Combined approaches to spinal cord injury therapy
- Authors: Davletshin E.F.1, Shulman I.A.2, Mukhamedshina Y.O.1,2,3
-
Affiliations:
- Kazan (Volga Region) Federal University
- Republic Clinical Hospital
- Kazan State Medical University
- Issue: Vol 32, No 1 (2025)
- Pages: 281-292
- Section: Reviews
- Submitted: 01.04.2024
- Accepted: 02.05.2024
- Published: 08.04.2025
- URL: https://journals.eco-vector.com/0869-8678/article/view/629852
- DOI: https://doi.org/10.17816/vto629852
- ID: 629852
Cite item
Abstract
Currently, regenerative medicine (cell therapy) or motor rehabilitation approaches are being used to overcome the consequences of spinal cord injury. However, the efficacy of these approaches at the preclinical research stage does not always translate into successful implementation in clinical practice. In particular, complete recovery from functional deficits caused by severe spinal cord injury is often not possible. In this context, the development of combined approaches based on cell transplantation and neuromodulation is needed to enhance the neuroregenerative effect. The addition of dosed motor training to the overall treatment plan and in the context of combined approaches may have a significant supportive effect. In this review, we focused on evaluating clinical trials that used combinations of different approaches to gain an understanding of the mechanisms underlying their therapeutic effects. Despite the positive therapeutic outcomes of combined approaches, further research is needed into the emerging cellular and molecular changes involved in the reorganisation of neuronal connections.
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About the authors
Eldar F. Davletshin
Kazan (Volga Region) Federal University
Email: eldar.davletschin@gmail.com
ORCID iD: 0000-0001-8784-3200
Russian Federation, Kazan
Ilya A. Shulman
Republic Clinical Hospital
Email: ilyashul@mail.ru
ORCID iD: 0000-0001-8933-8347
SPIN-code: 9337-8690
MD
Russian Federation, KazanYana O. Mukhamedshina
Kazan (Volga Region) Federal University; Republic Clinical Hospital; Kazan State Medical University
Author for correspondence.
Email: yana.k-z-n@mail.ru
ORCID iD: 0000-0002-9435-340X
SPIN-code: 8569-9002
MD, Dr. Sci (Medicine), associate professor
Russian Federation, Kazan; Kazan; KazanReferences
- Gage FH, Temple S. Neural stem cells: generating and regenerating the brain. Neuron. 2013;80(3):588–601. doi: 10.1016/j.neuron.2013.10.037
- Sandberg CJ, Vik-Mo EO, Behnan J, et al. Transcriptional profiling of adult neural stem-like cells from the human brain. PLoS One. 2014;9(12):e114739. doi: 10.1371/journal.pone.0114739
- Pino A, Fumagalli G, Bifari F, Decimo I. New neurons in adult brain: distribution, molecular mechanisms and therapies. Biochem Pharmacol. 2017;141:4–22. doi: 10.1016/j.bcp.2017.07.003
- Paul A, Chaker Z, Doetsch F. Hypothalamic regulation of regionally distinct adult neural stem cells and neurogenesis. Science. 2017;356(6345):1383–1386. doi: 10.1126/science.aal3839
- Mothe AJ, Tator CH. Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci. 2013;31(7):701–713. doi: 10.1016/j.ijdevneu.2013.07.004
- Zhu Y, Uezono N, Yasui T, Nakashima K. Neural stem cell therapy aiming at better functional recovery after spinal cord injury. Dev Dyn. 2018;247(1):75–84. doi: 10.1002/dvdy.24558
- Lu P, Ceto S, Wang Y, et al. Prolonged human neural stem cell maturation supports recovery in injured rodent CNS. J Clin Invest. 2017;127(9):3287–3299. doi: 10.1172/JCI92955
- Deng J, Zhang Y, Xie Y, et al. Cell Transplantation for Spinal Cord Injury: Tumorigenicity of Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cells. Stem Cells Int. 2018;2018:5653787. doi: 10.1155/2018/5653787
- Nagoshi N, Tsuji O, Nakamura M, Okano H. Cell therapy for spinal cord injury using induced pluripotent stem cells. Regen Ther. 2019;11:75–80. doi: 10.1016/j.reth.2019.05.006
- Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol. 2014;5:68. doi: 10.3389/fimmu.2014.00068
- Yao L, He C, Zhao Y, et al. Human umbilical cord blood stem cell transplantation for the treatment of chronic spinal cord injury: Electrophysiological changes and long-term efficacy. Neural Regen Res. 2013;8(5):397–403. doi: 10.3969/j.issn.1673-5374.2013.05.002
