Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia

Nature Medicine volume 24, pages 1677–1682 (2018)Cite this article

Subjects

A Publisher Correction to this article was published on 23 October 2018

This article has been updated

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 paralysis1,2,3. 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Progression of EES-enabled stepping performance on a treadmill.
Fig. 2: Progression of EES-enabled stepping performance over ground.
Fig. 3: Step cycle characteristics during EES-enabled stepping over ground.
Fig. 4: Independent standing and stepping during a single MMR session.

Data availability

Raw and processed datasets are available from the corresponding author upon request.

Change history

  • 23 October 2018

    In the version of this article originally published, Dimitry G. Sayenko’s affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the author, and the rest of the affiliations have been renumbered accordingly. The error has been corrected in the HTML and PDF versions of this article.

References

  1. Harkema, S. 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 377, 1938–1947 (2011).

    Article  Google Scholar 

  2. 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).

    Article  Google Scholar 

  3. van den Brand, R. et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).

    Article  Google Scholar 

  4. 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).

    Article  Google Scholar 

  5. Gerasimenko, Y. P. et al. Epidural spinal cord stimulation plus quipazine administration enable stepping in complete spinal adult rats. J. Neurophysiol. 98, 2525–2536 (2007).

    Article  CAS  Google Scholar 

  6. Ichiyama, R. M., Gerasimenko, Y. P., Zhong, H., Roy, R. R. & Edgerton, V. R. Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation. Neurosci. Lett. 383, 339–344 (2005).

    Article  CAS  Google Scholar 

  7. Lavrov, I. et al. Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats. J. Neurosci. 28, 6022–6029 (2008).

    Article  CAS  Google Scholar 

  8. Capogrosso, M. et al. A brain–spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539, 284–288 (2016).

    Article  Google Scholar 

  9. Wenger, N. et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat. Med. 22, 138–145 (2016).

    Article  CAS  Google Scholar 

  10. 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).

    Article  Google Scholar 

  11. Lavrov, I. et al. Facilitation of stepping with epidural stimulation in spinal rats: role of sensory input. J. Neurosci. 28, 7774–7780 (2008).

    Article  CAS  Google Scholar 

  12. Dimitrijevic, M. R., Gerasimenko, Y. & Pinter, M. M. Evidence for a spinal central pattern generator in humans. Ann. NY Acad. Sci. 860, 360–376 (1998).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Danner, S. M. et al. Human spinal locomotor control is based on flexibly organized burst generators. Brain 138, 577–588 (2015).

    Article  Google Scholar 

  15. Rattay, F., Minassian, K. & Dimitrijevic, M. R. Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 2. quantitative analysis by computer modeling. Spinal Cord 38, 473–489 (2000).

    Article  CAS  Google Scholar 

  16. Kakulas, B. A. Pathology of spinal injuries. Cent. Nerv. Syst. Trauma 1, 117–129 (1984).

    Article  CAS  Google Scholar 

  17. Dimitrijevic, M. R., Dimitrijevic, M. M., McKay, W. B. & Sherwood, A. M. EMG evidence of suprasegmental influence on motor unit activity in paralyzed muscles. Clin. Neurophysiol. 56, S68 (1983).

    Google Scholar 

  18. Dimitrijević, M. R. Residual motor functions in spinal cord injury. Adv. Neurol. 47, 138–155 (1988).

    PubMed  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Dimitrijevic, M. R. et al. Human spinal cord motor control that is partially or completely disconnected from the brain. Am. J. Neuroprot. Neuroregen. 8, 12–26 (2016).

    Article  Google Scholar 

  21. Minassian, K. & Hofstoetter, U. S. Spinal cord stimulation and augmentative control strategies for legmovement after spinal paralysis in humans. CNS Neurosci. Ther. 22, 262–270 (2016)..

    Article  Google Scholar 

  22. Sherwood, A. M., Dimitrijevic, M. R. & McKay, W. B. Evidence of subclinical brain influence in clinically complete spinal cord injury: discomplete SCI. J. Neurol. Sci. 110, 90–98 (1992).

    Article  CAS  Google Scholar 

  23. Field-Fote, E. C. & Roach, K. E. Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: a randomized clinical trial. Phys. Ther. 91, 48–60 (2011).

