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Neuromodulation of spinal networks can improve motor control after spinal cord injury (SCI). The objectives of this study were to (1) determine whether individuals with chronic paralysis can stand with the aid of non-invasive electrical spinal stimulation with their knees and hips extended without trainer assistance, and (2) investigate whether postural control can be further improved following repeated sessions of stand training. Using a double-blind, balanced, within-subject cross-over, and sham-controlled study design, 15 individuals with SCI of various severity received transcutaneous electrical spinal stimulation to regain self-assisted standing. The primary outcomes included qualitative comparison of need of external assistance for knee and hip extension provided by trainers during standing without and in the presence of stimulation in the same participants, as well as quantitative measures, such as the level of knee assistance and amount of time spent standing without trainer assistance. None of the participants could stand unassisted without stimulation or in the presence of sham stimulation. With stimulation all participants could maintain upright standing with minimum and some ( n  = 7) without external assistance applied to the knees or hips, using their hands for upper body balance as needed. Quality of balance control was practice-dependent, and improved with subsequent training. During self-initiated body-weight displacements in standing enabled by spinal stimulation, high levels of leg muscle activity emerged, and depended on the amount of muscle loading. Our findings indicate that the lumbosacral spinal networks can be modulated transcutaneously using electrical spinal stimulation to facilitate self-assisted standing after chronic motor and sensory complete paralysis.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI.

Electrical neuromodulation of spinal networks improves the control of movement of the paralyzed limbs after spinal cord injury (SCI). However, the potential of noninvasive spinal stimulation to facilitate postural trunk control during sitting in humans with SCI has not been investigated. We hypothesized that transcutaneous electrical stimulation of the lumbosacral enlargement can improve trunk posture. Eight participants with non-progressive SCI at C3-T9, American Spinal Injury Association Impairment Scale (AIS) A or C, performed different motor tasks during sitting. Electromyography of the trunk muscles, three-dimensional kinematics, and force plate data were acquired. Spinal stimulation improved trunk control during sitting in all tested individuals. Stimulation resulted in elevated activity of the erector spinae, rectus abdominis, and external obliques, contributing to improved trunk control, more natural anterior pelvic tilt and lordotic curve, and greater multi-directional seated stability. During spinal stimulation, the center of pressure (COP) displacements decreased to 1.36 ± 0.98 mm compared with 4.74 ± 5.41 mm without stimulation (p = 0.0156) in quiet sitting, and the limits of stable displacement increased by 46.92 ± 35.66% (p = 0.0156), 36.92 ± 30.48% (p = 0.0156), 54.67 ± 77.99% (p = 0.0234), and 22.70 ± 26.09% (p = 0.0391) in the forward, backward, right, and left directions, respectively. During self-initiated perturbations, the correlation between anteroposterior arm velocity and the COP displacement decreased from r = 0.5821 (p = 0.0007) without to r = 0.5115 (p = 0.0039) with stimulation, indicating improved trunk stability. These data demonstrate that the spinal networks can be modulated transcutaneously with tonic electrical spinal stimulation to physiological states sufficient to generate a more stable, erect sitting posture after chronic paralysis.

Paralysis of the upper extremities following cervical spinal cord injury (SCI) significantly impairs one's ability to live independently. While regaining hand function or grasping ability is considered one of the most desired functions in tetraplegics, limited therapeutic development in this direction has been demonstrated to date in humans with a high severe cervical injury. The underlying hypothesis is that after severe cervical SCI, nonfunctional sensory-motor networks within the cervical spinal cord can be transcutaneously neuromodulated to physiological states that enable and amplify voluntary control of the hand. Improved voluntary hand function occurred within a single session in every subject tested. After eight sessions of non-invasive transcutaneous stimulation, combined with training over 4 weeks, maximum voluntary hand grip forces increased by ∼325% (in the presence of stimulation) and ∼225% (when grip strength was tested without simultaneous stimulation) in chronic cervical SCI subjects (American Spinal Injury Association Impairment Scale [AIS] B, n = 3; AIS C, n = 5) 1-21 years post-injury). Maximum grip strength improved in both the left and right hands and the magnitude of increase was independent of hand dominance. We refer to the neuromodulatory method used as transcutaneous enabling motor control to emphasize that the stimulation parameters used are designed to avoid directly inducing muscular contractions, but to enable task performance according to the subject's voluntary intent. In some subjects, there were improvements in autonomic function, lower extremity motor function, and sensation below the level of the lesion. Although a neuromodulation-training effect was observed in every subject tested, further controlled and blinded studies are needed to determine the responsiveness of a larger and broader population of subjects varying in the type, severity, and years post-injury. It appears rather convincing, however, that a "central pattern generation" phenomenon as generally perceived in the lumbosacral networks in controlling stepping neuromodulator is not a critical element of spinal neuromodulation to regain function among spinal networks.

