Recruitment of unmyelinated C-fibers mediates the bladder-inhibitory effects of tibial nerve stimulation in a continuous-fill anesthetized rat model.

Although percutaneous tibial nerve stimulation is considered a clinically effective therapy for treating overactive bladder, the mechanism by which overactive bladder symptoms are suppressed remains unclear. The goal of the present study was to better understand the role of specific neural inputs (i.e., fiber types) on the bladder-inhibitory effects of tibial nerve stimulation (TNS). In 24 urethane-anesthetized rats, a continuous suprapubic saline infusion model was used to achieve repeated filling and emptying of the bladder. A total of 4 TNS trials (pulse frequency: 5 Hz) were applied in randomized order, where each trial used different amplitude settings: 1) no stimulation (control), 2) Aß-fiber activation, 3) Aδ-fiber activation, and 4) C-fiber activation. Each stimulation trial was 30 min in duration, with an intertrial washout period of 60-90 min. Our findings showed that TNS evoked statistically significant changes in bladder function (e.g., bladder capacity, residual volume, voiding efficiency, and basal pressure) only at stimulation amplitudes that electrically recruited unmyelinated C-fibers. In a subset of experiments, TNS also resulted in transient episodes of overflow incontinence. It is noted that changes in bladder function occurred only during the poststimulation period. The bladder-inhibitory effects of TNS in a continuous bladder filling model suggests that electrical recruitment of unmyelinated C-fibers has important functional significance. The implications of these findings in percutaneous tibial nerve stimulation therapy should be further investigated.

Frequency-dependent inhibition of bladder function by saphenous nerve stimulation in anesthetized rats.

AIMS: Percutaneous tibial nerve stimulation (PTNS) is an effective neuromodulation therapy for treating overactive bladder (OAB). The therapeutic effects are achieved by repeatedly applying electrical stimulation through a percutaneous needle electrode that is used to target the tibial nerve (TN). Anatomical studies indicate there can be multiple saphenous nerve (SAFN) branches located near the site of electrical stimulation, and therefore we investigated the possibility of evoking a bladder-inhibitory reflex by electrically activating the SAFN. MATERIALS AND METHODS: Acute experiments were conducted in 26 urethane-anesthetized rats. Changes in bladder contraction rate (BCR) and bladder capacity were measured in response to 10-min SAFN stimulation trials. Electrical pulses were applied at 25 µA and at stimulation frequencies between 2 Hz and 50 Hz. RESULTS: We report that SAFN stimulation at 20 Hz was most effective at reflexively decreasing the BCR (53.8 ± 5.4% from baseline) and also increasing the bladder capacity (145.8 ± 43.5% from baseline). In contrast, SAFN stimulation at other frequencies yielded inconsistent changes in bladder function. Carry-over effects were minimized by randomizing the sequence of SAFN stimulation trials and also by allowing the bladder to return to the baseline conditions. CONCLUSIONS: With notable changes in both the BCR and bladder capacity, our findings provide evidence of a novel bladder-inhibitory reflex in anesthetized rats that is mediated by the SAFN. Further work is needed to determine the clinical relevance of this neural pathway.

A pilot feasibility study of treating overactive bladder patients with percutaneous saphenous nerve stimulation.

AIMS: Effective long-term treatment of overactive bladder (OAB) remains a significant clinical challenge. We present our initial experience with a new bladder neuromodulation method that electrically targets the saphenous nerve (SAFN). METHODS: A total of 18 OAB patients (female, 55-84 years) were provided with percutaneous SAFN stimulation. The SAFN was targeted with a needle electrode inserted below the medial condyle of the tibia. Activation of the SAFN was confirmed by the patient's perception of paresthesia radiating down the leg. Electrical stimulation was applied for 30 min and subsequently repeated weekly for 3 months. The effects of stimulation were assessed by a 4-day bladder diary and quality-of-life questionaire (OAB-q). RESULTS: Percutaneous SAFN stimulation was confirmed in all 16 patients who completed the study, and no adverse events were reported. Positive response to SAFN stimulation was achieved in 87.5% (14 of 16) of patients, as determined by either a minimum 50% reduction in bladder symptoms or a minimum 10 point increase in the HRQL total score. CONCLUSIONS: Electrical activation of the SAFN was consistently achieved using anatomical landmarks and patient feedback. The procedure was well tolerated and, based on our small cohort of patients, appears efficacious, and safe. This pilot study provides early feasibility data that points to a promising new intervention for treating OAB.

