A brain-spine interface alleviating gait deficits after spinal cord injury in primates
Marco Capogrosso, Tomislav Milekovic, David Borton, Fabien Wagner, Eduardo Martin Moraud, Jean-Baptiste Mignardot, Nicolas Buse, Jerome Gandar, Quentin Barraud, David Xing, Elodie Rey, Simone Duis, Yang Jianzhong, Wai Kin D Ko, Qin Li, Peter Detemple, Tim Denison, Silvestro Micera, Erwan Bezard, Jocelyne Bloch, Grégoire Courtine, Marco Capogrosso, Tomislav Milekovic, David Borton, Fabien Wagner, Eduardo Martin Moraud, Jean-Baptiste Mignardot, Nicolas Buse, Jerome Gandar, Quentin Barraud, David Xing, Elodie Rey, Simone Duis, Yang Jianzhong, Wai Kin D Ko, Qin Li, Peter Detemple, Tim Denison, Silvestro Micera, Erwan Bezard, Jocelyne Bloch, Grégoire Courtine
Abstract
Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis. Theoretically, this strategy could also restore control over leg muscle activity for walking. However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges. Recently, it was shown in rats that epidural electrical stimulation of the lumbar spinal cord can reproduce the natural activation of synergistic muscle groups producing locomotion. Here we interface leg motor cortex activity with epidural electrical stimulation protocols to establish a brain-spine interface that alleviated gait deficits after a spinal cord injury in non-human primates. Rhesus monkeys (Macaca mulatta) were implanted with an intracortical microelectrode array in the leg area of the motor cortex and with a spinal cord stimulation system composed of a spatially selective epidural implant and a pulse generator with real-time triggering capabilities. We designed and implemented wireless control systems that linked online neural decoding of extension and flexion motor states with stimulation protocols promoting these movements. These systems allowed the monkeys to behave freely without any restrictions or constraining tethered electronics. After validation of the brain-spine interface in intact (uninjured) monkeys, we performed a unilateral corticospinal tract lesion at the thoracic level. As early as six days post-injury and without prior training of the monkeys, the brain-spine interface restored weight-bearing locomotion of the paralysed leg on a treadmill and overground. The implantable components integrated in the brain-spine interface have all been approved for investigational applications in similar human research, suggesting a practical translational pathway for proof-of-concept studies in people with spinal cord injury.
Conflict of interest statement
The authors declare competing financial interests: G.C., D.B., M.C., S.M., E.M.M. and J.B. hold various patents in relation with the present work. T.D. and N.B are Medtronic employees. In review of the manuscript they contributed to technical accuracy but did not influence the results or the content of the manuscript. E.B. reports personal fees from Motac Neuroscience Ltd UK and is a shareholder of Motac Holding UK and Plenitudes SARL France. G.C., S.M. and J.B. are founders and shareholders of G–Therapeutics BV.
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References
- Ethier C, Oby ER, Bauman MJ, Miller LE. Restoration of grasp following paralysis through brain-controlled stimulation of muscles. Nature. 2012;485:368–371. doi: 10.1038/nature10987.
- Collinger JL, et al. High-performance neuroprosthetic control by an individual with tetraplegia. Lancet. 2013;381:557–564. doi: 10.1016/S0140-6736(12)61816-9.
- Hochberg LR, et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature. 2012;485:372–375. doi: 10.1038/nature11076.
- Bouton CE, et al. Restoring cortical control of functional movement in a human with quadriplegia. Nature. 2016 doi: 10.1038/nature17435.
- Mushahwar VK, Guevremont L, Saigal R. Could cortical signals control intraspinal stimulators? A theoretical evaluation. IEEE Trans Neural Syst Rehabil Eng. 2006;14:198–201. doi: 10.1109/TNSRE.2006.875532.
- Ho CH, et al. Functional electrical stimulation and spinal cord injury. Physical medicine and rehabilitation clinics of North America. 2014;25:631–654. doi: 10.1016/j.pmr.2014.05.001. ix.
- Kapadia N, et al. A randomized trial of functional electrical stimulation for walking in incomplete spinal cord injury: Effects on walking competency. J Spinal Cord Med. 2014;37:511–524. doi: 10.1179/2045772314Y.0000000263.
- 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. doi: 10.1126/scitranslmed.3008325.
- Wenger N, et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nature medicine. 2016;22:138–145. doi: 10.1038/nm.4025.
- Moraud EM, et al. Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury. Neuron. 2016;89:814–828. doi: 10.1016/j.neuron.2016.01.009.
- Sherrington C. Flexion-reflex of the limb, crossed extension reflex, and reflex stepping and standing. J Physiol (Lond) 1910;40:28–121.
