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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 (Vallone et al 2021 J. Neural Eng. 18 0460a2). 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.

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., Frontiers in Medical Technology, 3

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.

Recent studies have shown that direct nerve stimulation can be used to provide sensory feedback to hand amputees. The intensity of the elicited sensations can be modulated using the amplitude or frequency of the injected stimuli. However, a comprehensive comparison of the effects of these two encoding strategies on the amputees’ ability to control a prosthesis has not been performed. In this paper, we assessed the performance of two trans-radial amputees controlling a myoelectric hand prosthesis while receiving grip force sensory feedback encoded using either linear modulation of amplitude (LAM) or linear modulation of frequency (LFM) of direct nerve stimulation (namely, bidirectional prostheses). Both subjects achieved similar and significantly above-chance performance when they were asked to exploit LAM or LFM in different tasks. The feedbacks allowed them to discriminate, during manipulation through the robotic hand, objects of different compliances and shapes or different placements on the prosthesis. Similar high performances were obtained when they were asked to apply different levels of force in a random order on a dynamometer using LAM or LFM. In contrast, only the LAM strategy allowed the subjects to continuously modulate the grip pressure on the dynamometer. Furthermore, when long-lasting trains of stimulation were delivered, LFM strategy generated a very fast adaptation phenomenon in the subjects, which caused them to stop perceiving the restored sensations. Both encoding approaches were perceived as very different from the touch feelings of the healthy limb (natural). These results suggest that the choice of specific sensory feedback encodings can have an effect on user performance while grasping. In addition, our results invite the development of new approaches to provide more natural sensory feelings to the users, which could be addressed by a more biomimetic strategy in the future., Scientific Reports, 8, ISSN:2045-2322

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., Journal of Neural Engineering, 17 (2), ISSN:1741-2560, ISSN:1741-2552

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 during in vitro and in vivo characterization. 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.

Objective: To study motor cortex plasticity after a period of training with a new prototype of bidirectional hand prosthesis in three left trans-radial amputees, correlating these changes with the modification of Phantom Limb Pain (PLP) in the same period., Methods: Each subject underwent a brain motor mapping with Transcranial Magnetic Stimulation (TMS) and PLP evaluation with questionnaires during a six-month training with a prototype of bidirectional hand prosthesis., Results: The baseline motor maps showed in all three amputees a smaller area of muscles representation of the amputated side compared to the intact limb. After training, there was a partial reversal of the baseline asymmetry. The two subjects affected by PLP experienced a statistically significant reduction of pain., Conclusions: Two apparently opposite findings, the invasion of the "deafferented" cortex by neighbouring areas and the "persistence" of neural structures after amputation, could vary according to different target used for measurement. Our results do not support a correlation between PLP and motor cortical changes., Significance: The selection of the target and of the task is essential for studies investigating motor brain plasticity. This study boosts against a direct and unique role of motor cortical changes on PLP genesis. (C) 2020 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.

Direct stimulation of peripheral nerves can successfully provide sensory feedback to amputees while using hand prostheses. Recent clinical studies have addressed this important limitation of current prostheses solutions using different implantable electrode concepts. Longevity of the electrodes is key to success. We have improved the long-term stability of the polyimide-based transverse intrafascicular multichannel electrode (TIME) that showed promising performance in clinical trials by integration of silicon carbide adhesion layers. The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. Here, we present the characterization of the electrical properties of the thin-film metallization as well as material status post explantationem for the first time. The TIMEs showed reliable performance in terms of eliciting sensation and stayed within the electrochemical safe limits maintaining a good working range with respect to amplitude modulation. After termination of the trials and explantation of the probes, no signs of corrosion or morphological change to the thin-film metallization was observed by means of electrochemical and optical analysis. Damage to the metallization was assigned exclusively to mechanical impacts during explantation and handling. The results indicate that thin-film metallization on polymer substrates is applicable in permanent implant system.

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.

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).

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.

International audience; ObjectiveThe 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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.SignificanceSomatosensory 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.

Summary 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 Download : Download video (33MB)

Objective: To systematically review the psychometric properties and clinical utility of measures of sensation in neurological conditions to inform future research studies and clinical practice. Data sources: Electronic databases (MEDLINE, CINAHL, EMBASE and AMED) were searched from their inception to December 2010. Review methods: Search terms were used to identify articles that investigated any sensory measures in neurological conditions. Data about their psychometric properties and clinical utility were extracted and analyzed independently. The strength of the psychometric properties and clinical utility were assessed following recommendations. 1 Results: Sixteen sensory measures were identified. Inter-rater reliability and redundancy of testing protocols are particular issues for this area of assessment. Eleven were rejected because they were not available for a researcher or clinician to use. Of the remaining five measures, the Erasmus MC modifications of the Nottingham Sensory Assessment and the Sensory section of the Fugl–Meyer Assessment showed the best balance of clinical utility and psychometric properties. Conclusion: Many measures of sensory impairment have been used in research but few have been fully developed to produce robust data and be easy to use. At present, the sensory section of the Fugl–Meyer Assessment and the Erasmus MC modifications of the Nottingham Sensory Assessment show the most effective balance of usability and robustness, when delivered according to the operating instructions.

