Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions.

Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions.SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

BACKGROUND: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. METHODS: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. RESULTS: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. CONCLUSIONS: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

Disruption of layer-specific visual processing in a model of focal neocortical epilepsy.

The epileptic brain is the result of a sequence of events transforming normal neuronal populations into hyperexcitable networks supporting recurrent seizure generation. These modifications are known to induce fundamental alterations of circuit function and, ultimately, of behavior. However, how hyperexcitability affects information processing in cortical sensory circuits is not yet fully understood. Here, we investigated interlaminar alterations in sensory processing of the visual cortex in a mouse model of focal epilepsy. We found three main circuit dynamics alterations in epileptic mice: (i) a spreading of visual contrast-driven gamma modulation across layers, (ii) an increase in firing rate that is layer-unspecific for excitatory units and localized in infragranular layers for inhibitory neurons, and (iii) a strong and contrast-dependent locking of firing units to network activity. Altogether, our data show that epileptic circuits display a functional disruption of layer-specific organization of visual sensory processing, which could account for visual dysfunction observed in epileptic subjects. Understanding these mechanisms paves the way to circuital therapeutic interventions for epilepsy.

Immersive VR for upper-extremity rehabilitation in patients with neurological disorders: a scoping review.

BACKGROUND: Neurological disorders, such as stroke and chronic pain syndromes, profoundly impact independence and quality of life, especially when affecting upper extremity (UE) function. While conventional physical therapy has shown effectiveness in providing some neural recovery in affected individuals, there remains a need for improved interventions. Virtual reality (VR) has emerged as a promising technology-based approach for neurorehabilitation to make the patient's experience more enjoyable. Among VR-based rehabilitation paradigms, those based on fully immersive systems with headsets have gained significant attention due to their potential to enhance patient's engagement. METHODS: This scoping review aims to investigate the current state of research on the use of immersive VR for UE rehabilitation in individuals with neurological diseases, highlighting benefits and limitations. We identified thirteen relevant studies through comprehensive searches in Scopus, PubMed, and IEEE Xplore databases. Eligible studies incorporated immersive VR for UE rehabilitation in patients with neurological disorders and evaluated participants' neurological and motor functions before and after the intervention using clinical assessments. RESULTS: Most of the included studies reported improvements in the participants rehabilitation outcomes, suggesting that immersive VR represents a valuable tool for UE rehabilitation in individuals with neurological disorders. In addition, immersive VR-based interventions hold the potential for personalized and intensive training within a telerehabilitation framework. However, further studies with better design are needed for true comparison with traditional therapy. Also, the potential side effects associated with VR head-mounted displays, such as dizziness and nausea, warrant careful consideration in the development and implementation of VR-based rehabilitation programs. CONCLUSION: This review provides valuable insights into the application of immersive VR in UE rehabilitation, offering the foundation for future research and clinical practice. By leveraging immersive VR's potential, researchers and rehabilitation specialists can design more tailored and patient-centric rehabilitation strategies, ultimately improving the functional outcome and enhancing the quality of life of individuals with neurological diseases.

Swine Pudendal Nerve as a Model for Neuromodulation Studies to Restore Lower Urinary Tract Dysfunction.

Lower urinary tract dysfunction, such as incontinence or urinary retention, is one of the leading consequences of neurological diseases. This significantly impacts the quality of life for those affected, with implications extending not only to humans but also to clinical veterinary care. Having motor and sensory fibers, the pudendal nerve is an optimal candidate for neuromodulation therapies using bidirectional intraneural prostheses, paving the way towards the restoration of a more physiological urination cycle: bladder state can be detected from recorded neural signals, then an electrical current can be injected to the nerve based on the real-time need of the bladder. To develop such prostheses and investigate this novel approach, animal studies are still required since the morphology of the target nerve is fundamental to optimizing the prosthesis design. This study aims to describe the porcine pudendal nerve as a model for neuromodulation studies aiming at restoring lower urinary tract dysfunction. Five male farm pigs were involved in the study. First, a surgical procedure to access the porcine pudendal nerve without muscle resection was developed. Then, an intraneural interface was implanted to confirm the presence of fibers innervating the external urethral sphincter by measuring its electromyographic activity. Finally, the morphophysiology of the porcine pudendal nerve at the level of surgical exposure was described by using histological and immunohistochemical characterization. This analysis confirmed the fasciculate nature of the nerve and the presence of mixed fibers with a spatial and functional organization. These achievements pave the way for further pudendal neuromodulation studies by using a clinically relevant animal model with the potential for translating the findings into clinical applications.

