Significant advancements in spinal epidural stimulation (ES) strategies to enable volitional motor control in persons with a complete spinal cord injury (SCI) have generated much excitement in the field of neurorehabilitation. Still, an obvious gap lies in the ability of ES to effectively generate a robust locomotor stepping response after a complete SCI in rodents, but not in humans. In order to reveal potential discrepancies between rodent and human studies that account for this void, in this review, we summarize the findings of studies that have utilized ES strategies to enable successful hindlimb stepping in spinal rats. Recent clinical and preclinical evidence indicates that motor training with ES plays a crucial role in tuning spinal neural circuitry to generate meaningful motor output. Concurrently administered pharmacology can also facilitate the circuitry to provide near optimal motor performance in SCI rats. However, as of today, the evidence for pharmacological agents to enhance motor function in persons with complete SCI is insignificant. These and other recent findings discussed in this review provide insight into addressing the translational gap, guide the design of relevant preclinical experiments, and facilitate development of new approaches for motor recovery in patients with complete SCIs.
AngeliCAEdgertonVRGerasimenkoYPHarkemaSJ. 2014. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain137(pt 5):1394–409.
2.
BertrandSCazaletsJR.2002. The respective contribution of lumbar segments to the generation of locomotion in the isolated spinal cord of newborn rat. Eur J Neurosci16(9):1741–50.
3.
CapogrossoMWengerNRaspopovicSMusienkoPBeauparlantJBassi LucianiL, and others. 2013. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. J Neurosci33(49):19326–40.
4.
CarhartMRHeJHermanRD’LuzanskySWillisWT. 2004. Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury. IEEE Trans Neural Syst Rehabil Eng12(1):32–42.
5.
CazaletsJRBertrandS.2000. Coupling between lumbar and sacral motor networks in the neonatal rat spinal cord. Eur J Neurosci12(8):2993–3002.
6.
CourtineGGerasimenkoYvan den BrandRYewAMusienkoPZhongH, and others. 2009. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci12(10):1333–42.
7.
CowleyKCSchmidtBJ. 1997. Regional distribution of the locomotor pattern-generating network in the neonatal rat spinal cord. J Neurophysiol77(1):247–59.
8.
CuellarCATapiaJAJuárezVQuevedoJLinaresPMartínezL, and others. 2009. Propagation of sinusoidal electrical waves along the spinal cord during a fictive motor task. J Neurosci29(3):798–810.
9.
de LeonRDDyCJ. 2017. What did we learn from the animal studies of body weight-supported treadmill training and where do we go from here?J Neurotrauma. doi:10.1089/neu.2016.4561. Epub Jan13.
10.
DimitrijevicMRGerasimenkoYPinterMM. 1998. Evidence for a spinal central pattern generator in humans. Ann N Y Acad Sci860:360–76.
11.
DomingoAAl-YahyaAAAsiriYEngJJLamT; Spinal Cord Injury Rehabilitation Evidence Research Team. 2012. A systematic review of the effects of pharmacological agents on walking function in people with spinal cord injury. J Neurotrauma29(5):865–79.
12.
DonatiARShokurSMoryaECamposDSMoioliRCGittiCM, and others. 2016. Long-term training with a brain-machine interface-based gait protocol induces partial neurological recovery in paraplegic patients. Sci Rep6:30383.
13.
DoseFDeumensRForgetPTaccolaG.2016. Staggered multi-site low-frequency electrostimulation effectively induces locomotor patterns in the isolated rat spinal cord. Spinal Cord54(2):93–101.
14.
EdgertonVRCourtineGGerasimenkoYPLavrovIIchiyamaRMFongAJ, and other. 2008. Training locomotor networks. Brain Res Rev57(1):241–54.
15.
EdgertonVRTillakaratneNJBigbeeAJde LeonRDRoyRR. 2004. Plasticity of the spinal neural circuitry after injury. Annu Rev Neurosci27:145–67.
16.
EtlinABlivisDBen-ZwiMLev-TovA.2010. Long and short multifunicular projections of sacral neurons are activated by sensory input to produce locomotor activity in the absence of supraspinal control. J Neurosci30(31):10324–36.
17.
EtlinAFinkelEMorYO’DonovanMJAnglisterALev-TovA.2013. Characterization of sacral interneurons that mediate activation of locomotor pattern generators by sacrocaudal afferent input. J Neurosci33(2):734–47.
