BACKGROUND:Intracortical microstimulation (ICMS) of the somatosensory cortex activates neurons around the stimulating electrodes and can elicit tactile sensations. OBJECTIVE:It is not clear how the direct activation of cortical neurons influences their ability to process additional tactile inputs originating from the skin. METHODS:In a human implanted with chronic microelectrode arrays in both left and right somatosensory cortices, we presented mechanical vibration to the skin while simultaneously delivering ICMS and quantified the effects of combined mechanical and electrical stimulation on tactile perception. RESULTS:We found that subthreshold ICMS enhanced sensitivity to touch on the skin, as evidenced by a reduction in vibrotactile detection thresholds (median: 1.5 dB), but subthreshold vibration did not systematically impact the detectability of ICMS. Suprathreshold vibration led to an increase in ICMS thresholds (median: 2.4 dB) but suprathreshold ICMS had little impact on vibrotactile thresholds. The ICMS-induced enhancement of vibrotactile sensitivity was location dependent with the effect size decreasing as the projected field of the stimulating electrode and the locus of vibratory stimulation became farther apart. CONCLUSION:These results demonstrate that targeted microstimulation of cortex alone can focally enhance tactile sensitivity, potentially enabling restoration or strengthening of retained tactile sensations after injury.

The clinical success of brain computer interfaces (BCI) depends on overcoming both biological and material challenges to ensure a long-term stable connection for neural recording and stimulation. This study systematically quantified damage that microelectrodes sustained during chronical implantation in three people with tetraplegia for 956–2130 days. Using scanning electron microscopy (SEM), we imaged 980 microelectrodes from eleven Neuroport arrays tipped with platinum (Pt, n = 8) and sputtered iridium oxide film (SIROF, n = 3). Arrays were implanted/explanted from posterior parietal, motor and somatosensory cortices across three clinical sites (Caltech/UCLA, Caltech/USC, APL/Johns Hopkins). From the electron micrographs, we quantified and correlated physical damage with functional outcomes measured in vivo, prior to explant (recording quality, noise, impedance and stimulation ability).Despite greater physical degradation, SIROF electrodes were twice as likely to record neural activity than Pt (measured by SNR). For SIROF, 1 kHz impedance significantly correlated with all physical damage metrics, recording metrics, and stimulation performance, suggesting a reliable measurement of in vivo degradation. We observed a new degradation type, primarily on stimulated electrodes (“pockmarked” vs “cracked”) electrodes; however, no significant degradation due to stimulation or amount of charge delivered. We hypothesize erosion of the silicon shank accelerates damage to the electrode / tissue interface, following damage to the tip metal.These findings link quantitative measurements to the microelectrodes’ physical condition and their capacity to record/stimulate. These data could lead to improved manufacturing processes or novel electrode designs to improve long-term performance of BCIs, making them vitally important as multi-year clinical trials of BCIs are becoming more common. Statement of significance Long-term performance stability of the electrode-tissue interface is essential for clinical viability of brain computer interface (BCI) devices; currently, materials degradation is a critical component for performance loss. Across three human participants, ten micro-electrode arrays (plus one control) were implanted for 956–2130 days. Using scanning electron microscopy (SEM), we analyzed degradation of 980 electrodes, comparing two types of commonly implanted electrode tip metals: Platinum (Pt) and Sputtered Iridium Oxide Film (SIROF). We correlated observed degradation with in vivo electrode performance: recording (signal-to-noise ratio, noise, impedance) and stimulation (evoked somatosensory percepts). We hypothesize penetration of the electrode tip by biotic processes leads to erosion of the supporting silicon core, which then accelerates further tip metal damage. These data could lead to improved manufacturing processes or novel electrode designs towards the goal of a stable BCI electrical interface, spanning a multi-decade participant lifetime.

Invasive brain-machine interfaces can help restore function through the control of external devices while the addition of intracortical microstimulation (ICMS) can elicit sensations of touch and help provide further benefits for individuals living with sensorimotor deficits. However, the extent of tactile information that can be conveyed through ICMS has not been fully explored. In a human participant with spinal cord injury and chronically implanted microelectrode arrays, we used ICMS to the somatosensory cortex to provide grip force feedback in the hands during grasping of objects with varying stiffness with a robotic arm. Using only ICMS-evoked touch sensations, the participant was able to identify between two and three objects with an accuracy of 92% and 67%, respectively. In a compliant grasping task with the goal of grasping a delicate object without crushing it, objects were deformed on average only 2.8 mm with ICMS-based touch feedback compared to 8.7 mm without. These results demonstrate that ICMS-evoked touch sensations to the hands can be used to provide force-based feedback for perceiving object properties and enable more precise grasping during closed-loop control of a robotic limb through a cortical interface.