A major goal of neuroprosthetics is to design artificial limbs that are experienced (‘embodied’) like real limbs. However, despite important technological advances, this goal has not been reached and prosthesis embodiment is still very limited. Differently from our physical body, current bionic limbs do not provide the continuous multisensory feedback required for a limb to be experienced as one’s own. Here, we present a novel neuroprosthetic approach that combines peripheral neurotactile stimulation—inducing tactile sensation on the missing limb—and immersive digital technology—providing visual illumination of the prosthetic hand. We tested whether coherent multisensory visuo-tactile neural stimulation (VTNS)1 induced higher prosthesis embodiment and reduced the distorted perception of the phantom limb (telescoping, ie, the phantom limb is perceived as shorter than the intact limb). Patient 1 and patient 2 are transradial left forearm chronic amputees, who suffered upper limb telescoping. Patients were implanted with transverse intrafascicular multichannel electrodes (TIMEs), which induced the sensation of a vibration in a circumscribed skin region of the finger 2 via medial nerve stimulation in patient 1 (online supplementary figure 1A) and in a skin region of finger 5 via ulnar nerve stimulation in patient 2 (online supplementary figure 1B and material 1). Neurotactile stimulation2 was coupled with automatised visual illumination of a skin region on the patient’s prosthetic hand that corresponded to the somatotopic location of touch sensations experienced on the phantom hand (VTNS; online supplementary video 1, online supplementary figure 1, online supplementary material 1). VTNS was administered in two conditions, either with synchronous visual and neurotactile stimulation or in a control condition of asynchronous stimulation (1.5–2.5s delay). ### Supplementary data [jnnp-2018-318570-supp1.pdf] ### Supplementary video [jnnp-2018-318570-supp1.mp4] Prosthesis embodiment was measured via a questionnaire, whereas changes in phantom limb perception were tested via a body landmark task where patients indicated the perceived position of different parts of the phantom limb …

High neural selectivity is an important indicator of how well a neural electrode will perform in a clinical setup. Among other factors, neural selectivity of an electrode strongly depends on its implant location. Today, the neural selectivity is evaluated by performing animal experiments and consequent offline analysis. The most selective electrode implant location is therefore difficult to predict. Here we developed a software tool to characterize neural electrodes' selectivity in real-time, in vivo. A graphical user interface (GUI) allows controlling the software tool. Our tool is adapted to use a commercially available neurostimulator (TDT, Tucker-Davis Technologies, US) but can be easily adapted to other systems. Electromyographic ( EMG) recruitment curves and selectivity indexes (SIs) were obtained stimulating the sciatic nerve of four pigs. The functionality, execution time of stimulation and correct SI calculation by the software-platform were evaluated by testing twelve intraneural electrodes.

Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object’s size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.

Current myoelectric prostheses allow upper-limb amputees to regain voluntary motor control of their artificial limb by exploiting residual muscle function in the forearm1. However, the over-reliance on visual cues resulting from a lack of sensory feedback is a common complaint2,3. Recently, several groups have provided tactile feedback in upper-limb amputees by using implanted electrodes4,5,6,7,8, surface nerve stimulation9,10 or sensory substitution11,12. These approaches have led to improved function and prosthesis embodiment4,5,6,7,13,14. 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 trans-radial amputees to regain high and close-to-natural remapped proprioceptive acuity, with a median joint angle reproduction accuracy of 9.1° and a median threshold to detection of passive movements of 9.5°, which was compatible with results obtained in healthy subjects15,16,17. The simultaneous delivery of position information and somatotopic tactile feedback allowed both amputees to discriminate object size and compliance with high levels of accuracy (75.5%). These results demonstrate that touch information delivered via somatotopic neural stimulation and position information delivered via sensory substitution can be exploited simultaneously and efficiently by trans-radial amputees. This study paves the way towards more sophisticated bidirectional bionic limbs conveying rich, multimodal sensations.

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., Brain and Behavior, 10 (11), ISSN:2162-3279

The modulation of the cervical vagus nerve (VN) using neural electrodes has shown great potential to treat cardiovascular, inflammatory, intestinal, or respiratory dysfunctions. Intraneural electrodes have shown great potentials for other neuroprosthetic applications. Therefore, their use for VN modulation could have great potential. Here we optimized an intraneural electrode originally developed for use in lower limb amputees. Based on histological data from the VN of 100 histological sections we adapted and optimized the dimensions of the Quick-to-implant peripheral neural electrode (Q-PINE). Parts of the Q- PINE were substituted to increase biocompatibility. The platinum-iridium (Pt/Ir) wires were substituted with a polyimide thin-film structure to optimize the electrodes' impedance. Mechanical and electrochemical characterization was performed to exclude negative alterations resulting from the design and material changes. The dimensional adaptation and material substitutions of the Q- PINE did not alter its mechanical or electrochemical properties. The tfQPINE shows promising results for the successful application with the VN.

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.