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Am J Obstet Gynecol. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: Am J Obstet Gynecol. 2016 October ; 215(4): 449.e1–449.e17. doi:10.1016/j.ajog.2016.04.056.
URGENCY URINARY INCONTINENCE AND THE INTEROCEPTIVE NETWORK: A FUNCTIONAL MRI STUDY Loren H. KETAI, MD1, Yuko M. KOMESU, MD1, Mr. Andrew B. DODD, MS2, Rebecca G. ROGERS, MD1, Mr. Josef M. LING, BA2, and Andrew R. MAYER, PhD.2 1University
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2Mind
of New Mexico Health Sciences Center, Albuquerque, New Mexico
Research Network, Albuquerque, New Mexico
Abstract Background—Treatment of urgency urinary incontinence has focused on pharmacologically treating detrusor overactivity. Recent recognition that altered perception of internal stimuli (interoception) plays a role in urgency urinary incontinence suggests that exploration of abnormalities of brain function in this disorder could lead to better understanding of urgency incontinence and its treatment.
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Objectives—1) To evaluate the relationship between bladder filling, perceived urgency and activation at brain sites within the interoceptive network in urgency urinary incontinence 2) To identify coactivation of other brain networks that could affect interoception during bladder filling in urgency incontinence 3) To demonstrate interaction between these sites prior to bladder filling by evaluating their resting state connectivity Study Design—We performed an observational cohort study using functional magnetic resonance imaging to compare brain function in 53 women with urgency urinary incontinence and 20 Controls. Whole-brain voxel-wise ANCOVAs were performed to examine differences in functional brain activation between groups during a task consisting of bladder filling, hold (static volume) and withdrawal phases. The task was performed at three previously established levels of baseline bladder volume, the highest exceeding strong desire to void volume. All women continuously rated their urge on a 0–10 point Likert scale throughout the task and a mixed measures ANOVA was used to test for differences in urge ratings. Empirically derived regions of interest from analysis of activation during the task were used as seeds for examining group differences in resting state functional connectivity.
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Results—In both urgency urinary incontinent participants and Controls changes in urge ratings were greatest during bladder filling initiated from a high baseline bladder volume and urgency incontinent participants’ rating changes were greater than Controls. During this bladder filling phase urgency incontinent participant’s activation of the interoceptive network was greater than
Corresponding Author: Yuko M Komesu MD University of New Mexico Health Sciences Center Department of Obstetrics and Gynecology MSC 10 5580 1 University of New Mexico Albuquerque, New Mexico 87131-0001, U.S.A. Phone: +1-505-272-9712, Fax: +1-505-272-1336, [email protected]. This work was presented at the American Urogynecologic Society’s Pelvic Floor Disorder’s Week Conference (formerly the American Urogynecologic Society’s 36th Annual Scientific Meeting), October 15–17, 2015, Seattle, Washington and at the International Urogynecologic Society Meeting, Nice, France, June 2015.
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Controls, including in the left insula and the anterior and middle cingulate cortex. Urgency Incontinent Participant’s activation was also greater than Controls at sites in the Ventral Attention Network and Posterior Default Mode Network. Urgency incontinent participant’s connectivity was greater than Controls between a middle cingulate seed point and the Dorsal Attention Network, a “top down” attentional network. Control connectivity was greater between the mid-cingulate seed point and the Ventral Attention Network, a “bottom up” attentional network,
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Conclusions—Increasing urge was associated with greater urgency incontinent participant than Control activation of the interoceptive network and activation in networks that are determinants of self-awareness (Default Mode Network) and of response to unexpected external stimuli (Ventral Attention Network). Differences in connectivity between interoceptive networks and opposing attentional networks (Ventral Attention Network versus Dorsal Attention Network) were present even before bladder filling (in the resting state). These findings are strong evidence for a central nervous system component of urgency urinary incontinence that could be mediated by brain directed therapies. Keywords attentional and interoceptive networks; brain activation and networks; fMRI; resting state functional connectivity; urgency urinary incontinence in women
Introduction
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Urgency urinary incontinence (UUI), involuntary urine loss associated with urgency,1 affects millions of women daily and significantly impairs their quality of life. Treatment of UUI with medications has focused on mediating detrusor overactivity and resulting incontinence. Compliance with these medications is limited by frequency of their side-effects relative to the frequency of their therapeutic success.2 Recognition that altered perceptual awareness plays a role in UUI suggests that an alternative approach, addressing abnormalities in brain function, may have a role in UUI treatment.3 Women with urgency incontinence manifest abnormal activation of portions of the brain that govern interoception, the perception and interpretation of physiologic stimuli arising within the body.4 These abnormalities, and the effect they have on other regions in the brain, likely modulate abnormal storage in UUI.5,6 Abnormalities in interoception also have the potential to modify urge perception which may be important in the genesis or persistence of UUI.
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Most investigation of abnormal brain activation relies on functional MRI (fMRI) performed using blood oxygen level dependent (BOLD) contrast imaging. FMRI can assess localized brain activity that occurs in response to administered stimuli or prompted tasks. Areas of the brain that show coherent neural activation and deactivation, are described as demonstrating “functional connectivity”, and together constitute “functional networks”. The definition of functional networks, based on temporal correlations of brain activation, has proven a very robust technique, demonstrating reproducible spatial localization of these networks among many populations.7,8
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Each functional network interconnects spatially distinct areas of the brain that together implement a unique component of cognition.9,10. Individual networks have been identified as having nodes at consistent anatomical sites. Representative nodes include those in the interoceptive network (anterior cingulate cortex, insula), dorsal attention network (dorsolateral prefrontal cortex or “frontal eye fields”), the ventral attention network (ventrolateral prefrontal cortex and temporoparietal junction) and the default network (medial temporal lobe, posterior cingulate cortex) (Table 1).7,8,11
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Pioneering fMRI work by Griffiths reported increased activation of the interoceptive network, including the insula and anterior cingulate cortex (ACC), in response to bladder filling among UUI patients.4 Within the interoceptive network the insula functions as the key switching center for processing visceral sensation while the cingulate cortex, is responsible for integrating emotional context with interoception.12 Similar abnormalities of interoceptive network activation are seen in patients with fibromyalgia and irritable bowel syndrome (IBS), diseases sometimes termed “hypervigilant” states.13,14 In hypervigilant states, interoceptive network activation is heightened and its connectivity to other neural networks is altered.15
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More complete understanding of how “hypervigilant” changes in brain function affect urge perception may help guide therapy that is directed towards the brain rather than the bladder. We sought a unique approach that would evaluate the relationship between changing bladder volumes and both interoceptive network activation and perceived urge. We also sought to identify coactivation of executive control networks in the prefrontal cortex (PFC) that could affect perception by interacting with the interoceptive network. Other hypervigilant states demonstrate both altered brain activation in response to stimuli and altered patterns of fluctuations in BOLD signal while the individual is at rest. Those brain regions which demonstrate similar fluctuations in BOLD signal over time during rest are considered as having resting state functional connectivity.7,8,9,10 These resting fluctuations in signal within a functional network can be much greater in magnitude than changes in a specific brain region during a task or stimulus and, therefore, can provide much greater signal to noise.7 Accordingly, after identifying sites in the brain that were activated during increased urge we sought to evaluate resting state functional connectivity between those specific sites and functional networks. In order to accomplish this, as far as we know, we compared the largest cohort of UUI participants and comparably aged controls yet published.16,17
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We hypothesized that UUI participants would experience increased activation of the interoceptive network in response to bladder filling relative to Controls and that this activation would be accompanied by increased urge. We also hypothesized that the pattern of prefrontal cortex (PFC) executive control network co-activation with the interoceptive network would differ between UUI participants and Controls. Last, we hypothesized that sites of altered interoceptive activity in UUI would also show altered resting state functional connectivity. Identification of differences in brain activation and functional connectivity in women with UUI would identify aspects of brain function that might be targeted by behavioral and other brain directed therapies, and provide a means to measure the efficacy of those therapies in treating this often refractory abnormality.
