Investigation of Brain Mechanisms Involved in the Urinary Continence Mechanism Associated With Aging

Current data suggest that bladder control comprises 3 cerebral circuits that maintain continence by suppressing the voiding reflex in the midbrain. In the UUI phenotype that responded to BFB (Biofeedback assisted pelvic floor muscle therapy), the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Although the investigators have an emerging picture of the brain's role in UUI, the investigators have only rudimentary understanding of what is 'normal', i.e. how the brain normally controls the bladder. Moreover, the investigators do not know whether this control mechanism is the same across the lifespan, or whether it changes owing to the impact of aging. Thus, the investigators aims are to characterize the brain's normal role in bladder control in both young and old people, to determine the changes in brain structure and function that lead to bladder control failure (UUI), and to examine how such changes differ between young and old individuals. To address the aims, the investigators will utilize detailed neuroimaging to evaluate 80 asymptomatic women and 80 women with UUI, each group divided into young (18-45) and old (65+ years) individuals. The study will enable the investigators to define the brain's key structures, functional activity, and mechanisms involved in normal bladder control, and to identify the differences in these elements among those with UUI, both young and old.

By elucidating the mechanisms that mediate the brain's control (and loss of control) of bladder function, the proposed study should enhance the investigators working model, deepen the understanding of the impact of aging, and identify better targets for the treatment of UUI. It may thereby enable scientists to develop novel and more effective new therapies based on the revolution in neuroscience-and more hope for UUI sufferers.

Inclusion criteria

• 'Old' (community-dwelling, mentally and functionally intact ambulatory women aged 65+ years) or 'Young' (equivalent women aged 18-45)
• 'Wet' (those who meet the International Continence Society definition of urgency urinary incontinence (urinary leakage accompanied by a sudden, strong urge to void which is difficult to defer) >5 times per week, for 3 months despite treatment for reversible causes (e.g., Urinary tract infection) and confirmed by a mean of one episode per day of UUI on 3-day bladder diary) or 'Dry' (women without current or past UUI or other lower urinary tract symptoms.) Infrequent stress incontinence of a small amount is acceptable.
• Urge-predominant mixed incontinence is acceptable provided the subject is able to differentiate between stress incontinence (SUI - leakage that coincides instantaneously with cough, laugh, exercise) and urgency incontinence, i.e., leakage accompanied by a sudden strong urge to void that is difficult to defer.
• Those with current or previous use of anticholinergic/beta-3 agonist medications will be considered for the study if they are willing to go through a washout period of at least 4 weeks of duration.

Exclusion criteria

Dry Groups

• Current or prior treatment for UUI
• Leakage on bladder diary not ascribed to minimal SUI (see bullet above)

All Groups: 'Wet' or 'Dry'; 'Young' or 'Old'

• Cognitive impairment:

• MoCA<26
• inability to perform a voiding diary/pad test
• inability to reliably take daily medication
• inability to comply with fMRI testing
• Impaired mobility

o Timed up and go test ≥ 12 secs

• Medical instability:

• severe uncontrolled hypertension >180mmHg systolic or >100mmHg diastolic
• potential major changes in medical management over the course of the study period (i.e. upcoming surgery/treatment)
• frailty according to the Fried criteria
• MRI incompatibility:

• contraindicated metal implants
• claustrophobia
• unidentified/untested compatibility of metal implants
• Medication incompatibility:

• allergy to study medication (all prophylactic antibiotic choices)
• interaction of prophylactic antibiotic choices with current medications
• expected change in medication during the study
• Neurological conditions:

• spinal cord injury;
• multiple sclerosis
• clinically apparent lesions (e.g. lacunae associated with stroke)
• prior stroke
• Parkinson's Disease/ALS/MSA
• any clinically apparent neurological condition
• Lower urinary tract comorbidities/treatment:

• history of pelvic irradiation
• bladder or advanced uterine cancer
• possible urethral obstruction (advanced prolapse [POP-Q>II] or Qmax<12 ml/s on free flow)
• urinary retention (PVR >200 ml)
• Interstitial Cystitis/Bladder Pain Syndrome
• artificial sphincter implant
• Botox treatment for UUI within 1 year
• Neuromodulation treatment for UUI
• Other comorbidities:

• uncontrolled depression (PHQ-9 ≥10)