Both intracortical microstimulation (ICMS) and peripheral nerve stimulation (PNS) can restore tactile sensation to people living with physical disabilities, such as spinal cord injury (SCI) or amputation. While both techniques have demonstrated success in evoking meaningful sensations in the upper limb, they have only been investigated in separate studies with different patient populations, and thus their perceptual characteristics have never been systematically compared to determine the relative advantages and limitations of each approach. In this study, we directly compared the perceived sensations evoked by ICMS and PNS to those evoked by mechanical touch in a participant with sensory incomplete spinal cord injury. We observed that ICMS evoked more localized percepts and felt more qualitatively similar to natural touch than PNS, whereas PNS evoked higher intensity and more reliable percepts than ICMS. We also found that, across stimulation approaches, the perceived naturalness ratings of sensations were more strongly related to the other perceptual variables than to stimulation variables, suggesting that naturalness is a higher order perceptual dimension that is cognitively constructed by the participant. Our results indicate that ICMS may be the better sensory stimulation approach for conveying naturalistic touch experiences during haptic exploration, due to its similarity to mechanical touch in perceptual quality. In contrast, PNS may be the better stimulation modality to deliver consistent and effective sensory feedback during closed-loop functional tasks, due to its higher reliability. These insights provide a framework for future development of patient-specific sensory neuroprostheses based on the needs and goals of the user.

Peripheral nerve stimulation (PNS) is a promising technique for restoring touch to people with neurological injuries. However, its application remains limited because past studies solely focused on people with limb loss and because the optimal paradigm for encoding touch information is still unclear. This study investigated PNS as a modality to restore touch in an individual with sensory-incomplete spinal cord injury (SCI) and quantified intracortical activity in primary somatosensory cortex (S1) resulting from PNS. S1 activity serves as an objective measure to compare and refine PNS paradigms to ultimately improve the effectiveness of PNS as sensory feedback in bidirectional neuroprostheses. We found that PNS delivered to the median and ulnar nerves via chronically-implanted, multi-contact cuff electrodes consistently evoked hand sensations with intensities that reliably scaled with stimulation pulse width (PW). In S1, increasing PNS PW recruited larger cortical populations, increased multi-unit firing rates, and shortened latencies between PNS onset and peak S1 activation. Interestingly, most S1 responses to PNS had strong onset transients, like those previously observed in response to mechanical indentation. Because our PNS paradigm was designed to recruit a population of peripheral afferents synchronously at a fixed frequency, our results suggest that central mechanisms play a role in producing cortical onset transients. This study supports PNS as a viable sensory feedback approach for individuals with incomplete SCI and reveals the representation of electrically-evoked sensory percepts in human cortex for the first time. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03898804 ### Funding Statement This study was funded by the Congressionally Directed Medical Research Program Spinal Cord Injury Research Program, Clinical Trial Award SC18038 and by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, R01NS119160. Additional funds were provided as part of start up support from the Case Western Reserve University Department of Biomedical Engineering. ### 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 study is part of the Reconnecting the Hand and Arm to the Brain (ReHAB) clinical trial (ClinicalTrials.gov #[NCT03898804][1]). All procedures were reviewed and approved by the University Hospitals Cleveland Medical Center's Institutional Review Board. The U. S. Food and Drug Administration also approved the devices and procedures for this study under an Investigational Device Exemption. 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=NCT03898804&atom=%2Fmedrxiv%2Fearly%2F2025%2F09%2F12%2F2025.09.09.25335042.atom

