In-vivo testing of a novel wireless intraspinal microstimulation interface for restoration of motor function following spinal cord injury.

BACKGROUND: Spinal cord injury causes a drastic loss in motor and sensory function. Intraspinal microstimulation (ISMS) is an electrical stimulation method developed for restoring motor function by activating the spinal networks below the level of injury. Current ISMS technology uses fine penetrating microwires to stimulate the ventral horn of the lumbar enlargement. The penetrating wires traverse the dura mater through a transdural conduit that connects to an implantable pulse generator. OBJECTIVE: A wireless, fully intradural ISMS implant was developed to mitigate the potential complications associated with the transdural conduit, including tethering and leakage of cerebrospinal fluid. METHODS: Two wireless floating microelectrode array (WFMA) devices were implanted in the lumbar enlargement of an adult domestic pig. Voltage transients were used to assess the electrochemical stability of the interface. Manual flexion and extension movements of the spine were performed to evaluate the mechanical stability of the interface. Post-mortem 9T MRI imaging was used to confirm the location of the electrodes. RESULTS: The WFMA-based ISMS interface successfully evoked extension and flexion movements of the hip joint. Stimulation thresholds remained stable following manual extension and flexion of the spine. CONCLUSION: The preliminary results demonstrate the surgical feasibility as well as the functionality of the proposed wireless ISMS system.

Bimanual coordination and spinal cord neuromodulation: how neural substrates of bimanual movements are altered by transcutaneous spinal cord stimulation.

Humans use their arms in complex ways that often demand two-handed coordination. Neurological conditions limit this impressive feature of the human motor system. Understanding how neuromodulatory techniques may alter neural mechanisms of bimanual coordination is a vital step towards designing efficient rehabilitation interventions. By non-invasively activating the spinal cord, transcutaneous spinal cord stimulation (tSCS) promotes recovery of motor function after spinal cord injury. A multitude of research studies have attempted to capture the underlying neural mechanisms of these effects using a variety of electrophysiological tools, but the influence of tSCS on cortical rhythms recorded via electroencephalography remains poorly understood, especially during bimanual actions. We recruited 12 neurologically intact participants to investigate the effect of cervical tSCS on sensorimotor cortical oscillations. We examined changes in the movement kinematics during the application of tSCS as well as the cortical activation level and interhemispheric connectivity during the execution of unimanual and bimanual arm reaching movements that represent activities of daily life. Behavioral assessment of the movements showed improvement of movement time and error during a bimanual common-goal movement when tSCS was delivered, but no difference was found in the performance of unimanual and bimanual dual-goal movements with the application of tSCS. In the alpha band, spectral power was modulated with tSCS in the direction of synchronization in the primary motor cortex during unimanual and bimanual dual-goal movements and in the somatosensory cortex during unimanual movements. In the beta band, tSCS significantly increased spectral power in the primary motor and somatosensory cortices during the performance of bimanual common-goal and unimanual movements. A significant increase in interhemispheric connectivity in the primary motor cortex in the alpha band was only observed during unimanual tasks in the presence of tSCS. Our observations provide, for the first time, information regarding the supra-spinal effects of tSCS as a neuromodulatory technique applied to the spinal cord during the execution of bi- and unimanual arm movements. They also corroborate the suppressive effect of tSCS at the cortical level reported in previous studies. These findings may guide the design of improved rehabilitation interventions using tSCS for the recovery of upper-limb function in the future.

The use of digital image correlation for measurement of strain fields in a novel wireless intraspinal microstimulation interface.

BACKGROUND: Intraspinal microstimulation (ISMS) has emerged as a promising neuromodulation technique for restoring standing and overground walking in individuals with spinal cord injury. Current and emerging ISMS implant designs connect the electrodes to the stimulator through lead wires that cross the dura mater. To reduce possible complications associated with transdural leads such as tethering and leakage of cerebrospinal fluid, we aim to develop a wireless, fully intradural ISMS implant based on our prior work in the cortex with the Wireless Floating Microelectrode Array (WFMA). Although we have extensive data about WFMA cortical stability, its mechanical and electrical stability in the spinal cord remains unknown. One of the quantifiable metrics to assess long-term implant stability is mechanical strain. OBJECTIVE: The aim of the current work is to develop a method to assess implant stability by measuring strain fields in a surrogate of the human spinal cord. METHODS: A physical model of the spinal cord was studied using an electromechanical testing apparatus, simulating typical spinal cord motion. Strain fields were digitally analyzed using an optical method known as digital image correlation (DIC). RESULTS: Displacement and strain were visualized using contour plots. The strain values in the vicinity of each WFMA device were significantly different from the strain values in the same locations in the control surrogate spinal cord. CONCLUSION: The results demonstrate that DIC can be used for in-vitro screening of intraspinal implants. Accurate optical strain measurements will enable researchers to optimize implant design over a wide range of motion conditions.

