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.

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.

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.

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.

The effect of age on lower urinary tract function: a study in women.

OBJECTIVES: To identify age-associated changes in female lower urinary tract function across a wide age spectrum, controlling for detrusor overactivity (DO). DESIGN: Secondary analysis of a cross-sectional study of DO and aging. Eligible volunteers were stratified by age group and presence of DO. SETTING: Community-based volunteers, evaluated in research laboratory. PARTICIPANTS: Eighty-five ambulatory, nondemented, community-dwelling female volunteers, with and without bladder symptoms suggestive of DO, recruited by advertising, mean age 54 (range 22-90); 75% Caucasian, 21% African American. MEASUREMENTS: Comprehensive assessment included bladder diary, uroflowmetry, and detailed videourodynamics. Predefined urodynamic and diary variables were examined for association with age and DO. Mean values of these variables were calculated for subgroups aged 20 to 39, 40 to 59, and 60 and older (14 subjects > or =70). RESULTS: Maximum urethral closure pressure, detrusor contraction strength, and urine flow rate declined significantly with age (P<.001, P<.001, P=.006, respectively), regardless of whether DO was present. Most elderly individuals continued to empty their bladder almost completely, with normal voiding frequency. Mean number of nocturnal voids was less than one in all age groups. Bladder capacity did not decrease with age (mean 522 mL in oldest group) but was smaller in subjects with DO. Bladder sensation diminished significantly with age (P<.001) but was stronger in subjects with DO. CONCLUSION: Female bladder and urethral function appear to deteriorate throughout adult life, whether DO is present or not. Specifically, detrusor contractility, bladder sensation, and urethral pressure decline. The common belief that bladder capacity shrinks with age may be related to DO rather than to aging itself.

The pontine micturition centres.

OBJECTIVE: To review recent literature on the function of the two postulated pontine regions (the M- and L-regions) concerned with lower urinary tract control. MATERIAL AND METHODS: The work reviewed is based on stimulation and lesion experiments and post-operative follow-up in the cat, supported by acute chemical stimulation and blocking experiments in the rat and PET functional brain scanning in humans. RESULTS AND CONCLUSIONS: The M-region in the cat, homologous to Barrington's micturition centre and to a similar area in humans, is a small region both specific and necessary to voiding, the origin of the final common pathway to bladder and urethra, and the locus of co-ordination of the bladder and the striated sphincter. The L-region in the cat is part of a larger, less specific area that probably serves sphincter control in various circumstances, not exclusively micturition. The homolog of this region in the human or in the rat has not been adequately established.

The CNS and bladder dysfunction.

The brain's role in the development and maintenance of bladder control is critical, although its precise role in patient-reported complaints such as urgency and urine leakage is unknown. Functional brain imaging studies have advanced our knowledge of brain activity during the micturition cycle, showing multiple neuronal circuits involved as parts of a 'brain-bladder control network.' Yet, new advances need to be made in order to incorporate this knowledge into existing models of neuroanatomy and of clinical syndromes of bladder dysfunction and related clinical practice. This short article explains why and how brain imaging methods are poised to achieve that goal and decode the role of the brain in widely prevalent clinical conditions related to bladder dysfunction.

Parameters of bladder function in pre-, peri-, and postmenopausal continent women without detrusor overactivity.

AIMS: To determine normative data for lower urinary tract function in asymptomatic continent women without detrusor overactivity (DO) across the age span. METHODS: Healthy female volunteers aged > or =20 years were recruited from the community. Comprehensive assessment included bladder diary, physical examination, uroflowmetry, and video-urodynamics. Continent women without history of frequent urgency and without DO were selected. Data on bladder storage, voiding and urethral sphincter function, urine output and frequency are presented for pre-, peri-, and postmenopausal women. RESULTS: Twenty-four asymptomatic women (mean age 50.2 years, range 22-80 years) met the inclusion criteria, including 7 pre- (29.2 years), 7 peri- (48.8 years), and 10 postmenopausal (66.0 years) women. For all subjects, maximum single voided volume in bladder diary was 500 ml and maximum cystometric capacity was 580 ml (median values). Strong desire to void (SDV) was reported at 287, 366, and 425 ml for pre-, peri-, and postmenopausal groups, respectively. The maximum flow rate was 25, 32, and 23 ml/sec in uroflowmetry and 23, 24, and 18 ml/sec in pressure-flow study, respectively. Median post-void residual volume (PVR) was below 20 ml in all groups. At maximum flow rate subjects voided with detrusor pressures of 29, 26, and 24 cm H(2)O, respectively. Maximum urethral closure pressure was 94, 74, and 42 cm H(2)O, respectively. CONCLUSIONS: We provide normative data on bladder function in asymptomatic, continent, pre-, peri-, and postmenopausal women without DO.

Omnibus permutation tests of the overall null hypothesis in datasets with many covariates.

