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Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis
Open accessAbstract
Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI.
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“However, this recovery required wearable motion sensors to detect motor intentions from residual movements or compensatory strategies to initiate the preprogrammed stimulation sequences5.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“He had previously participated in the STIMO clinical trial (clinicaltrials.gov, NCT02936453), which involved a five-month neurorehabilitation programme supported by targeted epidural electrical stimulation of the spinal cord4,5.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“The delivery of epidural electrical stimulation over the lumbar spinal cord has enabled many individuals with spinal cord injury to regain adaptive control over the activity of otherwise paralysed muscles.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“First, the physiological principles underlying targeted epidural electrical stimulation of the spinal cord have now been validated in nine out nine treated individuals with incomplete4 and complete5 injuries6.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“In turn, recruiting these dorsal root entry zones with preprogrammed spatiotemporal sequences replicates the physiological activation of leg motor pools underlying standing and walking4,5,11,13,14.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“In turn, optimized configurations of anodes and cathodes can steer electric fields towards specific subsets of dorsal root entry zones to modulate well-defined ensembles of motor neuron pools5,9,25.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“This programme enabled him to regain the ability to step with the help of a front-wheel walker.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“Indeed, we were able to configure stimulation programs that restored stepping within one day in three participants with complete sensorimotor paralysis5.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“This recovery has been documented in various independent studies, including in participants with complete sensorimotor paralysis5,6,30–34.”
From Walking naturally after spinal cord injury using a brain–spine interface (2023) · cites this paper as [5]
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“The last three participants were implanted with a new paddle lead that was specifically developed to target the dorsal roots involved in the control of trunk and leg movements18 (ONWARD Medical).”
From The neurons that restore walking after paralysis (2022) · cites this paper as [18]
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Neurocritical care and neuromonitoring considerations in acute pediatric spinal cord injury
Thomas, A. X., & Erklauer, J. (2024) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2024.101122 · Cited by 3
Functional magnetic resonance imaging of the lumbosacral cord during a lower extremity motor task
Kündig, C. W., Finsterbusch, J., Freund, P., & Dávid, G. (2024) · Imaging Neuroscience · doi:10.1162/imag_a_00227 · Cited by 3
“For example, the rostrocaudal location of two muscle projectomes was even found to be inverted in an individual with spinal cord injury ( Rowald et al., 2022).”
Response to “Competing Narratives: Moving the Field Forward on Spinal Cord Stimulation”
Eldabe, S. S., Nevitt, S. J., Bentley, A., Mekhail, N. A., Gilligan, C. J., Billet, B., Staats, P. S., Maden, M., Soliday, N., Leitner, A., et al. (2024) · Clinical Journal of Pain · doi:10.1097/ajp.0000000000001232 · Cited by 3
Wu, N., Wu, Z. Z., Zhang, C., Wu, C., Huo, X., Bai, J., & Zhang, G. (2024) · Scientific Reports · doi:10.1038/s41598-024-81775-3 · Cited by 3
Role of Epidural Electrode Stimulation in Three Patients with Incomplete AIS D Spinal Cord Injury
Chen, Y.-C., Huang, X.-L., Cheng, H.-Y., Wu, C.-C., Wu, M.-Y., Yan, L.-C., Chen, S.-Y., Tsai, S., & Lin, S. (2025) · Biomedicines · doi:10.3390/biomedicines13010155 · Cited by 3
“This study applied EES exclusively to target weak muscles involved in SCI participants, diverging from the spatiotemporal EES used in previous studies [18,28].”
Zheng, Y., Cao, L., Zhao, D., Yang, Q. P., Gu, C., Mao, Y.-R., Zhu, G., Zhu, Y., Zhao, J., & Xu, D. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00628 · Cited by 3
Joshi, K., Smith, N., Rejc, E., Ugiliweneza, B., Harkema, S. J., & Angeli, C. (2025) · Biomedicines · doi:10.3390/biomedicines13020394 · Cited by 3
“Using task-specific scES, Rowald et al. (2022) also observed decreased spinal lordosis and time to perform trunk flexion and extension tasks in individuals with thoracic SCI [16].”
Moncomble, L., Neveu, P., Raimond, C., & Guérout, N. (2025) · Advanced technology in neuroscience . · doi:10.4103/atn.atn-d-24-00021 · Cited by 4
Gao, S., Hu, Y., Li, S., Li, W., & Sheng, W. (2025) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-025-05674-7 · Cited by 3
“Although tough challenges remain, robust clinical evidence supports neuromodulation-induced functional recovery following injury [25].”
