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Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

Nature Medicine volume 22, pages 138–145 (2016)Cite this article

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Abstract

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

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Figure 1: Spatiotemporal activation of hindlimb motoneuron during locomotion.
Figure 2: Design, fabrication and validation of spatially selective spinal implants.
Figure 3: Software to adjust spatiotemporal neuromodulation in real-time during locomotion.
Figure 4: Spatiotemporal neuromodulation reproduces the natural pattern of motoneuron activation.
Figure 5: Selective and gradual modulation of extension and flexion components.
Figure 6: Spatiotemporal neuromodulation improves motor control after clinically relevant SCI.

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Acknowledgements

We thank people who have helped over the past 6 years to take care of injured animals and to test multiple iterations of neural implants. We also would like to thank D. Pioletti for providing access to the microcomputed tomography scanner. N.W. is a participant in the Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. Funding was provided by the European Commission's Seventh Framework Programme (CP-IP 258654, NeuWALK, G.C., S.M., E.B., J.B. and P.D.); a Starting Grant from the European Research Council (ERC 261247, Walk Again, G.C.); the Russian Science Foundation (RSF grant 14-15-00788, P.M.) and the Swiss National Science Foundation Centre of Competence in Research (NCCR) in Robotics (G.C., S.L., S.M.), Dynamo project (S.M.) and NanoTera.ch program (SpineRepair) (G.C., S.L. and S.M.).

Author information

Author notes

  1. Nikolaus Wenger, Eduardo Martin Moraud and Jerome Gandar: These authors contributed equally to this work.

Authors and Affiliations

  1. International Paraplegic Foundation Chair in Spinal Cord Repair, Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland

    Nikolaus Wenger, Jerome Gandar, Pavel Musienko, Laetitia Baud, Camille G Le Goff, Quentin Barraud, Natalia Pavlova, Nadia Dominici, Leonie Asboth, Simone Duis, Julie Kreider, Rubia van den Brand & Grégoire Courtine

  2. Department of Neurology with Experimental Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Nikolaus Wenger

  3. Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Nikolaus Wenger

  4. Bertarelli Foundation Chair in Translational Neuroengineering, Center for Neuroprosthetics and Institute of Bioengineering, School of Bioengineering, EPFL, Lausanne, Switzerland

    Eduardo Martin Moraud, Marco Capogrosso, Andrea Mortera, Jack DiGiovanna & Silvestro Micera

  5. Motor Physiology Laboratory, Pavlov Institute of Physiology, St. Petersburg, Russia

    Pavel Musienko & Natalia Pavlova

  6. Laboratory of Neuroprosthetics, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia

    Pavel Musienko

  7. Department of Nonpulmonary Tuberculosis, Lab of Neurophysiology and Experimental Neurorehabilitation, Children's Surgery and Orthopedic Clinic, Institute of Physiopulmonology, St. Petersburg, Russia

    Pavel Musienko

  8. The BioRobotics Institute, Scuola Superiore Sant'Anna, Pisa, Italy

    Marco Capogrosso & Silvestro Micera

  9. MOVE Research Institute Amsterdam, Faculty of Behavioural and Movement Sciences, VU University Amsterdam, Amsterdam, the Netherlands

    Nadia Dominici

  10. Bertarelli Foundation Chair in Neuroprosthetic Technology, Center for Neuroprosthetics and Institute of Bioengineering, EPFL, Lausanne, Switzerland

    Ivan R Minev, Arthur Hirsch & Stéphanie P Lacour

  11. Micromotive GmbH, Mainz, Germany

    Oliver Haverbeck & Silvio Kraus

  12. Fraunhofer Institute for Chemical Technology–Mainz Institute for Microtechnology (ICT–IMM), Mainz, Germany

    Felix Schmitz & Peter Detemple

  13. Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Jocelyne Bloch & Grégoire Courtine

  14. Motac Neuroscience Inc., Beijing, China

    Erwan Bézard

  15. University of Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

    Erwan Bézard

  16. CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

    Erwan Bézard

Authors
  1. Nikolaus Wenger
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  2. Eduardo Martin Moraud
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  3. Jerome Gandar
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Contributions

P.M. and M.C. contributed equally as second authors to this work. N.W., P.M., J.B., N.P. and G.C. developed and performed the surgeries. N.W., E.M.M., J.G., P.M., J.D., L.B., S.D., M.C., L.A. and G.C. performed in vivo experiments. N.W., E.M.M., J.G., C.G.L.G., L.A., N.D. and G.C. analyzed functional data. N.W., E.M.M. and J.G. conducted the statistical analysis. S.P.L., P.D., I.R.M., A.H., P.M., O.H., S.K. and F.S. developed the implant technology. M.C., A.M. and S.M. conducted computational simulations. J.K., Q.B. and N.P. conducted anatomical evaluations. N.W., E.M.M., P.M., M.C., J.D., S.M., E.B. and G.C. conceived experiments. R.v.d.B., E.B., J.B., L.B. and S.D. were responsible for the animal models. N.W., E.M.M., L.A., J.G., C.G.L.G., and G.C. prepared the figures with the help of the other authors. G.C. wrote the manuscript, and all authors contributed to its editing. G.C. supervised and coordinated all the aspects of the work.

Corresponding author

Correspondence to Grégoire Courtine.

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Competing interests

G.C., N.W., P.M., M.C., L.A., J.B., I.R.M., E.M.M., S.M. and S.P.L. hold various patents on electrode implant designs (WO2011/157714), chemical neuromodulation therapies (WO2015/000800), spatiotemporal neuromodulation algorithms (WO2015/063127), and robot-assisted rehabilitation enabled by neuromodulation therapies (WO2013/179230). G.C., S.L., S.M. and J.B. are founders and shareholders of G-Therapeutics SA, a company developing neuroprosthetic systems in direct relationship with the present work.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1–2 (PDF 11392 kb)

Tailored spinal implant to achieve spatial selectivity.

This movie illustrates the spatial distribution of hindlimb motoneurons, the design of spatially selective spinal implant targeting specific subsets of dorsal roots, and the ability of stimulation delivered through this implant to elicit limb and direction specific motor responses (MP4 23363 kb)

Spatiotemporal neuromodulation therapies after complete SCI.

This movie shows the reconstructed spatiotemporal map of motoneuron activation during locomotion in intact rats, the online monitoring system, the complete SCI model, the ability of spatiotemporal neuromodulation to reproduce natural motoneuron activation dynamics during locomotion, and the tuning of extension versus flexion hotspots with increase in stimulation amplitude. (MP4 25020 kb)

Spatiotemporal neuromodulation improves motor control after clinically relevant SCI.

This movie shows the anatomical impact of the contusion SCI, the ability of spatiotemporal neuromodulation to enable robust locomotion early after the injury, and the ability of spatiotemporal neuromodulation to enable locomotion overground and along a staircase in the chronic stage of the SCI. (MP4 27666 kb)

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Wenger, N., Moraud, E., Gandar, J. et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat Med 22, 138–145 (2016). https://doi.org/10.1038/nm.4025

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