Enhancing recovery from peripheral nerve injury using treadmill training
Introduction
Injured axons in peripheral nerves regenerate better than those in the central nervous system, but the functional outcomes observed clinically after peripheral nerves are injured are often so poor that some form of long term disability results (Brushart, 1998, Frostick et al., 1998). The three reasons most often given for these poor outcomes are: (1) that the regeneration of axons in injured peripheral nerves is slow and not all axons participate, leading to a functionally inadequate reinnervation of muscles (Fu and Gordon, 1995, Fu and Gordon, 1997, Gordon, 2009); (2) that regenerating motor axons are misdirected and reinnervate functionally inappropriate targets (Evans et al., 1991, de Ruiter et al., 2008); and (3) that plastic changes in the central nervous system (CNS) that accompany peripheral axotomy alter the relationship of circuitry in the CNS and the reinnervated muscles (Alvarez et al., 2010). Currently, there is no accepted medical treatment for traumatic peripheral nerve injuries that addresses these concerns. The standard of care is to provide a tension free repair of cut nerves and allow the process of regeneration to proceed.
Exercise as a means of improving brain health and function has received considerable recent attention (Adlard and Cotman, 2004, Adlard et al., 2004) at least in part because it has been shown to induce the synthesis of both brain derived neurotrophic factor (BDNF) and its receptor, trkB, in rats and to promote recovery after CNS injury (Gomez-Pinilla et al., 2001, Hutchinson et al., 2004, Molteni et al., 2004, Ploughman et al., 2005). Therapeutic exercise thus could form a useful means of stimulation to the growth of regenerating peripheral axons that would require very little clinical intervention. Because it activates motor and primary afferent neurons naturally, via their own neural circuits, one might expect that exercise could produce enhanced axon regeneration without increasing the misdirection of those axons to inappropriate targets. Additionally, this natural activation might have effects on the CNS consequences of peripheral nerve injury. Indeed, we have found that exercise in the form of treadmill training has beneficial effects on all three of the critical aspects of recovery from peripheral nerve injury listed above. In the review that follows, we will delineate these effects and discuss the need for and direction of future studies.
Section snippets
Treadmill training enhances axon regeneration in cut peripheral nerves
Physical activity during the recovery period has been shown to improve motor function after spinal cord injury, both clinically and in experimental animals (Skinner et al., 1996, Edgerton et al., 1997, Hutchinson et al., 2004). Improvements in both sensory and motor functions have been described. Along with the successful effects of treadmill training in spinal cord injured cats by Rossignol and colleagues (Chau et al., 1998), Edgerton and colleagues have advocated treadmill exercise as a
Effects of treadmill training on misdirection of regenerating axons
In the mammalian CNS, motoneurons innervating functionally different groups of muscles are topographically localized (McHanwell and Biscoe, 1981, Nicolopoulos-Stournaras and Iles, 1983, Swett et al., 1986, Yakovenko et al., 2002). That is, the motor nuclei of different muscle groups lie in spatially distinct locations in the brainstem and spinal cord. Following peripheral nerve injury, individual muscles or even groups of muscles are likely to be reinnervated by a somewhat different cadre of
Treadmill training and CNS plasticity
Following nerve transection in the periphery, a series of changes occurs in the circuitry of the spinal cord or brainstem. Nearly half of the synaptic inputs onto the somata and proximal dendrites of motoneurons are withdrawn following peripheral axotomy, a process known as synaptic stripping (Blinzinger and Kreutzberg, 1968, Hamberger et al., 1970, Lindå et al., 1992, Oliveira et al., 2008). Although the withdrawal of injured primary afferent terminals following peripheral nerve injury can
Conclusions
Limitations in three different aspects of the biology of responses to traumatic injury to peripheral nerves have been postulated to contribute to the poor functional outcomes observed in human patients. Treadmill training applied following traumatic peripheral nerve injury results in demonstrable improvements in each of these three areas. Regenerating axons grow considerably farther in treadmill trained animals than they do in untrained controls. This enhancement of axon regeneration is
Acknowledgements
This work was completed with support from NIH Grants NS057190 (A.W.E.) and K12GM000680 (J.C.W. and M.J.S.).
