Changes in brain response to urgency before and after treatment of urgency urinary incontinence with onabotulinumtoxin A.

INTRODUCTION: To better understand the role of the brain in urgency urinary incontinence (UUI), we used onabotulinumtoxin A (BoNTA) as a probe to evaluate changes in the brain's response to urgency in successful and unsuccessful treatment. Because BoNTA acts peripherally, brain changes observed should represent a reaction to changes in bladder function caused by BoNTA, or changes in the brain's compensatory mechanisms, rather than a direct effect of BoNTA on the brain. METHODS: We recruited 20 women aged over 60 years with nonneurogenic UUI who were to undergo treatment with onabotulinum A toxin injected intravesically. We performed a baseline evaluation which included a 3-day bladder diary and functional magnetic resonance imaging with an urgency provocation task; we repeated this evaluation 6 weeks posttreatment. We performed an analysis of variance on a priori selected regions of interest and post hoc voxel-wise analysis on responders and nonresponders to treatment. RESULTS: We found a significant interaction in the right insula [F(1,18) = 5.5, p = 0.031]; activity was different during urgency provocation in responders and non-responders to therapy, before and after therapy. The supramarginal gyrus (SMG) and inferior frontal gyrus (IFG) also displayed significant interactions (p < 0.005). Activity in the periaqueductal gray and prefrontal cortex was correlated with number of leakage episodes (p < 0.05). CONCLUSION: The changes seen in the brain control mechanism after therapy likely reflect reduced bladder sensation caused by BoNTA's peripheral action. We ascribe the SMG and IFG changes to a coping mechanism for urgency which is reduced in those who respond well to treatment.

Testing a new, intensified infusion-withdrawal protocol for urinary urgency provocation in brain-bladder studies.

INTRODUCTION: The brain's role in bladder control has become an important area of study in the last 15 years. Typically, the brain's role in urinary urgency has been studied by repeated infusion and withdrawal of fluid, per catheter, to provoke urgency sensation during a whole brain magnetic resonance imaging (MRI) scan. Since this technique generally requires a large group size, we tested a more intense infusion-withdrawal protocol in an attempt to improve signal to noise ratio and repeatability of the signal which would, in turn, allow us to further probe subtypes of urgency urinary incontinence. METHODS: A total of 12 women over the age of 60 were recruited to test a new "intense" infusion withdrawal protocol. They underwent this new protocol during a functional brain MRI scan. The primary outcome was comparison of activity within the insula, medial pre-frontal cortex and dorsal anterior cingulate cortex/supplementary motor area (dACC/SMA). Immediate test-retest repeatability was measured using intraclass correlation. Secondary exploratory evaluation of differences in the whole brain between protocols was conducted. RESULTS: There was no significant difference in signal in any of the a priori regions of interest between protocols. Test-retest repeatability in the new protocol was poor compared to the original protocol, and variability was higher. Three participants were not able to tolerate the "intense" protocol. CONCLUSION: The small improvement in signal to noise ratio of the new protocol was not sufficient to overcome the poorly tolerated intense filling protocol.

Investigation of urinary storage symptoms in Parkinson's disease utilizing structural MRI techniques.

BACKGROUND: Lower urinary tract symptoms occur in 27% to 86% of patients with Parkinson's disease (PD), however, the mechanisms responsible for bladder dysfunction are not fully understood. This study utilized magnetic resonance imaging (MRI) to test the hypothesis that key brainstem bladder control areas (including the pontine micturition center and the pontine continence center (PCC) and their links with the basal ganglia are important in the development of urinary storage symptoms in PD. METHODS: Seventeen patients with PD completed a "bladder symptom questionnaire" and underwent diffusion-weighted MRI (1.5 T). Storage symptom severity and MRI measures of white matter microstructural integrity were correlated using tract-based spatial statistics. RESULTS: Mean diffusivity in the ventral brainstem correlated significantly with the bladder symptom severity in areas close to the predicted anatomical co-ordinates of the PCC. Tracts seeded from these regions passed via areas involved in pelvic floor musculature control and urinary voiding including the cerebellum, pallidum, and precentral gyrus. CONCLUSION: We used diffusion-weighted MRI to investigate the role of the brainstem and its structural connections in the development of urinary storage symptoms in PD. Our data suggest that the brainstem degenerative change in the vicinity of the PCC may be implicated in the pathogenesis of storage symptoms in these patients.

