Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 May 15;34(10):1831-1840.
doi: 10.1089/neu.2016.4562. Epub 2017 Jan 13.

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

J Russell Huie  1 , Kazuhito Morioka  1 , Jenny Haefeli  1 , Adam R Ferguson  1   2
Affiliations
Review

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

J Russell Huie et al. J Neurotrauma. .

Abstract

Spinal cord injury (SCI) is a devastating syndrome that produces dysfunction in motor and sensory systems, manifesting as chronic paralysis, sensory changes, and pain disorders. The multi-faceted and heterogeneous nature of SCI has made effective rehabilitative strategies challenging. Work over the last 40 years has aimed to overcome these obstacles by harnessing the intrinsic plasticity of the spinal cord to improve functional locomotor recovery. Intensive training after SCI facilitates lower extremity function and has shown promise as a tool for retraining the spinal cord by engaging innate locomotor circuitry in the lumbar cord. As new training paradigms evolve, the importance of appropriate afferent input has emerged as a requirement for adaptive plasticity. The integration of kinematic, sensory, and loading force information must be closely monitored and carefully manipulated to optimize training outcomes. Inappropriate peripheral input may produce lasting maladaptive sensory and motor effects, such as central pain and spasticity. Thus, it is important to closely consider the type of afferent input the injured spinal cord receives. Here we review preclinical and clinical input parameters fostering adaptive plasticity, as well as those producing maladaptive plasticity that may undermine neurorehabilitative efforts. We differentiate between passive (hindlimb unloading [HU], limb immobilization) and active (peripheral nociception) forms of aberrant input. Furthermore, we discuss the timing of initiating exposure to afferent input after SCI for promoting functional locomotor recovery. We conclude by presenting a candidate rapid synaptic mechanism for maladaptive plasticity after SCI, offering a pharmacological target for restoring the capacity for adaptive spinal plasticity in real time.

Keywords: neuroplasticity; recovery; rehabilitation; spinal cord injury.

PubMed Disclaimer

Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
Peripheral nociceptive input alters AMPA receptor plasticity on motor neurons after complete SCI. (A) Nociceptive input was delivered by electrical stimulation to the tail of male rats that had received a complete spinal transection at the second thoracic vertebrae. Stimulation delivery was computer-controlled, and administered intermittently over the course of 6 min. (B) Optical detection of synaptic AMPA receptor subunits. Immunofluorescent expression of presynaptic marker (red, synaptophysin) and AMPA receptor subunit (green, GluA1 or GluA2) was assessed, as well as the colocalization of red and green puncta (yellow, colocalization), indicating synaptic AMPA receptor subunit expression. (C) Large L4–5 ventral horn neurons were assessed for colocalization of GluA1/2 and synaptophysin-positive synapses after nociceptive stimulation. Upper images show full neuropil area for a single confocal plane (“Full Cell”); lower images show a digitally isolated 2-μm wide cutout of the plasma membrane area in the single confocal plane (“Plasma Membrane”). (D) Extrasynaptic GluA1 was significantly increased 20 min after stimulation, whereas extrasynaptic GluA2 is significantly decreased (*p < 0.05). Synaptic colocalization of GluA1 and synaptophysin was also significantly increased (*p < 0.05), whereas synaptic GluA2/synaptophysin colocalization is unaltered by stimulation. These findings suggest a rapid increase in synaptic GluA2-lacking AMPA receptors in response to nociceptive input. Modified from Huie et al. SCI, spinal cord injury.
<b>FIG. 2.</b>
FIG. 2.
Theoretical model of the effect of peripheral input on the metaplasticity of spinal function after SCI. Appropriate peripheral sensory and proprioceptive input after SCI can strengthen excitatory tone to improve the capacity for adaptive spinal training. However, unmitigated peripheral input may overdrive excitability, resulting in synaptic saturation that induces maladaptive locomotor and sensory plasticity (e.g., impaired stepping, spasticity, chronic neuropathic pain). SCI places spinal cord circuitry into an unstable metaplastic state where spinal cord plasticity can take on either adaptive or maladaptive forms. From this perspective, therapeutic interventions aimed at re-tuning synaptic strength toward optimal adaptive plasticity, while limiting maladaptive plasticity, will be essential for improving functional recovery. Modified from Huie et al. SCI, spinal cord injury.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dobkin B.H. (2003). The Clinical Science of Neurologic Rehabilitation. Oxford University Press, 1 p
    1. van den Brand R., Mignardot J.-B., von Zitzewitz J., Le Goff C., Fumeaux N., Wagner F., Capogrosso M., Martin Moraud E., Micera S., Schurch B., Curt A., Carda S., Bloch J., and Courtine G. (2015). Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury. Ann. Phys. Rehabil. Med. 58, 232–237 - PubMed
    1. Lu P., Wang Y., Graham L., McHale K., Gao M., Wu D., Brock J., Blesch A., Rosenzweig E.S., Havton L.A., Zheng B., Conner J.M., Marsala M., and Tuszynski M.H. (2012). Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264–1273 - PMC - PubMed
    1. Angeli C.A., Edgerton V.R., Gerasimenko Y.P., and Harkema S.J. (2014). Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137, 1394–1409 - PMC - PubMed
    1. Lovely R.G., Gregor R.J., Roy R.R., and Edgerton V.R. (1986). Effects of training on the recovery of full-weight-bearing stepping in the adult spinal cat. Exp. Neurol. 92, 421–435 - PubMed

Publication types

MeSH terms

Substances