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Epidural electrical stimulation of the lumbar spinal cord is currently regaining momentum as a neuromodulation intervention in spinal cord injury (SCI) to modify dysregulated sensorimotor functions and augment residual motor capacity. There is ample evidence that it engages spinal circuits through the electrical stimulation of large-to-medium diameter afferent fibers within lumbar and upper sacral posterior roots. Recent pilot studies suggested that the surface electrode-based method of transcutaneous spinal cord stimulation (SCS) may produce similar neuromodulatory effects as caused by epidural SCS. Neurophysiological and computer modeling studies proposed that this noninvasive technique stimulates posterior-root fibers as well, likely activating similar input structures to the spinal cord as epidural stimulation. Here, we add a yet missing piece of evidence substantiating this assumption. We conducted in-depth analyses and direct comparisons of the electromyographic (EMG) characteristics of short-latency responses in multiple leg muscles to both stimulation techniques derived from ten individuals with SCI each. Post-activation depression of responses evoked by paired pulses applied either epidurally or transcutaneously confirmed the reflex nature of the responses. The muscle responses to both techniques had the same latencies, EMG peak-to-peak amplitudes, and waveforms, except for smaller responses with shorter onset latencies in the triceps surae muscle group and shorter offsets of the responses in the biceps femoris muscle during epidural stimulation. Responses obtained in three subjects tested with both methods at different time points had near-identical waveforms per muscle group as well as same onset latencies. The present results strongly corroborate the activation of common neural input structures to the lumbar spinal cord-predominantly primary afferent fibers within multiple posterior roots-by both techniques and add to unraveling the basic mechanisms underlying electrical SCS.

Posterior root-muscle (PRM) reflexes are short-latency spinal reflexes evoked by epidural or transcutaneous spinal cord stimulation (SCS) in clinical and physiological studies. PRM reflexes share key physiological characteristics with the H reflex elicited by electrical stimulation of large-diameter muscle spindle afferents in the tibial nerve. Here, we compared the H reflex and the PRM reflex of soleus in response to transcutaneous stimulation by studying their recovery cycles in ten neurologically intact volunteers and ten individuals with traumatic, chronic spinal cord injury (SCI). The recovery cycles of the reflexes, i.e., the time course of their excitability changes, were assessed by paired pulses with conditioning-test intervals of 20-5000 ms. Between the subject groups, no statistical difference was found for the recovery cycles of the H reflexes, yet those of the PRM reflexes differed significantly, with a striking suppression in the intact group. When comparing the reflex types, they did not differ in the SCI group, while the PRM reflexes were more strongly depressed in the intact group for durations characteristic for presynaptic inhibition. These differences may arise from the concomitant stimulation of several posterior roots containing afferent fibers of various lower extremity nerves by transcutaneous SCS, producing multi-source heteronymous presynaptic inhibition, and the collective dysfunction of inhibitory mechanisms after SCI contributing to spasticity. PRM-reflex recovery cycles additionally obtained for bilateral rectus femoris, biceps femoris, tibialis anterior, and soleus all demonstrated a stronger suppression in the intact group. Within both subject groups, the thigh muscles showed a stronger recovery than the lower leg muscles, which may reflect a characteristic difference in motor control of diverse muscles. Based on the substantial difference between intact and SCI individuals, PRM-reflex depression tested with paired pulses could become a sensitive measure for spasticity and motor recovery.

Lumbar central pattern generators (CPGs) control the basic rhythm and coordinate muscle activation underlying hindlimb locomotion in quadrupedal mammals. The existence and function of CPGs in humans have remained controversial. Here, we investigated a case of a male individual with complete thoracic spinal cord injury who presented with a rare form of self-sustained rhythmic spinal myoclonus in the legs and rhythmic activities induced by epidural electrical stimulation (EES). Analysis of muscle activation patterns suggested that the myoclonus tapped into spinal circuits that generate muscle spasms, rather than reflecting locomotor CPG activity as previously thought. The EES-induced patterns were fundamentally different in that they included flexor-extensor and left-right alternations, hallmarks of locomotor CPGs, and showed spontaneous errors in rhythmicity. These motor deletions, with preserved cycle frequency and period when rhythmic activity resumed, were previously reported only in animal studies and suggest a separation between rhythm generation and pattern formation. Spinal myoclonus and the EES-induced activity demonstrate that the human lumbar spinal cord contains distinct mechanisms for generating rhythmic multi-muscle patterns. The existence of dedicated spinal circuits generating locomotion in humans has remained controversial. Here, the authors study distinct forms of spontaneous and induced rhythmic leg activity in a paralyzed individual, providing insight into spinal rhythmogenesis and pattern formation.

