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.

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.

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.

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.

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.

A finite element modeling study of peripheral nerve recruitment by percutaneous tibial nerve stimulation in the human lower leg.

Percutaneous tibial nerve stimulation (PTNS) is a clinical therapy for treating overactive bladder (OAB), where an un-insulated stainless steel needle electrode is used to target electrically the tibial nerve (TN) in the lower leg. Recent studies in anesthetized animals not only confirm that bladder-inhibitory reflexes can be evoked by stimulating the TN, but this reflex can also be evoked by stimulating the adjacent saphenous nerve (SAFN). Although cadaver studies indicate that the TN and major SAFN branch(es) overlap at the location of stimulation, the extent to which SAFN branches are co-activated is unknown. In this study, we constructed a finite element model of the human lower leg and applied a numeric axon model (MRG model) to simulate the electrical recruitment of TN and SAFN fibers during PTNS. The model showed that up to 80% of SAFN fibers (located at the level of the needle electrode) can be co-activated when electrical pulses are applied at the TN activation threshold, the standard therapeutic amplitude. Both the location of the inserted electrode and stimulation amplitude were important variables that affected the recruitment of SAFN branches. This study suggests further work is needed to investigate the potential therapeutic effects of SAFN stimulation in OAB patients.

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.

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.

An Enhanced Method of Transcutaneously Stimulating the Tibial Nerve for the Treatment of Overactive Bladder.

Transcutaneous electrical nerve stimulation (TENS) can be used to electrically stimulate the tibial nerve for the purpose of treating overactive bladder. Although clinical benefits can be achieved, the overall therapeutic efficacy of TENS is limited. Inconsistent activation of the intended neural target and co-activation of cutaneous sensory fibers are considered key limiting factors. In this study, we propose a novel approach that combines TENS with an implanted, electrically-conductive nerve cuff to reduce the stimulation amplitude needed to activate the tibial nerve. This enhanced version of TENS (called eTENS) was designed using a computational model of the rat tibial nerve and subsequently tested in anesthetized rats. Our computational model showed that eTENS can reduce the nerve activation threshold by a factor of up to 2.6. Similar effects were also achieved by in vivo experiments (1.4 ± 0.1-fold decrease, n = 5). Among various design parameters, spatial alignment between the surface electrode and the nerve cuff was identified as an important factor. Our results show that eTENS can improve the selective activation of the rat tibial nerve, but further work is needed to evaluate its use in clinical therapies.

Optimizing the design of bipolar nerve cuff electrodes for improved recording of peripheral nerve activity.

OBJECTIVE: Differential measurement of efferent and afferent peripheral nerve activity offers a promising means of improving the clinical utility of implantable neuroprostheses. The tripolar nerve cuff electrode has historically served as the gold standard for achieving high signal-to-noise ratios (SNRs) of the recordings. However, the symmetrical geometry of this electrode array (i.e. electrically-shorted side contacts) precludes it from measuring electrical signals that can be used to obtain directional information. In this study, we investigated the feasibility of using a bipolar nerve cuff electrode to achieve high-SNR of peripheral nerve activity. APPROACH: A finite element model was implemented to investigate the effects of electrode design parameters-electrode length, electrode edge length (EEL), and a conductive shielding layer (CSL)-on simulated single fiber action potentials (SFAP) and also artifact noise signals (ANS). MAIN RESULTS: Our model revealed that the EEL was particularly effective in increasing the peak-to-peak amplitude of the SFAP (319%) and reducing the common mode ANS (67%) of the bipolar cuff electrode. By adding a CSL to the bipolar cuff electrode, the SNR was found to be 65.2% greater than that of a conventional tripolar cuff electrode. In vivo experiments in anesthetized rats confirmed that a bipolar cuff electrode can achieve a SNR that is 38% greater than that achieved by a conventional tripolar cuff electrode (p < 0.05). SIGNIFICANCE: The current study showed that bipolar nerve cuff electrodes can be designed to achieve SNR levels that are comparable to that of tripolar configuration. Further work is needed to confirm that these bipolar design parameters can be used to record bi-directional neural activity in a physiological setting.

Feasibility of Long-term Tibial Nerve Stimulation Using a Multi-contact and Wirelessly Powered Neurostimulation System Implanted in Rats.

