session and follow-up visit using a standardized checklist of potential TMS-related adverse effects. Blood pressure and heart rate are recorded at the beginning and end of each treatment session and at all study visits. Statistical Approach: Repeated measures ANOVA will assess changes across time points for primary and secondary endpoints. Paired t-tests will evaluate changes between baseline and each post-treatment time point. Cohen's d effect sizes will be calculated for all endpoints. The proportion of participants achieving clinically meaningful improvement will be reported using established minimal clinically important differences (MCID) where available. Both intention-to-treat and per-protocol analyses will be conducted. Last observation carried forward (LOCF) will be used for sensitivity analyses in cases of missing data. A p-value of 0.05 will be considered statistically significant. Exploratory subgroup analyses may be conducted based on baseline motor severity, cognitive status, disease duration, age, and sex.