Characterizing the transcutaneous electrical recruitment of lower leg afferents in healthy adults: implications for non-invasive treatment of overactive bladder.

BACKGROUND: As a potential new treatment for overactive bladder (OAB), we investigated the feasibility of non-invasively activating multiple nerve targets in the lower leg. METHODS: In healthy participants, surface electrical stimulation (frequency = 20 Hz, pulse width = 200 µs) was used to target the tibial nerve, saphenous nerve, medial plantar nerve, and lateral plantar nerve. At each location, the stimulation amplitude was increased to define the thresholds for evoking (1) cutaneous sensation, (2) target nerve recruitment and (3) maximum tolerance. RESULTS: All participants were able to tolerate stimulation amplitudes that were 2.1 ± 0.2 (range = 2.0 to 2.4) times the threshold for activating the target nerve. CONCLUSIONS: Non-invasive electrical stimulation can activate neural targets at levels that are consistent with evoking bladder-inhibitory reflex mechanisms. Further work is needed to test the clinical effects of stimulating one or more neural targets in OAB patients.

Inhibition and Excitation of Bladder Function by Tibial Nerve Stimulation Using a Wirelessly Powered Implant: An Acute Study in Anesthetized Cats.

PURPOSE: Tibial nerve stimulation is a minimally invasive neuromodulation treatment of overactive bladder. However, in addition to our limited understanding of the underlying mechanisms, there are also questions regarding the long-term delivery of tibial nerve stimulation therapy in patients. We aimed to characterize the effects of stimulation frequency using a wirelessly powered implantable stimulation device. METHODS AND MATERIALS: Six α-chloralose anesthetized adult male cats were used in this study. A multicontact lead was surgically implanted subcutaneously in the hind limb and used to stimulate the tibial nerve. Using an isovolumetric bladder a short duration of electrical pulses was applied at amplitudes 3 times the motor threshold and at frequencies from 2 to 20 Hz. RESULTS: Implant driven stimulation of the tibial nerve resulted in frequency dependent activation of bladder reflexes. Low frequency tibial nerve stimulation (2 Hz) consistently evoked excitatory responses (mean ± SE 32.9% ± 3.8%). In contrast, higher frequency tibial nerve stimulation (6 to 20 Hz) inhibited bladder function (overall mean 14.9% ± 2.4%). Although low foot motor thresholds were achieved at initial implantation (mean 0.83 ± 0.05 mA), a notable elevation in threshold amplitude was observed 5 hours after implantation. CONCLUSIONS: To our knowledge this study provides the first evidence of frequency dependent modulation of bladder function in anesthetized cats. The inhibitory influence of tibial nerve stimulation at frequencies above 6 Hz transitioned to an excitatory effect at 2 Hz. Taken together these preclinical data support the feasibility of using a wirelessly powered implantable device to potentially modulate bladder function in patients.

Reflex neuromodulation of bladder function elicited by posterior tibial nerve stimulation in anesthetized rats.