Semproni, F., Iacovacci, V., Musco, S., Onorati, S., Ibrahimi, M., & Menciassi, A. (2025) · APL Bioengineering · doi:10.1063/5.0278500 · Cited by 3
Keesey, R., Hofstoetter, U. S., Hu, Z., Lombardi, L., Hawthorn, R., Bryson, N. K., Alashqar, A., Rowald, A., Minassian, K., & Seáñez, I. (2026) · Nature Biomedical Engineering · doi:10.1038/s41551-026-01684-w · Cited by 14
Self-citationLøve, U. S., Kasch, H., Severinsen, K. E., Abrahamsen, J., Høyer, C., Forman, A., & Thomsen, H. H. (2022) · Neuromodulation Technology at the Neural Interface · doi:10.1016/j.neurom.2022.04.044 · Cited by 3
Procyk, E., & Meunier, M. (2022) · Current Research in Neurobiology · doi:10.1016/j.crneur.2022.100051 · Cited by 4
Neurons that promote recovery from paralysis identified
Huang, K. W., & Azim, E. (2022) · Nature · doi:10.1038/d41586-022-02234-5 · Cited by 3
Muscle Tendon Vibration: A Method for Estimating Kinesthetic Perception
Kavounoudias, A., Blanchard, C. C. V., Landelle, C., & Chancel, M. (2023) · Neuromethods · doi:10.1007/978-1-0716-3068-6_3 · Cited by 3
Self-citationModel-Based Nonlinear Control of a Class of Musculoskeletal Systems
Stolpe, R., & Morel, Y. (2023) · Proceedings of the ... American Control Conference/Proceedings of the American Control Conference · doi:10.23919/acc55779.2023.10156647 · Cited by 3
“Emulating the activity corresponding to a foot trajectory, and applying it through EES ([8, 9, 11-13]), one is able to elicit a voluntary sequence of actions supporting a walking pattern.”
BackgroundMethodInfluentialShang, P., Wen, L., Zheng, R., Cheng, R., Gao, Y., Wen, M., & Lin, M. (2024) · Advanced technology in neuroscience . · doi:10.4103/atn.atn-d-24-00001 · Cited by 3
Wang, S., Ma, R., Yuan, Q., Li, H., & Jiang, C. (2025) · IEEE Transactions on Neural Systems and Rehabilitation Engineering · doi:10.1109/tnsre.2025.3561122 · Cited by 3
“Clinical, experimental, and theoretical studies suggested that the therapeutic response to DBS is mainly associated with the axonal activation [33], [34] that electrical stimulation typically activates myelinated axons first, while unmyelinated axons are less likely to be activated [35], [36].”
Neuromechanical Coupling is Reflected in the Spatial Organization of the Spinal Motoneuron PoolsPreprint
Taitano, R. I., Yakovenko, S., & Gritsenko, V. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.09.499432 · Cited by 3
Fusing Electrical Stimulation and Wearable Robots with Humans to Restore and Enhance Mobility
Schauer, T., Fosch‐Villaronga, E., & Moreno, J. C. (2023) · Wiley eBooks · doi:10.1002/9781119857433.ch13 · Cited by 3
The Tabulae Paralytica: Multimodal single-cell and spatial atlases of spinal cord injuryPreprint
Skinnider, M. A., Gautier, M., Teo, A. Y. Y., Kathe, C., Hutson, T. H., Laskaratos, A., de Coucy, A., Regazzi, N., Aureli, V., James, N. D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.23.544348 · Cited by 3
Self-citationReliability of task-based fMRI in the dorsal horn of the human spinal cordPreprint
Dabbagh, A., Horn, U., Kaptan, M., Mildner, T., Müller, R., Lepsien, J., Weiskopf, N., Brooks, J. C. W., Finsterbusch, J., & Eippert, F. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.22.572825 · Cited by 3
Shaping a Collaborative, Sustainable, Accessible, and Reproducible Future for Computational ModelingPreprint
Guidon, M., Kaiser, D., Iavarone, E., Anderegg, S., Bisgaard, M., Bujard, C., Cassara, A. M., Crespo-Valero, P., Drobuliak, M., Fasse, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.12.656959 · Cited by 3
Self-citationAbou, L., Martínez-Navarro, O., & Kratz, A. (2024) · Spinal Cord · doi:10.1038/s41393-024-00984-9 · Cited by 2
“This is because despite the recent growing promising results to regain walking functions using neuromodulation and task-oriented therapy [26, 27], walking is strongly dependent of factors such as subject ’ s age and details of the injury (i.e., motor and sensory areas preserved) [28, 29].”
