Millions of people worldwide are living with movement and sensory impairments owing to spinal cord injury, stroke and other neurological conditions. Here we report a double neural bypass (DNB), a hybrid neuroprosthetic system designed to restore both immediate and lasting gains in movement and sensation after a severe, complete spinal cord injury. The DNB links an intracortical brain-computer interface with targeted and patterned neuromodulation of the spinal cord and cortex. This allows brain signals associated with movement intention to directly control the movement of the user's own hand in real time while also promoting long-term sensorimotor recovery-even after the system is turned off. The DNB system uses recurrent artificial neural networks and reinforcement learning for fine grasp control, together with patterned spinal cord stimulation and activity-informed intracortical microstimulation ('cortical mirroring') to promote neuroplasticity and durable recovery of function. In a participant with chronic C4 sensory/C5 motor complete tetraplegia, this hybrid approach enabled recovery of functional abilities including self-feeding and manipulation of delicate objects, while also producing significant and persistent improvements in elbow flexion and wrist tactile sensation. These findings demonstrate the potential of combining a sensorimotor neuroprosthesis with targeted brain and spinal neuromodulation to restore clinically relevant function in severe paralysis.

Spinal cord injury (SCI) affects millions worldwide, with over half of all cases resulting in tetraplegia, where a complete injury can cause profound motor and sensory loss in all four limbs1. Here, we demonstrate an artificial "double neural bypass" (DNB) that integrates a bidirectional intracortical brain-computer interface with targeted spinal and brain stimulation to promote restoration of upper limb function in severe, complete paralysis. This hybrid assistive-therapeutic approach restores both hand movement and tactile sensation simultaneously via cortical mediation while promoting significant persistent sensorimotor improvements. The DNB uses a stable nested neural decoding architecture with deep reinforcement learning for fine grasping, along with patterned brain microstimulation ("cortical mirroring") and spinal cord stimulation to promote real-time and long-term functional recovery. Using the DNB, our participant with chronic C4 sensory/C5 motor complete tetraplegia regained the ability to self-feed, grasp delicate objects, and experienced persistent recovery of arm flexion and wrist tactile sensation. These findings represent a major advance in restoring meaningful function after severe, complete SCI, demonstrating that bidirectional neuroprostheses combined with targeted brain and spinal neuromodulation can drive durable sensorimotor recovery and improve independence and quality of life. ### Competing Interest Statement CEB has financial interests in Neuvotion, Inc, a medical device company developing neurotechnologies for restoring function after stroke or spinal cord injury, and Sanguistat, LLC, a company developing neurostimulation technologies to reduce blood loss; he also has multiple patents in the field of neuroprosthetics and related fields. The remaining authors declare no competing interests. ### Clinical Trial The study is registered at ClinicalTrials.gov ([NCT03680872][1]) and was conducted under an Investigational Device Exemption (IDE G170200) issued by the US Food and Drug Administration (FDA). ### Funding Statement This study was funded by New York State Department of Health Spinal Cord Injury Research Board (Contract #C37718GG) and the Feinstein Institutes for Medical Research at Northwell Health with additional support from Blackrock Neurotech and Good Shepherd Rehabilitation Network. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the Northwell Health Institutional Review Board (IRB# 17-0840) and was in accordance with the Declaration of Helsinki. The participant provided written informed consent for study participation, and permission for the use of photos, along with audio and video recordings, in which he appears. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03680872&atom=%2Fmedrxiv%2Fearly%2F2025%2F08%2F21%2F2025.08.19.25330198.atom