IntroductionHand opening is reduced by abnormal wrist and finger flexor activity in many individuals with stroke. This flexor activity also limits hand opening produced by functional electrical stimulation (FES) of finger and wrist extensor muscles. Recent advances in electrical nerve block technologies have the potential to mitigate this abnormal flexor behavior, but the actual impact of nerve block on hand opening in stroke has not yet been investigated.MethodsIn this study, we applied the local anesthetic ropivacaine to the median and ulnar nerve to induce a complete motor block in 9 individuals with stroke and observed the impact of this block on hand opening as measured by hand pentagonal area. Volitional hand opening and FES-driven hand opening were measured, both while the arm was fully supported on a haptic table (Unloaded) and while lifting against gravity (Loaded). Linear mixed effect regression (LMER) modeling was used to determine the effect of Block.ResultsThe ropivacaine block allowed increased hand opening, both volitional and FES-driven, and for both unloaded and loaded conditions. Notably, only the FES-driven and Loaded condition’s improvement in hand opening with the block was statistically significant. Hand opening in the FES and Loaded condition improved following nerve block by nearly 20%.ConclusionOur results suggest that many individuals with stroke would see improved hand-opening with wrist and finger flexor activity curtailed by nerve block, especially when FES is used to drive the typically paretic finger and wrist extensor muscles. Such a nerve block (potentially produced by aforementioned emerging electrical nerve block technologies) could thus significantly address prior observed shortcomings of FES interventions for individuals with stroke.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating “avatars” (herein defined as an extension of “digital twins”) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

Tactile feedback from brain-controlled bionic hands can be partially restored via intracortical microstimulation (ICMS) of the primary somatosensory cortex. In ICMS, the location of percepts depends on the electrode's location and the percept intensity depends on the stimulation frequency and amplitude. Sensors on a bionic hand can thus be linked to somatotopically appropriate electrodes, and the contact force of each sensor can be used to determine the amplitude of a stimulus. Here we report a systematic investigation of the localization and intensity of ICMS-evoked percepts in three participants with cervical spinal cord injury. A retrospective analysis of projected fields showed that they were typically composed of a focal hotspot with diffuse borders, arrayed somatotopically in keeping with their underlying receptive fields and stable throughout the duration of the study. When testing the participants' ability to rapidly localize a single ICMS presentation, individual electrodes typically evoked only weak sensations, making object localization and discrimination difficult. However, overlapping projected fields from multiple electrodes produced more localizable and intense sensations and allowed for a more precise use of a bionic hand.

BACKGROUND AND OBJECTIVES:Brain-computer interfaces (BCIs) are being developed to restore mobility, communication, and functional independence to people with paralysis. Though supported by decades of preclinical data, the safety of chronically implanted microelectrode array BCIs in humans is unknown. We report safety results from the prospective, open-label, nonrandomized BrainGate feasibility study (NCT00912041), the largest and longest-running clinical trial of an implanted BCI. METHODS:Adults aged 18-75 years with quadriparesis from spinal cord injury, brainstem stroke, or motor neuron disease were enrolled through 7 clinical sites in the United States. Participants underwent surgical implantation of 1 or 2 microelectrode arrays in the motor cortex of the dominant cerebral hemisphere. The primary safety outcome was device-related serious adverse events (SAEs) requiring device explantation or resulting in death or permanently increased disability during the 1-year postimplant evaluation period. The secondary outcomes included the type and frequency of other adverse events and the feasibility of the BrainGate system for controlling a computer or other assistive technologies. RESULTS:From 2004 to 2021, 14 adults enrolled in the BrainGate trial had devices surgically implanted. The average duration of device implantation was 872 days, yielding 12,203 days of safety experience. There were 68 device-related adverse events, including 6 device-related SAEs. The most common device-related adverse event was skin irritation around the percutaneous pedestal. There were no safety events that required device explantation, no unanticipated adverse device events, no intracranial infections, and no participant deaths or adverse events resulting in permanently increased disability related to the investigational device. DISCUSSION:The BrainGate Neural Interface system has a safety record comparable with other chronically implanted medical devices. Given rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov Identifier: NCT00912041. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that the neurosurgically placed BrainGate Neural Interface system is associated with a low rate of SAEs defined as those requiring device explantation, resulting in death, or resulting in permanently increased disability during the 1-year postimplant period.

