Brain Response Induced by Peroneal Electrical Transcutaneous Neuromodulation Invented for Overactive Bladder Treatment, as Detected by Functional Magnetic Resonance Imaging.

OBJECTIVES: In this study, we aimed to investigate whether peroneal electrical Transcutaneous Neuromodulation invented for overactive bladder (OAB) treatment elicits activation in brain regions involved in neural regulation of the lower urinary tract. MATERIALS AND METHODS: Among 22 enrolled healthy female volunteers, 13 were eligible for the final analysis. Functional magnetic resonance imaging (fMRI) (Siemens VIDA 3T; Erlangen, Germany) was used to compare the brain region activation elicited by peroneal electrical Transcutaneous Neuromodulation with the activation elicited by sham stimulation. Each subject underwent brain fMRI recording during eight 30-second periods of rest, alternating with 30-second periods of passive feet movement using the sham device, mimicking the motor response to peroneal nerve stimulation. Subsequently, fMRI recording was performed during the analogic "off-on" stimulation paradigm using peroneal electrical transcutaneous neuromodulation. Magnetic resonance imaging data acquired during both paradigms were compared using individual and group statistics. RESULTS: During both peroneal electrical Transcutaneous Neuromodulation and sham feet movements, we observed activation of the primary motor cortex and supplementary motor area, corresponding to the cortical projection of lower limb movement. During peroneal electrical Transcutaneous Neuromodulation, we observed significant activations in the brain stem, cerebellum, cingulate gyrus, putamen, operculum, and anterior insula, which were not observed during the sham feet movement. CONCLUSIONS: Our study provides evidence that peroneal electrical Transcutaneous Neuromodulation elicits activation of brain structures that have been previously implicated in the perception of bladder fullness and that play a role in the ability to cope with urinary urgency. Our data suggest that neuromodulation at the level of supraspinal control of the lower urinary tract may contribute to the treatment effect of peroneal electrical Transcutaneous Neuromodulation in patients with OAB.

Differences between brain responses to peroneal electrical transcutaneous neuromodulation and transcutaneous tibial nerve stimulation, two treatments for overactive bladder.

OBJECTIVES: To compare brain responses to peroneal electrical transcutaneous neuromodulation (peroneal eTNM®) and transcutaneous tibial nerve stimulation (TTNS), two methods for treating overactive bladder (OAB), using functional magnetic resonance imaging (fMRI). The present study was not designed to compare their clinical efficacy. MATERIALS AND METHODS: This study included 32 healthy adult female volunteers (average age 38.3 years (range 22-73)). Brain MRI using 3 T scanner was performed during three 8-min blocks of alternating sequences. During each 8-min block, the protocol alternated between sham stimulation (30 s) and rest (30 s) for 8 repeats; then peroneal eTNM® stimulation (30 s) and rest (30 s) for 8 repeats; then, TTNS stimulation (30 s) and rest (30 s) for 8 repeats. Statistical analysis was performed at the individual level with a threshold of p = 0.05, family-wise error (FWE)-corrected. The resulting individual statistical maps were analyzed in group statistics using a one-sample t-test, p = 0.05 threshold, false discovery rate (FDR)-corrected. RESULTS: During peroneal eTNM®, TTNS, and sham stimulations, we recorded activation in the brainstem, bilateral posterior insula, bilateral precentral gyrus, bilateral postcentral gyrus, left transverse temporal gyrus, and right supramarginal gyrus. During both peroneal eTNM® and TTNS stimulations, but not sham stimulations, we recorded activation in the left cerebellum, right transverse temporal gyrus, right middle frontal gyrus, and right inferior frontal gyrus. Exclusively during peroneal eTNM® stimulation, we observed activation in the right cerebellum, right thalamus, bilateral basal ganglia, bilateral cingulate gyrus, right anterior insula, right central operculum, bilateral supplementary motor cortex, bilateral superior temporal gyrus, and left inferior frontal gyrus. CONCLUSIONS: Peroneal eTNM®, but not TTNS, induces the activation of brain structures that were previously implicated in neural control of the of bladder filling and play an important role in the ability to cope with urgency. The therapeutic effect of peroneal eTNM® could be exerted, at least in part, at the supraspinal level of neural control.

