On the use of wavelet denoising and spike sorting techniques to process electroneurographic signals recorded using intraneural electrodes.

Among the possible interfaces with the peripheral nervous system (PNS), intraneural electrodes represent an interesting solution for their potential advantages such as the possibility of extracting spikes from electroneurographic (ENG) signals. Their use could increase the precision and the amount of information which can be detected with respect to other processing methods. In this study, in order to verify this assumption, thin-film longitudinal intrafascicular electrodes (tfLIFE) were implanted in the sciatic nerve of rabbits. Various sensory stimuli were applied to the hind limb of the animal and the elicited ENG signals were recorded using the tfLIFEs. These signals were processed to determine whether the different types of information can be decoded. Signals were wavelet denoised and spike sorted. Support vector machines were trained to use the spike waveforms found to infer the stimulus applied to the rabbit. This approach was also compared with previously used ENG-processing methods. The results indicate that the combination of wavelet denoising and spike sorting techniques can increase the amount of information extractable from ENG signals recorded with intraneural electrodes. This strategy could allow the development of more effective closed-loop neuroprostheses and hybrid bionic systems connecting the human nervous system with artificial devices

Tutorial: A guide to techniques for analysing recordings from the peripheral nervous system

The nervous system, through a combination of conscious and automatic processes, enables the regulation of the body and its interactions with the environment. The peripheral nervous system is an excellent target for technologies that seek to modulate, restore or enhance these abilities as it carries sensory and motor information that most directly relates to a target organ or function. However, many applications require a combination of both an effective peripheral nerve interface and effective signal processing techniques to provide selective and stable recordings. While there are many reviews on the design of peripheral nerve interfaces, reviews of data analysis techniques and translational considerations are limited. Thus, this tutorial aims to support new and existing researchers in the understanding of the general guiding principles, and introduces a taxonomy for electrode configurations, techniques and translational models to consider

Spike Sorting of Muscle Spindle Afferent Nerve Activity Recorded with Thin-Film Intrafascicular Electrodes

Afferent muscle spindle activity in response to passive muscle stretch was recorded in vivo using thin-film longitudinal intrafascicular electrodes. A neural spike detection and classification scheme was developed for the purpose of separating activity of primary and secondary muscle spindle afferents. The algorithm is based on the multiscale continuous wavelet transform using complex wavelets. The detection scheme outperforms the commonly used threshold detection, especially with recordings having low signal-to-noise ratio. Results of classification of units indicate that the developed classifier is able to isolate activity having linear relationship with muscle length, which is a step towards online model-based estimation of muscle length that can be used in a closed-loop functional electrical stimulation system with natural sensory feedback

Implantable Transducers for Neurokinesiological Research and Neural Prostheses

The objective of this thesis was to develop a family of advanced electrical and mechanical interfaces to record activity of nerves and muscles during natural movements. These interfaces have applications in basic research and may eventually be refined for used in restoring voluntary control of movement in paralyzed persons. I) A muscle length gauge was designed that is based on piezoelectric crystals attached at the ends of a fluid filled extensible tubing. The in-vivo performance of these gauges was equal to previous length gauge designs. In addition, the ultrasound based design provided for the first time a direct muscle length calibration method. 2) An innovative nerve cuff closing technique was devised that does not reqmre suture closures. The new design uses interdigitated tubes to lock the opening and fix the lumen of a nerve cuff. The cuffs were tested in long-term mammalian implants and their performance matched or surpassed previous closure designs. The nerve cuff was further redesigned to include a more compliant cuff wall and wire electrodes. 3) Floating microelectrodes previously used for central nervous system recordings were adapted for chronic use in the peripheral nervous system. These electrodes proved disappointing in terms of signal quality and longevity. The reasons for failure are thought to be of both electrical and mechanical origin. 4) An innovative silicon micromachined peripheral single unit electrode was designed and tested. In the in-vivo tests, a limited number of recording sites successfully established short-term neural interfaces. However, the quality of the electrode performance, in terms of signal amplitude and ability to discriminate single unit potentials, was insufficient. 5) Using a finite difference model, a numerical simulation of static and dynamic electrical interactions between peripheral axons and microelectrode interfaces was derived. The model consisted of resistive and capacitive elements arranged in a 3-dimensional conductive universe (two spatial dimensions and time). Models of intrafascicular fine wire or silicon based electrodes were used to record simulated propagating action potentials. It was confirmed that electrode movement affected the recorded signal amplitude and that a dielectric layer on a silicon electrode accentuated the recorded potential field. A conducting back plane facing away from axon sources did not have a significant effect on the electrode recording properties. In conclusion, several novel implantable transducers were developed for use in neurokinesiological research. A numerical simulation of the axonal potentials recorded by intrafascicular electrodes helped interpret various shortcomings found in the in-vivo electrode performance. Although not attempted in the present thesis some of the developed technologies may have potential of transferring to clinical neural prostheses applications

Restoring Fine Motor Skills through Neural Interface Technology.

