rTMS as a Cognitive Rehabilitation Approach in Veterans with Parkinson's Disease

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More than 100,000 US Veterans living with Parkinson's disease (PD) currently receive PD-related care and services from the VA. In addition to motor complications, PD is characterized by progressive cognitive decline leading to long-term functional impairment and diminished quality of life. Approximately 20-55% of PD patients will develop mild cognitive impairment (PD-MCI) while up to 80% will develop dementia (PD-D). Since PD-MCI is a risk factor for developing PD-D, there is a critical need to develop treatments to improve cognition and slow or stop progression to PD-D. Limited treatment options for PD-MCI and PD-D and the possible need to tailor treatments to Veterans makes this an important research topic. Repetitive transcranial magnetic stimulation (rTMS) shows promise as an effective cognitive neurorehabilitation treatment. To date, no rTMS studies have assessed the effect of rTMS on cognitive function in PD-MCI. Nor has there been PD neurophysiological studies using rTMS to examine neural plasticity in cognitive neural networks. This CDA2 seeks to fill this gap by conducting a small scaled pilot randomized controlled trial (RCT) designed to assess the safety and therapeutic effects of rTMS on cognitive outcomes as well as on brain connectivity in Veterans with PD-MCI. PD-MCI participants will be randomized to either active rTMS or sham rTMS. Participants will complete a standardized neurocognitive battery assessment at baseline, endpoint (immediately after the 24 day intervention) and at a one month follow-up. The primary outcome is change in executive function. Secondary outcomes include performance on other cognitive domain tasks and a proximal measure of real-life function that captures relevant functional changes related to cognitive impairment in PD. Multi-modal neuroimaging, in a subsample of participants, will be used to study neural connectivity changes induced by rTMS. Changes in resting state functional connectivity, grey matter volume via voxel-based morphometry and white matter integrity via diffusion tensor imaging will be assessed at baseline and endpoint. To inform how to optimize rTMS treatment in PD-MCI, these changes will be correlated with changes in cognitive performance. Dr. Kletzel is an excellent candidate for a CDA2. She has been building a strong foundation for establishing a career as a VA clinical neuroscientist in the field of neurorehabilitation. Her preclinical neuroscience background combined with her post-doctoral and CDA1 clinical research training makes her uniquely suited to successfully address the research objectives. Dr. Kletzel's long-term career goal is to develop and optimize cognitive rehabilitation treatments for Veterans with PD so as to improve their function and quality of life. Her immediate career goals are to conduct her first small clinical RCT and use these data both to contribute to the field of neurocognitive rehabilitation as well as to secure a VA Merit grant as an independent investigator. To achieve these career goals, Dr. Kletzel has developed critical learning objectives set forth in her career plan. These include building upon and enhancing her clinical knowledge of PD and cognitive rehabilitation, expanding her skills of acquiring and analyzing multi-modal advanced neuroimaging data and developing her skills to conduct measurement research. Dr. Kletzel has assembled an impressive mentoring team to support her research and career plans. The team includes experts in the areas of PD and cognition, neuromodulation, neuroimaging and outcome measures. Completion of this CDA2 is expected to advance rehabilitative health care of Veterans who are affected by cognitive decline by providing necessary first steps towards developing a neuromodulatory cognitive intervention that has great potential to translate into clinical cognitive rehabilitation programs for Veterans with the goal of maximizing functional outcomes and improving quality of life.