Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.
Spinal cord injury (SCI) is a complex pathological condition and although several therapeutic approaches have shown potential in preclinical studies, few have progressed to clinical trials.
Understanding the spatial and temporal changes in transcription and chromatin accessibility in selected neuronal subpopulations after SCI could help identify key proteins that orchestrate specific changes in neuroplasticity.
The use of chondroitinase ABC and anti-NogoA treatment to reduce inhibitory signalling in the neuronal extrinsic environment after SCI has shown promise in terms of promoting axon sprouting and recovery.
Unprecedented long-distance axon regeneration, cell replacement and relay formation have been achieved using spinal cord-derived neural stem cell grafts combined with growth factors.
Neuromodulation strategies including electrical epidural stimulation and brain–machine interfaces have demonstrated impressive improvements in voluntary motor function, and wireless systems will further improve the clinical utility of these strategies.
Combining mechanism-based biological strategies with targeted technological interventions to augment neuroplasticity, followed by rehabilitation to direct circuit reorganization, could facilitate clinically meaningful recovery after SCI.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Orr, M. B. & Gensel, J. C. Spinal cord injury scarring and inflammation: therapies targeting glial and inflammatory responses. Neurotherapeutics 15, 541–553 (2018).
Ahuja, C. S., Martin, A. R. & Fehlings, M. Recent advances in managing a spinal cord injury secondary to trauma. F1000Res. 5, 1017 (2016).
Krucoff, M. O., Rahimpour, S., Slutzky, M. W., Edgerton, V. R. & Turner, D. A. Enhancing nervous system recovery through neurobiologics, neural interface training, and neurorehabilitation. Front. Neurosci. 10, 584 (2016).
Taccola, G., Sayenko, D., Gad, P., Gerasimenko, Y. & Edgerton, V. R. And yet it moves: recovery of volitional control after spinal cord injury. Prog. Neurobiol. 160, 64–81 (2018).
Sofroniew, M. V. Dissecting spinal cord regeneration. Nature 557, 343–350 (2018).
Onifer, S. M., Smith, G. M. & Fouad, K. Plasticity after spinal cord injury: relevance to recovery and approaches to facilitate it. Neurotherapeutics 8, 283–293 (2011).
Beattie, M. S. et al. Endogenous repair after spinal cord contusion injuries in the rat. Exp. Neurol. 148, 453–463 (1997).
Blesch, A. & Tuszynski, M. H. Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci. 32, 41–47 (2009).
Asboth, L. et al. Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion. Nat. Neurosci. 21, 576–588 (2018).
Mosberger, A. C. et al. Axotomized corticospinal neurons increase supra-lesional innervation and remain crucial for skilled reaching after bilateral pyramidotomy. Cereb. Cortex 28, 625–643 (2018).
Topka, H., Cohen, L. G., Cole, R. A. & Hallett, M. Reorganization of corticospinal pathways following spinal cord injury. Neurology 41, 1276–1283 (1991).
Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).
Hilton, B. J. et al. Re-establishment of cortical motor output maps and spontaneous functional recovery via spared dorsolaterally projecting corticospinal neurons after dorsal column spinal cord injury in adult mice. J. Neurosci. 36, 4080–4092 (2016).
Hollis, E. R. 2nd et al. Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nat. Neurosci. 19, 697–705 (2016).
Martin, J. H. Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury. Neural Regen. Res. 11, 1389–1391 (2016).
Jiang, Y. Q., Zaaimi, B. & Martin, J. H. Competition with primary sensory afferents drives remodeling of corticospinal axons in mature spinal motor circuits. J. Neurosci. 36, 193–203 (2016).
Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).
Bareyre, F. M., Kerschensteiner, M., Misgeld, T. & Sanes, J. R. Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury. Nat. Med. 11, 1355–1360 (2005).
Weidner, N., Ner, A., Salimi, N. & Tuszynski, M. H. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc. Natl. Acad. Sci. USA 98, 3513–3518 (2001).
Courtine, G. et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat. Med. 14, 69–74 (2008).
Kathe, C., Hutson, T. H., McMahon, S. B. & Moon, L. D. F. Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats. eLife 5, e18146 (2016).
Angeli, C. A. et al. Recovery of over-ground walking after chronic motor complete spinal cord injury. N. Engl. J. Med. 379, 1244–1250 (2018).
Wagner, F. B. et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 563, 65–71 (2018).