Transcutaneous stimulation of the human lumbosacral spinal cord is used to evoke spinal reflexes and to neuromodulate altered sensorimotor function following spinal cord injury. Both applications require the reliable stimulation of afferent posterior root fibers. Yet under certain circumstances, efferent anterior root fibers can be co-activated. We hypothesized that body position influences the preferential stimulation of sensory or motor fibers. Stimulus-triggered responses to transcutaneous spinal cord stimulation were recorded using surface-electromyography from quadriceps, hamstrings, tibialis anterior, and triceps surae muscles in 10 individuals with intact nervous systems in the supine, standing and prone positions. Single and paired (30-ms inter-stimulus intervals) biphasic stimulation pulses were applied through surface electrodes placed on the skin between the T11 and T12 inter-spinous processes referenced to electrodes on the abdomen. The paired stimulation was applied to evaluate the origin of the evoked electromyographic response; trans-synaptic responses would be suppressed whereas direct efferent responses would almost retain their amplitude. We found that responses to the second stimulus were decreased to 14%±5% of the amplitude of the response to the initial pulse in the supine position across muscles, to 30%±5% in the standing, and to only 80%±5% in the prone position. Response thresholds were lowest during standing and highest in the prone position and response amplitudes were largest in the supine and smallest in the prone position. The responses obtained in the supine and standing positions likely resulted from selective stimulation of sensory fibers while concomitant motor-fiber stimulation occurred in the prone position. We assume that changes of root-fiber paths within the generated electric field when in the prone position increase the stimulation thresholds of posterior above those of anterior root fibers. Thus, we recommend conducting spinal reflex or neuromodulation studies with subjects lying supine or in an upright position, as in standing or stepping.

Background: Transcutaneous spinal stimulation (TSS) is a noninvasive stimulation approach to modulate spinal reflex circuit excitability after spinal cord injury (SCI) Posterior root muscle (PRM) reflexes can be used to characterize the change in excitability of spinal reflex circuits after TSS; these responses are likely influenced by stimulus parameters. Methods: We compared PRM reflex responses to 3 TSS conditions: single-site continuous (SS-CONT), single-site burst (SS-BURST), and dual-site continuous (DS-CONT). Stimulation (frequency: 50 Hz, intensity: 80% soleus reflex threshold[RT]) was delivered for 30 min. The cathode was placed over the thoracic spine (T11–T12) and anodes placed paraumbilically; a second cathode over the lumbar spine (L1/2 or L2/3) was used for DS-CONT. PRM reflex responses in the soleus were elicited by paired 1 ms monophasic conditioning–test stimuli at a 50 ms interstimulus interval via the T11–12 cathode and paraumbilical anodes. Soleus PRM reflex indices included RT, response amplitude at 1.2xRT (RA1.2xRT), slope, area under the input–output curve (AUC). Paired-pulse indices were collected, including paired-pulse depression (PPD) and depression of the area under the curve (AUCdep). To assess the correlation between biomechanical and electrophysiologic measures of soleus spasticity, the ankle clonus drop test first drop excursion (FDE) was measured. All indices were measured at baseline and immediately post-intervention. Results: In whole-group analyses, PPD and AUCdep were significantly decreased. Significant decreases in PPD and AUCdep were identified only after the SS-CONT condition. No significant changes were identified in other PRM reflex indices after any of the 3 TSS conditions. No relationships between baseline FDE and any PRM reflex parameter were identified at baseline. Conclusions: With stimulation intensity of 80% soleus RT, modulation of targeted spinal reflex circuits was observed only in the SS-CONT condition when the response of the conditioning and test stimuli were considered. In addition, stretch-induced spasticity of the soleus may not be consistent with electrophysiologic testing.

