Individuals with spinal cord injury (SCI) can face decades with permanent disabilities. Advances in clinical management have decreased morbidity and improved outcomes, but no randomized clinical trial has demonstrated the efficacy of a repair strategy for improving recovery from SCI. Here, we summarize recent advances in biological and engineering strategies to augment neuroplasticity and/or functional recovery in animal models of SCI that are pushing toward clinical translation.
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National Spinal Cord Injury Statistical Center. Spinal cord injury (SCI) facts and figures at a glance https://www.nscisc.uab.edu/Public/Facts%202016.pdf (2016).
Fehlings, M. G. et al. A clinical practice guideline for the management of acute spinal cord injury: introduction, rationale, and scope. Global Spine J. 7 Suppl, 84S–94S (2017).
Anderson, K. D. Targeting recovery: priorities of the spinal cord-injured population. J. Neurotrauma 21, 1371–1383 (2004).
Fawcett, J. W. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45, 190–205 (2007).
Sofroniew, M. V. Dissecting spinal cord regeneration. Nature 557, 343–350 (2018).
Göritz, C. et al. A pericyte origin of spinal cord scar tissue. Science 333, 238–242 (2011).
Zhu, Y. et al. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol. Dis. 74, 114–125 (2015).
Burda, J. E. & Sofroniew, M. V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229–248 (2014).
Herrmann, J. E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243 (2008).
Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).
O’Shea, T. M., Burda, J. E. & Sofroniew, M. V. Cell biology of spinal cord injury and repair. J. Clin. Invest. 127, 3259–3270 (2017).
Tuszynski, M. H. & Steward, O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron 74, 777–791 (2012).
Murray, K. C. et al. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat. Med. 16, 694–700 (2010).
Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).
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).
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).
Ballermann, M. & Fouad, K. Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. Eur. J. Neurosci. 23, 1988–1996 (2006).
Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).
Rosenzweig, E. S. et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat. Neurosci. 13, 1505–1510 (2010).
Friedli, L. et al. Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Sci. Transl. Med. 7, 302ra134 (2015).
Belhaj-Saïf, A. & Cheney, P. D. Plasticity in the distribution of the red nucleus output to forearm muscles after unilateral lesions of the pyramidal tract. J. Neurophysiol. 83, 3147–3153 (2000).
Müllner, A. et al. Lamina-specific restoration of serotonergic projections after Nogo-A antibody treatment of spinal cord injury in rats. Eur. J. Neurosci. 27, 326–333 (2008).
Oudega, M. & Perez, M. A. Corticospinal reorganization after spinal cord injury. J. Physiol. (Lond.) 590, 3647–3663 (2012).
Baker, S. N. & Perez, M. A. Reticulospinal contributions to gross hand function after human spinal cord injury. J. Neurosci. 37, 9778–9784 (2017).
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. II et al. Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nat. Neurosci. 19, 697–705 (2016).
Asboth, L. et al. Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion. Nat. Neurosci. 21, 576–588 (2018).
Ruder, L., Takeoka, A. & Arber, S. Long-distance descending spinal neurons ensure quadrupedal locomotor stability. Neuron 92, 1063–1078 (2016).
Chen, B. et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell 174, 521–535 e513 (2018).
Kinoshita, M. et al. Genetic dissection of the circuit for hand dexterity in primates. Nature 487, 235–238 (2012).
Courtine, G. et al. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat. Neurosci. 12, 1333–1342 (2009).
Beauparlant, J. et al. Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury. Brain 136, 3347–3361 (2013).
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).
Dietz, V. Behavior of spinal neurons deprived of supraspinal input. Nat. Rev. Neurol. 6, 167–174 (2010).
Edgerton, V. R., Tillakaratne, N. J., Bigbee, A. J., de Leon, R. D. & Roy, R. R. Plasticity of the spinal neural circuitry after injury. Annu. Rev. Neurosci. 27, 145–167 (2004).
Lovett-Barr, M. R. et al. Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. J. Neurosci. 32, 3591–3600 (2012).
Navarrete-Opazo, A., Alcayaga, J., Sepúlveda, O., Rojas, E. & Astudillo, C. Repetitive intermittent hypoxia and locomotor training enhances walking function in incomplete spinal cord injury subjects: a randomized, triple-blind, placebo-controlled clinical trial. J. Neurotrauma 34, 1803–1812 (2017).
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
Kucukdereli, H. et al. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc. Natl Acad. Sci. USA 108, E440–E449 (2011).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).
Allen, N. J. et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486, 410–414 (2012).
Tyzack, G. E. et al. Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression. Nat. Commun. 5, 4294 (2014).