Functional electrical stimulation (FES) to activate nerves and muscles in paralyzed extremities has considerable promise to improve outcome after neurological disease or injury, especially in individuals who have upper motor nerve dysfunction due to central nervous system pathology. Because technology has improved, a wide variety of methods for providing electrical stimulation to create functional movements have been developed, including muscle stimulating electrodes, nerve stimulating electrodes, and hybrid constructs. However, in spite of decades of success in experimental settings with clear functional improvements for individuals with paralysis, the technology has not yet reached widespread clinical translation. In this review, we outline the history of FES techniques and approaches and describe future directions in evolution of the technology.

BACKGROUND AND OBJECTIVES:Paralysis after spinal cord injury involves damage to pathways that connect neurons in the brain to peripheral nerves in the limbs. Re-establishing this communication using neural interfaces has the potential to bridge the gap and restore upper extremity function to people with high tetraplegia. We report a novel approach for restoring upper extremity function using selective peripheral nerve stimulation controlled by intracortical microelectrode recordings from sensorimotor networks, along with restoration of tactile sensation of the hand using intracortical microstimulation. METHODS:A 27-year-old right-handed man with AIS-B (motor-complete, sensory-incomplete) C3-C4 tetraplegia was enrolled into the clinical trial. Six 64-channel intracortical microelectrode arrays were implanted into left hemisphere regions involved in upper extremity function, including primary motor and sensory cortices, inferior frontal gyrus, and anterior intraparietal area. Nine 16-channel extraneural peripheral nerve electrodes were implanted to allow targeted stimulation of right median, ulnar (2), radial, axillary, musculocutaneous, suprascapular, lateral pectoral, and long thoracic nerves, to produce selective muscle contractions on demand. Proof-of-concept studies were performed to demonstrate feasibility of using a brain-machine interface to read from and write to the brain for restoring motor and sensory functions of the participant's own arm and hand. RESULTS:Multiunit neural activity that correlated with intended motor action was successfully recorded from intracortical arrays. Microstimulation of electrodes in somatosensory cortex produced repeatable sensory percepts of individual fingers for restoration of touch sensation. Selective electrical activation of peripheral nerves produced antigravity muscle contractions, resulting in functional movements that the participant was able to command under brain control to perform virtual and actual arm and hand movements. The system was well tolerated with no operative complications. CONCLUSION:The combination of implanted cortical electrodes and nerve cuff electrodes has the potential to create bidirectional restoration of motor and sensory functions of the arm and hand after neurological injury.

Functional electrical stimulation (FES) may allow people who are paralyzed due to spinal cord injuries (SCIs) to regain the ability to move. Deep neural networks (DNNs) trained with reinforcement learning (RL) have been recently explored as a promising methodology to control FES systems to restore upper-limb movements. However, previous studies suggested that large asymmetries in antagonistic upper-limb muscle strengths could impair RL controller performance. In this work, we investigated the underlying causes of asymmetry-associated decreases in controller performance by comparing different Hill-type models of muscle atrophy, and by characterizing RL controller sensitivity to passive mechanical properties of the arm. Simulations indicated that RL controller performance is relatively insensitive to moderate (up to 50%) changes in tendon stiffness and in flexor muscle stiffness. However, the viable workspace for RL control was substantially affected by flexor muscle weakness and by extensor muscle stiffness. Furthermore, we uncovered that RL controller performance issues previously attributed to asymmetrical antagonistic muscle strength resulted from flexor muscle active forces that were insufficient to counteract extensor muscle passive resistance. The simulations supported the adoption of rehabilitation protocols for reaching tasks that prioritize decreasing muscle passive resistance, and counteracting passive resistance with increased antagonistic muscle strength.

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participant's hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multichannel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

Cervical spinal cord injuries frequently cause paralysis of all four limbs - a medical condition known as tetraplegia. Functional electrical stimulation (FES), when combined with an appropriate controller, can be used to restore motor function by electrically stimulating the neuromuscular system. Previous works have demonstrated that reinforcement learning can be used to successfully train FES controllers. Here, we demonstrate that transfer learning and curriculum learning can be used to improve the learning rates, accuracies, and workspaces of FES controllers that are trained using reinforcement learning.

