Mechanism of Action of Deep Brain Stimulation

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DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in neurosurgery. This program will promote the command of electrophysiology, electrochemistry, brain imaging and stereotactic and functional neurosurgery. Dr. Gary Sieck, Chair of Physiology and Biomedical Engineering, will serve as the primary mentor. A mentorship team of experts in brain imaging, electroanalytical chemistry, neuroengineering and neurosurgery will help the applicant elucidate the mechanisms by which Deep Brain Stimulation (DBS) treats Parkinson's disease. Our recent work demonstrates that subthalamic nucleus (STN) DBS may activate nerve endings to release neurotransmitters, including dopamine. The proposed experiments will entail electrophysiologic, electrochemical, and fluorescent microscopic recordings during DBS. The specific aims include the demonstration of 1) DBS results in changes in neuronal action potential firing and release of dopamine in the striatum. 2) The therapeutic benefit of STN DBS is mediated by dopamine release in the 6-OH DA lesioned rat model of Parkinson's disease. 3) STN DBS results in release of glutamate in the STN via astrocytic vesicular release mechanism. This study will be the first detailed analysis of the mechanism of DBS as it relates to DBS effect on astrocytic glutamate release and striatal dopamine release. Success in this project will open a new era in medical diagnosis and intervention, providing precise targeting of DBS electrodes and regulation of neurotransmitter that are critically involved in the therapeutic effectiveness of DBS. The applicant, Kendall Lee, M.D., Ph.D., is a new investigator and a neurosurgeon at the Mayo Clinic Rochester with a multidisciplinary background in neurology, neurosurgery, and neuroscience. He has demonstrated the ability to form unique and effective collaborations. To maximize the likelihood of success, the applicant has enlisted as advisors a highly skilled team of researchers: Charles Blaha, Ph.D. (expert in amperometry), Paul Garris, Ph.D. (expert in Parkinson's disease animal models and fast scan cyclic voltammetry), Eric Newman, Ph.D. (expert in astrocyte research), and Demetrius Maragonore, M.D. (Parkinson's disease Neurologist and researcher). In addition, Fredric Meyer, M.D. (Chair, Neurosurgery Mayo Clinic Rochester) will serve as career development advisor, to make certain a successful career in academic neurosurgery for the applicant.