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.

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.

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.

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.

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.

The prevalence of cognitive impairment in laryngology treatment-seeking patients.

OBJECTIVES/HYPOTHESIS: The incidence of cognitive impairment (CI) in the elderly general population is 10% to 20%. The incidence of CI in the elderly laryngology treatment-seeking population is unknown, and CI may impact decision making for elective medical/surgical treatment and negatively impact the outcome of voice/swallowing therapy. We sought to determine the prevalence of CI in elderly patients who are seeking laryngology care and to evaluate the feasibility of administering a cognitive screening instrument. STUDY DESIGN: Prospective, Cross-sectional. METHODS: One hundred fifty patients (≥65 years old) without a previous diagnosis of CI, seeking laryngology evaluation, were administered the Montreal Cognitive Assessment (MoCA) test by a trained physician. Other members of the clinical team were blinded to the MoCA results. RESULTS: Twenty-five percent of participants obtained a score diagnostic for at least mild CI. The results showed a correlation between the MoCA scores and 1) the time needed to complete the test, 2) participant age, and 3) participant education level. No differences were observed between gender, alcohol consumption, or use of medications that can affect cognition and MoCA score. CONCLUSION: One in four elderly laryngology treatment-seeking patients were found to have undiagnosed CI. This finding warrants consideration for CI screening for these patients being evaluated for voice therapy and elective surgery. Treatment decision making in this population may benefit from additional family involvement. LEVEL OF EVIDENCE: 2c Laryngoscope, 130: 2003-2007, 2020.

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.

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.

Bladder control, urgency, and urge incontinence: evidence from functional brain imaging.

AIM: To review brain imaging studies of bladder control in subjects with normal control and urge incontinence; to define a simple model of supraspinal bladder control; and to propose a neural correlate of urgency and possible origins of urge incontinence. METHODS: Review of published reports of brain imaging relevant to urine storage, and secondary analyses of our own recent observations. RESULTS: In a simple model of normal urine storage, bladder and urethral afferents received in the periaqueductal gray (PAG) are mapped in the insula, forming the basis of sensation; the anterior cingulate gyrus (ACG) provides monitoring and control; the prefrontal cortex makes voiding decisions. The net result, as the bladder fills, is inhibition of the pontine micturition center (PMC) and of voiding, together with gradual increase in insular response, corresponding to increasing desire to void. In urge-incontinent subjects, brain responses differ. At large bladder volumes and strong sensation, but without detrusor overactivity (DO), most cortical responses become exaggerated, especially in ACG. This may be both a learned reaction to previous incontinence episodes and the neural correlate of urgency. The neural signature of DO itself seems to be prefrontal deactivation. Possible causes of urge incontinence include dysfunction of prefrontal cortex or limbic system, suggested by weak responses and/or deactivation, as well as abnormal afferent signals or re-emergence of infantile reflexes. CONCLUSIONS: Bladder control depends on an extensive network of brain regions. Dysfunction in various parts may contribute to urge incontinence, suggesting that there are different phenotypes requiring different treatments.

Sex differences in hepatic gene expression in a rat model of ethanol-induced liver injury.

Sex differences in susceptibility to alcohol-induced liver injury have been observed in both humans and experimental animal models. Using a standard model of alcohol-induced fatty liver injury and microarray analysis, we have identified differential expression of hepatic genes in both sexes. The genes that exhibit differential expression are of three types: those that are changed only in male rats fed alcohol, those that change in only female rats fed alcohol, and those that change in both sexes, although not always in the same manner. Certain of the differentially expressed genes have previously been identified as participants in the induction of alcohol-induced liver injury. However, this analysis has identified a number of genes that heretofore have not been implicated in alcoholic liver injury; such genes may provide new areas of investigation into the pathogenesis of this disease.

Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats.

INTRODUCTION: Chronic alcohol consumption predisposes susceptible individuals to both acute and chronic pancreatitis. AIMS: Our hypothesis was that alcohol increases the risk of pancreatitis by disrupting defense mechanisms and/or enhancing injury-associated pathways through altered gene expression. Hence, we studied the expression of pancreatic genes in rats chronically exposed to ethanol. METHODOLOGY: Male Wistar rats were pair-fed liquid diets without and with ethanol for 4 weeks. Total RNA was extracted from rat pancreas and other organs. The mRNA expression patterns among pancreatic samples from ethanol-fed rats and controls were compared with use of mRNA differential display. The differentially expressed cDNA tags were isolated, cloned, and sequenced. RESULTS: One cDNA tag that was overexpressed in the pancreas showed 99% sequence homology to a rat pancreatic cholesterol esterase mRNA (CEL; Enzyme Commission number [EC] 3.1.1.13). The differential expression was confirmed by realtime PCR. Gene expression was also increased in the liver but not in the heart or brain of the alcohol-fed rats. Because CEL has fatty acid ethyl ester (FAEE)-generating activity and FAEEs play a major role in acute alcoholic pancreatitis, we determined the expression of other genes encoding for FAEE-generating enzymes and showed similar organ-specific expression patterns. CONCLUSION: Our results demonstrate that chronic ethanol consumption induced expression of FAEE-related genes in the pancreas and liver. This upregulation may be a central mechanism leading to acinar cell injury.

