Paul B. Yoo

High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog

OBJECTIVE Not fully understanding the type of axons activated during vagus nerve stimulation (VNS) is one of several factors that limit the clinical efficacy of VNS therapies. The main goal of this study was to characterize the electrical recruitment of both myelinated and unmyelinated fibers within the cervical vagus nerve. APPROACH In anesthetized dogs, recording nerve cuff electrodes were implanted on the vagus nerve following surgical excision of the epineurium. Both the vagal electroneurogram (ENG) and laryngeal muscle activity were recorded in response to stimulation of the right vagus nerve. MAIN RESULTS Desheathing the nerve significantly increased the signal-to-noise ratio of the ENG by 1.2 to 9.9 dB, depending on the nerve fiber type. Repeated VNS following nerve transection or neuromuscular block (1) enabled the characterization of A-fibers, two sub-types of B-fibers, and unmyelinated C-fibers, (2) confirmed the absence of stimulation-evoked reflex compound nerve action potentials in both the ipsilateral and contralateral vagus nerves, and (3) provided evidence of stimulus spillover into muscle tissue surrounding the stimulating electrode. SIGNIFICANCE Given the anatomical similarities between the canine and human vagus nerves, the results of this study provide a template for better understanding the nerve fiber recruitment patterns associated with VNS therapies.

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.

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.

Enhanced electrode design for peripheral nerve recording

Electrical recording of peripheral nerve activity using a nerve cuff electrode is a potential long-term solution for implementing a closed-loop controlled neuroprosthetic system. However, the clinical utility of this approach is significantly limited by various factors, such as poor signal-to-noise ratio (SNR) of the recorded electroneurogram (ENG). In this paper, we investigated the effects of (1) modifying the electrode contact dimensions and (2) implementing an external shielding layer on the ENG recorded by a nerve cuff electrode. Our preliminary findings from both computer simulations and animal experiments suggest that significant improvements in peripheral nerve recordings can be achieved.

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

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.

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.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.

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.

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.

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.

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.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.