Although posterior tibial nerve stimulation (PTNS) has been shown in both clinical and animal studies to elicit bladder-inhibitory reflexes, our understanding of the role of posterior tibial nerve (PTN) afferents that elicit these responses is significantly limited. To this end, we investigated the effects of frequency-dependant PTNS in urethane-anesthetized rats undergoing repeated urodynamic fills. Nerve stimulation trials (10 min) resulted in statistically significant inhibition of the urinary bladder, both during and after nerve stimulation (P < 0.05). PTNS applied at 5 Hz resulted in both acute and prolonged changes that corresponded to 38.0% and 34.1% reductions in the bladder contraction frequency, respectively. In contrast, PTNS applied at 10 Hz could only elicit an acute decrease (22.9%) in bladder activity. Subsequent electrical activation of individual PTN branches (lateral or medial plantar nerves) confirmed that these bladder reflexes are mediated by specific subsets of the PTN trunk. Both acute and prolonged inhibition of the bladder were achieved by electrical stimulation of the lateral plantar (10 and 20 Hz) and medial plantar (5 and 10 Hz) nerves. Finally, we report a bladder-excitatory reflex that is elicited by electrical activation of either the PTN trunk or lateral plantar nerve at 50 Hz. This study shows that multiple bladder reflexes are tuned to specific subsets of nerve afferents and stimulation frequencies, each of which provide novel insights into the physiological effects of PTNS.

Distribution, course, and spatial relationships of the saphenous nerve: A 3D neuroanatomical map for nerve stimulation.

The overall objective of this study was to construct a 3D neuroanatomical map of the saphenous nerve based on cartesian coordinate data to define its course in 3D space relative to bony and soft tissue landmarks. Ten lower limb embalmed specimens were meticulously dissected, digitized, laser scanned, and modelled in 3D. The course of the main branches, number of collateral branches, and relationship of saphenous nerve to the great saphenous vein were defined and quantified using the high-fidelity 3D models. In 60% of specimens, the saphenous nerve was found to have three branches in the leg, infrapatellar, anterior, and posterior. In 40% of specimens, the posterior branch was absent. Three landmarks were found to consistently localize the anterior branch: the medial border of tibia at the level of the tibial tuberosity, the medial border of tibia at the level of the mid-point of leg, and the mid-point of the anterior border of the medial malleolus. The posterior branch, when present, had variable branching patterns but did not extend as far distally as the medial malleolus in any specimen. Anatomically, the anterior and posterior branches at the level of the tibial tuberosity could be most advantageous for nerve stimulation due to their close proximity to the bifurcation of the saphenous nerve where the branches are larger and more readily localizable than distally. Additionally, the tibial tuberosity is a prominent landmark that can be easily identified in most individuals and could be used to localize the anterior and posterior branch using ultrasound or other imaging modalities. These findings will enable implementation of highly realistic computational models that can be used to simulate saphenous nerve stimulation using percutaneous and implanted devices.

Enhancing the selective electrical activation of human vagal nerve fibers: a comparative computational modeling study with validation in a rat sciatic model.

Objective.Vagus nerve stimulation (VNS) is an emerging treatment option for a myriad of medical disorders, where the method of delivering electrical pulses can vary depending on the clinical indication. In this study, we investigated the relative effectiveness of electrically activating the cervical vagus nerve among three different approaches: nerve cuff electrode stimulation (NCES), transcutaneous electrical nerve stimulation (TENS), and enhanced TENS (eTENS). The objectives were to characterize factors that influenced nerve activation and to compare the nerve recruitment properties as a function of nerve fiber diameter.Methods.The Finite Element Model, based on data from the Visible Human Project, was implemented in COMSOL. The three simulation types were compared under a range of vertical and horizontal displacements relative to the location of the vagus nerve. Monopolar anodic stimulation was examined, along with latency and activation of different fiber sizes. Nerve activation was determined via the activating function and McIntyre-Richardson-Grill models, and activation thresholds were validated in anin-vivorodent model.Results.While NCES produced the lowest activation thresholds, eTENS generally performed superior to TENS under the range of conditions and fiber diameters, producing activation thresholds up to three times lower than TENS. eTENS also preserved its enhancement when surface electrodes were displaced away from the nerve. Anodic stimulation revealed an inhibitory region that removed eTENS benefits. eTENS also outperformed TENS by up to four times when targeting smaller diameter nerve fibers, scaling similar to a cuff electrode. In latency and activation of smaller diameter nerve fibers, eTENS results resembled those of NCES more than a TENS electrode. Activation threshold ratios were consistent inin-vivovalidation.Significance.Our findings expand upon previously identified mechanisms for eTENS and further demonstrate how eTENS emulates a nerve cuff electrode to achieve lower activation thresholds. This work further characterizes considerations required for VNS under the three stimulation methods.