Terenzio, M., Schiavo, G. & Fainzilber, M. Compartmentalized signaling in neurons: from cell biology to neuroscience. Neuron 96, 667–679 (2017).
Curcio, M. & Bradke, F. Axon regeneration in the central nervous system: facing the challenges from the inside. Annu. Rev. Cell Dev. Biol. 34, 495–521 (2018).
Ruschel, J. et al. Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348, 347–352 (2015).
Sandner, B. et al. Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats. Exp. Neurol. 306, 250–259 (2018).
Zhao, W. et al. Mechanisms responsible for the inhibitory effects of epothilone B on scar formation after spinal cord injury. Neural Regen. Res. 12, 478–485 (2017).
Hellal, F. et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931 (2011).
Popovich, P. G., Tovar, C. A., Lemeshow, S., Yin, Q. & Jakeman, L. B. Independent evaluation of the anatomical and behavioral effects of Taxol in rat models of spinal cord injury. Exp. Neurol. 261, 97–108 (2014).
Mao, L. et al. Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor. Cell Death Dis. 8, e3162 (2017).
Hsu, S. T. et al. Effects of taxol on regeneration in a rat sciatic nerve transection model. Sci. Rep. 7, 42280 (2017).
Alabed, Y. Z., Grados-Munro, E., Ferraro, G. B., Hsieh, S. H. & Fournier, A. E. Neuronal responses to myelin are mediated by rho kinase. J. Neurochem. 96, 1616–1625 (2006).
Matsui, T. et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15, 2208–2216 (1996).
Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).
Fournier, A. E., Takizawa, B. T. & Strittmatter, S. M. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416–1423 (2003).
Ellezam, B. et al. Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog. Brain Res. 137, 371–380 (2002).
Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577 (2002).
Nishio, Y. et al. Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration or functional recovery after spinal cord injury in rats. Exp. Neurol. 200, 392–397 (2006).
Sahoo, P. K., Smith, D. S., Perrone-Bizzozero, N. & Twiss, J. L. Axonal mRNA transport and translation at a glance. J. Cell Sci. 131, jcs196808 (2018).
Terenzio, M. et al. Locally translated mTOR controls axonal local translation in nerve injury. Science 359, 1416–1421 (2018).
Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012).
Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).
Zukor, K. et al. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J. Neurosci. 33, 15350–15361 (2013).
Du, K. et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J. Neurosci. 35, 9754–9763 (2015).
Jin, D. et al. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nat. Commun. 6, 8074 (2015).
Liu, Y. et al. A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95, 817–833.e4 (2017).
Joshi, Y. et al. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain 138, 1843–1862 (2015).
Kolevzon, A. et al. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol. Autism 5, 54 (2014).
Tedeschi, A. et al. The calcium channel subunit alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron 92, 419–434 (2016).
Warner, F. M. et al. Early administration of gabapentinoids improves motor recovery after human spinal cord injury. Cell Rep. 18, 1614–1618 (2017).
Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat. Rev. Neurosci. 15, 637–654 (2014).
Chen, B. et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell 174, 1599 (2018).
Smith, D. S. & Skene, J. H. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J. Neurosci. 17, 646–658 (1997).
Moore, D. L. & Goldberg, J. L. Multiple transcription factor families regulate axon growth and regeneration. Dev. Neurobiol. 71, 1186–1211 (2011).
Tedeschi, A. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front. Mol. Neurosci. 4, 60 (2011).
Blackmore, M. G. et al. Kruppel-like factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc. Natl. Acad. Sci. USA 109, 7517–7522 (2012).
Li, W. Y. et al. AAV-KLF7 promotes descending propriospinal neuron axonal plasticity after spinal cord injury. Neural. Plast. 2017, 1621629 (2017).
Wang, Z., Reynolds, A., Kirry, A., Nienhaus, C. & Blackmore, M. G. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J. Neurosci. 35, 3139–3145 (2015).
Floriddia, E. M. et al. p53 regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. J. Neurosci. 32, 13956–13970 (2012).
Vassilev, L. T. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3, 419–421 (2004).
Sakamoto, K., Karelina, K. & Obrietan, K. CREB: a multifaceted regulator of neuronal plasticity and protection. J. Neurochem. 116, 1–9 (2011).
Siddiq, M. M. & Hannila, S. S. Looking downstream: the role of cyclic AMP-regulated genes in axonal regeneration. Front. Mol. Neurosci. 8, 26 (2015).
Gao, Y. et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621 (2004).
Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).
