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Electrochemical neuromodulation therapies to improve recovery after spinal cord injury

English title Electrochemical neuromodulation therapies to improve recovery after spinal cord injury
Applicant Courtine Grégoire
Number 160696
Funding scheme Sinergia
Research institution Laboratoire de Neurosciences Cognitives Brain Mind Institute Faculté des sciences de la vie
Institution of higher education EPF Lausanne - EPFL
Main discipline Neurology, Psychiatry
Start/End 01.12.2015 - 31.05.2019
Approved amount 1'875'000.00
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All Disciplines (2)

Discipline
Neurology, Psychiatry
Biomedical Engineering

Keywords (7)

Non-human primate; Spinal cord injury; Neuromodulation; Neurorehabilitation; Rat; Neural implant; Locomotion

Lay Summary (French)

Lead
Spinal cord injury (SCI) leads to motor impairments diminishing patients’ quality of life. Over the past decade, the applicants developed innovative spinal implants to deliver electrochemical stimulations that reactivate spinal circuits located below the injury. Robot-assisted rehabilitation enabled by these electrochemical stimulations promoted extensive neuroplasticity of residual neuronal pathways, which restored advanced leg motor control in paralyzed rats. To translate this therapy - the technology and treatment concepts - into a medical application in humans, we will optimize and evaluate our spinal implants, stimulation algorithms, control software and therapeutic concepts in a clinically relevant primate model of SCI. This work in non-human primates is crucial to establish a framework that will facilitate clinical translation.
Lay summary

Les lésions de la moelle épinière conduisent à un éventail de handicaps, y compris les troubles locomoteurs qui diminuent sérieusement la qualité de vie des patients. Durant la dernière décennie, les membres de ce consortium ont développé des implants innovants pour délivrer une neuromodulation électrique et chimique aux circuits de la moelle épinière controllant les membres inférieurs. Cette neuromodulation électrochimique instantanement re-active ces circuits nerveux. L’entraînement thérapeutique facilité par cette neuromodulation électrochimique et des systèmes robotiques induit une neuroplasticité des voies neuronales résiduelles, ce qui rétablie un contrôle moteur des pattes arrière chez les rats paralysés. Le but ultime de ce projet Sinergia est de transférer cette thérapie à une application médicale chez les patients humains. A cet effet, nous optimiserons et évaluerons nos implants spinaux, les algorithmes de stimulation, le logiciel de contrôle et les concepts thérapeutiques dans un modèle de lésion de la moelle épinière primate. Par rapport aux rongeurs, les humains et les primates partagent de nombreuses similitudes en termes de taille, de propriétés de contrôle moteur et de réponses aux lésions. Ce travail chez les primates est donc essentiel afin d'établir un cadre de transfert de savoir qui facilitera l'application de ces technologies et des concepts de traitement chez des patients humains. 

 

