Noninvasive brain stimulation in the treatment of functional urological and pelvic floor disorders: A scoping review.

Utilizing our research strategy, we identified 14 articles, with a prospective, non-randomized, randomized, controlled, open, and double-blind design. Oxford level of evidence utilized was 1 or 2. Details of our results are summarized in Table 1 . The average number of patients included in the studies is 10. Men and/or women were enrolled. Patients included had the followings diseases: MS, Parkinson's Disease (PD), Spinal cord injury (SCI), refractory pelvic pain, urologic pelvic pain syndrome (UCPPS), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), CPPS and endometriosis. The pelvic floor disorders retrieved exclusively pelvic pain, which was evaluated with various scales and questionnaires. LUTS were widely explored in different dimensions like urodynamics (UDS), scales, questionnaires, electromyography (EMG), functional magnetic resonance imaging (fMRI), and ultrasound (US).

A scoping review of the literature and ongoing clinical trials was conducted using Pubmed, Web of Science, Embase, and ClinicalTrial.gov , including all articles published in the subject matter until June 30th, 2022. The PRISMA’s guidelines [ 7 ] were applied, to match good practice recommendations for a literature review. A formula with keywords and MESH terms was used to identify articles and can be found in supplementary materials . Only articles in English or French were included, the software Covidence ® was utilized as a screening method to do a blind selection by two different reviewers. As part of the inclusion criteria, only abstracts or titles that included noninvasive transcranial therapy and pelvic floor or urinary disorders in human adult individuals were included. Review articles, case reports (<5 patients), letters, and protocol studies were excluded. Results from the literature search and selected articles are shown in the PRISMA flow chart in figure 2 . Full articles were retrieved for inclusion in the final selection and references from said articles were searched for applicable supplementary publications. Next, we reviewed the abstracts and full articles, and classified them using the updated Oxford Level of Evidence [ 8 ], identifying methodological quality, design and bias. Pelvic floor disorders were described according to the nature of the devices and the protocols used for delivery of the stimuli. Then, analysis of the effectiveness of treatment was made by individualizing the two possible indications (LUTS or pelvic pain), taking into account the number of patients in the studies.