Costa, L. M. et al. Rolipram promotes functional recovery after contusive thoracic spinal cord injury in rats. Behav. Brain Res. 243, 66–73 (2013).
Bielekova, B. et al. Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood–brain barrier disruption in multiple sclerosis. Mult. Scler. 15, 1206–1214 (2009).
Yan, Y. et al. Stat3 signaling is present and active during development of the central nervous system and eye of vertebrates. Dev. Dyn. 231, 248–257 (2004).
Bareyre, F. M. et al. In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. Proc. Natl. Acad. Sci. USA 108, 6282–6287 (2011).
Lang, C., Bradley, P. M., Jacobi, A., Kerschensteiner, M. & Bareyre, F. M. STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. EMBO Rep. 14, 931–937 (2013).
Saha, R. N. & Pahan, K. HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ. 13, 539–550 (2006).
Mueller, W. C. & von Deimling, A. Gene regulation by methylation. Recent Results Cancer Res. 171, 217–239 (2009).
Puttagunta, R. et al. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nat. Commun. 5, 3527 (2014).
Finelli, M. J., Wong, J. K. & Zou, H. Epigenetic regulation of sensory axon regeneration after spinal cord injury. J. Neurosci. 33, 19664–19676 (2013).
Cho, Y. & Cavalli, V. HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBO J. 31, 3063–3078 (2012).
Loh, Y. E. et al. Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration. Epigenetics 12, 77–92 (2017).
Hutson, T. H. et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Sci. Transl. Med. 11, eaaw2064 (2019).
Venkatesh, I. & Blackmore, M. G. Selecting optimal combinations of transcription factors to promote axon regeneration: why mechanisms matter. Neurosci. Lett. 652, 64–73 (2017).
Silver, J., Schwab, M. E. & Popovich, P. G. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7, a020602 (2014).
Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).
Alilain, W. J., Horn, K. P., Hu, H., Dick, T. E. & Silver, J. Functional regeneration of respiratory pathways after spinal cord injury. Nature 475, 196–200 (2011).
Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).
Rosenzweig, E. S. et al. Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury. Nat. Neurosci. 22, 1269–1275 (2019).
Burnside, E. R. et al. Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain 141, 2362–2381 (2018).
Miao, Q. L., Ye, Q. & Zhang, X. H. Perineuronal net, CSPG receptor and their regulation of neural plasticity. Sheng Li Xue Bao 66, 387–397 (2014).
Shen, Y. et al. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596 (2009).
Lang, B. T. et al. Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. Nature 518, 404–408 (2015).
Fry, E. J., Chagnon, M. J., Lopez-Vales, R., Tremblay, M. L. & David, S. Corticospinal tract regeneration after spinal cord injury in receptor protein tyrosine phosphatase sigma deficient mice. Glia 58, 423–433 (2010).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).
Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).
Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).
McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994).
Wang, K. C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).
Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).
GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a reticulon protein. Nature 403, 439–444 (2000).
Domeniconi, M. & Filbin, M. T. Overcoming inhibitors in myelin to promote axonal regeneration. J. Neurol. Sci. 233, 43–47 (2005).
Zorner, B. & Schwab, M. E. Anti-Nogo on the go: from animal models to a clinical trial. Ann. New Y. Acad. Sci. 1198, E22–E34 (2010).
Gonzenbach, R. R. et al. Delayed anti-Nogo-A antibody application after spinal cord injury shows progressive loss of responsiveness. J. Neurotrauma 29, 567–578 (2012).
Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).
Cafferty, W. B., McGee, A. W. & Strittmatter, S. M. Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci. 31, 215–220 (2008).
Pernet, V. & Schwab, M. E. The role of Nogo-A in axonal plasticity, regrowth and repair. Cell Tissue Res. 349, 97–104 (2012).
Liebscher, T. et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann. Neurol. 58, 706–719 (2005).
Freund, P. et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat. Med. 12, 790–792 (2006).
Freund, P. et al. Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates — re-examination and extension of behavioral data. Eur. J. Neurosci. 29, 983–996 (2009).
Wang, X. et al. Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion. J. Neurotrauma 31, 1955–1966 (2014).
Kucher, K. et al. First-in-man intrathecal application of neurite growth-promoting anti-Nogo-A antibodies in acute spinal cord injury. Neurorehabil. Neural. Repair 32, 578–589 (2018).
Chen, K. et al. Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats. Exp. Neurol. 292, 135–144 (2017).
