Cardiovascular Response to Intraneural Right Vagus Nerve Stimulation in Adult Minipig.

OBJECTIVE: This study explored intraneural stimulation of the right thoracic vagus nerve (VN) in sexually mature male minipigs to modulate safe heart rate and blood pressure response. MATERIAL AND METHODS: We employed an intraneural electrode designed for the VN of pigs to perform VN stimulation (VNS). This was delivered using different numbers of contacts on the electrode and different stimulation parameters (amplitude, frequency, and pulse width), identifying the most suitable stimulation configuration. All the parameter ranges had been selected from a computational cardiovascular system model. RESULTS: Clinically relevant responses were observed when stimulating with low current intensities and relatively low frequencies delivered with a single contact. Selecting a biphasic, charge-balanced square wave for VNS with a current amplitude of 500 µA, frequency of 10 Hz, and pulse width of 200 µs, we obtained heart rate reduction of 7.67 ± 5.19 beats per minute, systolic pressure reduction of 5.75 ± 2.59 mmHg, and diastolic pressure reduction of 3.39 ± 1.44 mmHg. CONCLUSION: Heart rate modulation was obtained without inducing any observable adverse effects, underlining the high selectivity of the intraneural approach.

Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.

OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.

Sensitivity to temporal parameters of intraneural tactile sensory feedback.

BACKGROUND: Recent studies have shown that neural stimulation can be used to provide artificial sensory feedback to amputees eliciting sensations referred on the amputated hand. The temporal properties of the neural stimulation modulate aspects of evoked sensations that can be exploited in a bidirectional hand prosthesis. METHODS: We previously collected evidence that the derivative of the amplitude of the stimulation (intra-digit temporal dynamics) allows subjects to recognize object compliance and that the time delay among stimuli injected through electrodes implanted in different nerves (inter-digit temporal distance) allows to recognize object shapes. Nevertheless, a detailed characterization of the subjects' sensitivity to variations of intra-digit temporal dynamic and inter-digit temporal distance of the intraneural tactile feedback has not been executed. An exhaustive understanding of the overall potentials and limits of intraneural stimulation to deliver sensory feedback is of paramount importance to bring this approach closer and closer to the natural situation. To this aim, here we asked two trans-radial amputees to identify stimuli with different temporal characteristics delivered to the same active site (intra-digit temporal Dynamic Recognition (DR)) or between two active sites (inter-digit Temporal distance Recognition (TR)). Finally, we compared the results achieved for (simulated) TR with conceptually similar experiments with real objects with one subject. RESULTS: We found that the subjects were able to identify stimuli with temporal differences (perceptual thresholds) larger than 0.25 s for DR and larger than 0.125 s for TR, respectively. Moreover, we also found no statistically significant differences when the subjects were asked to identify three objects during simulated 'open-loop' TR experiments or real 'closed-loop' tests while controlling robotic hand. CONCLUSIONS: This study is a new step towards a more detailed analysis of the overall potentials and limits of intraneural sensory feedback. A full characterization is necessary to develop more advanced prostheses capable of restoring all lost functions and of being perceived more as a natural limb by users.

A fast and accurate learning-based decoding algorithm for the classification of cardiovascular and respiratory challenges using intraneural electrodes in the pig vagus nerve.

Bioelectronic medicine is a new approach for developing closed-loop neuromodulation protocols on the peripheral nervous system (PNS) to treat a wide range of disorders currently treated with pharmacological approaches. Algorithms need to have low computational cost in order to acquire, process and model data for the modulation of the PNS in real time. Here, we present a fast learning-based decoding algorithm for the classification of cardiovascular and respiratory functional alterations (i.e., challenges) by using neural signals recorded from intraneural electrodes implanted in the vagus nerve of 5 pigs. Our algorithm relies on 9 handcrafted features, extracted following signal temporal windowing, and a multi-layer perceptron (MLP) for feature classification. We achieved fast and accurate classification of the challenges, with a computational time for feature extraction and prediction lower than 1.5 ms. The MLP achieved a balanced accuracy higher than 80 % for all recordings. Our algorithm could represent a step towards the development of a closed-loop system based on a single intraneural interface with both the potential of real time classification and selective modulation of the PNS.

