Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury
Nikolaus Wenger, Eduardo Martin Moraud, Jerome Gandar, Pavel Musienko, Marco Capogrosso, Laetitia Baud, Camille G Le Goff, Quentin Barraud, Natalia Pavlova, Nadia Dominici, Ivan R Minev, Leonie Asboth, Arthur Hirsch, Simone Duis, Julie Kreider, Andrea Mortera, Oliver Haverbeck, Silvio Kraus, Felix Schmitz, Jack DiGiovanna, Rubia van den Brand, Jocelyne Bloch, Peter Detemple, Stéphanie P Lacour, Erwan Bézard, Silvestro Micera, Grégoire Courtine, Nikolaus Wenger, Eduardo Martin Moraud, Jerome Gandar, Pavel Musienko, Marco Capogrosso, Laetitia Baud, Camille G Le Goff, Quentin Barraud, Natalia Pavlova, Nadia Dominici, Ivan R Minev, Leonie Asboth, Arthur Hirsch, Simone Duis, Julie Kreider, Andrea Mortera, Oliver Haverbeck, Silvio Kraus, Felix Schmitz, Jack DiGiovanna, Rubia van den Brand, Jocelyne Bloch, Peter Detemple, Stéphanie P Lacour, Erwan Bézard, Silvestro Micera, Grégoire Courtine
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.
Conflict of interest statement
G.C., N.W., P.M., M.C., A.L., J.V., M.C., I.M., E.M.M., S.M. and S.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 relationships with the present work.
Figures
References
- Borton D, Micera S, Millan Jdel R, Courtine G. Personalized neuroprosthetics. Science translational medicine. 2013;5:210rv212.
- Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron. 2013;77:406–424.
- Barthelemy D, Leblond H, Rossignol S. Characteristics and mechanisms of locomotion induced by intraspinal microstimulation and dorsal root stimulation in spinal cats. Journal of neurophysiology. 2007;97:1986–2000.
- Courtine G, et al. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nature neuroscience. 2009;12:1333–1342.
- van den Brand R, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012;336:1182–1185.
- Holinski BJ, Everaert DG, Mushahwar VK, Stein RB. Real–time control of walking using recordings from dorsal root ganglia. Journal of neural engineering. 2013;10:056008.
- Wenger N, et al. Closed–loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury. Science translational medicine. 2014;6:255ra133.
- Carhart MR, He J, Herman R, D'Luzansky S, Willis WT. Epidural spinal–cord stimulation facilitates recovery of functional walking following incomplete spinal–cord injury. IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society. 2004;12:32–42.
- Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014
- Gerasimenko Y, et al. Noninvasive Reactivation of Motor Descending Control after Paralysis. J Neurotrauma. 2015
- Herman R, He J, D'Luzansky S, Willis W, Dilli S. Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured. Spinal cord. 2002;40:65–68.
- Capogrosso M, et al. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013;33:19326–19340.
- Rattay F, Minassian K, Dimitrijevic MR. Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 2. quantitative analysis by computer modeling. Spinal cord. 2000;38:473–489.
- Ladenbauer J, Minassian K, Hofstoetter US, Dimitrijevic MR, Rattay F. Stimulation of the human lumbar spinal cord with implanted and surface electrodes: a computer simulation study. IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society. 2010;18:637–645.
- Hofstoetter US, et al. Periodic modulation of repetitively elicited monosynaptic reflexes of the human lumbosacral spinal cord. Journal of neurophysiology. 2015 jn 00136 02015.
- Gerasimenko YP, et al. Spinal cord reflexes induced by epidural spinal cord stimulation in normal awake rats. Journal of neuroscience methods. 2006;157:253–263.
- Sayenko DG, Angeli CA, Harkema SJ, Edgerton VR, Gerasimenko YP. Neuromodulation of evoked muscle potentials induced by epidural spinal cord stimulation in paralyzed individuals. Journal of neurophysiology. 2013
- Danner SM, et al. Human spinal locomotor control is based on flexibly organized burst generators. Brain. 2015;138:577–588.
- Edgerton VR, et al. Training locomotor networks. Brain research reviews. 2008;57:241–254.
- Rejc E, Angeli C, Harkema S. Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans. PloS one. 2015;10:e0133998.
- Yakovenko S, Mushahwar V, VanderHorst V, Holstege G, Prochazka A. Spatiotemporal activation of lumbosacral motoneurons in the locomotor step cycle. Journal of neurophysiology. 2002;87:1542–1553.
- Cappellini G, Ivanenko YP, Dominici N, Poppele RE, Lacquaniti F. Migration of motor pool activity in the spinal cord reflects body mechanics in human locomotion. Journal of neurophysiology. 2010;104:3064–3073.
- Ivanenko YP, et al. Temporal components of the motor patterns expressed by the human spinal cord reflect foot kinematics. Journal of neurophysiology. 2003;90:3555–3565.
