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.

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.

Transient and selective suppression of neural activity with infrared light.

Analysis and control of neural circuitry requires the ability to selectively activate or inhibit neurons. Previous work showed that infrared laser light selectively excited neural activity in endogenous unmyelinated and myelinated axons. However, inhibition of neuronal firing with infrared light was only observed in limited cases, is not well understood and was not precisely controlled. Using an experimentally tractable unmyelinated preparation for detailed investigation and a myelinated preparation for validation, we report that it is possible to selectively and transiently inhibit electrically-initiated axonal activation, as well as to both block or enhance the propagation of action potentials of specific motor neurons. Thus, in addition to previously shown excitation, we demonstrate an optical method of suppressing components of the nervous system with functional spatiotemporal precision. We believe this technique is well-suited for non-invasive investigations of diverse excitable tissues and may ultimately be applied for treating neurological disorders.

Hybrid electro-optical stimulation of the rat sciatic nerve induces force generation in the plantarflexor muscles.

Objective. Optical methods of neural activation are becoming important tools for the study and treatment of neurological disorders. Infrared nerve stimulation (INS) is an optical technique exhibiting spatially precise activation in the native neural system. While this technique shows great promise, the risk of thermal damage may limit some applications. Combining INS with traditional electrical stimulation, a method known as hybrid electro-optical stimulation, reduces the laser power requirements and mitigates the risk of thermal damage while maintaining spatial selectivity. Here we investigate the capability of inducing force generation in the rat hind limb through hybrid stimulation of the sciatic nerve. Approach. Hybrid stimulation was achieved by combining an optically transparent nerve cuff for electrical stimulation and a diode laser coupled to an optical fiber for infrared stimulation. Force generation in the rat plantarflexor muscles was measured in response to hybrid stimulation with 1 s bursts of pulses at 15 and 20 Hz and with a burst frequency of 0.5 Hz. Main results. Forces were found to increase with successive stimulus trains, ultimately reaching a plateau by the 20th train. Hybrid evoked forces decayed at a rate similar to the rate of thermal diffusion in tissue. Preconditioning the nerve with an optical stimulus resulted in an increase in the force response to both electrical and hybrid stimulation. Histological evaluation showed no signs of thermally induced morphological changes following hybrid stimulation. Our results indicate that an increase in baseline temperature is a likely contributor to hybrid force generation. Significance. Extraneural INS of peripheral nerves at physiologically relevant repetition rates is possible using hybrid electro-optical stimulation.

Spatial and temporal variability in response to hybrid electro-optical stimulation.

Hybrid electro-optical neural stimulation is a novel paradigm combining the advantages of optical and electrical stimulation techniques while reducing their respective limitations. However, in order to fulfill its promise, this technique requires reduced variability and improved reproducibility. Here we used a comparative physiological approach to aid the further development of this technique by identifying the spatial and temporal factors characteristic of hybrid stimulation that may contribute to experimental variability and/or a lack of reproducibility. Using transient pulses of infrared light delivered simultaneously with a bipolar electrical stimulus in either the marine mollusk Aplysia californica buccal nerve or the rat sciatic nerve, we determined the existence of a finite region of excitability with size altered by the strength of the optical stimulus and recruitment dictated by the polarity of the electrical stimulus. Hybrid stimulation radiant exposures yielding 50% probability of firing (RE50) were shown to be negatively correlated with the underlying changes in electrical stimulation threshold over time. In Aplysia, but not in the rat sciatic nerve, increasing optical radiant exposures (J cm⁻²) beyond the RE50 ultimately resulted in inhibition of evoked potentials. Accounting for the sources of variability identified in this study increased the reproducibility of stimulation from 35% to 93% in Aplysia and 23% to 76% in the rat with reduced variability.

Combined optical and electrical stimulation of neural tissue in vivo.

Low-intensity, pulsed infrared light provides a novel nerve stimulation modality that avoids the limitations of traditional electrical methods such as necessity of contact, presence of a stimulation artifact, and relatively poor spatial precision. Infrared neural stimulation (INS) is, however, limited by a 2:1 ratio of threshold radiant exposures for damage to that for stimulation. We have shown that this ratio is increased to nearly 6:1 by combining the infrared pulse with a subthreshold electrical stimulus. Our results indicate a nonlinear relationship between the subthreshold depolarizing electrical stimulus and additional optical energy required to reach stimulation threshold. The change in optical threshold decreases linearly as the delay between the electrical and optical pulses is increased. We have shown that the high spatial precision of INS is maintained for this combined stimulation modality. Results of this study will facilitate the development of applications for infrared neural stimulation, as well as target the efforts to uncover the mechanism by which infrared light activates neural tissue.