Voiding dysfunction (VD) leading to urinary retention and incomplete bladder emptying is a common neurogenic lower urinary tract dysfunction (NLUTD) in multiple sclerosis (MS) patients. Currently, the only moderately effective management for MS patients with VD is catheterization, urging us to look into other therapeutic options. Transcranial rotating permanent magnet stimulator (TRPMS) is a noninvasive, multifocal neuromodulator that simultaneously modulates multiple cortical regions and the strength of their functional connections, using oscillating magnetic field.[1] In this pilot clinical trial (ClinicalTrials.gov NCT03574610), we aimed to investigate the therapeutic effects of TRPMS in modulating brain regions of interest (ROI) engaged with voiding initiation to improve VD in MS women.

Ten MS women with NLUTD and VD [defined as having %post-void residual/bladder capacity (%PVR/BC) ≥ 40% or being in the lower 10th percentile of the Liverpool nomogram] were recruited and informed consents were collected for this Institutional Review Board (IRB)-approved study. Subjects underwent concurrent functional magnetic resonance imaging/urodynamic (fMRI/UDS) evaluation (Figure 1a). MRI-compatible catheters were placed in subjects, with tubing extended out to the control room to connect to a UDS machine to monitor the bladder cycle during fMRI image acquisition. Bladder was filled with sterile saline until subjects signaled a strong desire to void. Subjects were then instructed to hold for 30 seconds, after which permission to void was given. Three to four cycles of bladder filling/emptying were performed.[2]
Predetermined ROI (Figure 1b) and their activation at voiding initiation were identified on patients’ baseline fMRI/UDS scans. Microstimulators were placed on the TRPMS cap corresponding to ROI to either stimulate or inhibit them. The treatment is therefore individualized for each patient based on their brain anatomy and activation at voiding initiation. Patients received ten 40-minute treatment sessions for two weeks on weekdays (Figure 1c). fMRI/UDS evaluation was performed again within one week post-treatment.[3]
Brain activation group analysis [via blood-oxygen-level-dependence (BOLD) signals averaged over ten patients] and clinical data (including non-instrumented uroflow and validated questionnaires regarding bladder symptoms) were collected and compared at baseline and post-treatment. At four-month follow-up, only clinical data were collected and compared to baseline.

After treatment, at voiding initiation, patients showed significantly increased activation in the right inferior frontal gyrus (IFG), one of the stimulated regions, along with other regions known to be activated at voiding initiation in healthy subjects such as the cingulate, temporal gyrus, cerebellum, and thalamus (Figure 2a). Additionally, at strong desire to void, we observed an increase in activation in brain regions associated with increasing bladder sensation, including the IFG, supplementary motor area, and thalamus, and decreased activation in the cerebellum, suggesting a more readily lifted micturition inhibition in preparation for voiding. 
%PVR/BC, one of the inclusion criteria used to define VD, significantly decreased (p=0.04). Other uroflow parameters also showed trends of improvement (Figure 2b). Significant improvement in bladder emptying and voiding symptoms was reported by patients via validated questionnaires, with significant difference observed in the Neurogenic Bladder Symptom Scores (NBSS) (Figure 2c). No treatment-related adverse effect was reported.
At four-month follow-up, all uroflow parameters of the first eight subjects moved closer to baseline values; however, there were still trends of improvement compared to baseline. Validated questionnaires showed continual trends of improvement, with significance in several sub-scores and questions regarding voiding symptoms.

Although regions such as the periaqueductal grey and pontine micturition center located in the brainstem have more extensive roles in bladder control and could serve as potential targets for intervention, they are located deeper in the brain and inaccessible with our current transcranial stimulation modalities. Therefore, we explored a noninvasive treatment for MS patients by modulating cortical regions that are known to be involved in at voiding initiation. Surprisingly, even though only cortical regions were modulated, following treatment we observed significant changes in other and deeper brain regions (in addition to modulated regions) that have been known to be involved in bladder control, both during voiding initiation and strong desire to void. These changes were also reflected in clinical improvement, both objectively through non-instrumented uroflow and subjectively through validated questionnaires, showing subjects’ improved ability to initiate voiding and empty their bladders. 
At four-month follow-up, uroflow parameters moved closer to baseline values, suggesting that treatment effects might have worn off after four months. However, statistical significance was observed in some of the questionnaires suggested that patients still perceived some improvement in symptoms. Although TRPMS modulation might have been able to strengthen the voiding network and functional connection of the nodes (brain regions) in each network immediately following treatment, these functional connections alter quicker than structural connections, possibly leading to bladder performance similar to baseline after four months. Therefore, future studies with longer treatment period or multiple treatment periods should be carried out to examine the lasting effects of TRPMS.

This is the first study to demonstrate the safety and efficacy of noninvasive, individualized multifocal cortical modulation in MS patients with VD. Modulating cortical regions controlling the initiation of voiding might lead to strengthening of the voiding network by inducing significant changes in activation and connectivity of both cortical and subcortical brain regions comprising the micturition circuits, resulting in clinical improvement in VD in female MS patients. Although future randomized control investigations are still needed, results of this study show the potential of TRPMS becoming a noninvasive, at-home treatment that could transform management of NLUTD in MS and other neuropathic patient populations.

Helekar SA, Convento S, Nguyen L, John BS, Patel A, Yau JM, et al. The strength and spread of the electric field induced by transcranial rotating permanent magnet stimulation in comparison with conventional transcranial magnetic stimulation. J Neurosci Methods. 2018;309:153-60.
Shy M, Fung S, Boone TB, Karmonik C, Fletcher SG, Khavari R. Functional magnetic resonance imaging during urodynamic testing identifies brain structures initiating micturition. J Urol. 2014;192(4):1149-54.
Tran K, Shi Z, Karmonik C, John B, Rajab H, Helekar SA, 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.