Complete sensorimotor integration and user acceptance of a neural prosthesis relies on system embodiment the incorporation of an external system into one's own body schema and representation. Embodiment of neural prostheses is an ambiguous concept with limited approaches for quantifying human and machine integration in a meaningful way. In an attempt to understand human sensory integration with external systems, we measured neural activity in the somatosensory cortex of a participant with chronically implanted microelectrode arrays during sensory events tied to either a virtual robotic hand touching an object or a virtual lamp lighting up. Sensory stimulation was delivered using either skin vibration or intracortical microstimulation (ICMS) and was mapped to the virtual systems. Through the brain-machine interface, we observed quantifiable cortical activity corresponding to tactile sensations perceived during the virtual tasks and even during instances when neural stimulation was expected but not delivered, demonstrating the presence of sensory-related neural activity even in the absence of tactile stimulation. Evoked sensory expectation signals were also observed in the motor cortex, although at reduced amplitudes. Evoked cortical activity corresponding to expectation of a sensory input could serve as objective cortical markers for better understanding sensorimotor integration and perceptual experiences when connecting humans with external systems.

BACKGROUND AND OBJECTIVES:The restoration of touch to fingers and fingertips is critical to achieving dexterous neuroprosthetic control for individuals with sensorimotor dysfunction. However, localized fingertip sensations have not been evoked via intracortical microstimulation (ICMS).METHODS:Using a novel intraoperative mapping approach, we implanted electrode arrays in the finger areas of left and right somatosensory cortex and delivered ICMS over a 2-year period in a human participant with spinal cord injury.RESULTS:Stimulation evoked tactile sensations in 8 fingers, including fingertips, spanning both hands. Evoked percepts followed expected somatotopic arrangements. The subject was able to reliably identify up to 7 finger-specific sites spanning both hands in a finger discrimination task. The size of the evoked percepts was on average 33% larger than a finger pad, as assessed via manual markings of a hand image. The size of the evoked percepts increased modestly with increased stimulation intensity, growing 21% as pulse amplitude increased from 20 to 80 µA. Detection thresholds were estimated on a subset of electrodes, with estimates of 9.2 to 35 µA observed, roughly consistent with prior studies.DISCUSSION:These results suggest that ICMS can enable the delivery of consistent and localized fingertip sensations during object manipulation by neuroprostheses for individuals with somatosensory deficits.CLINICALTRIALSGOV IDENTIFIER:NCT03161067.

Advances in intelligent robotic systems and brain-machine interfaces (BMI) have helped restore functionality and independence to individuals living with sensorimotor deficits; however, tasks requiring bimanual coordination and fine manipulation continue to remain unsolved given the technical complexity of controlling multiple degrees of freedom (DOF) across multiple limbs in a coordinated way through a user input. To address this challenge, we implemented a collaborative shared control strategy to manipulate and coordinate two Modular Prosthetic Limbs (MPL) for performing a bimanual self-feeding task. A human participant with microelectrode arrays in sensorimotor brain regions provided commands to both MPLs to perform the self-feeding task, which included bimanual cutting. Motor commands were decoded from bilateral neural signals to control up to two DOFs on each MPL at a time. The shared control strategy enabled the participant to map his four-DOF control inputs, two per hand, to as many as 12 DOFs for specifying robot end effector position and orientation. Using neurally-driven shared control, the participant successfully and simultaneously controlled movements of both robotic limbs to cut and eat food in a complex bimanual self-feeding task. This demonstration of bimanual robotic system control via a BMI in collaboration with intelligent robot behavior has major implications for restoring complex movement behaviors for those living with sensorimotor deficits.