Transcutaneous spinal cord stimulation of the cervical cord modulates lumbar networks.

It has been established that coordinated arm and leg (A&L) cycling facilitates corticospinal drive and modulation of cervico-lumbar connectivity and ultimately improves overground walking in people with incomplete spinal cord injury or stroke. This study examined the effect of noninvasive transcutaneous spinal cord stimulation (tSCS) on the modulation of cervico-lumbar connectivity. Thirteen neurologically intact adults participated in the study. The excitability of the Hoffmann (H) reflex elicited in the soleus muscle was examined under multiple conditions involving either the arms held in a static position or rhythmic arm cycling while tSCS was applied to either the cervical or lumbar cord. As expected, soleus H-reflex amplitude was significantly suppressed by 19.2% during arm cycling (without tSCS) relative to arms static (without tSCS). Interestingly, tSCS of the cervical cord with arms static significantly suppressed the soleus H-reflex (-22.9%), whereas tSCS over the lumbar cord did not suppress the soleus H-reflex (-3.8%). The combination of arm cycling with cervical or lumbar tSCS did not yield additional suppression of the soleus H-reflex beyond that obtained with arm cycling alone or cervical tSCS alone. The results demonstrate that activation of the cervical spinal cord through both rhythmic arm cycling and tonic tSCS significantly modulates the activity of lumbar networks. This highlights the potential for engaging cervical spinal cord networks through tSCS during rehabilitation interventions to enhance cervico-lumbar connectivity. This connectivity is influential in facilitating improvements in walking function after neurological impairment.NEW & NOTEWORTHY This is the first study to investigate the modulatory effects of transcutaneous spinal cord stimulation (tSCS) on cervico-lumbar connectivity. We report that both rhythmic activation of the cervical spinal cord through arm cycling and tonic activation of the cervical cord through tSCS significantly modulate the activity of lumbar networks. This suggests that engaging cervical spinal cord networks through tSCS during locomotor retraining interventions may not only enhance cervico-lumbar connectivity but also further improve walking capacity.

Non-gait-specific intervention for the rehabilitation of walking after SCI: role of the arms.

Arm movements modulate leg activity and improve gait efficiency; however, current rehabilitation interventions focus on improving walking through gait-specific training and do not actively involve the arms. The goal of this project was to assess the effect of a rehabilitation strategy involving simultaneous arm and leg cycling on improving walking after incomplete spinal cord injury (iSCI). We investigated the effect of 1) non-gait-specific training and 2) active arm involvement during training on changes in over ground walking capacity. Participants with iSCI were assigned to simultaneous arm-leg cycling (A&L) or legs only cycling (Leg) training paradigms, and cycling movements were assisted with electrical stimulation. Overground walking speed significantly increased by 0.092 ± 0.022 m/s in the Leg group and 0.27 ± 0.072m/s in the A&L group after training. Whereas the increases in the Leg group were similar to those seen after current locomotor training strategies, increases in the A&L group were significantly larger than those in the Leg group. Walking distance also significantly increased by 32.12 ± 8.74 m in the Leg and 91.58 ± 36.24 m in the A&L group. Muscle strength, sensation, and balance improved in both groups; however, the A&L group had significant improvements in most gait measures and had more regulated joint kinematics and muscle activity after training compared with the Leg group. We conclude that electrical stimulation-assisted cycling training can produce significant improvements in walking after SCI. Furthermore, active arm involvement during training can produce greater improvements in walking performance. This strategy may also be effective in people with other neural disorders or diseases. NEW & NOTEWORTHY This work challenges concepts of task-specific training for the rehabilitation of walking and encourages coordinated training of the arms and legs after spinal cord injury. Cycling of the legs produced significant improvements in walking that were similar in magnitude to those reported with gait-specific training. Moreover, active engagement of the arms simultaneously with the legs generated nearly double the improvements obtained by leg training only. The cervico-lumbar networks are critical for the improvement of walking.