Loss of motor function in the upper-limb, whether through paralysis or through loss of the limb itself, is a profound disability which affects a large population worldwide. Lifelike, fully-articulated prosthetic hands exist and are commercially available; however, there is currently no satisfactory method of controlling all of the available degrees of freedom. In order to generate better control signals for this technology, and help restore normal movement, it is necessary to interface directly with the nervous system. This thesis is intended to address several of the limitations of current neural interfaces and enable the long-term extraction of control signals for fine movements of the hand and fingers. The first study addresses the problems of low signal amplitudes and short implant lifetimes in peripheral nerve interfaces. In two rhesus macaques, we demonstrate the successful implantation of regenerative peripheral nerve interfaces (RPNI), which allowed us to record high amplitude, functionally-selective signals from peripheral nerves up to 20 months post-implantation. These signals could be accurately decoded into intended movement, and used to enable monkeys to control a virtual hand prosthesis. The second study presents a novel experimental paradigm for intracortical neural interfaces, which enables detailed investigation of fine motor information contained in primary motor cortex. We used this paradigm to demonstrate accurate decoding of continuous fingertip position and enable a monkey to control a virtual hand in closed-loop. This is the first demonstration of volitional control of fine motor skill enabled by a cortical neural interface. The final study presents the design and testing of a wireless implantable neural recording system. By extracting signal power in a single, configurable frequency band onboard the device, this system achieves low power consumption while maintaining decode performance, and is applicable to cortical, peripheral, and myoelectric signals. Taken together, these results represent a significant step towards clinical reality for neural interfaces, and towards restoration of full and dexterous movement for people with severe disabilities.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120648/1/irwinz_1.pd

Doctor of Philosophy

dissertationHigh-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss via electrical stimulation. The same device could also help restore volitional control to a prosthesis-using amputee, or sensation to a Spinal cord Injury (SCI) patient, via recordings from the still-viable peripheral nerves. The overall objective of these dissertations studies is to improve the usefulness of intrafascicular electrodes, such as the Utah Slanted Electrode Array (USEA), for neuroprosthetic devices for limb loss or spinal cord injury patients. Previous work in cat sciatic nerve has shown that stimulation through the USEA can remain viable for months after implant. However, stimulation parameters were not stable, and recordings were lost rapidly and were subject to strong contamination by myoelectrical activity from adjacent muscles. Recent research has shown that even when mobility is restored to a patient, either through prosthesis or functional electrical stimulation, difficulties in using the affected limbs arise from the lack of sensory input. In the absence of the usual proprioceptive and cutaneous inputs from the limb, planning and executing motions can be challenging and sometimes lead to the user's abandonment of prostheses. To begin to address this need, I examined the ability of USEAs in cat hindlimb nerves to activate primary sensory fibers by monitoring evoked potentials in somatosensory cortex via skull-screw electrodes. I iv also monitored evoked EMG responses, and determined that it is possible to recruit sensory or motor responses independently of one another. In the second study of this dissertation, I sought to improve the long-term stability of USEAs in the PNS by physically and electrically stabilizing and protecting the array. To demonstrate the efficacy of the stabilization and shielding technique, I examined the recording capabilities of USEA electrodes and their selectivity of muscle activation over the long term in cat sciatic nerve. In addition to long-term viability, clinically useful neuroprosthetic devices will have to be capable of interfacing with complex motor systems such as the human hand. To extend previous results of USEAs in cat hindlimb nerves and to examine selectivity when interfacing with a complex sensorimotor system, I characterized EMG and cortical somatosensory responses to acute USEA stimulation in monkey arm nerves. Then, to demonstrate the functional usefulness of stimulation through the USEA. I used multi-array, multi-electrode stimulation to generate a natural, coordinated grasp

Automated determination of peripheral nerve stimulation parameters to achieve desired effector response – a procedural routine, preliminary studies and proposal of improvements

