Electrical Stimulation of Regenerative Peripheral Nerve Interfaces (RPNIs) Induces Referred Sensations in People With Upper Limb Loss.

Individuals with upper limb loss lack sensation of the missing hand, which can negatively impact their daily function. Several groups have attempted to restore this sensation through electrical stimulation of residual nerves. The purpose of this study was to explore the utility of regenerative peripheral nerve interfaces (RPNIs) in eliciting referred sensation. In four participants with upper limb loss, we characterized the quality and location of sensation elicited through electrical stimulation of RPNIs over time. We also measured functional stimulation ranges (sensory perception and discomfort thresholds), sensitivity to changes in stimulation amplitude, and ability to differentiate objects of different stiffness and sizes. Over a period of up to 54 months, stimulation of RPNIs elicited sensations that were consistent in quality (e.g. tingling, kinesthesia) and were perceived in the missing hand and forearm. The location of elicited sensation was partially-stable to stable in 13 of 14 RPNIs. For 5 of 7 RPNIs tested, participants demonstrated a sensitivity to changes in stimulation amplitude, with an average just noticeable difference of 45 nC. In a case study, one participant was provided RPNI stimulation proportional to prosthetic grip force. She identified four objects of different sizes and stiffness with 56% accuracy with stimulation alone and 100% accuracy when stimulation was combined with visual feedback of hand position. Collectively, these experiments suggest that RPNIs have the potential to be used in future bi-directional prosthetic systems.

Long-term upper-extremity prosthetic control using regenerative peripheral nerve interfaces and implanted EMG electrodes.

Objective.Extracting signals directly from the motor system poses challenges in obtaining both high amplitude and sustainable signals for upper-limb neuroprosthetic control. To translate neural interfaces into the clinical space, these interfaces must provide consistent signals and prosthetic performance.Approach.Previously, we have demonstrated that the Regenerative Peripheral Nerve Interface (RPNI) is a biologically stable, bioamplifier of efferent motor action potentials. Here, we assessed the signal reliability from electrodes surgically implanted in RPNIs and residual innervated muscles in humans for long-term prosthetic control.Main results.RPNI signal quality, measured as signal-to-noise ratio, remained greater than 15 for up to 276 and 1054 d in participant 1 (P1), and participant 2 (P2), respectively. Electromyography from both RPNIs and residual muscles was used to decode finger and grasp movements. Though signal amplitude varied between sessions, P2 maintained real-time prosthetic performance above 94% accuracy for 604 d without recalibration. Additionally, P2 completed a real-world multi-sequence coffee task with 99% accuracy for 611 d without recalibration.Significance.This study demonstrates the potential of RPNIs and implanted EMG electrodes as a long-term interface for enhanced prosthetic control.

Upper limb prostheses: bridging the sensory gap.

Replacing human hand function with prostheses goes far beyond only recreating muscle movement with feedforward motor control. Natural sensory feedback is pivotal for fine dexterous control and finding both engineering and surgical solutions to replace this complex biological function is imperative to achieve prosthetic hand function that matches the human hand. This review outlines the nature of the problems underlying sensory restitution, the engineering methods that attempt to address this deficit and the surgical techniques that have been developed to integrate advanced neural interfaces with biological systems. Currently, there is no single solution to restore sensory feedback. Rather, encouraging animal models and early human studies have demonstrated that some elements of sensation can be restored to improve prosthetic control. However, these techniques are limited to highly specialized institutions and much further work is required to reproduce the results achieved, with the goal of increasing availability of advanced closed loop prostheses that allow sensory feedback to inform more precise feedforward control movements and increase functionality.

Use of regenerative peripheral nerve interfaces and intramuscular electrodes to improve prosthetic grasp selection: a case study.

