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.

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.

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.

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.

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.

Co-activation of saphenous nerve fibers: a potential therapeutic mechanism of percutaneous tibial nerve stimulation?

Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive and effective treatment for overactive bladder (OAB). However, clinical trials show that positive therapeutic outcomes among patients are difficult to predict (failure rate = 35% to 50%). Inconsistencies in the stimulation amplitudes used clinically and those used in preclinical animal studies led us to hypothesize that OAB therapy involves a secondary bladder-inhibitory pathway. In this paper, we implemented and tested a computer model of the human lower leg that investigated the differential activation of the saphenous nerve (SAFN) and tibial nerve (TN) during percutaneous electrical stimulation. Our preliminary findings show that concomitant activation of SAFN branches occurs during PTNS, which suggests the possibility that the SAFN may influence the clinical outcome of treatment.

Posterior tibial nerve stimulation using a wirelessly powered system in anesthetized cats.

Posterior Tibial Nerve Stimulation (PTNS) is an effective overactive bladder (OAB) therapy where electrical pulses are typically delivered once per week in a 12-week stimulation regime. While the mechanism of action remains unknown, effective long-term delivery of PTNS has recently become a subject of concern. To this end, a multi-contact electrode was surgically placed in the hind limb region of anesthetized cats to (1) investigate the feasibility of using a wirelessly powered system to stimulate PTN afferents and (2) characterize implant-driven effects of stimulation frequency on modulating bladder activity. Using an isovolumetric model, short-duration, supra-threshold stimulation trials were applied with frequencies ranging from 2-20 Hz. The results provide first pre-clinical evidence of frequency-dependent modulation of bladder function supporting the use of a novel therapeutic approach that can be clinically translated to potentially address multiple symptoms of lower urinary tract system.

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.

Selective co-stimulation of pudendal afferents enhances reflex bladder activation.

The loss of normal bladder function is common in persons with spinal cord injury (SCI) and negatively impacts their quality of life. Electrical stimulation of pudendal nerve afferents is a promising approach to restore control of bladder function. Pudendal afferent stimulation can generate reflex contraction of the bladder, but the resulting bladder voiding efficiency remains low. The objective of this work was t o evaluate selective co-stimulation of two branches of the pudendal nerve--the cranial urethral sensory nerve (CSN) and the dorsal nerve of the penis (DNP)--as a means to enhance reflex bladder activation and bladder voiding efficiency. In preclinical studies in anesthetized adult cats, co-stimulation of CSN and DNP evoked larger bladder contractions than individual stimulation of either CSN or DNP. In a parallel clinical experiment involving a participant with chronic SCI, co-stimulation of the proximal and distal urethra also produced synergistic augmentation of reflex bladder activity, and thus improved voiding efficiency when compared to reflex distension-evoked voiding. Selective co-stimulation of pudendal afferents is efficacious and should be considered in the development of neural prosthetics for restoration of bladder function in persons with SCI.

Effects of selective hypoglossal nerve stimulation on canine upper airway mechanics.

Electrical stimulation of the hypoglossal (XII) nerve has been demonstrated as an effective approach to treating obstructive sleep apnea. The physiological effects of conventional modes of stimulation (i.e., genioglossus activation or whole XII nerve stimulation), however, have yielded inconsistent and only partial alleviations of hypopneic or apneic events. Although selective stimulation of the multifasciculated XII nerve offers many stimulus options, it is not clear how these will functionally affect the upper airway (UAW). To study these effects, animal experiments in eight beagles were performed to investigate changes in the UAW resistance and critical pressure during simulated expiration (n = 4) and inspiration (n = 4). During expiration, nonselective XII nerve stimulation yielded the greatest improvement in UAW resistance (-0.66 +/- 0.11 cm H2O x l(-1) x min(-1)), compared with that for selective activation of the geniohyoid (-0.29 +/- 0.09 cm H2O x l(-1) x min(-1)), genioglossus (-0.31 +/- 0.12 cm H2O x l(-1) x min(-1)), and hyoglossus/styloglossus (0.37 +/- 0.06 cm H2O x l(-1) x min(-1)) muscles. For simulated inspiration, on the other hand, only whole XII nerve stimulation (-0.9 +/- 0.4 cm H2O) and coactivation of the genioglossus + hyoglossus/styloglossus muscles (-1.18 +/- 0.6 cm H2O) produced significant (P < 0.05) improvements in UAW stability (i.e., lowered critical pressure), compared with baseline (-0.52 +/- 0.32 cm H2O). The results of this study suggest that a multicontact nerve electrode can be used to achieve both UAW dilation and patency, comparable to that obtained with nonselective stimulation, by selectively activating the various branches of the XII nerve.

Selective stimulation of the canine hypoglossal nerve using a multi-contact cuff electrode.

Electrical activation of the tongue protrusor muscle has been demonstrated as an effective technique for alleviating upper airway (UAW) obstructions and is considered a potential treatment for obstructive sleep apnea (OSA). Recent studies, however, have shown marked improvements in UAW patency by coactivating the tongue protrudor and retractor muscles. As such, selective stimulation of the hypoglossal nerve (XII) using a single implantable device presents an attractive approach for treating OSA. In order to demonstrate the feasibility of such a device, the maximum achievable stimulation selectivity of the Flat Interface Nerve Electrode (FINE) was investigated. The XII nerve of beagles was stimulated with an acutely implanted FINE, while the corresponding neural and muscular responses were recorded and analyzed. The overall performance of the FINE, as depicted by the average of the maximum target-specific selectivity values, S(i), confirmed that high degrees of selectivity can be achieved at both the fascicular and muscular levels: 0.93 +/- 0.03 (n = 5) and 0.88 +/- 0.03 (n = 4), respectively. The results of this study demonstrate the feasibility of the FINE for selective stimulation of the XII nerve branches and the innervated tongue muscles.