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Context: Rehabilitation after spinal cord injury (SCI) relies on the use of exercise training, which has limited functional gains. There is a need to develop more efficient approaches to facilitate recovery after SCI., Methods: This review focuses on a neuromodulation method where transcranial magnetic stimulation (TMS) over the primary motor cortex is paired with transcutaneous electrical stimulation over a peripheral nerve to induce plasticity at corticospinal-motoneuronal synapses. These two stimuli are applied at precise inter-stimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing-dependent plasticity applied alone or in combination with exercise training., Results: Transmission in residual corticospinal axons, assessed using TMS and maximal voluntary motor output, increased after stimulation combined with exercise training in persons with SCI. There were also significant improvements in functional outcomes, including walking speed and grasping function, which persisted after 6-9 months post stimulation. Moreover, the data suggested that the effects of the stimulation protocol can be augmented with a higher number of sessions and with multiple stimulation sites in the spinal cord., Conclusions: Voluntary movement is enhanced in people with SCI through the strengthening of corticospinal-motoneuronal synapses using paired stimulation. This neuromodulation technique represents a novel powerful strategy to facilitate functional recovery after SCI.

Purpose of Review: This review focuses on a relatively new neuromodulation method where transcranial magnetic stimulation over the primary motor cortex is paired with transcutaneous electrical stimulation over a peripheral nerve to induce plasticity at corticospinal-motoneuronal synapses., Recent Findings: Recovery of sensorimotor function after spinal cord injury largely depends on transmission in the corticospinal pathway. Significantly damaged corticospinal axons fail to regenerate and participate in functional recovery. Transmission in residual corticospinal axons can be assessed using non-invasive transcranial magnetic stimulation which combined with transcutaneous electrical stimulation can be used to improve voluntary motor output, as was recently demonstrated in clinical studies in humans with chronic incomplete spinal cord injury. These two stimuli are applied at precise inter-stimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing dependent plasticity., Summary: We discuss the neural mechanisms and application of this neuromodulation technique and its potential therapeutic effect on recovery of function in humans with chronic spinal cord injury., Competing Interests: Conflict of Interest Hang Jin Jo, Michael S.A. Richardson, Martin Oudega and Monica A. Perez declare no conflicts of interest relevant to this manuscript.

Background: Paired corticospinal-motoneuronal stimulation (PCMS) increases corticospinal transmission in humans with chronic incomplete spinal cord injury (SCI)., Objective/hypothesis: Here, we examine whether increases in the excitability of spinal motoneurons, by performing voluntary activity, could potentiate PCMS effects on corticospinal transmission., Methods: During PCMS, we used 100 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the hand representation of the primary motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the first dorsal interosseous (FDI) muscle ∼1-2 ms before antidromic potentials were elicited in motoneurons by electrical stimulation of the ulnar nerve. PCMS was applied at rest (PCMS rest ) and during a small level of isometric index finger abduction (PCMS active ) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the FDI muscle before and after each protocol in humans with and without (controls) chronic cervical SCI., Results: We found in control participants that MEPs elicited by TMS and electrical stimulation increased to a similar extent after both PCMS protocols for ∼30 min. Whereas, in humans with SCI, MEPs elicited by TMS and electrical stimulation increased to a larger extent after PCMS active compared with PCMS rest . Importantly, SCI participants who did not respond to PCMS rest responded after PCMS active and those who responded to both protocols showed larger increments in corticospinal transmission after PCMS active ., Conclusions: Our findings suggest that muscle contraction during PCMS potentiates corticospinal transmission. PCMS applied during voluntary activity may represent a strategy to boost spinal plasticity after SCI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) often results in impaired or absent sensorimotor function below the level of the lesion. Recent electrophysiological studies in humans with chronic incomplete SCI demonstrate that voluntary motor output can be to some extent potentiated by noninvasive stimulation that targets the corticospinal tract. We discuss emerging approaches that use transcranial magnetic stimulation (TMS) over the primary motor cortex and electrical stimulation over a peripheral nerve as tools to induce plasticity in residual corticospinal projections. A single TMS pulse over the primary motor cortex has been paired with peripheral nerve electrical stimulation at precise interstimulus intervals to reinforce corticospinal synaptic transmission using principles of spike-timing dependent plasticity. Pairs of TMS pulses have also been used at interstimulus intervals that mimic the periodicity of descending indirect (I) waves volleys in the corticospinal tract. This data, along with information about the extent of the injury, provides a new framework for exploring the contribution of the corticospinal tract to recovery of function following SCI.