Direct link to Lay Summary Last update: 04.11.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.
Squair Jordan W, Gautier Matthieu, Mahe Lois, Soriano Jan Elaine, Rowald Andreas, Bichat Arnaud, Cho Newton, Anderson Mark A, James Nicholas D, Gandar Jerome, Incognito Anthony V, Schiavone Giuseppe, Sarafis Zoe K, Laskaratos Achilleas, Bartholdi Kay, Demesmaeker Robin, Komi Salif, Moerman Charlotte, Vaseghi Bita, Scott Berkeley, Rosentreter Ryan, Kathe Claudia, Ravier Jimmy, McCracken Laura, Kang Xiaoyang, Vachicouras Nicolas, Fallegger Florian, Jelescu Ileana, Cheng YunLong, Li Qin, Buschman Rik, Buse Nicolas, Denison Tim, Dukelow Sean, Charbonneau Rebecca, Rigby Ian, Boyd Steven K, Millar Philip J, Moraud Eduardo Martin, Capogrosso Marco, Wagner Fabien B, Barraud Quentin, Bezard Erwan, Lacour Stéphanie P, Bloch Jocelyne, Courtine Grégoire, Phillips Aaron A (2021), Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury., in Nature, 590(7845), 308-314.
Soft, Implantable Bioelectronic Interfaces for Translational Research.
Schiavone Giuseppe, Fallegger Florian, Kang Xiaoyang, Barra Beatrice, Vachicouras Nicolas, Roussinova Evgenia, Furfaro Ivan, Jiguet Sébastien, Seáñez Ismael, Borgognon Simon, Rowald Andreas, Li Qin, Qin Chuan, Bézard Erwan, Bloch Jocelyne, Courtine Grégoire, Capogrosso Marco, Lacour Stéphanie P (2020), Soft, Implantable Bioelectronic Interfaces for Translational Research., in Advanced materials (Deerfield Beach, Fla.), 32(17), 1906512-1906512.
Corticotectal Projections From the Premotor or Primary Motor Cortex After Cortical Lesion or Parkinsonian Symptoms in Adult Macaque Monkeys: A Pilot Tracing Study.
Fregosi Michela, Contestabile Alessandro, Badoud Simon, Borgognon Simon, Cottet Jérôme, Brunet Jean-François, Bloch Jocelyne, Schwab Martin E, Rouiller Eric M (2019), Corticotectal Projections From the Premotor or Primary Motor Cortex After Cortical Lesion or Parkinsonian Symptoms in Adult Macaque Monkeys: A Pilot Tracing Study., in Frontiers in neuroanatomy, 13, 50-50.
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models.
Hutson Thomas H, Kathe Claudia, Palmisano Ilaria, Bartholdi Kay, Hervera Arnau, De Virgiliis Francesco, McLachlan Eilidh, Zhou Luming, Kong Guiping, Barraud Quentin, Danzi Matt C, Medrano-Fernandez Alejandro, Lopez-Atalaya Jose P, Boutillier Anne L, Sinha Sarmistha H, Singh Akash K, Chaturbedy Piyush, Moon Lawrence D F, Kundu Tapas K, Bixby John L, Lemmon Vance P, Barco Angel, Courtine Gregoire, Di Giovanni Simone (2019), Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models., in Science translational medicine, 11(487), 1-13.
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models.
Hutson Thomas H, Kathe Claudia, Palmisano Ilaria, Bartholdi Kay, Hervera Arnau, De Virgiliis Francesco, McLachlan Eilidh, Zhou Luming, Kong Guiping, Barraud Quentin, Danzi Matt C, Medrano-Fernandez Alejandro, Lopez-Atalaya Jose P, Boutillier Anne L, Sinha Sarmistha H, Singh Akash K, Chaturbedy Piyush, Moon Lawrence D F, Kundu Tapas K, Bixby John L, Lemmon Vance P, Barco Angel, Courtine Gregoire, Di Giovanni Simone (2019), Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models., in Science translational medicine, 11(487), 1-13.
Diversity of Cortico-descending Projections: Histological and Diffusion MRI Characterization in the Monkey.
Innocenti Giorgio M, Caminiti Roberto, Rouiller Eric M, Knott Graham, Dyrby Tim B, Descoteaux Maxime, Thiran Jean-Philippe (2019), Diversity of Cortico-descending Projections: Histological and Diffusion MRI Characterization in the Monkey., in Cerebral cortex (New York, N.Y. : 1991), 29(2), 788-801.
Configuration of electrical spinal cord stimulation through real-time processing of gait kinematics.
Capogrosso Marco, Wagner Fabien B, Gandar Jerome, Moraud Eduardo Martin, Wenger Nikolaus, Milekovic Tomislav, Shkorbatova Polina, Pavlova Natalia, Musienko Pavel, Bezard Erwan, Bloch Jocelyne, Courtine Grégoire (2018), Configuration of electrical spinal cord stimulation through real-time processing of gait kinematics., in Nature protocols, 13(9), 2031-2061.
Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury.
