An optoelectronic implantable neurostimulation platform allowing full MRI safety and optical sensing and communication.

A novel programmable implantable neurostimulation platform based on photonic power transfer has been developed for various clinical applications with the main focus of being safe to use with MRI scanners. The wires usually conveying electrical current from the neurostimulator to the electrodes are replaced by optical fibers. Photovoltaic cells at the tip of the fibers convert laser light to biphasic electrical impulses together with feedback signals with 54% efficiency. Furthermore, a biocompatible, implantable and ultra-flexible optical lead was developed including custom optical fibers. The neurostimulator platform incorporates advanced signal processing and optical physiological sensing capabilities thanks to a hermetically sealed transparent nonmetallic casing. Skin transparency also allowed the development of a high-speed optical transcutaneous communication channel. This implantable neurostimulation platform was first adapted to a vagus nerve stimulator for the treatment of epilepsy. This neurostimulator has been designed to fulfill the requirements of a class III long-term implantable medical device. It has been proven compliant with standard ISO/TS10974 for 1.5 T and 3 T MRI scanners. The device poses no related threat and patients can safely undergo MRI without specific or additional precautions. Especially, the RF induced heating near the implant remains below 2 °C whatever the MRI settings used. The main features of this unique advanced neurostimulator and its architecture are presented. Its functional performance is evaluated, and results are described with a focus on optoelectronics aspects and MRI safety.

Vagus nerve stimulation-induced laryngeal motor evoked potentials for response prediction and intensity titration in drug-resistant epilepsy.

OBJECTIVE: The objective of the study was to record Laryngeal Motor Evoked Potentials (LMEPs) in Vagus Nerve Stimulation (VNS)-implanted patients suffering from Drug-Resistant Epilepsy (DRE). Based on these recordings, LMEPs characteristics were evaluated and compared between responders (R) and non-responders (NR). Finally, possible under- or over-stimulation was assessed based on a physiological indicator of fiber engagement. METHODS: Mean dose-response curves were compared between R and NR. A Support Vector Machine (SVM) model was built based on both LMEP and dose-response curves features, to discriminate R from NR. For the exploration of possible under- or over-stimulation, a ratio between the clinically applied stimulation intensity and the intensity yielding to LMEP saturation was computed for each patient. RESULTS: A trend towards a greater excitability of the nerve was observed in R compared to NR. The SVM classifier discriminated R and NR with an accuracy of 80%. An ineffective attempt to overstimulate at current levels above what is usually necessary to obtain clinical benefits was suggested in NR. CONCLUSIONS: The SVM model built emphasizes a possible link between vagus nerve recruitment characteristics and treatment effectiveness. Most of the clinically responding patients receive VNS at a stimulation intensity 1-fold and 2-fold the intensity inducing LMEP saturation. SIGNIFICANCE: LMEP saturation could be a practical help in guiding the titration of the stimulation parameters using a physiological indicator of fiber engagement.

Optical birefringence changes in myelinated and unmyelinated nerves: A comparative study.

The measurement of birefringence variations related to nerve activity is a promising label-free technique for sensing compound neural action potentials (CNAPs). While widely applied in crustaceans, little is known about its efficiency on mammal peripheral nerves. In this work, birefringence recordings to detect CNAPs, and Stokes parameters measurements were performed in rat and lobster nerves. While single-trial detection of nerve activity in crustaceans was achieved successfully, no optical signal was detected in rats, even after extensive signal filtering and averaging. The Stokes parameters showed that a high degree of polarization of light is maintained in lobster sample, whereas an almost complete light depolarization occurs in rat nerve. Our results indicate that depolarization itself is not sufficient to explain the absence of birefringence signals in rats. We hypothesize that this absence comes from the myelin sheets, which constraint the birefringence changes to only take place at the nodes of Ranvier.

Chronic recording of the vagus nerve to analyze modulations by the light-dark cycle.

Objective.The vagus nerve is considered to play a key role in the circadian rhythm. Chronic continuous analysis of the vagus nerve activity could contribute to a better understanding of the role of the vagus nerve in light-dark modulations. This paper presents a continuous analysis of spontaneous vagus nerve activity performed in four rats.Approach.We analyzed the vagus electroneurogram (VENG) and electroencephalogram (EEG) over a recording period of 28 d. Spike activity and heart rate estimation were derived from the VENG, and slow-wave activity was derived from the EEG. The presence of repetitive patterns was investigated with periodograms, cosinor fitting, autocorrelation, and statistical tests. The light-dark variations derived from the VENG spikes were compared with EEG slow waves, an established metric in circadian studies.Results.Our results demonstrate that light-dark variations can be detected in long-term vagus nerve activity monitoring. A recording period of about 7 d is required to characterize accurately the VENG light-dark variations.Significance.As a major outcome of this study, vagus nerve recordings hold the promise to help understand circadian regulation.