Hyaluronic acid-based 3D culture model for in vitro testing of electrode biocompatibility.

This work describes the development of a robust and repeatable in vitro 3D culture model of glial scarring, which may be used to evaluate the foreign body response to electrodes and other implants in the central nervous system. The model is based on methacrylated hyaluronic acid, a hydrogel that may be photopolymerized to form an insoluble network. Hydrogel scaffolds were formed at four different macromer concentrations (0.50, 0.75, 1.00, and 1.50% (w/v)). As expected, the elastic modulus of the scaffolds increased with increasing macromer weight fraction. Adult rat brain tested under identical conditions had an elastic modulus range that spanned the elastic modulus of both the 0.50 and 0.75% (w/v) hydrogel samples. Gels formed with higher macromer weight fraction had decreased equilibrium swelling ratio and visibly thicker pore walls relative to gels formed with lower macromer weight fractions. Mixed glial cells (microglia and astrocytes) were then encapsulated in the HA scaffolds. Viability of the mixed cultures was most stable at a cell density of 1 × 10(7) cells/mL. Cell viability at the highest macromer weight fraction tested (1.50% (w/v)) was significantly lower than other tested gels (0.50, 0.75 and 1.00% (w/v)). The inflammatory response of microglia and astrocytes to a microelectrode inserted into the scaffold was assessed over a period of 2 weeks and closely represented that reported in vivo. Microglia responded first to the electrode (increased cell density at the electrode, and activated morphology) followed by astrocytes (appeared to line the electrode in a manner similar to glial scarring). All together, these results demonstrate the potential of the 3D in vitro model system to assess glial scarring in a robust and repeatable manner.

The mechanisms and evidence of efficacy of electrical stimulation for healing of pressure ulcer: a systematic review.

The objective of this article is to provide a systematic review of the efficacy of electrical stimulation in healing pressure ulcer and to review its mechanism of action. The Cochrane Library, PubMed, CINAHL, Medline, EMBASE, and NHS EED were searched for relevant interventional studies including randomized controlled trials (RCTs) and observational studies. A best-evidence synthesis was performed to summarize the results of the included studies. A total of seven RCTs and two observational studies met the inclusion criteria. Moderate level of evidence of efficacy with low risk of bias was shown in all seven RCTs. Although some studies have used continuous direct current, most other investigators opted to use high-voltage pulsed current to minimize the risk of skin burn and to achieve greater current penetration. Overall, the incidence of adverse effects was very low. Two studies that assessed the economic impacts of electrical stimulation revealed substantial health care cost savings. The mechanisms through which electrical stimulation exerts a positive effect on pressure ulcer healing are reasonably well established. Clinical trials have revealed a moderate level of evidence to support its use as an ancillary treatment modality for healing pressure ulcer. Recommendations regarding the optimal electrical stimulation parameters and dosage of use are provided. Further studies to investigate potential barriers that may impede widespread use in different clinical settings are needed.

In vitro biocompatibility evaluation of functional electrically stimulating microelectrodes on primary glia.

Neural interfacing devices interact with the central nervous system to alleviate functional deficits arising from disease or injury. This often entails the use of invasive microelectrode implants that elicit inflammatory responses from glial cells and leads to loss of device function. Previous work focused on improving implant biocompatibility by modifying electrode composition; here, we investigated the direct effects of electrical stimulation on glial cells at the electrode interface. A high-throughput in vitro system that assesses primary glial cell response to biphasic stimulation waveforms at 0 mA, 0.15 mA, and 1.5 mA was developed and optimized. Primary mixed glial cell cultures were generated from heterozygous CX3CR-1+/EGFP mice, electrically stimulated for 4 h/day over 3 days using 75 µm platinum-iridium microelectrodes, and biomarker immunofluorescence was measured. Electrodes were then imaged on a scanning electron microscope to assess sustained electrode damage. Fluorescence and electron microscopy analyses suggest varying degrees of localized responses for each biomarker assayed (Hoescht, EGFP, GFAP, and IL-1ß), a result that expands on comparable in vivo models. This system allows for the comparison of a breadth of electrical stimulation parameters, and opens another avenue through which neural interfacing device developers can improve biocompatibility and longevity of electrodes in tissue.

