Authors: *E. FORMENTO1, M. CAPOGROSSO2, K. MINASSIAN1, F. B. WAGNER1, J.-B. MIGNARDOT1, C. G. M. LE GOFF1, T. MILEKOVIC3, E. BEZARD4,5,6, J. BLOCH7, S. MICERA1, G. COURTINE1;
1École Polytechnique Fédérale De Lausanne, Geneve, Switzerland; 2Dept. of Med., Univ. of Fribourg, Fribourg, Switzerland; 3Fac. of Medicine, Dept. of Basic Neurosci., Univ. of Geneva, Geneva, Switzerland; 4Inst. des Maladies Neurodégénératives, CNRS, Bordeaux, France; 5Inst. des Maladies Neurodégénératives, Univ. of Bordeaux, Bordeaux, France; 6Inst. of Lab. Animal Sciences, China Acad. of Med. Sci., Beijing, China; 7Ctr. Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
Electrical neuromodulation of the spinal cord reversed leg paralysis in rodent and primate models of spinal cord injury (SCI), but has not mediated similar effects in people with paraplegia. Here, we combined computational modelling and experimental procedures in rodents, nonhuman primates and humans to decipher species-specific effects of epidural electrical stimulation (EES) on the production of leg movements. Computer simulations showed that EES interacts with proprioceptive feedback circuits that are naturally modulated during movement and critically contribute to motor pattern formation, both in rodents and humans. However, anatomical differences between rodents and humans dramatically alter these interactions. We found that the probability of antidromic collisions between EES-induced activity and movement-related information augments with the increase in afferent fibers length. Consequently, continuous EES disrupted the modulation of proprioceptive feedback circuits in humans, which strongly diminished the facilitation of movements with EES. We validated these results in rodents and humans with incomplete SCI. While continuous EES enabled robust locomotion in rats, the limited range of functional EES parameters prevented a similar facilitation of gait in humans. Simulations identified two stimulation strategies that effectively limited the cancellation of proprioceptive information. These strategies involved high-frequency low amplitude stimulation, and EES protocols encoding the natural proprioceptive information in the temporal and spatial structure of stimulation. We validated both strategies in nonhuman primates, whose anatomical properties are comparable to humans. While continuous EES induced co-activation of leg muscles, spatiotemporal EES enabled alternating extension and flexion movements of a paralyzed leg. These findings establish a mechanistic framework to design neuromodulation therapies that enable motor control in humans.
E. Formento: None. M. Capogrosso: None. K. Minassian: None. F.B. Wagner: None. J. Mignardot: None. C.G.M. Le Goff: None. T. Milekovic: None. E. Bezard: None. J. Bloch: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA. S. Micera: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA. G. Courtine: E. Ownership Interest (stock, stock options, royalty, receipt of intellectual property rights/patent holder, excluding diversified mutual funds); founder and shareholder of G-Therapeutics SA.
International Foundation for Research in Paraplegia Chair in Spinal Cord Repair
Bertarelli Foundation Chair in Translational Neuroengineering
LINK: Society for Neuroscience