BACKGROUND: The feasibility of selectively stimulating fascicles and fibers within peripheral nerves has been demonstrated by a number of groups. Although various multi-contact electrodes have been developed for this purpose, the lack of procedures for fast determination of stimulation parameters to produce the desired effector activity hampers the clinical application of these techniques. In this paper, we propose an automated search routine that may facilitate the determination of stimulation parameters. To verify the routine's performance, we also developed an another routine that performs systematic stimulus–response mapping (the mapping routine). METHOD: The mapping routine performs systematic mapping of all possible combinations of the allowed stimulation parameters (i.e. combinations of electrode contacts used to provide the stimulus and sets of stimulus parameters values) and the observed displacements. The proposed automated search routine, similarly to the mapping routine, maps stimulation parameters to muscle responses, but it first investigates stimuli of the low charge and during the mapping process it compares the recorded responses with the desired one. Depending on the result of that comparison, it decides whether the use of a particular combination of electrode contacts should be further investigated or skipped. Both approaches were implemented on a custom-made closed-loop FES platform and preliminary experiments were performed on a rat model. The rat's sciatic nerve was stimulated with a 12-contact cuff electrode and the resulting displacement of the rat's paw was determined using a MEMS accelerometer. RESULTS: The automated search routine was faster than the mapping routine; however, it failed to find correct stimulation parameters in one out of three searches. This could be due to unexpectedly high variability in the responses to a constant stimulus. CONCLUSION: Our initial tests have proven that the proposed method determines the desired stimulation parameters much more quickly than systematic stimulus–response mapping. However, the factors influencing the variability of responses to constant stimuli should be identified, and their influence diminished; the remaining essential variability can then be identified. Thereafter, the criteria influencing the search process should be investigated and refined. Further improvements to the search routine are also proposed

A ventral root interface for neuroprosthetic control of locomotion

Recent advances in state of the art prosthetic limbs have demonstrated unprecedented levels of dexterity and control within the constraints of an anthropomorphic structure. Unfortunately, patients still struggle to naturally control and rely upon relatively simpler lower limb devices with just one or two joints. For patients living with the loss of a limb, functional motor circuitry is still intact through the spinal cord and into the peripheral nerves, transforming higher level control signals into discrete muscle activations. An interface at the spinal roots can take advantage of this final output of the nervous system to control the device, completely avoiding some of the context sensitivity issues in higher level structures. Further, the anatomical separation of motor and sensory signals into distinct ventral and dorsal components and the relative stability of the spinal column provide a path towards a targeted neuroprosthetic interface. This dissertation develops and validates methods to target motor axons in the ventral roots with multielectrode arrays. We demonstrate the ability to chronically record well-isolated signals from diverse populations of motor axons and develop techniques to identify the muscles they innervate. We subsequently use these motor signals to estimate kinematics during locomotion as accurately as estimations from simultaneously recorded muscle activity in the intact limb, demonstrating that a ventral root prosthetic interface is possible for patients living with loss of limb