Prolonged inhibition of bladder function is evoked by low-amplitude electrical stimulation of the saphenous nerve in urethane-anesthetized rats.

To better understand the effects of saphenous nerve (SN) stimulation on bladder function, we investigated the duration of electrical stimulation as a key variable in eliciting urodynamic changes. SN stimulation is a novel approach to electrically modulating bladder function. In previous animal studies, bladder-inhibitory responses were evoked by low-amplitude (25 µA) stimulus pulses applied in short-duration (10 min) trials and at frequencies between 10 and 20 Hz. Experiments were performed in urethane-anesthetized rats that were separated into three groups: intravesical saline infusion + SN stimulation (group A), intravesical 0.1% acetic acid infusion + SN stimulation (group B), and intravesical saline infusion + no SN stimulation (group C). Changes in bladder function- basal bladder pressure (P base ), contraction amplitude (ΔP), and inter-contraction interval (T ICI )-were measured in response to stimulation trials applied for different durations (10, 20, and 40 min). Trials were also repeated at frequencies of 10 and 20 Hz. In group A, longer-duration (40 min) stimulation trials applied at 10 Hz evoked overflow incontinence (OI) episodes that were characterized by significant changes in P base (122.7 ± 9.1%, p = 0.026), ΔP (-60.8 ± 12.8%, p = 0.044), and T ICI (-43.2 ± 13.0%, p = 0.031). Stimulation-evoked OI was observed in 5 of 8 animals and lasted for 56.5 ± 10.7 min. In contrast, no significant changes in bladder function were observed in either group B or group C. Our findings show that longer-duration trials consisting of electrical pulses applied at 10 Hz are important stimulation parameters that elicit inhibitory bladder responses in anesthetized rodents.

Multiple pudendal sensory pathways reflexly modulate bladder and urethral activity in patients with spinal cord injury.

PURPOSE: Electrical stimulation of pudendal afferents can evoke reflex bladder contractions with relaxation of the external urethral sphincter in cats. This voiding reflex is mediated by pudendal sensory fibers innervating the penile and prostatic urethra that engage spinal and spinobulbospinal micturition pathways, respectively. However, clinical translation of this potential therapy in individuals with spinal cord injury is limited by the lack of evidence showing analogous reflex mechanisms in humans. We investigated excitatory pudendal-to-bladder reflexes in 7 individuals with chronic spinal cord injury. MATERIALS AND METHODS: We recorded isovolumetric bladder pressure and perineal electromyogram in response to intraurethral electrical stimulation at varying amplitudes and frequencies. RESULTS: Selective electrical stimulation of the proximal (29.7 ± 11.6 cm H(2)O) and distal urethral (23.3 ± 9.28 cm H(2)O) segments evoked sustained reflex bladder contractions in different subsets (3 each) of participants. In contrast, the corresponding reflex perineal electromyogram revealed a differential activation pattern between proximal and distal intraurethral stimulation (normalized electromyogram of 1.3 ± 0.2 and 0.3 ± 0.1, respectively, p <0.05). CONCLUSIONS: To our knowledge we report the first clinical evidence of 2 independent excitatory pudendal-to-bladder reflex pathways, which in turn differentially modulate efferent pudendal output. Each reflex mechanism involves complex interaction of multiple sensory inputs and may provide a neural substrate to restore micturition after spinal cord injury.

Mechanisms of reflex bladder activation by pudendal afferents.