A lightweight learning-based decoding algorithm for intraneural vagus nerve activity classification in pigs.

Objective.Bioelectronic medicine is an emerging field that aims at developing closed-loop neuromodulation protocols for the autonomic nervous system (ANS) to treat a wide range of disorders. When designing a closed-loop protocol for real time modulation of the ANS, the computational execution time and the memory and power demands of the decoding step are important factors to consider. In the context of cardiovascular and respiratory diseases, these requirements may partially explain why closed-loop clinical neuromodulation protocols that adapt stimulation parameters on patient's clinical characteristics are currently missing.Approach.Here, we developed a lightweight learning-based decoder for the classification of cardiovascular and respiratory functional challenges from neural signals acquired through intraneural electrodes implanted in the cervical vagus nerve (VN) of five anaesthetized pigs. Our algorithm is based on signal temporal windowing, nine handcrafted features, and random forest (RF) model for classification. Temporal windowing ranging from 50 ms to 1 s, compatible in duration with cardio-respiratory dynamics, was applied to the data in order to mimic a pseudo real-time scenario.Main results.We were able to achieve high balanced accuracy (BA) values over the whole range of temporal windowing duration. We identified 500 ms as the optimal temporal windowing duration for both BA values and computational execution time processing, achieving more than 86% for BA and a computational execution time of only ∼6.8 ms. Our algorithm outperformed in terms of BA and computational execution time a state of the art decoding algorithm tested on the same dataset (Valloneet al2021J. Neural Eng.180460a2). We found that RF outperformed other machine learning models such as support vector machines, K-nearest neighbors, and multi-layer perceptrons.Significance.Our approach could represent an important step towards the implementation of a closed-loop neuromodulation protocol relying on a single intraneural interface able to perform real-time decoding tasks and selective modulation of the VN.

Corrigendum: A Psychometric Platform to Collect Somatosensory Sensations for Neuroprosthetic Use.

[This corrects the article DOI: 10.3389/fmedt.2021.619280.].

Bioelectronic medicine for the autonomic nervous system: clinical applications and perspectives.

Bioelectronic medicine (BM) is an emerging new approach for developing novel neuromodulation therapies for pathologies that have been previously treated with pharmacological approaches. In this review, we will focus on the neuromodulation of autonomic nervous system (ANS) activity with implantable devices, a field of BM that has already demonstrated the ability to treat a variety of conditions, from inflammation to metabolic and cognitive disorders. Recent discoveries about immune responses to ANS stimulation are the laying foundation for a new field holding great potential for medical advancement and therapies and involving an increasing number of research groups around the world, with funding from international public agencies and private investors. Here, we summarize the current achievements and future perspectives for clinical applications of neural decoding and stimulation of the ANS. First, we present the main clinical results achieved so far by different BM approaches and discuss the challenges encountered in fully exploiting the potential of neuromodulatory strategies. Then, we present current preclinical studies aimed at overcoming the present limitations by looking for optimal anatomical targets, developing novel neural interface technology, and conceiving more efficient signal processing strategies. Finally, we explore the prospects for translating these advancements into clinical practice.

Computational approaches to decode grasping force and velocity level in upper-limb amputee from intraneural peripheral signals.