Bonizzato Marco, Pidpruzhnykova Galyna, DiGiovanna Jack, Shkorbatova Polina, Pavlova Natalia, Micera Silvestro, Courtine Grégoire (2018), Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury., in Nature communications, 9(1), 3015-3015.
Changes of motor corticobulbar projections following different lesion types affecting the central nervous system in adult macaque monkeys.
Fregosi Michela, Contestabile Alessandro, Badoud Simon, Borgognon Simon, Cottet Jérôme, Brunet Jean-François, Bloch Jocelyne, Schwab Martin E, Rouiller Eric M (2018), Changes of motor corticobulbar projections following different lesion types affecting the central nervous system in adult macaque monkeys., in The European journal of neuroscience, 48(4), 2050-2070.
Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model.
Schiavone Giuseppe, Wagner Fabien, Fallegger Florian, Kang Xiaoyang, Vachicouras Nicolas, Barra Beatrice, Capogrosso Marco, Bloch Jocelyne, Courtine Gregoire, Lacour Stephanie P (2018), Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model., in Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and, 2018, 1432-1435.
Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion.
Asboth Leonie, Friedli Lucia, Beauparlant Janine, Martinez-Gonzalez Cristina, Anil Selin, Rey Elodie, Baud Laetitia, Pidpruzhnykova Galyna, Anderson Mark A, Shkorbatova Polina, Batti Laura, Pagès Stephane, Kreider Julie, Schneider Bernard L, Barraud Quentin, Courtine Gregoire (2018), Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion., in Nature neuroscience, 21(4), 576-588.
Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord
Capogrosso Marco, Gandar Jerome, Greiner Nathan, Moraud Eduardo Martin, Wenger Nikolaus, Shkorbatova Polina, Musienko Pavel, Minev Ivan, Lacour Stephanie, Courtine Grégoire (2018), Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord, in Journal of Neural Engineering, 15(2), 026024-026024.
Ipsilateral corticotectal projections from the primary, premotor and supplementary motor cortical areas in adult macaque monkeys: a quantitative anterograde tracing study
Fregosi Michela, Rouiller Eric M. (2017), Ipsilateral corticotectal projections from the primary, premotor and supplementary motor cortical areas in adult macaque monkeys: a quantitative anterograde tracing study, in European Journal of Neuroscience, 46(8), 2406-2415.
Corticobulbar projections from distinct motor cortical areas to the reticular formation in macaque monkeys.
Fregosi Michela, Contestabile Alessandro, Hamadjida Adjia, Rouiller Eric M (2017), Corticobulbar projections from distinct motor cortical areas to the reticular formation in macaque monkeys., in The European journal of neuroscience, 45(11), 1379-1395.
A brain–spine interface alleviating gait deficits after spinal cord injury in primates
Capogrosso Marco, Milekovic Tomislav, Borton David, Wagner Fabien, Martin Moraud Eduardo, Mignardot Jean-Baptiste, Buse Nicolas, Gandar Jérome, Xing David, Rey Elodie, Duis Simone, Yang Jianzhong, Ko Wai Kin Daniel, Qin Li, Detemple Peter, Denison Tim, Micera Silvestro, Bezard Erwan, Bloch Jocelyn, Courtine Grégoire (2016), A brain–spine interface alleviating gait deficits after spinal cord injury in primates, in Nature , 284 -288.
Effects of dorsolateral prefrontal cortex lesion on motor habit and performance assessed with manual grasping and control of force in macaque monkeys
Badoud Simon, Borgognon Simon, Cottet Jérome, Chatagny Pauline, Moret Véronique, Fregosi Michaela, Kaeser Mélanie, Fortis Ekaterina, Schmidlin Eric, Bloch Jocelyn, Brunet Jean-François, Rouiller Eric M. (2016), Effects of dorsolateral prefrontal cortex lesion on motor habit and performance assessed with manual grasping and control of force in macaque monkeys, in Brain Structure and Function, 1-14.
The Crossed Projection to the Striatum in Two Species of Monkey and in Humans: Behavioral and Evolutionary Significance
Innocenti Giorgio M., Dyrby Tim B., Andersen Kasper Winther, Rouiller Eric M., Caminiti Roberto (2016), The Crossed Projection to the Striatum in Two Species of Monkey and in Humans: Behavioral and Evolutionary Significance, in Cerebral Cortex, 1-14.