18.
FrigonA.2012. Central pattern generators of the mammalian spinal cord. Neuroscientist18(1):56–69.
19.
GadPChoeJNandraMSZhongHRoyRRTaiYC, and others. 2013a. Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats. J Neuroeng Rehabil10:2.
20.
GadPLavrovIShahPZhongHRoyRREdgertonVR, and others. 2013b. Neuromodulation of motor-evoked potentials during stepping in spinal rats. J Neurophysiol110(6):1311–22.
21.
GadPRoyRRChoeJCreagmileJZhongHGerasimenkoY, and others. 2015. Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury. J Neurophysiol113(9):3386–96.
22.
GadPWoodbridgeJLavrovIZhongHRoyRRSarrafzadehM, and others. 2012. Forelimb EMG-based trigger to control an electronic spinal bridge to enable hindlimb stepping after a complete spinal cord lesion in rats. J Neuroeng Rehabil9:38.
23.
GerasimenkoIuPAvelevVDNikitinOALavrovIA. 2001. Initiation of locomotor activity in spinal cats by epidural stimulation of the spinal cord. Ross Fiziol Zh Im I M Sechenova87(9):1161–70.
24.
GerasimenkoYGorodnichevRPuhovAMoshonkinaTSavochinASelionovV, and others. 2015. Initiation and modulation of locomotor circuitry output with multisite transcutaneous electrical stimulation of the spinal cord in noninjured humans. J Neurophysiol113(3): 834–42.
25.
GerasimenkoYRoyRREdgertonVR. 2008. Epidural stimulation: comparison of the spinal circuits that generate and control locomotion in rats, cats and humans. Exp Neurol209(2):417–25.
26.
GerasimenkoYPAvelevVDNikitinOALavrovIA. 2003. Initiation of locomotor activity in spinal cats by epidural stimulation of the spinal cord. Neurosci Behav Physiol33(3):247–54.
27.
GerasimenkoYPIchiyamaRMLavrovIACourtineGCaiLZhongH, and others. 2007. Epidural spinal cord stimulation plus quipazine administration enable stepping in complete spinal adult rats. J Neurophysiol98(5):2525–36.
28.
GerasimenkoYPMakarovskiiANNikitinOA. 2002. Control of locomotor activity in humans and animals in the absence of supraspinal influences. Neurosci Behav Physiol32(4):417–23.
29.
GuertinPA.2016. Rationale for assessing safety and efficacy of drug candidates alone and in combination with medical devices: the case study of Spinalon™. Curr Pharm Des. Epub Dec7.
30.
HachmannJTJeongJHGrahnPJMalloryGWEvertzLQBieberAJ, and others. 2013. Large animal model for development of functional restoration paradigms using epidural and intraspinal stimulation. PLoS One8(12):e81443.
31.
HarkemaSGerasimenkoYHodesJBurdickJAngeliCChenY, and others. 2011. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet377(9781):1938–47.
32.
HermanRHeJD’LuzanskySWillisWDilliS.2002. Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured. Spinal Cord40(2):65–8.
33.
HuangHHeJHermanRCarhartMR. 2006. Modulation effects of epidural spinal cord stimulation on muscle activities during walking. IEEE Trans Neural Syst Rehabil Eng14(1):14–23.
34.
IchiyamaRMCourtineGGerasimenkoYPYangGJvan den BrandRLavrovIA, and others. 2008a. Step training reinforces specific spinal locomotor circuitry in adult spinal rats. J Neurosci28(29):7370–5.
35.
IchiyamaRMGerasimenkoYJindrichDLZhongHRoyRREdgertonVR. 2008b. Dose dependence of the 5-HT agonist quipazine in facilitating spinal stepping in the rat with epidural stimulation. Neurosci Lett438(3):281–5.
36.
IchiyamaRMGerasimenkoYPZhongHRoyRREdgertonVR. 2005. Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation. Neurosci Lett383(3):339–44.
37.
IslamovRRSokolovMEBashirovFVFadeevFOShmarovMMNaroditskiyBS, and others. 2017. A pilot study of cell-mediated gene therapy for spinal cord injury in mini pigs. Neuroscience letters644:67–75.