Effect duration of the initial course of peroneal electrical Transcutaneous NeuroModulation in patients with overactive bladder.

PURPOSE: The aim of this prospective 12-month follow-up study is to evaluate the persistence of the treatment effect achieved during the initial course of peroneal electrical Transcutaneous NeuroModulation (peroneal eTNM®) in patients with overactive bladder (OAB). METHODS: This study enrolled 21 female patients who participated in two previous clinical studies designed to assess the efficacy and safety of peroneal eTNM®. The patients were left without subsequent OAB treatment and were invited to attend regular follow-up visits every 3 months. The patient's request for additional treatment was considered an indicator of the withdrawal of the treatment effect of the initial course of peroneal eTNM®. The primary objective was the proportion of patients with persisting treatment effect at follow-up visit 12 months after initial course of peroneal eTNM®. Descriptive statistics are presented using median, correlation analyses were computed using a nonparametric Spearman correlation. RESULTS: The proportion of patients with persistent therapeutic effect of the initial course of peroneal eTNM® was 76%, 76%, 62% and 48% at 3, 6, 9 and 12 months, respectively. There was a significant correlation between patient reported outcomes and the number of severe urgency episodes with or without urgency incontinence as reported by patients at each follow-up visit (p = 0.0017). CONCLUSION: The treatment effect achieved during the initial phase of peroneal eTNM® persists for at least 12 months in 48% of patients. It is likely that the duration of effects is dependent on the length of the initial therapy.

Prospective, Randomized, Multicenter Trial of Peroneal Electrical Transcutaneous Neuromodulation vs Solifenacin in Treatment-naïve Patients With Overactive Bladder.

PURPOSE: We investigated the safety and efficacy of peroneal electrical transcutaneous neuromodulation using the URIS neuromodulation system in a home-based setting in comparison with standard treatment using solifenacin in treatment-naïve female patients with overactive bladder. MATERIALS AND METHODS: A total of 120 patients were screened, of whom 77 were randomized in a 2:1 ratio to 12 weeks of treatment with daily peroneal electrical transcutaneous neuromodulation or solifenacin 5 mg. The primary endpoint was safety; efficacy assessments included proportion of responders, defined as subjects with ≥50% reduction in bladder diary-derived variables; Overactive Bladder-Validated 8-question Screener, and European Quality of Life-5 Dimensions questionnaire; and treatment satisfaction after 12 weeks of therapy. RESULTS: Seventy-one out of 77 randomized patients completed the study. In the peroneal electrical transcutaneous neuromodulation group 6/51 (12%) patients reported a treatment-related adverse event vs 12/25 (48%) in the solifenacin group (P < .001). No clinically significant changes were observed in any other safety endpoint. The proportions of responders in the peroneal electrical transcutaneous neuromodulation group vs the solifenacin group were 87% vs 74% with respect to Patient Perception of Intensity of Urgency Scale grade 3 urgency episodes, 87% vs 75% with respect to grade 3+4 urgency episodes, and 90% vs 94% with respect to urgency incontinence episodes. In post hoc analyses we observed significant improvement over time in multiple efficacy variables in both treatment arms. CONCLUSIONS: Peroneal electrical transcutaneous neuromodulation is a safe and effective method for overactive bladder treatment associated with a significantly lower incidence of treatment-related adverse events compared to solifenacin and a considerably better benefit-risk profile.

Peroneal electrical transcutaneous neuromodulation in the home treatment of the refractory overactive bladder.