Do brain structural abnormalities differentiate separate forms of urgency urinary incontinence?

AIMS: Urgency urinary incontinence (UUI) is a major problem for seniors. The underlying mechanisms of disease and therapy are unknown. We sought structural brain abnormalities that might underlie the functional differences previously observed by functional Magnetic Resonance Imaging in UUI patients versus controls, or among UUI responders versus non-responders to therapy-and thereby reveal potential disease mechanisms and therapeutic targets. METHODS: Secondary study of a trial of biofeedback-assisted pelvic floor muscle training (BFB) in 60 women (>60 yrs) with UUI, plus 11 age-matched continent controls. Brain structural abnormalities were investigated using: (1) white-matter hyperintensities (WMH); (2) diffusion tensor imaging (DTI) to reveal white-matter pathways with impaired integrity; and (3) voxel-based morphometry (VBM) to show regions of atrophy or hypertrophy. RESULTS: WMH burden was greater in UUI patients than controls (globally and in superior longitudinal fasciculus and cingulum), suggesting a possible causal connection. WMH burden was unexpectedly greater in responders than non-responders to BFB, and appeared to increase in non-responders but not in responders. DTI revealed even worse integrity of the cingulum than was apparent by WMH. VBM showed parahippocampal atrophy in UUI. CONCLUSIONS: Many women with UUI have white-matter damage that interferes with pathways critical to bladder control; they can be taught by techniques like BFB to exert stronger control over the bladder. For others, in whom abnormalities of key brain areas are less marked, UUI's cause may reside elsewhere, and therapy targeting these brain centers may be less effective than therapy targeting the bladder or other brain centers.

Functional connectivity of the brain in older women with urgency urinary incontinence.

BACKGROUND: The brain's role in continence is critical but poorly understood. Although regions activated during bladder stimulation have been identified, little is known about the interaction between regions. In this secondary analysis we evaluate resting state and effective connectivity in older women treated for urgency urinary incontinence (UUI). METHOD: 54 women ≥60 years old with UUI and 10 continent women underwent fMRI scanning during provocation of urinary urgency, both before and after therapy. Response was defined by >50% reduction in leaks on bladder diary. Regions of interest (RoIs) were selected a priori: right insula, medial prefrontal cortex, and dorsal anterior cingulate cortex. Generalized psycho-physiological interaction (gPPI) was used to calculate "effective connectivity" between RoIs during urgency. We performed a one-way ANOVA pre-treatment between groups (continent/responders/non-responders), as well as a two-way mixed ANOVA between group and time (responders/non-responders; pre-/post-therapy) using false discovery rate (FDR) correction. Principal component analysis was used to assess the variance within RoIs. Exploratory voxel-wise connectivity analyses were conducted between each RoI and the rest of the brain. RESULTS: RoI-RoI connectivity analysis showed connectivity differences between controls, responders, and non-responders, although statistical significance was lost after extensive correction. Principal component analysis confirmed appropriate RoI selection. Voxel-wise analyses showed that connectivity in responders became more like that of controls after therapy (cluster-wise correction P < 0.05). In non-responders, no consistent changes were seen. CONCLUSION: These data support the postulate that responders and non-responders to therapy may represent different subsets of UUI, one with more of a central etiology, and one without.

Test-retest repeatability of patterns of brain activation provoked by bladder filling.

