Brain Targets in Patients With Bladder Emptying Difficulties

Study Overview
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Brief Summary
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The goal of this study is to identify brain centers specifically associated with initiation of voiding in patients with neurogenic bladder dysfunction. Currently there is no study that has evaluated brain centers involved in initiation of voiding in patients with neurogenic voiding dysfunction. Patients with neurogenic bladder secondary to etiologies such as Multiple Sclerosis, Parkinson's disease, and Cerebrovascular accidents will be recruited in this study. Patients will be categorized into 2 groups, those who have trouble emptying their bladder and those who urinate appropriately. Our existing and unique functional magnetic resonance imaging (fMRI)/ urodynamics (UDS) platform is an ideal platform to identify brain regions involved in bladder emptying disorders as seen in patients with neurogenic bladder dysfunction and will be used for this study. After characterizing brain regions involved in bladder emptying, the investigator propose to use noninvasive transcutaneous magnetic stimulation in a subset of patients with voiding dysfunction in aim 3.

Detailed Description
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Difficulty in bladder emptying (Voiding dysfunction,VD) is a costly urinary condition that leads to urinary tract infections/stones, sepsis, bladder loss, and permanent kidney damage. VD can be present in patients with or without neurologic/brain disorders. Currently the only available therapies for VD include bladder catheters or intermittent self-catheterization. Catheterization is a burden especially in patients with nerve damage, hand skills may be limited. The cost and morbid side effects of catheterizations in patients (blood in the urine, pain, trauma, strictures, and infections) requires investigators to develop new therapies that are beyond the bladder. Such new therapies could target the brain (where bladder control is located). In this proposal, investigators plan to further characterize the brain regions involved in bladder emptying for each patient and ,perform brain modulation, targeting these regions as a possible therapy for VD. Patients with bladder dysfunction will be divided into two groups: Group 1: patients with VD; and Group 2: patients without VD. Specific Aim 1: To evaluate brain pattern in both groups and compare them to each other at the time of bladder emptying. Specific Aim 2: To evaluate reliability of the nerve fibers in the brain and see whether damage to these fibers is related to difficulty emptying the bladder. Specific Aim 3: To perform non-invasive brain stimulation on specific regions of the brain responsible for bladder control to improve bladder emptying. This study is an interventional Study: The investigators have completed a well-powered study on twenty-seven female MS patients during their bladder storage phase. Aims 1 and 2 use the data from previously completed trial and investigators will perform additional imaging analysis on it. Aim 3 is a new and small trial in which investigators planned to modulate the regions of the brain that are related to bladder control. Approximately 16 study participants will be enrolled at Houston Methodist, and 16 throughout the study.

Official Title
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Supraspinal Mechanisms Involved in Voiding Dysfunction.

Conditions
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Neurogenic Bladder, Multiple Sclerosis, Voiding Dysfunction