38.
JilgeBMinassianKRattayFPinterMMGerstenbrandFBinderH, and others. 2004. Initiating extension of the lower limbs in subjects with complete spinal cord injury by epidural lumbar cord stimulation. Exp Brain Res154(3):308–26.
39.
KiehnO.2006. Locomotor circuits in the mammalian spinal cord. Annu Rev Neurosci29:279–306.
40.
KiehnOKjaerulffO.1998. Distribution of central pattern generators for rhythmic motor outputs in the spinal cord of limbed vertebrates. Ann N Y Acad Sci860:110–29.
41.
KoHYParkJHShinYBBaekSY. 2004. Gross quantitative measurements of spinal cord segments in human. Spinal Cord42(1):35–40.
42.
KowalczewskiJChongSLGaleaMProchazkaA.2011. In-home tele-rehabilitation improves tetraplegic hand function. Neurorehabil Neural Repair25(5):412–22.
43.
LavrovICourtineGDyCJvan den BrandRFongAJGerasimenkoY, and others. 2008a. Facilitation of stepping with epidural stimulation in spinal rats: role of sensory input. J Neurosci28(31):7774–80.
44.
LavrovIDyCJFongAJGerasimenkoYCourtineGZhongH, and others. 2008b. Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats. J Neurosci28(23):6022–9.
45.
LavrovIGerasimenkoYBurdickJZhongHRoyRREdgertonVR. 2015a. Integrating multiple sensory systems to modulate neural networks controlling posture. J Neurophysiol114(6):3306–14.
46.
LavrovIGerasimenkoYPIchiyamaRMCourtineGZhongHRoyRR, and others. 2006. Plasticity of spinal cord reflexes after a complete transection in adult rats: relationship to stepping ability. J Neurophysiol96(4):1699–710.
47.
LavrovIMusienkoPESelionovVAZdunowskiSRoyRREdgertonVR, and others. 2015b. Activation of spinal locomotor circuits in the decerebrated cat by spinal epidural and/or intraspinal electrical stimulation. Brain Res1600:84–92.
48.
Lev-TovADelvolveI.2000. Pattern generation in non-limb moving segments of the mammalian spinal cord. Brain Res Bull53(5):671–5.
49.
Lev-TovAEtlinABlivisD.2010. Sensory-induced activation of pattern generators in the absence of supraspinal control. Ann N Y Acad Sci1198:54–62.
50.
LiuJJordanLM. 2005. Stimulation of the parapyramidal region of the neonatal rat brain stem produces locomotor-like activity involving spinal 5-HT7 and 5-HT2A receptors. J Neurophysiol94(2):1392–404.
51.
MagnusonDSLovettRCoffeeCGrayRHanYZhangYP, and others. 2005. Functional consequences of lumbar spinal cord contusion injuries in the adult rat. J Neurotrauma22(5):529–43.
52.
MarcouxJRossignolS.2000. Initiating or blocking locomotion in spinal cats by applying noradrenergic drugs to restricted lumbar spinal segments. J Neurosci20(22):8577–85.
53.
McCreaDARybakIA. 2008. Organization of mammalian locomotor rhythm and pattern generation. Brain Res Rev57(1):134–46.
54.
McKayWBLimHKPriebeMMStokicDSSherwoodAM. 2004. Clinical neurophysiological assessment of residual motor control in post-spinal cord injury paralysis. Neurorehabil Neural Repair18(3):144–53.
55.
MinassianKJilgeBRattayFPinterMMBinderHGerstenbrandF, and others. 2004. Stepping-like movements in humans with complete spinal cord injury induced by epidural stimulation of the lumbar cord: electromyographic study of compound muscle action potentials. Spinal Cord42(7):401–16.
56.
MinassianKMcKayWBBinderHHofstoetterUS. 2016. Targeting lumbar spinal neural circuitry by epidural stimulation to restore motor function after spinal cord injury. Neurotherapeutics13(2):284–94.
57.
MinassianKPersyIRattayFPinterMMKernHDimitrijevicMR. 2007. Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity. Hum Mov Sci26(2):275–95.
58.
MoraudEMCapogrossoMFormentoEWengerNDiGiovannaJCourtineG, and others. 2016. Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron89(4):814–28.
59.