Activation of pudendal afferents can evoke bladder contraction or relaxation dependent on the frequency of stimulation, but the mechanisms of reflex bladder excitation evoked by pudendal afferent stimulation are unknown. The objective of this study was to determine the contributions of sympathetic and parasympathetic mechanisms to bladder contractions evoked by stimulation of the dorsal nerve of the penis (DNP) in α-chloralose anesthetized adult male cats. Bladder contractions were evoked by DNP stimulation only above a bladder volume threshold equal to 73 ± 12% of the distension-evoked reflex contraction volume threshold. Bilateral hypogastric nerve transection (to eliminate sympathetic innervation of the bladder) or administration of propranolol (a ß-adrenergic antagonist) decreased the stimulation-evoked and distension-evoked volume thresholds by -25% to -39%. Neither hypogastric nerve transection nor propranolol affected contraction magnitude, and robust bladder contractions were still evoked by stimulation at volume thresholds below the distension-evoked volume threshold. As well, inhibition of distention-evoked reflex bladder contractions by 10 Hz stimulation of the DNP was preserved following bilateral hypogastric nerve transection. Administration of phentolamine (an α-adrenergic antagonist) increased stimulation-evoked and distension-evoked volume thresholds by 18%, but again, robust contractions were still evoked by stimulation at volumes below the distension-evoked threshold. These results indicate that sympathetic mechanisms contribute to establishing the volume dependence of reflex contractions but are not critical to the excitatory pudendal to bladder reflex. A strong correlation between the magnitude of stimulation-evoked bladder contractions and bladder volume supports that convergence of pelvic afferents and pudendal afferents is responsible for bladder excitation evoked by pudendal afferents. Further, abolition of stimulation-evoked bladder contractions following administration of hexamethonium bromide confirmed that contractions were generated by pelvic efferent activation via the pelvic ganglion. These findings indicate that pudendal afferent stimulation evokes bladder contractions through convergence with pelvic afferents to increase pelvic efferent activity.

A voltage-controlled capacitive discharge method for electrical activation of peripheral nerves.

OBJECTIVES: A voltage-controlled capacitive discharge (VCCD) method was investigated as an alternative to rectangular stimulus pulses currently used in peripheral nerve stimulation therapies. METHODS AND MATERIALS: In two anesthetized Gottingen mini pigs, the threshold (total charge per phase) for evoking a compound nerve action potential (CNAP) was compared between constant current (CC) and VCCD methods. Electrical pulses were applied to the tibial and posterior cutaneous femoralis nerves using standard and modified versions of the Medtronic 3778 Octad. RESULTS: In contrast to CC stimulation, the combined application of VCCD pulses with a modified Octad resulted in a marked decrease (-73 ± 7.4%) in the stimulation threshold for evoking a CNAP. This was consistent for different myelinated fiber types and locations of stimulation. CONCLUSIONS: The VCCD method provides a highly charge-efficient means of activating myelinated fibers that could potentially be used within a wireless peripheral nerve stimulator system.

Computational Study on Spatially Distributed Sequential Stimulation for Fatigue Resistant Neuromuscular Electrical Stimulation.

Neuromuscular electrical stimulation (NMES) is used to artificially induce muscle contractions of paralyzed limbs in individuals with stroke or spinal cord injury, however, the therapeutic efficacy can be significantly limited by rapid fatiguing of the targeted muscle. A unique stimulation method, called spatially distributed sequential stimulation (SDSS), has been shown clinically to reduce fatiguing during FES, but further improvement is needed. The purpose of this study was to gain a better understanding of SDSS-induced neural activation in the human lower leg using a computational approach. We developed a realistic finite element model of the lower leg to investigate SDSS, by solving the electric field generated by SDSS and predicting neural activation. SDSS applied at 10 Hz was further compared with conventional transcutaneous stimulation that delivered electrical pulses at 40 Hz through a single electrode. We found that SDSS electrically activated multiple sub-populations of motor neurons within the TA muscle that fired at frequencies ranging between 10 Hz and 40 Hz. This complex nerve activation pattern depicts the mechanism of action of SDSS for reducing muscle fatigue during NMES.