Understanding the cortical representations of movements and their stability can shed light on improved brain-machine interface (BMI) approaches to decode these representations without frequent recalibration. Here, we characterize the spatial organization (somatotopy) and stability of the bilateral sensorimotor map of forearm muscles in an incomplete-high spinal-cord injury study participant implanted bilaterally in the primary motor and sensory cortices with Utah microelectrode arrays (MEAs). We built representation maps by recording bilateral multiunit activity (MUA) and surface electromyography (EMG) as the participant executed voluntary contractions of the extensor carpi radialis (ECR), and attempted motions in the flexor carpi radialis (FCR), which was paralytic. To assess stability, we repeatedly mapped and compared left- and right-wrist-extensor-related activity throughout several sessions, comparing somatotopy of active electrodes, as well as neural signals both at the within-electrode (multiunit) and cross-electrode (network) levels. Wrist motions showed significant activation in motor and sensory cortical electrodes. Within electrodes, firing strength stability diminished as the time increased between consecutive measurements (hours within a session, or days across sessions), with higher stability observed in sensory cortex than in motor, and in the contralateral hemisphere than in the ipsilateral. However, we observed no differences at network level, and no evidence of decoding instabilities for wrist EMG, either across timespans of hours or days, or across recording area. While map stability differs between brain area and hemisphere at multiunit/electrode level, these differences are nullified at ensemble level.

Defining eloquent cortex intraoperatively, traditionally performed by neurosurgeons to preserve patient function, can now help target electrode implantation for restoring function. Brain-machine interfaces (BMIs) have the potential to restore upper-limb motor control to paralyzed patients but require accurate placement of recording and stimulating electrodes to enable functional control of a prosthetic limb. Beyond motor decoding from recording arrays, precise placement of stimulating electrodes in cortical areas associated with finger and fingertip sensations allows for the delivery of sensory feedback that could improve dexterous control of prosthetic hands. In this study, the authors demonstrated the use of a novel intraoperative online functional mapping (OFM) technique with high-density electrocorticography to localize finger representations in human primary somatosensory cortex. In conjunction with traditional pre- and intraoperative targeting approaches, this technique enabled accurate implantation of stimulating microelectrodes, which was confirmed by postimplantation intracortical stimulation of finger and fingertip sensations. This work demonstrates the utility of intraoperative OFM and will inform future studies of closed-loop BMIs in humans.

Advances in brain-machine interfaces have helped restore function and independence for individuals with sensorimotor deficits; however, providing efficient and effective sensory feedback remains challenging. Intracortical microstimulation (ICMS) of sensorimotor brain regions is a promising technique for providing bioinspired sensory feedback. In a human participant with chronically-implanted microelectrode arrays, we provided ICMS to the primary somatosensory cortex to generate tactile percepts in his hand. In a 3-choice object identification task, the participant identified virtual objects using tactile sensory feedback and no visual information. We evaluated three different stimulation paradigms, each with a different weighting of the grip force and its derivative, to explore the potential benefits of a more bioinspired stimulation strategy. In all paradigms, the participant's ability to identify the objects was above-chance, with object identification accuracy reaching 80% correct when using only sustained grip force feedback and 76.7% when using equal weighting of both sustained grip force and its derivative. These results demonstrate that bioinspired ICMS can provide sensory feedback that is functionally beneficial in sensorimotor tasks. Designing more efficient stimulation paradigms is important because it will allow us to 1) provide safer stimulation delivery methods that reduce overall injected charge without sacrificing function and 2) more effectively transmit sensory information to promote intuitive integration and usage by the human body.

The complex nature of neural connections throughout the cerebral cortex has led to broad interest in understanding cortical functional networks of tactile perception and sensorimotor integration. Cortico-cortical evoked potentials (CCEPs) can be used as physiological markers to study and map cerebral networks in the brain. In a human participant with bi-hemispheric microelectrode array implants in sensorimotor regions of the brain, we found that intracortical microstimulation (ICMS) of the primary somatosensory cortex can lead to evoked responses in the motor cortex in the same hemisphere, indicating connectivity between these sensorimotor regions. Single ICMS pulses were not consciously perceived, but elicited a rapid evoked potential approximately 20 ms after stimulus onset. Multi-pulse ICMS trains, perceived as tactile sensations in the thumb, sustained over an approximately 33 ms period, led to a delayed evoked response roughly 80 ms after stimulus onset. This work is important not only for better understanding the functional relationship between cortical areas, specifically somatosensory and motor cortices, but also to provide insight on pathways where neuromodulation techniques could be employed for rehabilitation or mitigation of sensorimotor neurodegenerative effects.

