Postsynaptic potentials of soleus motor neurons produced by transspinal stimulation: a human single-motor unit study.

Transspinal (or transcutaneous spinal cord) stimulation is a noninvasive, cost-effective, easily applied method with great potential as a therapeutic modality for recovering somatic and nonsomatic functions in upper motor neuron disorders. However, how transspinal stimulation affects motor neuron depolarization is poorly understood, limiting the development of effective transspinal stimulation protocols for rehabilitation. In this study, we characterized the responses of soleus α motor neurons to single-pulse transspinal stimulation using single-motor unit (SMU) discharges as a proxy given the 1:1 discharge activation between the motor neuron and the motor unit. Peristimulus time histogram, peristimulus frequencygram, and surface electromyography (sEMG) were used to characterize the postsynaptic potentials of soleus motor neurons. Transspinal stimulation produced short-latency excitatory postsynaptic potentials (EPSPs) followed by two distinct phases of inhibitory postsynaptic potentials (IPSPs) in most soleus motor neurons and only IPSPs in others. Transspinal stimulation generated double discharges at short interspike intervals in a few motor units. The short-latency EPSPs were likely mediated by muscle spindle group Ia and II afferents, and the IPSPs via excitation of group Ib afferents and recurrent collaterals of motor neurons leading to activation of diverse spinal inhibitory interneuronal circuits. Further studies are warranted to understand better how transspinal stimulation affects depolarization of α motor neurons over multiple spinal segments. This knowledge will be seminal for developing effective transspinal stimulation protocols in upper motor neuron lesions.NEW & NOTEWORTHY Transspinal stimulation produces distinct actions on soleus motor neurons: an early short-latency excitation followed by two inhibitions or only inhibition and doublets. These results show how transspinal stimulation affects depolarization of soleus α motor neurons in healthy humans.

Tapping into the human spinal locomotor centres with transspinal stimulation.

Human locomotion is controlled by spinal neuronal networks of similar properties, function, and organization to those described in animals. Transspinal stimulation affects the spinal locomotor networks and is used to improve standing and walking ability in paralyzed people. However, the function of locomotor centers during transspinal stimulation at different frequencies and intensities is not known. Here, we document the 3D joint kinematics and spatiotemporal gait characteristics during transspinal stimulation at 15, 30, and 50 Hz at sub-threshold and supra-threshold stimulation intensities. We document the temporal structure of gait patterns, dynamic stability of joint movements over stride-to-stride fluctuations, and limb coordination during walking at a self-selected speed in healthy subjects. We found that transspinal stimulation (1) affects the kinematics of the hip, knee, and ankle joints, (2) promotes a more stable coordination at the left ankle, (3) affects interlimb coordination of the thighs, and (4) intralimb coordination between thigh and foot, (5) promotes greater dynamic stability of the hips, (6) increases the persistence of fluctuations in step length variability, and lastly (7) affects mechanical walking stability. These results support that transspinal stimulation is an important neuromodulatory strategy that directly affects gait symmetry and dynamic stability. The conservation of main effects at different frequencies and intensities calls for systematic investigation of stimulation protocols for clinical applications.

Soleus H-reflex amplitude modulation during walking remains physiological during transspinal stimulation in humans.

The soleus H-reflex modulation pattern was investigated during stepping following transspinal stimulation over the thoracolumbar region at 15, 30, and 50 Hz with 10 kHz carry-over frequency above and below the paresthesia threshold. The soleus H-reflex was elicited by posterior tibial nerve stimulation with a single 1 ms pulse at an intensity that the M-wave amplitudes ranged from 0 to 15% of the maximal M-wave evoked 80 ms after the test stimulus, and the soleus H-reflex was half the size of the maximal H-reflex evoked on the ascending portion of the recruitment curve. During treadmill walking, the soleus H-reflex was elicited every 2 or 3 steps, and stimuli were randomly dispersed across the step cycle which was divided in 16 equal bins. For each subject and condition, the soleus M-wave and H-reflex were normalized to the maximal M-wave. The soleus background electromyographic (EMG) activity was estimated as the linear envelope for 50 ms duration starting at 100 ms before posterior tibial nerve stimulation for each bin. The gain was determined as the slope of the relationship between the soleus H-reflex and the soleus background EMG activity. The soleus H-reflex phase-dependent amplitude modulation remained unaltered during transspinal stimulation, regardless frequency, or intensity. Similarly, the H-reflex slope and intercept remained the same for all transspinal stimulation conditions tested. Locomotor EMG activity was increased in knee extensor muscles during transspinal stimulation at 30 and 50 Hz throughout the step cycle while no effects were observed in flexor muscles. These findings suggest that transspinal stimulation above and below the paresthesia threshold at 15, 30, and 50 Hz does not block or impair spinal integration of proprioceptive inputs and increases activity of thigh muscles that affect both hip and knee joint movement. Transspinal stimulation may serve as a neurorecovery strategy to augment standing or walking ability in upper motoneuron lesions.

