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Targeted-Plasticity in the Corticospinal Tract After Human Spinal Cord Injury.

ABSTRACT: 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.

SUBMITTER: Christiansen L

PROVIDER: S-EPMC6095776 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeted-Plasticity in the Corticospinal Tract After Human Spinal Cord Injury.

Christiansen Lasse L Perez Monica A MA

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20180701 3

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 ...[more]

PMID: 29946981

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Project description:Rehabilitative exercise in humans with spinal cord injury aims to engage residual neural networks to improve functional recovery. We hypothesized that exercise combined with non-invasive stimulation targeting spinal synapses further promotes functional recovery. Twenty-five individuals with chronic incomplete cervical, thoracic, and lumbar spinal cord injury were randomly assigned to 10 sessions of exercise combined with paired corticospinal-motor neuronal stimulation (PCMS) or sham-PCMS. In an additional experiment, we tested the effect of PCMS without exercise in 13 individuals with spinal cord injury with similar characteristics. During PCMS, 180 pairs of stimuli were timed to have corticospinal volleys evoked by transcranial magnetic stimulation over the primary motor cortex arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles (depending on the injury level), 1-2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of a peripheral nerve. Participants exercised for 45 min after all protocols. We found that the time to complete subcomponents of the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) and the 10-m walk test decreased on average by 20% after all protocols. However, the amplitude of corticospinal responses elicited by transcranial magnetic stimulation and the magnitude of maximal voluntary contractions in targeted muscles increased on overage by 40-50% after PCMS combined or not with exercise but not after sham-PCMS combined with exercise. Notably, behavioural and physiological effects were preserved 6 months after the intervention in the group receiving exercise with PCMS but not in the group receiving exercise combined with sham-PCMS, suggesting that the stimulation contributed to preserve exercise gains. Our findings indicate that targeted non-invasive stimulation of spinal synapses might represent an effective strategy to facilitate exercise-mediated recovery in humans with different degrees of paralysis and levels of spinal cord injury.

Project description:After CNS trauma such as spinal cord injury, the ability of surviving neural elements to sprout axons, reorganize neural networks and support recovery of function is severely restricted, contributing to chronic neurological deficits. Among limitations on neural recovery are myelin-associated inhibitors functioning as ligands for neuronal Nogo receptor 1 (NgR1). A soluble decoy (NgR1-Fc, AXER-204) blocks these ligands and provides a means to promote recovery of function in multiple preclinical rodent models of spinal cord injury. However, the safety and efficacy of this reagent in non-human primate spinal cord injury and its toxicological profile have not been described. Here, we provide evidence that chronic intrathecal and intravenous administration of NgR1-Fc to cynomolgus monkey and to rat are without evident toxicity at doses of 20 mg and greater every other day (≥2.0 mg/kg/day), and far greater than the projected human dose. Adult female African green monkeys underwent right C5/6 lateral hemisection with evidence of persistent disuse of the right forelimb during feeding and right hindlimb during locomotion. At 1 month post-injury, the animals were randomized to treatment with vehicle (n = 6) or 0.10-0.17 mg/kg/day of NgR1-Fc (n = 8) delivered via intrathecal lumbar catheter and osmotic minipump for 4 months. One animal was removed from the study because of surgical complications of the catheter, but no treatment-related adverse events were noted in either group. Animal behaviour was evaluated at 6-7 months post-injury, i.e. 1-2 months after treatment cessation. The use of the impaired forelimb during spontaneous feeding and the impaired hindlimb during locomotion were both significantly greater in the treatment group. Tissue collected at 7-12 months post-injury showed no significant differences in lesion size, fibrotic scar, gliosis or neuroinflammation between groups. Serotoninergic raphespinal fibres below the lesion showed no deficit, with equal density on the lesioned and intact side below the level of the injury in both groups. Corticospinal axons traced from biotin-dextran-amine injections in the left motor cortex were equally labelled across groups and reduced caudal to the injury. The NgR1-Fc group tissue exhibited a significant 2-3-fold increased corticospinal axon density in the cervical cord below the level of the injury relative to the vehicle group. The data show that NgR1-Fc does not have preclinical toxicological issues in healthy animals or safety concerns in spinal cord injury animals. Thus, it presents as a potential therapeutic for spinal cord injury with evidence for behavioural improvement and growth of injured pathways in non-human primate spinal cord injury.

Dataset Information

Targeted-Plasticity in the Corticospinal Tract After Human Spinal Cord Injury.

Publications

Targeted-Plasticity in the Corticospinal Tract After Human Spinal Cord Injury.

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