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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.

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.

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.

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

As part of a project aimed to develop a novel, non-invasive techniques for comprehensive assessment of supraspinal-spinal connectivity in humans, the present study sought to explore the convergence of descending vestibulospinal and corticospinal pathways onto lumbosacral motor pools. Transcutaneous electrical spinal stimulation-evoked motor potentials were recorded from knee and ankle flexors and extensors in resting neurologically intact participants. Descending influences on lumbosacral motor neurons were studied using galvanic vestibular (GVS) or transcranial magnetic stimulation (TMS) to elicit descending vestibulospinal or corticospinal volleys, respectively. Facilitatory conditioning effects of descending corticospinal volleys were manifested by a significant increase of spinally evoked motor potentials in recorded knee and ankle muscles bilaterally, and were observed at the 10-30 ms conditioning-test intervals (CTIs); whereas, facilitatory conditioning effects of vestibulospinal volleys manifested at longer latencies (CTIs of 90 and 110 ms), and lasted up to 250 ms. TMS mediated volleys revealed the conditioning effects at both short and long latencies, suggestive of both direct and indirect influence. In contrast, vestibulospinally mediated conditioning effects occurred at longer latencies, consistent with this pathway's known anatomical and functional interfaces with other descending systems including the reticulospinal pathway and, suggestively, propriospinal interneurons. Our work demonstrates the utility and sensitivity of transcutaneous spinal stimulation in human neurophysiological studies as a technique for quantitative characterization of excitatory conditioning effects in multiple lumbosacral motor pools, obtained through descending pathways. This characterization becomes critical in understanding the neuroplasticity in the central nervous system during motor learning and neurological recovery.

Background: Transcutaneous spinal stimulation (TSS) and neuromuscular electrical stimulation (NMES) can facilitate self-assisted standing in individuals with paralysis. However, individual variability in responses to each modality may limit their effectiveness in generating the necessary leg extension force for full body weight standing. To address this challenge, we proposed combining TSS and NMES to enhance leg extensor muscle activation, with optimizing timing adjustment to maximize the interaction between the two modalities. Methods: To assess the effects of TSS and NMES on knee extension and plantarflexion force, ten neurologically intact participants underwent three conditions: (1) TSS control, (2) NMES control, and (3) TSS + NMES. TSS was delivered between the T10 and L2 vertebrae, while NMES was delivered to the skin over the right knee extensors and plantarflexors. TSS and NMES were administered using a 15 Hz train of three 0.5 ms biphasic pulses. During the TSS + NMES condition, the timing between modalities was adjusted in increments of ¼ the interval within a 15 Hz frequency, i.e., 66, 49.5, 33, 16.5, and 1 ms. Results: NMES combined with TSS, produced synergistic effects even on non-targeted muscle groups, thereby promoting leg extension across multiple joints in the kinematic chain. The sequence of NMES or TSS trains relative to each other did not significantly impact motor output. Notably, a delay of 16.5 to 49.5 ms between interleaved TSS and NMES pulses, each delivered at 15 Hz, results in more robust and synergistic responses in knee extensors and plantarflexors. Conclusions: By adjusting the timing between TSS and NMES, we can optimize the combined use of these modalities for functional restoration. Our findings highlight the potential of integrated TSS and NMES protocols to enhance motor function, suggesting promising avenues for therapeutic applications, particularly in the rehabilitation of individuals with SCI. [ABSTRACT FROM AUTHOR]

