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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Data availability

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

Additional information

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

References

  1. 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).

  2. 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).

  3. 3.

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

  4. 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).

  5. 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).

  6. 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).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 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).

  11. 11.

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

  12. 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).

  13. 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).

  14. 14.

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

  15. 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).

  16. 16.

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

  17. 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).

  18. 18.

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

  19. 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).

  20. 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).

  21. 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)..

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 26.

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

  27. 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).

  28. 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).

  29. 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. 30.

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

  31. 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).

  32. 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).

  33. 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).

  34. 34.

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

  35. 35.

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

  36. 36.

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

  37. 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).

  38. 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).

  39. 39.

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

  40. 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).

  41. 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).

  42. 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).

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

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

    • Yury P. Gerasimenko
  8. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    • Kendall H. Lee
    •  & Kristin D. Zhao

Authors

  1. Search for Megan L. Gill in:

  2. Search for Peter J. Grahn in:

  3. Search for Jonathan S. Calvert in:

  4. Search for Margaux B. Linde in:

  5. Search for Igor A. Lavrov in:

  6. Search for Jeffrey A. Strommen in:

  7. Search for Lisa A. Beck in:

  8. Search for Dimitry G. Sayenko in:

  9. Search for Meegan G. Van Straaten in:

  10. Search for Dina I. Drubach in:

  11. Search for Daniel D. Veith in:

  12. Search for Andrew R. Thoreson in:

  13. Search for Cesar Lopez in:

  14. Search for Yury P. Gerasimenko in:

  15. Search for V. Reggie Edgerton in:

  16. Search for Kendall H. Lee in:

  17. Search for Kristin D. Zhao in:

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.

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.

Corresponding authors

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

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–8

  2. Reporting Summary

  3. Supplementary Video 1

    Comparison of trainer-assisted

  4. Supplementary Video 2

    Progression of EES-enabled stepping performance over ground

  5. Supplementary Video 3

    EES-enabled standing and stepping during a single MMR session

About this article

Publication history

Received

Accepted

Published

DOI

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