Objective. Recent results have shown the potentials of neural interfaces to provide sensory feedback to subjects with limb amputation increasing prosthesis usability. However, their advantages for decoding motor control signals over current methods based on electromyography (EMG) are still debated. In this study we compared a standard EMG-based method with approaches that use peripheral intraneural data to infer distinct levels of grasping force and velocity in a trans-radial amputee.Approach. Surface EMG (three channels) and intraneural signals (collected with transverse intrafascicular multichannel electrodes, TIMEs, 56 channels) were simultaneously recorded during the amputee's intended grasping movements. We sorted single unit activity (SUA) from each neural signal and then we identified the most informative units. EMG envelopes were extracted from the recorded EMG signals. A reference support vector machine (SVM) classifier was used to map EMG envelopes into desired force and velocity levels. Two decoding approaches using SUA were then tested and compared to the EMG-based reference classifier: (a) SVM classification of firing rates into desired force and velocity levels; (b) reconstruction of covariates (the grasp cue level or EMG envelopes) from neural data and use of covariates for classification into desired force and velocity levels.Main results.Using EMG envelopes as reconstructed covariates from SUA yielded significantly better results than the other approaches tested, with performance similar to that of the EMG-based reference classifier, and stable over three different recording days. Of the two reconstruction algorithms used in this approach, a linear Kalman filter and a nonlinear point process adaptive filter, the nonlinear filter gave better results.Significance.This study presented a new effective approach for decoding grasping force and velocity from peripheral intraneural signals in a trans-radial amputee, which relies on using SUA to reconstruct EMG envelopes. Being dependent on EMG recordings only for the training phase, this approach can fully exploit the advantages of implanted neural interfaces and potentially overcome, in the medium to long term, current state-of-the-art methods. (Clinical trial's registration number: NCT02848846).

Simultaneous decoding of cardiovascular and respiratory functional changes from pig intraneural vagus nerve signals.

Objective. Bioelectronic medicine is opening new perspectives for the treatment of some major chronic diseases through the physical modulation of autonomic nervous system activity. Being the main peripheral route for electrical signals between central nervous system and visceral organs, the vagus nerve (VN) is one of the most promising targets. Closed-loop VN stimulation (VNS) would be crucial to increase effectiveness of this approach. Therefore, the extrapolation of useful physiological information from VN electrical activity would represent an invaluable source for single-target applications. Here, we present an advanced decoding algorithm novel to VN studies and properly detecting different functional changes from VN signals.Approach. VN signals were recorded using intraneural electrodes in anaesthetized pigs during cardiovascular and respiratory challenges mimicking increases in arterial blood pressure, tidal volume and respiratory rate. We developed a decoding algorithm that combines discrete wavelet transformation, principal component analysis, and ensemble learning made of classification trees.Main results. The new decoding algorithm robustly achieved high accuracy levels in identifying different functional changes and discriminating among them. Interestingly our findings suggest that electrodes positioning plays an important role on decoding performances. We also introduced a new index for the characterization of recording and decoding performance of neural interfaces. Finally, by combining an anatomically validated hybrid neural model and discrimination analysis, we provided new evidence suggesting a functional topographical organization of VN fascicles.Significance. This study represents an important step towards the comprehension of VN signaling, paving the way for the development of effective closed-loop VNS systems.

A Psychometric Platform to Collect Somatosensory Sensations for Neuroprosthetic Use.

Somatosensory neuroprostheses exploit invasive and non-invasive feedback technologies to restore sensorimotor functions lost to disease or trauma. These devices use electrical stimulation to communicate sensory information to the brain. A sensation characterization procedure is thus necessary to determine the appropriate stimulation parameters and to establish a clear personalized map of the sensations that can be restored. Several questionnaires have been described in the literature to collect the quality, type, location, and intensity of the evoked sensations, but there is still no standard psychometric platform. Here, we propose a new psychometric system containing previously validated questionnaires on evoked sensations, which can be applied to any kind of somatosensory neuroprosthesis. The platform collects stimulation parameters used to elicit sensations and records subjects' percepts in terms of sensation location, type, quality, perceptual threshold, and intensity. It further collects data using standardized assessment questionnaires and scales, performs measurements over time, and collects phantom limb pain syndrome data. The psychometric platform is user-friendly and provides clinicians with all the information needed to assess the sensory feedback. The psychometric platform was validated with three trans-radial amputees. The platform was used to assess intraneural sensory feedback provided through implanted peripheral nerve interfaces. The proposed platform could act as a new standardized assessment toolbox to homogenize the reporting of results obtained with different technologies in the field of somatosensory neuroprosthetics.