Implantable Electrodes for Upper Limb Prosthetic Control

This thesis describes a study investigating implantable interfaces with muscles and peripheral nerves. Current prostheses for upper limb amputees do not provide intuitive control over hand, wrist and elbow motion. By implanting electrodes for recording and stimulating onto muscles and into nerves in the amputation stump a greater number of control signals may be made available, signals which will be used to control dextrous hand movements. An implantable epimysial interface was developed using a bone-anchored device to hard-wire signals across the skin barrier. In a single ovine model pilot study the bone-anchor was implanted transtibially and the epimysial electrode was place superficially to m. peroneus teritus. Physiological signals were obtained over 12 weeks during treadmill walking. The external connector on the bone-anchor failed at 12 weeks, correlating with a drop in signal quality in an otherwise robust interface integrated with bone and skin tissue. The ovine bone-anchor model was repeated in 6 sheep for 19 weeks, with epimysial recordings made regularly. Increasing signal quality was seen during the study and was significantly greater from implanted electrodes compared with skin surface electrodes at 19 weeks (p = 0.016). Some complications with skin-implant integration were observed in proximally located implants. Crosstalk between muscles was assessed using pre-terminal nerve stimulation, and was found to be dependent upon muscle location and innervation. The ovine m. peroneus teritus model was used to assess recovery following targeted muscle reinnervation. Muscle signal recovery was observed approximately one month after surgery correlating with the start of functional recovery (assessed by force plate analysis). These studies indicate that a suitably modified bone-anchored device may be suitable for signal transmission in human patients, providing a stable, long-term solution to both prosthesis attachment and control. The potential of nerve interfaces for prosthetic control was investigated. The microchannel neural interface (MNI) was chosen because it overcomes limitations with other neural microarray designs: signal strength; cross-talk, and the locations of Nodes of Ranvier. MNIs confine regenerating nerves to small, ∼ 100 µm diameter, insulating tubes, this increases the length within which nerve signals can be recorded and amplifies the recorded signals. However, in vivo MNIs can become occluded by fibrosis that reduces or prevents axon regeneration. Two in vitro studies of neurocompatibility were carried out to investigate strategies for improving axon regeneration within microchannels. The first in vitro study compared the effect of different adsorbed endoneurial basement membrane proteins on PC-12 cell neurite extension on silicone substrates. The optimal protein coating concentrations for poly-D-lysine, collagen-IV and laminin-2,(-4) were determined. The optimal concentrations were compared with mixtures of basement membrane proteins, the effect of mixture coating order and constitution were investigated. It was found that endoneurial BM proteins significantly enhance neurite outgrowth compared with controls. Two coatings were suggested as most suited for improving neural regeneration within microchannels: a single layer coating of 10 µg/cm2 collagen-IV; and a mixed coating of 10 µg/cm2 collagen-IV, 1 µg/cm2 laminin-2,(-4), and 0.175 µg/cm2 nidogen-1. The second in vitro study investigated the effect of grooved, roughened and multi-scale silicone surfaces on on PC-12 cell neurite extension. Deeper, narrower grooves were shown to increase the extent of neurite alignment, while resulting in fewer, longer, neurites. Roughening surfaces was shown to increase the amount of protein (collagen-IV) which adsorbed from solution and increase the number of neurites each cell extended. Surfaces with multiscale topographies synergistically increased the number and length of neurites and guided neurite growth along the groove direction. MNIs were manufactured for in vivo testing. These MNIs were used to determine the effect of adsorbed endoneurial basement membrane proteins on nerve regeneration in vivo, but the multiscale topographies were not applied during manufacturing. Four alternative manufacturing methods were investigated and iterative improvements were made to create a stacked interface with multiple microchannel layers. Microchannel layers were created by laser patterning silicone and metal foil components, followed by plasma bonding to create a 3-dimensional structure with 150 µm deep, 200 µm wide microchannels. Electrode impedances of 27.2 ± 19.8 kΩ at 1kHz were achieved by DC etching. The method overcomes some current limitations on electrode connectivity and microchannel sealing, and may improve recording capabilities over single layer designs by increasing the ratio of electrodes to microchannels. Manufactured MNIs were tested in a rat sciatic nerve transection model. Following implantation nerves were allowed to regenerate for one and two months. First, suture and fibrin glue were compared as MNI fixation methods for one month, the nerve regenerated within the fibrin glue, outside the interface lumen, therefore sutures were chosen as a long term fixation method. The influence of endoneurial basement membrane protein coatings, identified previously, on nerve regeneration with MNIs was investigated. Nerves regenerated through the MNIs over two months and began to reinnervate the distal limb. Improvements in the sciatic function index were observed over two months, with no significant differences between protein coated and control interfaces. Some weak histological evidence for the use of protein coatings was found, with axon diameters increased distal to protein coated MNIs. Electromyographic and electroneurographic recordings demonstrated similar signal amplitudes to previous studies. In order to bring the research described in this thesis to clinical practice further engineering improvements to the design and manufacture of electrodes, which utilise materials or coatings to enhance neurocompatibility, is required. Avenues for further research are discussed and additional experiments and investigations are described. By combining developments in implantable muscle and nerve interfaces with surgical techniques and improvements in neurocompatibility the promise of upper limb prosthetic control may be realised

Doctor of Philosophy

dissertationThis dissertation provides an in-depth evaluation of microstimulation of the primary visual cortex (V1) using chronically implanted Utah Electrode Arrays (UEAs) in macaque monkeys for use as a visual prosthesis. Within the scope of this dissertation are several significant contributions. First, a minimally invasive and robust device for head fixation was developed. In comparison to other available designs, this device improved long-term outcomes by providing a stronger, less invasive interface that reduced the risk of infection. This device made it possible to acquire chronic microstimulation data in macaque monkeys. It has been tested on three animals and has provided a stable interface for over two years. Second, this dissertation is the first to describe the factors influencing the performance and safety of microstimulation of V1 with the UEA. Two UEAs were implanted in V1 of two macaque monkeys, and experiments were performed several months following implantation. The electrical and recording properties of the electrodes and the high-resolution visuotopic organization of V1 were measured. In addition, threshold stimulation levels that evoked behavioural responses using single electrodes were determined. Periodic microstimulation at currents up to 96 pA did not impair the ability to record neural signals and did not affect the animal's vision where the UEAs were implanted. It was discovered, however, that microstimulation at these levels evoked behavioural responses on only 8 of 82 systematically stimulated electrodes. It was suggested that the ability to evoke behavioral responses may depend on the location of the electrode tips within the cortical layers of V1, the distance of the electrode tips to neuronal somata, and the inability of nonhuman primates to recognize and respond to a generalized set of evoked percepts. Finally, this dissertation is the first to describe the spatial and temporal characteristics of microstimulation of V1 with the UEA over chronic time periods. Two years after implantation, it was found that consistent behavioural responses could be evoked during simultaneous stimulation of multiple contiguous electrodes. Saccades to electrically-evoked targets using groups of nine electrodes showed that the animal could discriminate spatially distinct percepts with a resolution comparable to the current epiretinal prostheses. These results demonstrate chronic perceptual functionality and provide evidence for the feasibility of a UEA-based visual prosthesis for the blind