Wang, D. & Fawcett, J. The perineuronal net and the control of CNS plasticity. Cell Tissue Res. 349, 147–160 (2012).
Schwab, M. E. & Strittmatter, S. M. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol. 27, 53–60 (2014).
Bradbury, E. J. & McMahon, S. B. Spinal cord repair strategies: why do they work? Nat. Rev. Neurosci. 7, 644–653 (2006).
García-Alías, 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).
Mironova, Y. A. & Giger, R. J. Where no synapses go: gatekeepers of circuit remodeling and synaptic strength. Trends Neurosci. 36, 363–373 (2013).
Onishi, K., Hollis, E. & Zou, Y. Axon guidance and injury-lessons from Wnts and Wnt signaling. Curr. Opin. Neurobiol. 27, 232–240 (2014).
Norenberg, M. D., Smith, J. & Marcillo, A. The pathology of human spinal cord injury: defining the problems. J. Neurotrauma 21, 429–440 (2004).
Fleming, J. C. et al. The cellular inflammatory response in human spinal cords after injury. Brain 129, 3249–3269 (2006).
Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008).
Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).
Sun, F. et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480, 372–375 (2011).
He, Z. & Jin, Y. Intrinsic control of axon regeneration. Neuron 90, 437–451 (2016).
Chen, Q. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).
Chandran, V. et al. A systems-level analysis of the peripheral nerve intrinsic axonal growth program. Neuron 89, 956–970 (2016).
Yoon, C. & Giger, R. J. Inside out: core network of transcription factors drives axon regeneration. Neuron 89, 881–884 (2016).
de Lima, S. et al. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc. Natl Acad. Sci. USA 109, 9149–9154 (2012).
Baldwin, K. T., Carbajal, K. S., Segal, B. M. & Giger, R. J. Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration. Proc. Natl Acad. Sci. USA 112, 2581–2586 (2015).
Ozdinler, P. H. & Macklis, J. D. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat. Neurosci. 9, 1371–1381 (2006).
Bei, F. et al. Restoration of visual function by enhancing conduction in regenerated axons. Cell 164, 219–232 (2016).
Alto, L. T. et al. Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat. Neurosci. 12, 1106–1113 (2009).
Bonner, J. F. et al. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J. Neurosci. 31, 4675–4686 (2011).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).
Plantman, S. et al. Integrin-laminin interactions controlling neurite outgrowth from adult DRG neurons in vitro. Mol. Cell. Neurosci. 39, 50–62 (2008).
Edwards, T. J. & Hammarlund, M. Syndecan promotes axon regeneration by stabilizing growth cone migration. Cell Reports 8, 272–283 (2014).
Farhy Tselnicker, I., Boisvert, M. M. & Allen, N. J. The role of neuronal versus astrocyte-derived heparan sulfate proteoglycans in brain development and injury. Biochem. Soc. Trans. 42, 1263–1269 (2014).
Masu, M. Proteoglycans and axon guidance: a new relationship between old partners. J. Neurochem. 139 Suppl 2, 58–75 (2016).
Baier, H. & Bonhoeffer, F. Axon guidance by gradients of a target-derived component. Science 255, 472–475 (1992).
Horn, K. P., Busch, S. A., Hawthorne, A. L., van Rooijen, N. & Silver, J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J. Neurosci. 28, 9330–9341 (2008).
Blesch, A. & Tuszynski, M. H. Transient growth factor delivery sustains regenerated axons after spinal cord injury. J. Neurosci. 27, 10535–10545 (2007).
Adams, K. L. & Gallo, V. The diversity and disparity of the glial scar. Nat. Neurosci. 21, 9–15 (2018).
Windle, W. F., Clemente, C. D. & Chambers, W. W. Inhibition of formation of a glial barrier as a means of permitting a peripheral nerve to grow into the brain. J. Comp. Neurol. 96, 359–369 (1952).
Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).
Brosius Lutz, A. & Barres, B. A. Contrasting the glial response to axon injury in the central and peripheral nervous systems. Dev. Cell 28, 7–17 (2014).
Mason, C. A., Edmondson, J. C. & Hatten, M. E. The extending astroglial process: development of glial cell shape, the growing tip, and interactions with neurons. J. Neurosci. 8, 3124–3134 (1988).
Raper, J. & Mason, C. Cellular strategies of axonal pathfinding. Cold Spring Harb. Perspect. Biol. 2, a001933 (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).
Mokalled, M. H. et al. Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science 354, 630–634 (2016).
Richardson, P. M. & Issa, V. M. Peripheral injury enhances central regeneration of primary sensory neurones. Nature 309, 791–793 (1984).
