Spinal cord injury: overview of experimental approaches used to restore locomotor activity

AbstractSpinal cord injury affects more than 2.5 million people worldwide and can lead to paraplegia and quadriplegia. Anatomical discontinuity in the spinal cord results in disruption of the impulse conduction that causes temporary or permanent changes in the cord’s normal functions. Although axonal regeneration is limited, damage to the spinal cord is often accompanied by spontaneous plasticity and axon regeneration that help improve sensory and motor skills. The recovery process depends mainly on synaptic plasticity in the preexisting circuits and on the formation of new pathways through collateral sprouting into neighboring denervated territories. However, spontaneous recovery after spinal cord injury can go on for several years, and the degree of recovery is very limited. Therefore, the development of new approaches that could accelerate the gain of motor function is of high priority to patients with damaged spinal cord. Although there are no fully restorative treatments for spinal injury, various rehabilitative approaches have been tested in animal models and have reached clinical trials. In this paper, a closer look will be given at the potential therapies that could facilitate axonal regeneration and improve locomotor recovery after injury to the spinal cord. This article highlights the application of several interventions including locomotor training, molecular and cellular treatments, and spinal cord stimulation in the field of rehabilitation research. Studies investigating therapeutic approaches in both animal models and individuals with injured spinal cords will be presented.

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Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats

Journal of Neurophysiology ◽

10.1152/jn.01044.2012 ◽

2013 ◽

Vol 109 (12) ◽

pp. 2909-2922 ◽

Cited By ~ 31

Author(s):

Marina Martinez ◽

Hugo Delivet-Mongrain ◽

Serge Rossignol

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Treadmill Training ◽

Locomotor Training ◽

Locomotor Recovery ◽

Thoracic Level ◽

Spinal Circuitry ◽

Cord Injury ◽

Locomotor Deficits ◽

Spinal Hemisection

After a spinal hemisection at thoracic level in cats, the paretic hindlimb progressively recovers locomotion without treadmill training but asymmetries between hindlimbs persist for several weeks and can be seen even after a further complete spinal transection at T13. To promote optimal locomotor recovery after hemisection, such asymmetrical changes need to be corrected. In the present study we determined if the locomotor deficits induced by a spinal hemisection can be corrected by locomotor training and, if so, whether the spinal stepping after the complete spinal cord transection is also more symmetrical. This would indicate that locomotor training in the hemisected period induces efficient changes in the spinal cord itself. Sixteen adult cats were first submitted to a spinal hemisection at T10. One group received 3 wk of treadmill training, whereas the second group did not. Detailed kinematic and electromyographic analyses showed that a 3-wk period of locomotor training was sufficient to improve the quality and symmetry of walking of the hindlimbs. Moreover, after the complete spinal lesion was performed, all the trained cats reexpressed bilateral and symmetrical hindlimb locomotion within 24 h. By contrast, the locomotor pattern of the untrained cats remained asymmetrical, and the hindlimb on the side of the hemisection was still deficient. This study highlights the beneficial role of locomotor training in facilitating bilateral and symmetrical functional plastic changes within the spinal circuitry and in promoting locomotor recovery after an incomplete spinal cord injury.

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Paired Immunoglobulin-like Receptor B Knockout Does Not Enhance Axonal Regeneration or Locomotor Recovery after Spinal Cord Injury

Journal of Biological Chemistry ◽

10.1074/jbc.m110.163493 ◽

2010 ◽

Vol 286 (3) ◽

pp. 1876-1883 ◽

Cited By ~ 47

Author(s):

Yuka Nakamura ◽

Yuki Fujita ◽

Masaki Ueno ◽

Toshiyuki Takai ◽

Toshihide Yamashita

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Locomotor Recovery ◽

Cord Injury

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Is the Recovery of Stepping Following Spinal Cord Injury Mediated by Modifying Existing Neural Pathways or by Generating New Pathways? A Perspective

Physical Therapy ◽

10.1093/ptj/81.12.1904 ◽

2001 ◽

Vol 81 (12) ◽

pp. 1904-1911 ◽

Cited By ~ 34

Author(s):

Ray D de Leon ◽

Roland R Roy ◽

V Reggie Edgerton

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Weight Bearing ◽

Gait Training ◽

Neural Pathways ◽

Neuronal Regeneration ◽

Locomotor Recovery ◽

Cord Injury ◽

Descending Input

Abstract The recovery of stepping ability following a spinal cord injury may be achieved by restoring anatomical connectivity within the spinal cord. However, studies of locomotor recovery in animals with complete spinal cord transection suggest that the adult mammalian spinal cord can acquire the ability to generate stepping after all descending input is eliminated and in the absence of neuronal regeneration. Moreover, rehabilitative gait training has been shown to play a crucial role in teaching existing spinal pathways to generate locomotion and appropriately respond to sensory feedback. This brief review presents evidence that neural networks in the mammalian spinal cord can be modulated pharmacologically and/or with task-specific behavioral training to generate weight-bearing stepping after a spinal injury. Further, the role that spinal learning can play in the management of humans with spinal cord injury is discussed in relation to interventions that are designed primarily to enhance neuronal regeneration.

