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Transcutaneous spinal cord or transspinal stimulation over the thoracolumbar enlargement, the spinal location of motoneurons innervating leg muscles, modulates neural circuits engaged in the control of movement. The extent to which daily sessions (e.g. repeated) of transspinal stimulation affects soleus H-reflex excitability in individuals with chronic spinal cord injury (SCI) remains largely unknown. In this study, we established the effects of repeated cathodal transspinal stimulation on soleus H-reflex excitability and spinal inhibition in individuals with and without chronic SCI. Ten SCI and 10 healthy control subjects received monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at subthreshold and suprathreshold intensities of the right soleus transspinal evoked potential (TEP). SCI subjects received an average of 16 stimulation sessions, while healthy control subjects received an average of 10 stimulation sessions. Before and one or two days post intervention, we used the soleus H reflex to assess changes in motoneuron recruitment, homosynaptic depression following single tibial nerve stimuli delivered at 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and postactivation depression following paired tibial nerve stimuli at the interstimulus intervals of 60, 100, 300, and 500 ms. Soleus H-reflex excitability was decreased in both legs in motor incomplete and complete SCI but not in healthy control subjects. Soleus H-reflex homosynaptic and postactivation depression was present in motor incomplete and complete SCI but was of lesser strength to that observed in healthy control subjects. Repeated transspinal stimulation increased homosynaptic depression in all SCI subjects and remained unaltered in healthy controls. Postactivation depression remained unaltered in all subject groups. Lastly, transspinal stimulation decreased the severity of spasms and ankle clonus. The results indicate decreased reflex hyperexcitability and recovery of spinal inhibitory control in the injured human spinal cord with repeated transspinal stimulation. Transspinal stimulation is a noninvasive neuromodulation method for restoring spinally-mediated afferent reflex actions after SCI in humans.

Targeted neuromodulation strategies that strengthen neuronal activity are in great need for restoring sensorimotor function after chronic spinal cord injury (SCI). In this study, we established changes in the motoneuron output of individuals with and without SCI after repeated noninvasive transspinal stimulation at rest over the thoracolumbar enlargement, the spinal location of leg motor circuits. Cases of motor incomplete and complete SCI were included to delineate potential differences when corticospinal motor drive is minimal. All 10 SCI and 10 healthy control subjects received daily monophasic transspinal stimuli of 1-ms duration at 0.2 Hz at right soleus transspinal evoked potential (TEP) subthreshold and suprathreshold intensities at rest. Before and two days after cessation of transspinal stimulation, we determined changes in TEP recruitment input-output curves, TEP amplitude at stimulation frequencies of 0.1, 0.125, 0.2, 0.33 and 1.0 Hz, and TEP postactivation depression upon transspinal paired stimuli at interstimulus intervals of 60, 100, 300, and 500 ms. TEPs were recorded at rest from bilateral ankle and knee flexor/extensor muscles. Repeated transspinal stimulation increased the motoneuron output over multiple segments. In control and complete SCI subjects, motoneuron output increased for knee muscles, while in motor incomplete SCI subjects motoneuron output increased for both ankle and knee muscles. In control subjects, TEPs homosynaptic and postactivation depression were present at baseline, and were potentiated for the distal ankle or knee flexor muscles. TEPs homosynaptic and postactivation depression at baseline depended on the completeness of the SCI, with minimal changes observed after transspinal stimulation. These results indicate that repeated transspinal stimulation increases spinal motoneuron responsiveness of ankle and knee muscles in the injured human spinal cord, and thus can promote motor recovery. This noninvasive neuromodulation method is a promising modality for promoting functional neuroplasticity after SCI.

The spinal cord is an integration center for descending, ascending, and segmental neural signals. Noninvasive transspinal stimulation may thus constitute an effective method for concomitant modulation of local and distal neural circuits. In this study, we established changes in cortical excitability and input/output function of corticospinal and spinal neural circuits before, at 0–15 and at 30–45 minutes after cathodal, anodal, and sham transspinal direct current stimulation (tsDCS) to the thoracic region in healthy individuals. We found that intracortical inhibition was different among stimulation polarities, however remained unchanged over time. Intracortical facilitation increased after cathodal and anodal tsDCS delivered with subjects seated, and decreased after cathodal tsDCS delivered with subjects lying supine. Both cathodal and anodal tsDCS increased corticospinal excitability, yet facilitation was larger and persisted for 30 minutes post stimulation only when cathodal tsDCS was delivered with subjects lying supine. Spinal input/output reflex function was decreased by cathodal and not anodal tsDCS. These changes may be attributed to altered spontaneous neural activity and membrane potentials of corticomotoneuronal cells by tsDCS involving similar mechanisms to those mediating motor learning. Our findings indicate that thoracic tsDCS has the ability to concomitantly alter cortical, corticospinal, and spinal motor output in humans.

The objectives of this study were to establish cortical and subcortical contributions to neuroplasticity induced by noninvasive repetitive transspinal stimulation in human subjects free of any neurological disorder. To meet our objectives, before and after 40 minutes of transspinal stimulation we established changes in tibialis anterior (TA) motor-evoked potentials (MEPs) in response to paired transcranial magnetic stimulation (TMS) pulses at interstimulus intervals (ISIs) consistent with I-wave periodicity. In order to establish to what extent similar actions are exerted at the spinal cord and motor axons, changes in soleus H-reflex and transspinal evoked potential (TEP) amplitude following transspinal and group Ia afferent conditioning stimulation, respectively, were established. After 40 min of transspinal stimulation, the TA MEP consecutive peaks of facilitation produced by paired TMS pulses were significantly decreased supporting for depression of I-waves. Additionally, the soleus H-reflex and ankle TEP depression following transspinal and group Ia afferent conditioning stimulation was potentiated at intervals when both responses interacted at the spinal cord and nerve axons. These findings support the notion that repetitive transspinal stimulation decreases corticocortical inputs onto corticospinal neurons and promotes a surround inhibition in the spinal cord and nerve axons. This novel method may be a suitable neuromodulation tool to alter excitability at cortical and subcortical levels in neurological disorders.