Functional electrical stimulation (FES) can be used to restore motor function to people with paralysis caused by spinal cord injuries (SCIs). However, chronically-paralyzed FES-stimulated muscles can fatigue quickly, which may decrease FES controller performance. In this work, we explored the feasibility of using deep neural network (DNN) controllers trained with reinforcement learning (RL) to control FES of upper-limb muscles after SCI. We developed upper-limb biomechanical models that exhibited increased muscle fatigability, decreased muscle recovery, and decreased muscle strength, as observed in people with chronic SCIs. Simulations confirmed that controller training time and controller performance are impaired to varying degrees by muscle fatigability. Also, the simulations showed that large muscle strength asymmetries between opposing muscles can substantially impair controller performance. However, the results of this study suggest that controller performance for highly-fatigable musculoskeletal systems can be preserved by allowing for rest between movements. Overall, the results suggest that RL can be used to successfully train FES controllers, even for highly-fatigable musculoskeletal systems.

High-level spinal cord injuries often result in paralysis of all four limbs, leading to decreased patient independence and quality of life. Coordinated functional electrical stimulation (FES) of paralyzed muscles can be used to restore some motor function in the upper extremity. To coordinate functional movements, FES controllers should be developed to exploit the complex characteristics of human movement and produce the intended movement kinematics and/or kinetics. Here, we demonstrate the ability of a controller trained using reinforcement learning to generate desired movements of a horizontal planar musculoskeletal model of the human arm with 2 degrees of freedom and 6 actuators. The controller is given information about the kinematics of the arm, but not the internal state of the actuators. In particular, we demonstrate that a technique called "hindsight experience replay" can improve controller performance while also decreasing controller training time.

Intracortical brain-computer interfaces (iBCIs) have the potential to restore hand grasping and object interaction to individuals with tetraplegia. Optimal grasping and object interaction require simultaneous production of both force and grasp outputs. However, since overlapping neural populations are modulated by both parameters, grasp type could affect how well forces are decoded from motor cortex in a closed-loop force iBCI. Therefore, this work quantified the neural representation and offline decoding performance of discrete hand grasps and force levels in two human participants with tetraplegia. Participants attempted to produce three discrete forces (light, medium, hard) using up to five hand grasp configurations. A two-way Welch ANOVA was implemented on multiunit neural features to assess their modulation to force and grasp Demixed principal component analysis (dPCA) was used to assess for population-level tuning to force and grasp and to predict these parameters from neural activity. Three major findings emerged from this work: (1) force information was neurally represented and could be decoded across multiple hand grasps (and, in one participant, across attempted elbow extension as well); (2) grasp type affected force representation within multiunit neural features and offline force classification accuracy; and (3) grasp was classified more accurately and had greater population-level representation than force. These findings suggest that force and grasp have both independent and interacting representations within cortex, and that incorporating force control into real-time iBCI systems is feasible across multiple hand grasps if the decoder also accounts for grasp type.

Hybrid kinetic and kinematic intracortical brain-computer interfaces (iBCIs) have the potential to restore functional grasping and object interaction capabilities in individuals with tetraplegia. This requires an understanding of how kinetic information is represented in neural activity, and how this representation is affected by non-motor parameters such as volitional state (VoS), namely, whether one observes, imagines, or attempts an action. To this end, this work investigates how motor cortical neural activity changes when three human participants with tetraplegia observe, imagine , and attempt to produce three discrete hand grasping forces with the dominant hand. We show that force representation follows the same VoS-related trends as previously shown for directional arm movements; namely, that attempted force production recruits more neural activity compared to observed or imagined force production. Additionally, VoS-modulated neural activity to a greater extent than grasping force. Neural representation of forces was lower than expected, possibly due to compromised somatosensory pathways in individuals with tetraplegia, which have been shown to influence motor cortical activity. Nevertheless, attempted forces (but not always observed or imagined forces) could be decoded significantly above chance, thereby potentially providing relevant information towards the development of a hybrid kinetic and kinematic iBCI.

