Kristian Rauhe Harreby

Stimulation Selectivity of the “Thin-Film Longitudinal Intrafascicular Electrode” (tfLIFE) and the “Transverse Intrafascicular Multi-Channel Electrode” (TIME) in the Large Nerve Animal Model

Neural prostheses are limited by the availability of peripheral neural electrodes to record the users intention or provide sensory feedback through functional electrical stimulation. Our objective was to compare the ability of the novel “transverse intrafascicular multi-channel electrode” (TIME) and an earlier generation “thin-film longitudinal intrafascicular electrode” (tfLIFE) to selectively stimulate nerve fascicles and activate forelimb muscles in pigs. TIME was designed to access a larger subpopulation of fascicles than tfLIFE and should therefore be able to selectively activate a larger number of muscles. Electrodes were implanted in the median nerve, and sequential electric stimulation was applied to individual contacts. The compound muscle action potentials of seven muscles were recorded to quantify muscle recruitment. As expected, TIME was able to recruit more muscles with higher selectivity than tfLIFE (significant difference when comparing the performance of an entire electrode); a similar activation current was used (no significant difference). Histological analysis revealed that electrodes were located between fascicles, which influenced the selectivity and activation current level. In conclusion, TIME is a viable neural interface for selective activation of multiple fascicles in human-sized nerves that may assist to pave the way for future neuroprosthesis applications.

Development of a neurotechnological system for relieving phantom limb pain using transverse intrafascicular electrodes (TIME)

Abstract Phantom limb pain (PLP) is a chronic condition that develops in the majority of amputees. The underlying mechanisms are not completely understood, and thus, no treatment is fully effective. Based on recent studies, we hypothesize that electrical stimulation of afferent nerves might alleviate PLP by giving sensory input to the patient if nerve fibers can be activated selectively. The critical component in this scheme is the implantable electrode structure. We present a review of a novel electrode concept to distribute highly selective electrode contacts over the complete cross section of a peripheral nerve to create a distributed activation of small nerve fiber ensembles at the fascicular level, the transverse intrafascicular multichannel nerve electrode (TIME). The acute and chronic implantations in a small animal model exhibited a good surface and structural biocompatibility as well as excellent selectivity. Implantation studies on large animal models that are closer to human nerve size and anatomical complexity have also been conducted. They proved implant stability and the ability to selectively activate nerve fascicles in a limited proximity to the implant. These encouraging results have opened the way forward for human clinical trials in amputees to investigate the effect of selective electrical stimulation on PLP.

The effect of spinal cord stimulation on seizure susceptibility in rats.

Objectives:  Spinal cord stimulation (SCS) activates the thalamus, which may be involved in generation of seizures. SCS may therefore influence seizure susceptibility. We investigated the effect of SCS on seizure susceptibility when performed at low frequency (4 Hz) and a frequency in the typical range of SCS treatment (54 Hz).

Biosafety assessment of an intra-neural electrode (TIME) following sub-chronic implantation in the median nerve of Göttingen minipigs

Before a novel peripheral nerve interface can be applied in a neural prosthesis for human use, it is important to determine the biocompatibility of the device. The aim of the present study was to assess the biosafety of the recently developed transverse intrafascicular multi-channel electrode (TIME) in a large nerve animal model. Six TIMEs were implanted (33-38 days) into the median nerves of Göttingen minipigs, and nerve specimens were harvested for histological analysis. We analyzed samples from the area of the implant and from control regions. We found an expected layer of fibrosis around the implant and fibroblasts in both the implant and control region, however, we found no significant presence of inflammatory cells or necrosis. Our results indicated that the TIME may be an attractive, biocompatible neural interface for future neuroprosthesis applications in the clinic setting.

The Effect of Spinal Cord Stimulation on Epileptic Seizures.

