SUPRASPINAL TARGETS IN NEUROGENIC VOIDING DYSFUNCTION

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Project Summary/Abstract Dr. Khavari is in her final year of the Multidisciplinary K12 Urologic Research Career Development Program (Lamb: Director; Boone: Co-Director) from NIDDK and is applying for the Individual Career Development Award (K23) to support her transition into a fully independent surgeon-scientist in the fields of neurourology and voiding dysfunction. K23 award will specifically provide Dr. Khavari the support needed to develop expertise in 2 areas: (1) Advanced functional Magnetic Resonance Imaging (fMRI) protocol design and data analysis; (2) Application of Transcranial Rotating Permanent Magnet Stimulator (TRPMS) in a clinical trial. To achieve her goals, Dr. Khavari has assembled an expert multidisciplinary team of collaborators and advisors in neuroimaging (Karmonik), neuroscience (Masdeu and Helekar), neurourology (Chai and Daneshgari), and urologic research (Boone and Lamb). Dr. Boone, the chair of her Department, is a leading expert in neuro-urological research and has mentored many junior faculty to independent investigators and will serve as her Primary Mentor. Neurogenic voiding dysfunction (VD) is morbid, costly, and leads to urinary tract infections, stones, sepsis, and permanent renal failure. Currently, the only available therapy for VD is catheterization, which is a burden, especially in neurogenic patients, such as Multiple Sclerosis (MS), who commonly exhibit lower extremity spasms and compromised hand dexterity. The cost and morbid side effects (hematuria, pain, trauma, strictures, and infections) associated with catheterizations, urge us to look into potential therapeutic options beyond the bladder, such as supraspinal targets. Yet, the current understanding of supraspinal centers, and their roles in initiating or modulating voiding, is rudimentary in patients with neurogenic VD. Dr. Khavari will use preliminary data and the raw database from her established simultaneous fMRI and urodynamics platform to determine whether, in female MS subjects: Aim 1: Activation patterns of preselected grey matter Regions of Interest (ROI)s are different among MS patients with versus without VD, specifically those with Detrusor Sphincter Dyssenergia. Aim 2: Damage to preselected white matter tracts involved in bladder control provides an independent predictive measure for VD. Aim 3: Targeted cortical stimulation in ROIs in MS patients with VD causes changes in ROIs that better recapitulate the activation patterns in patients without VD or healthy controls. Aim 3 will be a pilot trial using an individualized TRPMS targeting personalized ROIs in selected MS patients with VD. Dr. Khavari’s ongoing research and current career development plans exemplify her commitment to becoming an independent investigator in patient-oriented research. Her project has the potential to improve our ability to understand brain control of bladder, suggest new diagnostic methods, and provide crucial steps towards therapeutic options for the morbid and intractable condition, VD, in patients with neurogenic (e.g. MS or Strokes) or non-neurogenic VD (e.g. underactive bladder or Fowler’s syndrome). This proposal, and the subsequent planed R01, will lay the foundation for future clinical trials addressing therapies for VD.