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.

Abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence.

The regions of the supraspinal network that controls urinary bladder behavior are well known, but little is known about their interconnections. We tested the feasibility of using physiophysiological interaction to explore the effective connections of the network and to seek disease-related differences in connectivity. This was a secondary analysis of fMRI data obtained from women aged 26-85 years, 11 with urge urinary incontinence and 10 with normal bladder function. In each subject, fMRI BOLD images were obtained during a period with full bladder and strong bladder sensation (without detrusor overactivity) while repeatedly infusing and withdrawing a small amount of liquid in and out of the bladder. Regions of interest included right insula (RI) and anterior cingulate gyrus (ACG), both consistently involved in bladder control. Other regions effectively connected to them were identified by significant correlation between their fMRI signal and the interaction RIxACG. Among normal subjects, many regions involved in bladder control were effectively connected with RI/ACG, including frontotemporal and sensorimotor cortex, forebrain, midbrain and pontine regions. The sign of the correlation with RIxACG was near-uniformly positive, perhaps suggesting mainly inhibitory connections. Among urge-incontinent subjects, the effective connectivity was shifted to a parieto-temporal complex, while the sign of the correlation was predominantly negative, perhaps consistent with excitation (recruitment) of accessory pathways in an attempt to maintain bladder control. Thus, physiophysiological interaction yields potentially important information about the connectivity of the bladder control network and its changes in disease.

Cerebral control of the bladder in normal and urge-incontinent women.

AIM: To identify age-related changes in the normal brain/bladder control system, and differences between urge incontinence in younger and older women, as shown by brain responses to bladder filling; and to use age, bladder volume, urge incontinence and detrusor overactivity (DO) as probes to reveal control system function. Functional MRI was used to examine regional brain responses to bladder infusion in 21 females (26-85 years): 11 "cases" with urge incontinence and DO (proven previously) and 10 normal "controls". Responses and their age dependence were determined at small and large bladder volumes, in whole brain and in regions of interest representing right insula and anterior cingulate (ACG). In "controls", increasing bladder volume/sensation led to increasing insular responses; with increasing age, insular responses became weaker. In younger "cases", ACG responded abnormally strongly at large bladder volumes/strong sensation. Elderly "cases" showed strong ACG responses even at small bladder volume but more moderate responses at larger volumes; if DO occurred, pontine micturition center (PMC) activation did not increase. CONCLUSION: Among normal "controls", increasing age leads to decreased responses in brain regions involved in bladder control, including right insula, consistent with its role in mapping normal bladder sensations. Strong ACG activation occurs in urge-incontinent "cases" and may be a sign of urgency, indicating recruitment of alternative pathways when loss of bladder control is feared. Easier ACG provocation in older "cases" reflects lack of physiological reserve or different etiology. ACG responses seem associated with PMC inhibition: reduced ACG activity accompanies failure of inhibition (DO).

Effect of biofeedback on psychological burden and symptoms in older women with urge urinary incontinence.

OBJECTIVES: To determine the effect of biofeedback (BFB) therapy on psychological burden of urge urinary incontinence (UI) and whether prior depression or current depressive symptoms affect older women's response to BFB. DESIGN: Secondary analysis of an ongoing trial. SETTING: Academic medical center. PARTICIPANTS: Forty-two community-dwelling women aged 60 and older with urge UI. INTERVENTION: BFB and behavioral training in urge suppression provided over 8 weeks. MEASUREMENTS: UI frequency on 3-day bladder diary, psychological burden assessed using Urge Impact Scale (URIS-24) total and subscale scores, history of depression, and depressive symptoms on the Mental Component Subscale (MCS) of the Medical Outcomes Study 36-item Short Form Survey (SF-36). Age and chronic conditions were included as covariates. RESULTS: BFB improved UI (by 45%, P=.001) and psychological burden (P=.001 for total URIS-24 score and for all three of its subscales; P=.01 for SF36-MCS). However, although the magnitude of UI improvement was equivalent for those with and without a history of depression, improvement in psychological outcomes was twice as great in those with a history of depression, especially on the perception of control subscale, and improvement was not related to baseline depressive symptoms. CONCLUSION: In older women with urge UI, BFB significantly improves psychological burden, especially in those with a history of depression, in whom psychological burden is linked to change in perception of control. Psychological factors are relevant outcome measures for UI, and these data suggest that focusing on UI frequency alone may have underestimated BFB's efficacy and additional therapeutic benefits.