REPORT-SCS: minimum reporting standards for spinal cord stimulation studies in spinal cord injury.

Objective.Electrical spinal cord stimulation (SCS) has emerged as a promising therapy for recovery of motor and autonomic dysfunctions following spinal cord injury (SCI). Despite the rise in studies using SCS for SCI complications, there are no standard guidelines for reporting SCS parameters in research publications, making it challenging to compare, interpret or reproduce reported effects across experimental studies.Approach.To develop guidelines for minimum reporting standards for SCS parameters in pre-clinical and clinical SCI research, we gathered an international panel of expert clinicians and scientists. Using a Delphi approach, we developed guideline items and surveyed the panel on their level of agreement for each item.Main results.There was strong agreement on 26 of the 29 items identified for establishing minimum reporting standards for SCS studies. The guidelines encompass three major SCS categories: hardware, configuration and current parameters, and the intervention.Significance.Standardized reporting of stimulation parameters will ensure that SCS studies can be easily analyzed, replicated, and interpreted by the scientific community, thereby expanding the SCS knowledge base and fostering transparency in reporting.

Safety of mapping the motor networks in the spinal cord using penetrating microelectrodes in Yucatan minipigs.

OBJECTIVE: The goal of this study was to assess the safety of mapping spinal cord locomotor networks using penetrating stimulation microelectrodes in Yucatan minipigs (YMPs) as a clinically translational animal model. METHODS: Eleven YMPs were trained to walk up and down a straight line. Motion capture was performed, and electromyographic (EMG) activity of hindlimb muscles was recorded during overground walking. The YMPs underwent a laminectomy and durotomy to expose the lumbar spinal cord. Using an ultrasound-guided stereotaxic frame, microelectrodes were inserted into the spinal cord in 8 animals. Pial cuts were made to prevent tissue dimpling before microelectrode insertion. Different locations within the lumbar enlargement were electrically stimulated to map the locomotor networks. The remaining 3 YMPs served as sham controls, receiving the laminectomy, durotomy, and pial cuts but not microelectrode insertion. The Porcine Thoracic Injury Behavioral Scale (PTIBS) and hindlimb reflex assessment results were recorded for 4 weeks postoperatively. Overground gait kinematics and hindlimb EMG activity were recorded again at weeks 3 and 4 postoperatively and compared with preoperative measures. The animals were euthanized at the end of week 4, and the lumbar spinal cords were extracted and preserved for immunohistochemical analysis. RESULTS: All YMPs showed transient deficits in hindlimb function postoperatively. Except for 1 YMP in the experimental group, all animals regained normal ambulation and balance (PTIBS score 10) at the end of weeks 3 and 4. One animal in the experimental group showed gait and balance deficits by week 4 (PTIBS score 4). This animal was excluded from the kinematics and EMG analyses. Overground gait kinematic measures and EMG activity showed no significant (p > 0.05) differences between preoperative and postoperative values, and between the experimental and sham groups. Less than 5% of electrode tracks were visible in the tissue analysis of the animals in the experimental group. There was no statistically significant difference in damage caused by pial cuts between the experimental and sham groups. Tissue damage due to the pial cuts was more frequently observed in immunohistochemical analyses than microelectrode tracks. CONCLUSIONS: These findings suggest that mapping spinal locomotor networks in porcine models can be performed safely, without lasting damage to the spinal cord.

Laser-Microfabricated Polymer Multielectrodes for Intraspinal Microstimulation.