Human Cervical Epidural Spinal Electrogram Topographically Maps Distinct Volitional Movements
Shukla, P. D., Burke, J. F., Kunwar, N., Presbrey, K. N., Balakid, J. P., Yaroshinsky, M. S., Louie, K. H., Jacques, L. G., Shirvalkar, P. R., & Wang, D. D. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.2258-23.2024 · Cited by 3
Yassine, S., Audet, J., Lecomte, C. G., Mari, S., Merlet, A. N., Harnie, J., Rybak, I. A., Prilutsky, B. I., & Frigon, A. (2025) · Journal of Neurophysiology · doi:10.1152/jn.00331.2025 · Cited by 2
Yan, D., Guo, Z., Liu, H., Wang, X., Liang, F., Jie, J., & Yin, M. (2025) · Scientific Reports · doi:10.1038/s41598-025-19555-w · Cited by 2
“In the future, models could be constructed using MRI and CT scans to increase the complexity of the model and achieve more accurate simulation results 4,46 .”
The effect of device-based neuromodulation on the motor recovery of patients with spinal cord injury
Li, J., Chen, T., Yan, X., & Luo, L. (2025) · Spinal Cord · doi:10.1038/s41393-025-01133-6 · Cited by 2
“…effects in restoring control over motor and autonomic functions above the spinal cord, even in patients with long-term injuries [56]. eSCS enabled three patients with chronic complete paralysis to regain standing, walking, cycling, swimming, and trunk control abilities within one day [57].”
Repurposing of Chemokine Antagonists for Combined Phase‐Resolved Spinal Cord Injury Treatment
Belogurov, A. A., Telegin, G. B., Чернов, А. С., Kudriaeva, A. A., Minakov, A. N., Rodionov, M. V., Kazakov, V. A., Паликов, В. А., Poluektov, Y. M., Ziganshin, R., et al. (2025) · Advanced Science · doi:10.1002/advs.202516569 · Cited by 2
Mo, L., Chen, L., Liao, Y., Ren, Y., Li, B., Song, Z., Xu, W., Liang, F., Fan, Q., Han, X., et al. (2025) · BIO Integration · doi:10.15212/bioi-2025-0171 · Cited by 2
“Second, the current amplitude of EES used to elicit the passive movements in this study was higher than the sensation threshold, which is the same as previously reported [2, 5].”
Wankner, M., Visser-Vandewalle, V. E. R. M., Andrade, P., & Heiden, P. (2026) · Life · doi:10.3390/life16010179 · Cited by 3
“In individuals with chronic motor-complete paraplegia, lumbosacral epidural stimulation combined with intensive rehabilitation has enabled weight-bearing standing, volitional control of paralyzed muscles, and even overground walking [11–13].”
Mirkiani, S., O’Sullivan, C. L., Arefadib, A., Tyreman, N., Sari, K., Wilson, D., Tawakol, O., Troyk, P. R., Fox, R., & Mushahwar, V. K. (2026) · Scientific Reports · doi:10.1038/s41598-026-42212-9 · Cited by 2
“The relatively low selectivity of eSCS also requires time-consuming mapping procedures to identify optimal electrode layout and anode–cathode configurations 8,10 .”
InfluentialPromises and performance in brain–machine interfaces: will AI be our saviour?
Saldanha, P., Vaupel, M., Dunn, B. A., & Whitlock, J. R. (2026) · The European Physical Journal Special Topics · doi:10.1140/epjs/s11734-026-02169-2 · Cited by 2
“While Meta, Neuralink, and Synchron are prominent players, many others in academia and industry are pushing the frontiers [10, 11, 28, 30, 42, 45].”
Nanomaterial-enabled physical rehabilitation: mechanisms, evidence, and translational pathways
Niazi, S. K. (2026) · Frontiers in Rehabilitation Sciences · doi:10.3389/fresc.2026.1763655 · Cited by 2
“When combined with epidural electrical stimulation, these materials amplified functional improvements compared with stimulation alone (90).”
The optimization of neuroprosthetic interfaces relying on biophysical and surrogate digital twins
Verardo, C., Fossati, V., Toni, L., Pierantoni, L., Losanno, E., Agnesi, F., & Romeni, S. (2026) · npj Biomedical Innovations. · doi:10.1038/s44385-026-00076-8 · Cited by 4
Xie, F., Bai, C., Luan, X., & Xu, J. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1861870 · Cited by 2
“In contrast, spatiotemporally targeted stimulation activates appropriate dorsal roots during specific gait phases and better preserves the physiological sensorimotor loop (15, 16, 22).”