Long-term recovery of limb function is a significant unmet need in people with paralysis. Targeted neuromodulation through epidural stimulation of the spinal cord, when paired with intense physical therapy, has shown promising results towards restoring volitional control of the upper limb in people with tetraplegia. Non-invasive neuromodulation of the cervical spinal cord using transcutaneous spinal cord stimulation (tSCS) has shown similar improvements in upper-limb motor control rehabilitation. However, the potential rehabilitative effects of activating specific cervical spinal segments in a targeted fashion using tSCS has largely remained unexplored. We show in two individuals with SCI that tSCS of the cervical spinal cord resulted in up to 1136% increase in exerted force, with minimal physical therapy. We also show, for the first time, the effectiveness of targeted tSCS in restoring strength (407% increase) and dexterity to the digits in an individual with paralysis of the hand due to a peripheral nerve injury. Furthermore, we believe this is the first study to document a 3-point improvement in sensation in people with SCI or peripheral injury after receiving tSCS. Lastly, participant gains persisted after a one-month period void of stimulation, suggesting tSCS may lead to lasting benefits. Non-invasive targeted spinal cord stimulation shows tremendous promise as a safe and effective therapeutic approach with broad applications.### Competing Interest StatementCEB has financial interests in Sanguistat, LLC and Neuvotion, Inc. and multiple patents in the neurostimulation field. SE has financial interests in Neuvotion, Inc. The remaining authors have no conflicting financial interests.### Clinical TrialNCT04755699### Funding StatementThis study was funded through support provided by Feinstein Institutes for Medical Research at Northwell Health.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All procedures were approved by the Northwell Health Institutional Review Board.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

Long-term recovery of limb function is a significant unmet need in people with paralysis. Neuromodulation of the spinal cord through epidural stimulation, when paired with intense activity-based training, has shown promising results toward restoring volitional limb control in people with spinal cord injury. Non-invasive neuromodulation of the cervical spinal cord using transcutaneous spinal cord stimulation (tSCS) has shown similar improvements in upper-limb motor control rehabilitation. However, the motor and sensory rehabilitative effects of activating specific cervical spinal segments using tSCS have largely remained unexplored. We show in two individuals with motor-complete SCI that targeted stimulation of the cervical spinal cord resulted in up to a 1,136% increase in exerted force, with weekly activity-based training. Furthermore, this is the first study to document up to a 2-point improvement in clinical assessment of tactile sensation in SCI after receiving tSCS. Lastly, participant gains persisted after a one-month period void of stimulation, suggesting that targeted tSCS may lead to persistent recovery of motor and sensory function.

Peripheral nerve injury can lead to chronic pain, paralysis, and loss of sensation, severely affecting quality of life. Spinal cord stimulation has been used in the clinic to provide pain relief arising from peripheral nerve injuries, however, its ability to restore function after peripheral nerve injury have not been explored. Neuromodulation of the spinal cord through transcutaneous spinal cord stimulation (tSCS), when paired with activity-based training, has shown promising results towards restoring volitional limb control in people with spinal cord injury. We show, for the first time, the effectiveness of targeted tSCS in restoring strength (407% increase from 1.79 ± 1.24 N to up to 7.3 ± 0.93 N) and significantly increasing hand dexterity in an individual with paralysis due to a peripheral nerve injury (PNI). Furthermore, this is the first study to document a persisting 3-point improvement during clinical assessment of tactile sensation in peripheral injury after receiving 6 weeks of tSCS. Lastly, the motor and sensory gains persisted for several months after stimulation was received, suggesting tSCS may lead to long-lasting benefits, even in PNI. Non-invasive spinal cord stimulation shows tremendous promise as a safe and effective therapeutic approach with broad applications in functional recovery after debilitating injuries.