Decoding of grasping tasks from intraneural recordings in trans-radial amputee.

OBJECTIVE: A major challenge in neuroprosthetics is the restoration of sensory-motor hand functions in upper-limb amputees. Neuroprostheses based on the direct re-connection of the peripheral nerves may be an interesting approach for re-establishing the natural and effective bidirectional control of hand prostheses. Recent results have shown that transverse intrafascicular multi-channel electrodes (TIMEs) can restore natural and sophisticated sensory feedback. However, the potential of using TIME-recorded motor intraneural signals to decode grasping tasks has not as yet been explored. APPROACH: In this study, we show that several hand-movement intentions can be decoded from intraneural signals recorded using four TIMEs implanted in the median and ulnar nerves of an upper limb amputee. Experimental sessions were performed over a week, from day 16 to day 23 after the surgical operation. Intraneural activity was recorded during several hand motor tasks imagined by the subject and processed offline. MAIN RESULTS: We obtained a very high decoding accuracy considering 11 class states (up to 83%). These results confirm that neural signals recorded by multi-channel intraneural electrodes can be used to decode several movement intentions with high accuracy. Moreover, we were able to use same TIME channels for decoding over one week within the first month, even if the stability has to be confirmed during long-term experiments. SIGNIFICANCE: Therefore, TIMEs could be used in the future to achieve a complete bidirectional approach exploiting neural pathways, to make a more natural and intuitive new generation of hand prostheses that have a closer resemblance to a healthy hand.

Q-PINE: A quick to implant peripheral intraneural electrode.

Objective. The implantation of intraneural electrodes in amputees has been observed to be effective in providing subjects with sensory feedback. However, this implantation is challenging and time consuming. Surgeons must be especially trained to execute the implantation. Therefore, we aimed at developing a novel peripheral intraneural electrode and insertion mechanism, which could drastically reduce the overall implantation time while achieving a high neural selectivity.Approach.A new insertion method based on hollow microneedles was developed to realize the prompt and effective simultaneous implantation of up to 14 active sites in a transversal manner. Each needle guided two Pt/Ir microwires through the nervous tissue. After the insertion, the microneedles were released, leaving behind the microwires. Each microwire had one active site, which was coated with poly-3,4-ethylenedioxythiophene (PEDOT) to enhance the electrochemical properties. The active sites were characterized by evaluating the impedance, charge storage capacity, and maximum injectable charge. Twelve quick to implant peripheral intraneural electrodes (Q-PINEs) were implanted in four pig sciatic nerves to evaluate the implantation time and neural selectivity. We compared the stimulation of the sciatic nerve with that of its branches.Main results. The average surgical access time was 23 min. The insertion time for 12 electrodes was 6.7 min (std. ±1.6 min). The overall implantation time was reduced by 40.3 min compared to the previously reported values. The Q-PINE system demonstrated a satisfactory performance duringin vitroandin vivocharacterization. The electrochemical results showed that the PEDOT coating successfully increased the electrochemical parameters of the active sites.Significance.With an average impedance of 1.7 kΩ, a maximum charge level of 76.2 nC could be achieved per active site. EMG recruitment curves showed that 46% of the active sites exhibited selective stimulation of four out of six muscles. The histological analysis indicated that the microwires successfully penetrated the nerve and single fascicles.

Hand Control With Invasive Feedback Is Not Impaired by Increased Cognitive Load.

Recent experiments have shown that neural stimulation can successfully restore sensory feedback in upper-limb amputees improving their ability to control the prosthesis. However, the potential advantages of invasive sensory feedback with respect to non-invasive solutions have not been yet identified. Our hypothesis was that a difference would appear when the subject cannot focus all the attention to the use of the prosthesis, but some additional activities require his/her cognitive attention, which is a quite common situation in real-life conditions. To verify this hypothesis, we asked a trans-radial amputee, equipped with a bidirectional hand prosthesis, to perform motor tasks also in combination with a cognitive task. Sensory feedback was provided via intraneural (invasive) or electro-tactile (non-invasive) stimulation. We collected also data related to self-confidence. While both approaches were able to significantly improve the motor performance of the subject when no additional cognitive effort was asked, the manual accuracy was not affected by the cognitive task only when intraneural feedback was provided. The highest self-confidence was obtained when intraneural sensory feedback was provided. Our findings show that intraneural sensory feedback is more robust to dual tasks than non-invasive feedback. This is the first direct comparison between invasive and non-invasive approaches for restoring sensory feedback and it could suggest an advantage of using invasive solutions. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02848846.

