Adaptation of the Two-CAP method for conduction velocity distribution estimation in multi-channel recordings

Closed-loop neural interfaces capable of both stimulating and recording from peripheral nerves have the potential to enhance the long-term efficacy of neural implants. One challenge associated with closed loop interfaces is the accurate estimation of the distribution of active fibre conduction velocities (DCV) when recording the immediate effect of stimulation. DCV estimation has been performed in monopolar surface recordings using the Two-CAP method. This work extends the Two-CAP method and demonstrates its application to bipolar in-vivo recordings made with multiple-electrode arrays. A sensitivity analysis was conducted using simulated data with ground truth to ascertain the stability and limits of the algorithm before experimental data was examined. The sensitivity analysis highlighted that recording distance shows a considerable impact on the performance of this extended Two-CAP method, as well as the velocity interval chosen when creating the model. The in-vivo data was also compared against an equivalent simulated model, and a relatively low mean squared error was obtained when comparing the two distributions

An in-vitro system for closed loop neuromodulation of peripheral nerves

Current neuromodulation research relies heavily on in-vivo animal experiments for developing novel devices and paradigms, which can be costly, time-consuming, and ethically contentious. As an alternative to this, in-vitro systems are being developed for examining explanted tissue in a controlled environment. However, these systems are typically tailored for cellular studies. Thus, this paper describes the development of an in-vitro system for electrically recording and stimulating large animal nerves. This is demonstrated experimentally using explanted pig ulnar nerves, which show evoked compound action potentials (eCAPs) when stimulated. These eCAPs were examined both in the time and velocity domain at a baseline temperature of 20° C, and at temperatures increasing up to those seen in-vivo (37°C). The results highlight that as the temperature is increased within the in-vitro system, faster conduction velocities (CVs) similar to those present in-vivo can be observed. To our knowledge, this is the first time an in-vitro peripheral nerve system has been validated against in-vivo data, which is crucial for promoting more widespread adoption of such systems for the optimisation of neural interfaces

The effect of peripheral high-frequency electrical stimulation on the primary somatosensory cortex in pigs

This study implements the use of Danish Landrace pigs as subjects for the long-term potentiation (LTP)-like pain model. This is accomplished by analyzing changes in the primary somatosensory cortex (S1) in response to electrical stimulation on the ulnar nerve after applying high-frequency electrical stimulation (HFS) on the ulnar nerve. In this study, eight Danish Landrace pigs were electrically stimulated, through the ulnar nerve, to record the cortically evoked response in S1 by a 16-channel microelectrode array (MEA). Six of these pigs were subjected to HFS (four consecutive, 15 mA, 100 Hz, 1000 µs pulse duration) 45 min after the start of the experiment. Two pigs were used as control subjects to compare the cortical response to peripheral electrical stimulation without applying HFS. Low-frequency components of the intracortical signals (0.3–300 Hz) were analyzed using event-related potential (ERP) analysis, where the minimum peak during the first 30–50 ms (N1 component) in each channel was detected. The change in N1 was compared over time across the intervention and control groups. Spectral analysis was used to demonstrate the effect of the intervention on the evoked cortical oscillations computed between 75 ms and 200 ms after stimulus. ERP analysis showed an immediate increase in N1 amplitude that became statistically significant 45 mins after HFS (p < 0.01) for the intervention group. The normalized change in power in frequency oscillations showed a similar trend. The results show that the LTP-like pain model can be effectively implemented in pigs using HFS since the cortical responses are comparable to those described in humans

The Use of the Velocity Selective Recording Technique to Reveal the Excitation Properties of the Ulnar Nerve in Pigs

Decoding information from the peripheral nervous system via implantable neural interfaces remains a significant challenge, considerably limiting the advancement of neuromodulation and neuroprosthetic devices. The velocity selective recording (VSR) technique has been proposed to improve the classification of neural traffic by combining temporal and spatial information through a multi-electrode cuff (MEC). Therefore, this study investigates the feasibility of using the VSR technique to characterise fibre type based on the electrically evoked compound action potentials (eCAP) propagating along the ulnar nerve of pigs in vivo. A range of electrical stimulation parameters (amplitudes of 50 μA–10 mA and pulse durations of 100 μs, 500 μs, 1000 μs, and 5000 μs) was applied on a cutaneous and a motor branch of the ulnar nerve in nine Danish landrace pigs. Recordings were made with a 14 ring MEC and a delay-and-add algorithm was used to convert the eCAPs into the velocity domain. The results revealed two fibre populations propagating along the cutaneous branch of the ulnar nerve, with mean velocities of 55 m/s and 21 m/s, while only one dominant fibre population was found for the motor branch, with a mean velocity of 63 m/s. Because of its simplicity to provide information on the fibre selectivity and direction of propagation of nerve fibres, VSR can be implemented to advance the performance of the bidirectional control of neural prostheses and bioelectronic medicine applications