Millions of people worldwide suffer motor or sensory impairment due to stroke, spinal cord injury, multiple sclerosis, traumatic brain injury, diabetes, and motor neuron diseases such as ALS (amyotrophic lateral sclerosis). A brain-computer interface (BCI), which links the brain directly to a computer, offers a new way to study the brain and potentially restore impairments in patients living with these debilitating conditions. One of the challenges currently facing BCI technology, however, is to minimize surgical risk while maintaining efficacy. Minimally invasive techniques, such as stereoelectroencephalography (SEEG) have become more widely used in clinical applications in epilepsy patients since they can lead to fewer complications. SEEG depth electrodes also give access to sulcal and white matter areas of the brain but have not been widely studied in brain-computer interfaces. Here we show the first demonstration of decoding sulcal and subcortical activity related to both movement and tactile sensation in the human hand. Furthermore, we have compared decoding performance in SEEG-based depth recordings versus those obtained with electrocorticography electrodes (ECoG) placed on gyri. Initial poor decoding performance and the observation that most neural modulation patterns varied in amplitude trial-to-trial and were transient (significantly shorter than the sustained finger movements studied), led to the development of a feature selection method based on a repeatability metric using temporal correlation. An algorithm based on temporal correlation was developed to isolate features that consistently repeated (required for accurate decoding) and possessed information content related to movement or touch-related stimuli. We subsequently used these features, along with deep learning methods, to automatically classify various motor and sensory events for individual fingers with high accuracy. Repeating features were found in sulcal, gyral, and white matter areas and were predominantly phasic or phasic-tonic across a wide frequency range for both HD (high density) ECoG and SEEG recordings. These findings motivated the use of long short-term memory (LSTM) recurrent neural networks (RNNs) which are well-suited to handling transient input features. Combining temporal correlation-based feature selection with LSTM yielded decoding accuracies of up to 92.04 ± 1.51% for hand movements, up to 91.69 ± 0.49% for individual finger movements, and up to 83.49 ± 0.72% for focal tactile stimuli to individual finger pads while using a relatively small number of SEEG electrodes. These findings may lead to a new class of minimally invasive brain-computer interface systems in the future, increasing its applicability to a wide variety of conditions.

OBJECTIVES:Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. METHODS:18 patients with SLE and with musculoskeletal pain ≥4 on a 10 cm Visual Analogue Scale were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. RESULTS:taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. CONCLUSION:taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.

Background: Paralysis and neuropathy, affecting millions of people worldwide, can be accompanied by significant loss of somatosensation. With tactile sensation being central to achieving dexterous movement, brain-computer interface (BCI) researchers have used intracortical and cortical surface electrical stimulation to restore somatotopically-relevant sensation to the hand. However, these approaches are restricted to stimulating the gyral areas of the brain. Since representation of distal regions of the hand extends into the sulcal regions of human primary somatosensory cortex (S1), it has been challenging to evoke sensory percepts localized to the fingertips. Objective/hypothesis: Targeted stimulation of sulcal regions of S1, using stereoelectroencephalography (SEEG) depth electrodes, can evoke focal sensory percepts in the fingertips. Methods: Two participants with intractable epilepsy received cortical stimulation both at the gyri via high-density electrocorticography (HD-ECoG) grids and in the sulci via SEEG depth electrode leads. We characterized the evoked sensory percepts localized to the hand. Results: We show that highly focal percepts can be evoked in the fingertips of the hand through sulcal stimulation. fMRI, myelin content, and cortical thickness maps from the Human Connectome Project elucidated specific cortical areas and sub-regions within S1 that evoked these focal percepts. Within-participant comparisons showed that percepts evoked by sulcal stimulation via SEEG electrodes were significantly more focal (80% less area; p = 0.02) and localized to the fingertips more often, than by gyral stimulation via HD-ECoG electrodes. Finally, sulcal locations with consistent modulation of high-frequency neural activity during mechanical tactile stimulation of the fingertips showed the same somatotopic correspondence as cortical stimulation. Conclusions: Our findings indicate minimally invasive sulcal stimulation via SEEG electrodes could be a clinically viable approach to restoring sensation.

In 2015, a group of neuroscientists and engineers assembled to watch a man play the video game Guitar Hero. He held the simplified guitar interface gingerly, using the fingers of his right hand to press down on the fret buttons and his left hand to hit the strum bar. What made this mundane bit of game play so extraordinary was the fact that the man had been paralyzed from the chest down for more than three years, without any use of his hands. Every time he moved his fingers to play a note, he was playing a song of restored autonomy.

