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Sexual dysfunction can be caused by impaired neurotransmission from the peripheral to the central nervous system. Therefore, it is important to evaluate the input of sensory information from the peripheral genital area and investigate the control mechanisms in the spinal cord to clarify the pathological basis of sensory abnormalities in the genital area. However, an in vivo evaluation system for the spinal cord–penile neurotransmission mechanism has not yet been developed. Here, urethane-anesthetized rats were used to evaluate neuronal firing induced by innocuous or nociceptive stimulation of the penis using extracellular recording or patch-clamp techniques in the lumbosacral spinal dorsal horn and electrophysiological evaluation in the peripheral pelvic nerves. As a result, innocuous and nociceptive stimuli-evoked neuronal firing was successfully recorded in the deep and superficial spinal dorsal horns, respectively. The innocuous stimuli-evoked nerve firing was also recorded in the pelvic nerve. These firings were suppressed by lidocaine. To the best of our knowledge, this is the first report of a successful quantitative evaluation of penile stimuli-evoked neuronal firing. This method is not only useful for analyzing the pathological basis of spinal cord–penile neurotransmission in sexual dysfunction but also provides a useful evaluation system in the search for new treatments.

PURPOSE: The urinary bladder generates phasic contractions via action potentials generated in pre- and then postganglionic neurons. Whilst the frequency-dependence of postganglionic neurons to generate contractions has been quantified, the dynamic range of preganglionic neurons is less clear and if intramural ganglia exert frequency-dependent modulation of transmission between pre- and postganglionic neurons. The phosphodiesterase type 5 inhibitor sildenafil reduces neurotransmitter release from postganglionic fibres to detrusor smooth muscle and an additional question was if there was also a preganglionic action. This study aimed to compare the frequency range of bladder contractile activation by pre- and postganglionic stimulation in pig and rat bladders and if sildenafil exerted additional preganglionic actions.METHODS: An arterially-perfused ex vivo pig bladder preparation was used for preganglionic (pelvic nerve) and mixed pre-and postganglionic (direct bladder wall) stimulation at 36°C and postganglionic mediated contractions achieved by field-stimulation of in vitro isolated detrusor strips. With rats, pelvic nerve stimulation was carried out in vivo and postganglionic stimulation also with isolated detrusor strips.RESULTS: All contractions were abolished by 2% lignocaine indicating they are nerve-mediated. Stimulation targets were verified with hexamethonium that completely abolished pelvic nerve responses by had no effect on detrusor strips; responses to mixed bladder wall stimulation were partially reduced. The frequency-dependence of contractile activation was similar whether by pre- or postganglionic stimulation in both pigs and rats. Sildenafil reduced contractions to preganglionic stimulation significantly more than to postganglionic stimulation. Mixed pre- and postganglionic stimulation were reduced by an intermediate extent.CONCLUSION: Intramural ganglia offer no frequency-dependent modulation under the experimental conditions used here and the sildenafil data are consistent with multiple sites of action underlying generation of bladder contractions. A translational aspect of these findings is discussed in terms of setting stimulation parameters for neuromodulation protocols.

Objective To evaluate the functional outcomes of nerve-sparing surgery for deep infiltrating endometriosis (DIE) with or without posterolateral parametrectomy. Methods A multicenter, observational, retrospective, cohort study was performed including all symptomatic women who underwent nerve-sparing laparoscopic excision of DIE and preoperative and postoperative assessment of functional outcomes through validated questionnaires between April 2019 and March 2020. Women with posterolateral parametrial DIE (P-group) and women with no parametrial involvement (NP-group) were compared in terms of preoperative and postoperative functional outcomes related to pelvic organs assessed through validated questionnaires (KESS and GIQLI for bowel function, BFLUTS for urinary function, and FSFI for sexual function); pain symptoms at 3-month follow up assessed through an 11-point visual analogue scale (VAS) for dyschezia, dysmenorrhea, dyspareunia and chronic pelvic pain; surgical outcomes; and rate of urinary voiding dysfunction at 3-month follow up. Results One-hundred patients were included: 69 in the P-group and 31 in the NP-group. Preoperative and postoperative values of questionnaires, pain symptoms, and postoperative complication rates were comparable between the two groups, except for postoperative dyspareunia and sexual dysfunction, which were statistically higher in the P-group. Only patients in the P-group experienced urinary voiding dysfunction, but no statistical significance was reached (P = 0.173). Conclusion Posterolateral parametrectomy for DIE appears to be associated with a higher risk of postoperative dyspareunia and sexual dysfunction.