References (86)
- et al.
Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression
Neuroscience
(2004) - et al.
The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise
Neurosci. Lett.
(2004) - et al.
Electrical stimulation combined with exercise increase axonal regeneration after peripheral nerve injury
Exp. Neurol.
(2009) - et al.
Specificity of muscle reinnervation after epineurial and individual fascicular suture of the rat sciatic nerve
J. Hand Surg. [Am]
(1983) - et al.
Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model
Exp. Neurol.
(2008) - et al.
Selective reinnervation: a comparison of recovery following microsuture and conduit nerve repair
Brain Res.
(1991) - et al.
Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP
Neuron
(2000) - et al.
Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones
Brain Res. Brain Res. Rev.
(2005) - et al.
Sciatic nerve transection in the adult rat: abnormal EMG patterns during locomotion by aberrant innervation of hindleg muscles
Exp. Neurol.
(2000) - et al.
Treadmill training enhances the recovery of normal stepping patterns in spinal cord contused rats
Exp. Neurol.
(2009)
A conditioning lesion induces changes in gene expression and axonal transport that enhance regeneration by increasing the intrinsic growth state of axons
Exp. Neurol.
Peripheral axotomy induces depletion of the vesicular glutamate transporter VGLUT1 in central terminals of myelinated afferent fibres in the rat spinal cord
Brain Res.
Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation
Neuron
Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-1 and insulin-like growth factor 1 after focal ischemia
Neuroscience
Treadmill training promotes axon regeneration in injured peripheral nerves
Exp. Neurol.
Electrical stimulation and testosterone differentially enhance expression of regeneration-associated genes
Exp. Neurol.
Effects of exercise and fetal spinal cord implants on the H-reflex in chronically spinalized adult rats
Brain Res.
Motoneurons of the rat sciatic nerve
Exp. Neurol.
Axotomy-induced alterations in the electrophysiological characteristics of neurons
Prog. Neurobiol.
Axonal protein synthesizing activity in motoneurons during the early outgrowth period following neurotomy
Exp. Neurol.
Exercise training improves functional recovery and motor nerve conduction velocity after sciatic nerve crush lesion in the rat
Arch. Phys. Med. Rehabil.
Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury
Exp. Neurol.
Permanent reorganization of Ia afferent synapses on motoneurons after peripheral nerve injury
Ann. NY Acad. Sci.
Resource Book for the Design of Animal Exercise Protocols
Treadmill training after spinal cord injury: good but not better
Neurology
Sorting of beta-actin mRNA and protein to neurites and growth cones in culture
J. Neurosci.
Displacement of synaptic terminals from regenerating motoneurons by microglial cells
Z. Zellforsch.
Treadmill training and functional recovery after peripheral nerve injury
Abstr. Soc. Neurosci.
Axonal transport of membranous and nonmembranous cargoes: a unified perspective
J. Cell Biol.
Nerve repair and grafting
Alteration in connections between muscle and anterior horn motoneurons after peripheral nerve repair
Science
Early locomotor training with clonidine in spinal cats
J. Neurophysiol.
H-Reflex up conditioning encourages recovery of EMG activity and H reflexes after sciatic nerve transection and repair in rats
J. Neurosci.
Transformation of nonfunctional spinal circuits into functional states after the loss of brain input
Nat. Neurosci.
Complimentary actions of BDNF and neurotrophin-3 on the firing patterns and synaptic composition of motoneurons
J. Neurosci.
Nerve growth factor regulates the firing patterns and synaptic composition of motoneurons
J. Neurosci.
Novel quantitative phenotypes of exercise training in mouse models
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Use-dependent plasticity in spinal stepping and standing
Adv. Neurol.
Plasticity of the spinal neural circuitry after injury
Annu. Rev. Neurosci.
Voluntary wheel running improves recovery from a moderate spinal cord injury
J. Neurotraum.
Enhancing axon regeneration in peripheral nerves also increases functionally inappropriate reinnervation of targets
J. Comp. Neurol.
Treadmill training enhances axon regeneration in injured mouse peripheral nerves without increased loss of topographic specificity
J. Comp. Neurol.
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