Maier, I. C. et al. Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain 132, 1426–1440 (2009).
Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R. & Tetzlaff, W. Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20, 637–647 (2017).
Abbaszadeh, H. A. et al. Stem cell transplantation and functional recovery after spinal cord injury: a systematic review and meta-analysis. Anat. Cell Biol. 51, 180–188 (2018).
Priest, C. A., Manley, N. C., Denham, J., Wirth, E. D. 3rd & Lebkowski, J. S. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen. Med. 10, 939–958 (2015).
Curtis, E. et al. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell 22, 941–950.e6 (2018).
Cyranoski, D. Japan’s approval of stem-cell treatment for spinal-cord injury concerns scientists. Nature 565, 544–545 (2019).
Mitsui, T., Shumsky, J. S., Lepore, A. C., Murray, M. & Fischer, I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J. Neurosci. 25, 9624–9636 (2005).
Bonner, J. F., Blesch, A., Neuhuber, B. & Fischer, I. Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J. Neurosci. Res. 88, 1182–1192 (2010).
Lu, P. et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264–1273 (2012).
Lu, P. et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83, 789–796 (2014).
Kadoya, K. et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat. Med. 22, 479–487 (2016).
Brock, J. H., Graham, L., Staufenberg, E., Im, S. & Tuszynski, M. H. Rodent neural progenitor cells support functional recovery after cervical spinal cord contusion. J. Neurotrauma 35, 1069–1078 (2018).
Rosenzweig, E. S. et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat. Med. 24, 484–490 (2018).
Dulin, J. N. et al. Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts. Nat. Commun. 9, 84 (2018).
Kumamaru, H., Lu, P., Rosenzweig, E. S., Kadoya, K. & Tuszynski, M. H. Regenerating corticospinal axons innervate phenotypically appropriate neurons within neural stem cell grafts. Cell Rep. 26, 2329–2339.e4 (2019).
Steward, O., Sharp, K. G., Yee, K. M., Hatch, M. N. & Bonner, J. F. Characterization of ectopic colonies that form in widespread areas of the nervous system with neural stem cell transplants into the site of a severe spinal cord injury. J. Neurosci. 34, 14013–14021 (2014).
Romero, M. I. et al. Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J. Neurosci. 20, 4435–4445 (2000).
Hofstetter, C. P. et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat. Neurosci. 8, 346–353 (2005).
Angeli, C. A., Edgerton, V. R., Gerasimenko, Y. P. & Harkema, S. J. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137, 1394–1409 (2014).
Gerasimenko, Y. P. et al. Noninvasive reactivation of motor descending control after paralysis. J. Neurotrauma 32, 1968–1980 (2015).
Grahn, P. J. et al. Enabling task-specific volitional motor functions via spinal cord neuromodulation in a human with paraplegia. Mayo Clin. Proc. 92, 544–554 (2017).
Chen, K. H. et al. The effect of chronic intracortical microstimulation on the electrode-tissue interface. J. Neural. Eng. 11, 026004 (2014).
Minev, I. R. et al. Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).
Yu, K. J. et al. Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex. Nat. Mater. 15, 782–791 (2016).
Guo, Y. et al. Biocompatibility and magnetic resonance imaging characteristics of carbon nanotube yarn neural electrodes in a rat model. Biomed. Eng. Online 14, 118 (2015).
James, N. D., McMahon, S. B., Field-Fote, E. C. & Bradbury, E. J. Neuromodulation in the restoration of function after spinal cord injury. Lancet Neurol. 17, 905–917 (2018).
Rejc, E., Angeli, C. A., Atkinson, D. & Harkema, S. J. Motor recovery after activity-based training with spinal cord epidural stimulation in a chronic motor complete paraplegic. Sci. Rep. 7, 13476 (2017).
Moraud, E. M. et al. Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89, 814–828 (2016).
Capogrosso, M. et al. A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539, 284–288 (2016).
Hofstoetter, U. S., Freundl, B., Binder, H. & Minassian, K. Common neural structures activated by epidural and transcutaneous lumbar spinal cord stimulation: elicitation of posterior root-muscle reflexes. PLoS One 13, e0192013 (2018).
Mills, P. B. & Dossa, F. Transcutaneous electrical nerve stimulation for management of limb spasticity: a systematic review. Am. J. Phys. Med. Rehabil. 95, 309–318 (2016).
Takeoka, A., Vollenweider, I., Courtine, G. & Arber, S. Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury. Cell 159, 1626–1639 (2014).