The restoration of cutaneous sensation to fingers and fingertips is critical to achieving dexterous prosthesis control for individuals with sensorimotor dysfunction. However, localized and reproducible fingertip sensations in humans have not been reported via intracortical microstimulation (ICMS) in humans. Here, we show that ICMS in a human participant was capable of eliciting percepts in 7 fingers spanning both hands, including 6 fingertip regions (i.e., 3 on each hand). Median percept size was estimated to include 1.40 finger or palmar segments (e.g., one segment being a fingertip or the section of upper palm below a finger). This was corroborated with a more sensitive manual marking technique where median percept size corresponded to roughly 120% of a fingertip segment. Percepts showed high intra-day consistency, including high performance (99%) on a blinded finger discrimination task. Across days, there was more variability in percepts, with 75.8% of trials containing the modal finger or palm region for the stimulated electrode. These results suggest that ICMS can enable the delivery of localized fingertip sensations during object manipulation by neuroprostheses. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03161067 ### Funding Statement This research was developed with funding from the Defense Advanced Research Projects Agency's (DARPA; Arlington, VA) Revolutionizing Prosthetics program (contract number N66001-10-C-4056). Development of experimental setup and support for regulatory submissions associated with this study were provided by a grant from the Alfred E. Mann Foundation. Study software infrastructure and study preparation were developed with internal funding from Johns Hopkins University Applied Physics Laboratory and Johns Hopkins University. ### 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: This study was conducted under Investigational Device Exemption (IDE, 170010) by the Food and Drug Administration (FDA) for the purpose of evaluating bilateral sensory and motor capabilities of microelectrode array implants. The study protocol was approved by the FDA, the Johns Hopkins Institutional Review Board (JH IRB) and NIWC Pacific IRB. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data is not publicly available at this time.

ABSTRACT Most daily tasks require simultaneous control of both hands. Here we demonstrate simultaneous classification of gestures in both hands using multi-unit activity recorded from bilateral motor and somatosensory cortices of a tetraplegic participant. Attempted gestures were classified using hierarchical linear discriminant models trained separately for each hand. In an online experiment, gestures were continuously classified and used to control two robotic arms in a center-out movement task. Bimanual trials that required keeping one hand still resulted in the best performance (70.6%), followed by symmetric movement trials (50%) and asymmetric movement trials (22.7%). Our results indicate that gestures can be simultaneously decoded in both hands using two independently trained hand models concurrently, but online control using this approach becomes more difficult with increased complexity of bimanual gesture combinations. This study demonstrates the potential for restoring simultaneous control of both hands using a bilateral intracortical brain-machine interface.

Volitional rhythmic motor behaviors such as limb cycling and locomotion exhibit spatial and timing regularity. Such rhythmic movements are executed in the presence of exogenous visual and nonvisual cues, and previous studies have shown the pivotal role that vision plays in guiding spatial and temporal regulation. However, the influence of nonvisual information conveyed through auditory or touch sensory pathways, and its effect on control, remains poorly understood. To characterize the function of nonvisual feedback in rhythmic arm control, we designed a paddle juggling task in which volunteers bounced a ball off a rigid elastic surface to a target height in virtual reality by moving a physical handle with the right hand. Feedback was delivered at two key phases of movement: visual feedback at ball peaks only and simultaneous audio and haptic feedback at ball-paddle collisions. In contrast to previous work, we limited visual feedback to the minimum required for jugglers to assess spatial accuracy, and we independently perturbed the spatial dimensions and the timing of feedback. By separately perturbing this information, we evoked dissociable effects on spatial accuracy and timing, confirming that juggling, and potentially other rhythmic tasks, involves two complementary processes with distinct dynamics: spatial error correction and feedback timing synchronization. Moreover, we show evidence that audio and haptic feedback provide sufficient information for the brain to control the timing synchronization process by acting as a metronome-like cue that triggers hand movement. NEW & NOTEWORTHY Vision contains rich information for control of rhythmic arm movements; less is known, however, about the role of nonvisual feedback (touch and sound). Using a virtual ball bouncing task allowing independent real-time manipulation of spatial location and timing of cues, we show their dissociable roles in regulating motor behavior. We confirm that visual feedback is used to correct spatial error and provide new evidence that nonvisual event cues act to reset the timing of arm movements.

Animals have a remarkable ability to keep time both with and without cues, as humans know from experience. Whether for dancing, making music in a group, playing sports, or speaking with another, we often seamlessly detect environmental cues, cognitively analyze them, and coordinate our behavior to

The richness of the biological world is a testament to the diversity of life, the conditions under which it can endure, and the remarkable array of robust solutions to environmental challenges. Animals have, over millions of years, evolved complex computations to parse the richness of their natural sensory milieu, as well as mechanisms to transcribe this information into appropriate motor actions. For designers of mechanical systems and robotics, biology represents a vast library of possibilities and solutions. It is natural, of course, to seek to imitate these solutions in terms of robotic systems trying to address similar challenges.