Tapping Into the Human Spinal Locomotor Centres With Transspinal Stimulation.

Human locomotion is controlled by spinal neuronal networks of similar properties, function, and organization to those described in animals. Transspinal stimulation affects the spinal locomotor networks and is used to improve standing and walking ability in paralyzed people. However, the function of locomotor centers during transspinal stimulation at different frequencies and intensities is not known. Here, we document the 3D joint kinematics and spatiotemporal gait characteristics during transspinal stimulation at 15, 30, and 50 Hz at sub-threshold and supra-threshold stimulation intensities. We document the temporal structure of gait patterns, dynamic stability of joint movements over stride-to-stride fluctuations, and limb coordination during walking at a self-selected speed in healthy subjects. We found that transspinal stimulation 1) affects the kinematics of the hip, knee, and ankle joints, 2) promotes a more stable coordination at the left ankle, 3) improves interlimb coordination of the thighs, 4) improves intralimb coordination between thigh and foot, 5) promotes greater dynamic stability of the hips, and lastly 6) affects the mechanical stability of the joints. These results support that transspinal stimulation is an important neuromodulatory strategy that directly affects gait symmetry and dynamic stability. The conservation of main effects at different frequencies and intensities calls for systematic investigation of stimulation protocols for clinical applications.

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

Background: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown. Methods: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30-minutes of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30-minutes of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder and sexual function are taken. Discussion: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach. Trial registration: ClinicalTrials.gov: NCT04807764; Registered on March 19, 2021.

Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial.

BACKGROUND: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown. METHODS: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30 min of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30 min of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder, and sexual function are taken. DISCUSSION: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because, in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT04807764 . Registered on March 19, 2021.

Physiological effects of cathodal electrode configuration for transspinal stimulation in humans.

Transspinal stimulation modulates neuronal excitability and promotes recovery in upper motoneuron lesions. The recruitment input-output curves of transspinal evoked potentials (TEPs) recorded from knee and ankle muscles, and their susceptibility to spinal inhibition, were recorded when the position, size, and number of the cathode electrode were arranged in four settings or protocols (Ps). The four Ps were the following: 1) one rectangular electrode placed at midline (KNIKOU-LAB4Recovery or K-LAB4Recovery; P-KLAB), 2) one square electrode placed at midline (P-2), 3) two square electrodes 1 cm apart placed at midline (P-3), and 4) one square electrode placed on each paravertebral side (P-4). P-KLAB and P-3 required less current to reach TEP threshold or maximal amplitudes. A rightward shift in TEP recruitment curves was evident for P-4, whereas the slope was increased for P-2 and P-4 compared with P-KLAB and P-3. TEP depression upon single and paired transspinal stimuli was pronounced in ankle TEPs but was less prominent in knee TEPs. TEP depression induced by single transspinal stimuli at 1.0 Hz was similar for most TEPs across protocols, but TEP depression induced by paired transspinal stimuli was different between protocols and was replaced by facilitation at 100-ms interstimulus interval for P-4. Our results suggest that P-KLAB and P-3 are preferred based on excitability threshold of motoneurons. P-KLAB produced more TEP depression, thereby maximizing the engagement of spinal neuronal pathways. We recommend P-KLAB to study neurophysiological mechanisms underlying transspinal stimulation or when used as a neuromodulation method for recovery in neurological disorders.NEW & NOTEWORTHY Transspinal stimulation with a rectangular cathode electrode (P-KLAB) requires less current to produce transspinal evoked potentials and maximizes spinal inhibition. We recommend P-KLAB for neurophysiological studies or when used as a neuromodulation method to enhance motor output and normalize muscle tone in neurological disorders.