Intervention / Treatment
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* Device: Transcranial Rotating Permanent Magnet Stimulator (TRPMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for subjects with neurogenic bladder: Patients with clinical diagnosis of neurogenic bladder History of any neurologic illness or injury (including but not limited to spinal cord injury, Multiple Sclerosis, Stroke, spina bifida, Parkinson's, major spine surgery) 18 years or older Specifics for MS patients: Adult female patients with clinically stable MS [Expanded Disability Status Score (EDSS) ≤6.5], with bladder symptoms ≥3 months, will be screened. Patients will be considered to have VD if they have an increased Postvoid Residual (≥ 20% Maximum Cystometric Capacity). Patients who perform self-catheterization will be included in the VD category as well. Exclusion Criteria: Exclusion Criteria for subjects with neurogenic bladder: Men (for aims 1 and 2 only), anatomical bladder outlet obstruction (anti-incontinence procedures, urethral strictures, or advanced pelvic organ prolapse). Severe debilitating MS, history of seizures, pregnancy or planning to become pregnant, contraindications to MRI, history of augmentation cystoplasty. Patients with active urinary tract infection (UTI) can be treated and subsequently screened for the trial. Positive urine pregnancy test at enrollment (There are no known risks to a subject's fetus. There is no known teratogenic risk associated with urodynamics or fMRI) - Cognitively impaired patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects with Multiple Sclerosis and Voiding Dysfunction<br>Subjects with Multiple Sclerosis (MS) and voiding dysfunction (VD). In this group 'Transcranial Rotating Permanent Magnet Stimulator (TRPMS)' device will be used. | Device: Transcranial Rotating Permanent Magnet Stimulator (TRPMS)<br>* TRPMS is a wearable non-invasive transcranial rotating permanent magnet stimulator. It has been determined to be a Non Significant Risk device by the FDA. The amount and frequency of therapy are prescribed by the physician, and the device is custom configured to the patient to deliver the required amount of treatment. The device does not turn on until it is time for the treatment. It consists of three main parts: Neoprene cap with microstimulator(s), stimulator console (device controller box) and the tablet with TRPMS app which activates the console. The neoprene cap prevents the microstimulator(s) from coming in direct contact with the scalp. Microstimulators deliver the magnetic stimulation to the brain based on a prescription program uploaded in the stimulator controller.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Brain Activity After Treatment Measured Using Functional MRI | Here we measured changes in brain activation in modulated brain regions of interest (ROI) via blood oxygen level-dependent (BOLD) signals during strong desire to void and voiding initiation (attempt). We determined if there was a significant increase or decrease in activity (voxel signal) after treatment using the following criteria: 1) increase in activation was defined as T-value greater than 2.074 and 2) decrease in activation was defined as T-value less than 2.074. | Baseline to three weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Objective Clinical Outcomes Following Treatment | The objective clinical assessment included changes in post void residual (PVR), voided volume (VV) and bladder capacity (BC) in participants after treatment as compared to baseline. PVR measures the volume of urine (cc/mL) that is left after voiding. VV measures the volume of urine that is voided (cc/mL). BC measures the volume of urine (cc/mL) the bladder has a capacity to hold, this value is calculated by adding the VV + PVR values obtained. | Baseline, after treatment and 4 month follow up | 
| Changes in %Post-Void Residual/Bladder Capacity (PVR/BC) Following Treatment | Objective clinical assessments included changes in post void residual (PVR) and bladder capacity in participants after treatment. PVR measures the volume of urine (cc/mL) that is left after voiding. BC measures the volume of urine (cc/mL) the bladder has a capacity to hold. % PVR/BC measures how much of the overall volume is left after voiding, showing how efficient a voiding is before and after treatment. | Baseline, after treatment and 4 month follow up | 
| Changes in Non-instrumented Uroflow Variable Qmax Following Treatment | The objective clinical assessment included changes in non-instrumented uroflow variables such as Qmax, in participants after treatment as compared to baseline. Qmax values reported here correspond to the peak urine flow (mL/s) seen during uroflowmetry testing. | Baseline, after treatment and 4 month follow up | 
| Changes in Liverpool Nomogram Following Treatment | The objective clinical assessment included changes in non-instrumented uroflow variables such as Liverpool nomogram in participants after treatment as compared to baseline. The Liverpool nomogram provides normal reference ranges for the maximum and average urine flow rates over a wide range of voided volumes. It is presented as a percentile ranking depending on the flow rate and voided volume for each participant. | Baseline, after treatment and 4 month follow-up | 
| Changes in Subjective Clinical Outcomes Following Treatment - Urinary Distress Inventory, Short Form (UDI-6) Questionnaire | Our subjective clinical assessment included changes in validated questionnaires. This assessment has 6 questions and is used to assess life quality and symptom distress for urinary incontinence in women. We report raw scores here for questions pertaining to voiding symptoms. Each question has the following score range: 0-4 (with the highest score associated with worse symptoms). | Baseline, after treatment and 4 month follow up | 
| Changes in Subjective Clinical Outcomes Following Treatment - American Urological Association Symptom Score (AUASS) Questionnaire | Our subjective clinical assessment included changes in validated questionnaires. This assessment has 8 questions and is used to assess how bothersome urinary symptoms are and quality of life. We report raw scores here for questions pertaining to voiding symptoms. Questions 1-7 have the following score range: 0-5 (with the highest score associated with worse symptoms). The last question pertains to quality of life and has a score range of: 0-6 (with the highest score associated with very reduced quality of life). | Baseline, after treatment and 4 month follow up | 
| Changes in Subjective Clinical Outcomes Following Treatment - Neurogenic Bladder Symptom Score (NBSS) Questionnaire | Our subjective clinical assessment included changes in validated questionnaires. This assessment has 24 questions that measure bladder symptoms across 3 different domains: incontinence (score range: 0-29), storage and voiding (score range: 0-22), and consequences (score range: 0-23); the highest score is associated with worse symptoms. The last question focuses on quality of life scored from 0 (pleased) to 4 (unhappy). We report raw scores here for all domains and QoL. | Baseline, after treatment and 4 month follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurogenic bladder, Functional Neuroimaging, Transcranial Rotating Permanent Magnet Stimulator (TRPMS)