Noninvasive stimulation is produced by two main techniques, magnetic fields (TMS, Transcranial Rotating Permanent Magnet Stimulator-TRPMS) and electric current (tDCS). LUTS was studied in 5 articles [ 9 - 13 ], pelvic pain for the 8 others [ 14 - 21 ] and 1 [ 22 ] both of them. rTMS was the most common technique used by authors in 10 publications, including the first study by Centonze et al.[ 9 ] in 2007. The Magstim Company (UK) provided the first device for medical use in the field of depression and then pain. For both LUT and pelvic pain, 9 of the authors used the Magstim 200, Magstim Rapid2, or Bistim2 ( Figure 1B ). Only the Pinot-Monange et al. [ 17 ] study used the MagProX100 (Magventure Tonika Elektronic, Denmark) device. During treatment the stimulator was connected to the figure-of-eight coil and was held over the head with the handle pointing backward, to elicit a “motor hotspot”. The dominant hemisphere or both sides when possible was targeted [ 19 ]. The area near Cz-vertex in the 10-20 System to elicit the “soleus muscle hotspot” was the cortex target in four LUTS treatment studies. For pelvic and LUT pain, the C3 and/or C4 area corresponding to the M1 (primary cortex motor) was chosen by 5 authors. This area elicits the first interosseous hand muscle and the pelvic floor area. Only Yani et al. [ 18 ] tested the supplementary motor area (SMA) for pelvic pain. The therapeutic protocol varied from one study to another. For LUTS treatment, the frequency varied from 1 to 5Hz, 900 to 1000 stimuli with 65 to 120% MSO/RMT. For pelvic pain treatment, the frequency varied from 10 to 20Hz, 1500 to 2000 stimuli, and 80 to 110% resting motor threshold (RMT) with an average of 20 minutes of treatment. However, Calabro et al. [ 20 ] preferred to use 5Hz and 110% active motor threshold (AMT) over RMT, for the need of the study that couples rTMS with recorded focal muscle vibration. To go further, Yani et al. tested two types of stimuli: 10hz and 1Hz therapy, by applying the principle that cortex areas inhibition and stimulation are frequency dependent. tDCS is an alternative noninvasive treatment that uses direct electrical currents to stimulate the same specific brain areas. Two electrodes are placed over the head to modulate cortical activity. Only 2 studies explored this modality with a specially developed battery-driven, constant current stimulator (Schneider Electronic, Germany). They used a 1 or 2mA current, to stimulate the M1 for 20min therapy. A third study used 2 devices (Active Dose Company, Thailand) to stimulate simultaneously the M1 and the dorsolateral prefrontal cortex, with a 0,3mA intensity for each area. The most recent study, a pilot experiment from Khavari et al. represents the next step of the stimulation protocols. The paradigm investigated in this study was based on the concept that cortex areas involved in LUT function are numerous so modulations must be multiple and simultaneous, with both stimulation and inhibition targets. They used a custom made TRPMS device, able to produce multiple focal magnetic fields at the same time. Areas targeted for LUTS therapy were F3, F4, C3, C4, and Cz, 3 areas were inhibited and 2 were stimulated for a total of 40 min of treatment. Therapeutic protocols were delivered once a day, five consecutive days for 10 studies. Others varied from one unique session to 10 consecutive ones. One or two weeks was the most common duration. Assessment of measurement tools for primary and secondary outcomes followed a very heterogenous design, depending on the various study designs. Over the six studies exploring noninvasive stimulation with magnetic fields (rTMS or TRPMS), 3 are about MS, 2 for SCI, and 1 for PD patients. The patient's symptoms were overactive bladder, with or without urethral sphincter dyssynergia, or underactive bladder. They had significant improvements with TMS. Post void reduction decrease for 3 authors with 2 Pdet-Qmax positive association. Bladder capacity increased for 2 and decreased for 1. Patients felt subjectively better during the voiding phase, according to results obtained by multiple validated questionnaires. The International Prostate Symptom Score and the first sensation of bladder filling were greater for PD patients as reported by Brusa et al. [ 10 ]. Vasquez et al. [ 11 ] explored eliciting modulation of the pudendo-anal reflex (PAR) in response to rTMS with EMG in SCI patients, results were analyzed for its basic science findings. The therapy displayed a significant facilitating effect on the PAR, which confirm a real motor effect in the theoretical LUT area. These results are limited and the last recommendations on TMS therapy, highlight the lack of evidence on LUT treatment [ 5 ]. All study populations were small (N≤13), except for Vasquez et al., and more power is essential to asses a clinical effect. However, all of these data converged and showed a real effect on various populations of patients. The rTMS and tDCS studies were tested in 7 complex pelvic pain studies. All patients had medical and surgical treatment failure with a diagnosis of refractory pelvic pain for bladder pain syndrome/interstitial cystitis or UCPPS which include CP and CPPS. Kang et al. [ 15 ] studied neuropathic pain in SCI patients, while Pinot-Monange et al. tested rTMS for endometriosis. A significant decrease in pain was present in eight articles with analogic or numeric pain scales (visual analogue scale -VAS- numeric rating scale). Bladder pain index showed an improvement for two of the studies. Country and disease-specific scales for various dimensions of pelvic pain (Functionnal Pelvic Pain Syndrom, Neuropathic Pain Syndrom Inventory, McGill, National Institute of Health Chronic Prostatitis Symptom Index, Oswestry Disability Index) were also effective to ensure the efficacy of rTMS and tDCS. In addition, two studies looked for the mechanism of action underneath analgesic therapy. Simis et al. [ 16 ] utilized magnetic resonance spectroscopy (MRS) to explore the central neural network and its activity with tDCS. They found a positive correlation between thalamus and pelvic pain levels. MRS positive and negative correlations between primary cortex motor and VAS-level Pelvic pain patients were also discovered. In a more physiopathological study design with an EMG and fMRI protocol, Yani et al. confirmed a bond between the SMA and pelvic floor pain. Refractory pain is difficult to manage, patients are constantly suffering and the therapeutic options available often fail, emphasizing the importance of the analgesic effect of noninvasive stimulation demonstrated by Rossini et al. [ 4 ]. Applications for pelvic pain are a logical way for the field of rTMS to continue to grow, as can be seen from the increase in publications over the last decade. In a multidisciplinary approach, this new therapeutic offers new hope for patients. However, more studies are needed to move in this direction. The lasting effect of noninvasive brain stimulation on treating PFDs is variable and relies on many different parameters. One of the most relevant to compare is the total number of days of stimulation provided. The range of effect duration when stimulation occurred for five consecutive days was about one to four weeks. In contrast, when patients were treated for two weeks, the effects lasted about one to four months as shown by multiple site stimulation delivered via TRPMS by Khavari et al. The effects of tDCS and rTMS appear similar in the absence of a comparative study. Ten studies had safety evaluations in their protocols. None found any serious adverse effects using the different devices. Headaches were rare and only reported in 5 to 10% of cases. With the stimulation parameters set up by the studies described in this review, side effects were demonstrated to be very low compared to safety recommendations for rTMS[ 23 ]. Additionally, although tDCS has been used extensively in experimental research and side effects are low, there is a lack of data about safety in symptomatic patient protocols [ 24 ]. Our study protocol is limited by the lack of assessment of the risk of bias and of certainty, as recommended by the PRISMA checklist. With an average number of 10 patients included in studies (except for the El Habayashi study, which enrolled 40 subjects), the statistical differences reported here for various clinical and paraclinical parameters are to be considered as exploratory data from pilot studies. Although the design of the studies is Oxford Level 1 or 2, with prospective controlled trials, these results should only be considered as validating preliminary effects of noninvasive stimulation in the indication of pelvic floor disorders. In addition, only 5 out of 14 studies are blinded and placebo-controlled. Therefore, the short duration of stimulation does not rule out a potential placebo effect.

