Neurourology and Urodynamics 33:493–501 (2014) Examining Mechanisms of Brain Control of Bladder Function With Resting State Functional Connectivity MRI Rahel Nardos, 1,2 * William Thomas Gregory, 1 Christine Krisky, 1 Amanda Newell, 1 Binyam Nardos, 3 Bradley Schlaggar, 3 and Damien A. Fair 1 1 Oregon Health and Science University, Portland, Oregon 2 Kaiser Permanente, Clackamas, Oregon 3 Washington University Aims: This aim of this study is to identify the brain mechanisms involved in bladder control. Methods: We used fMRI to identify brain regions that are activated during bladder filling. We then used resting state connectivity fMRI (rs-fcMRI) to assess functional connectivity of regions identified by fMRI with the rest of the brain as the bladder is filled to capacity. Results: Female participants (n ¼ 20) were between ages 40 and 64 with no significant history of symptomatic urinary incontinence. Main effect of time (MET) fMRI analysis resulted in 20 regions of interest (ROIs) that have significant change in BOLD signal (z ¼ 3.25, P <0.05) over the course of subtle bladder filling and emptying regardless of full versus empty bladder state. Bladder-state by time (BST) fMRI analysis resulted in three ROIs that have significant change in BOLD signal (z ¼ 3.25, P <0.05) over the course of bladder runs comparing full versus empty bladder state. Rs-fcMRI fixed effects analysis identified significant changes in connectivity between full and empty bladder states in seven brain regions (z ¼ 4.0) using the three BST ROIs and sixteen brain regions (z ¼ 7) using the twenty MET ROIs. Regions identified include medial frontal gyrus, posterior cingulate (PCC), inferiolateral temporal and post-central gyrus, amygdale, the caudate, inferior parietal lobe as well as anterior and middle cingulate gyrus. Conclusions: There is significant and vast changes in the brain’s functional connectivity when bladder is filled suggesting that the central process responsible for the increased control during the full bladder state appears to largely rely on the how distributed brain systems are functionally integrated. Neurourol. Urodynam. 33:493–501, 2014. # 2013 Wiley Periodicals, Inc. Key words: brain bladder control; brain imaging; overactive bladder; functional MRI; resting state connectivity MRI; urgency incontinence INTRODUCTION Understanding the functional brain circuitry involved in normal bladder control is key to identifying central abnormali- ties in patients with bladder control problems. Urgency Urinary incontinence (UUI), defined as involuntary and unpredictable leakage of urine accompanied by or immediately preceded by urgency, affects 19.1% of women between 65 and 74 years of age in the United States. The prevalence is twice that seen in men. 1 Although UUI is a common problem in women with profound clinical, social, economical, and psychological con- sequences, 1–3 little is understood about its underlying patho- physiology. Currently, UUI is assumed to be associated with or caused by an end organ pathology involving involuntary bladder muscle contractions known as detrusor overactivity (DO) observed on urodynamic examinations. 4 DO, however, is absent in almost 50% of patients with UUI 5 suggesting the presence of an alternate etiology perhaps at the level of the central nervous system. Recent functional MRI (fMRI) and PET studies have identified increased brain activity in higher order cognitive control centers during bladder filling and voiding in normal sub- jects. 6–10 Some studies have also compared differences in blood oxygen level dependent (BOLD) activation patterns between subjects with and without urge incontinence during bladder filling protocols. 11,12 Another advanced imaging technique that is valuable to study normal and abnormal brain function is resting-state functional connectivity MRI (rs-fcMRI). While fMRI is a non-invasive neuroimaging modality with relatively high spatiotemporal resolution used to investigate BOLD activity in individual brain regions when subjects are engaged in particular tasks, 13 rs-fcMRI can demonstrate how activity in multiple brain regions correlate with one another at rest. Resting-state functional connectivity MRI is based on the discovery that spontaneous low-frequency (<0.1 Hz) BOLD signal fluctuations in sometimes distant, but functionally related brain regions, show strong temporal correlations at rest. 14 In effect, rs-fcMRI evaluates regional interactions that occur when a subject is not performing an explicit task (i.e., subjects are ‘‘at rest’’). 14–23 By cross-correlating the time series for the BOLD signal fluctuations of a particular brain region (seed region or region of interest) with the time series of other regions, one can determine which regions may have a history of coactivation which inturn can be a surrogate for functional integration. The aim of our study is to identify brain regions that are activated during bladder filling using fMRI and assess functional connectivity with the rest of the brain as the bladder is filled to capacity using rs-fcMRI. Understanding how Dirk De Ridder led the peer-review process as the Associate Editor responsible for the paper. Conflict of interest: none. Contract grant sponsor: Pfizer OAB-LUTS Competitive; Contract grant sponsor: OHSU New Faculty Institutional Support; Contract grant sponsor: Advanced Imaging Research Center at OHSU  Correspondence to: Rahel Nardos, Mail Code: L466, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3107. E-mail: nardosr@ohsu.edu Received 15 March 2013; Accepted 7 June 2013 Published online 3 July 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22458 # 2013 Wiley Periodicals, Inc.