Objective:Therapeutic hypothermia after cardiac arrest improves survival and functional outcomes, whereas hyperthermia is harmful. The optimal method of tracking the effect of temperature on neurologic recovery after cardiac arrest has not been elucidated. We studied the recovery of cortical electrical function by quantitative electroencephalography after 7-min asphyxial cardiac arrest, using information quantity (IQ). Design:Laboratory investigation. Setting:University medical school and animal research facility. Subjects:A total of 28 male Wistar rats. Interventions:Using an asphyxial cardiac arrest rodent model, we tracked quantitative electroencephalography of 6-hr immediate postresuscitation hypothermia (at 33°C), normothermia (37°C), or hyperthermia (39°C) (n = 8 per group). Neurologic recovery was evaluated using the Neurologic Deficit Score. Four rats were included as a sham control group. Measurements and Main Results:Greater recovery of IQ was found in rats treated with hypothermia (IQ = 0.74), compared with normothermia (IQ = 0.60) and hyperthermia (IQ = 0.56) (p < .001). Analysis at different intervals demonstrated a significant separation of IQ scores among the temperature groups within the first 2 hrs postresuscitation (p < .01). IQ values of >0.523 at 60 mins postresuscitation predicted good neurologic outcome (72-hr Neurologic Deficit Score of ≥60), with a specificity of 100% and sensitivity of 81.8%. IQ was also significantly lower in rats that died prematurely compared with survivors (p < .001). IQ values correlated strongly with 72-hr Neurologic Deficit Score as early as 30 mins post–cardiac arrest (Pearson’s correlation 0.735, p < .01) and maintained a significant association throughout the 72-hr experiment. No IQ difference was noted in sham rats with temperature manipulation. Conclusions:The enhanced recovery provided by hypothermia and the detrimental effect by hyperthermia were robustly detected by early quantitative electroencephalographic markers. IQ values during the first 2 hrs after cardiac arrest accurately predicted neurologic outcome at 72 hrs.

We propose an improved quantitative measure of EEG during brain injury and recovery after cardiac arrest. In our previous studies, we proposed a measure, information quantity (IQ), to detect the early effects of temperature manipulation on the EEG signals recorded from the scalp. IQ incorporates the wavelet transform and the Shannon entropy in full bands from delta to gamma. Unlike IQ, here we separately calculate IQ in each subband, i.e., the new measure is IQ in each subband. We will call it subband IQ (SIQ). We demonstrate the performance of the proposed method by comparing SIQ with IQ in terms of how well the meausres predict actual neurological outcomes. Thirteen rats, based on 7-min cardiac arrest were used. The experimental results show that the proposed measure was more highly correlated to neurological outcome than IQ.

Background Therapeutic hypothermia after cardiac arrest (CA) improves survival and functional outcomes, while hyperthermia is harmful. The optimal tool for tracking the effect of temperature manipulation on recovery of cortical electrical function has not been elucidated. Previously, we demonstrated that good neurological recovery is associated with higher relative electroencephalographic (EEG) entropy, measured by information quantity (IQ). Methods We investigated the effect of temperature manipulation on neurological recovery after asphyxial CA in a rodent model using quantitative EEG (qEEG). Twenty-four rats were evenly divided into 3 groups (n=8 per group, randomly assigned), based on 6 hours of hypothermia (T=33°C), normothermia (T=37°C) or hyperthermia (T=39°C) immediately after resuscitation from 7-minute asphyxial CA. Temperature was maintained using surface cooling and warming. Neurological recovery was evaluated using serial Neurological Deficit Score (NDS) calculation. Results Greater recovery of IQ was found in rats treated with hypothermia (0.74±0.03), compared to normothermia (0.60±0.03) and hyperthermia (0.56±0.03) (p<0.001). qEEG analysis at different intervals demonstrated a significant separation of IQ scores between the groups only within the first 2 hours of resuscitation (p<0.01). The 72-hour NDS of the hypothermia group (74, 61–74; Median, 25 th –75 th percentile) was also significantly improved compared to the normothermia (49, 47– 61) and hyperthermia (43, 0 –50) groups (p<0.001). The IQ values correlated strongly with the 72-hour NDS as early as 30 minutes after resuscitation (Pearson correlation 0.735, 2-tailed significance p=0.01) and maintained a significant association throughout the 72-hour experiment. Conclusions Early qEEG was sensitive to the benefit of hypothermia as well as the harmful effect of hyperthermia post-CA and predicted neurological recovery at 72 hours.