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Objective: The purpose of this systematic review was to characterize methodologies reported in the literature to elicit and record pudendal somatosensory evoked potentials (SEPs) in human adults., Methods: We conducted an electronic literature search in MEDLINE, Embase, CENTRAL, and CINAHL for studies that elicited pudendal SEPs via electrical stimulation and recorded responses though electroencephalography. From included studies, we extracted methodological details of how the SEPs were evoked and recorded., Results: 132 studies were included in our review. The majority of participants were male (n = 6742/8526, 79%). Almost all studies stimulated the dorsal nerve of penis/clitoris. Stimulus parameters varied, with most standardizing stimulus intensity to 2-4x perceptual threshold, pulse duration to 0.1-0.2 ms, and frequency to 3 Hz. The number of stimuli recorded varied by clinical population., Conclusions: Our results demonstrate the inconsistencies of pudendal SEP methodology in the literature, with the majority (77%) of publications not reporting enough detail to reasonably replicate their protocol. Most research to date has been conducted in males, highlighting the paucity of female pelvic neurophysiology research., Significance: We propose a Pudendal SEP Reporting Checklist for adequate reporting of pudendal SEP protocols. Optimal sex- and patient-specific methodologies to investigate all branches of the pudendal nerve need to be established., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective . Previous preclinical and clinical studies have demonstrated that pudendal nerve is a promising target for restoring bladder control. The spatial proximity between the pudendal nerve and its accompanying blood vessels in the pudendal canal provides an opportunity for endovascular neurostimulation, which is a less invasive approach compared to conventional chronically implanted electrodes. In this study, we investigated the feasibility of excitatory stimulation and kilohertz-frequency block of the compound pudendal nerve in sheep using a stent-mounted electrode array. Approach . In a set of acute animal experiments, a commercially available hexapolar electrode catheter was introduced in the unilateral internal pudendal artery to deliver bipolar electrical stimulation of the adjacent compound pudendal nerve. The catheter electrode was replaced with a custom-made stent-mounted electrode array and the stimulation sessions were repeated. Global electromyogram activity of the pelvic floor and related sphincter muscles was recorded with a monopolar electrode placed within the urethra concurrently. Main results . We demonstrated the feasibility of endovascular stimulation of the pudendal nerve with both electrode types. The threshold current of endovascular stimulation was influenced by electrode-nerve distance and electrode orientation. Increasing the axial inter-electrode distance significantly decreased threshold current. Endovascular kilohertz-frequency nerve block was possible with the electrode catheter. Significance . The present study demonstrated that endovascular stimulation of the pudendal nerve with the stent-mounted electrode array may be a promising less invasive alternative to conventional implantable electrodes, which has important clinical implications in the treatment of urinary incontinence. Endovascular blocking of pudendal nerve may provide an alternative solution to the bladder-sphincter dyssynergia problem in bladder management for people with spinal cord injury., (Creative Commons Attribution license.)

Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; -1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5-2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with β-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of β-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Female sexual dysfunction (FSD) affects an estimated 40% of women. Unfortunately, FSD is understudied, leading to limited treatment options for FSD. Neuromodulation has shown some success in alleviating FSD symptoms. We developed a pilot study to investigate the short-term effect of electrical stimulation of the dorsal genital nerve and tibial nerve on sexual arousal in healthy women, women with FSD, and women with spinal cord injury (SCI) and FSD., Materials and Methods: This study comprises a randomized crossover design in three groups: women with SCI, women with non-neurogenic FSD, and women without FSD or SCI. The primary outcome measure was change in vaginal pulse amplitude (VPA) from baseline. Secondary outcome measures were changes in subjective arousal, heart rate, and mean arterial pressure from baseline. Participants attended one or two study sessions where they received either transcutaneous dorsal genital nerve stimulation (DGNS) or tibial nerve stimulation (TNS). At each session, a vaginal photoplethysmography sensor was used to measure VPA. Participants also rated their level of subjective arousal and were asked to report any pelvic sensations., Results: We found that subjective arousal increased significantly from before to after stimulation in DGNS study sessions across all women. TNS had no effect on subjective arousal. There were significant differences in VPA between baseline and stimulation, baseline and recovery, and stimulation and recovery periods among participants, but there were no trends across groups or stimulation type. Two participants with complete SCIs experienced genital sensations., Conclusions: To our knowledge, this is the first study to measure sexual arousal in response to short-term neuromodulation in women. This study indicates that short-term DGNS but not TNS can increase subjective arousal, but the effect of stimulation on genital arousal is inconclusive. This study provides further support for DGNS as a treatment for FSD., Competing Interests: Conflict of Interest Tim M. Bruns reports serving on the Scientific Advisory Board and received stock options for Stimulai Therapeutics. Priyanka Gupta reports serving on the Medical Advisory Board and received stock options for Stimulai Therapeutics. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction and Hypothesis: Preclinical studies have shown that neuromodulation can increase vaginal blood perfusion, but the effect on vulvar blood perfusion is unknown. We hypothesized that pudendal and tibial nerve stimulation could evoke an increase in vulvar blood perfusion., Methods: We used female Sprague-Dawley rats for non-survival procedures under urethane anesthesia. We measured perineal blood perfusion in response to 20-minute periods of pudendal and tibial nerve stimulation using laser speckle contrast imaging (LSCI). After a thoracic-level spinalization and a rest period, we repeated each stimulation trial. We calculated average blood perfusion before, during, and after stimulation for three perineal regions (vulva, anus, and inner thigh), for each nerve target and spinal cord condition., Results: We observed a significant increase in vulvar, anal, and inner thigh blood perfusion during pudendal nerve stimulation in spinally intact and spinalized rats. Tibial nerve stimulation had no effect on perineal blood perfusion for both spinally intact and spinalized rats., Conclusions: This is the first study to examine vulvar hemodynamics with LSCI in response to nerve stimulation. This study demonstrates that pudendal nerve stimulation modulates vulvar blood perfusion, indicating the potential of pudendal neuromodulation to improve genital blood flow as a treatment for women with sexual dysfunction. This study provides further support for neuromodulation as a treatment for women with sexual arousal disorders. Studies in unanesthetized animal models of genital arousal disorders are needed to obtain further insights into the mechanisms of neural control over genital hemodynamics., (© 2022. The International Urogynecological Association.)

Background: Vaginal lubrication and contractions are among the top difficulties affecting sexual intercourse in women after spinal cord injury., Aim: This study aimed at determining if pudendal nerve stimulation (PNS) can improve vaginal lubrication and induce increases in vaginal pressure., Methods: In anesthetized cats, a small piece of cotton was inserted into the vagina for 10 minutes with or without PNS to measure vaginal wetness by the weight increase of the vaginal cotton. Then, a small balloon catheter was inserted into the vagina to measure the pressure increase induced by PNS. Intensity response of the vagina to PNS (30 Hz, 0.2 ms, 5 seconds) was determined at 1-4 times of intensity threshold (T) for PNS to induce an observable vaginal pressure increase. Frequency response was determined at 2T intensity in a range of PNS frequencies (5-50 Hz). Finally, fatigue in vaginal pressure was determined by applying PNS (30 Hz, 2T) either continuously or intermittently (5 seconds on and 5 seconds off) for 4 minutes., Outcomes: The effectiveness of PNS in increasing vaginal wetness and pressure is evaluated., Results: PNS significantly (P = .0327) increased the measurement of vaginal wetness from 15.8 ± 3.8 mg during control without stimulation to 32.4 ± 4.7 mg after stimulation. Vaginal pressure increased as PNS intensity or frequency increased. PNS (30 Hz, 2T) induced vaginal pressure increase ≥80% of the maximal response. Intermittent PNS induced significantly (P = .0354) smaller fatigue (45.6 ± 3.7%) in vaginal pressure than continuous PNS (69.1 ± 3.0%) during the 4-minute stimulation., Clinical Translation: This study raises the possibility of developing a novel pudendal neuromodulation device to improve female sexual function after spinal cord injury., Strengths & Limitations: This study provides preclinical data supporting the development of a novel pudendal neuromodulation device. The limitation includes the lack of chemical analysis of the vaginal secretion., Conclusion: PNS can improve vaginal lubrication and induce increases in vaginal pressure. Chen J, Zhong Y, Wang J, et al. Vaginal Lubrication and Pressure Increase Induced by Pudendal Nerve Stimulation in Cats. J Sex Med 2022;19:1517-1523., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