Transcranial noninvasive brain stimulation has become a feasible therapy for LUT and pelvic pain treatment in the near future, and the evidence of its effectiveness is numerous. Although, thorough knowledge of cortical control will be required to better target and stimulate/modulate areas of interest. As even if the areas of interest are identified, the intricate neural control and interaction between different areas remain ill-defined. The modulation of one, or even several areas at the same time playing a role on LUT opens a door to incredible possibilities, still largely unknown. Further studies, with larger participant numbers, are absolutely necessary to validate the extent, intensity and duration of these therapeutic effects.

Brain transcranial stimulation is a technique that uses neuronal membrane depolarization to initiate action potentials to modulate their excitability. This depolarization can be induced by an electric or magnetic stimulus. This principle was first described in 1994 by Rossini et al. [ 1 ]. When subjected to external perturbations, the neural network reorganizes and interacts with each other in different ways, this mechanism is the basis of cortical plasticity. Repetitive pulses for several minutes with a magnetic or electric field applied to the brain cortex can induce network change, with more long-lasting effects. Early approaches with electrical high voltage have been supplanted by two more comfortable and painless techniques, transcranial magnetic stimulation (TMS) in 1985 by Barker et al. [ 2 ] and transcranial direct current stimulation (tDCS) by Nitsche and Paulus, in 2000 [ 3 ]. Therapeutic applications can be achieved by stimulation or inhibition of a given cortical network. With neuronavigation and noninvasive stimulation technology advancement in the last twenty years, stimulation targeting more specific brain regions has become feasible ( Figure 1 ). Research in brain behavior, psychiatric disorders, depression, and neurogenic pain were then developed. Although repetitive TMS (rTMS) has been around for decades, only recently has it become a fundamental therapy for depression, yielding great results. Not only has it received clearance for clinical use by the Food and Drug Administration (FDA) in the United States, but it has also become a recommended application for depression by the International Federation of Clinical Neurophysiology (IFCN) [ 4 ]. Moreover, recent research on neuropathic and non-neuropathic pain, as shown in a review by Lefaucheur et al. [ 5 ], has demonstrated a consistent painkiller effect of this noninvasive therapy. Therefore, establishing rTMS as a novel multidimensional therapeutic option for various pathologies that are difficult to treat. The time has come to extend the scope of noninvasive neurostimulation to a new field: functional pelvic floor disorders. Lower urinary tract symptoms (LUTS), pelvic pain, or bowel issues are possible applications for this therapy. The principle of cortical neuromodulation comes directly from the application of electrical currents to peripheral nerves [ 4 ]. Peripheral neuromodulation is a well-established therapy, commonly utilized to improve LUTS and pain. It makes sense to try brain stimulation where peripheral neurostimulation has shown effectiveness. A recent review by Ruiz et al. [ 6 ] underlines the applicability of rTMS in Multiple Sclerosis (MS) for spasticity, manual dexterity, gait, and memory. They highlight its promising application in urology for LUTS. However, due to the heterogeneity of stimulation strategies and protocol design, it is difficult to know whether noninvasive transcranial stimulation could indeed be beneficial in this indication. Here, we performed a scoping review of the current literature to identify the current use of noninvasive transcranial stimulation for functional urological and pelvic floor disorders.