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).
Neumann, S. & Woolf, C. J. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91 (1999).
Pearse, D. D. et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat. Med. 10, 610–616 (2004).
Williams, R. R., Henao, M., Pearse, D. D. & Bunge, M. B. Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant. 24, 115–131 (2015).
Shih, C. H., Lacagnina, M., Leuer-Bisciotti, K. & Pröschel, C. Astroglial-derived periostin promotes axonal regeneration after spinal cord injury. J. Neurosci. 34, 2438–2443 (2014).
Zhang, S., Alvarez, D. J., Sofroniew, M. V. & Deming, T. J. Design and synthesis of nonionic copolypeptide hydrogels with reversible thermoresponsive and tunable physical properties. Biomacromolecules 16, 1331–1340 (2015).
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).
Anderson, K. D. et al. Safety of autologous human schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma 34, 2950–2963 (2017).
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., Jones, L. L., Snyder, E. Y. & Tuszynski, M. H. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp. Neurol. 181, 115–129 (2003).
Kadoya, K. et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat. Med. 22, 479–487 (2016).
Abematsu, M. et al. Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J. Clin. Invest. 120, 3255–3266 (2010).
Rosenzweig, E. S. et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat. Med. 24, 484–490 (2018).
Pivetta, C., Esposito, M. S., Sigrist, M. & Arber, S. Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin. Cell 156, 537–548 (2014).
Winter, C. C. et al. Transplantable living scaffolds comprised of micro-tissue engineered aligned astrocyte networks to facilitate central nervous system regeneration. Acta Biomater. 38, 44–58 (2016).
Gao, M. et al. Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection. Biomaterials 34, 1529–1536 (2013).
Elliott Donaghue, I., Tam, R., Sefton, M. V. & Shoichet, M. S. Cell and biomolecule delivery for tissue repair and regeneration in the central nervous system. J. Control. Release 190, 219–227 (2014).
O’Shea, T. M. et al. In Smart Materials for Tissue Engineering Applications (ed. Wang, Q.) 529–557 (Royal Society of Chemistry, 2017).
Grillner, S. Biological pattern generation: the cellular and computational logic of networks in motion. Neuron 52, 751–766 (2006).
Kiehn, O. Locomotor circuits in the mammalian spinal cord. Annu. Rev. Neurosci. 29, 279–306 (2006).
Bachmann, L. C. et al. Deep brain stimulation of the midbrain locomotor region improves paretic hindlimb function after spinal cord injury in rats. Sci. Transl. Med. 5, 208ra146 (2013).
Radhakrishna, M. et al. Double-blind, placebo-controlled, randomized phase I/IIa study (safety and efficacy) with buspirone/levodopa/carbidopa (SpinalonTM) in subjects with complete AIS A or motor-complete AIS B spinal cord injury. Curr. Pharm. Des. 23, 1789–1804 (2017).
Gerasimenko, Y. P. et al. Noninvasive reactivation of motor descending control after paralysis. J. Neurotrauma 32, 1968–1980 (2015).
Wenger, N. et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat. Med. 22, 138–145 (2016).
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).
Angeli, C., Edgerton, V. R., Gerasimenko, Y. & Harkema, S. Reply: No dawn yet of a new age in spinal cord rehabilitation. Brain 138, e363 (2015).
Herman, R., He, J., D’Luzansky, S., Willis, W. & Dilli, S. Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured. Spinal Cord 40, 65–68 (2002).
van den Brand, R. et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).
Danner, S. M. et al. Human spinal locomotor control is based on flexibly organized burst generators. Brain 138, 577–588 (2015).
Wagner, F. B. et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 563, 65–71 (2018).
Gill, M. L. et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat. Med. 24, 1677–1682 (2018).
Minev, I. R. et al. Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).
Holinski, B. J. et al. Intraspinal microstimulation produces over-ground walking in anesthetized cats. J. Neural Eng. 13, 056016 (2016).
Zimmermann, J. B., Seki, K. & Jackson, A. Reanimating the arm and hand with intraspinal microstimulation. J. Neural Eng. 8, 054001 (2011).
Kasten, M. R., Sunshine, M. D., Secrist, E. S., Horner, P. J. & Moritz, C. T. Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury. J. Neural Eng. 10, 044001 (2013).
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).
Lu, D. C. et al. Engaging cervical spinal cord networks to reenable volitional control of hand function in tetraplegic patients. Neurorehabil. Neural Repair 30, 951–962 (2016).