Collaboration

Group / person Country
Types of collaboration
Prof. Patrick Aebischer (EPFL) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Armin Curt (Balgrist University Hospital) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Erwan Bézard (CNRS, Bordeaux) France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
UCB PHARMA Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Prof. Henri-Marcel Hoogewoud (Hôpital Fribourgeois) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Peter Detemple (IMM) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon conference Talk given at a conference Patterned Epidural Stimulation After SCI 16.06.2019 Waterville valley, United States of America Courtine Grégoire;
Gordon Conference Poster Anatomical and functional propreties of the lumbar corticospinal tract in rodents and non-human primates 16.06.2019 Waterville valley, United States of America Bloch Jocelyne; Courtine Grégoire; Rouiller Eric; Barraud Quentin; Galan Katia; Borgognon Simon; Bichat Arnaud;
NeuroFrance Talk given at a conference Targeted neurotechnologies to restore walking after paralysis / Neurotechnologies pour restaurer la marche après une paralysie 22.05.2019 Marseille, France Courtine Grégoire;
Frontiers Forum 2019 - Science Unlimited Talk given at a conference From wheelchair to walking after spinal cord injury 09.05.2019 Montreux, Switzerland Courtine Grégoire;
Society for Neuroscience meeting Poster Noradrenergic pathways and epidural electrical stimulation synergistically modulate proprioceptive feedback circuits in order to restore locomotion after spinal cord injury 03.11.2018 San diego, United States of America Barraud Quentin; Bartholdi Kay Alexander; Courtine Grégoire;
Society for Neuroscience Poster Personalized brain-spine interfaces in freely-behaving non-human primates 03.11.2018 San Diego, United States of America Courtine Grégoire; Borgognon Simon; Rouiller Eric;
spinal research network meeting Talk given at a conference Targeted neurotechnologies enabling walking after paralysis 07.09.2018 London, Great Britain and Northern Ireland Courtine Grégoire;
spinal research network meeting Talk given at a conference Neurotechnologies to improve functional recovery after spinal cord injury 01.09.2017 London, Great Britain and Northern Ireland Barraud Quentin;
Society for Neuroscience, Poster Noradrenergic pathways and epidural electrical stimulation synergistically modulate proprioceptive feedback circuits in order to restore locomotion after spinal cord injury 13.11.2016 San Diego , United States of America Courtine Grégoire; Bartholdi Kay Alexander; Barraud Quentin;
Neurosciences: le cerveau révèle ses secrets, opportunités pour une meilleure qualité de vie“. BioAlps Networking Day 2016 Individual talk Repousser les limites du savoir 02.11.2016 Genève, Switzerland Rouiller Eric;
Colloque des Neurosciences Cliniques, Individual talk “Soft neuroprosthetics: from wearable to implantable interfaces 02.11.2016 Lausanne , Switzerland Lacour Stéphanie;
Training Course in animal experimentation LTK20E, Talk given at a conference “Non-human primates: Swiss context, importance, history and perspectives 05.09.2016 Fribourg , Switzerland Rouiller Eric;


Self-organised

Title Date Place
Translational neuprosthetics 10.06.2017 Fribourg, Switzerland
Translational Neurosciences: Scientific committee 28.03.2017 Fribourg , Switzerland
“Non-human primates”, 05.09.2016 Fribourg, Switzerland
Symposium SM3: Soft Materials for Compliant and Bioinspired Electronics” 28.03.2016 Phoenix, United States of America

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions FESN L'homme cérébral International 2019
Media relations: radio, television Field Trip campus Biotech World Conf of Science journalist International Western Switzerland German-speaking Switzerland 2019
Talks/events/exhibitions Journée des Classes Western Switzerland 2019
Talks/events/exhibitions National Geographic Explorer Festival International 2019
Talks/events/exhibitions SATW TechToday Western Switzerland 2019
Talks/events/exhibitions Soirée de L'espoir IRP Western Switzerland 2019
Talks/events/exhibitions Neuroscience school of advanced studies International 2018
Media relations: print media, online media Take a fantastic 3D voyage through the brain with new immersive virtual reality system Université de Geneve press release Western Switzerland 2017

Awards

Title Year
Robert Bing Prize 2021
HarveyPrize, IET 2020
Rolex Award https://www.rolex.org/fr/rolex-awards/finalists/gregoire-courtine 2019
MIT Technology Review, top ten Breakthrough Technologies 2017

Associated projects

Number Title Start Funding scheme
149902 Dynamic neural network models for the design of neuroprostheses for the therapy of Motor Disorders (DYNAMO) 01.11.2013 Project funding
167912 Design of epidural implants and electrical stimulation protocols for the recovery of ARM control after spinal cord injury (D-ARM) 01.11.2016 Ambizione
149643 Mechanisms of motor recovery from brain lesion 01.10.2013 Project funding
183519 Neuroprosthetic Platform for Personalized and Implantable Systems: Application to Reverse Paralysis and Restore Hearing 01.05.2019 Sinergia
150801 High-density, multi-electrode array recordings in behaving monkeys - Fribourg application 01.10.2014 R'EQUIP
146925 Restoring supraspinal control of locomotion after severe and chronic spinal cord injury 01.07.2013 Project funding