Brain reactions to the use of sensorized hand prosthesis in amputees.

OBJECTIVE: We investigated for the first time the presence of chronic changes in the functional organization of sensorimotor brain areas induced by prolonged training with a bidirectional hand prosthesis. METHODS: A multimodal neurophysiological and neuroimaging evaluation of brain functional changes occurring during training in five consecutive amputees participating to experimental trials with robotic hands over a period of 10 years was carried out. In particular, modifications to the functional anatomy of sensorimotor brain areas under resting conditions were explored in order to check for eventual changes with respect to baseline. RESULTS: Full evidence is provided to demonstrate brain functional changes, and some of them in both the hemispheres and others restricted to the hemisphere contralateral to the amputation/prosthetic hand. CONCLUSIONS: The study describes a unique experimental experience showing that brain reactions to the prolonged use of an artificial hand can be tracked for a tailored approach to a fully embedded artificial upper limb for future chronic uses in daily activities.

Morphological Neural Computation Restores Discrimination of Naturalistic Textures in Trans-radial Amputees.

Humans rely on their sense of touch to interact with the environment. Thus, restoring lost tactile sensory capabilities in amputees would advance their quality of life. In particular, texture discrimination is an important component for the interaction with the environment, but its restoration in amputees has been so far limited to simplified gratings. Here we show that naturalistic textures can be discriminated by trans-radial amputees using intraneural peripheral stimulation and tactile sensors located close to the outer layer of the artificial skin. These sensors exploit the morphological neural computation (MNC) approach, i.e., the embodiment of neural computational functions into the physical structure of the device, encoding normal and shear stress to guarantee a faithful neural temporal representation of stimulus spatial structure. Two trans-radial amputees successfully discriminated naturalistic textures via the MNC-based tactile feedback. The results also allowed to shed light on the relevance of spike temporal encoding in the mechanisms used to discriminate naturalistic textures. Our findings pave the way to the development of more natural bionic limbs.

Intraneural sensory feedback restores grip force control and motor coordination while using a prosthetic hand.

OBJECTIVE: Tactile afferents in the human hand provide fundamental information about hand-environment interactions, which is used by the brain to adapt the motor output to the physical properties of the object being manipulated. A hand amputation disrupts both afferent and efferent pathways from/to the hand, completely invalidating the individual's motor repertoire. Although motor functions may be partially recovered by using a myoelectric prosthesis, providing functionally effective sensory feedback to users of prosthetics is a largely unsolved challenge. While past studies using invasive stimulation suggested that sensory feedback may help in handling fragile objects, none explored the underpinning, relearned, motor coordination during grasping. In this study, we aimed at showing for the first time that intraneural sensory feedback of the grip force (GF) improves the sensorimotor control of a transradial amputee controlling a myoelectric prosthesis. APPROACH: We performed a longitudinal study testing a single subject (clinical trial registration number NCT02848846). A stacking cups test (CUP) performed over two weeks aimed at measuring the subject's ability to finely regulate the GF applied with the prosthesis. A pick and lift test (PLT), performed at the end of the study, measured the level of motor coordination, and whether the subject transferred the motor skills learned in the CUP to an alien task. MAIN RESULTS: The results show that intraneural sensory feedback increases the subject's ability in regulating the GF and allows for improved performance over time. Additionally, the PLT demonstrated that the subject was able to generalize and transfer her manipulation skills to an unknown task and to improve her motor coordination. SIGNIFICANCE: Our findings suggest that intraneural sensory feedback holds the potential of restoring functionally effective tactile feedback. This opens up new possibilities to improve the quality of life of amputees using a neural prosthesis.

