Brain Activity Among Children With Overactive Bladder and Daytime Urinary Incontinence and Healthy Children

Study Overview
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Brief Summary
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The aim of this study is to investigate whether the activity in brain areas controlling the bladder is different among children suffering from Overactive Bladder (OAB) and Daytime Urinary Incontinence (DUI) compared to age- and gender-matched healthy children without bladder symptoms. Moreover, the aim is to investigate if sacral transcutaneous electric nerve stimulation (TENS) has a central mechanism of action. Children with OAB and DUI will be recruited from involved pediatric departments, and functional magnetic resonance imaging (fMRI) will be performed before and after 10 weeks of sacral TENS. In healthy children without bladder symptoms, only the baseline fMRI will be performed.

Detailed Description
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Daytime Urinary Incontinence (DUI) is a common condition among children affecting 2.1-21.8 % of children aged 4.5-17 years. DUI is most often caused by a functional overactive bladder (OAB) leading to urgent desire to void (urgency) and frequent urinations (frequency). In some children with functional OAB and DUI, the bladder detrusor is overactive when performing a urodynamic investigation, but this is not evident for all children suffering from OAB and DUI. The etiology of OAB and DUI is not yet fully established and might be multifactorial. A few studies among adults have shown that adult women with OAB and DUI has more activity in brain areas controlling the bladder compared to adult women without bladder symptoms. Moreover, one study among adult women has shown a decrease in brain activity in areas controlling the bladder after sacral TENS treatment. This has led to a hypothesis that increased activity in the brain is a pathophysiological mechanism of OAB and DUI. Brain activity among children with OAB and DUI has not yet been investigated. Therefore, the objectives of this study is: To investigate the activity in brain areas controlling the bladder among children with OAB and DUI and age- and gender-matched children without bladder symptoms AND To investigate if sacral TENS has a centrally modulatory effect on the brain activity in areas controlling the bladder among children with OAB and DUI. Methods: The study consists of two sub-studies. The first sub-study is a cross-sectional study, whereas the second sub-study is an interventional cohort study. Forty-five children with OAB and DUI and 20 healthy children without bladder symptoms will be recruited. The study includes one structural MRI as well as two sessions of functional MRIs (only one functional MRI for healthy participants), one session prior to and after 10 weeks of sacral TENS treatment. The functional MRI session consist of a functional MRI with full bladder followed by a functional MRI with empty bladder. Moreover, the study participants and/or their parents are asked to fill in frequency and volume charts, Dry Pie, screening tools to rule out attention deficit hyperactivity disorder and autism spectrum disorders, and quality of life-questionnaires (WHO-5 and PinQ).

Official Title
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Brain Activity Among Children With Overactive Bladder and Daytime Urinary Incontinence and Healthy Children, and Modulation of Brain Activity by Transcutaneous Electrical Nerve Stimulation - a Functional Magnetic Resonance Imaging Study

Conditions
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Urinary Incontinence, Daytime Wetting, Urination Disorders, Urination Involuntary, Urologic Diseases, Lower Urinary Tract Symptoms, Urological Manifestations, Behavioral Symptoms, Mental Disorders, Elimination Disorders