Spinal cord stimulation (SCS) has been applied to relieve chronic pain for decades. Recent studies suggested that SCS also might alleviate epileptic seizures, but the most effective stimulation parameters are not known. The objective of this work was to investigate the role of SCS frequency in alleviating spike‐and‐wave (SW) discharges induced in rats by pentylenetetrazole (PTZ) infusion.

Subchronic stimulation performance of transverse intrafascicular multichannel electrodes in the median nerve of the Göttingen minipig.

This work evaluated the subchronic stimulation performance of an intraneural multichannel electrode (transverse intrafascicular multichannel electrode, TIME) in a large human-sized nerve. One or two TIMEs were implanted in the right median nerve above the elbow joint in four pigs for a period of 32 to 37 days (six TIMEs in total). The ability of the contact sites to recruit five muscles in the forelimb was assessed via their evoked electromyographic responses. Based on these responses, a selectivity index was defined. Four TIMEs were able to selectively recruit a subset of muscles throughout the implantation period. The required recruitment current significantly increased, while there was a tendency for the recruitment selectivity to decrease over time. Histological assessment showed that all TIMEs remained inside the nerve and that they were located between fascicles. The average thickness of the encapsulation of the electrode was estimated to be 115.4 ± 51.5 μm (mean ± SD). This study demonstrates the feasibility of keeping the TIME electrodes fixed and functional inside a large polyfascicular human-sized nerve in a subchronic setting.

Early Detection of Epileptic Seizures in Pigs Based on Vagus Nerve Activity

Vagus nerve stimulation is currently used as a treatment of otherwise intractable epilepsy. The efficacy of the treatment does, however, remain modest, but could potentially be improved by on-demand stimulation. A method for early seizure detection in rats based on vagus nerve activity was described previously. Such methods could enable closed loop on-demand stimulation. In this study, we tested the method in three pigs. Early prediction of seizures, i.e. prior to the onset of tonic-clonic seizures, was possible in all animals, whereas administration of adrenaline did not provoke false detections.

The Effect of Spinal Cord Stimulation on Epileptic Seizures Suppression.

Spinal cord stimulation (SCS) has been applied for the treatment of chronic pain for decades. Recent studies have shown that SCS may also reduce or prevent epileptic seizures, but it is not known which stimulation parameters may be effective. The objective of the present study was to investigate the effect of several SCS frequencies on seizures induced in rats by pentylenetetrazole (PTZ) infusion. The effect was evaluated by analysing electrocorticogram (ECoG) recordings. SCS using 0.3 and 0.8 mA biphasic 100/500 μs pulses delivered at five frequencies was administered in two rats in 60 s stimulation sessions. The present results indicate that 130 and 180 Hz SCS may have anti-epileptic effects and 30 Hz SCS may be pro-convulsive. Further data are needed to validate these results to establish an effective SCS pattern.

Comparison of stimulation selectivity in monopolar and bipolar configuration using the Transversal Intrafascicular Multichannel Electrode (TIME) - Preliminary results

The Transversal Intrafascicular Multichannel Electrode (TIME) is intended to be implanted transversally in the nerve and address several fascicles or subgroups of nerve fibres with one device. It has been already shown that TIME allows to achieve high selectivity of stimulation when using monopolar configuration, i.e. when current is delivered through one of the sites of the TIME against small needle electrode placed in the proximity of the nerve. Results of the current study suggest that using bipolar configuration, i.e. when current is delivered through one of the TIME sites against an other site of the same electrode, could allow to further enhance selectivity of stimulation. However, higher charge of the stimulation may be necessary to achieve similar level of muscle activation, as compared to the monopolar configuration.

The Influence of Vagus Nerve and Spinal Cord Stimulation on the Ictal Fast Ripple Activity in a Spike-and-Wave Rat Model of Seizures.

Fast ripple (FR) activity has received increasing attention as a potential epileptic marker. The current knowledge on how neurostimulation affects FRs is, however, very limited. In this study, we assess the influence of the vagus nerve stimulation (VNS) and spinal cord stimulation (SCS) frequency on ictal FRs associated with spike‐and‐wave (SW) seizures.