High-resolution mapping of the human brainstem during continence and micturition: noninvasive in vivo 7 Tesla fMRI study

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The lower urinary tract (LUT) – bladder, bladder neck, urethra, and urethral sphincter – is controlled by a complex neural network. A delicate and complex switch/relay exists between storage of urine (continence) and voluntary voiding (micturition) and, in humans, control over this switch is located in the brainstem regions known as the pontine storage center (PSC), the pontine micturition center (PMC) and the periaqueductal gray (PAG). Over the last two decades, despite significant research in the brain control of LUT, our understanding of the brainstem in humans has remained rudimentary. 7Tesla magnetic resonance imaging (MRI) has demonstrated improved ability for mapping of the brainstem, a region historically posing challenges to obtain fMRI data due to its location close to many large arteries and ventricles, yet encompassing some of the most important regions of the bladder cycle, such as the PAG, PSC and PMC (Regions of Interest-RoIs for this study) highlighting the significance and the priority of this proposed research. The overall objective of this proposal is to use a noninvasive fMRI protocol that allows for evaluation of the brainstem during continence and micturition in real-time, using high-resolution neuroimaging (7T fMRI) in both men and women with the following two specific aims: Aim 1: Assessing activation patterns of brainstem RoIs during continence and micturition within and between cohorts of healthy men and women; and Aim 2: Comparing activation patterns of brainstem RoIs obtained in Aim 1 to our previous data from Multiple Sclerosis (MS) patients obtained on 3T and 7T MRI supported by my current K23 award. The proposed R03 project is a prospective two- year human trial that includes a novel and noninvasive micturition fMRI paradigm evaluating the brainstem at rest with empty bladder and with full bladder following accelerated hydration (noninvasive bladder filling by consuming water) and micturition using 7T fMRI in healthy men and women. Over the past five years, my research team has established a 3T fMRI brain-bladder platform and have successfully used it in healthy controls, patients with LUTD, including MS, and men with Benign Prostatic hyperplasia. I have the appropriate resources, collaboration, experience and expertise to complete the proposed study in time and within budget. Currently, I am in my final two years of her K23 Mentored Patient-Oriented Research Career Development Award from NIDKK and have successfully executed and published on aims 1 and 2 of my K23 proposal (Aim 3 is ongoing and with projected completion in 2021). This proposed R03 study will be the first 7T MRI study evaluating the brain and specifically brainstem control over LUT, creating the seminal 7 T database for future studies in patients with LUTD and providing a more accurate roadmap for potential therapeutic and neuromodulation options. The results from this study will complement my research to prepare strong preliminary data for future R01 studies to evaluate patients with lower urinary tract dysfunction (LUTD), specifically patients with underactive bladder.