MurgMBinderHDimitrijevicMR. 2000. Epidural electric stimulation of posterior structures of the human lumbar spinal cord: 1. Muscle twitches—a functional method to define the site of stimulation. Spinal Cord38(7):394–402.
60.
MusienkoPHeutschiJFriedliLvan den BrandRCourtineG.2012. Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury. Exp Neurol235(1):100–9.
61.
MusienkoPEZeleninPVOrlovskyGNDeliaginaTG. 2010. Facilitation of postural limb reflexes with epidural stimulation in spinal rabbits. J Neurophysiol103(2):1080–92.
62.
NandraMSLavrovIAEdgertonVRTaiYC. 2011. A parylene-based microelectrode array implant for spinal cord stimulation in rats. Conf Proc IEEE Eng Med Biol Soc2011:1007–10.
63.
OrlovskyGDeliaginaTGrillnerS.1999. Neuronal control of locomotion: from mollusc to man. Oxford, England: Oxford University Press.
64.
PérezTTapiaJAMirassoCRGarcía-OjalvoJQuevedoJCuellarCA, and others. 2009. An intersegmental neuronal architecture for spinal wave propagation under deletions. J Neurosci29(33):10254–63.
65.
RejcEAngeliCHarkemaS.2015. Effects of lumbosacral spinal cord epidural stimulation for standing after chronic complete paralysis in humans. PLoS One10(7):e0133998.
66.
RossignolSChauCBrusteinEGirouxNBouyerLBarbeauH, and others. 1998. Pharmacological activation and modulation of the central pattern generator for locomotion in the cat. Ann N Y Acad Sci860:346–59.
67.
RossignolSFrigonA.2011. Recovery of locomotion after spinal cord injury: some facts and mechanisms. Annu Rev Neurosci34:413–40.
68.
RoyRRHarkemaSJEdgertonVR. 2012. Basic concepts of activity-based interventions for improved recovery of motor function after spinal cord injury. Arch Phys Med Rehabil93(9):1487–97.
69.
SayenkoDGAngeliCHarkemaSJEdgertonVRGerasimenkoYP. 2014. Neuromodulation of evoked muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals. J Neurophysiol111(5):1088–99.
70.
SayenkoDGAtkinsonDADyCJGurleyKMSmithVLAngeliC, and others. 2015a. Spinal segment-specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans. J Appl Physiol (1985) 118(11):1364–74.
71.
SayenkoDGAtkinsonDAFloydTCGorodnichevRMMoshonkinaTRHarkemaSJ, and others. 2015b. Effects of paired transcutaneous electrical stimulation delivered at single and dual sites over lumbosacral spinal cord. Neurosci Lett609:229–34.
72.
ShahPKGerasimenkoYShyuALavrovIZhongHRoyRR, and others. 2012. Variability in step training enhances locomotor recovery after a spinal cord injury. Eur J Neurosci36(1):2054–62.
73.
ShahPKSureddiSAlamMZhongHRoyRREdgertonVR, and others. 2016. Unique spatiotemporal neuromodulation of the lumbosacral circuitry shapes locomotor success after spinal cord injury. J Neurotrauma33(18):1709–23.
74.
ShahPKGerasimenkoY. 2017. Multi-site spinal stimulation strategies to enhance locomotion after paralysis. Erratum in Neural Regen ResJan12(1):161–2.
75.
SharrardWJ.1964. The segmental innervation of the lower limb muscles in man. Ann R Coll Surg Engl35:106–22.
76.
SlawinskaUMajczynskiHDaiYJordanLM. 2012. The upright posture improves plantar stepping and alters responses to serotonergic drugs in spinal rats. J Physiol590(pt 7):1721–36.
77.
van den BrandRHeutschiJBarraudQDiGiovannaJBartholdiKHuerlimannM, and others. 2012. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science336(6085):1182–5.
78.
WaiblH.1973. Contributions to the topography of the spinal cord of the Albino rat (Rattus norvegicus). Berlin, Germany: Springer.
79.
WengerNMoraudEMGandarJMusienkoPCapogrossoMBaudL, and others. 2016. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat Med22(2):138–45.
80.
WengerNMoraudEMRaspopovicSBonizzatoMDiGiovannaJMusienkoP, and others. 2014. Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury. Sci Transl Med6(255):255ra133.