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Materials & Methods Participants
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The current study represents a sub-sample from an on-going randomized controlled trial comparing hypnotherapy versus pharmacotherapy for treatment of UUI (NCT01829425). Female participants were recruited from an academic urogynecology clinic and from the community at large between March 2013 and May 2015. UUI participants were nonpregnant woman ≥ 18 years old who; 1) had ≥3 urgency urinary incontinence episodes/week for ≥3 months 2) were without significant neurologic illness or pelvic organ prolapse beyond the hymen and 3) had OAB Awareness Tool scores ≥ 8).18 Both participants with UUI and Controls without UUI underwent bedside cystometrics at which time “strong desire to void” volumes, defined as bladder volumes eliciting a “persistent desire to pass urine without the fear of leakage,”10 were recorded. Controls were women between 46–80 years without UUI, with OAB Awareness Tool Scores 200 ml. Potential participants were excluded if they had contraindications to MRI. The University of New Mexico Institutional Review Board approved the study (#09–314) and all participants gave written informed consent. Fifty-six UUI participants and 23 Controls participated in this imaging study. Data for three UUI participants and three Controls were excluded secondary to acquisition issues or excessive head motion (3 times the inter-quartile range relative to their cohort based on frame-wise displacement).19 A total of 53 UUI participants and 20 Controls were included in the final functional task analysis. Clinical Assessment
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All participants completed a three day voiding diary and the OAB Awareness Tool questionnaire,18 and underwent cystometric testing. The OAB Awareness Tool (or OABv-8) is a validated screening tool for overactive bladder. Demographic and clinical data collection included ethnicity, race, age, parity, prior surgical history and body mass index (BMI). fMRI Scanner Tasks The fMRI task consisted of infusing the bladder with saline over 9 seconds (infuse phase), maintaining that volume over 19 seconds (hold phase), then withdrawing the same volume over 9 seconds (withdrawal phase). Task timing was maintained with Neurobehavioral Systems Presentation software. Specifically, a research nurse was given instructions over headphones along with a computerized timed count for all of the different task intervals (i.e. infusing and withdrawing fluids from bladder).
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Bladder filling and emptying volumes were determined based on participants’ strong desire volumes (See Supplement). The infuse/hold/withdraw cycle was repeated 6 times at low, medium and high fill (bladder) volumes (Supplement Figure 1). Because the task was designed to maximize urge but avoid incontinence, only bladder filling during the high volume infusion exceeded the strong desire to void volume in the majority of participants. Participants continuously (100 Hz sampling frequency) rated their urinary urge using a nonferrous key-press device positioned directly under their right hand. Urge levels were rated on
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a 11-point Likert scale (0 = “no urge” to 10 = “severe urge”) and were recorded real time during all phases of the scan (fill, hold and phase). To minimize neuronal activation associated with eye movements, subjects were instructed to maintain visual fixation throughout all trials on the centrally presented cross. Three 2 × 3 [Group × Phase] mixed measures ANOVA were used to test for differences in three direct measures of urge ratings. These were 1) the maximum rating 2) the dynamic range of ratings (maximum – minimum) and 3) the number of changes in subjective urge ratings during each phase of the task. Resting state connectivity data collection was performed with the participant’s bladder empty prior to the bladder filling task. During that time participants passively stared at a white cross for 5 minutes. Three additional UUI and one Control were motion outliers on resting state fMRI and were excluded from connectivity analysis.
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MR Imaging & Statistical Analysis
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T1-weighted echo planar images were collected on a 3T Siemens Trio Tim scanner. (See Supplement). Functional maps were calculated using FSL and AFNI. Time series images were first de-spiked, temporally interpolated to correct for slice-time acquisition differences, and spatially registered in two and three dimensional space to the second EPI image of the first run to minimize effects of head motion. The baseline EPI image (i.e., used for motion correction) was then aligned with the native T1 image using an affine transformation, followed by an affine alignment of the native T1 image to Talairach space. These two matrices were then concatenated and applied to functional data. Time-series data were subsequently blurred using a 6mm Gaussian full-width half-maximum filter. Deconvolution was used to generate a single hemodynamic response function for the entire bladder filling task relative to baseline. Specifically, the hemodynamic response was modelled from the onset of the infuse phase through withdrawal, plus 3 seconds to capture the return to baseline state (total time = 44 seconds or 22 images) (Supplement Figure 2). A separate urge regressor (definition Table 1) was calculated by convolution to capture neuronal changes uniquely associated with changes in urge across all phases.
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Three whole-brain voxel-wise ANCOVAs were performed to examine differences in functional activation across groups for each fill condition. The first factor corresponded to group (UUI vs. Controls), whereas the second factor corresponded to the number of modelled time-points in each phase (See Supplement). Group and the Group × Time interaction were the effects of interest in this statistical framework. An additional voxel-wise t-test was performed to detect differences in activation corresponding to the urge regressor. All functional results were corrected for false positives at p < 0.05 (p < 0.005; minimum cluster size = 1472 μl) based on 10,000 Monte-Carlo simulations). Although analysis of intergroup differences is by necessity complex, our prior work allowed for approximation of the necessary sample size. Results from prior evaluation of fMRI during bladder filling in OAB participants suggested that differences in BOLD signal between UUI participants and controls would yield an effect size of 0.8 (Cohen’s d)20. An allocation ratio of participants to controls of 3:1 was chosen to provide adequate samples size for subsequent pre-post treatment evaluation of fMRI in UUI participants, which is the specific aim of the previously described parent study. Assuming an effect size of 0.8 and a Am J Obstet Gynecol. Author manuscript; available in PMC 2017 October 01.
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participant to control allocation of 3:1, a group of 20 controls and 50 participants would achieve a power of 0.80 for detecting intergroup differences (alpha = .05) in percent signal change at an priori regions of interest (ROIs). Empirically derived regions of interest from analysis of activation were used as seed points for resting state functional connectivity analysis examining group differences in functional connectivity. Correlations were calculated between the time course of activation in these regions and the time course of activation in other brain sites. ROIs and brain sites showing increased connectivity were assigned to corresponding brain network based previously reported Talairach spatial coordinates (as defined by the brain’s anterior and posterior commissures) or Brodmann areas (defined by brain cytoarchitecture)7,9,21
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Clinical Measures By design, UUI and Control participant’s age, parity, and degree of prolapse did not differ (Table 2), nor did they differ by race or ethnicity (P>.05). BMI differed between UUI participants and Controls (p = 0.02). As expected, voiding diaries, OAB Awareness Scores and cystometric findings also differed between groups (Table 2). Urge Rating Results for High Fill Volumes
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The main effect of Group was significant for the maximum urge rating (p = .006), with UUI participants exhibiting higher overall ratings (7.4±2.1) relative to Controls (5.6±3.1). This occurred despite absence of significant differences between controls and participants in the number of changes in urge ratings (frequency of button pushes) (p > 0.10). A 2 × 6 [Group × Task Cycle] mixed measures ANOVA also showed no main effect of task cycle or interaction between group and cycle, indicating that habituation to stimuli did not play a role in fill ratings from either group (p > 0.10). The main effect of phase was significant for all three urge measures (all p< 0.001). Simple effects tests indicated the largest dynamic range of ratings and greatest number of rating changes occurred during infuse (I) compared to withdrawal (W) or hold (H) phases (I [3.7±2.1]>W [2.3±1.8]>H [1.7±1.1]) and (I [4.0±2.5]>(H [2.3±1.9] ≈ W [2.4±2.1]). The highest maximal urge rating occurred during hold phase (H [7.5±2.6]>I [6.5±2.6]>W [6.8±2.6]) (See Supplement Figure 3). Urge Rating Results for Medium and Low Bladder Fill Condition Volumes
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Urge ratings for low and medium bladder fill volumes demonstrated group and phase differences similar to the high bladder fill volumes. UUI participants recorded higher overall urge rating than Controls. The maximal dynamic range of urge sensation and the number of changes in urge sensation was greatest during the infuse phase of the task (See Supplement). FMRI Results from High Volume Bladder Filling Task Functional results from the whole-brain voxelwise 2 × 6 [Group × Time] ANCOVA for the infuse phase during high fill volumes demonstrated increased activation in UUI participants relative to deactivation in Controls across multiple brain networks (Figure 1). Specifically, increased activation was observed in the interoceptive network, ventral attention network
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(VAN), and the posterior default mode network (DMN). Interoceptive network activation occurred in the dorsal ACC; middle cingulate cortex (MCC) extending into the right posterior cingulate cortex (PCC); and left anterior insula/ventrolateral prefrontal cortex (VLPFC), which spanned both the interoceptive and VAN (Table 3). Additional activation sites within the VAN included the right VLPFC; right and left temporoparietal junction (TPJ). Posterior DMN activation occurred in the posterior medial cortex within both the right and left hemisphere, and included both the precuneus and PCC. Miscellaneous other areas of greater activation in UUI participants also occurred (Table 3). There was no significant Group × Time interaction.
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For the hold phase, there was no significant effect of Group or a Group × Time interaction. For the withdrawal phase, the main effect of Group indicated deactivation for Controls relative to near baseline levels in UUI participants within the bilateral precuneus (Supplement Figure 4). There was no significant Group × Time interaction for the withdrawal phase at the high fill volumes. Results from low and medium fill volumes are presented in Supplementary Materials. Urinary Urge Regressor Analysis A whole-brain analysis of differences in activation associated with the urge regressor indicated differences between groups confined to the right and left precentral gyrus including the primary motor cortex (Supplement Figure 5). Controls showed deactivation in these areas while UUI participants remained near baseline (Table 3). Resting State Functional Connectivity Analysis
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Group activation differences during the infuse phase within the MCC, right VLPFC, left VLPFC, and dACC served as empirical seeds for connectivity analyses. Results indicated no significant differences in connectivity between groups for the ACC seed. For the MCC seed, UUI participants showed a positive correlation with the left dorsolateral prefrontal cortex (DLPFC)/premotor cortex which was absent in Controls. In contrast, Controls exhibited a positive correlation between MCC and the right VLPFC extending into the insula which was absent in UUI participants. Controls showed significantly greater connectivity than UUI participants between VLPFC seeds and several other cortical sites (Figure 2, Table 4).