Objective.Advanced myoelectric hands enable users to select from multiple functional grasps. Current methods for controlling these hands are unintuitive and require frequent recalibration. This case study assessed the performance of tasks involving grasp selection, object interaction, and dynamic postural changes using intramuscular electrodes with regenerative peripheral nerve interfaces (RPNIs) and residual muscles.Approach.One female with unilateral transradial amputation participated in a series of experiments to compare the performance of grasp selection controllers with RPNIs and intramuscular control signals with controllers using surface electrodes. These experiments included a virtual grasp-matching task with and without a concurrent cognitive task and physical tasks with a prosthesis including standardized functional assessments and a functional assessment where the individual made a cup of coffee ('Coffee Task') that required grasp transitions.Main results.In the virtual environment, the participant was able to select between four functional grasps with higher accuracy using the RPNI controller (92.5%) compared to surface controllers (81.9%). With the concurrent cognitive task, performance of the virtual task was more consistent with RPNI controllers (reduced accuracy by 1.1%) compared to with surface controllers (4.8%). When RPNI signals were excluded from the controller with intramuscular electromyography (i.e. residual muscles only), grasp selection accuracy decreased by up to 24%. The participant completed the Coffee Task with 11.7% longer completion time with the surface controller than with the RPNI controller. She also completed the Coffee Task with 11 fewer transition errors out of a maximum of 25 total errors when using the RPNI controller compared to surface controller.Significance.The use of RPNI signals in concert with residual muscles and intramuscular electrodes can improve grasp selection accuracy in both virtual and physical environments. This approach yielded consistent performance without recalibration needs while reducing cognitive load associated with pattern recognition for myoelectric control (clinical trial registration number NCT03260400).

Restoration of Proprioceptive and Cutaneous Sensation Using Regenerative Peripheral Nerve Interfaces in Humans with Upper Limb Amputations.

SUMMARY: Without meaningful and intuitive sensory feedback, even the most advanced prosthetic limbs remain insensate and impose an enormous cognitive burden during use. The regenerative peripheral nerve interface can serve as a novel bidirectional motor and sensory neuroprosthetic interface. In previous human studies, regenerative peripheral nerve interfaces demonstrated stable high-amplitude motor electromyography signals with excellent signal-to-noise ratio for prosthetic control. In addition, they can treat and prevent postamputation pain by mitigating neuroma formation. In this study, the authors investigated whether electrical stimulation applied to regenerative peripheral nerve interfaces could produce appreciable proprioceptive and/or tactile sensations in two participants with upper limb amputations. Stimulation of the interfaces resulted in both participants reporting proprioceptive sensations in the phantom hand. Specifically, stimulation of participant 1's median nerve regenerative peripheral nerve interface activated a flexion sensation in the thumb or index finger, whereas stimulation of the ulnar nerve interface evoked a flexion sensation of the ring or small finger. Likewise, stimulation of one of participant 2's ulnar nerve interfaces produced a sensation of flexion at the ring finger distal interphalangeal joint. In addition, stimulation of participant 2's other ulnar nerve interface and the median nerve interface resulted in perceived cutaneous sensations that corresponded to each nerve's respective dermatome. These results suggest that regenerative peripheral nerve interfaces have the potential to restore proprioceptive and cutaneous sensory feedback that could significantly improve prosthesis use and embodiment.

Surgically Implanted Electrodes Enable Real-Time Finger and Grasp Pattern Recognition for Prosthetic Hands.

Currently available prosthetic hands are capable of actuating anywhere from five to 30 degrees of freedom (DOF). However, grasp control of these devices remains unintuitive and cumbersome. To address this issue, we propose directly extracting finger commands from the neuromuscular system. Two persons with transradial amputations had bipolar electrodes implanted into regenerative peripheral nerve interfaces (RPNIs) and residual innervated muscles. The implanted electrodes recorded local electromyography with large signal amplitudes. In a series of single-day experiments, participants used a high speed movement classifier to control a virtual prosthetic hand in real-time. Both participants transitioned between 10 pseudo-randomly cued individual finger and wrist postures with an average success rate of 94.7% and trial latency of 255 ms. When the set was reduced to five grasp postures, metrics improved to 100% success and 135 ms trial latency. Performance remained stable across untrained static arm positions while supporting the weight of the prosthesis. Participants also used the high speed classifier to switch between robotic prosthetic grips and complete a functional performance assessment. These results demonstrate that pattern recognition systems can use intramuscular electrodes and RPNIs for fast and accurate prosthetic grasp control.

Stimulation of zona incerta selectively modulates pain in humans.

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

A low-power band of neuronal spiking activity dominated by local single units improves the performance of brain-machine interfaces.