Despite autonomic dysfunction after spinal cord injury (SCI) being the major cause of death and a top health priority, the clinical management options for these conditions are limited to drugs with delayed onset and nonpharmacological interventions with equivocal effectiveness. We tested the capacity of electrical stimulation, applied transcutaneously over the spinal cord, to manage autonomic dysfunction in the form of orthostatic hypotension after SCI. We assessed beat-by-beat blood pressure (BP), stroke volume, and cardiac contractility (dP/dt; Finometer), as well as cerebral blood flow (transcranial Doppler) in 5 individuals with motor-complete SCI (4 cervical, 1 thoracic) during an orthostatic challenge with and without transcutaneous electrical stimulation applied at the TVII level. During the orthostatic challenge, all individuals experienced hypotension characterized by a 37 ± 4 mm Hg decrease in systolic BP, a 52 ± 10% reduction in cardiac contractility, and a 23 ± 6% reduction in cerebral blood flow (all p < 0.05), along with severe self-reported symptoms. Electrical stimulation completely normalized BP, cardiac contractility, cerebral blood flow, and abrogated all symptoms. Noninvasive transcutaneous electrical spinal cord stimulation may be a viable therapy for restoring autonomic cardiovascular control after SCI.

Spinal cord epidural stimulation has resulted in the initiation of voluntary leg movements and improvement in postural, bladder, and sexual function. However, one of the limitations in reaching the full potential of epidural stimulation for therapeutic purposes in humans has been the identification of optimal stimulation configurations that can neuromodulate the spinal cord for stepping. In the present work, we investigated the mechanisms underlying the specificity of interaction between the rostral and caudal spinal cord circuitries in enabling locomotion in spinal rats (n = 10) by epidural spinal cord stimulation. By using unique spatiotemporal epidural stimulation parameters of the lumbar and sacral spinal cords, a robust stepping pattern in spinal rats was observed with only six training sessions and as early as 3 weeks post-injury. Electrophysiological evidence reveals that in addition to frequency of stimulation pulses at the stimulation sites, the relative timing between stimulation pulses applied at the lumbar (L2) and sacral (S1) segments of the spinal cord heavily impacted stepping performance. Best stepping was established at a higher stimulation frequency (40 Hz vs. 5, 10, 15, and 20Hz) and at specific relative time-intervals between the stimulation pulses (L2 pulse applied at 18-25 msec after the onset of the S1 pulse; S1 pulse applied 0-7 msec after the L2 pulse). Our data suggest that controlling pulse-to-pulse timing at multiple stimulation sources provides a novel strategy to optimize spinal stepping by fine-tuning the physiological state of the locomotor networks. These findings hold direct relevance to the clinician who will incorporate electrical stimulation strategies for optimizing control of locomotion after complete paralysis., Competing Interests: Author Disclosure Statement V. Reggie Edgerton, Roland R. Roy, and Yury Gerasimenko hold shareholder interest in NeuroRecovery Technologies. Drs. Edgerton, Roy, and Gerasimenko also hold certain inventorship rights on intellectual property licensed by the Regents of the University of California to NeuroRecovery Technologies and its subsidiaries. For the remaining authors, there are no competing financial interests.

The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

The present prognosis for the recovery of voluntary control of movement in patients diagnosed as motor complete is generally poor. Herein we introduce a novel and noninvasive stimulation strategy of painless transcutaneous electrical enabling motor control and a pharmacological enabling motor control strategy to neuromodulate the physiological state of the spinal cord. This neuromodulation enabled the spinal locomotor networks of individuals with motor complete paralysis for 2-6 years American Spinal Cord Injury Association Impairment Scale (AIS) to be re-engaged and trained. We showed that locomotor-like stepping could be induced without voluntary effort within a single test session using electrical stimulation and training. We also observed significant facilitation of voluntary influence on the stepping movements in the presence of stimulation over a 4-week period in each subject. Using these strategies we transformed brain-spinal neuronal networks from a dormant to a functional state sufficiently to enable recovery of voluntary movement in five out of five subjects. Pharmacological intervention combined with stimulation and training resulted in further improvement in voluntary motor control of stepping-like movements in all subjects. We also observed on-command selective activation of the gastrocnemius and soleus muscles when attempting to plantarflex. At the end of 18 weeks of weekly interventions the mean changes in the amplitude of voluntarily controlled movement without stimulation was as high as occurred when combined with electrical stimulation. Additionally, spinally evoked motor potentials were readily modulated in the presence of voluntary effort, providing electrophysiological evidence of the re-establishment of functional connectivity among neural networks between the brain and the spinal cord.

Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials.

The serotonergic system is highly plastic, capable of adapting to changing afferent information in diverse mammalian systems. We hypothesized that removing supraspinal and/or peripheral input would play an important role in defining the distribution of one of the most prevalent serotonergic receptors, the 5-HT(1A) receptor (R), in the spinal cord. We investigated the distribution of this receptor in response to a complete thoracic (T7-T8) spinal cord transection (eliminating supraspinal input), or to spinal cord isolation (eliminating both supraspinal and peripheral input) in adult rats. Using two antibodies raised against either the second extracellular region (ECL(2)) or the third intracellular region (ICL(3)) of the 5-HT(1A)R, we compared the 5-HT(1A)R levels and distributions in specific laminae of the L3-L5 segments among the control, spinal cord-transected, and spinal cord-isolated groups. Each antibody labeled different populations of 5-HT(1A)R: ECL(2) labeled receptors in the axon hillock, whereas ICL(3) labeled receptors predominantly throughout the soma and proximal dendrites. Spinal cord transection increased the number of ECL(2)-positive cells in the medial region of laminae III-IV and lamina VII, and the mean length of the labeled axon hillocks in lamina IX. The number of ICL(3)-labeled cells was higher in lamina VII and in both the medial and lateral regions of lamina IX in the spinal cord-transected compared to the control group. In contrast, the length and number of ECL(2)-immunolabeled processes and ICL(3)-immunolabeled cells were similar in the spinal cord-isolated and control groups. Combined, these data demonstrate that the upregulation in 5-HT(1A)R that occurs with spinal cord transection alone is dependent on the presence of sensory input.

Studies have shown that treadmill training with body weight support is effective for enhancing locomotor recovery following a complete spinal cord transection (ST) in animals. However, there have been no studies that have investigated the extent that functional recovery in ST animals is dependent on the amount of activity imposed on the hindlimbs during training. In rats transected as neonates (P5), we used a robotic device to impose either a high or a low amount of hindlimb activity during treadmill training starting 23 days after transection. The rats were trained 5 days per week for 4 weeks. One group (n = 13) received 1000 steps/training session and a second group (n = 13) received 100 steps/training session. During training, the robotic device imposed the maximum amount of weight that each rat could bear on the hindlimbs, and counted the number of stepping movements during each session. After 4 weeks of training, the number of steps performed during treadmill testing was not significantly different between the two groups. However, the quality of stepping in the group that received 1000 steps/training session improved over a range of levels of weight bearing on the hindlimbs and at different treadmill speeds. In contrast, little improvement in the quality of stepping was observed in the group that received only 100 steps/training session. These findings indicate that the ability of the lumbar spinal cord to adjust to load- and speed-related sensory stimuli associated with stepping is dependent on the number of repetitions of the same activity that is imposed on the spinal circuits during treadmill training.

We review some basic and highly relevant concepts in the effort to develop improved rehabilitative interventions for subjects with spinal cord injury (SCI). Interventions that are likely to contribute to improved sensorimotor function include (1) practice of the specific motor task that needs to be improved; and (2) combining the training with one or more interventions--such as pharmacological modulation of the excitability of spinal neural networks, implantation of selected cell types such as olfactory ensheathing glia (OEG), and/or modulation of the excitability of the spinal cord via epidural stimulation. Upon improvement of the neural control of the musculature following SCI, it will always be prudent to maximize the torque output from these activation patterns by assuring that muscle mass is maintained. Therefore, it seems quite feasible that considerable improvement in locomotor performance can be achieved by improved coordination of motor pools, as well as effective recovery of muscle mass, which will assist in the potential generation of normal forces among agonistic and antagonistic muscle groups.