Millions of people worldwide suffer motor or sensory impairment due to stroke, spinal cord injury, multiple sclerosis, traumatic brain injury, diabetes, and motor neuron diseases such as ALS (amyotrophic lateral sclerosis). A brain-computer interface (BCI), which links the brain directly to a computer, offers a new way to study the brain and potentially restore function in patients living with debilitating conditions. One of the challenges currently facing BCI technology, however, is how to minimize surgical risk. Minimally invasive techniques, such as stereoelectroencephalography (SEEG) have become more widely used in clinical applications since they can lead to fewer complications. SEEG electrodes also give access to sulcal and white matter areas of the brain but have not been widely studied in brain-computer interfaces. We therefore investigated the viability of using SEEG electrodes in a BCI for recording and decoding neural signals related to movement and the sense of touch and compared its performance to electrocorticography electrodes (ECoG) placed on gyri. Initial poor decoding performance and the observation that most neural modulation patterns were variable trial-to-trial and transient (significantly shorter than the sustained finger movements studied), led to the development of a feature selection method based on temporal autocorrelation, a repeatability metric. An algorithm based on temporal autocorrelation was developed to isolate features that consistently repeated (required for accurate decoding) and possessed information content related to movement or touch-related stimuli. We subsequently used these features, along with deep learning methods, to automatically classify various motor and sensory events for individual fingers with high accuracy. Repeating features were found in sulcal, gyral, and white matter areas and were predominantly phasic or phasic-tonic across a wide frequency range for both HD (high density) ECoG and SEEG recordings. These findings motivated the use of long short-term memory (LSTM) recurrent neural networks (RNNs) which are well-suited to handling both transient and sustained input features. Combining temporal autocorrelation-based feature selection with LSTM yielded decoding accuracies of up to 92.04 +/- 1.51% for hand movements, up to 91.69 +/- 0.49% for individual finger movements, and up to 80.64 +/- 1.64% for focal tactile stimuli to the finger pads and palm while using a relatively small number of SEEG electrodes. These findings may lead to a new class of minimally invasive brain-computer interface systems in the future, increasing its applicability to a wider variety of conditions.

Devices interfacing with the brain through implantation in cortical or subcortical structures have great potential for restoration and rehabilitation in patients with sensory or motor dysfunction. Typical implantation surgeries are planned based on maps of brain activity generated from intact function. However, mapping brain activity for planning implantation surgeries is challenging in the target population due to abnormal residual function and, increasingly often, existing MRI-incompatible implanted hardware. Here, we present methods and results for mapping impaired somatosensory and motor function in an individual with paralysis and an existing brain–computer interface (BCI) device. Magnetoencephalography (MEG) was used to directly map the neural activity evoked during transcutaneous electrical stimulation and attempted movement of the impaired hand. Evoked fields were found to align with the expected anatomy and somatotopic organization. This approach may be valuable for guiding implants in other applications, such as cortical stimulation for pain and to improve implant targeting to help reduce the craniotomy size.

A) Photograph of an endoscope within the abdominal cavity with access to the intra-abdominal organs during transmural endoscopy. B) Photograph of a peripheral branch of the posterior Vagus nerve in a patient undergoing the POEM procedure

Background Cervical spinal cord injury severely affects grasping ability of its survivors. Fortunately, many individuals with tetraplegia retain residual arm movements that allow them to reach for objects. We propose a wearable technology that utilizes arm movement trajectory information and deep learning methods to determine grasp selection. Furthermore, we combined this approach with neuromuscular stimulation to determine if self-driven functional hand movement could be enabled in spinal cord injury participants. Methods Two cervical SCI participants performed arbitrary and natural reaching movements toward target objects in three-dimensional space, which were recorded using an inertial sensor worn on their wrist. Time series classifiers were trained to recognize the trajectories using either a Dynamic Time Warping (DTW) algorithm or a Long Short-Term Memory (LSTM) recurrent neural network . As an initial proof-of-concept, we demonstrate real-time classification of the arbitrary movements using DTW only (due to its implementation simplicity), which when used in combination with a high density neuromuscular stimulation sleeve with textile electrodes, enabled participants to perform functional grasping. Results Participants were able to consistently perform arbitrary two-dimensional and three-dimensional arm movements which could be classified with high accuracy. Furthermore, it was found that natural reaching trajectories for two different target objects (requiring two different grasp types) were distinct and also discriminable with high accuracy. In offline comparisons, LSTM (mean accuracies 99%) performed significantly better than DTW (mean accuracies 86 and 83%) for both arbitrary and natural reaching movements, respectively. Type I and II errors occurred more frequently for DTW (up to 60 and 15%, respectively), whereas it stayed under 5% for LSTM. Also, DTW achieved online accuracy of 79%. Conclusions We demonstrate the feasibility of utilizing arm trajectory information to determine grasp selection using a wearable inertial sensor along with DTW and deep learning methods. Importantly, this technology can be successfully used to control neuromuscular stimulation and restore functional independence to individuals living with paralysis. Trial registration NCT, NCT03385005 . Registered September 26, 2017

Background:Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Methods:Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Results:Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. Conclusions:These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.