OBJECTIVE: To assess short-term repeatability of an fMRI protocol widely used to assess brain control of the bladder. fMRI offers the potential to discern incontinence phenotypes as well as the mechanisms mediating therapeutic response. If so, this could enable more targeted efforts to enhance therapy. Such data, however, require excellent test-retest repeatability. METHODS: Fifty-nine older women (age ≥60 years) with urgency incontinence underwent two fMRI scans within 5-10 min with a concurrent bladder infusion/withdrawal protocol. Activity in three brain regions relevant to bladder control was compared using paired t tests and intra-class correlation. RESULTS: There were no statistically significant differences in brain activity between the two consecutive scans in the regions of interest. Intra-class correlation was 0.19 in the right insula, 0.32 in the dorsal anterior cingulate cortex/supplementary motor area, and 0.44 in the medial pre-frontal cortex. Such correlations are considered fair or poor, but are comparable to those from studies of other repeated fMRI tasks. CONCLUSIONS: This is the first evaluation of the repeatability of a bladder fMRI protocol. The technique used provides a framework for comparing different fMRI protocols applied to brain-bladder research. Despite universal patient response to the stimulus, brain response had limited repeatability within individuals. Improvement of the investigational protocol should magnify brain response and reduce variability. These results suggest that although analysis of fMRI data among groups of subjects yields valuable insight into bladder control, fMRI is not yet appropriate for evaluation of the brain's role in continence on an individual level.

Brain Mechanisms Underlying Urge Incontinence and its Response to Pelvic Floor Muscle Training.

PURPOSE: Urge urinary incontinence is a major problem, especially in the elderly, and to our knowledge the underlying mechanisms of disease and therapy are unknown. We used biofeedback assisted pelvic floor muscle training and functional brain imaging (functional magnetic resonance imaging) to investigate cerebral mechanisms, aiming to improve the understanding of brain-bladder control and therapy. MATERIALS AND METHODS: Before receiving biofeedback assisted pelvic floor muscle training functionally intact, older community dwelling women with urge urinary incontinence as well as normal controls underwent comprehensive clinical and bladder diary evaluation, urodynamic testing and brain functional magnetic resonance imaging. Evaluation was repeated after pelvic floor muscle training in those with urge urinary incontinence. Functional magnetic resonance imaging was done to determine the brain reaction to rapid bladder filling with urgency. RESULTS: Of 65 subjects with urge urinary incontinence 28 responded to biofeedback assisted pelvic floor muscle training with 50% or greater improvement of urge urinary incontinence frequency on diary. However, responders and nonresponders displayed 2 patterns of brain reaction. In pattern 1 in responders before pelvic floor muscle training the dorsal anterior cingulate cortex and the adjacent supplementary motor area were activated as well as the insula. After the training dorsal anterior cingulate cortex/supplementary motor area activation diminished and there was a trend toward medial prefrontal cortex deactivation. In pattern 2 in nonresponders before pelvic floor muscle training the medial prefrontal cortex was deactivated, which changed little after the training. CONCLUSIONS: In older women with urge urinary incontinence there appears to be 2 patterns of brain reaction to bladder filling and they seem to predict the response and nonresponse to biofeedback assisted pelvic floor muscle training. Moreover, decreased cingulate activation appears to be a consequence of the improvement in urge urinary incontinence induced by training while prefrontal deactivation may be a mechanism contributing to the success of training. In nonresponders the latter mechanism is unavailable, which may explain why another form of therapy is required.

International Continence Society guidelines on urodynamic equipment performance.

These guidelines provide benchmarks for the performance of urodynamic equipment, and have been developed by the International Continence Society to assist purchasing decisions, design requirements, and performance checks. The guidelines suggest ranges of specification for uroflowmetry, volume, pressure, and EMG measurement, along with recommendations for user interfaces and performance tests. Factors affecting measurement relating to the different technologies used are also described. Summary tables of essential and desirable features are included for ease of reference. It is emphasized that these guidelines can only contribute to good urodynamics if equipment is used properly, in accordance with good practice.

The neural control of micturition.

Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

Brain responses to bladder filling in older women without urgency incontinence.