The large power requirement of current brain-machine interfaces is a major hindrance to their clinical translation. In basic behavioural tasks, the downsampled magnitude of the 300-1,000 Hz band of spiking activity can predict movement similarly to the threshold crossing rate (TCR) at 30 kilo-samples per second. However, the relationship between such a spiking-band power (SBP) and neural activity remains unclear, as does the capability of using the SBP to decode complicated behaviour. By using simulations of recordings of neural activity, here we show that the SBP is dominated by local single-unit spikes with spatial specificity comparable to or better than that of the TCR, and that the SBP correlates better with the firing rates of lower signal-to-noise-ratio units than the TCR. With non-human primates, in an online task involving the one-dimensional decoding of the movement of finger groups and in an offline two-dimensional cursor-control task, the SBP performed equally well or better than the TCR. The SBP may enhance the decoding performance of neural interfaces while enabling substantial cuts in power consumption.

The future of upper extremity rehabilitation robotics: research and practice.

The loss of upper limb motor function can have a devastating effect on people's lives. To restore upper limb control and functionality, researchers and clinicians have developed interfaces to interact directly with the human body's motor system. In this invited review, we aim to provide details on the peripheral nerve interfaces and brain-machine interfaces that have been developed in the past 30 years for upper extremity control, and we highlight the challenges that still remain to transition the technology into the clinical market. The findings show that peripheral nerve interfaces and brain-machine interfaces have many similar characteristics that enable them to be concurrently developed. Decoding neural information from both interfaces may lead to novel physiological models that may one day fully restore upper limb motor function for a growing patient population.

A regenerative peripheral nerve interface allows real-time control of an artificial hand in upper limb amputees.

Peripheral nerves provide a promising source of motor control signals for neuroprosthetic devices. Unfortunately, the clinical utility of current peripheral nerve interfaces is limited by signal amplitude and stability. Here, we showed that the regenerative peripheral nerve interface (RPNI) serves as a biologically stable bioamplifier of efferent motor action potentials with long-term stability in upper limb amputees. Ultrasound assessments of RPNIs revealed prominent contractions during phantom finger flexion, confirming functional reinnervation of the RPNIs in two patients. The RPNIs in two additional patients produced electromyography signals with large signal-to-noise ratios. Using these RPNI signals, subjects successfully controlled a hand prosthesis in real-time up to 300 days without control algorithm recalibration. RPNIs show potential in enhancing prosthesis control for people with upper limb loss.

Cortical Decoding of Individual Finger Group Motions Using ReFIT Kalman Filter.

Objective: To date, many brain-machine interface (BMI) studies have developed decoding algorithms for neuroprostheses that provide users with precise control of upper arm reaches with some limited grasping capabilities. However, comparatively few have focused on quantifying the performance of precise finger control. Here we expand upon this work by investigating online control of individual finger groups. Approach: We have developed a novel training manipulandum for non-human primate (NHP) studies to isolate the movements of two specific finger groups: index and middle-ring-pinkie (MRP) fingers. We use this device in combination with the ReFIT (Recalibrated Feedback Intention-Trained) Kalman filter to decode the position of each finger group during a single degree of freedom task in two rhesus macaques with Utah arrays in motor cortex. The ReFIT Kalman filter uses a two-stage training approach that improves online control of upper arm tasks with substantial reductions in orbiting time, thus making it a logical first choice for precise finger control. Results: Both animals were able to reliably acquire fingertip targets with both index and MRP fingers, which they did in blocks of finger group specific trials. Decoding from motor signals online, the ReFIT Kalman filter reliably outperformed the standard Kalman filter, measured by bit rate, across all tested finger groups and movements by 31.0 and 35.2%. These decoders were robust when the manipulandum was removed during online control. While index finger movements and middle-ring-pinkie finger movements could be differentiated from each other with 81.7% accuracy across both subjects, the linear Kalman filter was not sufficient for decoding both finger groups together due to significant unwanted movement in the stationary finger, potentially due to co-contraction. Significance: To our knowledge, this is the first systematic and biomimetic separation of digits for continuous online decoding in a NHP as well as the first demonstration of the ReFIT Kalman filter improving the performance of precise finger decoding. These results suggest that novel nonlinear approaches, apparently not necessary for center out reaches or gross hand motions, may be necessary to achieve independent and precise control of individual fingers.