This study examined the effect of sacral neuromodulation on persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PudNS). In 10 α-chloralose-anesthetized cats, repetitive application of 30-min PudNS induced bladder underactivity evident as an increase in bladder capacity during a cystometrogram (CMG). S1 or S2 dorsal root stimulation (15 or 30 Hz) at 1 or 1.5 times threshold intensity (T) for inducing reflex hindlimb movement (S1) or anal sphincter twitch (S2) was applied during a CMG to determine if the stimulation can reverse the bladder underactivity. Persistent (>3 h) bladder underactivity consisting of a significant increase in bladder capacity to 163.1 ± 11.3% of control was induced after repetitive (1-10 times) application of 30-min PudNS. S2 but not S1 dorsal root stimulation at 15 Hz and 1 T intensity reversed the PudNS-induced bladder underactivity by significantly reducing the large bladder capacity to 124.3 ± 12.9% of control. Other stimulation parameters were not effective. After the induction of persistent underactivity, recordings of reflex bladder activity under isovolumetric conditions revealed that S2 dorsal root stimulation consistently induced the largest bladder contraction at 15 Hz and 1 T when compared with other frequencies (5-40 Hz) or intensities (0.25-1.5 T). This study provides basic science evidence consistent with the hypothesis that abnormal pudendal afferent activity contributes to the bladder underactivity in Fowler's syndrome and that sacral neuromodulation treats this disorder by reversing the bladder inhibition induced by pudendal nerve afferent activity.

The goal of this study is to induce low-pressure voiding by stimulation and bilateral 1 kHz post-stimulation block of the pudendal nerves. In anesthetized cats, wire hook electrodes were placed on the left and/or right pudendal nerves. Stimulus pulses (30 Hz, 0.2 ms) were applied to one pudendal nerve to induce a reflex bladder contraction and to produce contractions of the external urethral sphincter (EUS). High frequency (1 kHz) biphasic stimulation was applied to block axonal conduction in both pudendal nerves and block EUS activity. In 4 cats, a catheter was inserted into the distal urethra to perfuse and measure the back pressure caused by the EUS contraction. In another 5 cats, a catheter was inserted into the bladder dome and the urethra was left open to allow voiding. The 1 kHz stimulation (30-60 s, 0.5-5 mA) delivered via a wire hook electrode completely blocked pudendal nerve conduction for ≥2 min after terminating the stimulation, i.e., a post-stimulation block. The block gradually disappeared in 6-18 min. The block duration increased with increasing amplitude or duration of the 1 kHz stimulation. Without the 1 kHz block, 30 Hz stimulation alone induced high-pressure (90 cmH 2 O) voiding. When combined with the 1 kHz block, the 30 Hz stimulation induced low-pressure (≤50 cmH 2 O) voiding with a high voiding efficiency (80%). In summary, a minimally invasive surgical approach might be developed to restore voiding function after spinal cord injury by stimulation and block of the pudendal nerves using lead electrodes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The literature regarding the route of the dorsal nerve of the clitoris is sparse and lacks surgical focus. With an increasing number of procedures being performed on the labia, it is important to elucidate the route and note any variation from normal of the nerve., Methods: Fifty-one cadavers were dissected to yield 97 dorsal nerve of the clitoris samples. Measurements were taken from (1) the dorsal nerve of the clitoris penetration point of the perineal membrane to the urethra, (2) the nerve's penetration point of the perineal membrane to the pubic bone, (3) the angle of the clitoris to the branch point of the dorsal nerve of the clitoris, and (4) the branch point of the nerve to the distalmost point of the glans clitoris. Any anomalous branching patterns of the dorsal nerve of the clitoris were recorded and classified., Results: The means and standard deviations of each measurement were used to create a surgical danger zone. The mean of each measurement was (1) 34.63 mm, (2) 5.74 mm, (3) -3.07 mm, and (4) 30.40 mm, respectively. In addition, six distinct branching patterns were observed, organized, and classified based on the location and number of branches observed., Conclusions: The dorsal nerve of the clitoris has multiple branching patterns and typically travels along the same course in most women. Further investigation of the course and three-dimensional position of the dorsal nerve of the clitoris is warranted to preserve sexual sensation as the frequency of procedures involving the female pudendum increases., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Objective: To analyze and quantify sacral spinal excitability through bulbocavernosus reflex (BCR) stimulus-response curves., Methods: Thirty subjects with upper motor neuron lesions (UMN) and nine controls were included in this prospective, monocentric study. Sacral spinal excitability was assessed using stimulus-response curves of the BCR, modeled at different bladder filling volumes relative to the desire to void (as defined by the International Continence Society) during a cystometry. Variations in α (i.e. the slope of the stimulus-response curve) were considered as an indicator of the modulation of sacral spinal excitability., Results: In all subjects, α increased during bladder filling suggesting the modulation of spinal sacral excitability during the filling phase. This increase was over 30% in 96.7% of neurological subjects and 88.9% of controls. The increase was higher before the first sensation to void in the neurological population (163.15%), compared to controls, (29.91%), p < 0.001., Conclusions: We showed the possibility of using BCR stimulus-response curves to characterize sacral spinal response with an amplification of this response during bladder filling as well as a difference in this response amplification in patients with UMN in comparison with a control group., Significance: BCR, through stimulus-response curves, might be an indicator of pelvic-perineal exaggerated reflex response and possibly a tool for evaluating treatment effectiveness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Neurogenic bladder management after spinal cord injury (SCI) is very challenging. Daily urethral catheterization is most commonly used to empty the bladder, which causes frequent infections of the lower urinary tract. This study reports a novel idea to restore both continence and micturition after SCI by an implantable pudendal nerve stimulator (PNS). The PNS was surgically implanted in four cats with complete SCI at T9-T10 spinal level and tested weekly for 13-14 weeks under awake conditions. These chronic SCI cats consistently exhibited large residual bladder volumes (average 40-50 ml) due to their inability to void efficiently, while urine leakage also occurred frequently. The PNS which consisted of stimulating the pudendal nerve at 20-30 Hz to trigger a spinal reflex bladder contraction and at the same time blocking the pudendal nerves bilaterally with 10 kHz stimulation to relax the external urethral sphincter and reduce the urethral outlet resistance successfully induced highly efficient (average 80-100%), low pressure (<50 cmH 2 O) voiding. The PNS at 5 Hz also promoted urine storage by inhibiting reflex bladder activity and increasing bladder capacity. At the end of 14-week chronic testing, low pressure efficient voiding induced by PNS was further confirmed under anesthesia by directly measuring voiding pressure using a bladder catheter inserted through the bladder dome. This study demonstrated the efficacy and safety of the PNS in awake chronic SCI cats, suggesting that a novel neuroprosthesis can be developed for humans to restore bladder function after SCI by stimulating and/or blocking the pudendal nerves., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Reportedly, tetanic stimulation prior to transcranial electrical stimulation (TES) facilitates elicitation of motor evoked potentials (MEPs) by a mechanism involving increased corticomotoneuronal excitability in response to somatosensory input. However, the posttetanic MEP following stimulation of a pure sensory nerve has never been reported. Furthermore, no previous reports have described posttetanic MEPs in pediatric patients. The aim of this study was to investigate the efficacy of posttetanic MEPs in pediatric neurosurgery patients and to compare the effects on posttetanic MEP after tetanic stimulation of the sensory branch of the pudendal nerve versus the standard median and tibial nerves, which contain a mixture of sensory and motor fibers., Methods: In 31 consecutive pediatric patients with a mean age of 6.0 ± 5.1 years who underwent lumbosacral surgery, MEPs were elicited by TES without tetanic stimulation (conventional MEPs [c-MEPs]) and following tetanic stimulation of the unilateral median and tibial nerves (mt-MEPs) and the sensory branch of the pudendal nerve (p-MEP). Compound muscle action potentials were elicited from abductor pollicis brevis (APB), gastrocnemius (Gc), tibialis anterior (TA), and adductor hallucis (AH) muscles. The success rate of monitoring each MEP and the increases in the ratios of mt-MEP and p-MEP to c-MEP were investigated., Results: The success rate of monitoring p-MEPs was higher than those of mt-MEPs and c-MEPs (87.5%, 72.6%, and 63.3%, respectively; p < 0.01, adjusted by Bonferroni correction). The mean increase in the ratio of p-MEP to c-MEP for all muscles was significantly higher than that of mt-MEP to c-MEP (3.64 ± 4.03 vs 1.98 ± 2.23, p < 0.01). Subanalysis of individual muscles demonstrated significant differences in the increases in the ratios between p-MEP and mt-MEP in the APB bilaterally, as well as ipsilateral Gc, contralateral TA, and bilateral AH muscles., Conclusions: Tetanic stimulation prior to TES can augment the amplitude of MEPs during pediatric neurosurgery, the effect being larger with pudendal nerve stimulation than tetanic stimulation of the unilateral median and tibial nerves. TES elicitation of p-MEPs might be useful in pediatric patients in whom it is difficult to elicit c-MEPs.

Peripheral nerve injuries can significantly reduce quality of life. While some recover, most do not recover fully, resulting in neuropathic pain and loss of sensation and motor function. Research on the mechanisms of peripheral nerve regeneration could elucidate poor patient outcomes and potential treatments. This study was designed to determine if brain derived neurotrophic factor (BDNF) is necessary for pudendal nerve regeneration and functional recovery. Peripheral administration of tyrosine kinase B functional chimera (TrkB) was used to inhibit the BDNF regenerative pathway. Female Sprague-Dawley rats received tyrosine kinase B functional chimera (TrkB) or saline after a pudendal nerve crush (PNC) or Sham PNC and were divided into three groups: Sham PNC, PNC + Saline, and PNC + TrkB. Seven days after injury, relative β II tubulin expression (1.0 ± 0.2) was significantly decreased after PNC + TrkB compared to PNC + saline (2.9 ± 1.0). Three weeks after injury, BDNF plasma concentration (1320.8 ± 278.1 pg/ml) was significantly reduced in PNC + TrkB compared to PNC + saline rats (2053.4 ± 211.0 pg/ml). Pudendal nerve motor branch firing rate (54.0 ± 9.5 Hz) was significantly decreased in the PNC + TrkB group compared to the PNC + saline group (120.4 ± 17.1 Hz); while nerve firing rate of the PNC + saline group was not significantly different from sham PNC rats (121.8 ± 26.6 Hz). This study demonstrated that peripheral administration of TrkB bound free BDNF and inhibited the regenerative response after PNC. BDNF is necessary for normal PN motor branch recovery after PNC., (Published by Elsevier Inc.)

Although anatomical studies have indicated pudendal motoneurons to give off recurrent collaterals, they are not considered to make synapses onto interneurons, such as Renshaw cells, and rather terminate their own signals. No study till date has examined interneurons being driven by recurrent collaterals of pudendal motoneurons. Here, we aimed to investigate the existence of Renshaw cells driven by pudendal motoneurons along with the recurrent inhibition of the latter. Extracellular recordings were obtained from the ventral horn of the sacral spinal cord of anesthetized cats. Dorsal roots were sectioned, and motor axons were electrically stimulated. Renshaw-like cells driven by recurrent collaterals, with high-frequency firings at short latency discharge, were observed around Onuf's nucleus. However, the recurrent inhibitory post-synaptic potentials were not recorded by intracellular recordings from the pudendal motoneurons. In summary, we found Renshaw-like cells driven by pudendal motoneurons, but we could not identify the synaptic connection of these neurons.

Treatment options are limited for the approximately 40% of postmenopausal women worldwide who suffer from female sexual dysfunction (FSD). Neural stimulation has shown potential as a treatment for genital arousal FSD, however the mechanisms for its improvement are unknown. One potential cause of some cases of genital arousal FSD are changes to the composition of the vaginal microbiota, which is associated with vulvovaginal atrophy. The primary hypothesis of this study was that neural stimulation may induce healthy changes in the vaginal microbiome, thereby improving genital arousal FSD symptoms. In this study we used healthy rats, which are a common animal model for sexual function, however the rat vaginal microbiome is understudied. Thus this study also sought to examine the composition of the rat vaginal microbiota. Treatment rats (n = 5) received 30 minutes of cutaneous electrical stimulation targeting the genital branch of the pudendal nerve, and Control animals (n = 4) had 30-minute sessions without stimulation. Vaginal lavage samples were taken during a 14-day baseline period including multiple estrous periods and after twice-weekly 30-minute sessions across a six-week trial period. Analysis of 16S rRNA gene sequences was used to characterize the rat vaginal microbiota in baseline samples and determine the effect of stimulation. We found that the rat vaginal microbiota is dominated by Proteobacteria, Firmicutes, and Actinobacteria, which changed in relative abundance during the estrous cycle and in relationship to each other. While the overall stimulation effects were unclear in these healthy rats, some Treatment animals had less alteration in microbiota composition between sequential samples than Control animals, suggesting that stimulation may help stabilize the vaginal microbiome. Future studies may consider additional physiological parameters, in addition to the microbiome composition, to further examine vaginal health and the effects of stimulation., Competing Interests: No competing interests.

Introduction: Multisystem functional gains have been reported in males with spinal cord injury (SCI) after undergoing activity-based training (ABT), including increases in scoring of sexual function and reports of improved erectile function., Aim: This study aims to examine the effect of daily 60-minute locomotor training and exercise in general on sexual function in a rat SCI contusion model., Methods: Male Wistar rats received a T9 contusion SCI. Animals were randomized into 4 groups: a quadrupedal stepping group (SCI + QT), a forelimb-only exercise group (SCI + FT), a non-trained harnessed group (SCI + NT), and a home cage non-trained group (SCI + HC). The 2 non-trained groups were combined (SCI) post hoc. Daily training sessions were 60 minutes in duration for 8 weeks. Urine samples were collected during bi-weekly 24-hour metabolic cage behavioral testing. Latency, numbers of penile dorsiflexion, and glans cupping were recorded during bi-weekly penile dorsiflexion reflex (PDFR) testing. Terminal electromyography (EMG) recordings of the bulbospongiosus muscle (BSM) were recorded in response to stimulation of the dorsal nerve of the penis (DNP)., Outcomes: ABT after SCI had a significant effect on PDFR, as well as BSM EMG latency and burst duration., Results: SCI causes a significant decrease in the latency to onset of PDFR. After 8 weeks of ABT, SCI + QT animals had a significantly increased latency relative to the post-SCI baseline. BSM EMG response to DNP stimulation had a significantly decreased latency and increase in average and maximum amplitude in SCI + QT animals. SCI animals had a significantly longer burst duration than trained animals. Time between PDFR events, penile dorsiflexion, glans cupping, and urine testosterone were not affected by ABT., Clinical Implications: ABT has a positive influence on sexual function and provides a potential therapy to enhance the efficacy of current sexual dysfunction therapies in the male SCI population., Strengths and Limitations: Several significant small improvements in sexual function were found in a clinically relevant rat model of SCI using a readily available rehabilitative therapy. The limited findings could reflect insensitivity of the PDFR as a measure of erectile function., Conclusions: These results indicate that task-specific stepping and/or loading provide sensory input to the spinal cord impacting the neural circuitry responsible for sexual function. Steadman CJ, Hoey RF, Montgomery LR, et al. Activity-Based Training Alters Penile Reflex Responses in a Rat Model of Spinal Cord Injury. J Sex Med 2019; 16:1143-1154., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Aims: To analyze, in female rats, the anatomical and histological features of the urethra and its relationship with the vagina and clitoris, and its innervation., Methods: Seventeen adult female Wistar rats were used. Gross anatomy and acetylcholinesterase (AchE) histochemistry were performed to describe the urethral features, adjacent structures, and innervation. The histomorphometric characteristics of the urethra were determined in transversal, longitudinal, or coronal sections stained with Masson's Trichrome., Results: The female rat urethra is not a homogeneous tubular organ. The pre-pelvic and pelvic regions are firmly attached to the vagina with belt-like striated fibers forming a urethra-vaginal complex. The bulbar regions have curved segments and a narrow lumen. The clitoral region is characterized by a urethra-clitoral complex surrounded by a vascular plexus. The lumen area and thickness of the urethral layers significantly varied between regions (P < 0.05). Innervation of the urethra arrives from the major pelvic ganglion, the dorsal nerve of the clitoris (DNC), and the motor branch of the sacral plexus (MBSP)., Conclusions: Differential tissular composition of the urethra may underlie urinary continence and voiding dysfunction through different physiological mechanisms. The urethra-vagina complex seems to be the main site controlling urinary continence through active muscular mechanisms, while the bulbar urethra provides passive mechanisms and the urethra-clitoris complex seems to be crucial for distal urethral closure by means of a periurethral vascular network., (© 2019 Wiley Periodicals, Inc.)

Aims: Interstitial cystitis and bladder pain syndrome is a prevalent health concern with inadequate treatments. Neuromodulation has emerged as a therapeutic option to treat patients refractory to standard care. The objective of this study was to determine the efficacy and mechanism(s) of sensory pudendal nerve stimulation on bladder function in cystitis rats., Methods: Female rats were administered saline (n = 8) or cyclophosphamide (CYP, 150 mg/kg IP, n = 16) and single-trial cystometry experiments were conducted under urethane anesthesia 48 h after injection. Electrical stimulation (0.02-0.22 mA, 10-20 Hz) was delivered to the sensory branch of the pudendal nerve and its effect on the bladder and external urethral sphincter were measured. Stimulation trials were also conducted following bilateral hypogastric nerve transection (HGNT) or pharmacological inhibition of beta-adrenergic receptors (propranolol, 1 mg/kg IV) to determine the mechanisms of bladder inhibition., Results: CYP-induced cystitis decreased bladder capacity (P = 0.0352) and bladder compliance (P = 0.024) by up to 38% of control. Electrical stimulation of the sensory pudendal nerve increased bladder capacity (P < 0.0001) in control and CYP rats by up to 51-52% of their respective baselines. HGNT did not influence bladder inhibition generated by sensory pudendal nerve stimulation in control rats, whereas HGNT and propranolol decreased the efficacy of electrical stimulation in CYP rats., Conclusions: Sympathetic reflex activity mediates sensory pudendal nerve stimulation in CYP treated but not control rats. These studies demonstrate an alternative approach to neuromodulation in cystitis and establish mechanistic changes during stimulation that may enable the development of novel therapeutics., (© 2018 Wiley Periodicals, Inc.)

Aims: To test the hypothesis that the frequency of bladder non-voiding contractions (NVCs) can be used as a trigger event for closed-loop conditional inhibition of detrusor contractions via tibial nerve (TN) or dorsal penile nerve (DPN) stimulation., Methods: In urethane anaesthetized male Wistar rats, the bladder was filled continuously with saline to evoke contractions. To test the plausibility of conditional inhibition via the TN, electrical stimulation was switched on manually when the pressure increased above a threshold of 10 cmH 2 0 above the baseline. For testing conditional stimulation via the DPN, the pressure signal was continuously stored and a baseline threshold, the area under the curve (AUC) of the amplitude spectrum in the 0.2-20 Hz range of a 5 s window at the beginning of filling was calculated. When the AUC of subsequent pressure windows superseded the baseline threshold, the DPN was automatically stimulated., Results: TN stimulation failed to inhibit evoked voiding contractions. The NVC frequency spectrum based DPN stimulation successfully inhibited 70% of the evoked contractions and resulted in a 45% increase in bladder capacity (BC)., Conclusions: While, conditional TN stimulation failed to suppress bladder contractions, DPN stimulation, automatically triggered by an increased frequency of bladder non-voiding activity, resulted in bladder inhibition, and a consequential increase in BC. This study demonstrates the plausibility of using the frequency of NVCs as a trigger event for conditional inhibition of detrusor contractions., (© 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)

Aims: The external anal sphincter (EAS) is essential for maintaining fecal continence. Neurological disorders or traumatic injuries to muscle and nervous systems could lead to EAS denervation. Currently, there are no techniques available to document global innervation changes in the EAS in vivo. The aim of this study was to develop a novel approach to non-invasively estimate the number of functioning motor units (MUs) in the EAS and validate with immunofluorescent techniques in rats., Methods: Intra-rectal surface electromyography (EMG) signals of the EAS, induced by a series of intra-vaginally delivered pudendal nerve stimulations with different intensities, were recorded. Variation in EMG responses at different intensities was used to estimate the value of a single motor unit potential (SMUP) in order to perform the proposed EAS motor unit number estimation (MUNE) approach. The EAS MUNE was tested in 12 female Sprague-Dawley rats, and validated by comparing against the EAS myofiber counting results achieved by performing immunostaining of acetylcholine receptors in 7 of the 12 rats., Results: The mean MU number was 35 ± 9, with an averaged SMUP size of 52.49 ± 20.39 μV. The mean number of successfully identified myofibers was 652.7 ± 130.6 myofiber/EAS. Significance of linear regression between the immunofluorescent results and the MUNE was confirmed (P < 0.01)., Conclusions: Our study represents the first effort to non-invasively assess the innervation of the EAS in vivo using the rat as a pre-clinical model. This approach can potentially enable future clinical applications for advanced diagnosis and treatment of neurogenic EAS disorders., (© 2017 Wiley Periodicals, Inc.)

Objectives: Female sexual dysfunction (FSD) affects a significant portion of the population. Although treatment options for FSD are limited, neuromodulation for bladder dysfunction has improved sexual function in some women. A few studies have investigated peripheral neuromodulation for eliciting changes in vaginal blood flow, as a proxy for modulating genital sexual arousal, however results are generally transient. Our central hypothesis is that repeated or extended-duration pudendal nerve stimulation can elicit maintained vaginal blood flow increases., Materials and Methods: Under ketamine anesthesia, the pudendal nerve of 14 female rats was stimulated at varying frequencies (1-100 Hz) and durations (0.15-60 min). Vaginal blood perfusion was measured with a laser Doppler flowmetry probe. Changes in blood perfusion were determined through raw signal analysis and increases in the energy of neurogenic (0.076-0.200 Hz) and myogenic (0.200-0.740 Hz) frequency bands through wavelet analysis. Additionally, a convolution model was developed for a carry-over stimulation effect., Results: Each experiment had significant increases in vaginal blood perfusion due to pudendal nerve stimulation. In addition, there were large concurrent increases in neurogenic and myogenic frequency-band energy in 11/14 experiments, with an average maximal response at 31.3 min after stimulation initiation. An effective stimulation model with a 30-min carry-over effect had a stronger correlation to blood perfusion than the stimulation period itself., Conclusions: Repeated or extended-duration pudendal nerve stimulation can elicit maintained increases in vaginal blood perfusion. This work indicates the potential for pudendal neuromodulation as a method for increasing genital arousal as a potential treatment for FSD., (© 2017 International Neuromodulation Society.)

This study in α-chloralose-anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger reflex bladder activity. With the bladder distended at a volume ~90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large-amplitude (40-150 cmH 2 O) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline significantly ( P < 0.01) reduced bladder capacity to ~80% of the control capacity and significantly ( P < 0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS)-induced changes in bladder function, PNS was delivered following TNS. TNS of 30-min duration produced long-lasting poststimulation inhibition and significantly ( P < 0.01) increased bladder capacity to 140.5 ± 7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly ( P < 0.05) increased the duration of reflex bladder contractions to ~200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and nonobstructive urinary retention., (Copyright © 2017 the American Physiological Society.)

Objectives: This study was designed to investigate the clinical value of the bulbocavernosus reflex (BCR) and pudendal nerve somatosensory evoked potentials (PSEPs) in the differential diagnosis between multiple system atrophy (MSA) and Parkinson's disease (PD) in early stage., Materials and Methods: A total of 31 patients with MSA, 45 patients with PD, and 60 healthy participants were included in this study. A Keypoint EMG/EP system was used for BCR and PSEP measurements. Electrophysiological parameters were collected for statistical analysis., Results: The BCR elicitation rates were significantly lower in the patients with MSA than in the patients with PD (P<.05). Prolonged BCR latencies were found in the MSA group compared to the PD and control groups (P<.05). Bulbocavernosus reflex latencies were significantly prolonged in patients with MSA compared with PD patients showing early urogenital symptoms (P<.05). There was no significant difference in PSEP P41 latencies among the three groups (P=.434 in males, P=.948 in females). Both BCR and PSEP amplitudes were significantly lower in the MSA/PD group than in the control group (P<.001)., Conclusions: Pudendal nerve damage is more severe in MSA than in PD. Prolonged BCR latency may be valuable for distinguishing between MSA and PD in the early stages. BCR and PSEP testing may also contribute to localized and qualitative diagnosis of the distribution of neurodegenerative pathologies in these two disorders., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To explore the relationship between such a construct and an existing continence score., Methods: A retrospective study of incontinent patients who underwent anal physiology (AP) was performed. AP results and Cleveland Clinic Continence Scores (CCCS) were extracted. An anal physiology score (APS) was developed using maximum resting pressures (MRP), anal canal length (ACL), internal and external sphincter defects and pudendal terminal motor latency. Univariate associations between each variable, APS and CCCS were assessed. Multiple regression analyses were performed., Results: Of 508 (419 women) patients, 311 had both APS and CCCS measured. Average MRP was 51 mmHg (SD 23.2 mmHg) for men and 39 mmHg (19.2 mmHg) for women. Functional ACL was 1.7 cm for men and 0.7 cm for women. Univariate analyses demonstrated significant associations between CCCS and MRP ( P = 0.0002), ACL ( P = 0.0006) and pudendal neuropathy ( P < 0.0001). The association between APS and CCCS was significant ( P < 0.0001) but accounted for only 9.2% of the variability in CCCS. Multiple regression showed that the variables most useful in predicting CCCS were external sphincter defect, pudendal neuropathy and previous pelvic surgery, but only improving the scores predictive ability to 12.5%., Conclusion: This study shows that the ability of AP tests to predict continence scores improves when considered collectively, but that a constructed summation model before and after multiple regression is poor at predicting the variability in continence scores., Competing Interests: Conflict-of-interest statement: None of them has received fees for serving as a speaker, or been a consultant and/or an advisory board member for any organization(s). None has received research funding for this project. None owns stocks and/or shares relevant to this research. None owns any patents

Objective: Our goal is to develop an interface that integrates chronic monitoring of lower urinary tract (LUT) activity with stimulation of peripheral pathways., Approach: Penetrating microelectrodes were implanted in sacral dorsal root ganglia (DRG) of adult male felines. Peripheral electrodes were placed on or in the pudendal nerve, bladder neck and near the external urethral sphincter. Supra-pubic bladder catheters were implanted for saline infusion and pressure monitoring. Electrode and catheter leads were enclosed in an external housing on the back. Neural signals from microelectrodes and bladder pressure of sedated or awake-behaving felines were recorded under various test conditions in weekly sessions. Electrodes were also stimulated to drive activity., Main Results: LUT single- and multi-unit activity was recorded for 4-11 weeks in four felines. As many as 18 unique bladder pressure single-units were identified in each experiment. Some channels consistently recorded bladder afferent activity for up to 41 d, and we tracked individual single-units for up to 23 d continuously. Distension-evoked and stimulation-driven (DRG and pudendal) bladder emptying was observed, during which LUT sensory activity was recorded., Significance: This chronic implant animal model allows for behavioral studies of LUT neurophysiology and will allow for continued development of a closed-loop neuroprosthesis for bladder control.

This study investigated the role of γ-aminobutyric acid subtype B (GABA B ) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly ( P < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly ( P < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABA B receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABA B receptors in tibial neuromodulation of bladder overactivity in cats and that GABA B receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity., (Copyright © 2017 the American Physiological Society.)

Objective: Electrical stimulation of the pudendal nerve (PN) is a potential therapy for bladder dysfunction, but voiding efficiency (VE) produced by PN stimulation appears limited to 60-70%. We conducted experiments in rats and cats to investigate the hypothesis that introduction of artificial phasic bursting activity of the external urethral sphincter (EUS) would enhance VE under conditions where such activity was absent., Materials and Methods: Cystometry experiments were conducted in 17 urethane anesthetized female Sprague-Dawley rats and 4 α-chloralose anesthetized male cats. The effects of phasic stimulation of the pudendal motor branch on VE were quantified in intact conditions, following bilateral transection of the motor branch of the PN, and following subsequent bilateral transection of the sensory branch of the PN., Results: Artificial phasic bursting activity in the EUS generated by electrical stimulation of the motor branch of the PN increased VE in both rats and cats. Subsequent transection of the sensory branch of the PN abolished the increased VE elicited by phasic stimulation in both rats and cats., Conclusions: Artificial phasic EUS bursting restored efficient voiding in rats. Introduction of artificial phasic bursting in cats, which normally exhibit EUS relaxation while voiding, was also effective in promoting efficient voiding. In both species phasic EUS activity increased voiding efficiency via activation of pudendal sensory pathways. These results provide further insight into the function of phasic EUS activity in efficient voiding and highlight a novel approach to increase VE generated by pudendal afferent nerve stimulation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The aim of this study was to develop and evaluate a procedure for equine pudendal nerve block using a peripheral nerve locator. In the first experiment, six ponies were used to determine the relationship between elicited muscle contractions (anal, perineal or both) and nerves serving the perineal region (pudendal, caudorectal and perineal nerves) when methylene blue dye was injected using the electrolocation technique. This experiment showed that the pudendal nerve was approached effectively when both anal and perineal twitch were elicited during electrolocation. In a second experiment, seven Thoroughbred horses were used to evaluate the appropriate volume of anaesthetic solution for the nerve block. Immediately after euthanasia, lidocaine/methylene blue solution was injected after positive electrolocation. A stained segment of 2 cm or more of the nerve was considered effective and this was evaluated after dissection. Both 10 and 20 mL per injection site resulted in effective nerve staining. Finally, pudendal nerve block was performed and evaluated in 27 horses admitted for selected reproductive surgical procedures including perineoplasty, urethroplasty, clitorectomy in mares and penile examination, phallectomy and urethrostomy in geldings. Surgical time varied from several minutes to 3 h. The choice between lidocaine, mepivacaine or bupivacaine was based on the duration of analgesia required. In mares and males, a volume of 20 mL and 10 mL, respectively, was injected per site. The use of a peripheral nerve stimulator-guided pudendal nerve block is a feasible, safe and reliable alternative for both epidural and general anaesthesia, to provide peri-operative analgesia in clinical equine patients undergoing specific reproductive surgeries., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We aimed to examine the afferent mechanisms for the reflex inhibition of the rhythmic micturition contractions (RMCs) of the urinary bladder induced by stimulation of the perineal skin afferents in urethane-anesthetized rats. Electrical stimulation (pulse duration: 0.5 ms) was applied to the cutaneous branches of the pudendal nerve (CBPN) at frequencies of 0.1, 1, and 10 Hz for 1 min. Nerve fiber groups were defined by recording compound action potentials from CBPN. Activation of only Aβ fibers (0.2 V) produced an inhibition of RMCs at 7-11 min after the onset of stimulation (late inhibition), at any tested frequency. Additional activation of Aδ fibers (1 V) produced additional early inhibition (immediately after stimulation) at 1 and 10 Hz. Furthermore, additional activation of C fibers (10 V) at 10 Hz completely stopped RMCs for >10 min. This strong inhibition persisted after local application of capsaicin to the stimulating CBPN. We conclude that activities of Aβ, Aδ, and C afferent fibers, without capsaicin-sensitive channels, can contribute to the inhibition of bladder contractions., Competing Interests: The authors declare that they have no conflict of interest.

Aim: This study examined the role of glycinergic transmission in nociceptive and non-nociceptive bladder reflexes and in inhibition of these reflexes by pudendal nerve stimulation (PNS)., Methods: Cystometrograms (CMGs) were performed in α-chloralose anesthetized cats by intravesical infusion of saline or 0.25% acetic acid (AA) to trigger, respectively, non-nociceptive or nociceptive bladder reflexes. PNS at 2 or 4 times threshold (T) intensity for inducing anal twitch was used to inhibit the bladder reflexes. Strychnine (a glycine receptor antagonist) was administered in cumulative doses (0.001-0.3 mg/kg, i.v.) at 60-120 min intervals., Results: Strychnine at 0.001-0.3 mg/kg significantly (P < 0.05) increased bladder capacity and reduced contraction amplitude during saline CMGs but did not change these parameters during AA CMGs except at the 0.3 mg/kg dose which increased bladder capacity. Strychnine did not alter PNS inhibition during saline CMGs except at the highest dose at 2T intensity, but significantly (P < 0.05) suppressed PNS inhibition during AA CMGs after 0.001-0.003 mg/kg doses at 2T and 4T intensities. During AA CMGs strychnine (0.3 mg/kg) also unmasked a post-PNS excitatory effect that significantly reduced bladder capacity after termination of PNS., Conclusions: Glycinergic inhibitory neurotransmission in the central nervous system plays an unexpected role to tonically enhance the magnitude and reduce the bladder volume threshold for triggering the non-nociceptive bladder reflex. This is attributable to inhibition by glycine of another inhibitory mechanism. Glycine also has a minor role in PNS inhibition of the nociceptive bladder reflex. Neurourol. Urodynam. 35:798-804, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Background/purpose: Few studies have investigated the feasibility of using pudendal neuromodulation to regulate bladder function in spinal cord-injured (SCI) animals. The present study aimed to determine the effects of electrical activation of the pudendal sensory branch on improving voiding functions in rats 6 weeks after a spinal cord injury and to explore the underlying neuromodulatory mechanisms., Methods: Two urodynamic measurements were used to assess the effects of electrical stimulation (ES) on bladder and urethral functions: simultaneous recordings of the intravesical pressure (IVP) during continuous isotonic transvesical infusion (i.e., isotonic IVP) and external urethral sphincter (EUS) electromyography (EUS-EMG), and simultaneous recordings of transvesical pressure under isovolumetric conditions (i.e., isovolumetric IVP) and urethral perfusion pressure (UPP)., Results: Six weeks after the SCI, the rats showed voiding dysfunction, as indicated by abnormal cystometric measurements (e.g., increased volume threshold, increased contraction amplitude, and increased residual volume, and decreased voided volume). The voiding efficiency (VE) decreased to 13% after the SCI, but increased to 22-34% after applying pudendal afferent stimulation. In addition, pudendal stimulation significantly increased the EUS burst period and increased the difference between the UPP and the high-frequency oscillation (HFO) baselines, and changed the time offset between bladder and EUS activities. These findings suggest that pudendal afferent stimulation improved the VE by prolonging the micturition interval, decreased the urethral resistance, and recovered detrusor-sphincter dyssynergia during the voiding phase., Conclusion: This study demonstrates the feasibility of using pudendal neuromodulation in chronic SCI rats. These results could aid in developing an advanced neural prosthesis to restore bladder function in clinical settings., (Copyright © 2015. Published by Elsevier B.V.)

Objective: Few studies have investigated the feasibility of using chronic pudendal neuromodulation for improving voiding function in patients with diabetes who are also experiencing urinary retention. The present study investigated the effects of chronic electrical stimulation (ES) of the sensory branch of the pudendal nerve on voiding function in diabetic rats., Approach: A custom-made implantable microstimulation system was designed and manufactured for chronic implantation in normal control (NC) and diabetic rats. After three or six weeks of pudendal neuromodulation, the intravesical pressure, external urethral sphincter electromyograms (EUS-EMGs), and urine flow rate (UFR) of all rats were simultaneously recorded to assess the effects of chronic pudendal ES on voiding function. Morphological changes in pudendal axons were assessed through hematoxylin and eosin (H&E) staining., Significance: This study demonstrated the feasibility of using chronic pudendal neuromodulation for improving voiding function in diabetic rats. These results may facilitate the development of an advanced neural prosthesis for restoring bladder function in clinical settings.

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition., (Copyright © 2016 the American Physiological Society.)

Objective: To seek the predictive value of pudendal nerve function that need preventive anti-incontinence surgery at the same time following pelvic prolapse surgery in severe pelvic organ prolapse (POP) patients., Methods: Seventy women completed this study from January 2014 to June 2015 in Fuzhou General Hospital of Nanjing Military Command, dividing into four groups: POP with or without coexisting occult stress urinary incontinence (OSUI) in preoperation, women with persistent stress urinary incontinence (SUI) in postoperation, women without SUI in postoperation. The pudendal nerve function in preoperation was measured by using Solar Urodynamic Neuro Module, including pudendal nerve terminal motor latency (PNTML), and amplitude., Results: There were statistical significance on bilateral PNTML between POP coexisting OSUI group and only severe POP group [(2.62±0.23) versus (2.40±0.26) ms in right of PNTML, (2.55± 0.21) versus (2.37 ±0.30) ms in left of PNTML; all P<0.05], but no statistical significance on bilateral amplitude (P>0.05). Compared de novo SUI group with POP group in postoperation, de novo SUI group's right of PNTML was significantly increased [(2.74±0.16) versus (2.47±0.26) ms; P< 0.05]; and the right of PNTML was extending 2.5 standard deviation at least compared with the health's [(2.10±0.20) ms]., Conclusions: The PNTML of pudendal nerve of POP coexisting OSUI is severe than only severe POP, the velocity of nerve conduction is slowing, and PNTML extension has a predictive value for postoperative urinary incontinence. When the right of PNTML of preoperative POP increased by at least 2.5 standard deviations than health's, the risk of SUI postoperative strongly increased, and a anti-incontinence surgery at the same time following pelvic prolapse surgery should be adviced.

Background: Somatic afferent nerve stimuli are used for treating an overactive bladder (OAB), a major cause of nocturia in the elderly. Clinical evidence for this treatment is insufficient because of the lack of appropriate control stimuli. Recent studies on anesthetized animals show that gentle stimuli applied to perineal skin with a roller could inhibit micturition contractions depending on the roller's surface material. We examined the efficacy of gentle skin stimuli for treating nocturia., Methods: The study was a cross-over, placebo-controlled, double-blind randomized clinical study using two rollers with different effects on micturition contractions. Participants were elderly women (79-89 years) with nocturia. Active (soft elastomer roller) or placebo (hard polystyrene roller) stimuli were applied to perineal skin by participants for 1 min at bedtime. A 3-day baseline assessment period was followed by 3-day stimulation and 4-day resting periods, after which the participants were subjected to other stimuli for another 3 days. The primary outcome was change in the frequency of nighttime urination, for which charts were maintained during each 3-day period., Results: Twenty-four participants were randomized, of which 22 completed all study protocols. One participant discontinued treatment because of an adverse event (abdominal discomfort). In participants with OAB (n = 9), change from baseline in the mean frequency of urination per night during the active stimuli period (mean ± standard deviation, -0.74 ± 0.7 times) was significantly greater than that during placebo stimuli periods (-0.15 ± 0.8 times [p < 0.05]). In contrast, this difference was not observed in participants without OAB (n = 13)., Conclusions: These results suggest that gentle perineal stimulation with an elastomer roller is effective for treating OAB-associated nocturia in elderly women. Here the limitation was a study period too short to assess changes in the quality of sleep and life., Trial Registration: UMIN Clinical Trial Registry (CTR) UMIN000015809.

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders., (Copyright © 2016 the American Physiological Society.)

Although a complete thoracic spinal cord section in various mammals induces paralysis of voluntary movements, the spinal lumbosacral circuitry below the lesion retains its ability to generate hindlimb locomotion. This important capacity may contribute to the overall locomotor recovery after partial spinal cord injury (SCI). In rats, it is usually triggered by pharmacological and/or electrical stimulation of the cord while a robot sustains the animals in an upright posture. In the present study we daily trained a group of adult spinal (T7) rats to walk with the hindlimbs for 10 wk (10 min/day for 5 days/wk), using only perineal stimulation. Kinematic analysis and terminal electromyographic recordings revealed a strong effect of training on the reexpression of hindlimb locomotion. Indeed, trained animals gradually improved their locomotion while untrained animals worsened throughout the post-SCI period. Kinematic parameters such as averaged and instant swing phase velocity, step cycle variability, foot drag duration, off period duration, and relationship between the swing features returned to normal values only in trained animals. The present results clearly demonstrate that treadmill training alone, in a normal horizontal posture, elicited by noninvasive perineal stimulation is sufficient to induce a persistent hindlimb locomotor recovery without the need for more complex strategies. This provides a baseline level that should be clearly surpassed if additional locomotor-enabling procedures are added. Moreover, it has a clinical value since intrinsic spinal reorganization induced by training should contribute to improve locomotor recovery together with afferent feedback and supraspinal modifications in patients with incomplete SCI., (Copyright © 2015 the American Physiological Society.)

Aims: The aim of this study was to define normative values of skin temperature and thermal sensory threshold in the pudendal nerve territory., Methods: Warm and cold detection thresholds (using the method of limits) and skin temperature were measured in a group of 41 presumably healthy female volunteers aged 41 years (range: 23-66 years) at left thenar eminence and in the pudendal nerve territory. Outlying data were discarded and 95% normative values were derived assuming Normal distributions., Results: Room temperature averaged 24.3 ± 1.1°. Skin temperature and cold detection threshold value were greater anteriorly (clitoris, labia) than posteriorly (para-anal). Para-anal skin temperature and cold detection threshold value were also significantly lower on the right side than on the left side. The warm detection threshold was significantly lower at the clitoris level than at left and right labia. A significant positive effect of skin temperature on cold and warm detection thresholds values was noted especially at thenar and para-anal levels. Age had no effect on skin temperature but warm detection thresholds at clitoris were higher in older subjects. The only qualitative abnormalities observed were after-sensation (4.9%) and habituation (2.8%). Allodynia, dysesthesia, radiation, and dyslocalization were not observed. Two-sided normative values were determined for skin temperature, vertical, and horizontal differences, while one-sided values were derived for cold and warm detection thresholds as well as for their difference., Conclusions: Normative values for perineal skin temperature and thermal detection thresholds can be used as an alternative non-invasive way to evaluate pudendal neuropathy., (© 2014 Wiley Periodicals, Inc.)

Objectives: To investigate intrafascicular pudendal nerve stimulation in felines as a means to restore urinary function in acute models of urinary incontinence, overactive bladder, and underactive bladder., Materials and Methods: Felines were anesthetized, and high-electrode-count (48 electrodes; 25 electrodes/mm(2) ) electrode arrays were implanted intrafascicularly into the pudendal nerve trunk. Electrodes were mapped for their ability to selectively or nonselectively excite the external anal sphincter, external urethral sphincter, and the detrusor bladder muscle. Statistical analysis was carried out to quantify reflexive voiding efficiencies, mean impedances of the microelectrodes used in this study, and to determine what differences, if any, in bladder contraction amplitudes were evoked by different electrode configurations., Results: Multielectrode arrays implanted into the pudendal nerve trunk were able to selectively and nonselectively excite genitourinary muscles. After inducing urinary incontinence with bilateral pudendal nerve transections (proximal to the implants), electrical stimulation delivered through certain microelectrodes was able to significantly reduce leaking (p = 0.008). Electrical stimulation delivered through detrusor selective electrodes was able to inhibit reflexive bladder contractions and excite bladder contractions, depending on the stimulation frequency. Specific electrode configurations were able to drive significantly (p < 0.001) larger bladder contractions than other electrode configurations, depending on the preparation. Successful reflexively or electrically driven bladder contractions were achieved in 46% and 38% of the preparations, respectively, an observation that has not been noted in previously published feline pudendal stimulation studies., Conclusions: Multielectrode arrays implanted intrafascicularly into the pudendal nerve trunk may provide a promising new clinical neuromodulation therapy for the restoration of urinary function., (© 2014 International Neuromodulation Society.)

Defecation is thought to be achieved not only by contraction of the colon, but also by a rise in intra-abdominal pressure. In this study we recorded the discharges of nerves innervating the abdominal (Abd) muscles, diaphragm, external anal sphincter (EAS) muscle and pelvic floor (PF) muscles during induced defecation evoked by distention of an expellable balloon to reveal defecation-related muscle activities. The discharges of the Abd muscle and phrenic (Phr) nerves increased when rectal pressure increased. The discharges of the EAS and PF nerves usually increased in proportion to the pressure in the rectum and maintained a constant activity level, although some trials showed inhibition. The results suggest that activities of these muscles increase the intra-abdominal pressure.

Background: Normative current perception thresholds (CPTs) are used for the evaluation of sensory function in a variety of diseases., Aims: To evaluate the reproducibility of CPT measurements with sinusoidal current in healthy volunteers., Methods: Neuroselective CPT evaluations of the median and pudendal nerve in healthy volunteers were repeated with 1 week interval (T1 and T2)., Results: In the study group (N = 41) no difference between genders for age (MW-U: P = 0.91) and BMI (t-test: P = 0.18) were found. No significant difference between T1 and T2 was found (Paired t-test: all P-values > 0.05), although the intraclass correlation for each person was low. The variability of measures for the pudendal nerve was: ICC 2 kHz: 0.41; 250 Hz: 0.30; 5 Hz: 0.38, and for the median nerve respectively: 0.58; 0.46; 0.40. Normal CPTs were shown for the pudendal nerve: 2 kHz: 51%; 250 Hz: 76%; 5 Hz: 71%, and median nerve respectively: 78%; 98%; 80%. The pudendal nerve showed more deviating values compared to the median nerve., Conclusion: Both nerves showed deviating values. CPT values with sinusoidal current assessed with 1 week interval, showed a weak intraclass correlation. This finding limits the use of CPT values with this current for longitudinal studies., (© 2014 Wiley Periodicals, Inc.)

Pudendal nerve-spinal pathways are involved in urethrogenital sensation, pain and sexual activity. However, details of these pathways and their modulation are unclear. We examined spinal pathways activated by the urethrogenital reflex (UGR) and visualized by c-Fos immunoreactivity in reflexly activated neurons within spinal cord. In anesthetized female guinea pigs, a balloon was inserted into the urethra and inflated with short-repeat or long-continuous distension to activate the UGR. A second balloon recorded reflex contractions of the vagina and uterus. Two control groups had either no balloon or a vaginal balloon (VB) only. Ninety minutes after UGR activation, c-Fos immunoreactivity in L3 and S2 spinal segments was examined. Reflex activated c-Fos immunoreactivity also was investigated in some animals with acute spinal transections at either L4 or T12 levels. There was no significant difference in spinal c-Fos expression between the control groups. Short-repeat distension reliably induced a UGR and a two- to threefold increase in c-Fos-expressing neurons throughout dorsal, intermediate and lateral spinal gray matter at S2 and about twofold increase in superficial dorsal horn at L3. T12 transection had little effect on c-Fos expression at either spinal level. However, after L4 transection, UGR generation was associated with a four- to sixfold increase in c-Fos-expressing neurons in lateral horn (LH) and central canal areas at S2, and but only 20-30% increase at L3. Thus, UGR activates preganglionic neurons projecting to pelvic viscera in both sacral and lumbar spinal cord. The reflex also must activate ascending and descending spinal inhibitory circuits that suppress c-Fos-expression in neurons at both sacral and lumbar spinal levels., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Childbirth injures muscles and nerves responsible for urinary continence. Mesenchymal stem cells (MSCs) or their secretome given systemically could provide therapeutic benefit for this complex multisite injury. We investigated whether MSCs or their secretome, as collected from cell culture, facilitate recovery from simulated childbirth injury. Age-matched female Sprague-Dawley rats received pudendal nerve crush and vaginal distension (PNC+VD) and a single intravenous (iv) injection of 2 million MSCs or saline. Controls received sham injury and iv saline. Additional rats received PNC+VD and a single intraperitoneal (ip) injection of concentrated media conditioned by MSCs (CCM) or concentrated control media (CM). Controls received a sham injury and ip CM. Urethral and nerve function were assessed with leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings 3 wk after injury. Urethral and pudendal nerve anatomy were assessed qualitatively by blinded investigators. Quantitative data were analyzed using one-way ANOVA and Holm-Sidak post hoc tests with P < 0.05 indicating significant differences. Both LPP and PNSBP were significantly decreased 3 wk after PNC+VD with saline or CM compared with sham-injured rats, but not with MSC or CCM. Elastic fiber density in the urethra increased and changed in orientation after PNC+VD, with a greater increase in elastic fibers with MSC or CCM. Pudendal nerve fascicles were less dense and irregularly shaped after PNC+VD and had reduced pathology with MSC or CCM. MSC and CCM provide similar protective effects after PNC+VD, suggesting that MSCs act via their secretions in this dual muscle and nerve injury.

