Impact of sleep on chronobiology of micturition among healthy older adults.

Nocturia (waking to void) is prevalent among older adults. Disruption of the well-described circadian rhythm in urine production with higher nighttime urine output is its most common cause. In young adults, their circadian rhythm is modulated by the 24-h secretory pattern of hormones that regulate salt and water excretion, including antidiuretic hormone (ADH), renin, angiotensin, aldosterone, and atrial natriuretic peptide (ANP). The pattern of hormone secretion is less clear in older adults. We investigated the effect of sleep on the 24-h secretion of these hormones in healthy older adults. Thirteen participants aged ≥65 yr old underwent two 24-h protocols at a clinical research center 6 wk apart. The first used a habitual wake-sleep protocol, and the second used a constant routine protocol that removed the influence of sleep, posture, and diet. To assess hormonal rhythms, plasma was collected at 8:00 am, 12:00 pm, 4:00 pm, and every 30 min from 7:00 pm to 7:00 am. A mixed-effects regression model was used to compare subject-specific and mean trajectories of hormone secretion under the two conditions. ADH, aldosterone, and ANP showed a diurnal rhythm that peaked during sleep in the wake-sleep protocol. These nighttime elevations were significantly attenuated within subjects during the constant routine. We conclude that sleep has a masking effect on circadian rhythm amplitude of ADH, aldosterone, and ANP: the amplitude of each is increased in the presence of sleep and reduced in the absence of sleep. Disrupted sleep could potentially alter nighttime urine output in healthy older adults via this mechanism.NEW & NOTEWORTHY Nocturia (waking to void) is the most common cause of sleep interruption among older adults, and increased nighttime urine production is its primary etiology. We showed that in healthy older adults sleep affects the 24-h secretory rhythm of hormones that regulate salt-water balance, which potentially alters nighttime urine output. Further studies are needed to elucidate the impact of chronic insomnia on the secretory rhythms of these hormones.

Neuroimaging of situational urgency and incontinence provoked by personal urgency cues.

INTRODUCTION: Situational triggers for urinary urgency and incontinence (UUI) such as "latchkey incontinence" and running water are often reported clinically, but no current clinical tools exist to directly address symptoms of UUI provoked by environmental stimuli. Previously we have shown that urgency and leakage can be reproduced during urodynamic studies with exposure to personal urgency-related images. Here we investigate the neural signatures associated with such situational triggers to inform potential therapies for reducing reactivity to these personal urgency-related cues among women with situational UUI. METHOD: We recruited 23 women with situational UUI who took photographs of their personal "urgency trigger" and "safe" situations and were exposed to them in a magnetic resonance imaging (MRI) scanner. We identified brain areas that were more active during urgency versus safe image exposure. RESULTS: We found that, during urgency image exposure, main components of the attention network and decision-related processes, the middle and medial frontal gyri, were more active (p < 0.01). In addition, areas well known to be involved in the continence mechanism, such as the cingulate and parahippocampal areas, were also more active during urgency image exposure. CONCLUSION: Exposure to personal situational urgency images activated different areas of the brain compared with safe environments, highlighting the complex brain mechanisms that provoke real-world urgency. Using brain and behavioral-based therapies which target the attentional areas identified here and extinguish cue reactivity might reduce symptom burden in this subset of UUI sufferers.

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.

Reproducing situationally triggered urgency incontinence in a controlled environment.

INTRODUCTION: Patients with lower urinary tract symptoms often report urgency and incontinence episodes which are triggered by environmental scenarios, for example, "latch-key incontinence." To better understand the extent of this phenomenon, and how best to reduce its impact, we tested ways to recreate these situational cues in a controlled environment and obtain cue reactivity measures. METHODS: We developed a standardized set of urgency cue scenarios from interviews with sufferers of situational urgency urinary incontinence (UUI), personalized urgency, and safe cue sets consisting of photographs of specific locations, and measurements of cue reactivity during computer-based presentation and urodynamic monitoring. RESULTS: Common urgency and safe cues were identified for the standardized cue set. Exposure to these standardized cues elicited change in bladder sensation in 7 of 12 participants. Participants created personalized cue sets with photographs depicting their own urgency triggering scenarios; exposure to personalized cue photos elicited change in sensation in 11 of 12 participants. In addition, personalized cues elicited measurable detrusor overactivity and leakage during urodynamic monitoring. Safe cues reduced bladder sensation in five participants. CONCLUSION: We developed a computer-based means of displaying cue photos which elicited cue reactivity from women suffering from situational urgency incontinence. Cue reactivity was increased by personalizing photos of cue scenarios and obtaining physiological measures from urodynamics. We have developed an appropriate way to test cue reactivity in women with situational UUI.

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.

Nocturnal Polyuria in Older Women with Urge Urinary Incontinence: Role of Sleep Quality, Time in Bed and Medications Used.