Closed-Loop Continuous Hand Control via Chronic Recording of Regenerative Peripheral Nerve Interfaces.

Loss of the upper limb imposes a devastating interruption to everyday life. Full restoration of natural arm control requires the ability to simultaneously control multiple degrees of freedom of the prosthetic arm and maintain that control over an extended period of time. Current clinically available myoelectric prostheses do not provide simultaneous control or consistency for transradial amputees. To address this issue, we have implemented a standard Kalman filter for continuous hand control using intramuscular electromyography (EMG) from both regenerative peripheral nerve interfaces (RPNI) and an intact muscle within non-human primates. Seven RPNIs and one intact muscle were implanted with indwelling bipolar intramuscular electrodes in two rhesus macaques. Following recuperations, function-specific EMG signals were recorded and then fed through the Kalman filter during a hand-movement behavioral task to continuously predict the monkey's finger position. We were able to reconstruct continuous finger movement offline with an average correlation of and a root mean squared error (RMSE) of 0.12 between actual and predicted position from two macaques. This finger movement prediction was also performed in real time to enable closed-loop neural control of a virtual hand. Compared with physical hand control, neural control performance was slightly slower but maintained an average target hit success rate of 96.70%. Recalibration longevity measurements maintained consistent average correlation over time but had a significant change in RMSE ( ). Additionally, extracted single units varied in amplitude by a factor of +18.65% and -25.85% compared with its mean. This is the first demonstration of chronic indwelling electrodes being used for continuous position control via the Kalman filter. Combining these analyses with our novel peripheral nerve interface, we believe that this demonstrates an important step in providing patients with more naturalistic control of their prosthetic limbs.

Sacrificial Crystal Templated Hyaluronic Acid Hydrogels As Biomimetic 3D Tissue Scaffolds for Nerve Tissue Regeneration.

Pores are key features of natural tissues and the development of tissues scaffolds with biomimetic properties (pore structures and chemical/mechanical properties) offers a route to engineer implantable biomaterials for specific niches in the body. Here we report the use of sacrificial crystals (potassium dihydrogen phosphate or urea) that act as templates to impart pores to hyaluronic acid-based hydrogels. The mechanical properties of the hydrogels were analogous to the nervous system (in the Pascal regime), and we investigated the use of the potassium dihydrogen phosphate crystal-templated hydrogels as scaffolds for neural progenitor cells (NPCs), and the use of urea crystal-templated hydrogels as scaffolds for Schwann cells. For NPCs cultured inside the porous hydrogels, assays for the expression of Nestin are inconclusive, and assays for GFAP and BIII-tubulin expression suggest that the NPCs maintain their undifferentiated phenotype more effectively than the controls (with glial fibrillary acidic protein (GFAP) and BIII-tubulin expression at ca. 50% relative to the chemically/mechanically equivalent not templated control hydrogels). For Schwann cells cultured within these hydrogels, assays for the expression of S100 protein or Myelin basic protein confirm the expression of both proteins, albeit at lower levels on the templated hydrogels (ca. 50%) than on the chemically/mechanically equivalent not templated control hydrogels. Such sacrificial crystal templated hydrogels represent platforms for biomimetic 3D tissue scaffolds for the nervous system.

Electroactive Tissue Scaffolds with Aligned Pores as Instructive Platforms for Biomimetic Tissue Engineering.

Tissues in the body are hierarchically structured composite materials with tissue-specific chemical and topographical properties. Here we report the preparation of tissue scaffolds with macroscopic pores generated via the dissolution of a sacrificial supramolecular polymer-based crystal template (urea) from a biodegradable polymer-based scaffold (polycaprolactone, PCL). Furthermore, we report a method of aligning the supramolecular polymer-based crystals within the PCL, and that the dissolution of the sacrificial urea yields scaffolds with macroscopic pores that are aligned over long, clinically-relevant distances (i.e., centimeter scale). The pores act as topographical cues to which rat Schwann cells respond by aligning with the long axis of the pores. Generation of an interpenetrating network of polypyrrole (PPy) and poly(styrene sulfonate) (PSS) in the scaffolds yields electroactive tissue scaffolds that allow the electrical stimulation of Schwann cells cultured on the scaffolds which increases the production of nerve growth factor (NGF).