Phillips, A. A. et al. An autonomic neuroprosthesis: noninvasive electrical spinal cord stimulation restores autonomic cardiovascular function in individuals with spinal cord injury. J. Neurotrauma 35, 446–451 (2017).
Hachmann, J. T. et al. Electrical neuromodulation of the respiratory system after spinal cord injury. Mayo Clin. Proc. 92, 1401–1414 (2017).
Minassian, K., McKay, W. B., Binder, H. & Hofstoetter, U. S. Targeting lumbar spinal neural circuitry by epidural stimulation to restore motor function after spinal cord injury. Neurotherapeutics 13, 284–294 (2016).
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 computational model for epidural electrical stimulation of spinal sensorimotor circuits. J. Neurosci. 33, 19326–19340 (2013).
Gaunt, R. A., Prochazka, A., Mushahwar, V. K., Guevremont, L. & Ellaway, P. H. Intraspinal microstimulation excites multisegmental sensory afferents at lower stimulus levels than local alpha-motoneuron responses. J. Neurophysiol. 96, 2995–3005 (2006).
Barolat, G., Myklebust, J. B. & Wenninger, W. Enhancement of voluntary motor function following spinal cord stimulation—case study. Appl. Neurophysiol. 49, 307–314 (1986).
Nudo, R. J. & Masterton, R. B. Descending pathways to the spinal cord: a comparative study of 22 mammals. J. Comp. Neurol. 277, 53–79 (1988).
Minassian, K. et al. 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 Cord 42, 401–416 (2004).
Carhart, M. R., He, J., Herman, R., D’Luzansky, S. & Willis, W. T. Epidural spinal-cord stimulation facilitates recovery of functional walking following incomplete spinal-cord injury. IEEE Trans. Neural Syst. Rehabil. Eng. 12, 32–42 (2004).
Capogrosso, M. et al. A brain–spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539, 284–288 (2016).
Tripodi, M., Stepien, A. E. & Arber, S. Motor antagonism exposed by spatial segregation and timing of neurogenesis. Nature 479, 61–66 (2011).
Levine, A. J. et al. Identification of a cellular node for motor control pathways. Nat. Neurosci. 17, 586–593 (2014).
Formento, E. et al. Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury. Nat. Neurosci. 21, 1728–1741 (2018).
Wenger, N. et al. Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury. Sci. Transl. Med. 6, 255ra133 (2014).
Gilja, V. et al. Clinical translation of a high-performance neural prosthesis. Nat. Med. 21, 1142–1145 (2015).
Jarosiewicz, B. et al. Virtual typing by people with tetraplegia using a self-calibrating intracortical brain-computer interface. Sci. Transl. Med. 7, 313ra179 (2015).
Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).
Collinger, J. L. et al. High-performance neuroprosthetic control by an individual with tetraplegia. Lancet 381, 557–564 (2013).
Bouton, C. E. et al. Restoring cortical control of functional movement in a human with quadriplegia. Nature 533, 247–250 (2016).
Ajiboye, A. B. et al. Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration. Lancet 389, 1821–1830 (2017).
Ethier, C., Oby, E. R., Bauman, M. J. & Miller, L. E. Restoration of grasp following paralysis through brain-controlled stimulation of muscles. Nature 485, 368–371 (2012).
Moritz, C. T., Perlmutter, S. I. & Fetz, E. E. Direct control of paralysed muscles by cortical neurons. Nature 456, 639–642 (2008).
Flesher, S. N. et al. Intracortical microstimulation of human somatosensory cortex. Sci. Transl. Med. 8, 361ra141 (2016).
Bonizzato, M. et al. Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury. Nat. Commun. 9, 3015 (2018).
Borton, D., Micera, S., Millán, JdelR. & Courtine, G. Personalized neuroprosthetics. Sci. Transl. Med. 5, 210rv2 (2013).
Lacour, S. P., Courtine, G. & Guck, J. Materials and technologies for soft implantable neuroprostheses. Nat. Rev. Mater. 1, 16063 (2016).
Côté, M. P., Murray, M. & Lemay, M. A. Rehabilitation strategies after spinal cord injury: inquiry into the mechanisms of success and failure. J. Neurotrauma 34, 1841–1857 (2017).
Torres-Espín, A., Beaudry, E., Fenrich, K. & Fouad, K. Rehabilitative training in animal models of spinal cord injury. J. Neurotrauma 35, 1970–1985 (2018).
Carmel, J. B. & Martin, J. H. Motor cortex electrical stimulation augments sprouting of the corticospinal tract and promotes recovery of motor function. Front. Integr. Neurosci. 8, 51 (2014).
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).