After spinal cord injury, lower urinary tract functions may be disrupted. Trans-rectal stimulation of the pudendal nerve may enable patients to regain these functions via minimally invasive means. Using a finite element model of a wearable trans-rectal stimulator in the pelvic region, and a computational model of mammalian nerve fiber, various electrode configurations and the corresponding required current levels were studied. A configuration requiring considerably lower current level than previously reported was identified. For this configuration, the strength-duration curve was simulated and the effect of different stimulus waveforms on the required current was studied. In addition, the study examined whether a multi-electrode device could selectively activate different terminal branches of the pudendal nerve.

Individuals with spinal cord injury or neurological disorders have problems in urinary bladder storage and in voiding function. In these people, the detrusor of bladder contracts at low volume and this causes incontinence. The goal of bladder control is to increase the bladder capacity by electrical stimulation of relative nerves such as pelvic nerves, sacral nerve roots or pudendal nerves. For this purpose, the bladder pressure has to be monitored continuously. In this paper, we propose a method for real-time estimating the bladder pressure using artificial neural network. The method is based upon measurements of electroneurogram (ENG) signal of pudendal nerve. This approach yields synthetic bladder pressure estimates during bladder contraction. The experiments were conducted on three rats. The results show that neural predictor can provide accurate estimation and prediction of bladder pressure with good generalization ability. The average error of 1-second and 5-second ahead prediction of bladder pressure are 9.62% and 10.54%, respectively.

In rats, axons of external urethral sphincter (EUS) motoneurons travel through the anastomotic branch of the pudendal nerve (ABPD) and anastomotic branch of the lumbosacral trunk (ABLT) and converge in the motor branch of the sacral plexus (MBSP). The aim of the present study was to determine in female rats the contribution of these somatomotor pathways and urethral sensory innervation from the dorsal nerve of the clitoris on urinary continence and voiding. EUS electromyographic (EMG) activity during cystometry, leak point pressure (LPP), and voiding efficiency (VE) were assessed in anesthetized virgin Sprague-Dawley female rats before and after transection of the above nerve branches. Transection of the MBSP eliminated EUS EMG, decreased LPP by 50%, and significantly reduced bladder contraction duration, peak pressure, intercontraction interval, and VE. Transection of the ABPD or ABLT decreased EUS EMG discharge and LPP by 25% but did not affect VE. Transection of the dorsal nerve of the clitoris did not affect LPP but reduced contraction duration, peak pressure, intercontraction interval, and VE. We conclude that somatomotor control of micturition is provided by the MBSP with axons travelling through the ABPD and ABLT. Partial somatomotor urethral denervation induces mild urinary incontinence, whereas partial afferent denervation induces voiding dysfunction. ABPD and ABLT pathways could represent a safeguard ensuring innervation to the EUS in case of upper nerve damage. Detailed knowledge of neuroanatomy and functional innervation of the urethra will enable more accurate animal models of neural development, disease, and dysfunction in the future.

Background: For the evaluation of sensory innervation, normative data are necessary as a comparison., Aims: To compare our current perception thresholds (CPTs) with normative data from other research., Methods: Healthy volunteers were assessed for 2000, 250, and 5 Hz CPTs of the median and pudendal nerve and data were compared with other studies., Results: Normative data in the studied group n = 41 (male: 21; female: 20) for the median nerve, 2 kHz, 250 Hz, and 5 Hz were respectively: 241.85 ± 67.72 (140-444); 106.27 ± 39.12 (45-229); 82.05 ± 43.40 (13-271). Pudendal nerve CPTs 250 Hz were: 126.44 ± 69.46 (6-333). For men 2 kHz: 349.95 ± 125.76 (100-588); 5 Hz: 132.67 ± 51.81 (59-249) and women 2 kHz:226.20 ± 119.65 (64-528); 5 Hz: 92.45 ± 44.66 (35-215). For the median nerve no statistical differences for gender were shown. For the pudendal nerve, only 250 Hz showed no difference for gender (t-test: 0.516). Comparison of our data with CPTs of other normative data showed no agreement for the pudendal nerve. For the median nerve only 2 kHz showed agreement in three studies and for 5 Hz with one study., Conclusion: Comparing normative data of multiple studies shows a variety of results and poor agreement. Therefore, referring to normative data of other studies should be handled with caution.

Electrical stimulation of pudendal afferents can inhibit bladder contractions and increase bladder capacity. Recent results suggest that stimulation-evoked bladder inhibition is mediated by a mechanism other than activation of sympathetic bladder efferents in the hypogastric nerve, generating α-adrenergic receptor-mediated inhibition at the vesical ganglia and/or β-adrenergic receptor-mediated direct inhibition of the detrusor muscle. We investigated several inhibitory neurotransmitters that may instead be necessary for stimulation-evoked inhibition and found that intravenous picrotoxin, a noncompetitive GABAA antagonist, significantly and reversibly blocked pudendal afferent stimulation-evoked inhibition of bladder contractions in a dose-dependent manner. Similarly, intravenous picrotoxin also blocked pudendal afferent stimulation-evoked inhibition of nociceptive bladder contractions evoked by acetic acid infusion. Furthermore, intrathecal administration of picrotoxin at the lumbosacral spinal cord also blocked bladder inhibition by pudendal afferent stimulation. On the other hand, glycinergic, adrenergic, or opioidergic mechanisms were not necessary for bladder inhibition evoked by pudendal afferent stimulation. These results identify a lumbosacral spinal GABAergic mechanism of bladder inhibition evoked by pudendal afferent stimulation., (Copyright © 2014 the American Physiological Society.)

Objective: The study aims to determine the functionality of a wireless-controlled implantable stimulator designed for stimulation and block of the pudendal nerve., Materials and Methods: In five cats under α-chloralose anesthesia, the stimulator was implanted underneath the skin on the left side in the lower back along the sacral spine. Two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves in addition to one bipolar cuff electrode that was implanted on the left side central to the tripolar cuff electrode. The stimulator provided high-frequency (5-20 kHz) biphasic stimulation waveforms to the two tripolar electrodes and low-frequency (1-100 Hz) rectangular pulses to the bipolar electrode. Bladder and urethral pressures were measured to determine the effects of pudendal nerve stimulation (PNS) or block., Results: The maximal (70-100 cmH2O) urethral pressure generated by 20-Hz PNS applied via the bipolar electrode was completely eliminated by the pudendal nerve block induced by the high-frequency stimulation (6-15 kHz, 6-10 V) applied via the two tripolar electrodes. In a partially filled bladder, 20-30 Hz PNS (2-8 V, 0.2 ms) but not 5 Hz stimulation applied via the bipolar electrode elicited a large sustained bladder contraction (45.9 ± 13.4 to 52.0 ± 22 cmH2O). During cystometry, the 5 Hz PNS significantly (p < 0.05) increased bladder capacity to 176.5 ± 27.1% of control capacity., Conclusions: The wireless-controlled implantable stimulator successfully generated the required waveforms for stimulation and block of pudendal nerve, which will be useful for restoring bladder functions after spinal cord injury., (© 2013 International Neuromodulation Society.)