Repetitive Transcranial Magnetic Stimulation (rTMS) as a Cognitive Rehabilitation Approach for Veterans with Parkinson's Disease and Mild Cognitive Impairment: Protocol for a Randomized Sham-Controlled Trial (Preprint)

<sec> <title>BACKGROUND</title> Parkinson’s Disease (PD) is characterized by motor symptoms as well as progressive cognitive decline leading to long-term functional impairment and diminished quality of life. Mild cognitive impairment in PD (PD-MCI) is a risk factor for developing PD related dementia (PD-D); there is a critical need to develop treatments to improve cognition and slow or stop progression to PD-D. Repetitive transcranial magnetic stimulation (rTMS) shows promise as an effective cognitive neurorehabilitation treatment. </sec> <sec> <title>OBJECTIVE</title> 1) To test safety and feasibility of a 10 session, high frequency rTMS protocol applied to the left DLPFC among Veterans with PD-MCI. 2) To test efficacy of rTMS to improve cognitive test performance among Veterans with PD-MCI. </sec> <sec> <title>METHODS</title> This is a double blind randomized controlled trial. We will enroll US military Veterans with PD-MCI. Participants will be randomized to either active or sham rTMS treatment groups. Participants will receive 10 treatment sessions. Participants will be scheduled to receive 2 treatment sessions per day. Treatment days do not need to be consecutive, rather they can be spread across approximately 10 days (e.g., Monday, Wednesday, Thursday, Monday, Tuesday, Wednesday). Participants randomized to active rTMS will receive stimulation applied to the left DLPFC at 110% RMT, 15Hz rate, 5 seconds per train, 10 second ITI, and a total of 40 trains per session. Each patient will receive approximately 3000 pulses per session. Sham stimulation will be given at the same parameters as the real rTMS; however, no magnetic field will be produced on the placebo side of the A/P coil. This study protocol was approved by the Edward Hines Jr. Veterans Administration (VA) Hospital and Jesse Brown VA Medical Center Institutional Review Boards. This study protocol was prospectively registered on ClinicalTrials.gov (NCT03836950). This study includes a Food and Drug Administration Investigational Device Exemption (IDE: G190076). </sec> <sec> <title>RESULTS</title> Safety will be assessed by the number of research related adverse events experienced by the active rTMS group compared to the sham rTMS group. Feasibility will be assessed by protocol completion rates. To examine preliminary effects of rTMS, participants will complete a standardized neurocognitive battery assessment at baseline, endpoint and at a one-month follow-up. The primary study outcome is the change in score from baseline to endpoint for the NIH sponsored Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) executive composite score. A 6-year research plan timeline was developed, including a no-cost extension due to the COVID-19 pandemic. As of April 2025, a total of 18 Veterans with PD-MCI completed the RCT phase. Data collection is ongoing and will be completed by October 2025. We expect the results of this study to be available by October 2026. </sec> <sec> <title>CONCLUSIONS</title> The knowledge gained on safety, feasibility and efficacy of rTMS will set the stage for future research optimizing therapeutic gains for existing cognitive rehabilitation treatments or developing new and adjunct treatments for PD-MCI. </sec> <sec> <title>CLINICALTRIAL</title> NCT03836950 </sec>