    Article  Google Scholar 

  24. Harkema, S. J., Schmidt-Read, M., Lorenz, D. J., Edgerton, V. R. & Behrman, A. L. Balance and ambulation improvements in individuals with chronic incomplete spinal cord injury using locomotor training-based rehabilitation. Arch. Phys. Med. Rehabil. 93, 1508–1517 (2012).

    Article  Google Scholar 

  25. Forrest, G. F. et al. Neuromotor and musculoskeletal responses to locomotor training for an individual with chronic motor complete AIS-B spinal cord injury. J. Spinal Cord Med. 31, 509–521 (2008).

    Article  Google Scholar 

  26. Dobkin, B. et al. Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology 66, 484–493 (2006).

    Article  CAS  Google Scholar 

  27. Rejc, E., Angeli, C. A., Bryant, N. & Harkema, S. J. Effects of stand and step training with epidural stimulation on motor function for standing in chronic complete paraplegics. J. Neurotrauma 34, 1787–1802 (2017).

    Article  Google Scholar 

  28. 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).

    Article  Google Scholar 

  29. Rejc, E., Angeli, C. & Harkema, S. Effects of lumbosacral spinal cord epidural stimulation for standing after chronic complete paralysis in humans. PLoS One 10, e0133998 (2015).

  30. Gerasimenko, Y. P. et al. Noninvasive reactivation of motor descending control after paralysis. J. Neurotrauma 32, 1968–1980 (2015).

    Article  Google Scholar 

  31. 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).

    Article  Google Scholar 

  32. Gad, P. et al. Weight bearing over-ground stepping in an exoskeleton with non-invasive spinal cord neuromodulation after motor complete paraplegia. Front. Neurosci. 11, 333 (2017).

    Article  Google Scholar 

  33. Huang, H., He, J., Herman, R. & Carhart, M. R. Modulation effects of epidural spinal cord stimulation on muscle activities during walking. IEEE Trans. Neural. Syst. Rehabil. Eng. 14, 14–23 (2006).

    Article  Google Scholar 

  34. Shah, P. K. & Lavrov, I. Spinal epidural stimulation strategies: clinical implications of locomotor studies in spinal rats. Neuroscientist. 23, 664–680 (2017).

    Article  Google Scholar 

  35. Courtine, G. & Bloch, J. Defining ecological strategies in neuroprosthetics. Neuron 86, 29–33 (2015).

    Article  CAS  Google Scholar 

  36. Moritz, C. T. Now is the critical time for engineered neuroplasticity. Neurotherapeutics 15, 628–634 (2018).

    Article  Google Scholar 

  37. Shah, P. K. et al. Variability in step training enhances locomotor recovery after a spinal cord injury. Eur. J. Neurosci. 36, 2054–2062 (2012).

    Article  Google Scholar 

  38. Behrman, A. L. & Harkema, S. J. Locomotor training after human spinal cord injury: a series of case studies. Phys. Ther. 80, 688–700 (2000).

    CAS  PubMed  Google Scholar 

  39. Harkema, S. J., Behrman, A. L. & Barbeau, H. in Locomotor Training: Principles and Practice, 54–84 (Oxford University Press, Oxford, UK, 2011).

  40. Sayenko, D. G., Angeli, C., Harkema, S. J., Edgerton, V. R. & Gerasimenko, Y. P. Neuromodulation of evoked muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals. J. Neurophysiol. 111, 1088–1099 (2014).

    Article  Google Scholar 

  41. Sayenko, D. G. et al. Spinal segment–specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans. J. Appl. Physiol. 118, 1364–1374 (2015).

    Article  Google Scholar 

  42. Sayenko, D. G. et al. Effects of paired transcutaneous electrical stimulation delivered at single and dual sites over lumbosacral spinal cord. Neurosci. Lett. 609, 229–234 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the participant for his time, effort, and continuous feedback throughout the study. We also thank C. Blaha, J. Chen, B. Cloud, T. Gardner, D. Hare, Y. Li, A. Mendez, C. Mitrovich, A. Schmeling, T. Scrabeck, M. Shaft, C. Stoppel, B. Wessel, and L. Zoecklein as well as the surgical team for their support during EES system implantation. K.H.L. received funding from The Grainger Foundation. K.H.L. and K.D.Z. received funding from the Jack Jablonski Bel13ve in Miracles Foundation, Mayo Clinic Rehabilitation Medicine Research Center, Mayo Clinic Transform the Practice, and Craig H. Neilsen Foundation. P.J.G. was supported by Regenerative Medicine Minnesota and the Mayo Clinic Center for Regenerative Medicine. J.S.C. was supported by the Mayo Clinic Graduate School of Biomedical Sciences. V.R.E. received funding from the Dana and Albert R. Broccoli Charitable Foundation, the Christopher and Dana Reeve Foundation, and the Walkabout Foundation.