BCI (brain-computer interface) and functional electrical stimulation (FES) technologies have advanced significantly over the last several decades. Recent efforts have involved the integration of these technologies with the goal of restoring functional movement in paralyzed patients. Implantable BCIs have provided neural recordings with increased spatial resolution and have been combined with sophisticated neural decoding algorithms and increasingly capable FES systems to advance efforts toward this goal. This chapter reviews historical developments that have occurred as the exciting fields of BCI and FES have evolved and now overlapped to allow new breakthroughs in medicine, targeting restoration of movement and lost function in users with disabilities.

Objective. The vagus nerve has been implicated in a variety of immune responses, and the number of studies using mouse models to unravel key mechanisms has increased. However, as of yet, there is no electrode that can chronically record neural activity from the mouse vagus nerve due to its small diameter. Such recordings are critical to understand the role of these biomarkers for translational research. Approach. In this study, we developed a methodology for surgically implanting the wrappable microwires onto the vagus nerve of mice. Similar to a cuff electrode, we wrapped de-insulated ends of microwires around the vagus nerve and re-insulated them on the nerve with Kwik-Sil. The recording fidelity of the wrappable microwire on the vagus nerve was validated in an acute, anesthetized model by comparing performance to commercially-available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). Main results. In an acute setting, the wrappable microwire successfully recorded spontaneous CAPs with similar signal-to-noise ratios (SNR) and peak-to-peak amplitude to commercially available electrodes. In chronic, awake recordings, viable SNRs were obtained from the wrappable microwires between 30 and 60 d (n = 8). Weekly impedance measurements showed no correlation with SNR or time, indicating device stability, and the electrodes recorded CAPs for the duration of the recording period. Significance. To the best of our knowledge, this is the first reported chronic, awake neural interface with the mouse vagus nerve. This approach can facilitate clinical translation for bioelectronic medicine in preclinical disease models of interest with the creation of more clinically relevant preclinical models.

Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), while other parameters selectively lowered serum TNFα levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.

Abstract Background Cervical spinal cord injury severely affects grasping ability of its survivors. Fortunately, many individuals with quadriplegia retain residual arm movements that allow them to reach for objects. We propose a wearable technology that utilizes pattern recognition and deep learning methods to automatically classify arm trajectories and infer grasping intentions. Further, this technology can enable individuals with SCI to grasp objects without assistance via neuromuscular stimulation. Methods Two cervical SCI participants performed various reaching movements and smooth trajectories in space, which were recorded using an inertial sensor worn on their wrist. Time series classifiers were trained to recognize the trajectories using either a Dynamic Time Warping (DTW) algorithm or a Long Short-Term Memory (LSTM) recurrent neural network. Successful trajectory prediction in real-time was demonstrated using DTW, which when used in combination with a high density neuromuscular stimulation sleeve with textile electrodes, enabled participants to perform functional grasps. Results In offline comparisons, LSTM (mean accuracies 98% and 99%) performed significantly better than DTW (mean accuracies 94% and 83%) for both 2D and 3D reaching movements, respectively. Type I and II errors occurred more frequently for DTW (up to 38% and 15%, respectively), whereas it stayed under 3% for LSTM. Also, DTW achieved online accuracy of 79 ± 5%. Conclusions We demonstrate the feasibility of inferring grasping intention from reaching trajectories using wearable sensors. Importantly, this technology can be successfully used to control neuromuscular stimulators and restore functional independence to individuals living with paralysis. Trial registration: NCT, NCT03385005. Registered September 26, 2017, https://clinicaltrials.gov/ct2/show/NCT03385005