Mechano-neuromodulation of autonomic pelvic nerves was demonstrated for the first time using a triboelectric neurostimulator integrated with flexible neural clip interface. The detailed stimulation parameters such as current, pulse width, and charges generated by the proposed TENG were investigated for the stimulation of autonomic pelvic nerve. In in vivo experiments, different beats per minute (BPM) were delivered to the nerves to investigate the effect of stimulation frequency on mechano-neurostimulation while monitoring changes in bladder pressure and the occurrence of micturition. Furthermore, different numbers of pulses were applied to stimulate the pelvic nerve. The bladder contractions with micturition were observed when applying more than 50 BPM as well as one pulse. Comparison of stimulation was performed using a commercial stimulator with the similar long-pulse widths as generated by TENGs. In addition, chronic implantation of flexible clip interface was demonstrated with functionality test of the interface. The results demonstrate that this technology may potentially be used for self-powered mechano-neuromodulation for bladder function in the future.

Introduction Chronic pelvic pain of unknown origin (CPPU) affects the quality of life (QoL) of up to 20% of women. The 2005 Cochrane Review, based on randomized controlled trials (RCTs), stated that the pathogenesis of CPPU is poorly understood and its treatment is empirical and ineffective. Totally ignored were the high cure rates from uterosacral ligament (USL) repair, the principal subject of this review. Material and methods We carried out a review of literature on USL causation, diagnosis, and treatment of CPPU, selecting only the literature relevant to USL. Results The first mention of CPPU being caused by lax USLs was in the pre-WWII German literature by Heinrich Martius. In 1993, CPPU was described as one of the 4 pillars of the posterior fornix syndrome (PFS- CPPU, urgency, nocturia, abnormal bladder emptying). Cure/improvement of CPPU was reported by widely geographically separated surgical groups using squatting-based pelvic floor exercises and by shortening and reinforcing USLs with tension tapes, literally a reverse transvaginal tape. Patients can potentially be cured either by native tissue ligament repair or in older women a posterior sling can be tested using a speculum test or even menstrual tampons. Conclusions This technology, based on USL pathogenesis, which can be tested for potential cure, non-surgical or surgical, offers hope for women for a condition previously considered incurable. Chronic pelvic pain, bladder and bowel incontinence occur in predictable symptom groupings, which are associated with apical prolapse. USL repair, whether native tissue or (preferably) using a posterior sling has the potential to improve clinical practice, QoL for women and open new research directions.

A pelvic nerve array is custom designed for implantation onto the pelvic nerve of male rats. This device is used for long-term (recovery) experiments. The device can electrically stimulate the pelvic nerve as well as record electrically evoked or spontaneous neural activity. Previously, we have successfully implanted rats for 2 months with no reports of biological adverse complications or damage sustained to the array. The surgical procedure is performed under anesthesia and should incorporate all local requirements for standards of animal experimentation, including methods of anesthesia, surgical environment, and post-operative monitoring and care.

Bioelectronic neural interfaces that deliver adaptive therapeutic stimulation in an intelligent manner must be able to sense and stimulate activity within the same nerve. Existing minimally-invasive peripheral neural interfaces can provide a read-out of the aggregate level of activity via electrical recordings of nerve activity, but these recordings are limited in terms of their specificity. Computational simulations can provide fine-grained insight into the contributions of different neural populations to the extracellular recording, but integration of the signals from individual nerve fibers requires knowledge of spread of current in the complex (heterogenous, anisotropic) extracellular space. We have developed a model which uses the open-source EIDORS package for extracellular stimulation and recording in the pelvic nerve. The pelvic nerve is the primary source of autonomic innervation to the pelvic organs, and a prime target for electrical stimulation to treat a variety of voiding disorders. We simulated recordings of spontaneous and electrically-evoked activity using biophysical models for myelinated and unmyelinated axons. As expected, stimulus thresholds depended strongly on both fibre type and electrode-fibre distance. In conclusion, EIDORS can be used to accurately simulate extracellular recording in complex, heterogenous neural geometries.

To investigate the feasibility of erectile function restoration by the genitofemoral nerve to pelvic nerve transfer in rats.Thirty-six male rats were included in this study. Rats in the nerve transfer group (n = 12) were subjected to pelvic nerve, sacral roots, and L6 roots transection and then bilateral genitofemoral nerve to pelvic nerve transfer, rats in the nerve resection group (n = 12) were subjected to pelvic nerve, sacral roots, and L6 roots transection without nerve transfer, and rats in the control group (n = 12) served as controls. After reinnervation, intracavernous pressure (ICP) assessment was performed. Fluoro-Gold was injected into the corpus cavernosum. Immediately before euthanasia, transferred nerves were stimulated to test penile intracavernous pressure. The L6, S1, and L1-2 spinal cord segments were used for retrogradely labeled neurons. Regenerative nerve morphologic examination assessment was performed.Genitofemoral nerve stimulation induced an increase in ICP in the nerve transfer group. The mean ICP in this group was (33.8 ± 9.4 mm Hg), which is higher than the mean value in the nerve resection group (3.9 ± 1.0 mm Hg) but lower than that in the control group (69.8 ± 12.2 mm Hg; P.05). The formation of new neural pathways was confirmed by the appearance of Fluoro-Gold labeled neurons in the L-1 and L-2 spinal cord segments in the nerve transfer group. Regenerative nerve morphologic examination showed good axonal regeneration after genitofemoral nerve transfer.Nerve regeneration can be obtained by genitofemoral nerve to pelvic nerve transfer, and erectile function can be restored.

This collection describes the procedures required to implant a pelvic nerve array and bladder catheter into male Sprague-Dawley rats as well as cystometry and electrophysiological testing in awake animals. This collection includes protocols for: STAGE 1: Implantation of a pelvic nerve array in rats STAGE 2: Cystometry in awake rats STAGE 3: Electrophysiological recording of electrically-evoked compound action potentials

A pelvic nerve array is custom designed for implantation onto the pelvic nerve of male rats. This device is used for long-term (recovery) experiments. The device can electrically stimulate the pelvic nerve as well as record electrically evoked or spontaneous neural activity. Previously, we have successfully implanted rats for 2 months with no reports of biological adverse complications or damage sustained to the array. The surgical procedure is performed under anesthesia and should incorporate all local requirements for standards of animal experimentation, including methods of anesthesia, surgical environment, and post-operative monitoring and care.

BackgroundTreatment of female pelvic malignancies often causes pelvic nerve damage. Magnetic resonance (MR) neurography mapping the female pelvic innervation could aid in treatment planning.PurposeTo depict female autonomic and somatic pelvic innervation using a modified 3D NerveVIEW sequence.Material and MethodsProspective study in 20 female volunteers (n = 6 normal, n = 14 cervical pathology) who underwent a modified 3D short TI inversion recovery (STIR) turbo spin-echo (TSE) scan with a motion-sensitive driven equilibrium (MSDE) preparation radiofrequency pulse and flow compensation. Modifications included offset independent trapezoid (OIT) pulses for inversion and MSDE refocusing. Maximum intensity projections (MIP) were evaluated by two observers (Observer 1, Observer 2); image quality was scored as 2 = high, 1 = medium, or 0 = low with the sciatic nerve serving as a reference. Conspicuity of autonomic superior (SHP) and bilateral inferior hypogastric plexuses (IHP), hypogastric nerves, and somatic pelvic nerves (sciatic, pudendal) was scored as 2 = well-defined, 1 = poorly defined, or 0 = not seen, and inter-observer agreement was determined.ResultsImages were of medium to high quality according to both observers agreeing in 15/20 (75%) of individuals. SHP and bilateral hypogastric nerves were seen in 30/60 (50%) of cases by both observers. Bilateral IHP was seen in 85% (34/40) by Observer 1 and in 75% (30/40) by Observer 2. Sciatic nerves were well identified in all cases, while pudendal nerves were seen bilaterally by Observer 1 in 65% (26/40) and by Observer 2 in 72.5% (29/40). Agreement between observers for scoring nerve conspicuity was in the range of 60%–100%.ConclusionModified 3D NerveVIEW renders high-quality images of the female autonomic and pudendal nerves.

Aims To produce an animal model of peripheral neurogenic detrusor underactivity (DU) and to evaluate the effect of TRPV4 receptor activation in this DU model. Methods In female Sprague-Dawley rats, bilateral pelvic nerve crush (PNC) was performed by using sharp forceps. After 10 days, awake cystometrograms (CMG) were recorded in sham and PNC rats. A TRPV4 agonist (GSK 1016790A) with or without a TRPV4 antagonist (RN1734) were administered intravesically and CMG parameters were compared before and after drug administration in each group. The TRPV4 transcript level in the bladder mucosa and histological changes were also evaluated. Results In CMG, PNC rats showed significant increases in intercontraction intervals (ICI), number of non-voiding contractions (NVCs), baseline pressure, threshold pressure, bladder capacity, voided volumes, and post-void residual (PVR) compared to sham rats. Contraction amplitude and voiding efficiency were significantly decreased in PNC rats. In PNC rats, intravesical application of GSK1016790A (1.5 μM) significantly decreased ICI, bladder capacity, voided volume, and PVR without increasing NVCs, and these effects were blocked by RN1734 (5.0 μM). In contrast, 1.5 μM GSK1016790A had no significant effects on CMG parameters in normal rats. TRPV4 expression within the bladder mucosa of PNC rats was increased in association with urothelial thickening. Conclusions Rats with bilateral PNC showed characteristics of DU, and this model seems appropriate for further evaluation of peripheral neurogenic mechanisms of DU. Also, TRPV4 receptors, the activation of which reduced bladder capacity and PVR, could be a target for DU treatment.

In the last 30 years, with increasing cesarean section rates, the incidence of the placenta accreta spectrum has also increased. It is estimated that by the year 2020 there will be nearly 9000 cases annually in the United States. Currently, no consensus exists regarding optimal management. Conventional treatment by cesarean-hysterectomy is challenging, with a high maternal morbidity due to massive hemorrhage, and surgical complications such as urinary tract, bowel and pelvic nerve injury, in addition to loss of fertility and its accompanying psychological trauma. Innovative approaches seek to preserve the uterus with the adherent placenta in situ, thus maintaining fertility and potentially reducing hemorrhage and adjacent organ injury. This review reports strategies for conservative treatment of such conditions, based on the current literature.

INTRODUCTION AND OBJECTIVES:Prostatic inflammation has a positive relationship with male lower urinary tract symptoms with benign prostatic hyperplasia. Although pelvic neural cross-talk is reporte...

This paper reports direct stimulation of bladder pelvic nerve using a battery-free neural clip interface. We implanted a flexible neural clip interface combined with a triboelectric nanogenerator (TENG) on a bladder pelvic nerve in rats to directly modulate bladder functions for the first time. The stimulation parameters such as currents, pulse width, and charges generated by the TENG were characterized. In an in vivo experiment, different numbers of pulses were applied to stimulate the pelvic nerve while monitoring changes in bladder pressure and the occurrence of micturition. The bladder contraction with micturition was observed for all experiments, except when applying a single pulse for the stimulation. The results demonstrate that this technology may potentially be used for direct modulation of bladder function.

Objectives: High-frequency (kHz) stimulation of preganglionic pelvic nerve afferents can inhibit voiding in both anesthetized and conscious rats. The afferents travel via the S1 sacral nerve root, which is easier to access than the distal pelvic nerve fibers within the abdominal cavity. We therefore investigated whether voiding could be inhibited by high-frequency stimulation at S1 and how this compared to distal pelvic nerve stimulation. Methods: Urethane-anesthetized rats were instrumented to record bladder pressure and abdominal wall electromyogram and to stimulate the distal preganglionic pelvic nerve bundle and S1 sacral root. Saline was infused continuously into the bladder to evoke repeated voiding. Stimulation was initiated within 1–2 sec of the onset of the steep rise in bladder pressure signaling an imminent void. Results: In six rats, stimulation of the distal pelvic nerve bundle (1‑3 kHz sinusoidal waveform 1 mA, 60 sec) supressed the occurrence of an imminent void. Voiding resumed within 70 ± 13.0 sec (mean ± SEM) of stopping stimulation. Stimulation (using the same parameters) of the S1 root at the level of the sacral foramen suppressed voiding for the entire stimulation period in three rats and deferred voiding for 35–56 sec (mean 44.0 ± 3.2 sec) in the remaining three. Stimulation at either site when the bladder was approximately half full, as estimated from previous intervoid intervals, had no effect on voiding. Conclusions: This preliminary study provides proof-of-concept for the sacral root as an accessible target for high-frequency stimulation that may be developed as an “on demand” neuromodulation paradigm to suppress unwanted urinary voids. Conflict of Interest: The authors reported no conflict of interest.

INTRODUCTION AND OBJECTIVE:There is still a lack of sufficient research on the mechanism behind neurogenic bladder (NB) treatment. The aim of this study is to explore the effect of over-expressed s...

Diarrhea is a gastrointestinal symptom associated with systemic anaphylaxis and could be induced by increased colonic motility. We determined colonic motility and expulsion by measuring the intracolonic pressure (ICP) and expelled fluid weight in anesthetized rats during anaphylactic hypotension. Substantial systemic hypotension occurred in every sensitized rat after antigen injection. One min after antigen injection, ICP began to increase and remained elevated for 5 min, which was revealed to represent tonic contraction by the video-recording procedure, and was accompanied by increased colonic fluid expulsion. Parasympathectomy composed of subdiaphragmatic vagotomy combined with pelvic nerve transection reduced the duration of the tonic contraction, but not expelled colonic fluid. Furthermore, denervation of afferent parasympathetic nerves produced essentially the same effect as parasympathectomy. Sympathectomy did not significantly change any parameters. In conclusion, the colonic motility during anaphylactic hypotension is characterized by 5-min lasting tonic contraction which is associated with increased colonic fluid expulsion and is involved by parasympathetic nerves, especially their afferents, but not sympathetic nerves, in anesthetized rats.

OBJECTIVE Neural stimulation to restore bladder function has traditionally relied on open-loop approaches that used pre-set parameters, which do not adapt to suboptimal outcomes. The goal of this study was to examine the effectiveness of a novel closed-loop stimulation paradigm for improving micturition or bladder voiding. APPROACH We compared the voiding efficiency obtained with this closed-loop framework against open-loop stimulation paradigms in anesthetized rats. The bladder pressures that preceded voiding, and the minimum current amplitudes for stimulating the pelvic nerves to evoke bladder contractions, were first calibrated for each animal. An automated closed-loop system was used to initiate voiding upon bladder fullness, adapt the stimulation current by using real-time bladder pressure changes to classify voiding outcomes, and halt stimulation when the bladder had been emptied or when the safe stimulation limit was reached. MAIN RESULTS In vivo testing demonstrated that the closed-loop system achieved high voiding efficiency or VE (75.7% ± 3.07%, mean ± standard error of the mean) and outperformed open-loop systems with either conserved number of stimulation epochs (63.2% ± 4.90% VE) or conserved charge injected (32.0% ± 1.70% VE). Post-hoc analyses suggest that the classification algorithm can be further improved with data from additional closed-loop experiments. SIGNIFICANCE This novel approach may be applied to an implantable device for treating underactive bladder (

Spinal cord epidural stimulation (SCS) represents a form of neuromodulation for the management of spasticity and pain. This technology has recently emerged as a new approach for potentially augmenting locomotion and voiding function in humans and rodents after spinal cord injury. However, the effect of SCS on micturition has not been studied extensively. Here, SCS was first applied as a direct stimulus onto individual segmental levels of the lumbar spinal cord in rats to map evoked external urethral sphincter (EUS) electromyography activity and SCS-induced voiding contractions. SCS of L2-3 inhibited EUS tonic activity, and SCS on L3 (L3/SCS) inhibited EUS tonic activity and elicited EUS bursting. In contrast, SCS of L1 and L4-6 evoked EUS tonic contractions, which resembled the urethral guarding reflex during bladder storage. Next, the effects of a bilateral pelvic nerve crush (PNC) injury on urodynamic function were examined at 14 days post-operatively. The PNC injury resulted in decreased voiding efficiency and maximum intravesical pressure, whereas the post-voiding residual volume was increased, suggestive of an underactive bladder. Finally, L3/SCS was performed to induce a voiding contraction and enable voiding in rats with a PNC injury. Voiding efficiency was significantly increased, and the residual volume was decreased by L3/SCS in rats after the PNC injury. We conclude that L3/SCS may be used to induce micturition reflexes in a partially filled bladder, reduce urethral resistance, and augment bladder emptying after PNC injury.

Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1–3 kHz, 1–2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (

This paper demonstrates batteryless remote modulation of bladder function using an active neural clip interfaces in rats. The proposed clip interface not only provides quick and conformal implantation on a small pelvic nerve in a rat, but also applies gentle pressure on the nerve to keep the clip interface in place. This novel clip interface is integrated with a micro PCB, and components for wireless mid-field transfer. The tiny and wirelessly powered neural clip can be implanted on the small visceral pelvic nerve located deeply in the body, and it provides remote modulation of micturition in rats. This result indicates that the proposed wireless neural clip could enable wireless modulation of small peripheral somatic and visceral nerves, thus advancing implantable bioelectronics in the near future.

Several lines of recent evidence suggest that pelvic innervation is altered in endometriosis-affected women, and there is a strong presumption that nerve fibers demonstrated in eutopic endometrium (of women with endometriosis) and in endometriotic lesions play roles in the generation of chronic pelvic pain. The recent observation of sensory C, sensory A-delta, sympathetic and parasympathetic nerve fibers in the functional layer of endometrium of most women affected by endometriosis, but not demonstrated in most women who do not have endometriosis, was a surprise. Nerve fiber densities were also greatly increased in myometrium of women with endometriosis and in endometriotic lesions compared with normal peritoneum. Chronic pelvic pain is complex, and endometriosis is only one condition which contributes to this pain. The relationship between the presence of certain nerve fibers and the potential for local pain generation requires much future research. This paper reviews current knowledge concerning nerve fibers in endometrium, myometrium and endometriotic lesions, and discusses avenues of research that may improve our knowledge and lead to enriched understanding and management of endometriotic pain symptoms.

Transanal rectal surgery and particularly transanal endoscopic microsurgery are becoming increasingly utilized in a variety of settings. In well-selected cases, oncologic outcomes are comparable to more radical techniques, and operative complications are decreased with the less invasive procedures. Due to the necessity for anal dilation during transanal approaches however, concern over functional outcomes has developed. As the medical community focused on these functional results however, it became clear that compared to radical resection, transanal surgery compares favorably; disturbances due to pelvic nerve injury are notably less, and though incontinence often presents early post-operatively, it dissipates and has little effect upon patient quality of life. Both patient- and surgeon-related factors appear to influence functional outcomes, allowing for both improvements in surgical technique and clarity of patient expectations.

Objective. Neuromodulation of autonomic nerve activity to regulate physiological processes is an emerging field. Vagal stimulation has received most attention whereas the potential of modulate visceral function by targeting autonomic nerves within the abdominal cavity remains under-exploited. Surgery to locate intra-abdominal targets is inherently more stressful than for peripheral nerves. Electrode leads risk becoming entrapped by intestines and loss of functionality in the nerve-target organ connection could result from electrode migration or twisting. Since nociceptor afferents are intermingled with similar-sized visceral autonomic fibres, stimulation may induce pain. In anaesthetised rats high frequency stimulation of the pelvic nerve can suppress urinary voiding but it is not known how conscious animals would react to this procedure. Our objective therefore was to determine how rats tolerated chronic implantation of cuff electrodes on the pelvic nerve, whether nerve stimulation would be aversive and whether nerve-bladder functionality would be compromised. Approach. We carried out a preliminary de-risking study to investigate how conscious rats tolerated chronic implantation of electrodes on the pelvic nerve, their responsiveness to intermittent high frequency stimulation and whether functionality of the nerve-bladder connection became compromised. Main results. Implantation of cuff electrodes was well-tolerated. The normal diurnal pattern of urinary voiding was not disrupted. Pelvic nerve stimulation (up to 4 mA, 3 kHz) for 30 min periods evoked mild alerting at stimulus onset but no signs of pain. Stimulation evoked a modest (

Urge Urinary Incontinence: ‘a sudden and uncontrollable desire to void which is impossible to defer’ is extremely common and considered the most bothersome of lower urinary tract conditions. Current treatments rely on pharmacological, neuromodulatory and neurotoxicological approaches to manage the disorder, by reducing the excitability of the bladder muscle. However, some patients remain refractory to treatment. An alternative approach would be to temporarily suppress activity of the micturition control circuitry at the time of need i.e. urgency. In this study we investigated, in a rat model, the utility of high frequency pelvic nerve stimulation to produce a rapid onset, reversible suppression of voiding. In urethane-anaesthetised rats periodic voiding was induced by continuous infusion of saline into the bladder whilst recording bladder pressure and electrical activity from the external urethral sphincter. High frequency (1-3kHz), sinusoidal pelvic nerve stimulation initiated at the onset of the sharp rise in bladder pressure signalling an imminent void aborted the detrusor contraction. Urine output was suppressed and tone in the external urethral sphincter increased. Stimulating the right or left nerve was equally effective). The effect was rapid in onset, reversible and reproducible and evoked only minimal ‘off target’ side effects on blood pressure, heart rate, respiration, uterine pressure or rectal pressure. Transient contraction of abdominal wall was observed in some animals. Stimulation applied during the filling phase evoked a small, transient rise in bladder pressure and increased tonic activity in the EUS, but no urine output. Suppression of micturition persisted after section of the contralateral pelvic nerve or after ligation of the nerve distal to the electrode cuff on the ipsilateral side. We conclude that high frequency pelvic nerve stimulation initiated at the onset of an imminent void provides a potential means to control urinary continence.

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2. PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.

Neural modulation technology and the capability to affect organ function have spawned the new field of bioelectronic medicine. Therapeutic interventions depend on wireless bioelectronic neural interfaces that can conformally and easily attach to small (few hundred micrometers) nerves located deep in the body without neural damage. Besides size, factors like flexibility and compliance to attach and adapt to visceral nerves associated moving organs are of paramount importance and have not been previously addressed. This study proposes a novel flexible neural clip (FNC) that can be used to interface with a variety of different peripheral nerves. To illustrate the flexibility of the design, this study stimulates the pelvic nerve, the vagus nerve, and branches of the sciatic nerve and evaluates the feasibility of the design in modulating the function of each of these nerves. It is found that this FNC allows fine‐tuning of physiological processes such as micturition, heart rate, and muscle contractions. Furthermore, this study also tests the ability of wirelessly powered FNC to enable remote modulation of visceral pelvic nerves located deep in the body. These results show that the FNC can be used with a range of different nerves, providing one of the critical pieces in the field of bioelectronics medicines.

There has been substantial recent interest in the development of bioelectronic medicines (also known as “electroceuticals”) [1]. Bioelectronic medicines consist of implantable devices capable of treating diseases by modulation of the nervous system. While substantial progress has been made in the treatment of some central nervous system disorders such as Parkinson's Disease by deep brain stimulation [2], recently attention is focused on development of neuromodulation strategies for the peripheral nervous system [3]. The development of strategies for interfacing with and modulating the activity of peripheral nerves to the viscera may offer the prospect of extending bioelectronic medicine beyond diseases of the central nervous system, to the much larger class of non-neurological diseases that can be affected by electrical signalling in the peripheral nervous system, ranging from hypertension [4] to sleep apnea [5], rheumatoid arthritis [6] and sepsis [7].

To investigate the prevalence of vulvodynia in Portugal and factors associated with this condition.In a cross-sectional study, an online survey was distributed by email and posted on a website and social networks. Women aged at least 18 years who were living in Portugal were eligible to complete the survey between June 1 and November 30, 2013. Participants had to have had symptoms for at least 6 months to be deemed to have vulvodynia.Overall, 1229 questionnaires were included in analyses. A total of 80 (6.5%) women had vulvodynia at the time of the survey, and 117 (9.5%) had had it previously; lifetime prevalence was 16.0%. Pregnancy and type of delivery were not associated with vulvodynia. Women who had ever taken oral contraceptives were significantly more likely to have ever had vulvodynia (P0.010). Candidiasis, genital herpes, urinary tract infections, depression, and premenstrual syndrome were associated with ever having had vulvodynia (P0.01). Pain syndromes were associated with ever having had vulvodynia, especially fibromyalgia and bladder pain syndrome (P0.001). Scoliosis and hysterectomy were also significantly associated (P0.01).The prevalence of vulvodynia in Portugal is similar to that elsewhere. Three main groups of factors might lead to vulvodynia: local inflammatory factors, general pain susceptibility, and pelvic nerve interference.

Background Mechanosensitive afferents innervating the bladder increase their firing rate as the bladder fills and pressure rises. However, the relationship between afferent firing rates and intravesical pressure is not a simple linear one. Firing rate responses to pressure can differ depending on prior activity, demonstrating hysteresis in the system. Though this hysteresis has been commented on in published literature, it has not been quantified. Results Sixty-six bladder afferents recorded from sacral dorsal root ganglia in five alpha-chloralose anesthetized felines were identified based on their characteristic responses to pressure (correlation coefficient ≥ 0.2) during saline infusion (2 ml/min). For saline infusion trials, we calculated a maximum hysteresis ratio between the firing rate difference at each pressure and the overall firing rate range (or Hmax) of 0.86 ± 0.09 (mean ± standard deviation) and mean hysteresis ratio (or Hmean) of 0.52 ± 0.13 (n = 46 afferents). For isovolumetric trials in two experiments (n = 33 afferents) Hmax was 0.72 ± 0.14 and Hmean was 0.40 ± 0.14. Conclusions A comprehensive state model that integrates these hysteresis parameters to determine the bladder state may improve upon existing neuroprostheses for bladder control.

Background: This study evaluated the effect of imipramine, which inhibits colonic afferents, on responses of the peripheral afferent nerve innervating bladder to noxious urinary bla

The afferent nervous system plays an important role in the regulation of lower urinary tract (LUT) function. Multiple methods to study the afferent nervous system in the LUT have been described. This overview focuses on extracellular afferent nerve recordings of the pelvic and hypogastric nerves in cat, rat, mouse, and guinea pig from in vivo and in vitro models and considers how such recordings may lend to the understanding of interspecies differences. Neurourol. Urodynam 30:647-652, 2011.

Complications from needle placement and exit during a TOT procedure exist and must be considered when placing the needle through the area of the obturator fossa., Background and Objectives: Five cases of pelvic nerve complications after transobturator tape (TOT) inside-out surgical procedures for stress urinary incontinence are presented. Methods: We conducted a chart review of patients with complications referred to our practice. Results: Five patients with nerve complications after TOT inside-out procedures were investigated. Pudendal neuropathy and interstitial cystitis were seen in this series of patients with several patients having myofascial pain in the lower abdominal area. Conclusions: Although not commonly reported, complications from needle placement and from the area of needle exit in a TOT procedure can exist, and the surgeon must be careful when placing the needle through the area of the obturator fossa.

The aim of this animal study was to investigate the effect of intraoperative pelvic nerve stimulation on internal anal sphincter electromyographic signals in order to evaluate its possible use for neuromonitoring during nerve-sparing pelvic surgery. Eight pigs underwent low anterior rectal resection. The intersphincteric space was exposed, and the internal (IAS) and external anal sphincter (EAS) were identified. Electromyography of both sphincters was performed with bipolar needle electrodes. Intermittent bipolar electric stimulation of the inferior hypogastric plexus and the pelvic splanchnic nerves was carried out bilaterally. The recorded signals were analyzed in its frequency spectrum. In all animals, electromyographic recordings of IAS and EAS were successful. Intraoperative nerve stimulation resulted in a sudden amplitude increase in the time-based electromyographic signals of IAS (1.0 (0.5-9.0) mu V vs. 4.0 (1.0-113.0) mu V) and EAS (p < 0.001). The frequency spectrum of IAS in the resting state ranged from 0.15 to 5 Hz with highest activity in median at 0.77 Hz (46 cycles/min). Pelvic nerve stimulation resulted in an extended spectrum ranging from 0.15 to 20 Hz. EAS signals showed higher frequencies mainly in a range of 50 to 350 Hz. However, after muscle relaxation with pancuronium bromide, only the low frequency spectrum of the IAS signals was still present. Intraoperative verification of IAS function by stimulation of pelvic autonomic nerves is possible. The IAS electromyographic response could be used to monitor pelvic autonomic nerve preservation.

Information about colorectal distension (i.e., colorectal dilation by increased intraluminal pressure) is primarily encoded by stretch-sensitive colorectal afferents in the pelvic nerve (PN). Despite anatomic differences between rectum and distal colon, little is known about the functional roles of colonic vs. rectal afferents in the PN pathway or the quantitative nature of mechanosensory encoding. We utilized an in vitro mouse colorectum-PN preparation to investigate pressure-encoding characteristics of colorectal afferents. The colorectum with PN attached was dissected, opened longitudinally, and pinned flat in a Sylgard-lined chamber. Action potentials of afferent fibers evoked by circumferential stretch (servo-controlled force actuator) were recorded from the PN. Stretch-sensitive fibers were categorized into the following four groups: colonic muscular, colonic muscular/mucosal, rectal muscular, and rectal muscular/mucosal. Seventy-nine stretch-sensitive PN afferents evenly distributed into the above four groups were studied. Rectal muscular afferents had significantly greater stretch-responses than the other three groups. Virtually all rectal afferents (98%) had low thresholds for response and encoded stimulus intensity into the noxious range without obvious saturation. Most colonic afferents (72%) also had low thresholds (18 mmHg) for response. These high-threshold colonic afferents were sensitized to stretch by inflammatory soup; response threshold was significantly reduced (from 23 to 12 mmHg), and response magnitude significantly increased. These results suggest that the encoding of mechanosensory information differs between colonic and rectal stretch-sensitive PN afferents. Rectal afferents have a wide response range to stretch, whereas high-threshold colonic afferents likely contribute to visceral nociception.

Female rats exhibit a conditioned place preference (CPP) for a context paired with mating. The present experiment tested the hypothesis that the activation of the pelvic nerve mediates the reinforcing effects of mating for female rats. Rats underwent bilateral pelvic nerve or sham transection and then received paced mating, nonpaced mating, or the control treatment during a CPP procedure. Pelvic nerve transection did not affect the CPP for paced or nonpaced mating. In tests of paced mating behavior, contact-return latencies following intromissions were significantly shorter in rats with pelvic nerve transection than they were in rats with sham transections. These results show that the pathway conveying the reinforcing effects of mating stimulation does not depend on the integrity of the pelvic nerve, but that activation of the pelvic nerve contributes to the display of paced mating behavior.

Urinary incontinence (UI) is the involuntarily urination that usually effects older people or is the result of an injury. UI affects more than eleven million people and the cost of incontinence management in the United States in 2000 was $19.5 billion. Where conventional physical therapies have failed, pelvic nerve stimulation is a promising form of regulating the bladder long term. Piezoresistive pressure sensors consist of two variable resistance values and two known resistance values that are represented on a daughterboard. This unknown resistance represents the change in pressure. The filling and voiding of the bladder was characterized through acute surgeries. It was found that the pressure sensor successfully detects changes in the bladder. Based on the collected data an implantable package can be assembled for chronic surgeries. The package consists of a bionode to record and stimulate the pelvic nerve, a powernode to apply a voltage, and a daughterboard. The next phase of the research is to thoroughly test the implantable package by placing the rat inside a cavity that will wirelessly power the device to regulate the bladder. Future applications of this will be long term use in humans with the ability to control the stimulus through a smart phone application. This research can improve the overall health and quality of life of patients by giving them back control of their bodies.

Recurrent inhibition of the bladder C fibre reflex was studied in adult female cats anaesthetized with α-chloralose. Test reflexes were evoked by electrical stimulation of bladder Aδ and C afferents in the right pelvic nerve and were recorded from the proximal end of a small ipsilateral pelvic nerve branch, transected close to the bladder. Such test reflexes were consistently depressed by repetitive electrical stimulation of the contralateral bladder pelvic nerve (20 Hz, 20 s) at intensities sufficient to recruit axons of bladder preganglionic neurones. The inhibition could be evoked after transection of the left dorsal roots S1–S4 and the sympathetic supply to the bladder but was abolished by transection of the pelvic nerve central to the site of stimulation. Hence, it most likely involved central recurrent collaterals of antidromically activated bladder preganglionic neurones. The reflex suppression was quite considerable – maximal C fibre reflexes were reduced to a group mean of 25% (± 9% confidence interval) of their control size. The effect had a slow onset, requiring a few seconds of conditioning stimulation to be revealed, and was very long lasting (minutes). Naloxone (0.01–0.5 mg kg−1i.v.) abolished the recurrent inhibition of both the C fibre and Aδ bladder reflexes, while inhibition from afferents in the dorsal clitoris nerve remained unchanged. It is concluded that the segmental bladder C fibre reflex and the spino-ponto-spinal Aδ micturition reflex are both targets of recurrent inhibition from bladder parasympathetic preganglionic neurones and that the effect involves an enkephalinergic mechanism.