Transcutaneous spinal cord stimulation is a non-invasive method for neuromodulation of sensorimotor function. Its main mechanism of action results from the activation of afferent fibers in the posterior roots—the same structures as targeted by epidural stimulation. Here, we investigated the influence of sagittal spine alignment on the capacity of the surface-electrode-based stimulation to activate these neural structures. We evaluated electromyographic responses evoked in the lower limbs of ten healthy individuals during extension, flexion, and neutral alignment of the thoracolumbar spine. To control for position-specific effects, stimulation in these spine alignment conditions was performed in four different body positions. In comparison to neutral and extended spine alignment, flexion of the spine resulted in a strong reduction of the response amplitudes. There was no such effect on tibial-nerve evoked H reflexes. Further, there was a reduction of post-activation depression of the responses to transcutaneous spinal cord stimulation evoked in spinal flexion. Thus, afferent fibers were reliably activated with neutral and extended spine alignment. Spinal flexion, however, reduced the capacity of the stimulation to activate afferent fibers and led to the co-activation of motor fibers in the anterior roots. This change of action was due to biophysical rather than neurophysiological influences. We recommend applying transcutaneous spinal cord stimulation in body positions that allow individuals to maintain a neutral or extended spine.

Epidural electrical stimulation (EES) applied over the human lumbosacral spinal cord provides access to afferent fibers from virtually all lower-extremity nerves. These afferents connect to spinal networks that play a pivotal role in the control of locomotion. Studying EES-evoked responses mediated through these networks can identify some of their functional components. We here analyzed electromyographic (EMG) responses evoked by low-frequency (2–6 Hz) EES derived from eight individuals with chronic, motor complete spinal cord injury. We identified and separately analyzed three previously undescribed response types: first, crossed reflexes with onset latencies of ~55 ms evoked in the hamstrings; second, oligosynaptic reflexes within 50 ms post-stimulus superimposed on the monosynaptic posterior root-muscle reflexes in the flexor muscle tibialis anterior, but with higher thresholds and no rate-sensitive depression; third, polysynaptic responses with variable EMG shapes within 50–450 ms post-stimulus evoked in the tibialis anterior and triceps surae, some of which demonstrated consistent changes in latencies with graded EES. Our observations suggest the activation of commissural neurons, lumbar propriospinal interneurons, and components of the late flexion reflex circuits through group I and II proprioceptive afferent inputs. These potential neural underpinnings have all been related to spinal locomotion in experimental studies.

Epidural spinal cord stimulation (SCS) is currently regarded as a breakthrough procedure for enabling movement after spinal cord injury (SCI), yet one of its original applications was for spinal spasticity. An emergent method that activates similar target neural structures non-invasively is transcutaneous SCS. Its clinical value for spasticity control would depend on inducing carry-over effects, because the surface-electrode-based approach cannot be applied chronically. We evaluated single-session effects of transcutaneous lumbar SCS in 12 individuals with SCI by a test-battery approach, before, immediately after and 2 h after intervention. Stimulation was applied for 30 min at 50 Hz with an intensity sub-threshold for eliciting reflexes in lower extremity muscles. The tests included evaluations of stretch-induced spasticity (Modified Ashworth Scale [MAS] sum score, pendulum test, electromyography-based evaluation of tonic stretch reflexes), clonus, cutaneous-input-evoked spasms, and the timed 10 m walk test. Across participants, the MAS sum score, clonus, and spasms were significantly reduced immediately after SCS, and all spasticity measures were improved 2 h post-intervention, with large effect sizes and including clinically meaningful improvements. The effect on walking speed varied across individuals. We further conducted a single-case multi-session study over 6 weeks to explore the applicability of transcutaneous SCS as a home-based therapy. Self-application of the intervention was successful; weekly evaluations suggested progressively improving therapeutic effects during the active period and carry-over effects for 7 days. Our results suggest that transcutaneous SCS can be a viable non-pharmacological option for managing spasticity, likely working through enhancing pre- and post-synaptic spinal inhibitory mechanisms, and may additionally serve to identify responders to treatments with epidural SCS.

Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord 1 – 3 applied during neurorehabilitation 4 , 5 (EES REHAB ) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EES REHAB in mice. We applied single-nucleus RNA sequencing 6 – 9 and spatial transcriptomics 10 , 11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type 12 , 13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EES REHAB , whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours. Transcriptomic analysis following epidural electrical stimulation of the lumbar spinal cord during neurorehabilitation in mice identifies a population of neurons that orchestrates the restoration of walking following paralysis.