- Cheng H, Liu X, Hua R, et al. Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. J Transl Med. 2014;12:253. doi: 10.1186/s12967-014-0253-7
- Wewetzer K, Verdú E, Angelov DN, Navarro X. Olfactory ensheathing glia and Schwann cells: two of a kind? Cell Tissue Res. 2002;309(3):337–345. doi: 10.1007/s00441-002-0607-y
- Oudega M. Schwann cell and olfactory ensheathing cell implantation for repair of the contused spinal cord. Acta Physiol (Oxf). 2007;189(2):181–189. doi: 10.1111/j.1748-1716.2006.01658.x
- Saberi H, Moshayedi P, Aghayan HR, et al. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett. 2008;443(1):46–50. doi: 10.1016/j.neulet.2008.07.041
- Gant KL, Guest JD, Palermo AE, et al. Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury. J Neurotrauma. 2022;39(3–4):285–299. doi: 10.1089/neu.2020.7590
- Santamaria AJ, Benavides FD, Saraiva PM, et al. Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia. Front Neurol. 2021;11:514181. doi: 10.3389/fneur.2020.514181
- Anderson KD, Guest JD, Dietrich WD, et al. Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury. J Neurotrauma. 2017;34(21):2950–2963. doi: 10.1089/neu.2016.4895
- Chen L, Huang H, Xi H, et al. A prospective randomized double-blind clinical trial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries. Cell Transplant. 2014;23 Suppl 1:S35–S44. doi: 10.3727/096368914X685014
- Khan S, Mafi P, Mafi R, Khan W. A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion. Curr Stem Cell Res Ther. 2018;13(4):316–323. doi: 10.2174/1574888X11666170907120030
- Cofano F, Boido M, Monticelli M, et al. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int J Mol Sci. 2019;20(11):2698. doi: 10.3390/ijms20112698
- Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods Mol Biol. 2016;1416:123–146. doi: 10.1007/978-1-4939-3584-0_7
- Maacha S, Sidahmed H, Jacob S, et al. Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis. Stem Cells Int. 2020;2020:4356359. doi: 10.1155/2020/4356359
- Mukhamedshina YO, Akhmetzyanova ER, Kostennikov AA, et al. Adipose-Derived Mesenchymal Stem Cell Application Combined With Fibrin Matrix Promotes Structural and Functional Recovery Following Spinal Cord Injury in Rats. Front Pharmacol. 2018;9:343. doi: 10.3389/fphar.2018.00343
- Satti HS, Waheed A, Ahmed P, et al. Autologous mesenchymal stromal cell transplantation for spinal cord injury: A Phase I pilot study. Cytotherapy. 2016;18(4):518–522. doi: 10.1016/j.jcyt.2016.01.004
- Albu S, Kumru H, Coll R, et al. Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study. Cytotherapy. 2021;23(2):146–156. doi: 10.1016/j.jcyt.2020.08.008
- Yang Y, Pang M, Chen YY, et al. Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial. Neural Regen Res. 2020;15(8):1532–1538. doi: 10.4103/1673-5374.274347
- Vaquero J, Zurita M, Rico MA, et al. Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: Safety and efficacy of the 100/3 guideline. Cytotherapy. 2018;20(6):806–819. doi: 10.1016/j.jcyt.2018.03.032
- Wang Y, Yi H, Song Y. The safety of MSC therapy over the past 15 years: a meta-analysis. Stem Cell Res Ther. 2021;12(1):545. doi: 10.1186/s13287-021-02609-x
- Oraee-Yazdani S, Akhlaghpasand M, Golmohammadi M, et al. Combining cell therapy with human autologous Schwann cell and bone marrow-derived mesenchymal stem cell in patients with subacute complete spinal cord injury: safety considerations and possible outcomes. Stem Cell Res Ther. 2021;12(1):445. doi: 10.1186/s13287-021-02515-2
- Xiao Z, Tang F, Zhao Y, et al. Significant Improvement of Acute Complete Spinal Cord Injury Patients Diagnosed by a Combined Criteria Implanted with NeuroRegen Scaffolds and Mesenchymal Stem Cells. Cell Transplant. 2018;27(6):907–915. doi: 10.1177/0963689718766279
- Muthu S, Jeyaraman M, Gulati A, Arora A. Current evidence on mesenchymal stem cell therapy for traumatic spinal cord injury: systematic review and meta-analysis. Cytotherapy. 2021;23(3):186–197. doi: 10.1016/j.jcyt.2020.09.007
- Szymoniuk M, Litak J, Sakwa L, et al. Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury. Cells. 2022;12(1):120. doi: 10.3390/cells12010120
- Oh SK, Choi KH, Yoo JY, et al. A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury. Neurosurgery. 2016;78(3):436–447. doi: 10.1227/NEU.0000000000001056