The corticospinal tract contributes to the control of finger muscles during precision and power grip. The involvement of different sets of cortical interneuronal circuits during these distinct grasping behaviors remains unknown. To examine this question in humans we used noninvasive transcranial magnetic stimulation (TMS) over the hand representation of the primary motor cortex to elicit motor evoked potentials (MEPs) in an intrinsic finger muscle during index finger abduction (control task), precision grip, and power grip. The TMS coil was oriented to induce currents in the brain in the latero-medial (LM), posterior-anterior (PA), and anterior-posterior (AP) direction to preferentially activate corticospinal axons directly and early and late synaptic inputs to corticospinal neurons, respectively. We found that AP-LM MEP latency differences were consistently longer during power grip compared with index finger abduction and precision grip, while PA-LM differences remained similar across tasks. Short-interval intracortical facilitation, targeting AP but not PA inputs, increased during power grip compared with other tasks. Our novel findings suggest that cortical structures activated by PA and AP stimuli are differentially active during precision and power grip. We propose that a preferential recruitment of late synaptic inputs to corticospinal neurons may be achieved when humans perform a power grip., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

It has been proposed that ipsilateral motor pathways play a role in the control of ipsilateral movements and recovery of function after injury. However, the extent to which ipsilateral motor pathways are engaged in voluntary activity in intact humans remains largely unknown. Using transcranial magnetic stimulation over the arm representation of the primary motor cortex, we examined ipsilateral motor-evoked potentials (iMEPs) in a proximal arm muscle during increasing levels of unilateral and bilateral isometric force in a sitting position. We demonstrate that iMEP area and amplitude decreased during bilateral contraction of homonymous (elbow flexor) muscles and increased during bilateral contraction of heteronymous (elbow flexor and extensor) muscles compared with a unilateral contraction, regardless of the level of force tested. To further understand the neuronal inputs involved in the bilateral effects, we examined the contribution from neck afferents projecting onto ipsilateral motor pathways. Medial (away from the muscle tested) and lateral (toward the muscle tested) rotation of the head enhanced bilateral iMEP effects from homonymous and heteronymous muscles, respectively. In contrast, head flexion and extension exerted nonspecific bilateral effects on iMEPs. Intracortical inhibition, in the motor cortex where iMEPs originated, showed modulation compatible with the changes in iMEPs. We conclude that ipsilateral projections to proximal arm muscles can be selectively modulated by voluntary contraction of contralateral arm muscles, likely involving circuits mediating asymmetric tonic neck reflexes acting, at least in part, at the cortical level. The pattern of bilateral actions may represent a strategy to engage ipsilateral motor pathways in a motor behavior., (Copyright © 2014 the authors 0270-6474/14/3313924-11$15.00/0.)

Baclofen is a GABAB receptor agonist commonly used to relief spasticity related to motor disorders. The effects of baclofen on voluntary motor output are limited and not yet understood. Using noninvasive transcranial magnetic and electrical stimulation techniques, we examined electrophysiological measures probably involving GABAB (long-interval intracortical inhibition and the cortical silent period) and GABAA (short-interval intracortical inhibition) receptors, which are inhibitory effects mediated by subcortical and cortical mechanisms. We demonstrate increased active long-interval intracortical inhibition and prolonged cortical silent period during voluntary activity of an intrinsic finger muscle in humans with chronic incomplete cervical spinal cord injury (SCI) compared with age-matched controls, whereas resting long-interval intracortical inhibition was unchanged. However, long-term (~6 years) use of baclofen decreased active long-interval intracortical inhibition to similar levels as controls but did not affect the duration of the cortical silent period. We found a correlation between signs of spasticity and long-interval intracortical inhibition in patients with SCI. Short-interval intracortical inhibition was decreased during voluntary contraction compared with rest but there was no effect of SCI or baclofen use. Together, these results demonstrate that baclofen selectively maintains use-dependent modulation of largely subcortical but not cortical GABAB neuronal pathways after human SCI. Thus, cortical GABA(B) circuits may be less sensitive to baclofen than spinal GABAB circuits. This may contribute to the limited effects of baclofen on voluntary motor output in subjects with motor disorders affected by spasticity.

This article reviews neural interface technology and its relationship with neuroplasticity. Two types of neural interface technology are reviewed, highlighting specific technologies that the authors directly work with: (1) neural interface technology for neural recording, such as the micro-ECoG BCI system for hand prosthesis control, and the comprehensive rehabilitation paradigm combining MEG-BCI, action observation, and motor imagery training; (2) neural interface technology for functional neural stimulation, such as somatosensory neural stimulation for restoring somatosensation, and non-invasive cortical stimulation using rTMS and tDCS for modulating cortical excitability and stroke rehabilitation. The close interaction between neural interface devices and neuroplasticity leads to increased efficacy of neural interface devices and improved functional recovery of the nervous system. This symbiotic relationship between neural interface technology and the nervous system is expected to maximize functional gain for individuals with various sensory, motor, and cognitive impairments, eventually leading to better quality of life.