Comments Brain Activation
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An important goal of this study was to investigate the effect of bladder filling on the perception of urge and activation of the interoceptive and associated neural networks in UUI participants compared to Controls. Our results indicate increased activation within the interoceptive network, including the ACC, MCC and left anterior insula, for UUI participants relative to Controls. Results also identified concurrent activation in two additional networks. In general terms these networks, the DMN and VAN are respectively determinants of self-awareness and of response to unexpected external stimuli.9, 10
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Differential activation of the interoceptive network was only observed when the bladder was filled above strong desire to void volumes. The absence of group differences in brain activation at low and medium (bladder) fill volumes is consistent with Griffith’s work demonstrating that abnormal brain activation in UUI increases markedly only as strong desire volumes are approached.4 The observation that neural activation occurred only during the filling phase is novel, though the mechanism underlying the finding is unknown. Possibilities including plateauing of mediator (e.g. ATP) release within the bladder once filling has ceased and alteration of CNS processing of bladder sensation when afferent signal from the bladder stabilizes.22
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Activation within the interoceptive network included the ACC and the contiguous MCC. This co-occurring activation of the ACC/MCC may represent both the affective component of urinary urge and cognitive initiation of the efferent motor response. The latter can be facilitated by the close association of the MCC with the supplementary motor area which activates during voluntary contracture of the pelvic floor musculature, a response that can be used to maintain continence.3,23 Among UUI participants, components of the interoceptive network were accompanied by activation of the bilateral VLPFC and TPJ. The latter are components of the VAN, a “bottom-up” attentional system which detects unexpected stimuli and triggers attentional shifts.24,25 Increased activation of the VAN has been reported in IBS and in anxiety disorders where it may be responsible for increased stimulus-driven attention.26, 27 Thus, increased activation within the VLPFC in UUI may indicate an abnormally strong orienting response to bladder stimuli, subsequently accompanied by over-monitoring.
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Our data also show different activation patterns in Controls and UUI participants with respect to the posterior medial cortex, specifically the PCC and precuneus which constitute the posterior node of the DMN. Normally the DMN is activated during the resting state, such as when individuals engage in self-reflection, self-awareness or introspective mental imagery. It is deactivated when cognition is oriented toward a task.28,29,30 In contrast to the expected deactivation during the bladder filling task, among UUI participants the posterior node of the DMN activated during bladder filling and remained near baseline during bladder emptying. In patients with IBS and in patients with urologic pelvic pain syndrome similar abnormal posterior DMN activation has been linked to increased connectivity between the posterior node of the DMN and the interoceptive network.31,32 This may represent a mechanisms by which perceptions of physiologic states manifest an abnormal effect on patients’ self-awareness.33
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Urge ratings data show that changes in perceived urge were greatest during bladder infusion, the only phase during which group differences in brain activation occurred. Despite higher overall urge ratings during the hold phase no group differences in activation were observed while bladder volumes were static. These findings suggest that change in urge, rather than static bladder distension, drives activation of the interoceptive and VAN in UUI.
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Resting State Functional Connectivity
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An important goal of this study was to evaluate resting state functional connectivity in women with UUI compared to Controls. Earlier work evaluating connectivity in UUI analyzed group differences in task-related rather than resting state connectivity.17 Fluctuations in resting signal are much greater in magnitude than task related fluctuation and provide a 3:1 improvement in signal to noise.7 Analysis of resting state functional connectivity benefits from this improved signal to noise ratio. Only one prior work has addressed resting state functional connectivity in UUI, assessing connectivity in over 50 brain sites (seed points) in 16 participants with UUI.16 That study successfully demonstrated numerous areas of connectivity, but did not attempt to relate connectivity to specific functional networks.
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In contrast to the prior work we focused our study on connectivity between a small number of empirically derived seed points. When evaluated with this focused analysis Controls showed increased resting state functional connectivity between the MCC and the right VLPFC relative to UUI. Controls also demonstrated increased connectivity and between the VLPFC and somatosensory and motor cortices. In contrast UUI showed greater connectivity between the MCC and DLPFC. The DLPFC is a component of dorsal attentional networks (DAN), which mediates “top down” voluntary allocation of attention. Increased connectivity between the DAN and interoceptive cortex has been demonstrated in patients with fibromyalgia.34 This increased connectivity to the DAN may indicate “top down” support for goal directed orientation (e.g. maintaining continence). Subsequent activation of the VLPFC in UUI during bladder filling would then represent inability of the DAN to maintain “top down” goal directed focus in the face of “bottom up” VAN mediated reorientation to the stimulus of bladder filling.35
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Limitations
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Although we were able to demonstrate differences in PFC activation in UUI we were not able to demonstrate the deactivation in the medial PFC which has been demonstrated in Griffith’s and Tadic’s work.3 In their model, deactivation of the medial PFC represents suppression of micturition by an executive control function of the brain. It is possible that the rapid filling of the bladder in our model altered the response from the PFC, increasing “bottom up” input from the VLPC at the expense of “top down” input from other sites. Alternatively the absence of medial PFC deactivation may reflect failure to induce urgency. Last, it is also possible that Griffith’s method of assessing brain activation, subtracting withdrawal phase BOLD signal from infuse phase BOLD signal may accentuate findings of deactivation. No deactivation of medial PFC is noted in Nardos’s study which used a method of signal assessment similar to ours. The absence of intergroup differences in the urge regressor is unlikely to be related mechanics of bladder filling, but may be caused by the mathematical model used. Despite the strong association between brain activation and direct measures of changing urge the regressor did not account for unique variation in BOLD signal. This may reflect lack of independence between the urge regressor and other regressors in the design matrix.
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Last, because participants were continuously rating their urge during the bladder filling task it is possible that group differences in the cognitive process of rating urge, rather than the sensation of urge itself, contributed to group differences in brain activation. Absence of group differences in the number of rating changes (frequency of button pushes) suggests that there were no group differences in the motor component of rating but does not exclude group differences in the cognitive component. Conclusion
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In summary, this study is the first to demonstrate that during bladder filling abnormal activation of the interoceptive network, VAN and DMN is concurrent with increased urgency in UUI. Analysis of more extensive resting state functional connectivity data than previously published also shows UUI to be associated with altered connectivity of these networks prior to bladder filling. These findings do not determine whether brain abnormalities are causal or a response to abnormal signaling from the bladder. Whether or not abnormal bladder signaling is the genesis of UUI, functional brain abnormalities likely accentuate UUI symptoms. In either case, therapies directed towards restoring normal function to the interceptive, attentional and default mode networks have the potential to mediate incontinence, urgency or both in UUI.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments Author Manuscript
Research reported in this publication was supported by the National Center for Complementary & Integrative Health of the National Institutes of Health under Award Number R01AT007171. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study is registered with ClinicalTrials.gov; https://clinicaltrials.gov ID#: NCT01829425 Disclosures: Dr. Ketai & Dr. Komesu are Co-PIs for the NIH Award noted above (R01AT007171) and Dr. Mayer and Dr. Rogers are Co-Investigators for this same award. Dr. Rebecca Rogers: DSMB chair for the TRANSFORM trial sponsored by ASTORA; royalties from UPtoDate and McGraw Hill for scientific writings
References
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1. Haylen BT, de Ridder D, Freeman RM. An International Urogynecological Association (IUGA)/ International Continence Society (ICS) Joint Report on the Terminology for Female Pelvic Floor Dysfunction. Neurourol Urodyn. 2010; 29:4–20. [PubMed: 19941278] 2. Shamliyan, T.; Wyman, J.; Kane, RL. Comparative Effectiveness Review No 36. AHRQ Publication No. 11(12)-EHC074-EF. Rockville, MD: Agency for Healthcare Research and Quality; Apr. 2012 Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and Comparative Effectiveness. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm. 3. Griffiths D, Clarkson B, Tadic SD, Resnick NM. Brain Mechanisms Underlying Urge Incontinence and its Response to Pelvic Floor Muscle Training. J Urol. 2015; 194(3):708–15. [PubMed: 25828973] 4. Griffiths D, Derbyshire S, Stenger A, Resnick N. Brain control of normal and overactive bladder. J Urology. 2005; 174:1862–67.