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy.

Vagus Nerve Electroneurogram-Based Detection of Acute Pentylenetetrazol Induced Seizures in Rats.

On-demand stimulation improves the efficacy of vagus nerve stimulation (VNS) in refractory epilepsy. The vagus nerve is the main peripheral parasympathetic connection and seizures are known to exhibit autonomic symptoms. Therefore, we hypothesized that seizure detection is possible through vagus nerve electroneurogram (VENG) recording. We developed a metric able to measure abrupt changes in amplitude and frequency of spontaneous vagus nerve action potentials. A classifier was trained using a "leave-one-out" method on a set of 6 seizures and 3 control recordings to utilize the VENG spike feature-based metric for seizure detection. We were able to detect pentylenetetrazol (PTZ) induced acute seizures in 6/6 animals during different stages of the seizure with no false detection. The classifier detected the seizure during an early stage in 3/6 animals and at the onset of tonic clonic stage of the seizure in 3/6 animals. EMG and motion artefacts often accompany epileptic activity. We showed the "epileptic" neural signal to be independent from EMG and motion artefacts. We confirmed the existence of seizure related signals in the VENG recording and proved their applicability for seizure detection. This detection might be a promising tool to improve efficacy of VNS treatment by developing new responsive stimulation systems.

Infrared neurostimulation inex-vivorat sciatic nerve using 1470 nm wavelength.

Objective.To design and implement a setup forex-vivooptical stimulation for exploring the effect of several key parameters (optical power and pulse duration), activation features (threshold, spatial selectivity) and recovery characteristics (repeated stimuli) in peripheral nerves.Approach.A nerve chamber allowing ex-vivo electrical and optical stimulation was designed and built. A 1470 nm light source was chosen to stimulate the nerve. A photodiode module was implemented for synchronization of the electrical and optical channels.Main results. Compound neural action potentials (CNAPs) were successfully generated with infrared light pulses of 200-2000µs duration and power in the range of 3-10 W. These parameters determine a radiant exposure for stimulation in the range 1.59-4.78 J cm-2. Recruitment curves were obtained by increasing durations at a constant power level. Neural activation threshold is reached at a mean radiant exposure of 3.16 ± 0.68 J cm-2and mean pulse energy of 3.79 ± 0.72 mJ. Repetition rates of 2-10 Hz have been explored. In eight out of ten sciatic nerves (SNs), repeated light stimuli induced a sensitization effect in that the CNAP amplitude progressively grows, representing an increasing number of recruited fibres. In two out of ten SNs, CNAPs were composed of a succession of peaks corresponding to different conduction velocities.Significance.The reported sensitization effect could shed light on the mechanism underlying infrared neurostimulation. Our results suggest that, in sharp contrast with electrical stimuli, optical pulses could recruit slow fibres early on. This more physiological order of recruitment opens the perspective for specific neuromodulation of fibre population who remained poorly accessible until now. Short high-power light pulses at wavelengths below 1.5µm offer interesting perspectives for neurostimulation.

Analysing vagus nerve spontaneous activity using finite element modelling.

Objective.Finite element modelling has been widely used to understand the effect of stimulation on the nerve fibres. Yet the literature on analysis of spontaneous nerve activity is much scarcer. In this study, we introduce a method based on a finite element model, to analyse spontaneous nerve activity with a typical bipolar electrode recording setup, enabling the identification of spontaneously active fibres. We applied our method to the vagus nerve, which plays a key role in refractory epilepsy.Approach.We developed a 3D model including dynamic action potential (AP) propagation, based on the vagus nerve geometry. The impact of key recording parameters-inter-electrode distance and temperature-and uncontrolled parameters-fibre size and position in the nerve-on the ability to discriminate active fibres were quantified. A specific algorithm was implemented to detect and classify APs from recordings, and tested on six ratin-vivovagus nerve recordings.Main results.Fibre diameters can be discriminated if they are below 3µm and 7µm, respectively for inter-electrode distances of 2 mm and 4 mm. The impact of the position of the fibre inside the nerve on fibre diameter discrimination is limited. The range of active fibres identified by modelling in the vagus nerve of rats is in agreement with ranges found at histology.Significance.The nerve fibre diameter, directly proportional to the AP propagation velocity, is related to a specific physiological function. Estimating the source fibre diameter is thus essential to interpret neural recordings. Among many possible applications, the present method was developed in the context of a project to improve vagus nerve stimulation therapy for epilepsy.

Recording of spontaneous vagus nerve activity during Pentylenetetrazol-induced seizures in rats.