InfluentialLima, M. A. B., Menezes, K., Xerez, D. R., Côrtes, B. A., Menezes, J. R. L., de Holanda, G. S., Silva, A. D., Leite, E. S., Franco, O. B., de Faria, M. A. A. M., et al. (2026) · Spinal Cord · doi:10.1038/s41393-026-01238-6 · Cited by 3
Metadata
- Authors
- Rowald, A., Komi, S., Demesmaeker, R., Baaklini, E., Hernandez-Charpak, S. D., Paoles, E., Montanaro, H., Cassara, A., Becce, F., Lloyd, B., Newton, T., Ravier, J., Kinany, N., D’Ercole, M., Paley, A., Hankov, N., Varescon, C., McCracken, L., Vat, M., Caban, M., Watrin, A., Jacquet, C., Bole-Feysot, L., Harte, C., Lorach, H., Galvez, A., Tschopp, M., Herrmann, N., Wacker, M., Geernaert, L., Fodor, I., Radevich, V., Van Den Keybus, K., Eberle, G., Pralong, E., Roulet, M., Ledoux, J.-B., Fornari, E., Mandija, S., Mattera, L., Martuzzi, R., Nazarian, B., Benkler, S., Callegari, S., Greiner, N., Fuhrer, B., Froeling, M., Buse, N., Denison, T., Buschman, R., Wende, C., Ganty, D., Bakker, J., Delattre, V., Lambert, H., Minassian, K., van den Berg, C. A. T., Kavounoudias, A., Micera, S., Van De Ville, D., Barraud, Q., Kurt, E., Kuster, N., Neufeld, E., Capogrosso, M., Asboth, L., Wagner, F. B., Bloch, J., & Courtine, G.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- ETH Zurich (CH)
- Foundation for Research on Information Technologies in Society (CH)
- Scuola Superiore Sant'Anna (IT)
- École Polytechnique Fédérale de Lausanne (CH)
- University Medical Center Utrecht (NL)
- Centre National de la Recherche Scientifique (FR)
- Medtronic (United States) (US)
- Technical University of Munich (DE)
- Medical University of Vienna (AT)
- Radboud University Medical Center (NL)
- University of Fribourg (CH)
- Corresponding author
- Bloch, Jocelyne
- Courtine, Grégoire
- ORCID
- Rowald, Andreas
- Komi, Salif
- Demesmaeker, Robin
- Baaklini, Edeny
- Hernandez-Charpak, Sergio Daniel
- Montanaro, Hazael
- Cassara, Antonino
- Becce, Fabio
- Lloyd, Bryn
- Newton, Taylor
- Kinany, Nawal
- Hankov, Nicolas
- Varescon, Camille
- McCracken, Laura
- Caban, Miroslav
- Lorach, Henri
- Fodor, Isabelle
- Eberle, Grégoire
- Ledoux, Jean-Baptiste
- Fornari, Eleonora
- Mandija, Stefano
- Martuzzi, Roberto
- Nazarian, Bruno
- Callegari, Simone
- Greiner, Nathan
- Fuhrer, Benjamin
- Froeling, Martijn
- Buschman, Rik
- Minassian, Karen
- Kavounoudias, Anne
- Micera, Silvestro
- Van De Ville, Dimitri
- Barraud, Quentin
- Kurt, Erkan
- Kuster, Niels
- Neufeld, Esra
- Capogrosso, Marco
- Asboth, Leonie
- Wagner, Fabien B.
- Bloch, Jocelyne
- Courtine, Grégoire
- Venue
- Nature Medicine
- Published
- 2022-02
- Volume
- 28
- Issue
- 2
- Pages
- 260-271
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W4210917455
- Cited by
- 455
- References
- 72
- Citations by year
- 2026: 83 · 2025: 113 · 2024: 94 · 2023: 93 · 2022: 72
- FWCI
- 62.99
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- CINECA IRIS Institutional Research Information System (Sant'Anna School of Advanced Studies) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Keywords
- epidural stimulation, spinal cord injury, complete paralysis, dorsal root stimulation, neurorehabilitation, swimming, standing
- MeSH terms
- Humans, Leg, Paralysis, Spinal Cord, Spinal Cord Injuries, Walking, Spinal Cord Stimulation
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