Supraspinal Control of Lower Urinary Tract Function in Healthy Controls and Patients With Bladder Dysfunction

Study Overview
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Brief Summary
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The purpose of this study is to provide profound insight into the supraspinal neuronal mechanisms and networks responsible for lower urinary tract (LUT) control and to verify, amend or adjust neuronal circuitry models established from findings in healthy subjects in the context of neurogenic and non-neurogenic LUT dysfunction.

Detailed Description
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The subject recruitment will be performed within the Neuro-Urology outpatient clinic at the Balgrist University Hospital and in collaboration with the Departments of Neurology, Urology and Gynecology at the University Hospital Zürich. The following subject groups will be recruited: 1) healthy controls (n=22), Non-neurogenic overactive bladder (NNOAB) patients (n=20), multiple sclerosis (MS) patients with OAB (n=15), MS patients without OAB (n=15), spinal cord injury (SCI) patients with neurogenic detrusor overactivity (n=24). After inclusion, all subjects and patients will undergo one to two functional magnetic resonance imaging (fMRI) sessions. NNOAB patients might undergo an additional fMRI session after receiving overactive bladder (OAB) treatment (such as antimuscarinics, intradetrusor injections of botulinum toxin type A). Spinal cord injury (SCI) patients with neurogenic detrusor overactivity will undergo an additional fMRI session 5-7 weeks after intradetrusor injections of botulinum toxin type A. High-resolution anatomical images and functional blood-oxygen-level-dependent (BOLD)-signal sensitive images will be acquired. In addition to the fMRI, diffusion tensor imaging (DTI) sequences will be recorded after the anatomical scans to provide information about the structural supraspinal connectivity. Study endpoints are changes of the BOLD signal in regard to location and intensity, structural and functional connectivity (FC) between previously described supraspinal centers involved in LUT control, and statistical differences of changes in BOLD signals, structural and functional connectivity between patients and healthy controls. All acquired fMRI data will be transferred to an off-line workstation running BrainVoyager QX or Statistical Parametric Mapping (SPM) Version 8. The functional data will be pre-processed for motion correction, spatial smoothing, linear trend removal, and temporal high-pass filtering. With both programs statistical analysis and graphical presentation of the results can be performed. The DTI records will be evaluated with SPM8, BrainVoyager QX or other programs like Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) and DTI-Studio. To estimate FC we will use SPM8 or the brain connectivity toolbox. Both softwares allow the estimation of rest- and task-related connectivity on single subject and group level with corrected statistical threshold. Overall, 96 subjects for the main study are estimated to be sufficient to demonstrate significant differences between groups.

Official Title
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The Bladder and the Brain - Investigation of the Supraspinal Neural Control of Lower Urinary Tract Function in Healthy Subjects and Patients With Neurogenic and Non-neurogenic Bladder Dysfunction Using Advanced Neuroimaging Techniques

Conditions
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Neurogenic Lower Urinary Tract Dysfunction, Multiple Sclerosis, Overactive Bladder, Spinal Cord Injury