Brain and spinal cord paired stimulation coupled with locomotor training facilitates motor output in human spinal cord injury.

Combined interventions for neuromodulation leading to neurorecovery have gained great attention by researchers to resemble clinical rehabilitation approaches. In this randomized clinical trial, we established changes in the net output of motoneurons innervating multiple leg muscles during stepping when transcranial magnetic stimulation (TMS) of the primary motor cortex was paired with transcutaneous spinal (transspinal) stimulation over the thoracolumbar region during locomotor training. TMS was delivered before (TMS-transspinal) or after (transspinal-TMS) transspinal stimulation during the stance phase of the less impaired leg. Ten individuals with chronic incomplete or complete SCI received at least 20 sessions of training. Each session consisted of 240 paired stimuli delivered over 10-min blocks for 1 h during robotic assisted step training on a motorized treadmill. Body weight support, leg guidance force and treadmill speed were adjusted based on each subject's ability to step without knee buckling or toe dragging. Most transspinal evoked potentials (TEPs) recorded before and after each intervention from ankle and knee muscles during assisted stepping were modulated in a phase-dependent pattern. Transspinal-TMS and locomotor training affected motor neuron output of knee and ankle muscles with ankle TEPs to be modulated in a phase-dependent manner. TMS-transspinal and locomotor training increased motor neuron output for knee but not for ankle muscles. Our results support that targeted brain and spinal cord stimulation alters responsiveness of neurons over multiple spinal segments in people with chronic SCI. Noninvasive stimulation of the brain and spinal cord along with locomotor training is a novel neuromodulation method that can become a promising modality for rehabilitation in humans after SCI.

Brain and spinal cord paired stimulation coupled with locomotor training affects polysynaptic flexion reflex circuits in human spinal cord injury.

Neurorecovery from locomotor training is well established in human spinal cord injury (SCI). However, neurorecovery resulting from combined interventions has not been widely studied. In this randomized clinical trial, we established the tibialis anterior (TA) flexion reflex modulation pattern when transcranial magnetic stimulation (TMS) of the primary motor cortex was paired with transcutaneous spinal cord (transspinal) stimulation over the thoracolumbar region during assisted step training. Single pulses of TMS were delivered either before (TMS-transspinal) or after (transspinal-TMS) transspinal stimulation during the stance phase of the less impaired leg. Eight individuals with chronic incomplete or complete SCI received at least 20 sessions of paired stimulation during assisted step training. Each session consisted of 240 paired stimuli delivered over 10-min blocks for 1 h during robotic-assisted step training with the Lokomat6 Pro®. Body weight support, leg guidance force and treadmill speed were adjusted based on each participant's ability to step without knee buckling or toe dragging. Both the early and late TA flexion reflex remained unaltered after TMS-transspinal and locomotor training. In contrast, the early and late TA flexion reflexes were significantly depressed during stepping after transspinal-TMS and locomotor training. Reflex changes occurred at similar slopes and intercepts before and after training. Our findings support that targeted brain and spinal cord stimulation coupled with locomotor training reorganizes the function of flexion reflex pathways, which are a part of locomotor networks, in humans with varying levels of sensorimotor function after SCI.Trial registration number NCT04624607; Registered on November 12, 2020.

Adapting Human-Based Transcutaneous Spinal Cord Stimulation to Develop a Clinically Relevant Animal Model.

