Afferent Hyperactivity Mechanisms in Overactive Bladder Syndrome



 DESCRIPTION (provided by applicant): The overarching goal of this career development award is to provide a comprehensive training program to prepare Dr. Reynolds for an independently funded clinical research career focused on outcomes of treatments for patients with overactive bladder (OAB). Dr. Reynolds is an Assistant Professor of Urologic Surgery and board-certified urologist with clinical subspecialty fellowship training in Female Pelvic Medicine and Reconstructive Surgery (FPMRS) and an advanced degree in health services and outcomes research (Masters of Public Health, MPH). Dr. Reynolds' near-term goal is to acquire additional expertise in clinical and translational research techniques while continuing a productive line of investigation into the clinical manifestations and treatment effects of underlying afferent nerve or visceral hyperactivity (a proposed mechanism for OAB). This award will allow him to meet this goal with formal graduate-level coursework and protection for 5 years of mentored research. Dr. Reynolds has assembled a multidisciplinary mentoring team to help accomplish this goal. His primary mentor is Stephen Bruehl, PhD, who has a well-established track record of high impact clinical and translational research in mechanisms of chronic pain and visceral hypersensitivity. His career development is further benefited by two co-mentors: David Penson, MD, MPH, is a urologist and experienced investigator with expertise in comparative effectiveness and outcomes research in quality of life and survivorship of prostate cancer; and Roger Dmochowski, MD, MMHC, is a urologist and an internationally recognized expert in overactive bladder and functional bladder disorders. Vanderbilt University Medical Center provides a rich environment for research and the training of young investigators with centralized oversight of all mentored physician scientists through the Office of Clinical & Translational Scientist Development, including the Vanderbilt Physician Scientist Development program that provides funding for Dr. Reynolds' protected time for research and career development activities. Furthermore, as a member of the Vanderbilt Center for Health Services Research and the Center for Surgical Quality and Outcomes Research, Dr. Reynolds has immediate access to investigators, invited speakers, and state-of-the-art core research facilities. His long-term goal s to become an independently-funded surgeon-scientist with the unique skills and training to bridge translational, clinical and health services studies within a large translational OAB research program that will impact the care of patients with this disease. The strong mentorship, additional training, and environment detailed in this proposal will position him to ultimately reac this objective. The research proposal will examine how spinally-mediated afferent hyperactivity, specifically central sensitization (CS), contributes to manifestations of OAB in women and affects treatment outcomes. CS is an induced state of spinal hypersensitivity and a well-recognized mechanism of centrally amplified pain perception. The presence of CS is routinely indexed in the pain literature by noninvasive experimental assessment of temporal summation in response to repetitive, brief evoked pain stimuli. It is proposed to underlie pathophysiology of several disorders often referred to as "CS syndromes," such as fibromyalgia, irritable bowel syndrome, migraine, idiopathic low back pain, chronic fatigue syndrome, and interstitial cystitis/bladder pain syndrome. Although the etiology of OAB remains unclear, a substantive body of animal and ex vivo research implicates altered neuronal signaling with both increased afferent nerve activity (including activation of normally quiescent c-fibers that are also involved in pain transmission) and altered CNS processing of excitatory signals. Experimental evidence suggests mechanisms of pelvic organ cross-talk which have been implicated in OAB appear analogous, if not identical, to mechanisms of CS. However, a reliable means to assess such changes has remained elusive, and therefore whether and how pathophysiologic mechanisms might contribute to OAB patient phenotypes and influence treatment outcomes is unknown. There is presently no objective marker for OAB diagnosis, prognosis or treatment response. As a result, there is a disconnect between scientific research findings on disease mechanisms and principles of patient management. The proposed research aims to address these significant knowledge gaps by leveraging established clinical research methods commonly used by investigators studying chronic pain and functional disorders. We hypothesize that similar central sensitization contributes to OAB phenotype in a subset of patients, that presence of central sensitization in OAB can be indexed by temporal summation of evoked pain stimuli, and that presence of this mechanism may have implications for OAB treatment outcomes. In Aim 1, Dr. Reynolds will compare the degree of temporal summation between women with and without OAB. In Aim 2, using cluster analysis on symptoms and clinical data, Dr. Reynolds will identify empirically defined subgroups of women and associate phenotypes of those subgroups with results of temporal summation. Finally, in Aim 3, the predictability of increased temporal summation and subgroup phenotypes on short-term treatment outcomes will be assessed in an observational cohort study.