BACKGROUND: Vagus nerve stimulation is a treatment for refractory epilepsy. The vagus nerve carries parasympathetic information and innervates multiple organs. As seizures are commonly associated with autonomic manifestations, we believe that biomarkers for diseases affecting autonomic functions such as epilepsy can be found in vagus nerve signals. NEW METHOD: We present a method to record vagus nerve electroneurogram (VENG) and detect in the VENG single unit activity in anesthetized rats during Pentylenetetrazol induced seizures using a true tripolar cuff electrode. RESULTS: The VENG consisted of high amplitude bursts and lower amplitude bursts synchronous to respiration and heartbeat respectively. The average spikes exhibited a triphasic shape with duration below 1.5ms and root mean square amplitude varied between 5.5 +/- 0.2 µV and 11.4 +/- 3.1 µV depending on the type of recording. An increase of the contact distance resulted in a signal amplitude increase. Application of Lidocaine led to a total disappearance of the recorded spontaneous spiking of the nerve. COMPARISON WITH EXISTING METHODS: True tripolar cuff electrodes exhibited a better performance in terms of artefact rejection, stability and reproducibility of the signal compared to commonly used hook electrodes which is of special interest in seizures where important motion and EMG artifacts are expected. CONCLUSION: We present a new method to record single unit activity of the vagus nerve during acute chemically induced seizures in rats and verified the neural origin of the recorded signals. This recording method might be a powerful tool to develop seizure biomarkers based on VENG.

Embedded System for Prosthetic Control Using Implanted Neuromuscular Interfaces Accessed Via an Osseointegrated Implant.

Despite the technological progress in robotics achieved in the last decades, prosthetic limbs still lack functionality, reliability, and comfort. Recently, an implanted neuromusculoskeletal interface built upon osseointegration was developed and tested in humans, namely the Osseointegrated Human-Machine Gateway. Here, we present an embedded system to exploit the advantages of this technology. Our artificial limb controller allows for bioelectric signals acquisition, processing, decoding of motor intent, prosthetic control, and sensory feedback. It includes a neurostimulator to provide direct neural feedback based on sensory information. The system was validated using real-time tasks characterization, power consumption evaluation, and myoelectric pattern recognition performance. Functionality was proven in a first pilot patient from whom results of daily usage were obtained. The system was designed to be reliably used in activities of daily living, as well as a research platform to monitor prosthesis usage and training, machine-learning-based control algorithms, and neural stimulation paradigms.

In Vivo Photonic Stimulation of Sciatic Nerve with a 1470 nm Laser.

Photonic stimulation is a new modality of nerve stimulation, which could overcome some of the electrical stimulation limitations. In this paper, we present the results of photonic stimulation of rodent sciatic nerve with a 1470 nm laser. Muscle activation was observed with radiant exposure of 0.084 J/cm².

Inductive Powering of Subcutaneous Stimulators: Key Parameters and Their Impact on the Design Methodology.

Inductive powering of implantable medical devices involves numerous factors acting on the system efficiency and safety in adversarial ways. This paper lightens up their role and identifies a procedure enabling the system design. The latter enables the problem to be decoupled into four principal steps: the frequency choice, the magnetic link optimization, the secondary circuit and then finally the primary circuit designs. The methodology has been tested for the powering system of a device requirering a power of 300mW and implanted at a distance of 15 to 30mm from the outside power source. It allowed the identification of the most critical parameters. A satisfying efficiency of 34% was reached at 21mm and tend to validate the proposed design procedure.

A novel implantable vagus nerve stimulation system (ADNS-300) for combined stimulation and recording of the vagus nerve: pilot trial at Ghent University Hospital.

PURPOSE: Vagus nerve stimulation (VNS) is an established treatment for refractory epilepsy. The ADNS-300 is a new system for VNS that includes a rechargeable stimulus generator and an electrode for combined stimulation and recording. In this feasibility study, three patients were implanted with ADNS-300 for therapeutic VNS. In addition, compound action potentials (CAPs) were recorded to evaluate activation of the vagus nerve in response to VNS. METHODS: Three patients were implanted with a cuff-electrode around the left vagus nerve, that was connected to a rechargeable pulse generator under the left clavicula. Two weeks after surgery, therapeutic VNS (0.25-1.25 mA, 500 µs, 30s on, 10 min off and 30Hz) was initiated and stimulus-induced CAPs were recorded. RESULTS: The ADNS-300 system was successfully implanted in all three patients and patients were appropriately stimulated during six months of follow-up. A reduction in seizure frequency was demonstrated in two patients (43% and 40% in patients 1 and 3, respectively), while in patient 2 seizure frequency remained unchanged. CAPs could be recorded in patients 1 and 2, proving stimulation-induced activation of the vagus nerve. CONCLUSION: This feasibility study demonstrates that the ADNS-300 system can be used for combined therapeutic stimulation (in 3/3 patients) and recording of CAPs in response to VNS (in 2/3 patients) up to three weeks after surgery. Implantation in a larger number of patients will lead to a better understanding of the electrophysiology of the vagus nerve, which in turn could result in more adequate and individualized VNS parameter choice.