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Locomotor Training After Human Spinal Cord Injury: A Series of Case Studies

Physical Therapy ◽

10.1093/ptj/80.7.688 ◽

2000 ◽

Vol 80 (7) ◽

pp. 688-700 ◽

Cited By ~ 373

Author(s):

Andrea L Behrman ◽

Susan J Harkema

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Sensory Information ◽

Locomotor Training ◽

Overground Walking ◽

Thoracic Spinal Cord ◽

Human Spinal Cord ◽

Thoracic Spinal ◽

Cord Injury

AbstractMany individuals with spinal cord injury (SCI) do not regain their ability to walk, even though it is a primary goal of rehabilitation. Mammals with thoracic spinal cord transection can relearn to step with their hind limbs on a treadmill when trained with sensory input associated with stepping. If humans have similar neural mechanisms for locomotion, then providing comparable training may promote locomotor recovery after SCI. We used locomotor training designed to provide sensory information associated with locomotion to improve stepping and walking in adults after SCI. Four adults with SCIs, with a mean postinjury time of 6 months, received locomotor training. Based on the American Spinal Injury Association (ASIA) Impairment Scale and neurological classification standards, subject 1 had a T5 injury classified as ASIA A, subject 2 had a T5 injury classified as ASIA C, subject 3 had a C6 injury classified as ASIA D, and subject 4 had a T9 injury classified as ASIA D. All subjects improved their stepping on a treadmill. One subject achieved overground walking, and 2 subjects improved their overground walking. Locomotor training using the response of the human spinal cord to sensory information related to locomotion may improve the potential recovery of walking after SCI.

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Locomotor recovery after spinal cord injury: intimate dependence between axonal regeneration and re-connection

Neural Regeneration Research ◽

10.4103/1673-5374.320977 ◽

2022 ◽

Vol 17 (3) ◽

pp. 553

Author(s):

HectorRamiro Quinta

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Locomotor Recovery ◽

Cord Injury

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Locomotor training improves reciprocal and nonreciprocal inhibitory control of soleus motoneurons in human spinal cord injury

Journal of Neurophysiology ◽

10.1152/jn.00872.2014 ◽

2015 ◽

Vol 113 (7) ◽

pp. 2447-2460 ◽

Cited By ~ 9

Author(s):

Maria Knikou ◽

Andrew C. Smith ◽

Chaithanya K. Mummidisetty

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Reciprocal Inhibition ◽

H Reflex ◽

Medial Gastrocnemius ◽

Locomotor Training ◽

Step Cycle ◽

Human Spinal Cord ◽

Cord Injury

Pathologic reorganization of spinal networks and activity-dependent plasticity are common neuronal adaptations after spinal cord injury (SCI) in humans. In this work, we examined changes of reciprocal Ia and nonreciprocal Ib inhibition after locomotor training in 16 people with chronic SCI. The soleus H-reflex depression following common peroneal nerve (CPN) and medial gastrocnemius (MG) nerve stimulation at short conditioning-test (C-T) intervals was assessed before and after training in the seated position and during stepping. The conditioned H reflexes were normalized to the unconditioned H reflex recorded during seated. During stepping, both H reflexes were normalized to the maximal M wave evoked at each bin of the step cycle. In the seated position, locomotor training replaced reciprocal facilitation with reciprocal inhibition in all subjects, and Ib facilitation was replaced by Ib inhibition in 13 out of 14 subjects. During stepping, reciprocal inhibition was decreased at early stance and increased at midswing in American Spinal Injury Association Impairment Scale C (AIS C) and was decreased at midstance and midswing phases in AIS D after training. Ib inhibition was decreased at early swing and increased at late swing in AIS C and was decreased at early stance phase in AIS D after training. The results of this study support that locomotor training alters postsynaptic actions of Ia and Ib inhibitory interneurons on soleus motoneurons at rest and during stepping and that such changes occur in cases with limited or absent supraspinal inputs.

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Locomotor Training Progression and Outcomes After Incomplete Spinal Cord Injury

Physical Therapy ◽

10.1093/ptj/85.12.1356 ◽

2005 ◽

Vol 85 (12) ◽

pp. 1356-1371 ◽

Cited By ~ 120

Author(s):

Andrea L Behrman ◽

Anna R Lawless-Dixon ◽

Sandra B Davis ◽

Mark G Bowden ◽

Preeti Nair ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Spinal Injury ◽

Walking Ability ◽

Locomotor Training ◽

Full Time ◽

Incomplete Spinal Cord Injury ◽

Weight Support ◽

Walking Activity ◽

Cord Injury

Abstract Background and Purpose. The use of locomotor training with a body-weight–support systemand treadmill (BWST) and manual assistance has increased in rehabilitation. The purpose of this case report isto describe the process for retraining walking in a person with an incomplete spinal cord injury (SCI) using the BWST and transferring skills from the BWST to overground assessment and community ambulation. Case Description. Following discharge from rehabilitation, a man with an incomplete SCI at C5–6 and an American Spinal Injury Association (ASIA) Impairment Scale classification of D participated in 45sessions of locomotor training. Outcomes. Walking speed and independence improved from 0.19 m/s as a home ambulator using a rolling walker and a right ankle-foot orthosis to 1.01 m/s as a full-time ambulator using a cane only for communitymobility. Walking activity (X̄±SD) per 24 hours increased from 1,054±543 steps to 3,924±1,629 steps. Discussion. In a person with an incomplete SCI, walking ability improved after locomotor trainingthat used a decision-making algorithm and progression across training environments.

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PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure

10.1101/446963 ◽

2018 ◽

Author(s):

Arnau Hervera ◽

Luming Zhou ◽

Ilaria Palmisano ◽

Eilidh McLachlan ◽

Guiping Kong ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Axonal Regeneration ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Spinal Injury ◽

Gene Expression Response ◽

Cord Injury ◽

Expression Response

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small molecule inhibitors targeting key epigenetic enzymes in DRG neurons we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3 thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.

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