OBJECTIVE: The overall goal of this study was to design, fabricate, and characterize a new polymer-based multielectrode for the spinal cord for the application of intraspinal microstimulation (ISMS). METHODS: Three-channel multielectrodes were fabricated from modified poly(dimethylsiloxane) (PDMS) and platinum-iridium (Pt-Ir) foil using nanosecond laser microfabrication techniques. These devices were compared against traditional 50 µm diameter Pt-Ir microwire electrodes mechanically and electrochemically in bench environments, and were assessed electrochemically and functionally in vivo in a domestic pig model. RESULTS: Polymer-based multielectrodes were significantly more flexible than microwire electrodes (p < 0.05) and had greater charge storage capacities in phosphate buffered saline (p < 0.05). In a domestic pig model, multielectrodes had significantly greater charge injection limits than microwire electrodes (p < 0.05). When stimulating within the quadriceps motor pool in the spinal cord, multielectrodes generated strong knee extensor joint torques of up to 4.4 ± 0.3 Nm and were able to extend the knee by up to 26 ± 1°. However, histological analyses showed that polymer-based multielectrodes, implanted with half-needle insertion aids, produced greater acute tissue damage compared to microwire electrodes (p < 0.05). Alternative insertion methods for these flexible electrodes should be explored to reduce acute tissue damage. CONCLUSION: The PDMS-based three-channel multielectrodes demonstrated improved flexibility and charge injection capabilities over traditional microwire electrodes, and were able to produce functional responses in vivo. SIGNIFICANCE: Polymer-based multielectrodes demonstrate improved functionality over microwire electrodes while remaining more flexible than silicon multielectrode designs. These features may in the future permit polymer-based multielectrodes to implement ISMS with greater efficacy and biocompatibility compared to traditional technologies.

Neural Substrates of Transcutaneous Spinal Cord Stimulation: Neuromodulation across Multiple Segments of the Spinal Cord.

Transcutaneous spinal cord stimulation (tSCS) has the potential to promote improved sensorimotor rehabilitation by modulating the circuitry of the spinal cord non-invasively. Little is currently known about how cervical or lumbar tSCS influences the excitability of spinal and corticospinal networks, or whether the synergistic effects of multi-segmental tSCS occur between remote segments of the spinal cord. The aim of this review is to describe the emergence and development of tSCS as a novel method to modulate the spinal cord, while highlighting the effectiveness of tSCS in improving sensorimotor recovery after spinal cord injury. This review underscores the ability of single-site tSCS to alter excitability across multiple segments of the spinal cord, while multiple sites of tSCS converge to facilitate spinal reflex and corticospinal networks. Finally, the potential and current limitations for engaging cervical and lumbar spinal cord networks through tSCS to enhance the effectiveness of rehabilitation interventions are discussed. Further mechanistic work is needed in order to optimize targeted rehabilitation strategies and improve clinical outcomes.

Impedance Variation and Learning Strategies in Human-Robot Interaction.

In this survey, various concepts and methodologies developed over the past two decades for varying and learning the impedance or admittance of robotic systems that physically interact with humans are explored. For this purpose, the assumptions and mathematical formulations for the online adjustment of impedance models and controllers for physical human-robot interaction (HRI) are categorized and compared. In this systematic review, studies on: 1) variation and 2) learning of appropriate impedance elements are taken into account. These strategies are classified and described in terms of their objectives, points of view (approaches), and signal requirements (including position, HRI force, and electromyography activity). Different methods involving linear/nonlinear analyses (e.g., optimal control design and nonlinear Lyapunov-based stability guarantee) and the Gaussian approximation algorithms (e.g., Gaussian mixture model-based and dynamic movement primitives-based strategies) are reviewed. Current challenges and research trends in physical HRI are finally discussed.

Machine-learned Adaptive Switching in Voluntary Lower-limb Exoskeleton Control: Preliminary Results.

Lower-limb exoskeletons utilize fixed control strategies and are not adaptable to user's intention. To this end, the goal of this study was to investigate the potential of using temporal-difference learning and general value functions for predicting the next possible walking mode that will be selected by users wearing exoskeletons in order to reduce the effort and cognitive load while switching between different modes of walking. Experiments were performed with a user wearing the Indego exoskeleton and given the authority to switch between five walking modes that were different in terms of speed and turn direction. The user's switching preferences were learned and predicted from device-centric and room-centric measurements by considering similarities in the movements being performed. A switching list was updated to show the most probable future next modes to be selected by the user. In contrast to other approaches that either can only predict a single time-step or require intensive offline training, this work used a computationally inexpensive method for learning and has the potential of providing temporally extended sets of predictions in real-time. Comparing the number of required manual switches between the machine-learned switching list and the best possible static lists showed an average decrease of 42.44% in the required switches for the machine-learned adaptive strategy. These promising results will facilitate the path for real-time application of this technique.

Overground gait kinematics and muscle activation patterns in the Yucatan mini pig.