- Cao QL, Howard RM, Dennison JB, Whittemore SR. Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol. 2002;177(2):349–359. doi: 10.1006/exnr.2002.7981
- Alexanian AR, Fehlings MG, Zhang Z, Maiman DJ. Transplanted neurally modified bone marrow-derived mesenchymal stem cells promote tissue protection and locomotor recovery in spinal cord injured rats. Neurorehabil Neural Repair. 2011;25(9):873–880. doi: 10.1177/1545968311416823
- Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A. Mesenchymal stem cell transplantation reduces glial cyst and improves functional outcome after spinal cord compression. World Neurosurg. 2014;81(1):183–190. doi: 10.1016/j.wneu.2012.08.014
- Gass GC, Camp EM. Physiological characteristics of trained Australian paraplegic and tetraplegic subjects. Med Sci Sports. 1979;11(3):256–259.
- Gass GC, Watson J, Camp EM, et al. The effects of physical training on high level spinal lesion patients. Scand J Rehabil Med. 1980;12(2):61–65.
- Gass GC, Camp EM, Davis HA, et al. The effects of prolonged exercise on spinally injured subjects. Med Sci Sports Exerc. 1981;13(5):277–283.
- Sandrow-Feinberg HR, Izzi J, Shumsky JS, et al. Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury. J Neurotrauma. 2009;26(5):721–731. doi: 10.1089/neu.2008.0750
- Smith AC, Knikou M. A Review on Locomotor Training after Spinal Cord Injury: Reorganization of Spinal Neuronal Circuits and Recovery of Motor Function. Neural Plast. 2016;2016:1216258. doi: 10.1155/2016/1216258
- Yu P, Zhang W, Liu Y, et al. The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury. Int Rev Neurobiol. 2019;147:199–217. doi: 10.1016/bs.irn.2019.08.003
- Petruska JC, Ichiyama RM, Jindrich DL, et al. Changes in motoneuron properties and synaptic inputs related to step training after spinal cord transection in rats. J Neurosci. 2007;27(16):4460–4471. doi: 10.1523/JNEUROSCI.2302-06.2007
- Ilha J, Centenaro LA, Broetto Cunha N, et al. The beneficial effects of treadmill step training on activity-dependent synaptic and cellular plasticity markers after complete spinal cord injury. Neurochem Res. 2011;36(6):1046–1055. doi: 10.1007/s11064-011-0446-x
- Fu J, Wang H, Deng L, Li J. Exercise Training Promotes Functional Recovery after Spinal Cord Injury. Neural Plast. 2016;2016:4039580. doi: 10.1155/2016/4039580
- Field-Fote EC, Roach KE. Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: a randomized clinical trial. Phys Ther. 2011;91(1):48–60. doi: 10.2522/ptj.20090359
- Lucareli PR, Lima MO, Lima FP, et al. Gait analysis following treadmill training with body weight support versus conventional physical therapy: a prospective randomized controlled single blind study. Spinal Cord. 2011;49(9):1001–1007. doi: 10.1038/sc.2011.37
- Wirz M, Mach O, Maier D, et al. Effectiveness of Automated Locomotor Training in Patients with Acute Incomplete Spinal Cord Injury: A Randomized, Controlled, Multicenter Trial. J Neurotrauma. 2017;34(10):1891–1896. doi: 10.1089/neu.2016.4643
- Chari A, Hentall ID, Papadopoulos MC, Pereira EA. Surgical Neurostimulation for Spinal Cord Injury. Brain Sci. 2017;7(2):18. doi: 10.3390/brainsci7020018
- Zheng Y, Mao YR, Yuan TF, et al. Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation. Neural Regen Res. 2020;15(8):1437–1450. doi: 10.4103/1673-5374.274332
- Marquez-Chin C, Popovic MR. Functional electrical stimulation therapy for restoration of motor function after spinal cord injury and stroke: a review. Biomed Eng Online. 2020;19(1):34. doi: 10.1186/s12938-020-00773-4
- Hofstoetter US, McKay WB, Tansey KE, et al. Modification of spasticity by transcutaneous spinal cord stimulation in individuals with incomplete spinal cord injury. J Spinal Cord Med. 2014;37(2):202–211. doi: 10.1179/2045772313Y.0000000149
- Levin MF, Hui-Chan CW. Relief of hemiparetic spasticity by TENS is associated with improvement in reflex and voluntary motor functions. Electroencephalogr Clin Neurophysiol. 1992;85(2):131–142. doi: 10.1016/0168-5597(92)90079-q
- Crone C, Nielsen J, Petersen N, et al. Disynaptic reciprocal inhibition of ankle extensors in spastic patients. Brain. 1994;117(5):1161–1168. doi: 10.1093/brain/117.5.1161
- Joodaki MR, Olyaei GR, Bagheri H. The effects of electrical nerve stimulation of the lower extremity on H-reflex and F-wave parameters. Electromyogr Clin Neurophysiol. 2001;41(1):23–28.