OBJECTIVE: Implant-driven tibial nerve stimulation therapy is an effective technique for treating overactive bladder. However, the monopolar lead design in the currently available implantable devices pose long-term therapeutic challenges in terms of efficiently and selectively delivering electrical pulses to the target. Hence, the purpose of this study was to (1) characterize the tibial nerve (TN) activation properties using a multi-contact implantable system and (2) evaluate the long-term stability of using such a neural interface in a preclinical model. MATERIALS AND METHODS: Ten adult Sprague-Dawley rats were used in this study. An implantable pulse generator was surgically inserted in the lower back region. The lead wire with 4 active electrodes was placed in parallel with the TN. The threshold for activating the TN was confirmed via movement of the hallux or toes as well as the foot EMG. The TN activation threshold was assessed biweekly, over a period of 12 weeks. RESULTS: Channel 1 exhibited the lowest motor threshold at T0 (mean = 0.58 ± 0.10 mA). A notable increase in motor twitch intensity was observed during the first test session (2 weeks) following surgical implantation (75.8 ± 30.5%, channel 1). Among the 10 rats tested, 8 rats successfully completed the 3-month study. CONCLUSION: Results from this study demonstrate the long-term feasibility of achieving tibial nerve stimulation with a multi-contact implantable device in a preclinical model. Future studies are warranted to assess the effects of using such a wirelessly powered system for treating lower urinary tract symptoms in patients.

Characterizing the reduction of stimulation artifact noise in a tripolar nerve cuff electrode by application of a conductive shield layer.

Tripolar nerve cuff electrodes have been widely used for measuring peripheral nerve activity. However, despite the high signal-to-noise ratio levels that can be achieved with this recording configuration, the clinical use of cuff electrodes in closed-loop controlled neuroprostheses remains limited. This is largely attributed to artifact noise signals that contaminate the recorded neural activity. In this study, we investigated the use of a conductive shield layer (CSL) as a means of reducing the artifact noise recorded by nerve cuff electrodes. Using both computational simulations and in vivo experiments, we found that the CSL can result in up to an 85% decrease in the recorded artifact signal. Both the electrical conductivity and the surface area of the CSL were identified as important design criteria. Although this study shows that the CSL can significantly reduce artifact noise in tripolar nerve cuff electrodes, long-term implant studies are needed to validate our findings.

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.

Modulation of heart rate by temporally patterned vagus nerve stimulation in the anesthetized dog.

Despite current knowledge of the myriad physiological effects of vagus nerve stimulation (VNS) in various mammalian species (including humans), the impact of varying stimulation parameters on nerve recruitment and physiological responses is not well understood. We investigated nerve recruitment, cardiovascular responses, and skeletal muscle responses to different temporal patterns of VNS across 39 combinations of stimulation amplitude, frequency, and number of pulses per burst. Anesthetized dogs were implanted with stimulating and recording cuff electrodes around the cervical vagus nerve, whereas laryngeal electromyogram (EMG) and heart rate were recorded. In seven of eight dogs, VNS-evoked bradycardia (defined as ≥10% decrease in heart rate) was achieved by applying stimuli at amplitudes equal to or greater than the threshold for activating slow B-fibers. Temporally patterned VNS (minimum 5 pulses per burst) was sufficient to elicit bradycardia while reducing the concomitant activation of laryngeal muscles by more than 50%. Temporal patterns of VNS can be used to modulate heart rate while minimizing laryngeal motor fiber activation, and this is a novel approach to reduce the side effects produced by VNS.

Electrical stimulation of the saphenous nerve in anesthetized rats: a novel therapeutic approach to treating overactive bladder.

Posterior Tibial Nerve Stimulation (PTNS) is a minimally invasive yet effective therapy for treating overactive bladder (OAB) symptoms with electrical stimulations applied at 20 Hz coupled with amplitudes approximating the foot-twitch threshold (T). However, pre-clinical studies indicate that PTNS-evoked bladder reflexes require stimulation amplitudes exceeding 2T. The objective of this work was to evaluate the presence of secondary low-threshold sensory pathways in the hind-limb region that can be a potential target of activation during clinical PTNS set-up. Given the close proximity of the electrode tip and the cutaneous branches in the lower leg, we hypothesized the concomitant activation of saphenous nerve (SAFN) afferents during percutaneous PTNS. To this end, urodynamic model was established in ten anesthetized rats to investigate (1) the isolated role of SAFN trunk in modulating bladder activity and (2) characterize frequency-dependent changes in inhibitory response at low stimulation amplitudes. Our pre-clinical findings suggest that direct stimulation of SAFN can elicit robust and consistent inhibitory effects at 20 Hz. This novel inhibitory reflex may rationalize the therapeutic effects of clinical PTNS therapy and support the feasibility of enhancing the current algorithm of incontinence care.