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5. Tadic SD, Griffiths D, Schaefer W, Cheng CI, Resnick NM. Brain activity measured by functional magnetic resonance imaging is related to patient reported urgency urinary incontinence severity. J Urol. 2010; 183:221–28. [PubMed: 19913803] 6. Griffiths D, Tadic SD, Schaefer W, Resnick NM. Brain Cerebral control of the bladder in normal and urge-incontinent women. Neuroimage. 2007 Aug 1; 37(1):1–7. [PubMed: 17574871] 7. Fox MD, Greicius M. Clinical applications of resting state functional connectivity. Front Syst Neurosci. 2010 Jun 17.4:19. [PubMed: 20592951] 8. Damoiseaux JS, Rombouts SA, Barkhof F, Scheltens P, Stam CJ, Smith SM, Beckmann CF. Consistent resting-state networks across healthy subjects. Proc Natl Acad Sci U S A. 2006 Sep 12; 103(37):13848–5. [PubMed: 16945915] 9. Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci. 2010; 14:277–290. [PubMed: 20493761] 10. Raichle ME. The restless brain: how intrinsic activity organizes brain function. Philos Trans R Soc London B Biol Sci. 2015; 370:1668. 11. Farb NA, Segal ZV, Anderson AK. Attentional modulation of primary interoceptive and exteroceptive cortices. Cereb Cortex. 2013 Jan; 23(1):114–26. [PubMed: 22267308] 12. Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ. The integration of negative affect pain and cognitive control in the cingulate cortex. Nat Rev Neurosci. 2011; 12(3): 154–67. [PubMed: 21331082] 13. Pujol J, Lơpez-Solà M, Ortiz H, et al. (2009) Mapping brain response to pain in fibromyalgia patients using temporal analysis of fMRI. PLoS ONE. 2009; 4(4):e5224. [PubMed: 19381292] 14. Labus JS, Naliboff BD, Berman SM, et al. Brain networks underlying perceptual habituation to repeated aversive visceral stimuli in patients with irritable bowel syndrome. Neuroimage. 2009; 47(3):952–60. [PubMed: 19501173] 15. Ichesco E, Schmidt-Wilcke T, Bhavsar R, et al. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain. 2014; 15(8):815–26. [PubMed: 24815079] 16. Nardos R, Karstens L, Carpenter S, et al. Abnormal functional connectivity in women with urgency urinary incontinence: Can we predict disease presence and severity in individual women using RsfcMRI. Neurourol Urodyn. 2015 May 1. [Epub ahead of print]. doi: 10.1002/nau.22767 17. Tadic SD, Griffiths D, Schaefer W, Resnick NM. Abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence. Neuroimage. 2008; 39:1647–65. [PubMed: 18089297] 18. Coyne KS, Zyczynski T, Margolis MK, Elinoff V, Roberts RG. Validation of an overactive bladder awareness tool for use in primary care settings. Adv Ther. 2005; 22(4):381–94. [PubMed: 16418145] 19. Mayer AR, Franco AR, Ling J, Canive JM. Assessment and quantification of head motion in neuropsychiatric functional imaging research as applied to schizophrenia. J Int Neuropsychol Soc. 2007; 13:839–45. [PubMed: 17697415] 20. Komesu YM, Ketai LH, Mayer AR, Teshiba TM, Rogers RG. Functional MRI of the Brain in Women with Overactive Bladder: Brain Activation During Urinary Urgency. Female Pelvic Med Reconstr Surg. 2011; 17(1):50–54. [PubMed: 21399722] 21. Viviani R. Emotion regulation, attention to emotion, and the ventral attentional network. Front Hum Neurosci. 2013 Nov 7.7:746. [PubMed: 24223546] 22. Cheng Y, Mansfield KJ, Allen W, Chess-Williams R, Burcher E, Moore KH. ATP during early bladder stretch is important for urgency in detrusor overactivity patients. Biomed Res Int. 2014; 2014:204604. [Epub]. [PubMed: 24971316] 23. Schrum S, Wolff S, van der Horst C, Kuhtz-Buschbeck JP. Motor cortical representation of the pelvic floor muscles. J Urol. 2011; 186:185–190. [PubMed: 21575960] 24. Vossel S, Geng J, Fink G. Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. Neuroscientist. 2014; 20(2):150–59. [PubMed: 23835449] 25. Farranta K, Uddina L. Asymmetric development of dorsal and ventral attention networks in the human brain. Dev Cogn Neurosci. 2015; 12:165–74. [PubMed: 25797238] 26. Sylvester CM, Corbetta M, Raichle ME, et al. Functional network dysfunction in anxiety and anxiety disorders. Trends Neurosci. 2012; 35(9):527–35. [PubMed: 22658924] Am J Obstet Gynecol. Author manuscript; available in PMC 2017 October 01.
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27. Lowen M, Mayer EA, Sjöberg M, et al. Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome. Aliment Pharmacol Ther. 2013; 37:1184–97. [PubMed: 23617618] 28. Bzdok D, Adrian Heeger A, Langner R, Angela Laird AR, Fox PT. Subspecialization in the human posterior medial cortex. NeuroImage. 2015; 106:55–71. [PubMed: 25462801] 29. Andrews-Hanna JR. The Brain’s Default Network and its Adaptive Role in Internal Mentation Neuroscientist. 2012; 18(3):251–70. [PubMed: 21677128] 31. Buckner RL. The serendipitous discovery of the brain’s default network. NeuroImage. 2012; 62:1137–45. [PubMed: 22037421] 31. Liu X, Silverman A, Kern M, et al. Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report. Neurogastroenterol Motil. 2016; 28:43–53. [PubMed: 26467966] 32. Martucci KT, Shirer WR, Bagarinao E, et al. The posterior medial cortex in urologic chronic pelvic pain syndrome: detachment from default mode network- a resting-state study from the MAPP Research Network. Pain. 2015; 156:1755–64. [PubMed: 26010458] 33. Koster EH, De Lissnyder E, Derakshan N, De Raedt R. Understanding depressive rumination from a cognitive science perspective: The impaired disengagement hypothesis. Clin Psychol Rev. 2011; 31:138–45. [PubMed: 20817334] 34. Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 2010; 62:2545–55. [PubMed: 20506181] 35. Corbetta M, Patel G, Shulman GL. The reorienting system of the human brain: from environment to theory of mind. Neuron. 2008; 58:306–324. [PubMed: 18466742]
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Figure 1.
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Panel A presents differences in activation between patients with urinary urgency incontinence (UUI) and Controls during the infuse phase of the high fill volume. The magnitude of p-values is denoted using dark blue (p < 0.005) and light blue (p < 0.001) coloring. Sagittal (X) and axial (Z) slice locations are given according to the Talaraich atlas. Percent signal change data for selected regions of interest (ROI) from the dorsal anterior [dACC], middle [MCC] cingulate cortex, anterior insula [aINS]/ventrolateral prefrontal cortex [VLPFC], VLPFC, temporal gyrus [TPJ] posterior medial cortex [PMC] (not pictured on these representative sections), premotor cortex [PMOT], visual cortex [Vis], posterior insula [pINS] and parahippocampal gyrus [PHpc] are presented in Panel B. Box-andwhiskers plots for Controls (red) and UUI (blue) represent total PSC from the infuse phase
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Figure 2.
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Functional connectivity analyses were performed with selected regions from the bladder distention task (Figure 2) that included the left (L) anterior insula/ventrolateral prefrontal cortex (aINS/VLPFC), right (R) VLPFC, and the middle cingulate cortex (MCC). Each panel is color coded to display regions of increased (p < 0.005: dark blue; p < 0.001: light blue) or decreased (p < 0.005: red; p < 0.001: yellow) connectivity for patients with urinary urgency incontinence (UUI) relative to Controls. Locations of the sagittal (X) and axial (Z) slices are given according to the Talairach atlas for the left (L) and right (R) hemispheres. The left inferior parietal lobe (IPL; Panel A) and left paracentral lobule (PCL; Panel B) exhibited significant group differences for the L aINS/VLPFC and R VLPFC seeds, respectively. The MCC seed (Panel C) resulted in group differences for both the left dorsolateral prefrontal cortex (DLPFC) and the right VLPFC. Fisher’s z transformed correlation values are presented in box-and-whisker plots for Controls (red) and UUI (blue) for all regions.
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Table 1
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Abbreviations & Descriptions
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Term
Abbreviation
Description
Anterior Cingulate Cortex
ACC
Anterior portion of the cingulate gyrus located in the medial cerebral hemisphere, important in emotion and pain processing
Brodmann’s Area
BA
Cerebral cortical regions mapped based on cell architecture
Brain Oxygen Level Dependent
BOLD
FMRI sequence which detects local changes in blood oxygen levels caused by increased cerebral blood (hemodynamic response) at sites of increased neural activity.
Default Mode Network
DMN
Brain regions activated when mind is not engaged in cognitive tasks and deactivated during cognitive tasks; nodes include the ventromedial prefrontal cortex (PFC) and posterior cingulate cortex.