Transcutaneous spinal cord stimulation (tSCS) as a neuromodulatory strategy has received great attention as a method to promote functional recovery after spinal cord injury (SCI). However, due to the noninvasive nature of tSCS, investigations have primarily focused on human applications. This leaves a critical need for the development of a suitable animal model to further our understanding of this therapeutic intervention in terms of functional and neuroanatomical plasticity and to optimize stimulation protocols. The objective of this study is to establish a new animal model of thoracolumbar tSCS that (1) can accurately recapitulate studies in healthy humans and (2) can receive a repeated and stable tSCS treatment after SCI with minimal restraint, while the electrode remains consistently positioned. We show that our model displays bilateral evoked potentials in multisegmental leg muscles characteristically comparable to humans. Our data also suggest that tSCS mainly activates dorsal root structures like in humans, thereby accounting for the different electrode-to-body-size ratio between the two species. Finally, a repeated tSCS treatment protocol in the awake rat after a complete spinal cord transection is feasible, tolerable, and safe, even with minimal body restraint. Additionally, repeated tSCS was capable of modulating motor output after SCI, providing an avenue to further investigate stimulation-based neuroplasticity and optimize treatment.

Transspinal stimulation and step training alter function of spinal networks in complete spinal cord injury.

STUDY DESIGN: Pilot study (case series). OBJECTIVE: The objective of this study was to establish spinal neurophysiological changes following high-frequency transspinal stimulation during robot-assisted step training in individuals with chronic motor complete spinal cord injury (SCI). SETTING: University research laboratory (Klab4Recovery). METHODS: Four individuals with motor complete SCI received an average of 18 sessions of transspinal stimulation over the thoracolumbar region with a pulse train at 333 Hz during robotic-assisted step training. Each session lasted ~1 h, with an average of 240 stimulations delivered during each training session. Before and after the combined intervention, we evaluated the amplitude modulation of the long-latency tibialis anterior (TA) flexion reflex and transspinal evoked potentials (TEP) recorded from flexors and extensors during assisted stepping, and the TEP recruitment curves at rest. RESULTS: The long-latency TA flexion reflex was depressed in all phases of the step cycle and the phase-dependent amplitude modulation of TEPs was altered during assisted stepping, while spinal motor output based on TEP recruitment curves was increased after the combined intervention. CONCLUSION: This is the first study documenting noninvasive transspinal stimulation coupled with locomotor training depresses flexion reflex excitability and concomitantly increases motoneuron output over multiple spinal segments for both flexors and extensors in people with motor complete SCI. While both transspinal stimulation and locomotor training may act via similar activity-dependent neuroplasticity mechanisms, combined interventions for rehabilitation of neurological disorders has not been systematically assessed. Our current findings support locomotor training induced neuroplasticity may be augmented with transspinal stimulation.

Neurophysiological Changes After Paired Brain and Spinal Cord Stimulation Coupled With Locomotor Training in Human Spinal Cord Injury.

Neurophysiological changes that involve activity-dependent neuroplasticity mechanisms via repeated stimulation and locomotor training are not commonly employed in research even though combination of interventions is a common clinical practice. In this randomized clinical trial, we established neurophysiological changes when transcranial magnetic stimulation (TMS) of the motor cortex was paired with transcutaneous thoracolumbar spinal (transspinal) stimulation in human spinal cord injury (SCI) delivered during locomotor training. We hypothesized that TMS delivered before transspinal (TMS-transspinal) stimulation promotes functional reorganization of spinal networks during stepping. In this protocol, TMS-induced corticospinal volleys arrive at the spinal cord at a sufficient time to interact with transspinal stimulation induced depolarization of alpha motoneurons over multiple spinal segments. We further hypothesized that TMS delivered after transspinal (transspinal-TMS) stimulation induces less pronounced effects. In this protocol, transspinal stimulation is delivered at time that allows transspinal stimulation induced action potentials to arrive at the motor cortex and affect descending motor volleys at the site of their origin. Fourteen individuals with motor incomplete and complete SCI participated in at least 25 sessions. Both stimulation protocols were delivered during the stance phase of the less impaired leg. Each training session consisted of 240 paired stimuli delivered over 10-min blocks. In transspinal-TMS, the left soleus H-reflex increased during the stance-phase and the right soleus H-reflex decreased at mid-swing. In TMS-transspinal no significant changes were found. When soleus H-reflexes were grouped based on the TMS-targeted limb, transspinal-TMS and locomotor training promoted H-reflex depression at swing phase, while TMS-transspinal and locomotor training resulted in facilitation of the soleus H-reflex at stance phase of the step cycle. Furthermore, both transspinal-TMS and TMS-transspinal paired-associative stimulation (PAS) and locomotor training promoted a more physiological modulation of motor activity and thus depolarization of motoneurons during assisted stepping. Our findings support that targeted non-invasive stimulation of corticospinal and spinal neuronal pathways coupled with locomotor training produce neurophysiological changes beneficial to stepping in humans with varying deficits of sensorimotor function after SCI.

Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury.

This study investigated the neuromodulatory effects of transspinal stimulation on soleus H-reflex excitability and electromyographic (EMG) activity during stepping in humans with and without spinal cord injury (SCI). Thirteen able-bodied adults and 5 individuals with SCI participated in the study. EMG activity from both legs was determined for steps without, during, and after a single-pulse or pulse train transspinal stimulation delivered during stepping randomly at different phases of the step cycle. The soleus H-reflex was recorded in both subject groups under control conditions and following single-pulse transspinal stimulation at an individualized exactly similar positive and negative conditioning-test interval. The EMG activity was decreased in both subject groups at the steps during transspinal stimulation, while intralimb and interlimb coordination were altered only in SCI subjects. At the steps immediately after transspinal stimulation, the physiological phase-dependent EMG modulation pattern remained unaffected in able-bodied subjects. The conditioned soleus H-reflex was depressed throughout the step cycle in both subject groups. Transspinal stimulation modulated depolarization of motoneurons over multiple segments, limb coordination, and soleus H-reflex excitability during assisted stepping. The soleus H-reflex depression may be the result of complex spinal inhibitory interneuronal circuits activated by transspinal stimulation and collision between orthodromic and antidromic volleys in the peripheral mixed nerve. The soleus H-reflex depression by transspinal stimulation suggests a potential application for normalization of spinal reflex excitability after SCI.

Rectus femoris hyperreflexia contributes to Stiff-Knee gait after stroke.

BACKGROUND: Stiff-Knee gait (SKG) after stroke is often accompanied by decreased knee flexion angle during the swing phase. The decreased knee flexion has been hypothesized to originate from excessive quadriceps activation. However, it is unclear whether hyperreflexia plays a role in this activation. The goal of this study was to establish the relationship between quadriceps hyperreflexia and knee flexion angle during walking in post-stroke SKG. METHODS: The rectus femoris (RF) H-reflex was recorded in 10 participants with post-stroke SKG and 10 healthy controls during standing and walking at the pre-swing phase. In order to attribute the pathological neuromodulation to quadriceps muscle hyperreflexia and activation, healthy individuals voluntarily increased quadriceps activity using electromyographic (EMG) feedback during standing and pre-swing upon RF H-reflex elicitation. RESULTS: We observed a negative correlation (R = - 0.92, p = 0.001) between knee flexion angle and RF H-reflex amplitude in post-stroke SKG. In contrast, H-reflex amplitude in healthy individuals in presence (R = 0.47, p = 0.23) or absence (R = - 0.17, p = 0.46) of increased RF muscle activity was not correlated with knee flexion angle. We observed a body position-dependent RF H-reflex modulation between standing and walking in healthy individuals with voluntarily increased RF activity (d = 2.86, p = 0.007), but such modulation was absent post-stroke (d = 0.73, p = 0.296). CONCLUSIONS: RF reflex modulation is impaired in post-stroke SKG. The strong correlation between RF hyperreflexia and knee flexion angle indicates a possible regulatory role of spinal reflex excitability in post-stroke SKG. Interventions targeting quadriceps hyperreflexia could help elucidate the causal role of hyperreflexia on knee joint function in post-stroke SKG.

Modulation of soleus H-reflex excitability following cervical transspinal conditioning stimulation in humans.