Classification of directionally specific vagus nerve activity using an upper airway obstruction model in anesthetized rodents.

Electrical signals from the peripheral nervous system have the potential to provide the necessary motor, sensory or autonomic information for implementing closed-loop control of neuroprosthetic or neuromodulatory systems. However, developing methods to recover information encoded in these signals is a significant challenge. Our goal was to test the feasibility of measuring physiologically generated nerve action potentials that can be classified as sensory or motor signals. A tetrapolar recording nerve cuff electrode was used to measure vagal nerve (VN) activity in a rodent model of upper airway obstruction. The effect of upper airway occlusions on VN activity related to respiration (RnP) was calculated and compared for 4 different cases: (1) intact VN, (2) VN transection only proximal to recording electrode, (3) VN transection only distal to the recording electrode, and (4) transection of VN proximal and distal to electrode. We employed a Support Vector Machine (SVM) model with Gaussian Kernel to learn a model capable of classifying efferent and afferent waveforms obtained from the tetrapolar electrode. In vivo results showed that the RnP values decreased significantly during obstruction by 91.7% ± 3.1%, and 78.2% ± 3.4% for cases of intact VN or proximal transection, respectively. In contrast, there were no significant changes for cases of VN transection at the distal end or both ends of the electrode. The SVM model yielded an 85.8% accuracy in distinguishing motor and sensory signals. The feasibility of measuring low-noise directionally-sensitive neural activity using a tetrapolar nerve cuff electrode along with the use of an SVM classifier was shown. Future experimental work in chronic implant studies is needed to support clinical translatability.

Conditional and continuous electrical stimulation increase cystometric capacity in persons with spinal cord injury.

AIMS: Individuals with spinal cord injury (SCI) exhibit neurogenic detrusor overactivity (NDO) causing high intravesicle pressures and incontinence. The first aim was to measure changes in maximum cystometric capacity (MCC) evoked by electrical stimulation of the dorsal genital nerve (DGN) delivered either continuously or conditionally (only during bladder contractions) in persons with SCI. The second aim was to use the external anal sphincter electromyogram (EMG(EAS)) for real-time control of conditional stimulation. METHODS: Serial filling cystometries were performed in nine volunteers with complete or incomplete supra-sacral SCI. Conditional stimulation was delivered automatically when detrusor pressure increased to 8-12 cmH(2)O above baseline. MCCs were measured for each treatment (continuous, conditional, and no stimulation) and compared using post-ANOVA Tukey HSD paired comparisons. Additional treatments in two subjects used the EMG(EAS) for automatic control of conditional stimulation. RESULTS: Continuous and conditional stimulation increased MCC by 63 +/- 73 ml (36 +/- 24%) and 74 +/- 71 ml (51 +/- 37%), respectively (P < 0.05), compared to no stimulation. There was no significant difference between MCCs for conditional and continuous stimulation, but conditional stimulation significantly reduced stimulation time (174 +/- 154 sec, or 27 +/- 17% of total time) as compared to continuous stimulation (469 +/- 269 sec, 100% of total time, P < 0.001). The EMG(EAS) algorithm provided reliable detection of bladder contractions (six of six contractions over four trials) and reduced stimulation time (21 +/- 8% of total time). CONCLUSIONS: Conditional stimulation generates increases in bladder capacity while substantially reducing stimulation time. Furthermore, EMG(EAS) was successfully used as a real-time feedback signal to control conditional electrical stimulation in a laboratory setting.

Finite element modeling and in vivo analysis of electrode configurations for selective stimulation of pudendal afferent fibers.

