Objective
Spinal cord injury (SCI) damages synaptic connections between corticospinal axons and motoneurons of many muscles, resulting in devastating paralysis. We hypothesized that strengthening ...corticospinal‐motoneuronal synapses at multiple spinal cord levels through Hebbian plasticity (i.e., “neurons that fire together, wire together”) promotes recovery of leg and arm function.
Methods
Twenty participants with chronic SCI were randomly assigned to receive 20 sessions of Hebbian or sham stimulation targeting corticospinal‐motoneuronal synapses of multiple leg muscles followed by exercise. Based on the results from this study, in a follow‐up prospective study, 11 more participants received 40 sessions of Hebbian stimulation targeting corticospinal‐motoneuronal synapses of multiple arm and leg muscles followed by exercise. During Hebbian stimulation sessions, 180 paired pulses elicited corticospinal action potentials by magnetic (motor cortex) and/or electrical (thoracic spine) stimulation allowing volleys to arrive at the spinal cord 1–2 milliseconds before motoneurons were activated retrogradely via bilateral electrical stimulation (brachial plexus, ulnar, femoral, and common peroneal nerves) for biceps brachii, first dorsal interosseous, quadriceps femoris, and tibialis anterior muscles as needed.
Results
We found in our randomized study that participants receiving Hebbian stimulation improved their walking speed and corticospinal function to a greater extent than individuals receiving sham stimulation. In agreement, prospective study participants improved their grasping and walking, corticospinal function, and quality of life metrics, exhibiting greater improvements with more sessions that persisted 9‐month post‐therapy.
Interpretation
Our findings suggest that multisite Hebbian stimulation, informed by the physiology of the corticospinal system, represents an effective strategy to promote functional recovery following SCI. ANN NEUROL 2023;93:1198–1213
Several experimental manipulations result in axonal regeneration in the central nervous system (CNS) when applied before or at the time of injury
1–6 but not when initiated after a delay
5–10, which ...would be clinically more relevant. As centrally injured neurons show signs of atrophy and degeneration
11–13, it raises the question whether chronically injured neurons are able to regenerate. To address this question, we used adult rodent primary sensory neurons that regenerate their central axon when their peripheral axon is cut (called conditioning) beforehand but not afterwards. We found that primary sensory neurons express regeneration-associated genes and efficiently regrow their axon in cell culture two months after a central lesion upon conditioning. Moreover, conditioning enables central axons to regenerate through a fresh lesion independent of a previous central lesion. Using in vivo imaging we demonstrated that conditioned neurons rapidly regrow their axons through a fresh central lesion. Finally, when single sensory axons were cut with a two-photon laser, they robustly regenerate within days after attaining growth competence through conditioning. We conclude that sensory neurons can acquire the intrinsic potential to regenerate their axons months after a CNS lesion, which they implement in the absence of traumatic tissue.
Objective
A motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through ...inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI.
Methods
Spasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n = 36) and motor incomplete (n = 30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation.
Results
We found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity.
Interpretation
These findings suggest that spasticity represents an easy‐to‐use clinical outcome that might help to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for motor complete SCI patients. ANN NEUROL 2024;95:71–86
It was previously reported that a tube holding chitosan carriers loaded with neurotrophin-3 (NT-3), after insertion into a 5 mm long transection gap in the adult rat spinal cord, triggered de novo ...neural tissue generation and functional recovery. Here, we report an effort to validate these findings using stringent blinding methodologies, which are crucial for robustness in reproducing biomedical studies. Radio frequency identification (RFID) chips were utilized to label rats that were randomly assigned into three experimental groups: transection with chitosan-NT-3 implant (C-NT3), transection only (T-controls), and laminectomy only (S-controls), blinding the experimenters to the treatments. Three months after surgery, animals only known by their RFID were functionally, electrophysiologically, and anatomically assessed. The data were then collected into the proper groups and statistically analyzed. Neural tissue with nestin-, Tuj1-, and NeuN-positive cells was found bridging the transection gap in C-NT3 rats, but not in T-controls. Motor- and somatosensory-evoked potentials were detected in C-NT3 rats and S-controls, but not in T-controls. Hind limb movement was significantly better in C-NT3 rats compared with T-controls. Our validation study indicates that C-NT3 implants facilitate neural tissue generation, at least in part, by eliciting endogenous neurogenesis. Our data support the use of C-NT3 implants for tissue remodeling in the injured spinal cord.
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Promoting axon growth after peripheral nerve injury may support recovery. Soluble laminin polymers formed at pH 4 (aLam) accelerate axon growth from adult dorsal root ganglion neurons ...in vitro. We used an adult rat model of a peripheral (peroneal) nerve crush to investigate whether an injection of aLam enhances axon growth and functional recovery in vivo. Rats that received an injection of aLam into the crush at 2 days post-injury show significant improvements in hind limb motor function at 2 and 5 weeks after injury compared with control rats that received phosphate-buffered saline. Functional improvement was not associated with changes in sensitivity to thermal or mechanical stimuli. Treatment with aLam decreased the occurrence of autophagia and abolished non-compliance with treadmill walking. Rats treated with aLam showed increased axon presence in the crush site at 2 weeks post-injury and larger axon diameter at 10 weeks post-injury compared with controls. Treatment with aLam did not affect Schwann cell presence or axon myelination. Our results demonstrated that aLam accelerates axon growth and maturity in a crushed peroneal nerve associated with expedited hind limb motor function recovery. Our data support the therapeutic potential of injectable aLam polymers for treatment of peripheral nerve crush injuries.
Incidence of peripheral nerve injury has been estimated to be as high as 5% of all cases entering a Level 1 trauma center and the majority of cases are young males. Peripheral nerves have some endogenous repair capabilities, but overall recovery of function remains limited, which typically has devastating effects on the individual, family, and society, as wages are lost and rehabilitation is extended until the nerves can repair. We report here that laminin polymers injected into a crush accelerated repair and recovery, had no adverse effects on sensory function, obliterated non-compliance for walking tests, and decreased the occurrence of autophagia. These data support the use of laminin polymers for safe and effective recovery after peripheral nerve injury.
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The efficacy of protein-based therapies for treating injured nervous tissue is limited by the short half-life of free proteins in the body. Affinity-based biomaterial delivery systems ...provide sustained release of proteins, thereby extending the efficacy of such therapies. Here, we investigated the biocompatibility of a novel coacervate delivery system based on poly(ethylene argininylaspartate diglyceride) (PEAD) and heparin in the damaged spinal cord. We found that the presence of the PEAD:heparin coacervate did not affect the macrophage response, glial scarring or nervous tissue loss, which are hallmarks of spinal cord injury. Moreover, the density of axons, including serotonergic axons, at the injury site and the recovery of motor and sensorimotor function were comparable in rats with and without the coacervate. These results revealed the biocompatibility of our delivery system and supported its potential to deliver therapeutic proteins to the injured nervous system.
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.
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.
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.
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.
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