Introduction: Spinal cord injury (SCI) animal models often utilize an open surgical laminectomy, which results in animal morbidity and also leads to changes in spinal canal diameter, spinal cord perfusion, cerebrospinal fluid flow dynamics, and spinal stability which may confound SCI research. Moreover, the use of open surgical laminectomy for injury creation lacks realism when considering human SCI scenarios. Methods: We developed a novel, image-guided, minimally invasive, large animal model of SCI which utilizes a kyphoplasty balloon inserted into the epidural space via an interlaminar approach without the need for open surgery. Results: The model was validated in 5 Yucatán pigs with imaging, neurofunctional, histologic, and electrophysiologic findings consistent with a mild compression injury. Discussion: Few large animal models exist that have the potential to reproduce the mechanisms of spinal cord injury (SCI) commonly seen in humans, which in turn limits the relevance and applicability of SCI translational research. SCI research relies heavily on animal models, which typically involve an open surgical, dorsal laminectomy which is inherently invasive and may have untoward consequences on animal morbidity and spinal physiology that limit translational impact. We developed a minimally invasive, large animal model of spinal cord injury which utilizes a kyphoplasty balloon inserted percutaneously into the spinal epidural space. Balloon inflation results in a targeted, compressive spinal cord injury with histological and electrophysiological features directly relevant to human spinal cord injury cases without the need for invasive surgery. Balloon inflation pressure, length of time that balloon remains inflated, and speed of inflation may be modified to achieve variations in injury severity and subtype. [ABSTRACT FROM AUTHOR]

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.

It was demonstrated previously that transcutaneous electrical stimulation of multiple sites over the spinal cord is more effective in inducing robust locomotor behavior as compared to the stimulation of single sites alone in both animal and human models. To explore the effects and mechanisms of interactions during multi-site spinal cord stimulation we delivered transcutaneous electrical stimulation to the single or dual locations over the spinal cord corresponding to approximately L2 and S1 segments. Spinally evoked motor potentials in the leg muscles were investigated using single and paired pulses of 1ms duration with conditioning-test intervals (CTIs) of 5 and 50ms. We observed considerable post-stimulation modulatory effects which depended on CTIs, as well as on whether the paired stimuli were delivered at a single or dual locations, the rostro-caudal relation between the conditioning and test stimuli, and on the muscle studied. At CTI-5, the paired stimulation delivered at single locations (L2 or S1) provided strong inhibitory effects, evidenced by the attenuation of the compound responses as compared with responses from either single site. In contrast, during L2-S1 paradigm, the compound responses were potentiated. At CTI-50, the magnitude of inhibition did not differ among paired stimulation paradigms. Our results suggest that electrical stimuli delivered to dual sites over the lumbosacral enlargement in rostral-to-caudal order, may recruit different populations of motor neurons initially through projecting sensory and intraspinal connections and then directly, resulting in potentiation of the compound spinally evoked motor potentials. The interactive and synergistic effects indicate multi-segmental convergence of descending and ascending influences on the neuronal circuitries during electrical spinal cord stimulation.

Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, remarkable recovery of the upper limb sensorimotor function during cervical spinal stimulation was demonstrated. In the present study, we sought to elucidate the neural mechanisms underlying the effects of transcutaneous spinal cord stimulation (tSCS) of the cervical spine. We hypothesized that cervical tSCS can be used to selectively activate the sensory route entering the spinal cord and transsynaptically converge on upper limb motor pools. To test this hypothesis, we applied cervical tSCS using paired stimuli (homosynaptic depression) and during passive muscle stretching of the wrist flexor (presynaptic inhibition via Ia afferents), voluntary hand muscle contraction (descending facilitation of motoneuron pool), and muscletendon vibration of the wrist (presynaptic inhibition via afferent occlusion). Our results demonstrate significant inhibition of the second evoked response during paired stimulus delivery, inhibition of responses during passive muscle stretching and muscle-tendon vibration, and facilitation during voluntary muscle contraction, which share similarities with responses evoked during lumbosacral tSCS. These results indicate that the route of the stimulation current transmission passes via afferents in the dorsal roots through the spinal cord to activate the motor pools and potentially interneuronal networks projecting to upper limb muscles. Using a novel stimulation paradigm, our study is the first to present evidence of the sensory neuronal pathway of the cervical tSCS propagation. Overall, our work demonstrates the utility and sensitivity of cervical tSCS to engage the sensory pathway projecting to the upper limbs. [ABSTRACT FROM AUTHOR]