BACKGROUND: Intraurethral electrical stimulation (IES) of pudendal afferent nerve fibers can evoke both excitatory and inhibitory bladder reflexes in cats. These pudendovesical reflexes are a potential substrate for restoring bladder function in persons with spinal cord injury or other neurological disorders. However, the complex distribution of pudendal afferent fibers along the lower urinary tract presents a challenge when trying to determine the optimal geometry and position of IES electrodes for evoking these reflexes. This study aimed to determine the optimal intraurethral electrode configuration(s) and locations for selectively activating targeted pudendal afferents to aid future preclinical and clinical investigations. METHODS: A finite element model (FEM) of the male cat urethra and surrounding structures was generated to simulate IES with a variety of electrode configurations and locations. The activating functions (AFs) along pudendal afferent branches innervating the cat urethra were determined. Additionally, the thresholds for activation of pudendal afferent branches were measured in alpha-chloralose anesthetized cats. RESULTS: Maximum AFs evoked by intraurethral stimulation in the FEM and in vivo threshold intensities were dependent on stimulation location and electrode configuration. CONCLUSIONS: A ring electrode configuration is ideal for IES. Stimulation near the urethral meatus or prostate can activate the pudendal afferent fibers at the lowest intensities, and allowed selective activation of the dorsal penile nerve or cranial sensory nerve, respectively. Electrode location was a more important factor than electrode configuration for determining stimulation threshold intensity and nerve selectivity.

Reduced genioglossus muscle activity caused by fluid overload in anesthetized rats.

INTRODUCTION: Although the precise cause of obstructive sleep apnea (OSA) remains unknown, various anatomical or structural factors are thought to influence upper airway patency. Recent clinical studies show that OSA is frequently observed among patients with fluid-retaining states, such as heart/renal failure and postsurgery. It is important to note that a cause-effect relationship is not yet established, and our understanding of the effects of fluid overload is limited. The goal of this study was to investigate an animal model that can characterize the physiological changes that occur in response to fluid overload. METHOD: Acute nonsurvival experiments were conducted in 16 Sprague-Dawley rats. Rats were initially anesthetized by inhaled isoflurane, while the femoral vein was cannulated and urethane (1.2-1.5 g/Kg body weight) was gradually delivered intravenously to induce anesthesia. Additional doses of urethane were delivered as necessary to maintain a surgical plane of anesthesia. A surgical incision was made on the cervical area to catheterize carotid artery to measure blood pressure. A pair of stainless-steel wires was injected into the tongue to measure genioglossus muscle activity (GGEMG). All physiological measurements were recorded as intravenous infusion of saline was provided to the rat (infusion rate = 22 ml/kg over 30 min). RESULTS: Acute saline overloading resulted in a 33% decrease in GGEMG, when compared to baseline. There was also a gradual drop in the respiratory rate (13% decrease) that reached statistical significance at 10 min after infusion was stopped. The blood pressure exhibited a 14% increase which subsequently returned to baseline within 40 min stopping infusion. There were no significant changes in the heart rate. CONCLUSION: The results of this study indicate that systemic fluid overload can affect significant changes in different physiological systems including reduction in genioglossus muscle activity, increase in blood pressure, and change autonomic nervous system function.

Transecting the hypogastric nerve to uncover the bladder-inhibitory pathways involved with saphenous nerve stimulation in anesthetized rats.

Saphenous (SAFN) nerve stimulation was recently shown in anesthetized rats to elicit bladder-inhibitory responses in a frequency-dependent manner; however, the mechanism of action is unknown. The goal of this study was to investigate the potential role of the hypogastric nerve (HGN) in this inhibitory pathway by examining stimulation-evoked changes in bladder function under four different experimental conditions: (1) HGN intact, saline infusion (HGNi-s), (2) HGN transected, saline infusion (HGNt-s), (3) HGN intact, acetic acid (AA) infusion (HGNi-a), and (4) HGN transected, AA infusion (HGNt-a). Experiments were conducted in 33 urethane-anesthetized female rats, where continuous bladder infusion was provided through a suprapubic catheter. The experimental protocol involved two, 40-min stimulation trials in which electrical pulses were applied to the SAFN at a set frequency (10 Hz) and two different amplitudes (50 µA and 100 µA). In all experimental groups, SAFN stimulation resulted in complete suppression of bladder activity with an incidence rate of 25% to 50%. However, significant changes in the measured urodynamic changes (e.g., basal pressure, contraction amplitude, and inter-contraction interval) were found only in the HGNt-a animals. Our findings suggest that the HGN does not mediate the inhibitory effects of SAFN stimulation and that bladder inhibition is achieved through a different mechanism of action.