- Dominici N, et al. Locomotor primitives in newborn babies and their development. Science. 2011;334:997–999.
- Kiehn O. Locomotor circuits in the mammalian spinal cord. Annual review of neuroscience. 2006;29:279–306.
- Berniker M, J A, Bizzi E, Tresch MC. Simplified and effective motor control based on muscle synergies to exploit musculoskeletal dynamics. PNAS. 2009;106:7601–7606.
- Lee DD, Seung HS. Learning the parts of objects by non–negative matrix factorization. Nature. 1999;401:788–791.
- Gaunt RA, Prochazka A, Mushahwar VK, Guevremont L, Ellaway PH. Intraspinal microstimulation excites multisegmental sensory afferents at lower stimulus levels than local alpha–motoneuron responses. Journal of neurophysiology. 2006;96:2995–3005.
- Lavrov I, et al. Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008;28:6022–6029.
- 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. 2004;42:401–416.
- Ichiyama RM, et al. Step training reinforces specific spinal locomotor circuitry in adult spinal rats. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008;28:7370–7375.
- Gad P, et al. Forelimb EMG–based trigger to control an electronic spinal bridge to enable hindlimb stepping after a complete spinal cord lesion in rats. Journal of neuroengineering and rehabilitation. 2012;9:38.
- Bioengineering N.I.o.B.I.a. Framework for a Research Study on Epidural Spinal Stimulation to Improve Bladder, Bowel, and Sexual Function in Individuals with Spinal Cord Injuries. National Institutes of Health; 2015.
- Bizzi E, Tresch MC, Saltiel P, d'Avella A. New perspectives on spinal motor systems. Nat Rev Neurosci. 2000;1:101–108.
- Bernstein N. The co–ordination and regulation of movements. Pergamon Press; Oxford: 1967.
- Giszter SF. Motor primitives–new data and future questions. Current opinion in neurobiology. 2015;33:156–165.
- La Scaleia V, Ivanenko YP, Zelik KE, Lacquaniti F. Spinal motor outputs during step–to–step transitions of diverse human gaits. Frontiers in human neuroscience. 2014;8:305.
- Hagglund M, et al. Optogenetic dissection reveals multiple rhythmogenic modules underlying locomotion. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:11589–11594.
- Levine AJ, et al. Identification of a cellular node for motor control pathways. Nature neuroscience. 2014;17:586–593.
- Tripodi M, Stepien AE, Arber S. Motor antagonism exposed by spatial segregation and timing of neurogenesis. Nature. 2011;479:61–66.
- Grillner S, Jessell TM. Measured motion: searching for simplicity in spinal locomotor networks. Current opinion in neurobiology. 2009;19:572–586.
- Arber S. Motor circuits in action: specification, connectivity, and function. Neuron. 2012;74:975–989.
- Bourane S, et al. Identification of a spinal circuit for light touch and fine motor control. Cell. 2015;160:503–515.
- Hart CB, Giszter SF. A neural basis for motor primitives in the spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30:1322–1336.
- Kargo WJ, Ramakrishnan A, Hart CB, Rome LC, Giszter SF. A simple experimentally based model using proprioceptive regulation of motor primitives captures adjusted trajectory formation in spinal frogs. Journal of neurophysiology. 2010;103:573–590.
- Sayenko DG, Angeli C, Harkema SJ, Edgerton VR, Gerasimenko YP. Neuromodulation of evoked muscle potentials induced by epidural spinal–cord stimulation in paralyzed individuals. J Neurophysiol. 2014;111:1088–1099.
- Zeng FG, Rebscher S, Harrison W, Sun X, Feng H. Cochlear implants: System design, integration, and evaluation. IEEE Rev Biomed Eng. 2008;1:115–142.
- Capaday C. The special nature of human walking and its neural control. Trends in neurosciences. 2002;25:370–376.
- Clarac F, Cattaert D, Le Ray D. Central control components of a 'simple' stretch reflex. Trends in neurosciences. 2000;23:199–208.
- Canbay S, et al. Anatomical relationship and positions of the lumbar and sacral segments of the spinal cord according to the vertebral bodies and the spinal roots. Clinical anatomy. 2014;27:227–233.
- Mariani B, Jimenez MC, Vingerhoets FJ, Aminian K. On–shoe wearable sensors for gait and turning assessment of patients with Parkinson's disease. IEEE Trans Biomed Eng. 2013;60:155–158.
- Afshar P, et al. A translational platform for prototyping closed–loop neuromodulation systems. Frontiers in neural circuits. 2012;6:117.
- Minev IR, et al. Biomaterials. Electronic dura mater for long–term multimodal neural interfaces. Science. 2015;347:159–163.
- Dominici N, et al. Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders. Nature medicine. 2012;18:1142–1147.
- Stieglitz T, Meyer JU. Implantable microsystems. Polyimide–based neuroprostheses for interfacing nerves. Med Device Technol. 1999;10:28–30.
Source: PubMed