Abstract

CLINICAL PROBLEMSpinal cord injury (SCI) leads to a range of disabilities, including locomotor impairments that seriously diminish patient quality of life. No treatment has shown efficacy to improve recovery after severe SCI. SOLUTIONS DEVELOPPED BY THE APPLICANTS IN RODENT MODELSOver the past decade, the applicants developed a novel electrochemical neuromodulation therapy that instantly transforms spinal circuits from non-functional to highly functional states (Nature Neuro-science, 2012). We used our well-controlled rodent model of severe SCI (Nature Medicine, 2008) to demonstrate that robot-assisted rehabilitation (Nature Medicine, 2012) enabled by this electrochemical neuromodulation therapy restored supraspinal control of locomotion in paralyzed rats. Recovery occurred through the extensive and ubiquitous plasticity of spared neural pathways (Science, 2012). To refine these interventions, the applicants developed an electrochemical spinal implant that exhibits unprecedented bio-integration below the dura mater (Science, 2015); and a control platform that adjusts neuromodulation parameters in real-time based on high-fidelity movement feedback (Science Trans Med, 2014). Using this hardware and software, we designed closed-loop control algorithms that achieve precise adjustment of leg movements during locomotion in rats with complete SCI.CHALLENGES FOR TRANSLATION TO HUMANSOur long-term goal is to translate our hardware, software and therapeutic concepts into medical applications for human patients. However, a series of challenges hinders rapid clinical implementation. (i) The ability of safe chemical agents to modulate the functional state of spinal locomotor circuits is unknown in primates. (ii) Electrochemical implants have been validated in rodents, but additional work is necessary to tailor the implants to the primate spinal cord. (ii) Implementation of closed-loop control policies in clinical settings requires a next-generation implanted pulse generator that is interfaced wirelessly with control software, mediating therapeutic effects. The Sinergia research program will accelerate the resolution of these challenges - and thus the road to clinical applications - through mechanistic work in rodents and translational studies in non-human primates. OBJECTIVESWe propose to address these challenges in three synergistic and highly collaborative projects: PROJECT A: We will conduct experiments in various transgenic mice models to decipher circuit-level mechanisms through which activation of noradrenergic receptors enhances the ability of electrical spinal cord stimulation to facilitate locomotion after SCI. The objective is to design a refined chemical neuromodulation therapy that will be applied to primates in project C-addressing challenge (i). PROJECT B: We will leverage our soft neurotechnology to design, fabricate and validate an electro-chemical spinal implant for primates. Quantification of the natural flexure and mechanics of the spine in freely moving Rhesus monkey will support the optimization of the spine-implant mechanical inter-face. We will conduct anatomical, computational, and functional experiments to tailor implants that achieve spatial selectivity in the modulation of leg movements-addressing challenge (ii). PROJECT C: We will test the hypothesis that the closed-loop electrochemical neuromodulation therapies developed in project A immediately enable locomotion in Rhesus monkeys with moderate SCI, and improve recovery when delivered during rehabilitation. To identify the mechanisms, we will con-duct high-resolution functional and anatomical experiments. First, we will record whole body kinematics, electromyographic activity, and motor cortex modulation during natural walking to gain insights into the reorganization of motor control strategies during the course of rehabilitation. Second, we will use virus-mediated tracing to quantify the reorganization of motor cortex axonal projections in the brainstem and spinal cord after injury, and in response to neuroprosthetic rehabilitation. Together, these activities address challenge (iii), while providing additional safety and mechanistic insights.STRATEGY AND GLOBAL IMPACTTo conduct this Sinergia research program, we gathered an unusually high number of applicants. However, we are convinced that the completion of our multidisciplinary objectives requires the coordinated efforts of translational neuroscientists, electrical engineers, neuroengineers and neurosurgeons. Only through this comprehensive effort that expands beyond isolated projects with short-term goals, can we reach our ultimate ambition: translate our neuroprosthetic platform into clinical applications.
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