A closed-loop hand prosthesis with simultaneous intraneural tactile and position feedback.

Current myoelectric prostheses allow transradial amputees to regain voluntary motor control of their artificial limb by exploiting residual muscle function in the forearm. However, the overreliance on visual cues resulting from a lack of sensory feedback is a common complaint. Recently, several groups have provided tactile feedback in upper limb amputees using implanted electrodes, surface nerve stimulation, or sensory substitution. These approaches have led to improved function and prosthesis embodiment. Nevertheless, the provided information remains limited to a subset of the rich sensory cues available to healthy individuals. More specifically, proprioception, the sense of limb position and movement, is predominantly absent from current systems. Here, we show that sensory substitution based on intraneural stimulation can deliver position feedback in real time and in conjunction with somatotopic tactile feedback. This approach allowed two transradial amputees to regain high and close-to-natural remapped proprioceptive acuity, with a median joint angle reproduction precision of 9.1° and a median threshold to detection of passive movements of 9.5°, which was comparable with results obtained in healthy participants. The simultaneous delivery of position information and somatotopic tactile feedback allowed both amputees to discriminate the size and compliance of four objects with high levels of performance (75.5%). These results demonstrate that tactile information delivered via somatotopic neural stimulation and position information delivered via sensory substitution can be exploited simultaneously and efficiently by transradial amputees. This study paves a way to more sophisticated bidirectional bionic limbs conveying richer, multimodal sensations.

Biomimetic Intraneural Sensory Feedback Enhances Sensation Naturalness, Tactile Sensitivity, and Manual Dexterity in a Bidirectional Prosthesis.

Peripheral intraneural stimulation can provide tactile information to amputees. However, efforts are still necessary to identify encoding strategy eliciting percepts that are felt as both natural and effective for prosthesis control. Here we compared the naturalness and efficacy of different encoding strategies to deliver neural stimulation to trans-radial amputees implanted with intraneural electrodes. Biomimetic frequency modulation was perceived as more natural, while amplitude modulation enabled better performance in tasks requiring fine identification of the applied force. Notably, the optimal combination of naturalness and sensitivity of the tactile feedback can be achieved with "hybrid" encoding strategies based on simultaneous biomimetic frequency and amplitude neuromodulation. These strategies improved the gross manual dexterity of the subjects during functional task while maintaining high levels of manual accuracy. They also improved prosthesis embodiment, reducing abnormal phantom limb perceptions ("telescoping effect"). Hybrid strategies are able to provide highly sensitive and natural percepts and should be preferred. VIDEO ABSTRACT.

Phantom somatosensory evoked potentials following selective intraneural electrical stimulation in two amputees.

OBJECTIVE: The aim of the paper is to objectively demonstrate that amputees implanted with intraneural interfaces are truly able to feel a sensation in the phantom hand by recording "phantom" somatosensory evoked potentials from the corresponding brain areas. METHODS: We implanted four transverse intrafascicular multichannel electrodes, available with percutaneous connections to a multichannel electrical stimulator, in the median and ulnar nerves of two left trans-radial amputees. Two channels of the implants that were able to elicit sensations during intraneural nerve stimulation were chosen, in both patients, for recording somatosensory evoked potentials. RESULTS: We recorded reproducible evoked responses by stimulating the median and the ulnar nerves in both cases. Latencies were in accordance with the arrival of somatosensory information to the primary somatosensory cortex. CONCLUSION: Our results provide evidence that sensations generated by intraneural stimulation are truly perceived by amputees and located in the phantom hand. Moreover, our results strongly suggest that sensations perceived in different parts of the phantom hand result in different evoked responses. SIGNIFICANCE: Somatosensory evoked potentials obtained by selective intraneural electrical stimulation in amputee patients are a useful tool to provide an objective demonstration of somatosensory feedback in new generation bidirectional prostheses.