Noninvasive transspinal stimulation of the thoracolumbar region, where leg motor circuits reside, produces prominent plasticity of brain and spinal cord circuits. However, reorganization of cortical and corticospinal excitability after multiple sessions (i.e. repeated) remains elusive. In this study, we investigated changes in intracortical inhibition, intracortical facilitation, and corticospinal excitability after 10 sessions of cathodal transcutaneous delivery of pulse or direct current stimulation, termed here transspinal (tsPCS, tsDCS), in resting healthy humans. tsPCS was delivered at sub- and supra-threshold intensities, while intensity for tsDCS ranged from 2.24 to 2.34 mA within a session. Intracortical inhibition and facilitation were assessed based on the tibialis anterior (TA) motor evoked potential (MEP) amplitude following subthreshold transcranial magnetic stimulation (TMS) at the conditioning-test (C-T) intervals of 1, 2, 3, 10, 15, 20, 25, and 30 ms. The TA MEP recruitment input–output curves were also assembled to establish changes in corticospinal excitability. For both transspinal stimulation protocols, the active cathodal electrode was placed over the T10 spinal process. Results indicated that repeated tsPCS did not alter intracortical inhibition or intracortical facilitation but decreased corticospinal excitability for the right M1 and increased corticospinal excitability for the left M1. tsDCS decreased intracortical inhibition, increased intracortical facilitation, did not affect the maximal MEP amplitude but increased the slope of the right TA MEP input–output curve. Neurophysiological changes may be attributed to neural mechanisms involved in learning and memory. These results support that noninvasive transspinal stimulation alters both cortical and corticospinal neural excitability in resting healthy humans.

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARC EX Therapy to improve arm and hand functions in people with chronic SCI. ARC EX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARC EX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARC EX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARC EX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 . Externally applied electrical stimulation over the cervical spinal cord improves arm and hand functions in people with chronic tetraplegia due to spinal cord injury.

Electromagnetic stimulation probes and modulates the neural systems that control movement. Key to understanding their effects is the muscle recruitment curve, which maps evoked potential size against stimulation intensity. Current methods to estimate curve parameters require large samples; however, obtaining these is often impractical due to experimental constraints. Here, we present a hierarchical Bayesian framework that accounts for small samples, handles outliers, simulates high-fidelity data, and returns a posterior distribution over curve parameters that quantify estimation uncertainty. It uses a rectified-logistic function that estimates motor threshold and outperforms conventionally used sigmoidal alternatives in predictive performance, as demonstrated through cross-validation. In simulations, our method outperforms non-hierarchical models by reducing threshold estimation error on sparse data and requires fewer participants to detect shifts in threshold compared to frequentist testing. We present two common use cases involving electrical and electromagnetic stimulation data and provide an open-source library for Python, called hbMEP, for diverse applications.

Electromagnetic stimulation probes and modulates the neural systems that control movement. Key to understanding their effects is the muscle recruitment curve, which maps evoked potential size against stimulation intensity. Current methods to estimate curve parameters require large samples; however, obtaining these is often impractical due to experimental constraints. Here, we present a hierarchical Bayesian framework that accounts for small samples, handles outliers, simulates high-fidelity data, and returns a posterior distribution over curve parameters that quantify estimation uncertainty. It uses a rectified-logistic function that estimates motor threshold and outperforms conventionally used sigmoidal alternatives in predictive performance, as demonstrated through cross-validation. In simulations, our method outperforms non-hierarchical models by reducing threshold estimation error on sparse data and requires fewer participants to detect shifts in threshold compared to frequentist testing. We present two common use cases involving electrical and electromagnetic stimulation data and provide an open-source library for Python, called hbMEP, for diverse applications.

While epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well-understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective, and responses would be strongest in the muscles innervated by the stimulated segment. Eighteen people undergoing clinically indicated cervical spine surgery were enrolled. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; eight arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline. These stronger responses were due to a combination of a decreased response threshold and steeper recruitment slope. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in responses to stimulation of adjacent cervical segments argues for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function. Competing Interest Statement Jason B. Carmel is a Founder and stock holder in BackStop Neural and a scientific advisor for SharperSense. Michael S. Virk has been a consultant and has received honorarium from Depuy Synthes, Globus Medical and BrainLab. Noam Y. Harel is a consultant for RubiconMD. K. Daniel Riew: Board of Directors: Global Spine Journal (Nonfinancial), NASS (Nonfinancial); Consulting: Happe Spine (Nonfinancial), Nuvasive; Royalties: Biomet; Speaking and/or Teaching Arrangements: Biomet, Medtronic (Travel Expense Reimbursement); Stock Ownership: Amedica, Axiomed, Benvenue, Expanding Orthopedics, Osprey, Paradigm Spine, Spinal Kinetics, Spineology, Vertiflex. The rest of the coauthors have nothing to disclose.

While epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well-understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective, and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-five people undergoing clinically indicated cervical spine surgery were consented to map motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argues for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function. A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline, and differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively. biorxiv;2022.01.29.478182v2/UFIG1F1ufig1