Enhanced transcutaneous electrical nerve stimulation achieved by a localized virtual bipole: a computational study of human tibial nerve stimulation.

OBJECTIVE: Electrical neuromodulation is a clinically effective therapeutic instrument, currently expanding into newer indications and larger patient populations. Neuromodulation technologies are also moving towards less invasive approaches to nerve stimulation. In this study, we investigated an enhanced transcutaneous electrical nerve stimulation (eTENS) system that electrically couples a conductive nerve cuff with a conventional TENS electrode. The objectives were to better understand how eTENS achieves lower nerve activation thresholds, and to test the feasibility of applying eTENS in a human model of peripheral nerve stimulation. APPROACH: A finite element model (FEM) of the human lower leg was constructed to simulate electrical stimulation of the tibial nerve, comparing TENS and eTENS. Key variables included surface electrode diameter, nerve cuff properties (conductivity, length, thickness), and cuff location. Enhanced neural excitability was predicted by relative excitability (RE > 1), derived using either the activating function (AF) or the nerve activation threshold (MRG model). MAIN RESULTS: Simulations revealed that a localized 'virtual bipole' was created on the target nerve, where the isopotential surface of the cuff resulted in large potential differences with the surrounding tissue. The cathodic part (nerve depolarization) of the bipole enhanced neural excitability, predicted by RE values of up to 2.2 (MRG) and 5.5 (AF) when compared to TENS. The MRG model confirmed that action potentials were initiated at the cathodic edge of the nerve cuff. Factors contributing to eTENS were larger surface electrodes, longer cuffs, cuff conductivity (>1×103 S m-1), and cuff position relative to the cathodic surface electrode. SIGNIFICANCE: This study provides a theoretical basis for designing and testing eTENS applied to various neural targets and data suggesting function of eTENS in large models of nerve stimulation. Although eTENS carries key advantages over existing technologies, further work is needed to translate this approach into effective clinical applications.

Intraurethral stimulation evokes bladder responses via 2 distinct reflex pathways.

PURPOSE: Recent animal studies have shown that selective activation of pudendal nerve branches can evoke bladder responses through 2 distinct reflex pathways. We examined intraurethral electrical stimulation as a minimally invasive means of selectively activating these pathways in the cat. MATERIALS AND METHODS: Bladder responses evoked by intraurethral electrical stimulation were measured in alpha-chloralose anesthetized male cats at different stimulation frequencies, stimulation intensities and intraurethral locations. RESULTS: Intraurethral electrical stimulation evoked inhibitory and excitatory bladder reflexes depending on stimulation frequency and location. Stimulation in the penile urethra 0 to 3 cm from the urethral meatus at 33 Hz evoked bladder contraction and at 10 Hz it evoked bladder relaxation. These responses were abolished after bilateral transection of the dorsal penile nerves. Stimulation in the membranous urethra 5 to 7 cm from the urethral meatus at 2, 10 and 33 Hz evoked bladder contractions. These responses were abolished after bilateral transection of the cranial sensory nerves. Following acute spinal cord transection bladder contractions were still evoked by 33 Hz stimulation in the penile urethra but not by stimulation at any frequency in the membranous urethra. CONCLUSIONS: Intraurethral electrical stimulation selectively evoked bladder responses by activating 2 distinct pudendal afferent pathways. Responses depended on stimulation frequency and location. Intraurethral electrical stimulation is a valid means of determining the pathways involved in bladder responses evoked by pudendal nerve stimulation.