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

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

Towards reliable spinal cord fMRI: Assessment of common imaging protocols.

Functional magnetic resonance imaging (fMRI) has revolutionized the investigation of brain function. Similar approaches can be translated to probe spinal mechanisms. However, imaging the spinal cord remains challenging, notably due to its size and location. Technological advances are gradually tackling these issues, though there is yet no consensus on optimal acquisition protocols. In this study, we assessed the performance of three sequences during a simple motor task and at rest, in 15 healthy humans. Building upon recent literature, we selected three imaging protocols: a sequence integrating outer volume suppression (OVS) and two sequences implementing inner field-of-view imaging (ZOOMit) with different spatial and temporal resolutions. Images acquired using the OVS sequence appeared more prone to breathing-induced signal fluctuations, though they exhibited a higher temporal signal-to-noise ratio than ZOOMit sequences. Conversely, the spatial signal-to-noise ratio was higher for the two ZOOMit schemes. In spite of these differences in signal properties, all sequences yielded comparable performance in detecting group-level task-related activity, observed in the expected spinal levels. Nevertheless, our results suggest a superior sensitivity and robustness of patterns imaged using the OVS acquisition scheme. To analyze the data acquired at rest, we deployed a dynamic functional connectivity framework, SpiCiCAP, and we evaluated the ability of the three acquisition schemes to disentangle intrinsic spinal signals. We demonstrated that meaningful subdivisions of the spinal cord's functional architecture could be uncovered for all three sequences, with similar spatio-temporal properties across acquisition parameters. Cleaner and more stable components were, however, obtained using ZOOMit sequences. This study emphasizes the potential of fMRI as a robust tool to image spinal activity in vivo and it highlights specificities and similarities of three acquisition methods. This represents a key step towards the establishment of standardized spinal cord fMRI protocols.

A brain-spine interface alleviating gait deficits after spinal cord injury in primates.

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.

Uncontrolled manifold analysis of the effects of a perturbation-based training on the organization of leg joint variance in cerebellar ataxia.

Walking patterns of persons affected by cerebellar ataxia (CA) are characterized by wide stride-to-stride variability ascribable to: the background pathology-related sensory-motor noise; the motor redundancy, i.e., an excess of elemental degrees of freedom that overcomes the number of variables underlying a specific task performance. In this study, we first tested the hypothesis that healthy and, especially, CA subjects can effectively exploit solutions in the domain of segmental angles to stabilize the position of either the foot or the pelvis (task performance) across heel strikes, in accordance with the uncontrolled manifold (UCM) theory. Next, we verified whether a specific perturbation-based training allows CA subjects to further take advantage of this coordination mechanism to better cope with their inherent pathology-related variability. Results always rejected the hypothesis of pelvis stabilization whereas supported the idea that the foot position is stabilized across heel strikes by a synergic covariation of elevation and azimuth angles of lower limb segments in CA subjects only. In addition, it was observed that the perturbation-based training involves a decreasing trend in the variance component orthogonal to the UCM in both groups, reflecting an improved accuracy of the foot control. Concluding, CA subjects can effectively structure the wide amount of pathology-related sensory-motor noise to stabilize specific task performance, such as the foot position across heel strikes. Moreover, the promising effects of the proposed perturbation-based training paradigm are expected to improve the coordinative strategy underlying the stabilization of the foot position across strides, thus ameliorating balance control during treadmill locomotion.

Effects of gait rehabilitation on motor coordination in stroke survivors: an UCM-based approach.

Post-stroke locomotion is usually characterized by asymmetrical gait patterns, compensatory movements of trunk and nonparetic limb, altered motor coordination, and wide inter-stride variability. This pilot study was designed to test a twofold hypothesis: post-stroke survivors can exploit the redundancy of the segmental angles to stabilize the 3D footpath trajectory during the swing phase, in accordance with the Uncontrolled Manifold (UCM) theory; an intense rehabilitative treatment improves both motor performance and outcomes of the UCM analysis. Ten stroke survivors underwent two evaluation sessions, before and after a conventional multidisciplinary intensive rehabilitation program, encompassing clinical tests and gait analysis, both overground and on treadmill. In addition, the UCM analysis was implemented to investigate whether variance of segmental angles is structured to minimize the inter-stride variability of the 3D footpath during the swing phase of treadmill locomotion. Both clinical and spatio-temporal parameters improved after the treatment, even if the statistical significance was reached for a limited set of them. The UCM analysis suggested that post-stroke survivors exploit the redundancy of lower limbs segmental angles mainly during the late swing, without significant differences between affected and unaffected sides. Thereafter, the main significant effects of the rehabilitative treatment consisted in strengthening the synergistic organization of the redundant segmental angles involving a more accurate control of the 3D footpath. Concluding, the UCM theory can be a promising tool to appraise the effects of a specific rehabilitative protocol on motor coordination in post-stroke survivors.

Brain network modulation in transradial amputee with finger perception restored through biomimetic intraneural stimulation.

INTRODUCTION/AIMS: The hand is a sophisticated tool which allows humans to interact with the external world mainly via the sense of touch. Previous evidences demonstrated that electrical stimulations of the nerve trunks governing the hand are able to restore touch perception in transradial amputees. The aim of this study was to evaluate the neurological correlates of restored perception by the evaluation of network characteristics of the brain connectome via EEG recordings in amputees utilizing a fully sensorized bionic hand. METHODS: A 48-year-old female with a left wrist traumatic disarticulation incurred 23 years prior to the study was enrolled for 6 months, during which experimental sessions were randomized. The control group included 12 healthy subjects performing a similar protocol. RESULTS: Results showed that in both amputee and control group, a trend of SW in delta and beta 1 is recognizable (Delta and Beta 1 opposite spread) selectively in the hemisphere contralateral to the stimulus. DISCUSSION: Delta increases (less orderly network) while Beta 1 decreases (more ordered network). It could be seen as a sign of higher attention and concentration of subjects to understand the perception and this monolateral modulation is similar to the bilateral attention given to the mathematical task difficulty's increment.

Data-driven body-machine interface for the accurate control of drones.

The accurate teleoperation of robotic devices requires simple, yet intuitive and reliable control interfaces. However, current human-machine interfaces (HMIs) often fail to fulfill these characteristics, leading to systems requiring an intensive practice to reach a sufficient operation expertise. Here, we present a systematic methodology to identify the spontaneous gesture-based interaction strategies of naive individuals with a distant device, and to exploit this information to develop a data-driven body-machine interface (BoMI) to efficiently control this device. We applied this approach to the specific case of drone steering and derived a simple control method relying on upper-body motion. The identified BoMI allowed participants with no prior experience to rapidly master the control of both simulated and real drones, outperforming joystick users, and comparing with the control ability reached by participants using the bird-like flight simulator Birdly.

Reactive Exercises with Interactive Objects: Interim Analysis of a Randomized Trial on Task-Driven NMES Grasp Rehabilitation for Subacute and Early Chronic Stroke Patients.

Enriched environments and tools are believed to promote grasp rehabilitation after stroke. We designed S2, an interactive grasp rehabilitation system consisting of smart objects, custom orthoses for selective grasp constraining, and an electrode array system for forearm NMES. Motor improvements and perceived usability of a new enriched upper limb training system for sub-acute stroke patients was assessed in this interim analysis. INCLUSION CRITERIA: sub-acute stroke patients with MMSE>20, ipsilesional MI>80%, and contralesional MI<80%. Effects of 30-min therapy supplements, conventional vs. S2 prototype, are compared through a parallel two-arms dose-matched open-label trial, lasting 27 sessions. Clinical centres: Asklepios Neurologische Klinik Falkenstein, Königstein im Taunus, Germany, and Clinica Villa Beretta, Costa Masnaga, Italy. Assessment scales: ARAT, System Usability, and Technology Acceptance. METHODOLOGY: 26 participants were block randomized, allocated to the study (control N=12, experimental N=14) and underwent the training protocol. Among them, 11 participants with ARAT score at inclusion below 35, n = 6 in the experimental group, and n = 5 in the control group were analysed. RESULTS: participants in the enriched treatment group displayed a larger improvement in the ARAT scale (+14.9 pts, pval=0.0494). Perceived usability differed between clinics. No adverse effect was observed in relation to the treatments. Trial status: closed. CONCLUSIONS: The S2 system, developed according to shared clinical directives, was tested in a clinical proof of concept. Variations of ARAT scores confirm the feasibility of clinical investigation for hand rehabilitation after stroke.

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

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

Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke.

Upper limb motor deficits in severe stroke survivors often remain unresolved over extended time periods. Novel neurotechnologies have the potential to significantly support upper limb motor restoration in severely impaired stroke individuals. Here, we review recent controlled clinical studies and reviews focusing on the mechanisms of action and effectiveness of single and combined technology-aided interventions for upper limb motor rehabilitation after stroke, including robotics, muscular electrical stimulation, brain stimulation and brain computer/machine interfaces. We aim at identifying possible guidance for the optimal use of these new technologies to enhance upper limb motor recovery especially in severe chronic stroke patients. We found that the current literature does not provide enough evidence to support strict guidelines, because of the variability of the procedures for each intervention and of the heterogeneity of the stroke population. The present results confirm that neurotechnology-aided upper limb rehabilitation is promising for severe chronic stroke patients, but the combination of interventions often lacks understanding of single intervention mechanisms of action, which may not reflect the summation of single intervention's effectiveness. Stroke rehabilitation is a long and complex process, and one single intervention administrated in a short time interval cannot have a large impact for motor recovery, especially in severely impaired patients. To design personalized interventions combining or proposing different interventions in sequence, it is necessary to have an excellent understanding of the mechanisms determining the effectiveness of a single treatment in this heterogeneous population of stroke patients. We encourage the identification of objective biomarkers for stroke recovery for patients' stratification and to tailor treatments. Furthermore, the advantage of longitudinal personalized trial designs compared to classical double-blind placebo-controlled clinical trials as the basis for precise personalized stroke rehabilitation medicine is discussed. Finally, we also promote the necessary conceptual change from 'one-suits-all' treatments within in-patient clinical rehabilitation set-ups towards personalized home-based treatment strategies, by adopting novel technologies merging rehabilitation and motor assistance, including implantable ones.

Motor improvement estimation and task adaptation for personalized robot-aided therapy: a feasibility study.

BACKGROUND: In the past years, robotic systems have become increasingly popular in upper limb rehabilitation. Nevertheless, clinical studies have so far not been able to confirm superior efficacy of robotic therapy over conventional methods. The personalization of robot-aided therapy according to the patients' individual motor deficits has been suggested as a pivotal step to improve the clinical outcome of such approaches. METHODS: Here, we present a model-based approach to personalize robot-aided rehabilitation therapy within training sessions. The proposed method combines the information from different motor performance measures recorded from the robot to continuously estimate patients' motor improvement for a series of point-to-point reaching movements in different directions. Additionally, it comprises a personalization routine to automatically adapt the rehabilitation training. We engineered our approach using an upper-limb exoskeleton. The implementation was tested with 17 healthy subjects, who underwent a motor-adaptation paradigm, and two subacute stroke patients, exhibiting different degrees of motor impairment, who participated in a pilot test undergoing rehabilitative motor training. RESULTS: The results of the exploratory study with healthy subjects showed that the participants divided into fast and slow adapters. The model was able to correctly estimate distinct motor improvement progressions between the two groups of participants while proposing individual training protocols. For the two pilot patients, an analysis of the selected motor performance measures showed that both patients were able to retain the improvements gained during training when reaching movements were reintroduced at a later stage. These results suggest that the automated training adaptation was appropriately timed and specifically tailored to the abilities of each individual. CONCLUSIONS: The results of our exploratory study demonstrated the feasibility of the proposed model-based approach for the personalization of robot-aided rehabilitation therapy. The pilot test with two subacute stroke patients further supported our approach, while providing encouraging results for the applicability in clinical settings. Trial registration This study is registered in ClinicalTrials.gov (NCT02770300, registered 30 March 2016, https://clinicaltrials.gov/ct2/show/NCT02770300).

A data-driven polynomial approach to reproduce the scar tissue outgrowth around neural implants.

Despite the huge complexity of the foreign body reaction, a quantitative assessment over time of the scar tissue thickness around implanted materials is needed to figure out the evolution of neural implants for long times. A data-driven approach, based on phenomenological polynomial functions, is able to reproduce experimental data. Nevertheless, a misuse of this strategy may lead to unsatisfactory results, even if standard indexes are optimized. In this work, an effective in silico procedure was presented to reproduce the scar tissue dynamics around implanted synthetic devices and to predict the capsule thickness for times before and after experimental detections.

Sensitivity to temporal parameters of intraneural tactile sensory feedback.

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

Bilateral Tactile Input Patterns Decoded at Comparable Levels But Different Time Scales in Neocortical Neurons.

The presence of contralateral tactile input can profoundly affect ipsilateral tactile perception, and unilateral stroke in somatosensory areas can result in bilateral tactile deficits, suggesting that bilateral tactile integration is an important part of brain function. Although previous studies have shown that bilateral tactile inputs exist and that there are neural interactions between inputs from the two sides, no previous study explored to what extent the local neuronal circuitry processing contains detailed information about the nature of the tactile input from the two sides. To address this question, we used a recently introduced approach to deliver a set of electrical, reproducible, tactile afferent, spatiotemporal activation patterns, which permits a high-resolution analysis of the neuronal decoding capacity, to the skin of the second forepaw digits of the anesthetized male rat. Surprisingly, we found that individual neurons of the primary somatosensory can decode contralateral and ipsilateral input patterns to comparable extents. Although the contralateral input was stronger and more rapidly decoded, given sufficient poststimulus processing time, ipsilateral decoding levels essentially caught up to contralateral levels. Moreover, there was a weak but significant correlation for neurons with high decoding performance for contralateral tactile input to also perform well on decoding ipsilateral input. Our findings shed new light on the brain mechanisms underlying bimanual haptic integration.SIGNIFICANCE STATEMENT Here we demonstrate that the spiking activity of single neocortical neurons in the somatosensory cortex of the rat can be used to decode patterned tactile stimuli delivered to the distal ventral skin of the second forepaw digits on both sides of the body. Even though comparable levels of decoding of the tactile input were achieved faster for contralateral input, given sufficient integration time each neuron was found to decode ipsilateral input with a comparable level of accuracy. Given that the neocortical neurons could decode ipsilateral inputs with such small differences between the patterns suggests that S1 cortex has access to very precise information about ipsilateral events. The findings shed new light on possible network mechanisms underlying bimanual haptic processing.

Functional imaging of rostrocaudal spinal activity during upper limb motor tasks.

The spinal cord is the main interface between the brain and the periphery. It notably plays a central role in motor control, as spinal motoneurons activate skeletal muscles involved in voluntary movements. Yet, the spinal mechanisms underlying human movement generation have not been completely elucidated. In this regard, functional magnetic resonance imaging (fMRI) represents a potential tool to probe spinal cord function non-invasively and with high spatial resolution. Nonetheless, a thorough characterization of this approach is still lacking, currently limiting its impact. Here, we aimed at systematically quantifying to which extent fMRI can reveal spinal cord activity along the rostrocaudal direction. We investigated changes in the blood oxygenation level dependent signal of the human cervical spinal cord during bimanual upper limb movements (wrist extension, wrist adduction and finger abduction) in nineteen healthy volunteers. Prior to scanning, we recorded the muscle activity associated with these movements in order to reconstruct the theoretical motor-pool output pattern using an anatomy-based mapping of the electromyographic (EMG) waveforms. EMG-derived spinal maps were characterized by distinct rostrocaudal patterns of activation, thus confirming the task-specific features of the different movements. Analogous activation patterns were captured using spinal cord fMRI. Finally, an additional fMRI dataset was acquired from a subset of the participants (n = 6) to deploy a multivoxel pattern analysis, which allowed successful decoding of movements. These combined results suggest that spinal cord fMRI can be used to image rostrocaudal activation patterns reflecting the underlying activity of the motoneuron pools innervating the task-related muscles. Spinal cord fMRI offers the prospect of a novel tool to study motor processes and potentially their modification following neurological motor disorders.