Voiding dysfunction (VD), incomplete bladder emptying, and urinary retention are common symptoms of neurogenic lower urinary tract dysfunction (NLUTD) in multiple sclerosis (MS). Unfortunately, options are limited when it comes to effective treatments for VD, especially for MS patients. One treatment option with moderate effectiveness is self-catheterization, but it can be significantly morbid or not feasible for MS patients to perform depending on the progression of their disease. To address this problem, we have considered an intervention beyond the genitourinary system. Because the central nervous system is heavily involved in the proper function of the micturition cycle, we proposed to test the efficacy of neuromodulation in improving voiding function in patients with MS. Transcranial Rotating Permanent Magnet Stimulator (TRPMS) is a non-invasive device that allows for simultaneous modulation of multiple cortical brain regions. For this pilot clinical trial on the therapeutic effects of TRPMS on neurogenic VD in MS women, we hypothesize that there are baseline predictors associated with successful response to this novel treatment. Specific aims are to determine if the following measures can predict the clinical outcome: 1. Baseline clinical and urodynamics parameters and 2. Baseline grey matter brain activation and white matter integrity of the brain from fMRI and diffuse tensor imaging modalities.

Ten women with MS and neurogenic VD were recruited. Neurogenic VD was defined as either having %PVR/BC ≥ 40%, being <10th percentile of the Liverpool nomogram, or performing self-catheterization. Participants received 10 daily TRPMS treatment sessions in a 2-week period. In each session, five pre-determined regions of interest (ROI) known to be related to the micturition cycle were modulated [1]: right inferior frontal gyrus (IFG), left dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), right middle frontal gyrus (MFG), and right dorsolateral prefrontal cortex (dlPFC) [1]. Prior to receiving TRPMS treatment, baseline clinical data including non-instrumented uroflow and urodynamics parameters, PVR, and bladder symptom questionnaire were collected. Baseline neuro-imaging data were obtained with 7 Tesla MRI and diffusion tensor imaging (DTI) modalities. Each participant underwent functional MRI concurrently with a urodynamic study during the entire micturition cycle. Brain activation group analysis (via blood-oxygen-level-dependent (BOLD) signal averaged across ten patients) at voiding initiation (or attempt of voiding initiation) was collected. In addition, to study the structural connectivity of the brain, DTI parameters—fractional anisotropy (FA) and mean diffusivity (MD) were extracted from each white matter tract. These white matter tracts were then aligned onto ICBM-DTI-81 atlas to analyze the structural connectivity of the brain. Response to TRPMS treatment was defined as accomplishing at least one of the following: 1) %PVR/BC ≤ 20% post-treatment if ≥ 40% at baseline, 2) %PVR/BC decrease by half its baseline value or more, or 3) Liverpool nomogram percentile ≥25% post-treatment if <10% at baseline. Each subject was then assigned to the responder or non-responder group, accordingly. The baseline data of each arm was evaluated for any association with successful response to treatment. Student’s t-test was used for BOLD signals. Fisher’s exact test was used for categorical variables. Welch’s T-test or Wilcoxon signed-rank test were used for continuous variables, depending on the data’s normality.

Ten MS women completed the two-week neuromodulation as planned. Six out of ten participants enrolled in the study showed improvement after TRPMS treatment, using the aforementioned response criteria. At baseline, the responder group (n=6) showed significantly lower values in the number of deliveries, first sensation of bladder filling (FSF) during UDS, and consequences domain in the neurogenic bladder symptom score (NBSS) questionnaire compared to non-responders (n=4), shown in Table 1. BOLD signal analysis revealed multiple cortical areas of the brain with significantly higher activation in several regions important in bladder function (Figure 1). There was no significant difference in the white matter integrity between the two groups based on the DTI analysis.

This is a small non-randomized pilot study and our results need to be interpreted with caution. However, more than half of the participants with MS and VD showed improvement in their voiding function following TRPMS. The significantly lower volume of the first sensation of the bladder during filling could be partially due to less severe NLUTD, evidenced by the significantly better NBSS consequences subscore. However, the disability burden of MS alone does not seem to have a significant contribution to response based on the statistical finding on EDSS. The significant difference in the number of deliveries should be taken with a careful evaluation, since pelvic floor muscle dysfunction (common with pregnancy and delivery) may serve as a confounding factor, possibly masking the therapeutic effect of TRPMS. Interestingly, two of the modulated cortical ROI—right inferior frontal gyrus and right middle frontal gyrus—showed higher activation in the responder group at baseline. In addition, the anterior cingulate gyrus and precentral gyrus which are other regions thought to be involved in initiation and continuation of voiding in healthy individuals exhibited significantly higher activation in the responder group [1,2]. Such functional connectivity patterns with higher activation in the responder group may reflect more preserved cortical integrity of the brain especially with regards to the micturition cycle. The absence of any significant difference in the white matter integrity is consistent with the lack of significant difference observed in the EDSS scores between the two groups. Even the two white matter tracts—superior longitudinal fasciculus (SLF) and anterior thalamic radiata (ATR)—thought to be related to the micturition cycle from literature did not show a significant difference in the DTI parameters between responders and non-responders [3]. This may be partially explained by the disease progression pattern of MS which is disseminated in time and space affecting distinctive areas of the white matter in different individuals.

TRPMS is a noninvasive and individualized tool designed to modulate—both stimulate and/or inhibit—multiple specific gray matter regions at the same time. It showed efficacy in more than half of this cohort. This study revealed baseline clinical/UDS parameters and functional connectivity that may predict successful response to TRPMS treatment. Such information could serve as the foundation and basis for inclusion criteria or better phenotyping for future trials investigating the effects of TRPMS in improving bladder function.

Tran K, Shi Z, Karmonik C, et al. Therapeutic effects of non-invasive, individualized, transcranial neuromodulation treatment for voiding dysfunction in multiple sclerosis patients: study protocol for a pilot clinical trial. Pilot Feasibility Stud. 2021;7(1):83. Published 2021 Mar 24. doi:10.1186/s40814-021-00825-z
Griffiths D. Neural control of micturition in humans: a working model. Nat Rev Urol. 2015;12(12):695-705. doi:10.1038/nrurol.2015.266
Tadic SD, Griffiths D, Murrin A, Schaefer W, Aizenstein HJ, Resnick NM. Brain activity during bladder filling is related to white matter structural changes in older women with urinary incontinence. Neuroimage. 2010;51(4):1294-1302. doi:10.1016/j.neuroimage.2010.03.016