AIMS: To investigate normal brain responses to bladder filling, especially when there is little or no sensation as in much of daily life. METHODS: We performed an functional magnetic resonance imaging (fMRI) study of brain responses to bladder filling in normal female subjects, evoked by infusion and withdrawal of fluid in and out of the bladder. Using the contrast (infusion-withdrawal), we imaged brain activity at small bladder volumes with weak filling sensation and also with full bladder and strong desire to void. RESULTS: Eleven women, average age 65 years (range: 60-71 years) were included. With full bladder and strong desire to void, filling provoked a well-known pattern of activation near the right insula and (as a trend) in the dorsal anterior cingulate cortex and supplementary motor area. There was no significant deactivation. With small bladder volume filling provoked widespread apparent deactivation and no significant activation. Apparent deactivation was associated with increased fMRI signal during withdrawal rather than decrease during infusion, suggesting artifact. A correction for global changes in cerebral blood flow eliminated it and revealed significant subcortical activation, although none in frontal or parietal cortex. CONCLUSIONS: In older women with normal bladder function, infusion into an already full bladder resulted in strong sensation and brain activation near the insula and in the dorsal anterior cingulate/supplementary motor complex. With near-empty bladder and little sensation, the situation during much of daily life, these cortical areas were not detectably activated, but activation in midbrain and parahippocampal regions presumably indicated unconscious monitoring of ascending bladder signals.

What predicts and what mediates the response of urge urinary incontinence to biofeedback?

AIMS: To better target a behavioral approach for urge urinary incontinence (UUI) and enhance its efficacy by (1) identifying predictors of response to biofeedback-assisted pelvic muscle training (BFB), and (2) determining factors that mediate response. METHODS: BFB (four biweekly visits) was administered to 183 women > 60 years (mean = 73.6). Before and after intervention, all underwent comprehensive evaluation and videourodynamic testing. Postulated predictors and mediators from four urodynamic domains, specified a priori, were correlated with reduction in UUI frequency. RESULTS: Median UUI frequency decreased from 3.2/day to 1/day (P =0.0001). UUI improved by ≥50% in 55% of subjects and by 100% in 13% of subjects. Frequent UUI predicted poor response (P < 0.01). Of the urodynamic parameters, only high amplitude and briskness of detrusor overactivity (DO) predicted decreased response (P < 0.05 and P < 0.01) and these could be measured only in the 43% of subjects with elicitable DO. Decreased DO elicitability was the only urodynamic variable that changed in concert with improvement and thus was a candidate mediator. Response was neither predicted nor mediated by proprioception/warning, cystometric capacity, detrusor contractility, sphincter strength, or baseline DO elicitability. CONCLUSIONS: Severe DO predicts poor response to BFB. Good response is mediated by reduction in DO elicitability. Other than baseline UUI frequency, there are no other clinically or urodynamically important predictors or mediators of BFB response in this population. BFB may be best for patients with less severe DO. Future research to enhance its efficacy might better focus on the brain than on the lower urinary tract.

Brain activity underlying impaired continence control in older women with overactive bladder.

AIMS: To identify, in subjects with overactive bladder (OAB), differences in brain activity between those who maintained and those who lost bladder control during functional magnetic resonance imaging (fMRI) of the brain with simultaneous urodynamics. METHODS: Secondary analysis of a cohort of older women (aged >60) with proven urgency urinary incontinence, who, in the scanner, either developed detrusor overactivity and incontinence (the "DO group") or did not (the "no DO" group). A priori hypothesis: during urgency provoked by bladder filling, without DO, activity in regions related to continence control is diminished in the DO group; specifically (1a) less activation in supplementary motor area (SMA) and (1b) less deactivation in prefrontal cortex (PFC) and parahippocampal complex (PH). We also explored phenotypic (clinical and urodynamic) differences between the groups. RESULTS: During urgency preceding DO, the DO group showed stronger activation in SMA and adjacent regions (hypothesis 1a rejected), and less deactivation in PH but no significant difference in PFC (hypothesis 1b partially accepted). These subjects were older, with more changes in brain's white matter, decreased tolerance of bladder filling and greater burden of incontinence. CONCLUSIONS: (1) In older women with OAB, brain activity in the SMA is greater among those with more easily elicitable DO, suggesting a compensatory response to failure of control elsewhere. (2) OAB is heterogeneous; one possible phenotype shows severe functional impairment attributable partly to age-related white matter changes. (3) Functional brain imaging coupled with urodynamics may provide CNS markers of impaired continence control in subjects with OAB.

