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.

Clinical Utility of ß3-Adrenoreceptor Agonists for the Treatment of Overactive Bladder: A Review of the Evidence and Current Recommendations.

This nonsystematic review provides a summary of current evidence on the use of ß3-adrenoreceptor agonists (ß3-ARAs) for the treatment for lower urinary tract symptoms. Soon after their discovery in 1989, ß3-ARs were identified as a predominant adrenoreceptor subtype in the human urinary bladder. Although it is widely believed that ß3-ARAs cause detrusor relaxation, the effect on bladder afferent signaling likely plays an important role in their mechanism of action as well. In 2011 and 2012, mirabegron was approved for clinical use in overactive bladder (OAB) patients. Pooled analysis of data from prospective randomized studies on >60,000 OAB patients showed that when compared to placebo, mirabegron was superior with respect to reducing the frequency, number, and severity of urgency episodes, number of incontinence episodes and increasing dry rate, but not in reduction of nocturia episodes. The only side effect showing significantly higher incidence than placebo was nasopharyngitis. Mirabegron is approved for OAB treatment in all age-groups and in pediatric patients with neurogenic bladder. Vibegron is another ß3-ARA approved for OAB treatment in the US and Japan. Several large, multicenter, double-blind, randomized trials have documented statistically significant superiority of vibegron over placebo on all efficacy end points. Other ß3-ARAs are being developed; however, to date none has been introduced to clinical use. All ß3-ARAs provide efficacy similar to anticholinergics. They have a favorable safety profile and are well tolerated. Due to their different mechanisms of action, combination of ß3-ARAs with anticholinergic compounds allows for increased efficacy.

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.