Dorsal Attention Network
DAN
Brain regions associated with focused attention on external stimuli responsible for goal directed “top-down” processing
Dorsolateral Prefrontal Cortex
DLPFC
Region in prefrontal cortex (PFC). A component of the executive control network and the dorsal attention network
Insula
INS
Cerebral cortical region within the lateral sulcus; an important component of the interoceptive system
Mid-Cingulate Cortex
MCC
Middle portion of cingulate gyrus located in the medial cerebral hemisphere; activated in emotion and pain processing as well as selection of motor response
Posterior Medial Cortex
PMC
Brain region including the precuneus and posterior cingulate; functions as the posterior node of the DMN
Regressor
“A hypothesized time course of BOLD activation caused by the manipulations of an independent variable or by another known source of variability”*
Ventral Attention Network
VAN
Brain regions activated in response to unexpected behavioral stimuli, a “bottom-up” network; includes the temporoparietal junction and ventral frontal/prefrontal cortex.
Ventrolateral Prefrontal Cortex
VLPFC
Brain region located in prefrontal cortex (PFC); a region which is part of the ventral attention network
*
Glossary in Huettel SA, Song AW, McCarthy G, eds. Functional Magnetic Resonance Imaging. Sunderland, MA: Sinauer Associates; 2014 G-12.
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Table 2
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Clinical Characteristics of Participants Controls (N=20)
Patients (N=53)
P value
Mean Age years (SD)
53.2 (5.8)
55.2 (10.8)
0.30*
Mean Body Mass Index in kg/m2 (SD)
25.9 (5.9)
30.1 (7.7)
0.02*
3 (15%)
13 (24.5%)
0.61**
Participant Characteristics
Mean Parity (%) 0
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1
2 (10%)
4 (5.5%)
2
10 (50%)
16 (30.2%)
3
5 (25%)
15 (28.3%)
4
–
4 (7.6%)
9
–
1 (1.9%)
3 (15)
8 (15.1)
1
6 (30)
16 (30.1)
2
11 (55)
29 (54.8)
SUI surgery
2 (10%)
9 (17.3%)
0.07**
Prolapse surgery
2 (10%)
5 (9.6%)
1.00**
Hysterectomy
5 (25%)
13 (25%)
1.00**
Cigarette smoker
2 (10%)
5 (9.4%)
1.00**
1.2 (1.4)
27.8 (6.4)
Controls* Motor Network
Right and Left Precentral Cortex *(Deactivation in Controls)
R: [49.9, −11.9, 35.2] L: [−50.9, −9.3, 29.1]
*
See Figure 1
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Table 4
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Resting Connectivity* Seed Point
Connected Site(s)
Center of Mass: [X, Y, Z]
Associated Network
Brodmann Areas (cluster volume)
Mid-Cingulate Cortex
Ventrolateral Prefrontal cortex [VLPFC] (right)
[43.5, 14.7, −6.0]
Ventral Attention (VAN)
13/22/38/47 (4565 μl)
Dorsolateral Prefrontal cortex (left)
[−36.9, 13.3, 41.5]
Dorsal Attention (DAN)
6/8/9 (1630 μl)
UUI Participants VLPFC (right)
Paracentral lobule Medial post central gyrus
[−9.7, −34.6, 53.9]
Somatosensory, Motor, Supplementary Motor
3/4/5/6/7/31 (3151 μl)
Inferior parietal lobule, Lateral post central gyrus
[−57.1, −32.6, 31.8]
Ventral Attention (VAN) Somatosensory
1/2/3/40 (6321 μl)
Controls Mid-Cingulate Cortex
Controls VLPFC (left)
Controls *
See Figure 2
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Am J Obstet Gynecol. Author manuscript; available in PMC 2017 October 01. Published in final edited form as: Am J Obstet Gynecol. 2016 October ; 215(4): 449.e1–449.e17. doi:10.1016/j.ajog.2016.04.056.
URGENCY URINARY INCONTINENCE AND THE INTEROCEPTIVE NETWORK: A FUNCTIONAL MRI STUDY Loren H. KETAI, MD1, Yuko M. KOMESU, MD1, Mr. Andrew B. DODD, MS2, Rebecca G. ROGERS, MD1, Mr. Josef M. LING, BA2, and Andrew R. MAYER, PhD.2 1University
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2Mind
of New Mexico Health Sciences Center, Albuquerque, New Mexico
Research Network, Albuquerque, New Mexico
Abstract Background—Treatment of urgency urinary incontinence has focused on pharmacologically treating detrusor overactivity. Recent recognition that altered perception of internal stimuli (interoception) plays a role in urgency urinary incontinence suggests that exploration of abnormalities of brain function in this disorder could lead to better understanding of urgency incontinence and its treatment.
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Objectives—1) To evaluate the relationship between bladder filling, perceived urgency and activation at brain sites within the interoceptive network in urgency urinary incontinence 2) To identify coactivation of other brain networks that could affect interoception during bladder filling in urgency incontinence 3) To demonstrate interaction between these sites prior to bladder filling by evaluating their resting state connectivity Study Design—We performed an observational cohort study using functional magnetic resonance imaging to compare brain function in 53 women with urgency urinary incontinence and 20 Controls. Whole-brain voxel-wise ANCOVAs were performed to examine differences in functional brain activation between groups during a task consisting of bladder filling, hold (static volume) and withdrawal phases. The task was performed at three previously established levels of baseline bladder volume, the highest exceeding strong desire to void volume. All women continuously rated their urge on a 0–10 point Likert scale throughout the task and a mixed measures ANOVA was used to test for differences in urge ratings. Empirically derived regions of interest from analysis of activation during the task were used as seeds for examining group differences in resting state functional connectivity.
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Results—In both urgency urinary incontinent participants and Controls changes in urge ratings were greatest during bladder filling initiated from a high baseline bladder volume and urgency incontinent participants’ rating changes were greater than Controls. During this bladder filling phase urgency incontinent participant’s activation of the interoceptive network was greater than
Corresponding Author: Yuko M Komesu MD University of New Mexico Health Sciences Center Department of Obstetrics and Gynecology MSC 10 5580 1 University of New Mexico Albuquerque, New Mexico 87131-0001, U.S.A. Phone: +1-505-272-9712, Fax: +1-505-272-1336, [email protected]. This work was presented at the American Urogynecologic Society’s Pelvic Floor Disorder’s Week Conference (formerly the American Urogynecologic Society’s 36th Annual Scientific Meeting), October 15–17, 2015, Seattle, Washington and at the International Urogynecologic Society Meeting, Nice, France, June 2015.
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Controls, including in the left insula and the anterior and middle cingulate cortex. Urgency Incontinent Participant’s activation was also greater than Controls at sites in the Ventral Attention Network and Posterior Default Mode Network. Urgency incontinent participant’s connectivity was greater than Controls between a middle cingulate seed point and the Dorsal Attention Network, a “top down” attentional network. Control connectivity was greater between the mid-cingulate seed point and the Ventral Attention Network, a “bottom up” attentional network,
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Conclusions—Increasing urge was associated with greater urgency incontinent participant than Control activation of the interoceptive network and activation in networks that are determinants of self-awareness (Default Mode Network) and of response to unexpected external stimuli (Ventral Attention Network). Differences in connectivity between interoceptive networks and opposing attentional networks (Ventral Attention Network versus Dorsal Attention Network) were present even before bladder filling (in the resting state). These findings are strong evidence for a central nervous system component of urgency urinary incontinence that could be mediated by brain directed therapies. Keywords attentional and interoceptive networks; brain activation and networks; fMRI; resting state functional connectivity; urgency urinary incontinence in women
Introduction
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Urgency urinary incontinence (UUI), involuntary urine loss associated with urgency,1 affects millions of women daily and significantly impairs their quality of life. Treatment of UUI with medications has focused on mediating detrusor overactivity and resulting incontinence. Compliance with these medications is limited by frequency of their side-effects relative to the frequency of their therapeutic success.2 Recognition that altered perceptual awareness plays a role in UUI suggests that an alternative approach, addressing abnormalities in brain function, may have a role in UUI treatment.3 Women with urgency incontinence manifest abnormal activation of portions of the brain that govern interoception, the perception and interpretation of physiologic stimuli arising within the body.4 These abnormalities, and the effect they have on other regions in the brain, likely modulate abnormal storage in UUI.5,6 Abnormalities in interoception also have the potential to modify urge perception which may be important in the genesis or persistence of UUI.
