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Principal Investigator: Becky D Clarkson
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $599,799
Funding agency: National Institute on Aging
PROJECT SUMMARY
Prevalent, morbid, and costly (>$20 billion/year in 2000), incontinence is a major problem, especially for older
adults, in whom the most common type is urgency urinary incontinence (UUI). Ascribed to bladder spasms,
UUI's actual causes are unknown, and therapy remains inadequate. Recent data suggest that one cause is
poor bladder control by the brain. In our recent R01 we used biofeedback (BFB) as a probe to explore this. The
exciting findings suggest that there are ≥ 2 brain (pheno)types of UUI; that they respond differently to BFB, and
via different mechanisms; and that their response can be predicted. Our proposed new study will extend this
work to examine mechanisms of drug treatments to identify potentially new targets for therapy.
Data suggest that bladder control comprises 3 cerebral circuits which maintain continence by suppressing the
voiding reflex in the midbrain. In the phenotype that responded to BFB, 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.
Yet, BFB is used less often than drugs to treat UUI. The mechanism(s) that mediate drug response are
unknown but likely involve changes in afferent activity ascending to the brain. The proposed study would be
the first to address this critical knowledge gap. It is based not only on insights generated from our BFB study,
but also on a pilot study of the bladder relaxant fesoterodine and our working model of brain/bladder control.
Our overall aim is to use fesoterodine as a physiological probe, to improve our understanding of the brain's role
in UUI and identify new targets for therapy. Specific aims are to: (1) test whether efficacy of drug therapy varies
by brain phenotype (the two identified in our BFB study or others that this study will identify); (2) confirm that
mPFC deactivation is a key therapeutic mechanism, regardless of intervention; (3) determine if drug therapy
normalizes brain response as a non-specific reaction to therapy; and (4) use newer MRI techniques to extend
our current methods and thereby confirm or refute our model of brain/bladder control.
To address these aims, we will randomize 150 women aged ≥ 60 years to receive 12 weeks of either fesoter-
odine or placebo and then switch them to the alternate therapy for another 12 weeks. The study will enable us
to correlate the change in CNS activation/deactivation with clinical response to therapy and also to discern
whether CNS changes revert as incontinence worsens following withdrawal of therapy (on placebo) and to
identify brain predictors and mechanisms of response.
The study will provide the first data on brain mechanisms involved in UUI response to a drug. Regardless of
results, it will contribute substantially to current understanding of UUI and continence, thereby enabling scien-
tists to develop new therapies based on the revolution in neuroscience—and more hope for UUI sufferers.
Terms: <Acetylcholine Agents><Address><Affect><After Care><After-Treatment><Aftercare><Anti-Cholinergics><Anticholinergic Agents><Anticholinergics><Area><BBB permeabilization><BBB permeable><Behavior Conditioning Therapy><Behavior Modification><Behavior Therapy><Behavior Treatment><Behavioral Conditioning Therapy><Behavioral Modification><Behavioral Therapy><Behavioral Treatment><Biofeedback><Bladder><Bladder Control><Bladder Dysfunction><Bladder Urinary System><Brain><Brain Nervous System><Brain region><Central Lobe><Cerebrum><Characteristics><Cholinergic Agents><Cholinergic Drugs><Clinical><Compensation><Complement><Complement Proteins><Conditioning Therapy><Cross-Over Trials><Crossover Trials><DWI (diffusion weighted imaging)><DWI-MRI><Data><Development><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disorder><Drug Design><Drug Therapy><Drugs><Elderly><Encephalon><Extravasation><Frustration><Hyperkinesia><Hyperkinesis><Hyperkinetic Movements><Image><Impairment><Incontinence><Insula><Insula of Reil><Intervention><Intervention Strategies><Investigation><Island of Reil><Knowledge><Leakage><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measures><Medial><Mediating><Mediator><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mesencephalon><Methods><Micturition Reflex><Mid-brain><Midbrain><Midbrain structure><Modeling><Muscarinic Agents><Muscarinics><Muscle Spasm><Muscular Spasm><NMR Imaging><NMR Tomography><Neurosciences><Nuclear Magnetic Resonance Imaging><Older Population><Pattern><Pelvic Floor Muscle><Peripheral><Pharmaceutical Preparations><Pharmacotherapy><Phenotype><Physiologic><Physiological><Pilot Projects><Placebo Control><Placebo Effect><Placebos><Prefrontal Cortex><QOL><Quality of life><Randomized><Reaction><Refractory><Relapse><Resistance><Resolution><Role><Scientist><Sham Treatment><Sorting><Spasm><Spillage><Techniques><Testing><Therapeutic><Training><Urgency to pass urine><Urgent desire to urinate><Urinary Incontinence><Urine><Withdrawal><Woman><Work><Zeugmatography><abnormal brain function><advanced age><aged><arterial spin labeling><arterial spin tagging><behavior intervention><behavioral intervention><bladder continence><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain control><brain dysfunction><brain impairment><cerebral><clinical practice><complementation><computer based prediction><cost><dMRI><design><designing><developmental><diffusion tensor imaging><drug action><drug efficacy><drug treatment><drug withdrawal><drug/agent><dysfunctional brain><expectancy effect><expectation effect><geriatric><imaging><improved><insight><interventional strategy><micturition control><micturition urgency><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><nocebo><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><older adult><older adulthood><older groups><older individuals><older person><pilot study><placebo controlled><placebo response><post treatment><predict responsiveness><predicting response><predictive modeling><randomisation><randomization><randomly assigned><resistant><resolutions><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><response><response to therapy><response to treatment><senior citizen><sham therapy><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><treatment effect><treatment response><treatment responsiveness><urinary bladder><urinary continence><urinary control><urinary urgency><urination control><urination urgency><voiding reflex>