Intervention / Treatment
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* Device: Sacral TENS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overactive Bladder as per International Children's Continence Society criteria (cases only). At least 2 incontinence episodes per week (cases only). No urinary tract symptoms (healthy participants only). More than 3 daily urinations. Normal clinical examination. Exclusion Criteria: Known urogenital abnormality affecting the lower urinary tract function. Prior surgery in the urinary tract (except circumcision). Known neurological diseases or prior cerebral surgery. Known neuropsychiatric disorders or suspicion of those by screening. Treatment with pharmacological agents affecting the brain function. Prior treatment with Enuresis Alarm or Transcutaneous Electrical Nerve Stimulation. Prior or current treatment with mirabegron or oxybutynin. Current urinary tract infection. Current constipation according to Rome IV-criteria or faecal incontinence. Claustrophobia. Metallic items in the body contraindicating MRI-scans. Abnormal uroflowmetry (healthy participants only).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Cross-sectional and interventional cohort study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transcutaneous Electric Nerve Stimulation (TENS)<br>Sacral TENS | Device: Sacral TENS<br>* Sacral TENS applied two hours daily for 10 weeks<br>* Other names: Urotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activity in brain areas controlling the bladder | Blood Oxygen Level Dependent (BOLD)-signals on functional MRIs, compared between children with Overactive Bladder and Daytime Urinary Incontinence and children without bladder symptoms. | Baseline | 
| Change in activity in brain areas controlling the bladder after TENS-treatment | Blood Oxygen Level Dependent (BOLD)-signals on functional MRIs, compared between responders and non-responders to TENS-treatment. | Baseline AND immediately after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural differences on MRI among children with OAB and DUI and healthy children | Volume of brain areas involved in bladder control (e.g. lateral nuclei in pons, prefrontal cortex, anterior cingulate cortex (ACC), insula, periaqueductal grey (PAG), the pontine micturition center (PMC), and hypothalamus) | Baseline | 
| Differences in Quality of Life (QoL) between children with OAB and DUI and healthy children | Assessment of QoL using WHO-5 among children with OAB and DUI and compare to QoL among children without bladder symptoms. | Baseline | 
| Change in WHO-5 score among children with OAB and DUI at baseline and after the intervention. | Assessment of QoL using WHO-5 among children with OAB and DUI prior to and after ten weeks of sacral TENS-treatment. WHO-5 (World Health Organization Quality of Life Brief Version) is a validated tool, assessing QoL as a total percent-score (range 0-100). A high score indicates better QoL. | Baseline AND immediately after the intervention | 
| Change in PinQ score among children with OAB and DUI at baseline and after the intervention. | Assessment of QoL using PinQ among children with OAB and DUI prior to and after ten weeks of sacral TENS treatment. PinQ (Pediatric Incontinence Questionnaire) is a validated tool, assessing QoL as a total score (range 0-80). A lower score indicates better QoL. | Baseline AND immediately after the intervention | 
| Change in WHO-5 score among children with OAB and DUI compared among responders and non-responders to sacral TENS treatment. | Assessment of QoL using WHO-5 and compare among responders and non-responders to sacral TENS-treatment. WHO-5 (World Health Organization Quality of Life Brief Version) is a validated tool, assessing QoL as a total percent-score (range 0-100). A high score indicates better QoL. | Immediately after the intervention | 
| Change in PinQ score among children with OAB and DUI compared among responders and non-responders to sacral TENS treatment. | Assessment of QoL using PinQ and compare among responders and non-responders to sacral TENS-treatment. PinQ (Pediatric Incontinence Questionnaire) is a validated tool, assessing QoL as a total score (range 0-80). A lower score indicates better QoL. | Immediately after the intervention | 
| Differences in maximum voided volume among responders and non-responders to sacral TENS treatment | Differences in maximum voided volume (MVV) in milliliters as assessed by the frequency and volume chart, compared among responders and non-responders to sacral TENS treatment. | Baseline AND immediately after the intervention | 
| Differences in voiding frequency among responders and non-responders to sacral TENS treatment | Differences in voiding frequency as assessed by the frequency and volume chart, compared among responders and non-responders to sacral TENS treatment. | Baseline AND immediately after the intervention | 
| Differences in VAS Urgency among responders and non-responders to sacral TENS treatment | Differences in VAS Urgency (visual analogue scale for urgency) in percent with a higher percent indicating a higher degree of urgency, compared among responders and non-responders to sacral TENS treatment. | Baseline AND immediately after the intervention | 
| Differences in urinary incontinence severity scores among responders and non-responders to sacral TENS treatment | Differences in urinary incontinence severity scores as assessed by Dry Pie, compared among responders and non-responders to sacral TENS treatment. | Baseline AND immediately after the intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcutaneous Electrical Nerve Stimulation, TENS, Functional Magnetic Resonance Imaging, fMRI