Author information

Author notes

  1. These authors contributed equally: Megan L. Gill, Peter J. Grahn.

  2. These authors jointly directed: Kendall H. Lee, Kristin D. Zhao

Authors and Affiliations

  1. Rehabilitation Medicine Research Center, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA

    Megan L. Gill, Margaux B. Linde, Jeffrey A. Strommen, Lisa A. Beck, Meegan G. Van Straaten, Daniel D. Veith, Andrew R. Thoreson, Cesar Lopez, Kendall H. Lee & Kristin D. Zhao

  2. Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA

    Peter J. Grahn, Igor A. Lavrov, Dina I. Drubach & Kendall H. Lee

  3. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA

    Jonathan S. Calvert

  4. Department of Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA

    Igor A. Lavrov

  5. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia

    Igor A. Lavrov

  6. Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA

    Dimitry G. Sayenko, Yury P. Gerasimenko & V. Reggie Edgerton

  7. Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA

    Dimitry G. Sayenko

  8. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia

    Yury P. Gerasimenko

  9. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Kendall H. Lee & Kristin D. Zhao

Authors
  1. Megan L. Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Grahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan S. Calvert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaux B. Linde
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Igor A. Lavrov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeffrey A. Strommen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lisa A. Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimitry G. Sayenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Meegan G. Van Straaten
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dina I. Drubach
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel D. Veith
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrew R. Thoreson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Cesar Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yury P. Gerasimenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. V. Reggie Edgerton
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kendall H. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kristin D. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.R.E., P.J.G., M.L.G., K.H.L., and K.D.Z. initiated the project. V.R.E., D.I.D., Y.P.G., M.L.G., P.J.G., I.A.L., K.H.L., A.R.T., D.G.S., J.A.S., M.G.v.S., and K.D.Z. designed the experiments with contributions from all authors. L.A.B., J.S.C., M.L.G., I.A.L., M.B.L., J.A.S., and K.H.L. performed clinical assessments. L.A.B., M.L.G., M.B.L., J.A.S., D.D.V., and M.G.V.S. designed and performed rehabilitation. V.R.E., Y.P.G., P.J.G., I.A.L., J.A.S., L.A.B., K.H.L., and D.G.S. performed intraoperative assessments, and K.H.L. performed surgical implantation of the device. L.A.B., J.S.C., M.L.G., P.J.G., M.B.L., I.A.L., A.R.T., M.G.V.S., D.D.V., D.G.S., Y.P.G., and V.R.E. contributed to stimulation setting refinement. L.A.B., J.S.C., P.J.G., A.R.T., C.L., M.G.V.S., D.D.V., D.G.S., Y.P.G., V.R.E., M.L.G., I.A.L., K.H.L., K.D.Z., and J.A.S. contributed to data collection, analysis, and interpretation. J.S.C., M.L.G., P.J.G., M.B.L., and I.A.L. drafted the manuscript with subsequent contribution from all authors. K.H.L. and K.D.Z. supervised all aspects of the work.

Corresponding authors

Correspondence to Kendall H. Lee or Kristin D. Zhao.

Ethics declarations

Competing interests

V.R.E. and Y.G. are shareholders in NeuroRecovery Technologies and hold inventorship rights on intellectual property licensed by the regents of the University of California to NeuroRecovery Technologies and its subsidiaries. K.H.L. previously served as a consultant to Medtronic’s Department of Technology Development focused on deep brain stimulation.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8

Reporting Summary

Supplementary Video 1

Comparison of trainer-assisted

Supplementary Video 2

Progression of EES-enabled stepping performance over ground

Supplementary Video 3

EES-enabled standing and stepping during a single MMR session

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gill, M.L., Grahn, P.J., Calvert, J.S. et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat Med 24, 1677–1682 (2018). https://doi.org/10.1038/s41591-018-0175-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-018-0175-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing