You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction (PD07)1 May 2024PD07-07 BILATERAL PUDENDAL NERVE BLOCK REDUCES URETHRAL PRESSURE IN SCI PATIENTS WITH DESD Christopher Chermansky, Vickie Polanco-Garcia, Andrew Moyer, William de Groat, and Changfeng Tai Christopher ChermanskyChristopher Chermansky , Vickie Polanco-GarciaVickie Polanco-Garcia , Andrew MoyerAndrew Moyer , William de GroatWilliam de Groat , and Changfeng TaiChangfeng Tai View All Author Informationhttps://doi.org/10.1097/01.JU.0001008552.16893.70.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We have previously shown in ASIA-A T9 SCI cats that DESD could be blocked with high frequency, biphasic, bilateral pudendal stimulation. Now we report on our initial SCI patients with DESD treated with our FDA-approved Nerve Block and Stimulation External Pulse Generator. METHODS: The study was approved by the WCG and University of Pittsburgh IRBs. Patients were recruited with ASIA-A SCI between T7 and L5 of at least 1-year duration. On urodynamics (UDS), they demonstrated DESD with or without NDO. A triple lumen urethral urodynamic catheter was placed to record detrusor and urethral pressures. Needle electrodes were placed in the anal sphincter to measure compound muscle action potentials (C-MAP). UDS commenced until capacity was reached. Crede maneuver was performed, and urethral and bladder pressures were recorded. Fluoroscopy was used to insert bilateral foramen needles medial to the ischial tuberosity toward the ischial spine. During insertion, each needle was stimulated at 5 Hz and 0.2 ms until optimal pudendal nerve stimulation was confirmed with C-MAP and anal twitch. Bilateral block began with stimulation at 1 kHz and 1mA for 30 seconds. If urethral pressure during Crede was not reduced to <50 cm H2O, the stimulation was repeated at 1 kHz and 3.8mA for 30 seconds, for 1 minute, for 2 minutes, and for 4 minutes. The primary endpoint was reduction in urethral pressure <50 cmH2O. Any adverse events (AEs) were recorded. RESULTS: A total of 3 patients completed the study. The first subject is a 56-year-old male with T9 ASIA-A SCI, and UDS showed DESD but no NDO. The urethral pressure in this first subject was reduced from 65 cm H2O to 35 cm H2O with a stimulation of 1 kHz and 3.8mA for 4 minutes. The second subject is a 46-year-old female with T9 ASIA-A SCI, and UDS showed both DESD and NDO. Because urethral pressure was difficult to measure from NDO, bladder leak point pressure was used and this was reduced from 70 cm H2O to 51 cm H2O with a stimulation of 1 kHz and 3.8mA for 4 minutes. The third subject is a 55-year-old male with T10 ASIA-A SCI, and UDS showed both DESD and NDO. The urethral pressure in this subject was reduced from 62 cm H2O to 23 cm H2O with a stimulation of 1 kHz and 3.8mA for 30 seconds. The only AE noted was mild nausea in one subject. CONCLUSIONS: Successful reductions in urethral or bladder leak point pressures were seen in 3 SCI patients with DESD using bilateral pudendal nerve stimulation at 1 kHz. The only adverse event was mild nausea. This study supports the development of an implantable device to treat DESD by bilateral pudendal nerve block using 1 kHz stimulation. Source of Funding: This study is funded by the Bridging the Gap Plus (BG+) program of the Defense Advanced Research Projects Agency (DARPA) under the contract N66001-20-C-4050 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e169 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Christopher Chermansky More articles by this author Vickie Polanco-Garcia More articles by this author Andrew Moyer More articles by this author William de Groat More articles by this author Changfeng Tai More articles by this author Expand All Advertisement PDF downloadLoading ...

Spinal cord injury (SCI) disrupts coordination between the bladder and the external urinary sphincter (EUS), leading to transient or permanent voiding impairment, which is more severe in males. Male versus female differences in spinal circuits related to the EUS as well as post-SCI rewiring are essential for understanding of sex-/gender-specific impairments and possible recovery mechanisms. To quantitatively assess differences between EUS circuits in males versus females and in spinal intact (SI) versus SCI animals, we retrogradely traced and counted EUS-related neurons. In transgenic ChAT-GFP mice, motoneurons (MNs), interneurons (INs), and propriospinal neurons (PPNs) were retrogradely trans-synaptically traced with PRV614-red fluorescent protein (RFP) injected into EUS. EUS-MNs in dorsolateral nucleus (DLN) were separated from other GFP+ MNs by tracing them with FluoroGold (FG). We found two morphologically distinct cell types in DLN: FG+ spindle-shaped bipolar (SB-MNs) and FG- rounded multipolar (RM-MNs) cholinergic cells. Number of MNs of both types in males was twice as large as in females. SCI caused a partial loss of MNs in all spinal nuclei. After SCI, males showed a fourfold rise in the number of RFP-labeled cells in retro-DLN (RDLN) innervating hind limbs. This suggests (a) an existence of direct synaptic interactions between spinal nuclei and (b) a post-SCI increase of non-specific inputs to EUS-MNs from other motor nuclei. Number of INs and PPNs deferred between males and females: In SI males, the numbers of INs and PPNs were ∼10 times larger than in SI females. SCI caused a twofold decrease of INs and PPNs in males but not in females.

Objective: To determine the role of ion concentrations and ion pump activity in conduction block of myelinated axon induced by a long-duration direct current (DC). Methods: A new axonal conduction model for myelinated axons based on the classical Frankenhaeuser-Huxley (FH) equations is developed that includes ion pump activity and allows the intracellular and extracellular Na+ and K+ concentrations to change with axonal activity. Results: Action potential generation, propagation, and acute DC block occurring within a short period (milliseconds) that do not significantly change the ion concentrations or trigger ion pump activity are successfully simulated by the new model in a similar way as the classical FH model. Different from the classical model, the new model also successfully simulates the post-stimulation block phenomenon, i.e., the axonal conduction block occurring after terminating a long-duration (30 seconds) DC stimulation as observed recently in animal studies. The model reveals a significant K+ accumulation outside the axonal node as the possible mechanism underlying the post-DC block that is slowly reversed by ion pump activity during the post-stimulation period. Conclusion: Changes in ion concentrations and ion pump activity play an important role in post-stimulation block induced by long-duration DC stimulation. Significance: Long-duration stimulation is used clinically for many neuromodulation therapies, but the effects on axonal conduction/block are poorly understood. This new model will be useful for better understanding of the mechanisms underlying long-duration stimulation that changes ion concentrations and triggers ion pump activity.

OBJECTIVE:The purpose of this study is to determine whether adaptively stepwise increasing the intensity of a high-frequency (10 kHz) biphasic stimulation (HFBS) can produce nerve conduction block without generating a large initial response. MATERIALS AND METHODS:In anesthetized cats, three cuff electrodes were implanted on the left pudendal nerve for stimulation or block. The urethral pressure increase induced by pudendal nerve stimulation was used to measure the pudendal nerve block induced by HFBS. RESULTS:HFBS applied suddenly with a large step increase in intensity induced a large (86 ± 16 cmH2O) urethral pressure increase before it blocked pudendal nerve conduction. However, HFBS applied by adaptively stepwise increasing the intensity every 10 to 60 seconds over a long period (33-301 minutes; average 108 ± 35 minutes) with many small intensity increases (0.005-0.1 mA) induced no response or low-amplitude high-frequency urethral pressure changes before it blocked pudendal nerve conduction. The minimal HFBS intensities required by the two different methods to block pudendal nerve conduction are similar. CONCLUSION:This study is important for better understanding the possible mechanisms underlying the HFBS-induced nerve block and provides the possibility of developing a new nerve block method for clinical applications in which an initial large response is a concern.

The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinate the activity of smooth and striated muscles of the bladder and urethral outlet. Although the neural units that can induce contraction and relaxation of the bladder and urethra are located in the lumbosacral spinal cord and peripheral nervous pathways, the coordination between different components of the lower urinary tract necessary for efficient micturition requires a hierarchical neural system, in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Then, voluntary micturition depends on suprapontine inputs from the forebrain that modulate the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the reflex micturition is a spinobulbospinal pathway that has essential connections between the lumbosacral spinal cord and brainstem structures such as the periaqueductal gray matter and Pontine micturition center, which can induce bladder contractions and reciprocal urethral relaxation during voiding. However, these suprapontine and spinobulbospinal pathways, which are responsible for voluntary and reflex voiding, respectively, are still immature in infants and young children, resulting in involuntary voiding, and are often impaired in adults due to diseases or injuries of the nervous system, leading to reemergence of involuntary micturition and urinary incontinence. This chapter summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling voluntary and reflex micturition.

AbstractThe purpose of this study was to determine how sensory neurons respond to high‐frequency membrane potential alternation between depolarization and hyperpolarization. Membrane currents were recorded from dissociated dorsal root ganglion (DRG) neurons of adult rats using the whole cell patch clamp technique in voltage clamp mode. Stepwise depolarization of the membrane was applied first to determine the threshold membrane potential for inducing an action potential (AP) current. Then, membrane potential alternation between depolarization (to +20 mV) and hyperpolarization (to −110 mV) was applied to the neuron for 10 s at different frequencies (10 Hz to 1 kHz). The tested DRG neurons had APs of either a long duration (>10 ms) or a short duration (<10 ms). Membrane potential alternation at ≥500 Hz completely disrupted the AP generation, disabled the ion channel gating function, and produced membrane current alternating symmetrically across zero. Replacing extracellular sodium with potassium increased the amplitude of the membrane current response and caused the membrane current to be larger during hyperpolarization than during depolarization. These results support the hypothesis that high‐frequency biphasic stimulation blocks axonal conduction by driving the potassium channel open constantly. Understanding neural membrane response to high‐frequency membrane potential alternation is important to reveal the possible mechanisms underlying axonal conduction block induced by high‐frequency biphasic stimulation.

You have accessJournal of UrologyCME1 Apr 2023PD23-01 EFFECT OF OPIOID RECEPTOR ANTAGONIST ON BLADDER UNDERACTIVITY INDUCED BY PROLONGED PUDENDAL AFFERENT STIMULATION Michael Pintauro, Jianan Jian, Jicheng Wang, Bing Shen, Zhijun Shen, Khari Goosby, Joseph Scolieri, Avanish Madhavaram, Jonathan Beckel, William De Groat, Christopher Chermansky, and Changfeng Tai Michael PintauroMichael Pintauro More articles by this author , Jianan JianJianan Jian More articles by this author , Jicheng WangJicheng Wang More articles by this author , Bing ShenBing Shen More articles by this author , Zhijun ShenZhijun Shen More articles by this author , Khari GoosbyKhari Goosby More articles by this author , Joseph ScolieriJoseph Scolieri More articles by this author , Avanish MadhavaramAvanish Madhavaram More articles by this author , Jonathan BeckelJonathan Beckel More articles by this author , William De GroatWilliam De Groat More articles by this author , Christopher ChermanskyChristopher Chermansky More articles by this author , and Changfeng TaiChangfeng Tai More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003296.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Fowler Syndrome, or non-obstructive urinary retention, is seen in young female patients. Although the cause is unknown, it is theorized that aberrant sensory nerves from the urethral sphincter cause inhibition of the central nervous system, thereby leading to urinary retention. Prior studies have suggested that the opioid receptor may be implicated in bladder overactivity and underactivity. We aimed to evaluate opioid receptor inhibition on bladder function in a feline model of Fowler’s Syndrome. METHODS: A total of 10 cats were anesthetized, ureters externalized via laparotomy, and urethral catheter placed. A tripolar cuff electrode was placed on the pudendal nerve. Multiple cystometrograms (CMGs) were performed to determine baseline bladder function (Control). Multiple pudendal nerve stimulations (PNS) were performed at 30-minute cycles (5 Hz, 0.2 ms) were applied at 4-6 times the intensity required to elicit anal contraction for 2-5 hours. The result was a stable, underactive bladder state (Post-PNS 1). Next, naloxone (1mg/kg IV) was administered, and CMGs obtained (Post-NX). A single 30-minute PNS was then performed to evaluate the combined effect of naloxone and PNS (Post-PNS 2). Lastly, a CMG was performed to examine any recovery (Post-Control). Primary outcomes were bladder capacity and contraction amplitude (contractility). RESULTS: Application of PNS produced a significant increase in bladder capacity and decrease in bladder amplitude, indicative of a state of bladder underactivity (Figure 1, * denotes significance p<0.05). Administration of naloxone significantly reduced the bladder capacity and increased contraction amplitude. Re-application of PNS led fully overcame the naloxone effect on capacity; however, the amplitude is a combined effect. This effect of re-stimulation lasted only for a short period (15-20 minutes) and Post-Control demonstrate a reduction in capacity indicating effects of the still present naloxone overcoming the PNS. CONCLUSIONS: Pharmacologic opioid receptor antagonism increased bladder contractility and reduced bladder capacity to baseline in our feline model of non-obstructive urinary retention. This is a new target for possible pharmacotherapy in the treatment of patients with Fowler's Syndrome. Source of Funding: 5R01DK121698-02 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e670 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Pintauro More articles by this author Jianan Jian More articles by this author Jicheng Wang More articles by this author Bing Shen More articles by this author Zhijun Shen More articles by this author Khari Goosby More articles by this author Joseph Scolieri More articles by this author Avanish Madhavaram More articles by this author Jonathan Beckel More articles by this author William De Groat More articles by this author Christopher Chermansky More articles by this author Changfeng Tai More articles by this author Expand All Advertisement PDF downloadLoading ...

OBJECTIVES:We examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI). METHODS:SCI was induced by Th8-9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6-S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme-linked immunosorbent assay. RESULTS:Sex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice. CONCLUSIONS:We demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6-S1 DRG and NGF in the bladder could be involved in SCI-induced lower urinary tract dysfunction in both sexes of mice.

AIMS:To determine the role of opioid and β-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation (PNS). METHODS:In α-chloralose anesthetized cats, 30-min PNS was applied repeatedly for 3-9 times to induce poststimulation or persistent bladder underactivity. Then, naloxone (opioid receptor antagonist, 1 mg/kg, IV) or propranolol (β-adrenergic receptor antagonist, 3 mg/kg, IV) was given to reverse the bladder underactivity. After the drug treatment, an additional 30-min PNS was applied to counteract the drug effect. Repeated cystometrograms were performed by slowly (1-2 mL/min) infusing the bladder with saline via a urethral catheter to determine the bladder underactivity and the treatment effects. RESULTS:Prolonged (2-4.5 h) PNS induced bladder underactivity evident as a large bladder capacity (169 ± 49% of control) and a reduced amplitude of bladder contraction (59 ± 17% of control). Naloxone fully reversed the bladder underactivity by reducing bladder capacity to 113 ± 58% and increasing the amplitude of bladder contraction to 104 ± 34%. After administration of naloxone an additional 30-min PNS temporarily increased the bladder capacity to the underactive bladder level (193 ± 74%) without changing the amplitude of the bladder contraction. Propranolol had no effect on bladder underactivity. CONCLUSIONS:A tonic enkephalinergic inhibitory mechanism in the CNS plays a critical role in the bladder underactivity induced by prolonged PNS, while the peripheral β-adrenergic receptor mechanism in the detrusor is not involved. This study provides basic science evidence consistent with the clinical observation that comorbid opioid usage may contribute to voiding dysfunction in patients with Fowler's syndrome.

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder–urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

AIMS:Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. MAIN METHODS:We used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 μg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. KEY FINDINGS:In capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (KA) and sustained delayed rectifier-type K+ (KDR) currents were significantly reduced by SCI. The reduction of KA, but not KDR, current density was reversed by the treatment with p38 MAPK inhibitor. SIGNIFICANCE:P38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in KA channel activity in SCI mice.

Objectives: This study aims to determine temperature effect on nerve conduction block induced by high-frequency (kHz)Materials and Methods: Frog sciatic nerve-muscle preparation was immersed in Ringer's solution at a temperature of 15 or 20 degrees C. To induce muscle contractions, a bipolar cuff electrode delivered low-frequency (0.25 Hz) stimulation to the nerve. To induce nerve block, a tripolar cuff electrode was placed distal to the bipolar cuff electrode to deliver HFBS (2 or 10 kHz). A bipolar hook electrode distal to the blocking electrode was used to confirm that the nerve block occurred locally at the site of HFBS. A thread tied onto the foot was attached to a force transducer to measure the muscle contraction force.Results: At 15 degrees C, both 2- and 10-kHz HFBSs elicited an initial transient muscle contraction and then produced nerve block during the stimulation (ie, acute block), with the 10 kHz having a significantly (p < 0.001) higher acute block threshold (5.9 +/- 0.8 mA peak amplitude) than the 2 kHz (1.9 +/- 0.3 mA). When the temperature was increased to 20 degrees C, the acute block threshold for the 10-kHz HFBS was significantly (p < 0.0001) decreased from 5.2 +/- 0.3 to 4.4 +/- 0.2 mA, whereas the 2-kHz HFBS induced a tonic muscle contraction during the stimulation but elicited nerve block after terminating the 2-kHz HFBS (ie, poststimulation block) with an increased block duration at a higher stimulation intensity. Conclusion: Temperature has an important influence on HFBS-induced nerve block. The blocking mechanisms underlying acute and poststimulation nerve blocks are likely to be very different.

This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system. This neural system coordinates the activity of two functional units in the LUT: the urinary bladder and an outlet including bladder neck, urethra, and striated muscles of the pelvic floor. During the storage phase, the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure and continence, and during the voiding phase, the outlet relaxes and the bladder contracts to promote efficient release of urine. SCI impairs voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following SCI, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However, the bladder does not empty efficiently because coordination between the bladder and urethral sphincter is lost. In animal models of SCI, hyperexcitability of silent C-fiber bladder afferents is a major pathophysiological basis of neurogenic LUTD, especially detrusor overactivity. Reflex plasticity is associated with changes in the properties of neuropeptides, neurotrophic factors, or chemical receptors of afferent neurons. Not only C-fiber but also Aδ-fiber could be involved in the emergence of neurogenic LUTD such as detrusor sphincter dyssynergia following SCI. Animal research using disease models helps us to detect the different contributing factors for LUTD due to SCI and to find potential targets for new treatments.

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.

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.

Objective. A new axonal conduction model was used to analyze the interaction between intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency (kHz) biphasic stimulation (HFBS). Approach. The model includes intracellular and extracellular sodium and potassium concentrations and ion pumps. First, the HFBS (1 kHz, 5.4 mA) was applied for a duration (59.4 s) long enough to produce an axonal conduction block after terminating the stimulation, i.e. a post-stimulation block. Then, the intensity of HFBS was reduced to a lower level for 4 s to determine if the axonal conduction block could be maintained. Main results. The block duration was shortened from 1363 ms to 5 ms as the reduced HFBS intensity was increased from 0 mA to 4.1 mA. The block was maintained for the entire tested period (4000 ms) if the reduced intensity was above 4.2 mA. At the low intensity (<4.2 mA) the membrane potential oscillation disrupted the post-stimulation block caused by the increased intracellular sodium concentration, while at the high intensity (>4.2 mA) the membrane potential oscillation was strong enough to maintain the block and further increased the intracellular sodium concentration. Significance. This study indicates a possibility to develop a new nerve block method to reduce the HFBS intensity, which can extend the battery life for an implantable nerve stimulator in clinical applications to block pain of peripheral origin.

Objective: This study aimed at determining whether stimulation of sacral spinal roots can induce penile erection in cats.Materials and Methods: In anesthetized cats, a 20-gauge catheter was inserted into the corpus cavernosum to measure the penile pressure. Stimulus pulses (5-80 Hz, 0.2 ms) were applied through bipolar hook electrodes to sacral ventral roots alone or to combined ventral and dorsal roots of a single S1-S3 segment to induce penile pressure increases and penile erection.Results: Stimulation of the S1 or S2 ventral root at 30 to 40 Hz induced observable penile erection with rigidity and the largest increase (169 +/- 11 cmH2O) in penile pressure. Continuous stimulation (10 minutes) of afferent and efferent axons by simultaneous stimulation of the S1 or S2 dorsal and ventral roots at 30 Hz also produced a large increase (190 +/- 8 cmH2O) in penile pressure that was sustainable during the entire stimulation period. After a complete spinal cord transection at the T9-T10 level, simultaneous stimulation of the S1 or S2 dorsal and ventral roots induced large (186 +/- 9 cmH2O) and sustainable increases in penile pressure.Conclusion: This study indicates the possibility to develop a novel neuromodulation device to restore penile erection after spinal cord injury using a minimally invasive surgical approach to insert a lead electrode through the sacral foramen to stimulate a sacral spinal root.

