Cited by 574Spinal Cord Injury ResearchStroke Rehabilitation and RecoveryProsthetics and Rehabilitation Robotics

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Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia

Gill, Megan L., Grahn, Peter J., Calvert, Jonathan S., Linde, Margaux B., Lavrov, Igor A., Strommen, Jeffrey A., Beck, Lisa A., Sayenko, Dimitry G., Van Straaten, Meegan G., Drubach, Dina I., Veith, Daniel D., Thoreson, Andrew R., Lopez, Cesar, Gerasimenko, Yury P., Edgerton, V. Reggie, Lee, Kendall H., Zhao, Kristin D.·2018·Nature Medicine

DOI 10.1038/s41591-018-0175-7

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Abstract

Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis 1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.

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Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study
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Evidence for a Spinal Central Pattern Generator in Humans a
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Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury
van den Brand, R., Heutschi, J., Barraud, Q., DiGiovanna, J., Bartholdi, K., Huerlimann, M., Friedli, L., Vollenweider, I., Moraud, E. M., Duis, S., et al. (2012) · Science · doi:10.1126/science.1217416 · Cited by 767
Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans
Angeli, C. A., Edgerton, V. R., Gerasimenko, Y. P., & Harkema, S. J. (2014) · Brain · doi:10.1093/brain/awu038 · Cited by 750
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A brain–spine interface alleviating gait deficits after spinal cord injury in primates
Capogrosso, M., Milekovic, T., Borton, D., Wagner, F., Moraud, E. M., Mignardot, J.-B., Buse, N., Gandar, J., Barraud, Q., Xing, D., et al. (2016) · Nature · doi:10.1038/nature20118 · Cited by 635
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Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI
Dobkin, B. H., Apple, D. F., Barbeau, H., Basso, M., Behrman, A. L., Deforge, D., Ditunno, J. F., Dudley, G., Elashoff, R. E., Fugate, L. P., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000202600.72018.39 · Cited by 474
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Wernig, A. (2006) · Neurology · doi:10.1212/01.wnl.0000249079.73112.38 · Cited by 414
Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury
Wenger, N., Moraud, E. M., Gandar, J., Musienko, P., Capogrosso, M., Baud, L., Le Goff, C. G., Barraud, Q., Pavlova, N., Dominici, N., et al. (2016) · Nature Medicine · doi:10.1038/nm.4025 · Cited by 369
Noninvasive Reactivation of Motor Descending Control after Paralysis
Gerasimenko, Y., Lu, D. C.-T., Modaber, M., Zdunowski, S., Gad, P. N., Sayenko, D. G., Morikawa, E., Haakana, P., Ferguson, A. R., Roy, R. R., et al. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.4008 · Cited by 319
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Reviewer #2 (Public Review): Operation regimes of spinal circuits controlling locomotion and role of supraspinal drives and sensory feedback
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“Spinal cord stimulation has been successfully implemented to control chronic pain and improve neurological disorders, including paralysis and non-motor symptoms following SCI [1–8].”
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“In this context, neuromodulation—particularly epidural spinal cord stimulation—has emerged as a promising strategy for reactivating dormant spinal networks and facilitating functional recovery (16, 17, 55).”
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“…which stimulation location and timing are dynamically adjusted across an electrode array to mimic the natural sequence of motor pool activation during a movement cycle—has produced more robust and rapid restoration of walking, including in individuals with chronic, complete paralysis [7,40,41].”
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“…participants—both AIS B (sensory-spared)—only after 81–278 training sessions (1 h each, once or twice daily) over 15–85 weeks (11); Gill et al. (41) reported independent treadmill stepping after complete paraplegia with a similar tonic approach combined with 43 weeks of multimodal…”
Influential
A Comprehensive Narrative Review on Autonomic Nervous System Pathophysiology in Spinal Cord Injury and the Use of Invasive and Non-Invasive Electrical Stimulation for Recovery
Sánchez-Lastra, K. Y., Atie-Harari, R., Castillo-Cuadros, M. F., Cuellar, C. A., & Pliego‐Carrillo, A. C. (2026) · Brain Sciences · doi:10.3390/brainsci16101139
Cascade-targeting delivery of calcium inhibitors for normalizing defective neuronal mitochondria following spinal cord injury
Zhou, P., Zhong, J., Zheng, S., Zhou, L., Zhou, L., Liu, S., Qin, R., Wen, G., 李志忠, Zhu, L., et al. (2026) · Chinese Chemical Letters · doi:10.1016/j.cclet.2026.113539
Restoration of volitional lower-limb movement after motor-complete spinal cord injury with brain-spine interface
Jiang, X., Shi, M., Liu, J., Chen, J., Yu, Y., Hu, F., Sun, W., Mao, L., Lin, Z., Guo, X., et al. (2026) · Med · doi:10.1016/j.medj.2026.101334

Authors: Gill, M. L., Grahn, P. J., Calvert, J. S., Linde, M. B., Lavrov, I. A., Strommen, J. A., Beck, L. A., Sayenko, D. G., Van Straaten, M. G., Drubach, D. I., Veith, D. D., Thoreson, A. R., Lopez, C., Gerasimenko, Y. P., Edgerton, V. R., Lee, K. H., & Zhao, K. D.
Affiliations: Mayo Clinic (US)
Houston Methodist (US)
Russian Academy of Sciences (RU)
University of California, Los Angeles (US)
Corresponding author: Lee, Kendall H.
Zhao, Kristin D.
ORCID: Grahn, Peter J.
Calvert, Jonathan S.
Linde, Margaux B.
Lavrov, Igor A.
Sayenko, Dimitry G.
Veith, Daniel D.
Thoreson, Andrew R.
Lopez, Cesar
Gerasimenko, Yury P.
Edgerton, V. Reggie
Lee, Kendall H.
Zhao, Kristin D.
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2018-09-24
Volume: 24
Issue: 11
Pages: 1677-1682
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-018-0175-7
OpenAlex: W2892074957
Cited by: 574
References: 43
Citations by year: 2026: 51 · 2025: 63 · 2024: 58 · 2023: 81 · 2022: 87 · 2021: 94 · 2020: 72 · 2019: 50 · 2018: 16
FWCI: 44.13
Type: journal article
Language: en
Update notices: correction (2018-10-23)
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: Nature
Topics: Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
Physical Sciences › Engineering › Biomedical Engineering › Prosthetics and Rehabilitation Robotics
Keywords: spinal cord injury, complete paraplegia, epidural stimulation, multimodal rehabilitation, task-oriented training, body weight support, standing, paraplegia
MeSH terms: Adult, Electric Stimulation, Transcutaneous Electric Nerve Stimulation, Electromyography, Humans, Male, Motor Activity, Nerve Net, Paralysis, Paraplegia, Spinal Cord Injuries, Muscle, Skeletal

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Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia

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