- Benavides FD, Jo HJ, Lundell H, et al. Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia. J Neurosci. 2020;40(13):2633–2643. doi: 10.1523/JNEUROSCI.2374-19.2020
- Inanici F, Samejima S, Gad P, et al. Transcutaneous Electrical Spinal Stimulation Promotes Long-Term Recovery of Upper Extremity Function in Chronic Tetraplegia. IEEE Trans Neural Syst Rehabil Eng. 2018;26(6):1272–1278. doi: 10.1109/TNSRE.2018.2834339
- Gad P, Lee S, Terrafranca N, et al. Non-Invasive Activation of Cervical Spinal Networks after Severe Paralysis. J Neurotrauma. 2018;35(18):2145–2158. doi: 10.1089/neu.2017.5461
- Balykin MV, Yakupov RN, Mashin VV, et al. The influence of non-invasive electrical stimulation of the spinal cord on the locomotor function of patients presenting with movement disorders of central genesis. Vopr Kurortol Fizioter Lech Fiz Kult. 2017;94(4):4–9. doi: 10.17116/kurort20179444-9
- McHugh LV, Miller AA, Leech KA, et al. Feasibility and utility of transcutaneous spinal cord stimulation combined with walking-based therapy for people with motor incomplete spinal cord injury. Spinal Cord Ser Cases. 2020;6(1):104. doi: 10.1038/s41394-020-00359-1
- Sayenko DG, Rath M, Ferguson AR, et al. Self-Assisted Standing Enabled by Non-Invasive Spinal Stimulation after Spinal Cord Injury. J Neurotrauma. 2019;36(9):1435–1450. doi: 10.1089/neu.2018.5956
- Riedy LW, Chintam R, Walter JS. Use of a neuromuscular stimulator to increase anal sphincter pressure. Spinal Cord. 2000;38(12):724–727. doi: 10.1038/sj.sc.3101088
- Deng Y, Dong Y, Liu Y, et al. A systematic review of clinical studies on electrical stimulation therapy for patients with neurogenic bowel dysfunction after spinal cord injury. Medicine (Baltimore). 2018;97(41):e12778. doi: 10.1097/MD.0000000000012778
- Tai C, Roppolo JR, de Groat WC. Spinal reflex control of micturition after spinal cord injury. Restor Neurol Neurosci. 2006;24(2):69–78.