INTRODUCTION AND OBJECTIVE: Neurodegenerative dis- eases, such as multiple sclerosis (MS), often lead to the development of neurogenic lower urinary tract symptoms (LUTS). We previously char- acterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The objective of this study was to identify genes and pathways linking neuroin fl ammation in the central nervous system with urinary bladder dysfunction to enhance our understanding of the mechanisms under- lying LUTS in demyelinating diseases. METHODS: Adult C57BL/6 male mice (N [ 12) received either an intracranial injection of MHV (6,000 PFU) or sterile saline (control). The lumbosacral (L6-S2) spinal cord (SC) segments and urinary bladders were collected during acute infection stage (week 1) and at the fi rst peak of demyelination (week 4) after inoculation with the virus. Total RNA was isolated and analyzed using Nanostring nCounter Neuroin fl ammation panel. The expression levels of 770 genes associated with neuroin fl ammation were assessed and compared between the specimens. RESULTS: Transcriptome analysis of SC specimens con fi rmed a signi fi cantly increased expression of 132 genes in MHV mice (tens to hundreds fold change) involved in the regulation of astrocyte, microglia and oligodendrocyte functions, neuroin fl ammation and immune responses. Out of 132 genes up-regulated in the SC, only 2 genes ( siglec1, 46-fold in the SC, 2.6-fold at 1 week and 1.8-fold at 4 weeks in the bladder; and zbp1 , 568-fold in the SC, 2.8-fold at 1 week and 2.2-fold at 4 weeks in the bladder) were up-regulated in the urinary bladders of MHV-infected mice. Additionally, two genes were signi fi cantly up-regulated ( ttr, 2.2-fold at 1week and 1.7-fold at 4 weeks; and ms4a4a, 2.3-fold at 1week and 1.6-fold at 4 weeks ), and two were down-regulated ( asb2, - 1.8-fold at 1 week and -1.6-fold at 4 weeks, and myct1, -1 .7-fold at 1week and -1.6-fold at 4 weeks ) exclusively in the urinary bladders of MHV mice. CONCLUSIONS: Two genes, siglec1 (encodes type 1 trans- membrane protein, expressed in microglia and macrophages, promotes neuroin fl ammation) and zbp1 (encodes a Z-DNA binding protein, plays role in the innate immune response) link the development of neuro- in fl ammation in the central nervous system with neurogenic changes in the urinary bladders of MHV-infected mice. Further research is needed to establish a functional relationship between expression of these genes and neurogenic LUTS. Spinal cord injury can cause intricate medical conditions, including detrusor overactivity and detrusor sphincter dyssynergia. The most commonly used treat- ment, intermittent self-catheterization, can predispose patients to urinary tract infections. This study reveals a novel implantable pudendal nerve stimulation (PSTIM) to restore continence and micturition functions in the setting of neurogenic bladder from SCI. METHODS: The T9-T10 level of spinal cord was transected entirely in two cats to establish a model for SCI. PSTIM was surgically implanted in the cats with three cuff electrodes surrounding bilateral pudendal nerves (two on left, one on right). The cat's bladder was emptied by Cred (cid:1) e's maneuver or stimulation of PSTIM. Urodynamics was performed via urethral catheter to test the PSTIM functions in the awake cats. Finally, the cats were anesthetized with alpha-chloralose for terminal experiments. Bilateral ureters were externalized, and a urodynamic catheter was inserted through the bladder dome. Urodynamics was performed to evaluate voiding with control conditions and with PSTIM in the anesthetized cats. Stimulation of channel 1 at 30 Hz induced low bladder pressure (about 60 cmH 2 0) under isovolumetric conditions by triggering spinal re fl ex bladder contraction. It also induced highly ef fi cient micturition (both > 95%) when combined with 10 kHz stimulation of bilateral pudendal nerves to relax the external urethral sphincter (channels 2 and 3). Additionally, stimulation of channel 1 at 5 Hz sup-pressed non-voiding contractions and signi fi cantly increased bladder capacity. In the anesthetized cats, control urodynamics demonstrated frequent low-pressure contractions ( < 50 cmH 2 0) with low-ef fi ciency voiding whereas PSTIM urodynamics demonstrated a low-pressure contraction with high-ef fi ciency voiding (91% vs. 12% emptied, p < 0.05) neuroprosthesis

Background Electrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. Objective To study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. Methods In the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with an external electric field at 2kHz, 5kHz or 10 kHz. Results Reproducible excitatory changes in rheobase and spontaneous firing were elicited during kHz-field application at all stimulating frequencies. The rheobase only decreased and spontaneous firing either was initiated in silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. Conclusion kHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.