PURPOSE: Nocturia is common and bothersome in older adults, especially those who are also incontinent. Since nocturnal polyuria is a major contributor, we examined factors associated with nocturnal polyuria in this population to identify those possibly amenable to intervention. MATERIALS AND METHODS: We analyzed baseline data from 2 previously completed studies of urge urinary incontinence. The studies involved 284 women (mean age ± SD 72.9 ± 7.9 years) who also completed 3-day voiding diaries. Participants with a nocturnal polyuria index greater than 33% were categorized as having nocturnal polyuria (nocturnal polyuria index = nocturnal urinary volume per 24-hour urine volume). Associations between nocturnal polyuria and various demographic, clinical and sleep related parameters were determined. RESULTS: Overall 55% of the participants had nocturnal polyuria. Multivariable regression analysis revealed that age, body mass index, use of angiotensin converting enzyme inhibitor/angiotensin receptor blocker, time spent in bed and duration of first uninterrupted sleep were independent correlates of nocturnal polyuria. Participants with a larger nocturnal excretion reported a shorter duration of uninterrupted sleep before first awakening to void and worse sleep quality despite spending similar time in bed. CONCLUSIONS: Body mass index, use of angiotensin converting enzyme inhibitor/angiotensin receptor blockers, time in bed and duration of uninterrupted sleep before first awakening to void are independently associated with nocturnal polyuria in older women with urge urinary incontinence, and are potentially modifiable. These findings also confirm the association between sleep and nocturnal polyuria. Further studies should explore whether interventions to reduce nocturnal polyuria and/or increase the duration of uninterrupted sleep before first awakening to void would help to improve sleep quality in this population and thereby reduce or eliminate the need for sedative hypnotics.

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.

A systematic review and activation likelihood estimation meta-analysis of the central innervation of the lower urinary tract: Pelvic floor motor control and micturition.

PURPOSE: Functional neuroimaging is a powerful and versatile tool to investigate central lower urinary tract (LUT) control. Despite the increasing body of literature there is a lack of comprehensive overviews on LUT control. Thus, we aimed to execute a coordinate based meta-analysis of all PET and fMRI evidence on descending central LUT control, i.e. pelvic floor muscle contraction (PFMC) and micturition. MATERIALS AND METHODS: A systematic literature search of all relevant libraries was performed in August 2020. Coordinates of activity were extracted from eligible studies to perform an activation likelihood estimation (ALE) using a threshold of uncorrected p <0.001. RESULTS: 20 of 6858 identified studies, published between 1997 and 2020, were included. Twelve studies investigated PFMC (1xPET, 11xfMRI) and eight micturition (3xPET, 5xfMRI). The PFMC ALE analysis (n = 181, 133 foci) showed clusters in the primary motor cortex, supplementary motor cortex, cingulate gyrus, frontal gyrus, thalamus, supramarginal gyrus, and cerebellum. The micturition ALE analysis (n = 107, 98 foci) showed active clusters in the dorsal pons, including the pontine micturition center, the periaqueductal gray, cingulate gyrus, frontal gyrus, insula and ventral pons. Overlap of PFMC and micturition was found in the cingulate gyrus and thalamus. CONCLUSIONS: For the first time the involved core brain areas of LUT motor control were determined using ALE. Furthermore, the involved brain areas for PFMC and micturition are partially distinct. Further neuroimaging studies are required to extend this ALE analysis and determine the differences between a healthy and a dysfunctional LUT. This requires standardization of protocols and task-execution.

Nocturnal Excretion in Healthy Older Women and Rationale for a Safer Approach to Sleep Disruption.

OBJECTIVES: Insomnia, especially difficulty maintaining sleep, is prevalent among older adults and increases the incidence of falls and fractures. Moreover, the drugs used to treat it exacerbate the risk. Yet current therapies fail to address one of its most common causes in older adults: nocturia and its primary contributor, nocturnal polyuria (NP), especially among the majority of individuals without lower urinary tract symptoms (LUTS). Therefore, we examined the factors associated with nocturia in two groups of such older women and the impact of nocturia on sleep. DESIGN: Secondary analysis of two observational studies of bladder function in carefully evaluated healthy older women. SETTING: Academic medical center. PARTICIPANTS: A total of 39 women without LUTS who had adequate fluid intake (ie, >1200 mL urine output/24 h recorded on their diary), normal videourodynamic testing, and normal daytime frequency (≤7 voids). MEASUREMENTS: Voided volumes and sleep duration obtained from subjects' 3-day voiding diary, and sleep quality from the Center for Epidemiologic Studies Depression Scale. Nighttime excretion of more than 33% of 24-hour urine volume was considered NP. RESULTS: Overall, 21 of these healthy subjects (54%) awakened at least once nightly to void, and 19 (90%) of them had NP. Compared with those without nocturia, participants with nocturia had shorter duration of the first uninterrupted sleep period (182 ± 100 vs 250 ± 60 min; P = .03), and they reported worse sleep quality. Two factors contributed independently to nocturia: (1) a larger proportion of 24-hour urine output at night (43.4 ± 7.4% vs 25.4 ± 5.5%; P = <.001) and (2) smaller bladder capacity (484 ± 157 mL vs 608 ± 167 mL; P = .02). CONCLUSIONS: Nocturia, NP, and reduced bladder capacity are very common even in healthy older women without LUTS and are associated with impaired sleep. Thus applying currently available modalities to address both NP and reduced bladder capacity may effectively treat sleep disruption without incurring the complications of sedative-hypnotics. J Am Geriatr Soc 67:2610-2614, 2019.