Objective.The objectives of this study were to assess gait biomechanics and the effect of overground walking speed on gait parameters, kinematics, and electromyographic (EMG) activity in the hindlimb muscles of Yucatan minipigs (YMPs).Approach.Nine neurologically-intact, adult YMPs were trained to walk overground in a straight line. Whole-body kinematics and EMG activity of hindlimb muscles were recorded and analyzed at six different speed ranges (0.4-0.59, 0.6-0.79, 0.8-0.99, 1.0-1.19, 1.2-1.39, and 1.4-1.6 m s-1). A MATLAB program was developed to detect strides and gait events automatically from motion-captured data. The kinematics and EMG activity were analyzed for each stride based on the detected events.Main results.Significant decreases in stride duration, stance and swing times and an increase in stride length were observed with increasing speed. A transition in gait pattern occurred at the 1.0 m s-1walking speed. Significant increases in the range of motion of the knee and ankle joints were observed at higher speeds. Also, the points of minimum and maximum joint angles occurred earlier in the gait cycle as the walking speed increased. The onset of EMG activity in the biceps femoris muscle occurred significantly earlier in the gait cycle with increasing speed.Significance.YMPs are becoming frequently used as large animal models for preclinical testing and translation of novel interventions to humans. A comprehensive characterization of overground walking in neurologically-intact YMPs is provided in this study. These normative measures set the basis against which the effects of future interventions on locomotor capacity in YMPs can be compared.

The effects of intermittent electrical stimulation on the prevention of deep tissue injury: varying loads and stimulation paradigms.

A pressure ulcer is a medical complication that arises in persons with decreased mobility and/or sensation. Deep pressure ulcers starting at the bone-muscle interface are the most dangerous, as they can cause extensive damage before showing any signs at the skin surface. We previously proposed a novel intervention called intermittent electrical stimulation (IES) for the prevention of deep tissue injury (DTI). In this study, we tested the effects of four paradigms of IES and one conventional pressure relief paradigm in preventing the formation of deep pressure ulcers in rats. Loading equivalent to 18, 28, or 38% of the body weight (BW) of each rat was applied to the triceps surae muscle in one hind limb. Treatment groups received IES every 10 min for either (i) 5 or 10 s with moderate or maximal contraction, or (ii) complete pressure removal every 10 min for 10 s (conventional pressure relief). The results showed that conventional pressure relief, emulating a wheelchair push-up every 10 min, was inadequate for the prevention of DTI. In contrast, all IES paradigms were equally effective in significantly reducing the extent of deep muscle damage caused by 28 or 38% BW pressure application. These findings suggest that, in conjunction with existing techniques, IES may be an effective intervention for the prophylactic prevention of DTI.

Simultaneous Cervical and Lumbar Spinal Cord Stimulation Induces Facilitation of Both Spinal and Corticospinal Circuitry in Humans.

Coupling between cervical and lumbar spinal networks (cervico-lumbar coupling) is vital during human locomotion. Impaired cervico-lumbar coupling after neural injuries or diseases can be reengaged via simultaneous arm and leg cycling training. Sensorimotor circuitry including cervico-lumbar coupling may further be enhanced by non-invasive modulation of spinal circuity using transcutaneous spinal cord stimulation (tSCS). This project aimed to determine the effect of cervical, lumbar, or combined tSCS on spinal reflex (Hoffmann [H-]) and corticospinal (motor evoked potential [MEP]) excitability during a static or cycling cervico-lumbar coupling task. Fourteen neurologically intact study participants were seated in a recumbent leg cycling system. H-reflex and MEP amplitudes were assessed in the left flexor carpi radialis (FCR) muscle during two tasks (Static and Cycling) and four conditions: (1) No tSCS, (2) tSCS applied to the cervical enlargement (Cervical); (3) tSCS applied to the lumbar enlargement (Lumbar); (4) simultaneous cervical and lumbar tSCS (Combined). While cervical tSCS did not alter FCR H-reflex amplitude relative to No tSCS, lumbar tSCS significantly facilitated H-reflex amplitude by 11.1%, and combined cervical and lumbar tSCS significantly enhanced the facilitation to 19.6%. Neither cervical nor lumbar tSCS altered MEP amplitude alone (+4.9 and 1.8% relative to legs static, No tSCS); however, combined tSCS significantly increased MEP amplitude by 19.7% compared to No tSCS. Leg cycling alone significantly suppressed the FCR H-reflex relative to static, No tSCS by 13.6%, while facilitating MEP amplitude by 18.6%. When combined with leg cycling, tSCS was unable to alter excitability for any condition. This indicates that in neurologically intact individuals where interlimb coordination and corticospinal tract are intact, the effect of leg cycling on cervico-lumbar coupling and corticospinal drive was not impacted significantly with the tSCS intensity used. This study demonstrates, for the first time, that tonic activation of spinal cord networks through multiple sites of tSCS provides a facilitation of both spinal reflex and corticospinal pathways. It remains vital to determine if combined tSCS can influence interlimb coupling after neural injury or disease when cervico-lumbar connectivity is impaired.