Tests of the overall null hypothesis in datasets with one outcome variable and many covariates can be based on various methods to combine the p-values for univariate tests of association of each covariate with the outcome. The overall p-value is computed by permuting the outcome variable. We discuss the situations in which this approach is useful and provide several examples. We use simulations to investigate seven omnibus test statistics and find that the Anderson-Darling and Fisher's statistics are superior to the others.

The impact of detrusor overactivity on bladder function in younger and older women.

PURPOSE: We examined the relationship of DO and aging, and bladder function in female volunteers. MATERIALS AND METHODS: We recruited 85 cognitively competent, fully functional female volunteers who were 22 to 90 years old (median age 54) with and without symptoms suggestive of DO. Comprehensive assessment included a bladder diary, uroflowmetry and videourodynamics. We examined predefined urodynamic and diary variables for associations with DO and age, summarizing results in the 3 subgroups no DO, intermediate DO and clinically relevant DO. RESULTS: Compared to women without DO those with DO showed a decrease in maximum cystometric capacity (558 vs 448 ml), mean daytime voided volume (260 vs 175 ml) and volume at strong desire to void (363 vs 283 ml) but an increase in maximum isovolumetric pressure (41 vs 64 cm H2O) and maximum detrusor pressure during involuntary contraction (intermediate and relevant DO 22 and 37 cm H2O, respectively). The positive association between increased detrusor contraction strength and DO was present at younger ages but absent in older subjects. Maximum urethral closure pressure and detrusor contraction strength decreased significantly with age. CONCLUSIONS: From young adulthood to old age DO appears to affect bladder function parameters. It is associated with decreased bladder capacity and increased bladder sensation. Moreover, in younger adults DO is also associated with increased detrusor contraction strength, which is an association not seen in older individuals. This age associated loss of muscle function may be related to sarcopenia, implying that different treatments may be appropriate in older adults.

Factors that distinguish continent from incontinent older adults with detrusor overactivity.

PURPOSE: In older adults detrusor overactivity (DO) is almost as common in continent individuals as in those with urge incontinence (UUI). Thus, UUI likely reflects the contribution of additional factors. We postulated that of functionally independent individuals in whom transient causes were excluded those in whom DO was accompanied by UUI would be more likely to have smaller functional bladder capacity, less warning and less ability to avert urine loss in the face of DO. MATERIALS AND METHODS: While blinded to continence status, we reviewed the records of all 52 cognitively intact and nonobstructed volunteers older than 65 years who had DO associated with urgency during urodynamic testing and had been asked to try to prevent leakage for 2 minutes. Of these individuals 31 were continent at home. RESULTS: In patients with UI mean functional bladder capacity +/- SD was smaller (313 +/- 153 vs 390 +/- 178 ml, p = 0.06) and warning was briefer (87 +/- 81 vs 120 +/- 116 ml), although the association with warning was less impressive (p = 0.14). The ability to forestall leakage for at least 2 minutes correlated strongly with being continent at home (p < 0.002). For continence detrusor suppression at the onset of DO was more important than sphincter contraction. CONCLUSIONS: Urge incontinence in older adults involves more than simply the presence of DO. Physical function, cognitive function and medications are already known to be important for continence. Our data suggest that functional bladder capacity and the ability to suppress involuntary contraction (and possibly warning) are also potentially important covariates. These factors may represent additional potential targets for behavioral and pharmacological therapy.

Cerebral control of bladder function.

Symptoms such as overactive bladder represent disorders of bladder control. Functional brain scanning by positron emission tomography and functional magnetic resonance imaging suggest that normal control is exerted by a network of regions in the emotional nervous system, including periaqueductal gray, thalamus, insula, anterior cingulate, and prefrontal cortex. The network receives afferent signals, converts them to bladder sensations, and brings them to conscious attention, together with an unpleasant affect (desire to void) that motivates bladder emptying and thus maintains homeostasis. In patients with poor control, brain response to bladder filling differs; cerebral control is abnormal, even in the absence of involuntary detrusor contraction. Behavioral therapy and electrical stimulation appear to be possible treatments.

Urge incontinence and impaired detrusor contractility in the elderly.

Among the elderly, both urge incontinence and elevated residual urine are common. When they occur together, they present a challenging clinical problem, called detrusor hyperactivity with impaired contractile function (DHIC). Impaired detrusor contractility has two aspects: elevated post-void residual urine volume and reduced detrusor contraction strength. Geriatric urge incontinence, especially in combination with reduced bladder sensation, is associated with specific cortical abnormalities: frontal and global cortical underperfusion and cognitive impairment. We have investigated, in 73 elderly incontinent patients, whether either aspect of impaired contractility is associated with urge incontinence, reduced sensation or these cortical abnormalities. For post-void residual urine, there are no significant associations. Detrusor contraction strength, however, is significantly increased (not impaired) if there is urge incontinence, reduced bladder sensation, or cortical underperfusion. Thus, DHIC appears to be a coincidental occurrence of two common conditions with different etiological factors.