Porcine Model of Cerebral Ischemic Stroke Utilizing Intracortical Recordings for the Continuous Monitoring of the Ischemic Area

Purpose: Our aim was to use intracortical recording to enable the tracking of ischemic infarct development over the first few critical hours of ischemia with a high time resolution in pigs. We employed electrophysiological measurements to obtain quick feedback on neural function, which might be useful for screening, e.g., for the optimal dosage and timing of agents prior to further pre-clinical evaluation. Methods: Micro-electrode arrays containing 16 (animal 1) or 32 electrodes (animal 2–7) were implanted in the primary somatosensory cortex of seven female pigs, and continuous electrical stimulation was applied at 0.2 Hz to a cuff electrode implanted on the ulnar nerve. Ischemic stroke was induced after 30 min of baseline recording by injection of endothelin-1 onto the cortex adjacent to the micro-electrode array. Evoked responses were extracted over a moving window of 180 s and averaged across channels as a measure of cortical excitability. Results: Across the animals, the cortical excitability was significantly reduced in all seven 30 min segments following endothelin-1 injection, as compared to the 30 min preceding this intervention. This difference was not explained by changes in the anesthesia, ventilation, end-tidal CO2, mean blood pressure, heart rate, blood oxygenation, or core temperature, which all remained stable throughout the experiment. Conclusions: The animal model may assist in maturing neuroprotective approaches by testing them in an accessible model of resemblance to human neural and cardiovascular physiology and body size. This would constitute an intermediate step for translating positive results from rodent studies into human application, by more efficiently enabling effective optimization prior to chronic pre-clinical studies in large animals

Pig Ulnar Nerve Recording with Sinusoidal and Temporal Interference Stimulation

Temporal interference stimulation has been suggested as a method to reach deep targets during transcutaneous electrical stimulation. Despite its growing use in transcutaneous stimulation therapies, the mechanism of its operation is not fully understood. Recent efforts to fill that gap have focused on computational modelling, in vitro and in vivo experiments relying on physical observations - e.g., sensation or movement. This paper expands the current range of experimental methods by demonstrating in vivo extraneural recordings from the ulnar nerve of a pig while applying temporal interference stimulation at a location targeting a distal part of the nerve. The main aim of the experiment was to compare neural activation using sinusoidal stimulation (100 Hz, 2 kHz, 4 kHz) and temporal interference stimulation (2 kHz and 4 kHz). The recordings showed a significant increase in the magnitude of stimulation artefacts at higher frequencies. While those artefacts could be removed and provided an indication of the depth of modulation, they resulted in the saturation of the amplifiers, limiting the stimulation currents and amplifier gains used. The results of the 100 Hz sine wave stimulation showed clear neural activity correlated to the stimulation waveform. However, this was not observed with temporal interference stimulation. The results suggest that, despite its greater penetration, higher currents might be required to observe a neural response with temporal interference stimulation, and more complex artefact rejection techniques may be required to validate the method.</p

Ex-vivo systems for neuromodulation:A comparison of ex-vivo and in-vivo large animal nerve electrophysiology

BACKGROUND: Little research exists on extending ex-vivo systems to large animal nerves, and to the best of our knowledge, there has yet to be a study comparing these against in-vivo data. This paper details the first ex-vivo system for large animal peripheral nerves to be compared with in-vivo results.NEW METHOD: Detailed ex-vivo and in-vivo closed-loop neuromodulation experiments were conducted on pig ulnar nerves. Temperatures from 20 °C to 37 °C were evaluated for the ex-vivo system. The data were analysed in the time and velocity domains, and a regression analysis established how evoked compound action potential amplitude and modal conduction velocity (CV) varied with temperature and time after explantation.MAIN RESULTS: Pig ulnar nerves were sustained ex-vivo up to 5 h post-explantation. CV distributions of ex-vivo and in-vivo data were compared, showing closer correspondence at 37 °C. Regression analysis results also demonstrated that modal CV and time since explantation were negatively correlated, whereas modal CV and temperature were positively correlated.COMPARISON WITH EXISTING METHODS: Previous ex-vivo systems were primarily aimed at small animal nerves, and we are not aware of an ex-vivo system to be directly compared with in-vivo data. This new approach provides a route to understand how ex-vivo systems for large animal nerves can be developed and compared with in-vivo data.CONCLUSION: The proposed ex-vivo system results were compared with those seen in-vivo, providing new insights into large animal nerve activity post-explantation. Such a system is crucial for complementing in-vivo experiments, maximising collected experimental data, and accelerating neural interface development.</p