- Parittotokkaporn S, Varghese C, O’Grady G, et al. Non-invasive neuromodulation for bowel, bladder and sexual restoration following spinal cord injury: A systematic review. Clin Neurol Neurosurg. 2020;194:105822. doi: 10.1016/j.clineuro.2020.105822
- Feloney MP, Stauss K, Leslie SW. Sacral Neuromodulation. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
- Lombardi G, Del Popolo G. Clinical outcome of sacral neuromodulation in incomplete spinal cord injured patients suffering from neurogenic lower urinary tract symptoms. Spinal Cord. 2009;47(6):486–491. doi: 10.1038/sc.2008.172
- van Ophoven A, Engelberg S, Lilley H, Sievert KD. Systematic literature review and meta-analysis of sacral neuromodulation (SNM) in patients with neurogenic lower urinary tract dysfunction (nLUTD): over 20 years’ experience and future directions. Adv Ther. 2021;38(4):1987–2006. doi: 10.1007/s12325-021-01650-9
- Hu M, Lai S, Zhang Y, et al. Sacral Neuromodulation for Lower Urinary Tract Dysfunction in Spinal Cord Injury: A Systematic Review and Meta-Analysis. Urol Int. 2019;103(3):337–343. doi: 10.1159/000501529
- Sharifiaghdas F. Sacral neuromodulation in congenital lumbo-sacral and traumatic spinal cord defects with neurogenic lower urinary tract symptoms: a single-center experience in children and adolescents. World J Urol. 2019;37(12):2775–2783. doi: 10.1007/s00345-019-02721-x
- Gupta P, Ehlert MJ, Sirls LT, Peters KM. Percutaneous tibial nerve stimulation and sacral neuromodulation: an update. Curr Urol Rep. 2015;16(2):4. doi: 10.1007/s11934-014-0479-1
- Daia C, Bumbea AM, Badiu CD, et al. Interferential electrical stimulation for improved bladder management following spinal cord injury. Biomed Rep. 2019;11(3):115–122. doi: 10.3892/br.2019.1227
- Moore JS, Gibson PR, Burgell RE. Neuromodulation via Interferential Electrical Stimulation as a Novel Therapy in Gastrointestinal Motility Disorders. J Neurogastroenterol Motil. 2018;24(1):19–29. doi: 10.5056/jnm17071
- Lavrov I, Gerasimenko YP, Ichiyama RM, et al. Plasticity of spinal cord reflexes after a complete transection in adult rats: relationship to stepping ability. J Neurophysiol. 2006;96(4):1699–1710. doi: 10.1152/jn.00325.2006
- Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuromodulation Appropriateness Consensus Committee. Neuromodulation. 2014;17(6):515–550. doi: 10.1111/ner.12208
- Lu DC, Edgerton VR, Modaber M, et al. Engaging Cervical Spinal Cord Networks to Reenable Volitional Control of Hand Function in Tetraplegic Patients. Neurorehabil Neural Repair. 2016;30(10):951–962. doi: 10.1177/1545968316644344
- Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014;137(5):1394–1409. doi: 10.1093/brain/awu038
- Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011;377(9781):1938–1947. doi: 10.1016/S0140-6736(11)60547-3
- Zhu H, Poon W, Liu Y, et al. Phase I-II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury. Cell Transplant. 2016;25(11):1925–1943. doi: 10.3727/096368916X691411
- Zhou XH, Ning GZ, Feng SQ, et al. Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: six cases, more than five years of follow-up. Cell Transplant. 2012;21 suppl 1:S39–S47. doi: 10.3727/096368912X633752
- Lima C, Escada P, Pratas-Vital J, et al. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24(1):10–22. doi: 10.1177/1545968309347685
- Megía García A, Serrano-Muñoz D, Taylor J, et al. Transcutaneous Spinal Cord Stimulation and Motor Rehabilitation in Spinal Cord Injury: A Systematic Review. Neurorehabil Neural Repair. 2020;34(1):3–12. doi: 10.1177/1545968319893298
- Hofstoetter US, Krenn M, Danner SM, et al. Augmentation of Voluntary Locomotor Activity by Transcutaneous Spinal Cord Stimulation in Motor-Incomplete Spinal Cord-Injured Individuals. Artif Organs. 2015;39(10):E176–E186. doi: 10.1111/aor.12615
- Gad P, Gerasimenko Y, Zdunowski S, et al. Weight Bearing Over-ground Stepping in an Exoskeleton with Non-invasive Spinal Cord Neuromodulation after Motor Complete Paraplegia. Front Neurosci. 2017;11:333. doi: 10.3389/fnins.2017.00333
- Islamov R, Bashirov F, Fadeev F, et al. Epidural Stimulation Combined with Triple Gene Therapy for Spinal Cord Injury Treatment. Int J Mol Sci. 2020;21(23):8896. doi: 10.3390/ijms21238896
- Islamov R, Bashirov F, Izmailov A, et al. New Therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation. Cells. 2022;11(1):144. doi: 10.3390/cells11010144
- Siddiqui AM, Islam R, Cuellar CA, et al. Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation. NPJ Regen Med. 2021;6(1):66. doi: 10.1038/s41536-021-00176-6
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