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Most investigation of abnormal brain activation relies on functional MRI (fMRI) performed using blood oxygen level dependent (BOLD) contrast imaging. FMRI can assess localized brain activity that occurs in response to administered stimuli or prompted tasks. Areas of the brain that show coherent neural activation and deactivation, are described as demonstrating “functional connectivity”, and together constitute “functional networks”. The definition of functional networks, based on temporal correlations of brain activation, has proven a very robust technique, demonstrating reproducible spatial localization of these networks among many populations.7,8
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Each functional network interconnects spatially distinct areas of the brain that together implement a unique component of cognition.9,10. Individual networks have been identified as having nodes at consistent anatomical sites. Representative nodes include those in the interoceptive network (anterior cingulate cortex, insula), dorsal attention network (dorsolateral prefrontal cortex or “frontal eye fields”), the ventral attention network (ventrolateral prefrontal cortex and temporoparietal junction) and the default network (medial temporal lobe, posterior cingulate cortex) (Table 1).7,8,11
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Pioneering fMRI work by Griffiths reported increased activation of the interoceptive network, including the insula and anterior cingulate cortex (ACC), in response to bladder filling among UUI patients.4 Within the interoceptive network the insula functions as the key switching center for processing visceral sensation while the cingulate cortex, is responsible for integrating emotional context with interoception.12 Similar abnormalities of interoceptive network activation are seen in patients with fibromyalgia and irritable bowel syndrome (IBS), diseases sometimes termed “hypervigilant” states.13,14 In hypervigilant states, interoceptive network activation is heightened and its connectivity to other neural networks is altered.15
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More complete understanding of how “hypervigilant” changes in brain function affect urge perception may help guide therapy that is directed towards the brain rather than the bladder. We sought a unique approach that would evaluate the relationship between changing bladder volumes and both interoceptive network activation and perceived urge. We also sought to identify coactivation of executive control networks in the prefrontal cortex (PFC) that could affect perception by interacting with the interoceptive network. Other hypervigilant states demonstrate both altered brain activation in response to stimuli and altered patterns of fluctuations in BOLD signal while the individual is at rest. Those brain regions which demonstrate similar fluctuations in BOLD signal over time during rest are considered as having resting state functional connectivity.7,8,9,10 These resting fluctuations in signal within a functional network can be much greater in magnitude than changes in a specific brain region during a task or stimulus and, therefore, can provide much greater signal to noise.7 Accordingly, after identifying sites in the brain that were activated during increased urge we sought to evaluate resting state functional connectivity between those specific sites and functional networks. In order to accomplish this, as far as we know, we compared the largest cohort of UUI participants and comparably aged controls yet published.16,17
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We hypothesized that UUI participants would experience increased activation of the interoceptive network in response to bladder filling relative to Controls and that this activation would be accompanied by increased urge. We also hypothesized that the pattern of prefrontal cortex (PFC) executive control network co-activation with the interoceptive network would differ between UUI participants and Controls. Last, we hypothesized that sites of altered interoceptive activity in UUI would also show altered resting state functional connectivity. Identification of differences in brain activation and functional connectivity in women with UUI would identify aspects of brain function that might be targeted by behavioral and other brain directed therapies, and provide a means to measure the efficacy of those therapies in treating this often refractory abnormality.
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Materials & Methods Participants
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The current study represents a sub-sample from an on-going randomized controlled trial comparing hypnotherapy versus pharmacotherapy for treatment of UUI (NCT01829425). Female participants were recruited from an academic urogynecology clinic and from the community at large between March 2013 and May 2015. UUI participants were nonpregnant woman ≥ 18 years old who; 1) had ≥3 urgency urinary incontinence episodes/week for ≥3 months 2) were without significant neurologic illness or pelvic organ prolapse beyond the hymen and 3) had OAB Awareness Tool scores ≥ 8).18 Both participants with UUI and Controls without UUI underwent bedside cystometrics at which time “strong desire to void” volumes, defined as bladder volumes eliciting a “persistent desire to pass urine without the fear of leakage,”10 were recorded. Controls were women between 46–80 years without UUI, with OAB Awareness Tool Scores 200 ml. Potential participants were excluded if they had contraindications to MRI. The University of New Mexico Institutional Review Board approved the study (#09–314) and all participants gave written informed consent. Fifty-six UUI participants and 23 Controls participated in this imaging study. Data for three UUI participants and three Controls were excluded secondary to acquisition issues or excessive head motion (3 times the inter-quartile range relative to their cohort based on frame-wise displacement).19 A total of 53 UUI participants and 20 Controls were included in the final functional task analysis. Clinical Assessment
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All participants completed a three day voiding diary and the OAB Awareness Tool questionnaire,18 and underwent cystometric testing. The OAB Awareness Tool (or OABv-8) is a validated screening tool for overactive bladder. Demographic and clinical data collection included ethnicity, race, age, parity, prior surgical history and body mass index (BMI). fMRI Scanner Tasks The fMRI task consisted of infusing the bladder with saline over 9 seconds (infuse phase), maintaining that volume over 19 seconds (hold phase), then withdrawing the same volume over 9 seconds (withdrawal phase). Task timing was maintained with Neurobehavioral Systems Presentation software. Specifically, a research nurse was given instructions over headphones along with a computerized timed count for all of the different task intervals (i.e. infusing and withdrawing fluids from bladder).
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Bladder filling and emptying volumes were determined based on participants’ strong desire volumes (See Supplement). The infuse/hold/withdraw cycle was repeated 6 times at low, medium and high fill (bladder) volumes (Supplement Figure 1). Because the task was designed to maximize urge but avoid incontinence, only bladder filling during the high volume infusion exceeded the strong desire to void volume in the majority of participants. Participants continuously (100 Hz sampling frequency) rated their urinary urge using a nonferrous key-press device positioned directly under their right hand. Urge levels were rated on
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a 11-point Likert scale (0 = “no urge” to 10 = “severe urge”) and were recorded real time during all phases of the scan (fill, hold and phase). To minimize neuronal activation associated with eye movements, subjects were instructed to maintain visual fixation throughout all trials on the centrally presented cross. Three 2 × 3 [Group × Phase] mixed measures ANOVA were used to test for differences in three direct measures of urge ratings. These were 1) the maximum rating 2) the dynamic range of ratings (maximum – minimum) and 3) the number of changes in subjective urge ratings during each phase of the task. Resting state connectivity data collection was performed with the participant’s bladder empty prior to the bladder filling task. During that time participants passively stared at a white cross for 5 minutes. Three additional UUI and one Control were motion outliers on resting state fMRI and were excluded from connectivity analysis.
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MR Imaging & Statistical Analysis
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T1-weighted echo planar images were collected on a 3T Siemens Trio Tim scanner. (See Supplement). Functional maps were calculated using FSL and AFNI. Time series images were first de-spiked, temporally interpolated to correct for slice-time acquisition differences, and spatially registered in two and three dimensional space to the second EPI image of the first run to minimize effects of head motion. The baseline EPI image (i.e., used for motion correction) was then aligned with the native T1 image using an affine transformation, followed by an affine alignment of the native T1 image to Talairach space. These two matrices were then concatenated and applied to functional data. Time-series data were subsequently blurred using a 6mm Gaussian full-width half-maximum filter. Deconvolution was used to generate a single hemodynamic response function for the entire bladder filling task relative to baseline. Specifically, the hemodynamic response was modelled from the onset of the infuse phase through withdrawal, plus 3 seconds to capture the return to baseline state (total time = 44 seconds or 22 images) (Supplement Figure 2). A separate urge regressor (definition Table 1) was calculated by convolution to capture neuronal changes uniquely associated with changes in urge across all phases.
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Three whole-brain voxel-wise ANCOVAs were performed to examine differences in functional activation across groups for each fill condition. The first factor corresponded to group (UUI vs. Controls), whereas the second factor corresponded to the number of modelled time-points in each phase (See Supplement). Group and the Group × Time interaction were the effects of interest in this statistical framework. An additional voxel-wise t-test was performed to detect differences in activation corresponding to the urge regressor. All functional results were corrected for false positives at p < 0.05 (p < 0.005; minimum cluster size = 1472 μl) based on 10,000 Monte-Carlo simulations). Although analysis of intergroup differences is by necessity complex, our prior work allowed for approximation of the necessary sample size. Results from prior evaluation of fMRI during bladder filling in OAB participants suggested that differences in BOLD signal between UUI participants and controls would yield an effect size of 0.8 (Cohen’s d)20. An allocation ratio of participants to controls of 3:1 was chosen to provide adequate samples size for subsequent pre-post treatment evaluation of fMRI in UUI participants, which is the specific aim of the previously described parent study. Assuming an effect size of 0.8 and a Am J Obstet Gynecol. Author manuscript; available in PMC 2017 October 01.
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participant to control allocation of 3:1, a group of 20 controls and 50 participants would achieve a power of 0.80 for detecting intergroup differences (alpha = .05) in percent signal change at an priori regions of interest (ROIs). Empirically derived regions of interest from analysis of activation were used as seed points for resting state functional connectivity analysis examining group differences in functional connectivity. Correlations were calculated between the time course of activation in these regions and the time course of activation in other brain sites. ROIs and brain sites showing increased connectivity were assigned to corresponding brain network based previously reported Talairach spatial coordinates (as defined by the brain’s anterior and posterior commissures) or Brodmann areas (defined by brain cytoarchitecture)7,9,21
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Clinical Measures By design, UUI and Control participant’s age, parity, and degree of prolapse did not differ (Table 2), nor did they differ by race or ethnicity (P>.05). BMI differed between UUI participants and Controls (p = 0.02). As expected, voiding diaries, OAB Awareness Scores and cystometric findings also differed between groups (Table 2). Urge Rating Results for High Fill Volumes
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The main effect of Group was significant for the maximum urge rating (p = .006), with UUI participants exhibiting higher overall ratings (7.4±2.1) relative to Controls (5.6±3.1). This occurred despite absence of significant differences between controls and participants in the number of changes in urge ratings (frequency of button pushes) (p > 0.10). A 2 × 6 [Group × Task Cycle] mixed measures ANOVA also showed no main effect of task cycle or interaction between group and cycle, indicating that habituation to stimuli did not play a role in fill ratings from either group (p > 0.10). The main effect of phase was significant for all three urge measures (all p< 0.001). Simple effects tests indicated the largest dynamic range of ratings and greatest number of rating changes occurred during infuse (I) compared to withdrawal (W) or hold (H) phases (I [3.7±2.1]>W [2.3±1.8]>H [1.7±1.1]) and (I [4.0±2.5]>(H [2.3±1.9] ≈ W [2.4±2.1]). The highest maximal urge rating occurred during hold phase (H [7.5±2.6]>I [6.5±2.6]>W [6.8±2.6]) (See Supplement Figure 3). Urge Rating Results for Medium and Low Bladder Fill Condition Volumes
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Urge ratings for low and medium bladder fill volumes demonstrated group and phase differences similar to the high bladder fill volumes. UUI participants recorded higher overall urge rating than Controls. The maximal dynamic range of urge sensation and the number of changes in urge sensation was greatest during the infuse phase of the task (See Supplement). FMRI Results from High Volume Bladder Filling Task Functional results from the whole-brain voxelwise 2 × 6 [Group × Time] ANCOVA for the infuse phase during high fill volumes demonstrated increased activation in UUI participants relative to deactivation in Controls across multiple brain networks (Figure 1). Specifically, increased activation was observed in the interoceptive network, ventral attention network
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(VAN), and the posterior default mode network (DMN). Interoceptive network activation occurred in the dorsal ACC; middle cingulate cortex (MCC) extending into the right posterior cingulate cortex (PCC); and left anterior insula/ventrolateral prefrontal cortex (VLPFC), which spanned both the interoceptive and VAN (Table 3). Additional activation sites within the VAN included the right VLPFC; right and left temporoparietal junction (TPJ). Posterior DMN activation occurred in the posterior medial cortex within both the right and left hemisphere, and included both the precuneus and PCC. Miscellaneous other areas of greater activation in UUI participants also occurred (Table 3). There was no significant Group × Time interaction.
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For the hold phase, there was no significant effect of Group or a Group × Time interaction. For the withdrawal phase, the main effect of Group indicated deactivation for Controls relative to near baseline levels in UUI participants within the bilateral precuneus (Supplement Figure 4). There was no significant Group × Time interaction for the withdrawal phase at the high fill volumes. Results from low and medium fill volumes are presented in Supplementary Materials. Urinary Urge Regressor Analysis A whole-brain analysis of differences in activation associated with the urge regressor indicated differences between groups confined to the right and left precentral gyrus including the primary motor cortex (Supplement Figure 5). Controls showed deactivation in these areas while UUI participants remained near baseline (Table 3). Resting State Functional Connectivity Analysis
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Group activation differences during the infuse phase within the MCC, right VLPFC, left VLPFC, and dACC served as empirical seeds for connectivity analyses. Results indicated no significant differences in connectivity between groups for the ACC seed. For the MCC seed, UUI participants showed a positive correlation with the left dorsolateral prefrontal cortex (DLPFC)/premotor cortex which was absent in Controls. In contrast, Controls exhibited a positive correlation between MCC and the right VLPFC extending into the insula which was absent in UUI participants. Controls showed significantly greater connectivity than UUI participants between VLPFC seeds and several other cortical sites (Figure 2, Table 4).
Comments Brain Activation
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An important goal of this study was to investigate the effect of bladder filling on the perception of urge and activation of the interoceptive and associated neural networks in UUI participants compared to Controls. Our results indicate increased activation within the interoceptive network, including the ACC, MCC and left anterior insula, for UUI participants relative to Controls. Results also identified concurrent activation in two additional networks. In general terms these networks, the DMN and VAN are respectively determinants of self-awareness and of response to unexpected external stimuli.9, 10
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Differential activation of the interoceptive network was only observed when the bladder was filled above strong desire to void volumes. The absence of group differences in brain activation at low and medium (bladder) fill volumes is consistent with Griffith’s work demonstrating that abnormal brain activation in UUI increases markedly only as strong desire volumes are approached.4 The observation that neural activation occurred only during the filling phase is novel, though the mechanism underlying the finding is unknown. Possibilities including plateauing of mediator (e.g. ATP) release within the bladder once filling has ceased and alteration of CNS processing of bladder sensation when afferent signal from the bladder stabilizes.22
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Activation within the interoceptive network included the ACC and the contiguous MCC. This co-occurring activation of the ACC/MCC may represent both the affective component of urinary urge and cognitive initiation of the efferent motor response. The latter can be facilitated by the close association of the MCC with the supplementary motor area which activates during voluntary contracture of the pelvic floor musculature, a response that can be used to maintain continence.3,23 Among UUI participants, components of the interoceptive network were accompanied by activation of the bilateral VLPFC and TPJ. The latter are components of the VAN, a “bottom-up” attentional system which detects unexpected stimuli and triggers attentional shifts.24,25 Increased activation of the VAN has been reported in IBS and in anxiety disorders where it may be responsible for increased stimulus-driven attention.26, 27 Thus, increased activation within the VLPFC in UUI may indicate an abnormally strong orienting response to bladder stimuli, subsequently accompanied by over-monitoring.
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Our data also show different activation patterns in Controls and UUI participants with respect to the posterior medial cortex, specifically the PCC and precuneus which constitute the posterior node of the DMN. Normally the DMN is activated during the resting state, such as when individuals engage in self-reflection, self-awareness or introspective mental imagery. It is deactivated when cognition is oriented toward a task.28,29,30 In contrast to the expected deactivation during the bladder filling task, among UUI participants the posterior node of the DMN activated during bladder filling and remained near baseline during bladder emptying. In patients with IBS and in patients with urologic pelvic pain syndrome similar abnormal posterior DMN activation has been linked to increased connectivity between the posterior node of the DMN and the interoceptive network.31,32 This may represent a mechanisms by which perceptions of physiologic states manifest an abnormal effect on patients’ self-awareness.33
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Urge ratings data show that changes in perceived urge were greatest during bladder infusion, the only phase during which group differences in brain activation occurred. Despite higher overall urge ratings during the hold phase no group differences in activation were observed while bladder volumes were static. These findings suggest that change in urge, rather than static bladder distension, drives activation of the interoceptive and VAN in UUI.
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Resting State Functional Connectivity
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An important goal of this study was to evaluate resting state functional connectivity in women with UUI compared to Controls. Earlier work evaluating connectivity in UUI analyzed group differences in task-related rather than resting state connectivity.17 Fluctuations in resting signal are much greater in magnitude than task related fluctuation and provide a 3:1 improvement in signal to noise.7 Analysis of resting state functional connectivity benefits from this improved signal to noise ratio. Only one prior work has addressed resting state functional connectivity in UUI, assessing connectivity in over 50 brain sites (seed points) in 16 participants with UUI.16 That study successfully demonstrated numerous areas of connectivity, but did not attempt to relate connectivity to specific functional networks.
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In contrast to the prior work we focused our study on connectivity between a small number of empirically derived seed points. When evaluated with this focused analysis Controls showed increased resting state functional connectivity between the MCC and the right VLPFC relative to UUI. Controls also demonstrated increased connectivity and between the VLPFC and somatosensory and motor cortices. In contrast UUI showed greater connectivity between the MCC and DLPFC. The DLPFC is a component of dorsal attentional networks (DAN), which mediates “top down” voluntary allocation of attention. Increased connectivity between the DAN and interoceptive cortex has been demonstrated in patients with fibromyalgia.34 This increased connectivity to the DAN may indicate “top down” support for goal directed orientation (e.g. maintaining continence). Subsequent activation of the VLPFC in UUI during bladder filling would then represent inability of the DAN to maintain “top down” goal directed focus in the face of “bottom up” VAN mediated reorientation to the stimulus of bladder filling.35
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Limitations
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Although we were able to demonstrate differences in PFC activation in UUI we were not able to demonstrate the deactivation in the medial PFC which has been demonstrated in Griffith’s and Tadic’s work.3 In their model, deactivation of the medial PFC represents suppression of micturition by an executive control function of the brain. It is possible that the rapid filling of the bladder in our model altered the response from the PFC, increasing “bottom up” input from the VLPC at the expense of “top down” input from other sites. Alternatively the absence of medial PFC deactivation may reflect failure to induce urgency. Last, it is also possible that Griffith’s method of assessing brain activation, subtracting withdrawal phase BOLD signal from infuse phase BOLD signal may accentuate findings of deactivation. No deactivation of medial PFC is noted in Nardos’s study which used a method of signal assessment similar to ours. The absence of intergroup differences in the urge regressor is unlikely to be related mechanics of bladder filling, but may be caused by the mathematical model used. Despite the strong association between brain activation and direct measures of changing urge the regressor did not account for unique variation in BOLD signal. This may reflect lack of independence between the urge regressor and other regressors in the design matrix.
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Last, because participants were continuously rating their urge during the bladder filling task it is possible that group differences in the cognitive process of rating urge, rather than the sensation of urge itself, contributed to group differences in brain activation. Absence of group differences in the number of rating changes (frequency of button pushes) suggests that there were no group differences in the motor component of rating but does not exclude group differences in the cognitive component. Conclusion
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In summary, this study is the first to demonstrate that during bladder filling abnormal activation of the interoceptive network, VAN and DMN is concurrent with increased urgency in UUI. Analysis of more extensive resting state functional connectivity data than previously published also shows UUI to be associated with altered connectivity of these networks prior to bladder filling. These findings do not determine whether brain abnormalities are causal or a response to abnormal signaling from the bladder. Whether or not abnormal bladder signaling is the genesis of UUI, functional brain abnormalities likely accentuate UUI symptoms. In either case, therapies directed towards restoring normal function to the interceptive, attentional and default mode networks have the potential to mediate incontinence, urgency or both in UUI.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments Author Manuscript
Research reported in this publication was supported by the National Center for Complementary & Integrative Health of the National Institutes of Health under Award Number R01AT007171. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The study is registered with ClinicalTrials.gov; https://clinicaltrials.gov ID#: NCT01829425 Disclosures: Dr. Ketai & Dr. Komesu are Co-PIs for the NIH Award noted above (R01AT007171) and Dr. Mayer and Dr. Rogers are Co-Investigators for this same award. Dr. Rebecca Rogers: DSMB chair for the TRANSFORM trial sponsored by ASTORA; royalties from UPtoDate and McGraw Hill for scientific writings
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Figure 1.
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Panel A presents differences in activation between patients with urinary urgency incontinence (UUI) and Controls during the infuse phase of the high fill volume. The magnitude of p-values is denoted using dark blue (p < 0.005) and light blue (p < 0.001) coloring. Sagittal (X) and axial (Z) slice locations are given according to the Talaraich atlas. Percent signal change data for selected regions of interest (ROI) from the dorsal anterior [dACC], middle [MCC] cingulate cortex, anterior insula [aINS]/ventrolateral prefrontal cortex [VLPFC], VLPFC, temporal gyrus [TPJ] posterior medial cortex [PMC] (not pictured on these representative sections), premotor cortex [PMOT], visual cortex [Vis], posterior insula [pINS] and parahippocampal gyrus [PHpc] are presented in Panel B. Box-andwhiskers plots for Controls (red) and UUI (blue) represent total PSC from the infuse phase
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Figure 2.
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Functional connectivity analyses were performed with selected regions from the bladder distention task (Figure 2) that included the left (L) anterior insula/ventrolateral prefrontal cortex (aINS/VLPFC), right (R) VLPFC, and the middle cingulate cortex (MCC). Each panel is color coded to display regions of increased (p < 0.005: dark blue; p < 0.001: light blue) or decreased (p < 0.005: red; p < 0.001: yellow) connectivity for patients with urinary urgency incontinence (UUI) relative to Controls. Locations of the sagittal (X) and axial (Z) slices are given according to the Talairach atlas for the left (L) and right (R) hemispheres. The left inferior parietal lobe (IPL; Panel A) and left paracentral lobule (PCL; Panel B) exhibited significant group differences for the L aINS/VLPFC and R VLPFC seeds, respectively. The MCC seed (Panel C) resulted in group differences for both the left dorsolateral prefrontal cortex (DLPFC) and the right VLPFC. Fisher’s z transformed correlation values are presented in box-and-whisker plots for Controls (red) and UUI (blue) for all regions.
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Table 1
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Abbreviations & Descriptions
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Term
Abbreviation
Description
Anterior Cingulate Cortex
ACC
Anterior portion of the cingulate gyrus located in the medial cerebral hemisphere, important in emotion and pain processing
Brodmann’s Area
BA
Cerebral cortical regions mapped based on cell architecture
Brain Oxygen Level Dependent
BOLD
FMRI sequence which detects local changes in blood oxygen levels caused by increased cerebral blood (hemodynamic response) at sites of increased neural activity.
Default Mode Network
DMN
Brain regions activated when mind is not engaged in cognitive tasks and deactivated during cognitive tasks; nodes include the ventromedial prefrontal cortex (PFC) and posterior cingulate cortex.
Dorsal Attention Network
DAN
Brain regions associated with focused attention on external stimuli responsible for goal directed “top-down” processing
Dorsolateral Prefrontal Cortex
DLPFC
Region in prefrontal cortex (PFC). A component of the executive control network and the dorsal attention network
Insula
INS
Cerebral cortical region within the lateral sulcus; an important component of the interoceptive system
Mid-Cingulate Cortex
MCC
Middle portion of cingulate gyrus located in the medial cerebral hemisphere; activated in emotion and pain processing as well as selection of motor response
Posterior Medial Cortex
PMC
Brain region including the precuneus and posterior cingulate; functions as the posterior node of the DMN
Regressor
“A hypothesized time course of BOLD activation caused by the manipulations of an independent variable or by another known source of variability”*
Ventral Attention Network
VAN
Brain regions activated in response to unexpected behavioral stimuli, a “bottom-up” network; includes the temporoparietal junction and ventral frontal/prefrontal cortex.
Ventrolateral Prefrontal Cortex
VLPFC
Brain region located in prefrontal cortex (PFC); a region which is part of the ventral attention network
*
Glossary in Huettel SA, Song AW, McCarthy G, eds. Functional Magnetic Resonance Imaging. Sunderland, MA: Sinauer Associates; 2014 G-12.
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Table 2
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Clinical Characteristics of Participants Controls (N=20)
Patients (N=53)
P value
Mean Age years (SD)
53.2 (5.8)
55.2 (10.8)
0.30*
Mean Body Mass Index in kg/m2 (SD)
25.9 (5.9)
30.1 (7.7)
0.02*
3 (15%)
13 (24.5%)
0.61**
Participant Characteristics
Mean Parity (%) 0
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1
2 (10%)
4 (5.5%)
2
10 (50%)
16 (30.2%)
3
5 (25%)
15 (28.3%)
4
–
4 (7.6%)
9
–
1 (1.9%)
3 (15)
8 (15.1)
1
6 (30)
16 (30.1)
2
11 (55)
29 (54.8)
SUI surgery
2 (10%)
9 (17.3%)
0.07**
Prolapse surgery
2 (10%)
5 (9.6%)
1.00**
Hysterectomy
5 (25%)
13 (25%)
1.00**
Cigarette smoker
2 (10%)
5 (9.4%)
1.00**
1.2 (1.4)
27.8 (6.4)
Controls* Motor Network
Right and Left Precentral Cortex *(Deactivation in Controls)
R: [49.9, −11.9, 35.2] L: [−50.9, −9.3, 29.1]
*
See Figure 1
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Table 4
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Resting Connectivity* Seed Point
Connected Site(s)
Center of Mass: [X, Y, Z]
Associated Network
Brodmann Areas (cluster volume)
Mid-Cingulate Cortex
Ventrolateral Prefrontal cortex [VLPFC] (right)
[43.5, 14.7, −6.0]
Ventral Attention (VAN)
13/22/38/47 (4565 μl)
Dorsolateral Prefrontal cortex (left)
[−36.9, 13.3, 41.5]
Dorsal Attention (DAN)
6/8/9 (1630 μl)
UUI Participants VLPFC (right)
Paracentral lobule Medial post central gyrus
[−9.7, −34.6, 53.9]
Somatosensory, Motor, Supplementary Motor
3/4/5/6/7/31 (3151 μl)
Inferior parietal lobule, Lateral post central gyrus
[−57.1, −32.6, 31.8]
Ventral Attention (VAN) Somatosensory
1/2/3/40 (6321 μl)
Controls Mid-Cingulate Cortex
Controls VLPFC (left)
Controls *
See Figure 2
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