INTRODUCTION AND HYPOTHESIS: The aim of this prospective, open-label, multicenter, noncomparative study was to evaluate the efficacy and safety of peroneal electrical transcutaneous neuromodulation (peroneal eTNM®) using the URIS® neuromodulation system as a home treatment for refractory overactive bladder (OAB). METHODS: The patients were treated with daily peroneal eTNM® for 30 min over a 6-week period. The primary endpoint was defined as the proportion of responders, i.e., participants with ≥ 50% reduction in the average daily sum of severe urgency episodes (defined as "I could not postpone voiding but had to rush to the toilet in order not to wet myself") and urgency incontinence episodes. In addition, bladder diary variables, symptom severity (OAB V8 questionnaire), treatment satisfaction (visual analog scale), and pain perception (visual analog scale) were evaluated at baseline (BL), at week 4 (W4), and at the end of treatment (EoT). Safety evaluations included monitoring of the incidence and severity of adverse events (AEs). Changes in time were analyzed using the nonparametric one-way ANOVA Friedman test for categorical variables and the Wilcoxon rank-sum test for the noncategorical variables. RESULTS: In total, 40 subjects were screened and 29 were included in the full analysis set. The proportion of responders was 86% at W4 and 79% at EoT. There was a significant reduction in frequency (p<0.001), number of severe urgency episodes (p< 0.001), number of urgency incontinence episodes (p=0.001), and number of nocturia episodes (p=0.002). There was a significant improvement in the OAB V8 score and treatment satisfaction (both p<0.001). Two mild treatment-related AEs were recorded. Both patients recovered without sequelae and completed the study. CONCLUSIONS: Peroneal eTNM® proved to be a highly effective and safe method for the home treatment of OAB, providing a therapeutic response in approximately 80% of patients.

Peroneal Electrical Transcutaneous NeuroModulation as a New Treatment for Patients with Overactive Bladder: An Initial Clinical Experience.

INTRODUCTION: The aim of this study was to determine whether peroneal electrical Transcutaneous NeuroModulation (peroneal eTNM®) using the URIS® neuromodulation system can be used in individuals with refractory overactive bladder (OAB). METHODS: Eighteen female patients with idiopathic OAB who failed previous behavioral and pharmacological therapy were enrolled. Patients were treated with the URIS® neuromodulation system using active electrodes placed on the popliteal fossa, targeting the peroneal nerve for 30 min once a week for 12 weeks. Changes in OAB symptoms and patient-reported outcomes from baseline to the end of the study were analyzed. A nonparametric Wilcoxon signed-rank test was used to assess changes in variables. Statistical significance was defined as p ≤ 0.05. RESULTS: We observed a significant reduction in micturition frequency (p = 0.022), number of severe urgency episodes (p < 0.001), urgency incontinence episodes (p = 0.001), and nocturia episodes (p = 0.027). A decrease in Patient Perception of Bladder Condition score (p < 0.001) was also observed. Posttreatment, 15 patients (83.3%) reported a moderate or significant reduction in their bladder bother. Throughout the study, two adverse events were recorded with no causal relationship to the study treatment. DISCUSSION/CONCLUSIONS: Our study documented a significant reduction in all OAB symptoms and an improvement in all patient-reported outcomes in patients treated with peroneal eTNM® using the URIS® neuromodulation system.

Peroneal Electric Transcutaneous NeuroModulation (eTNM®): A Novel Method for the Treatment of the Overactive Bladder.

Overactive bladder syndrome (OAB) is a prevalent medical problem with a significant impact on the quality of life of the affected individuals. Pharmacotherapy is considered the main treatment method, although it is discontinued in a significant proportion of patients due to inefficacy or associated side effects. If pharmacotherapy fails, patients can undergo peripheral neuromodulation of the somatic nerves of the lower limb or sacral neuromodulation; however, neither of these represents an ideal therapeutic tool. The Peroneal electric Transcutaneous NeuroModulation (Peroneal eTNM®), based on the selective stimulation of the peroneal nerve, is the new fully noninvasive neuromodulation method intended to treat OAB. The URIS® neuromodulation system, engineered to provide Peroneal eTNM®, consists of the URIS® device, URIS® active electrodes, and the biofeedback foot sensor (BFS). The unique design of the URIS® device and URIS® active electrodes allows for the use of a low voltage and current during neuromodulation, which significantly reduces the unpleasant sensations. The BFS allows for precise localization of the active electrodes and for continuous adjustment of the voltage and frequency to achieve the optimal therapeutic effect. The URIS® system adopts several principles of telemedicine, which makes it compatible with the US Food and Drug Administration (FDA) and European Union (EU) regulations for home-based use. This article describes both the Peroneal eTNM® method and the URIS® neuromodulation system, including its technical specifications and data from laboratory testing. Preclinical and early clinical data demonstrate the feasibility of this new method for noninvasive OAB treatment and possible implications for clinical practice.