This study demonstrates volitional arm and hand motions restored to a person living with complete tetraplegia due to high cervical spinal cord injury. Selective intramuscular functional electrical stimulation (FES) of paralyzed muscles throughout the upper extremity powered multiple reaching and grasping movements. An intracortical brain computer interface (iBCI) recorded neural signals from the participant’s contralateral motor cortex, extracted movement intentions from these signals, and commanded FES patterns to generate these intended movements. As a result of the combined technological approach, the participant could volitionally reach, grasp, and drink from a cup, demonstrating the feasibility of this FES + iBCI system to restore cortically-controlled functional arm and hand movements in persons with extensive paralysis.

Decoders optimized offline to reconstruct intended movements from neural recordings sometimes fail to achieve optimal performance online when they are used in closed-loop as part of an intracortical brain-computer interface (iBCI). This is because typical decoder calibration routines do not model the emergent interactions between the decoder, the user, and the task parameters (e.g. target size). Here, we investigated the feasibility of simulating online performance to better guide decoder parameter selection and design. Three participants in the BrainGate2 pilot clinical trial controlled a computer cursor using a linear velocity decoder under different gain (speed scaling) and temporal smoothing parameters and acquired targets with different radii and distances. We show that a user-specific iBCI feedback control model can predict how performance changes under these different decoder and task parameters in held-out data. We also used the model to optimize a nonlinear speed scaling function for the decoder. When used online with two participants, it increased the dynamic range of decoded speeds and decreased the time taken to acquire targets (compared to an optimized standard decoder). These results suggest that it is feasible to simulate iBCI performance accurately enough to be useful for quantitative decoder optimization and design.

Background Modern prosthetic hands are typically controlled using skin surface electromyographic signals (EMG) from remaining muscles in the residual limb. However, surface electrode performance is limited by changes in skin impedance over time, day-to-day variations in electrode placement, and relative motion between the electrodes and underlying muscles during movement: these limitations require frequent retraining of controllers. In the presented study, we used chronically implanted intramuscular electrodes to minimize these effects and thus create a more robust prosthetic controller. Methods A study participant with a transradial amputation was chronically implanted with 8 intramuscular EMG electrodes. A K Nearest Neighbor (KNN) regression velocity controller was trained to predict intended joint movement direction using EMG data collected during a single training session. The resulting KNN was evaluated over 12 weeks and in multiple arm posture configurations, with the participant controlling a 3 Degree-of-Freedom (DOF) virtual reality (VR) hand to match target VR hand postures. The performance of this EMG-based controller was compared to a position-based controller that used movement measured from the participant’s opposite (intact) hand. Surface EMG was also collected for signal quality comparisons. Results Signals from the implanted intramuscular electrodes exhibited less crosstalk between the various channels and had a higher Signal-to-Noise Ratio than surface electrode signals. The performance of the intramuscular EMG-based KNN controller in the VR control task showed no degradation over time, and was stable over the 6 different arm postures. Both the EMG-based KNN controller and the intact hand-based controller had 100% hand posture matching success rates, but the intact hand-based controller was slightly superior in regards to speed (trial time used) and directness of the VR hand control (path efficiency). Conclusions Chronically implanted intramuscular electrodes provide negligible crosstalk, high SNR, and substantial VR control performance, including the ability to use a fixed controller over 12 weeks and under different arm positions. This approach can thus be a highly effective platform for advanced, multi-DOF prosthetic control.

Intracortical brain-machine interfaces are a promising technology for allowing people with chronic and severe neurological disorders that resulted in loss of function to potentially regain those functions through neuroprosthetic devices. The penetrating microelectrode arrays used in almost all previous studies of intracortical brain-machine interfaces in people had a limited recording life (potentially due to issues with long-term biocompatibility), as well as a limited number of recording electrodes with limited distribution in the brain. Significant advances are required in this array interface to deal with the issues of long-term biocompatibility and lack of distributed recordings. The Musk and Neuralink manuscript proposes a novel and potentially disruptive approach to advancing the brain-electrode interface technology, with the potential of addressing many of these hurdles. Our commentary addresses the potential advantages of the proposed approach, as well as the remaining challenges to be addressed.