- Kiehn O. Decoding the organization of spinal circuits that control locomotion. Nat Rev Neurosci. 2016;17:224–238. doi: 10.1038/nrn.2016.9.
- Holinski BJ, Everaert DG, Mushahwar VK, Stein RB. Real-time control of walking using recordings from dorsal root ganglia. J Neural Eng. 2013;10:056008. doi: 10.1088/1741-2560/10/5/056008.
- Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain : a journal of neurology. 2014;137:1394–1409. doi: 10.1093/brain/awu038.
- Gerasimenko Y, et al. Noninvasive Reactivation of Motor Descending Control after Paralysis. J Neurotrauma. 2015 doi: 10.1089/neu.2015.4008.
- Danner SM, et al. Human spinal locomotor control is based on flexibly organized burst generators. Brain : a journal of neurology. 2015 doi: 10.1093/brain/awu372.
- Barthelemy D, Leblond H, Rossignol S. Characteristics and mechanisms of locomotion induced by intraspinal microstimulation and dorsal root stimulation in spinal cats. J Neurophysiol. 2007;97:1986–2000. doi: 10.1152/jn.00818.2006. 00818.2006 [pii]
- Shenoy KV, Carmena JM. Combining Decoder Design and Neural Adaptation in Brain-Machine Interfaces. Neuron. 2014;84:665–680. doi: 10.1016/j.neuron.2014.08.038.
- Shanechi MM, Hu RC, Williams ZM. A cortical-spinal prosthesis for targeted limb movement in paralysed primate avatars. Nature communications. 2014;5:3237. doi: 10.1038/ncomms4237.
- Zimmermann JB, Jackson A. Closed-loop control of spinal cord stimulation to restore hand function after paralysis. Frontiers in neuroscience. 2014;8:87. doi: 10.3389/fnins.2014.00087.
- Nishimura Y, Perlmutter SI, Eaton RW, Fetz EE. Spike-timing-dependent plasticity in primate corticospinal connections induced during free behavior. Neuron. 2013;80:1301–1309. doi: 10.1016/j.neuron.2013.08.028.
- Lemon RN. Descending pathways in motor control. Annu Rev Neurosci. 2008;31:195–218. doi: 10.1146/annurev.neuro.31.060407.125547.
- Friedli L, et al. Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates. Science translational medicine. 2015;7:302ra134. doi: 10.1126/scitranslmed.aac5811.
- Courtine G, et al. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? Nature medicine. 2007;13:561–566.
- Yin M, et al. Wireless Neurosensor for Full-Spectrum Electrophysiology Recordings during Free Behavior. Neuron. 2014;84:1170–1182. doi: 10.1016/j.neuron.2014.11.010.
- Yakovenko S, Mushahwar V, VanderHorst V, Holstege G, Prochazka A. Spatiotemporal activation of lumbosacral motoneurons in the locomotor step cycle. J Neurophysiol. 2002;87:1542–1553.
- 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.
- van den Brand R, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012;336:1182–1185. doi: 10.1126/science.1217416.
- Courtine G, Bloch J. Defining ecological strategies in neuroprosthetics. Neuron. 2015;86:29–33. doi: 10.1016/j.neuron.2015.02.039.
- Shoham S, Halgren E, Maynard EM, Normann RA. Motor-cortical activity in tetraplegics. Nature. 2001;413:793. doi: 10.1038/35101651.
- Courtine G, et al. Kinematic and EMG determinants in quadrupedal locomotion of a non-human primate (Rhesus) J Neurophysiol. 2005;93:3127–3145.
- Fraser GW, Chase SM, Whitford A, Schwartz AB. Control of a brain-computer interface without spike sorting. J Neural Eng. 2009;6:055004. doi: 10.1088/1741-2560/6/5/055004. S1741-2560(09)06199-0 [pii]
- Hochberg LR, et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature. 2012;485:372–375. -supplementary-information.
- Gilja V, et al. Clinical translation of a high-performance neural prosthesis. Nature medicine. 2015 doi: 10.1038/nm.3953.
- Aflalo T, et al. Neurophysiology. Decoding motor imagery from the posterior parietal cortex of a tetraplegic human. Science. 2015;348:906–910. doi: 10.1126/science.aaa5417.
- Milekovic T, Ball T, Schulze-Bonhage A, Aertsen A, Mehring C. Detection of Error Related Neuronal Responses Recorded by Electrocorticography in Humans during Continuous Movements. PLoS One. 2013;8:e55235. doi: 10.1371/journal.pone.0055235.
- Marieb EN. Human Anatomy & Physiology Hardcover. 6th edition edn. Pearson Education; 2003.
- Kuypers HGJM. Comprehensive Physiology. John Wiley & Sons, Inc; 2011.
Source: PubMed