Use of functional imaging to monitor central control of voiding in humans.

Bladder problems are frequently disorders of control, which is exercised from the brain. In such disorders, brain responses to bladder events are abnormal; therapy is accompanied by regional changes that may be measured by functional imaging and used to monitor the effect of treatment. The regional responses may be understood in terms of a tentative model of the bladder control system. The model helps also to interpret alterations in brain behavior (as imaged by functional scanning) that occur when afferent signals from bladder or urethra are changed experimentally or by an underlying disorder or treatment, for example, overactive bladder (urge/urgency incontinence). Successful treatment may either increase the ability to cope with the problem or may be curative. The direction of treatment-induced change of abnormal brain responses can distinguish these two possibilities and shed light on the therapeutic mechanism. In addition, brain activity in regions such as insula or dorsal anterior cingulate cortex may be regarded as a proxy for sensations such as desire to void or urgency, which are otherwise difficult to define or measure. Monitoring of brain responses in these regions offers an obvious way to test the effect of drugs.

Brain activity during bladder filling is related to white matter structural changes in older women with urinary incontinence.

Evidence from longitudinal studies in community-dwelling elderly links complaints of urgency and urinary incontinence with structural white matter changes known as white matter hyperintensities (WMH). How WMH might lead to incontinence remains unknown, since information about how they relate to neural circuits involved in continence control is lacking. The aim of this study was to investigate the role of WMH in altered brain activity in older women with urgency incontinence. In a cross-sectional study, we measured WMH, globally and in specific white matter tracts, and correlated them with regional brain activity measured by fMRI (combined with simultaneous urodynamic monitoring) during bladder filling and reported 'urgency'. We postulated that increase in global WMH burden would be associated with changes (either attenuation or reinforcement) in responses to bladder filling in brain regions involved in bladder control. Secondly, we proposed that such apparent effects of global WMH burden might be specifically related to the burden in a few critical white matter pathways. The results showed that regional activations (e.g. medial/superior frontal gyrus adjacent to dorsal ACG) and deactivations (e.g. perigenual ACG adjacent to ventromedial prefrontal cortex) became more prominent with increased global WMH burden, suggesting that activity aimed at suppressing urgency was augmented. Secondary analyses confirmed that the apparent effect of global WMH burden might reflect the presence of WMH in specific pathways (anterior thalamic radiation and superior longitudinal fasciculus), thus affecting connections between key regions and suggesting possible mechanisms involved in continence control.

Brain activity measured by functional magnetic resonance imaging is related to patient reported urgency urinary incontinence severity.

PURPOSE: We investigated the relationship between experimental neuroimaging and self-reported urinary incontinence measures. MATERIALS AND METHODS: We evaluated 14 functionally independent, community dwelling women older than 60 years with moderate to severe urgency urinary incontinence. All underwent detailed clinical assessment (3-day bladder diary, 24-hour pad test and quality of life assessment), urodynamic testing and functional brain scanning. Brain activity during reported urgency was assessed using a method that combines functional magnetic resonance imaging with simultaneous urodynamic monitoring during repeat bladder filling/emptying cycles. We used the statistical parametric mapping program SPM2 (http://www.fil.ion.ucl.ac.uk/spm/spm2.html) to correlate brain activity with relevant clinical covariates, including the number of urgency incontinent episodes, amount of urine leakage and psychological burden as assessed by the Urge Impact Scale questionnaire. RESULTS: Activity in rostral and subgenual anterior cingulate gyrus, insula, inferior frontal gyrus, orbitofrontal cortex, dorsal and posterior cingulate gyrus, parahippocampus, cuneus and parts of parietotemporal lobe correlated positively with daytime incontinence frequency and urine loss. Different brain regions correlated with the psychological burden and the associations were inverse, that is precuneus/cuneus and posterior cingulate gyrus, and superior temporal, supramarginal and transverse gyrus. CONCLUSIONS: As provoked by bladder filling, regional brain activity in the setting of self-reported urgency correlates significantly with incontinence severity in daily life and the associated psychological burden. Thus, observations made under experimental conditions correlate with patient real-life experience and suggest neural correlates of urgency incontinence symptoms that could serve as potential targets for future investigations.

A functional magnetic resonance imaging study of the effect of sacral neuromodulation on brain responses in women with Fowler's syndrome.

STUDY TYPE: Aetiology (case series). LEVEL OF EVIDENCE: 4. OBJECTIVE: To examine brain responses to bladder filling in young women with Fowler's syndrome (FS, a sphincter abnormality manifested by impaired voiding and bladder sensation), treated with sacral neuromodulation (SNM). PATIENTS AND METHODS: Six women, aged 18-39 years with FS underwent functional brain magnetic resonance imaging (fMRI) immediately after SNM and when untreated (baseline). Data were collected at four sessions: after SNM with an empty and a full bladder, and at baseline with an empty and a full bladder. In each session, 280 whole-brain scans were acquired while repeatedly infusing and withdrawing 50 mL of saline, using push-buttons to report changing desire to void. Data were analysed using Statistical Parametric Mapping. RESULTS: At baseline with an empty bladder, extensive responses (contrast = infusion-withdrawal) were almost exclusively negative ('deactivations'), e.g. in the right insula, seat of visceral sensation. Increased bladder volume and/or SNM treatment reduced deactivations and strengthened normal (positive) responses, e.g. in the periaqueductal grey (PAG) terminus of ascending spinal afferents. At baseline, there was significant correlation of brain responses with maximum urethral closure pressure. CONCLUSION: These data show that brain responses to bladder filling are abnormal in FS. The explanation for this that best explains the evidence is that the primary abnormality is an overactive urethra that generates abnormally strong inhibitory afferent signals, so effectively blocking bladder afferent activity at the sacral level and deactivating the PAG and higher centres, with consequent loss of bladder sensation and ability to void. Apparently, a normal mechanism for suppression of incontinence involving the striated urethral sphincter becomes exaggerated in FS and prevents voiding. SNM seems to act at the sacral level, by blocking inhibition by urethral afferents.

A decade of functional brain imaging applied to bladder control.

Over the last 10 years functional brain imaging has emerged as the most powerful technique for studying human brain function. Although the literature is now vast, including studies of every imaginable aspect of cortical function, the number of studies that have been carried out examining brain control of bladder function is relatively limited. Nevertheless those that have been reported have transformed our thinking. This article reviews that development in the context of emerging ideas of interoception and a working model of brain activity during bladder filling and emptying is proposed. Some studies have also been carried out using functional imaging methods to examine pathophysiological bladder conditions or the effect of treatments and these are reviewed and future work anticipated.

Cerebral control of the lower urinary tract: how age-related changes might predispose to urge incontinence.

Loss of bladder control (urge incontinence) is common in elderly; the cause is usually unknown. Functional imaging has revealed the brain network controlling responses to bladder filling. Age-related changes in this network might predispose to urge incontinence. We sought such changes in 10 continent, healthy women aged 30-79 years who underwent fMRI while fluid (approximately 20 ml) was repeatedly infused into and withdrawn from the bladder. Data were collected in 4 measurement blocks with progressively increasing bladder volumes and were analyzed by SPM2, using the contrast infuse-withdraw to quantify response to bladder infusion. Effective connectivity was examined by physiophysiological interaction (PhPI; see interpretation in Supplementary Material), with right insula (RI) and dorsal anterior cingulate cortex (dACC) as seed regions. Dependence on age and bladder volume (= block number) was assessed. Bladder infusion evoked expected activations. Activation decreased with age in bilateral insula and dACC. PhPI revealed connectivity with RI and dACC in regions that included bilateral putamen and R pontine micturition center. Interaction (connectivity) tended to increase with age in regions including L insula, L paracentral lobule and PAG. Consistent with a special role in maintaining continence, medial prefrontal cortex (mPFC) showed a trend to deactivation on bladder infusion that became more prominent in old age, and a trend to negative interaction (connectivity) that weakened significantly with age. Thus, with increasing age, weaker signals in the bladder control network as a whole and/or changes in mPFC function or connecting pathways may be responsible for the development of urge incontinence.