Intervention / Treatment
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* Other: fMRI
* Other: bladder filling
* Other: bladder cooling
* Other: additional post-treatment fMRI scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy controls Right handed MR suitability Written informed consent unimpaired LUT function MS patients with OAB Right handed MR suitability Written informed consent diagnosis of MS according to the McDonald criteria Expanded Disability Status Scale (EDSS) ≤ 6 OAB symptoms since > 6 months ≥ 3 episodes of urinary urgency frequency > 8/24h with or without detrusor overactivity MS patients without OAB Right handed MR suitability Written informed consent diagnosis of MS according to the McDonald criteria Expanded Disability Status Scale (EDSS) ≤ 6 Patients with NNOAB Right handed MR suitability Written informed consent idiopathic OAB symptoms since > 6 months ≥ 3 episodes of urinary urgency frequency > 8/24h refractory to antimuscarinic treatment for ≥ 1 month indication for intradetrusor injections of Botulinumtoxin Type A willingness and ability to perform self-catheterization SCI patients with neurogenic detrusor overactivity Right handed MR suitability Written informed consent neurogenic detrusor overactivity due to SCI indication for intradetrusor injections of botulinum toxin type A Exclusion Criteria: Healthy controls impaired LUT function pregnancy or breast feeding no informed consent any craniocerebral injury or surgery any permanent ferromagnetic implant any previous surgery of the LUT or genitalia any anatomical anomaly of the LUT or genitalia any LUT malignancy postvoid residual urine volume (PVR) > 150ml current urinary tract infection any LUT symptoms ≥ 3 episodes of urinary urgency frequency > 8/24h MS patients with OAB pregnancy or breast feeding any permanent ferromagnetic implant any neurological or psychological disease despite MS any craniocerebral injury or surgery any previous surgery of the LUT or genitalia any anatomical anomaly or malignancy of the LUT or genitalia any metabolic disease PVR > 150ml any concomitant treatment for the LUT (e.g. neuromodulation) Stress urinary incontinence any condition other than MS that might explain OAB symptoms current urinary tract infection indwelling catheters or the necessity to perform self-catheterization MS patients without OAB pregnancy or breast feeding any permanent ferromagnetic implant any neurological or psychological disease despite MS any craniocerebral injury or surgery any previous surgery of the LUT or genitalia any anatomical anomaly or malignancy of the LUT or genitalia any metabolic disease PVR > 150ml any concomitant treatment for the LUT (e.g. neuromodulation) Stress urinary incontinence any LUT symptoms ≥ 3 episodes of urinary urgency frequency > 8/24h indwelling catheters or the necessity to perform self-catheterization detrusor overactivity current urinary tract infection Patients with NNOAB pregnancy or planned within next 8 months, breast feeding any permanent ferromagnetic implant any neurological, psychological, metabolic or cardiovascular disease any craniocerebral injury or surgery any previous surgery of the LUT or genitalia within the last year or that is related to the OAB symptoms any anatomical anomaly or malignancy of the LUT or genitalia PVR > 150ml Stress urinary incontinence indwelling catheters or the necessity to perform self-catheterization any concomitant treatment for the LUT (e.g. neuromodulation) current urinary tract infection SCI patients with neurogenic detrusor overactivity pregnancy or breast feeding any permanent ferromagnetic implant any neurological or psychological disease despite SCI any craniocerebral injury or surgery any previous surgery of LUT of genitalia any anatomical anomaly or malignancy of the LUT or genitalia any metabolic disease any concomitant treatment for the LUT (e.g. neuromodulation) current urinary tract infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy controls<br>Procedure: 1-2 fMRI measurements within 4 weeks from first exam. Measurements include repetitive retrograde bladder filling via transurethral catheter at different bladder volumes and temperatures (e.g. bladder cooling, body warm or room temperature)of the filling liquid. | Other: fMRI<br>* 2 measurements using functional magnetic resonance imaging in a 3T scanner<br>Other: bladder filling<br>* Repetitive retrograde bladder filling via transurethral catheter with different filling volumes using body warm saline during each of the fMRI measurements.<br>Other: bladder cooling<br>* Retrograde bladder filling via transurethral catheter with 4-8°C saline during each of the fMRI measurements.<br>|
| Experimental: MS with OAB<br>Procedure: 1-2 fMRI measurements within 4 weeks from first exam. Measurements include repetitive retrograde bladder filling via transurethral catheter at different bladder volumes and temperatures of the filling liquid. | Other: fMRI<br>* 2 measurements using functional magnetic resonance imaging in a 3T scanner<br>Other: bladder filling<br>* Repetitive retrograde bladder filling via transurethral catheter with different filling volumes using body warm saline during each of the fMRI measurements.<br>Other: bladder cooling<br>* Retrograde bladder filling via transurethral catheter with 4-8°C saline during each of the fMRI measurements.<br>|
| Experimental: MS without OAB<br>Procedure: 1-2 measurements within 4 weeks from first exam. Measurements include repetitive bladder filling via transurethral catheter at different bladder volumes and temperatures of the filling liquid. | Other: fMRI<br>* 2 measurements using functional magnetic resonance imaging in a 3T scanner<br>Other: bladder filling<br>* Repetitive retrograde bladder filling via transurethral catheter with different filling volumes using body warm saline during each of the fMRI measurements.<br>Other: bladder cooling<br>* Retrograde bladder filling via transurethral catheter with 4-8°C saline during each of the fMRI measurements.<br>|
| Experimental: NNOAB<br>Procedure: 1-2 measurements within 4 weeks from first exam. Measurements include repetitive bladder filling via transurethral catheter at different bladder volumes and temperatures of the filling liquid plus additional post-treatment fMRI scan 5 to 7 weeks after OAB treatment (such as antimuscarinics, intradetrusor injections of botulinum toxin type A) | Other: fMRI<br>* 2 measurements using functional magnetic resonance imaging in a 3T scanner<br>Other: bladder filling<br>* Repetitive retrograde bladder filling via transurethral catheter with different filling volumes using body warm saline during each of the fMRI measurements.<br>Other: bladder cooling<br>* Retrograde bladder filling via transurethral catheter with 4-8°C saline during each of the fMRI measurements.<br>Other: additional post-treatment fMRI scan<br>* Should NNOAB or SCI patients receive a study independent OAB therapy by their treating physician after the 2nd fMRI scan, they will be invited for an additional third fMRI scan.<br>|
| Experimental: SCI with neurogenic detrusor overactivity<br>Procedure: 1-2 measurements within 4 weeks from first exam. Measurements include repetitive bladder filling via transurethral catheter at different bladder volumes and temperatures of the filling liquid plus 1 additional post-treatment fMRI scan 5 to 7 weeks after intradetrusor injections of botulinum toxin type A | Other: fMRI<br>* 2 measurements using functional magnetic resonance imaging in a 3T scanner<br>Other: bladder filling<br>* Repetitive retrograde bladder filling via transurethral catheter with different filling volumes using body warm saline during each of the fMRI measurements.<br>Other: bladder cooling<br>* Retrograde bladder filling via transurethral catheter with 4-8°C saline during each of the fMRI measurements.<br>Other: additional post-treatment fMRI scan<br>* Should NNOAB or SCI patients receive a study independent OAB therapy by their treating physician after the 2nd fMRI scan, they will be invited for an additional third fMRI scan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bold signal | During fMRI measurements the changes of BOLD signal intensity in respect to certain supraspinal areas (e.g. pons, insula, anterior cingulate cortex, thalamus, supplementary motor area, prefrontal cortex) will be evaluated. Variables are age, bladder volume, urgency and attention. | baseline and 4 weeks | 
| Structural and functional connectivity | Acquired data from the above mentioned measurements will be used to analyze structural and functional connectivity between supraspinal areas involved in the LUT control, especially between prefrontal, thalamus, insula, and anterior cingulate cortex. Variables are age, bladder volume, urgency and attention. Correlations of neuronal activity from the fMRI-data will be estimated using SPM8, brain connectivity tool box. | baseline and after potential OAB treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Side effects | Pain, Lower urinary tract infection | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lower urinary tract, bladder, supraspinal control, neuroimaging, functional magnetic resonance imaging, diffusion tensor imaging, functional connectivity, neurogenic lower urinary tract dysfunction, overactive bladder, multiple sclerosis, spinal cord injury