Recently, locomotor training has been shown to improve overground locomotion in patients with spinal cord injury (SCI). This has triggered renewed interest in the role of exercise in rehabilitation after SCI. However, there are no mouse models for voluntary exercise and recovery of function following SCI. Here, we report voluntary wheel running improves recovery from a SCI in mice. C57Bl/10 female mice received a 60-kdyne T9 contusion injury with an IH impactor after 3 weeks of voluntary wheel running or 3 weeks of standard single housing conditions. Following a 7-day recovery period, running mice were returned to their running wheels. Weekly open-field behavior measured locomotor recovery using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale and the Basso Mouse Scale (BMS) locomotor rating scale, a scale recently developed specifically for mice. Initial experiments using standard rung wheels show that wheel running impaired recovery, but subsequent experiments using a modified flat-surface wheel show improved recovery with exercise. By 14 days post SCI, the modified flat-surface running group had significantly higher BBB and BMS scores than the sedentary group. A repeated measures ANOVA shows locomotor recovery of modified flat-surface running mice was significantly improved compared to sedentary animals (p < 0.05). Locomotor assessment using a ladder beam task also shows a significant improvement in the modified flat-surface runners (p < 0.05). Finally, fibronectin staining shows no significant difference in lesion size between the two groups. These data represent the first mouse model showing voluntary exercise improves recovery after SCI.

We investigated the activation of lower limb motor pools by supraspinal and spinal networks after human spinal cord injury (SCI). We compared electromyographic (EMG) activity from six muscles during voluntarily attempted non-weight-bearing single-joint movements, multijoint movements approximating stepping in a supine position, and weight-bearing stepping on a treadmill with body weight support (BWST) in seven clinically incomplete and three clinically complete SCI subjects. Seven SCI subjects had previously completed Laufband therapy (a specific step training using variable levels of body weight support and manual assistance). Significant coactivation of agonists and antagonists and multijoint flexion or extension movements of the entire limb occurred during attempts at isolated knee or ankle single-joint movements in clinically incomplete SCI subjects. Further, some muscles that were not recruited during voluntary attempts at single-joint movements were activated during voluntary step-like multijoint movements (5/16 comparisons). This suggests that the residual voluntary motor control in incomplete SCI subjects evokes more generalized motor patterns (limb flexion or extension) rather than selective activation of individual muscles. Clinically incomplete and clinically complete SCI subjects could achieve greater activation of motor pools and more reciprocal patterns of activity between agonists and antagonists during weight bearing stepping than during non-weight-bearing voluntary movements. The EMG mean amplitudes were higher during stepping than during voluntary movements in 50/60 muscles studied (p < 0.05). These results suggest that stepping with knee and hip extension and flexion and alternating lower limb loading and unloading provides proprioceptive inputs to the spinal cord that increases motor recruitment and improves reciprocity between agonists and antagonists compared to voluntary efforts.

The neural circuitry of the lumbar spinal cord can generate alternating extension and flexion of the hindlimbs. The hindlimbs of adult cats with complete transection of the spinal cord at a low thoracic level (T12-T13) can perform full weight-supporting locomotion on a treadmill belt moving at a range of speeds. Some limitations in the locomotor capacity can be associated with a deficit in the recruitment level of the fast extensors during the stance phase and the flexors during the swing phase of a step cycle. The level of locomotor performance, however, can be enhanced by daily training on a treadmill while emphasizing full weight-support stepping and by providing appropriately timed sensory stimulation, loading, and/or pharmacologic stimulation of the hindlimb neuromuscular apparatus. Furthermore, there appears to be an interactive effect of these interventions. For example, the maximum treadmill speed that a spinal adult cat can attain and maintain is significantly improved with daily full weight-supporting treadmill training, but progressive recruitment of fast extensors becomes apparent only when the hindlimbs are loaded by gently pulling down on the tail during the stepping. Stimulation of the sural nerve at the initiation of the flexion phase of the step cycle can likewise markedly improve the locomotor capability. Administration of clonidine, in particular in combination with an elevated load, resulted in the most distinct and consistent alternating bursts of electromyographic activity during spinal stepping. These data indicate that the spinal cord has the ability to execute alternating activation of the extensor and flexor musculature of the hindlimbs (stepping) and that this ability can be improved by several interventions such as training, sensory stimulation, and use of some pharmacologic agents. Thus, it appears that the spinal cord, without supraspinal input, is highly plastic and has the potential to "learn," that is, to acquire and improve its ability to execute full weight-supporting locomotion on a treadmill belt.