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.

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.

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.