Wenger, N. et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat. Med. 22, 138–145 (2016).
Inanici, F. et al. Transcutaneous electrical spinal stimulation promotes long-term recovery of upper extremity function in chronic tetraplegia. IEEE Trans. Neural Syst. Rehabil. Eng. 26, 1272–1278 (2018).
Gomes-Osman, J. & Field-Fote, E. C. Cortical vs. afferent stimulation as an adjunct to functional task practice training: a randomized, comparative pilot study in people with cervical spinal cord injury. Clin. Rehabil. 29, 771–782 (2015).
Gomes-Osman, J. & Field-Fote, E. C. Improvements in hand function in adults with chronic tetraplegia following a multiday 10-Hz repetitive transcranial magnetic stimulation intervention combined with repetitive task practice. J. Neurol. Phys. Ther. 39, 23–30 (2015).
Alexeeva, N. & Calancie, B. Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: three case studies. J. Spinal Cord Med. 39, 50–57 (2016).
Bunday, K. L. & Perez, M. A. Motor recovery after spinal cord injury enhanced by strengthening corticospinal synaptic transmission. Curr. Biol. 22, 2355–2361 (2012).
Carmel, J. B., Berrol, L. J., Brus-Ramer, M. & Martin, J. H. Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth. J. Neurosci. 30, 10918–10926 (2010).
Carmel, J. B., Kimura, H. & Martin, J. H. Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J. Neurosci. 34, 462–466 (2014).
Song, W., Amer, A., Ryan, D. & Martin, J. H. Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury. Exp. Neurol. 277, 46–57 (2016).
Zareen, N. et al. Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury. Exp. Neurol. 297, 179–189 (2017).
Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).
Lebedev, M. A. & Nicolelis, M. A. Brain-machine interfaces: from basic science to neuroprostheses and neurorehabilitation. Physiol. Rev. 97, 767–837 (2017).
Bouton, C. E. et al. Restoring cortical control of functional movement in a human with quadriplegia. Nature 533, 247–250 (2016).
Alam, M., Rodrigues, W., Pham, B. N. & Thakor, N. V. Brain-machine interface facilitated neurorehabilitation via spinal stimulation after spinal cord injury: recent progress and future perspectives. Brain Res. 1646, 25–33 (2016).
Nishimura, Y., Perlmutter, S. I. & Fetz, E. E. Restoration of upper limb movement via artificial corticospinal and musculospinal connections in a monkey with spinal cord injury. Front. Neural. Circuits 7, 57 (2013).
Zimmermann, J. B. & Jackson, A. Closed-loop control of spinal cord stimulation to restore hand function after paralysis. Front. Neurosci. 8, 87 (2014).
Bonizzato, M. et al. Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury. Nat. Commun. 9, 3015 (2018).
Garcia-Alias, G., Barkhuysen, S., Buckle, M. & Fawcett, J. W. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151 (2009).
Zhao, R. R. et al. Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur. J. Neurosci. 38, 2946–2961 (2013).
Wahl, A. S. et al. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science 344, 1250–1255 (2014).
Takeoka, A. et al. Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J. Neurosci. 31, 4298–4310 (2011).
van den Brand, R. et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).
Lemon, R. N. Descending pathways in motor control. Annu. Rev Neurosci 31, 195–218 (2008).
Lawrence, D. G. & Kuypers, H. G. Pyramidal and non-pyramidal pathways in monkeys: anatomical and functional correlation. Science 148, 973–975 (1965).
Raposo, C. & Schwartz, M. Glial scar and immune cell involvement in tissue remodeling and repair following acute CNS injuries. Glia 62, 1895–1904 (2014).
Callahan, A. et al. Developing a data sharing community for spinal cord injury research. Exp. Neurol. 295, 135–143 (2017).
The authors declare no competing interests.
Peer review information
Nature Reviews Neurology thanks M. Tuszynski and other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hutson, T.H., Di Giovanni, S. The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration. Nat Rev Neurol 15, 732–745 (2019). https://doi.org/10.1038/s41582-019-0280-3
FBW7 protects against spinal cord injury by mitigating inflammation-associated neuronal apoptosis in mice
Biochemical and Biophysical Research Communications (2020)
Brain, Behavior, and Immunity (2020)
Botulinum Toxin and Neuronal Regeneration after Traumatic Injury of Central and Peripheral Nervous System
Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters
Gene Therapy (2020)