Variety Is the Spice of Life: Positive and Negative Effects of Noise in Electrical Stimulation of the Nervous System.

Noisy stimuli may hold the key for optimal electrical stimulation of the nervous system. Possible mechanisms of noise's impact upon neuronal function are discussed, including intracellular, extracellular, and systems-level mechanisms. Specifically, channel resonance, stochastic resonance, high conductance states, and network binding are investigated. These mechanisms are examined and possible directions of growth for the field are discussed, with examples of applications provided from the fields of deep brain stimulation or spinal cord injury. Together, this review highlights the theoretical basis and evidence base for the use of noise to enhance current stimulation paradigms of the nervous system.

Comparative neuroanatomy of the lumbosacral spinal cord of the rat, cat, pig, monkey, and human.

The overall goal of this work was to create a high-resolution MRI atlas of the lumbosacral enlargement of the spinal cord of the rat (Sprague-Dawley), cat, domestic pig, rhesus monkey, and human. These species were chosen because they are commonly used in basic and translational research in spinal cord injuries and diseases. Six spinal cord specimens from each of the studied species (total of 30 specimens) were fixed, extracted, and imaged. Sizes of the spinal cord segments, cross-sectional dimensions, and locations of the spinal cord gray and white matter were quantified and compared across species. The lumbar enlargement spans spinal cord levels L3-S1 in rats, L4-S1 in cats, L3-S1 in pigs, L2/L3-L7/S1 in monkeys, and T12/L1-S1/S2 in humans. The enlargements in pigs and humans are largest and most similar in size (length and cross-sectional area); followed by monkeys and cats; and followed by rats. The obtained atlas establishes a neuroanatomical reference for the intact lumbosacral spinal cord in these species. It can also be used to guide the planning of surgical procedures of the spinal cord and technology design and development of spinal cord neuroprostheses, as well as precise delivery of cells/drugs into target regions within the spinal cord parenchyma.

Pavlovian control of intraspinal microstimulation to produce over-ground walking.

OBJECTIVE: Neuromodulation technologies are increasingly used for improving function after neural injury. To achieve a symbiotic relationship between device and user, the device must augment remaining function, and independently adapt to day-to-day changes in function. The goal of this study was to develop predictive control strategies to produce over-ground walking in a model of hemisection spinal cord injury (SCI) using intraspinal microstimulation (ISMS). APPROACH: Eight cats were anaesthetized and placed in a sling over a walkway. The residual function of a hemisection SCI was mimicked by manually moving one hind-limb through the walking cycle. ISMS targeted motor networks in the lumbosacral enlargement to activate muscles in the other, presumably 'paralyzed' limb, using low levels of current (<130 µA). Four people took turns to move the 'intact' limb, generating four different walking styles. Two control strategies, which used ground reaction force and angular velocity information about the manually moved 'intact' limb to control the timing of the transitions of the 'paralyzed' limb through the step cycle, were compared. The first strategy used thresholds on the raw sensor values to initiate transitions. The second strategy used reinforcement learning and Pavlovian control to learn predictions about the sensor values. Thresholds on the predictions were then used to initiate transitions. MAIN RESULTS: Both control strategies were able to produce alternating, over-ground walking. Transitions based on raw sensor values required manual tuning of thresholds for each person to produce walking, whereas Pavlovian control did not. Learning occurred quickly during walking: predictions of the sensor signals were learned rapidly, initiating correct transitions after ≤4 steps. Pavlovian control was resilient to different walking styles and different cats, and recovered from induced mistakes during walking. SIGNIFICANCE: This work demonstrates, for the first time, that Pavlovian control can augment remaining function and facilitate personalized walking with minimal tuning requirements.