The aim of this study was to establish the effects of transcutaneous spinal cord (transspinal) stimulation over the cervical region on soleus H-reflex excitability in healthy subjects while at rest. Reflex effects were established at subthreshold and suprathreshold cervical transspinal conditioning stimulation intensities of the extensor carpi radialis transspinal evoked potential. Twenty soleus H-reflexes at 0.125 Hz were recorded randomly under control conditions and following transspinal conditioning stimulation at conditioning-test intervals that ranged from 0 to 55 ms and tested in increment of 5 ms steps and at 100 ms. Cervical transspinal stimulation at suprathreshold and not at subthreshold intensities produced short, medium, and long-latency soleus H-reflex facilitation. The observed facilitatory reflex effects are consistent with activation of excitatory components of long propriospinal neurons. We propose the use of cervical transspinal stimulation to potentiate excitatory neuronal interactions between arms and legs in neurological disorders.

Transspinal stimulation downregulates activity of flexor locomotor networks during walking in humans.

The objective of this study was to establish the effects of transspinal stimulation on short-latency tibialis anterior (TA) flexion reflex during walking in healthy humans. Single pulse transspinal stimulation was delivered at a conditioning-test (C-T) interval either after (~20 ms) or simultaneously with the last pulse of the pulse train (0 ms) delivered to the medial arch of the right foot. Transspinal stimulation was delivered at sub- and supra-threshold intensities of the spinally-mediated TA transspinal evoked potential. Stimulation was delivered randomly at different phases of the step cycle, based on the foot switch threshold signal, which was divided into 16 equal bins. The TA flexion reflex facilitation under control conditions occurred at heel contact and then progressively from late stance phase reaching its peak at early and late swing phases. Transspinal stimulation at a negative and suprathreshold 0 ms C-T interval depressed flexion reflex excitability at all phases of the step cycle. The short-latency TA flexion reflex depression was possibly mediated through spinal inhibitory interneurons acting at both pre- and post- motoneuronal sites or by transspinal stimulation affecting directly the activity of the flexor half spinal center. These results reveal direct actions of transspinal stimulation on human spinal locomotor networks.

Transspinal stimulation decreases corticospinal excitability and alters the function of spinal locomotor networks.

Locomotion requires the continuous integration of descending motor commands and sensory inputs from the legs by spinal central pattern generator circuits. Modulation of spinal neural circuits by transspinal stimulation is well documented, but how transspinal stimulation affects corticospinal excitability during walking in humans remains elusive. We measured the motor evoked potentials (MEPs) at multiple phases of the step cycle conditioned with transspinal stimulation delivered at sub- and suprathreshold intensities of the spinally mediated transspinal evoked potential (TEP). Transspinal stimulation was delivered before or after transcranial magnetic stimulation during which summation between MEP and TEP responses in the surface EMG was absent or present. Relationships between MEP amplitude and background EMG activity, silent period duration, and phase-dependent EMG amplitude modulation during and after stimulation were also determined. Ankle flexor and extensor MEPs were depressed by suprathreshold transspinal stimulation when descending volleys were timed to interact with transspinal stimulation-induced motoneuron depolarization at the spinal cord. MEP depression coincided with decreased MEP gain, unaltered MEP threshold, and unaltered silent period duration. Locomotor EMG activity of bilateral knee and ankle muscles was significantly depressed during the step at which transspinal stimulation was delivered but fully recovered at the subsequent step. The results support a model in which MEP depression by transspinal stimulation occurs via subcortical or spinal mechanisms. Transspinal stimulation disrupts the locomotor output of flexor and extensor motoneurons initially, but the intact nervous system has the ability to rapidly overcome this pronounced locomotor adaptation. In conclusion, transspinal stimulation directly affects spinal locomotor centers in healthy humans.NEW & NOTEWORTHY Lumbar transspinal stimulation decreases ankle flexor and extensor motor evoked potentials (MEPs) during walking. The MEP depression coincides with decreased MEP gain, unaltered MEP threshold changes, and unaltered silent period duration. These findings indicate that MEP depression is subcortical or spinal in origin. Healthy subjects could rapidly overcome the pronounced depression of muscle activity during the step at which transspinal stimulation was delivered. Thus, transspinal stimulation directly affects the function of spinal locomotor networks in healthy humans.

Repeated transspinal stimulation decreases soleus H-reflex excitability and restores spinal inhibition in human spinal cord injury.

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.

Repeated cathodal transspinal pulse and direct current stimulation modulate cortical and corticospinal excitability differently in healthy humans.

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.