Tazoe, T. & Perez, M. A. Effects of repetitive transcranial magnetic stimulation on recovery of function after spinal cord injury. Arch. Phys. Med. Rehabil. 96, S145–S155 (2015).
Long, J., Federico, P. & Perez, M. A. A novel cortical target to enhance hand motor output in humans with spinal cord injury. Brain 140, 1619–1632 (2017).
Mishra, A. M., Pal, A., Gupta, D. & Carmel, J. B. Paired motor cortex and cervical epidural electrical stimulation timed to converge in the spinal cord promotes lasting increases in motor responses. J. Physiol. (Lond.) 595, 6953–6968 (2017).
Dixon, L., Ibrahim, M. M., Santora, D. & Knikou, M. Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits. J. Neurophysiol. 116, 904–916 (2016).
Jackson, A., Mavoori, J. & Fetz, E. E. Long-term motor cortex plasticity induced by an electronic neural implant. Nature 444, 56–60 (2006).
Nishimura, Y., Perlmutter, S. I., Eaton, R. W. & Fetz, E. E. Spike-timing-dependent plasticity in primate corticospinal connections induced during free behavior. Neuron 80, 1301–1309 (2013).
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).
Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat. Rev. Neurosci. 10, 647–658 (2009).
Freund, P. et al. MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study. Lancet Neurol. 12, 873–881 (2013).
McPherson, J. G., Miller, R. R. & Perlmutter, S. I. Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury. Proc. Natl Acad. Sci. USA 112, 12193–12198 (2015).
Harkema, S. J. Plasticity of interneuronal networks of the functionally isolated human spinal cord. Brain Res. Rev. 57, 255–264 (2008).
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).
Gómez-Pinilla, F., Ying, Z., Roy, R. R., Hodgson, J. & Edgerton, V. R. Afferent input modulates neurotrophins and synaptic plasticity in the spinal cord. J. Neurophysiol. 92, 3423–3432 (2004).
Baraban, M., Koudelka, S. & Lyons, D. A. Ca2+ activity signatures of myelin sheath formation and growth in vivo. Nat. Neurosci. 21, 19–23 (2018).
López-Álvarez, V. M., Modol, L., Navarro, X. & Cobianchi, S. Early increasing-intensity treadmill exercise reduces neuropathic pain by preventing nociceptor collateral sprouting and disruption of chloride cotransporters homeostasis after peripheral nerve injury. Pain 156, 1812–1825 (2015).
Donati, A. R. et al. Long-term training with a brain-machine interface-based gait protocol induces partial neurological recovery in paraplegic patients. Sci. Rep. 6, 30383 (2016).
Gorgey, A. S. Robotic exoskeletons: the current pros and cons. World J. Orthop. 9, 112–119 (2018).
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).
Fouad, K., Bennett, D. J., Vavrek, R. & Blesch, A. Long-term viral brain-derived neurotrophic factor delivery promotes spasticity in rats with a cervical spinal cord hemisection. Front. Neurol. 4, 187 (2013).
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).
Overman, J. J. & Carmichael, S. T. Plasticity in the injured brain: more than molecules matter. Neuroscientist 20, 15–28 (2014).
Arber, S. & Costa, R. M. Connecting neuronal circuits for movement. Science 360, 1403–1404 (2018).
Rossignol, S., Dubuc, R. & Gossard, J. P. Dynamic sensorimotor interactions in locomotion. Physiol. Rev. 86, 89–154 (2006).
Dominici, N. et al. Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders. Nat. Med. 18, 1142–1147 (2012).
World Health Organisation (WHO). International perspectives on spinal cord injury http://apps.who.int/iris/bitstream/handle/10665/94190/9789241564663_eng.pdf (2013).
The authors kindly thank J. B. Mignardot for drafting the figures. This work was supported by a Consolidator Grant from the European Research Council (ERC-2015-CoG HOW2WALKAGAIN 682999 to G.G.), the Swiss National Science Foundation including a bonus of Excellence (310030B_166674) and the National Center of Competence in Research (NCCR) Robotics (to G.C.), the US National Institutes of Health R01NS084030 (to M.S.), the Dr Miriam and Sheldon G. Adelson Medical Foundation (to M.S.) and Wings for Life (to G.C. and M.S.).
G.C. holds various patents in relation to the reviewed work, and is a founder and shareholder of GTX medical, a company developing a therapy for spinal cord injury.
Peer review information: Hannah Stower was the primary editor(s) on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Courtine, G., Sofroniew, M.V. Spinal cord repair: advances in biology and technology. Nat Med 25, 898–908 (2019). https://doi.org/10.1038/s41591-019-0475-6
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