<p>The loss of the ability to walk as the result of neurological injury or disease critically impacts the mobility and everyday lifestyle of millions. The World Heath Organization (WHO) estimates that approximately 1% of the world's population needs the use of a wheelchair to assist their personal mobility. Advances in the field of brain-machine interfaces (BMIs) have recently demonstrated the feasibility of using neuroprosthetics to extract motor information from cortical ensembles for more effective control of upper-limb replacements. However, the promise of BMIs has not yet been brought to bear on the challenge of restoring the ability to walk. A future neuroprosthesis designed to restore walking would need two streams of information flowing between the user's brain and the device. First, the motor control signals would have to be extracted from the brain, allowing the robotic prosthesis to behave in the manner intended by the user. Second, and equally important would be the flow of sensory and proprioceptive information back to the user from the neuroprosthesis. Here, I contribute to the foundation of such a bi-directional brain machine interface for the restoration of walking in a series of experiments in two animal models, designed to show the feasibility of (1) extracting locomotor information from neuronal ensemble activity and (2) sending information back into the brain via cortical microstimulation. </p><p>In a set of experiments designed to investigate the extraction of locomotor parameters, I chronically recorded from ensembles of neurons in primary motor (M1) and primary somatosensory (S1) cortices in two adult female rhesus macaques as they walked bipedally, at various speeds, both forward and backward on a custom treadmill. For these experiments, rhesus monkeys were suitable because of their ability to walk bipedally in a naturalistic manner with training. I demonstrate that the kinematics of bipedal walking in rhesus macaques can be extracted from neuronal ensemble recordings, both offline and in real-time. The activity of hundreds of neurons was processed by a series of linear decoders to extract accurate predictions of leg joints in three dimensional space, as well as leg muscle electromyograms (EMGs). Using a multi-layered switching model allowed us to achieve increased extraction accuracy by segregating different behavioral modes of walking.</p><p>In a second set of experiments designed to investigate the usage of microstimulation as a potential artificial sensory channel, I instructed two adult female Aotus trivirgatus (owl monkeys) about the location of a hidden food reward using a series of cortical microstimulation patterns delivered to primary somatosensory (S1) cortex. The owl monkeys discriminated these microstimulation patterns and used them to guide reaching movements to one of two targets. Here, owl monkeys were used which were previously implanted with electrode arrays of high longevity and stability. These monkeys were previously trained on a somatosensory cued task, which allowed a quick transition to microstimulation cueing. The owl monkeys learned to interpret microstimulation patterns, and their skill and speed of learning new patterns improved over several months. Additionally, neuronal activity recorded on non-stimulated electrodes in motor (M1), premotor (PMD) and posterior parietal (PP) cortices allowed us to examine the immediate neural responses to single biphasic stimulation pulses as well as overall responses to the spatiotemporal pattern. Using this recorded neuronal activity, I showed the efficacy of several linear classification algorithms during microstimulation. </p><p>These results demonstrate that locomotor kinematic parameters can be accurately decoded from the activity of neuronal ensembles, that multichannel microstimulation is a viable information channel for sensorized prosthetics, and that the technical limitations of combining these techniques can be overcome. I propose that bi-directional BMIs integrating these techniques will one day restore the ability to walk to severely paralyzed patients.</p> / Dissertation

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Spinal cord injury causes the partial or total loss of the anatomical and functional continuity of the spinal cord tissue, leading to the damage of the organs controlled by nerves that branch off downstream the injury. This thesis analyses the mechanics of two possible treatments based on two different approaches: intraspinal microstimulation (ISMS) and tissue engineering. These two approaches have a common rationale, the delivery of electrical stimuli to the injured spinal cord. In the literature, the feasibility of the electrodes for ISMS is often limited to the analysis of stiffness. The mechanical validation of the device is then focused on the step after the in vivo implantation, considering the interplay with the surrounding tissue. In this work, the mechanical performance of an innovative intraspinal microstimulation device is evaluated thoroughly before the in vivo step, to avoid the waste of material, animals, and time. The study involves the characterisation of the single components (electrodes), prototypes, and possible failure mechanisms. A work on silk fibroin hydrogels for the regeneration of the spinal cord is also presented. Silk fibroin is a highly versatile material for biomedical purposes, and thus largely used in tissue engineering. Moreover, it has piezolectric properties subjected to micro and nanostructure. Given the proven benefits of electrical stimulation in the regeneration of the spinal cord after injury, different approaches studied in literature often require the use of external devices to generate electrical stimuli. This thesis aims to study the mechanical properties of silk fibroin hydrogels obtained by applying an electric field to silk fibroin solutions, to investigate the eventual increase of the microstructure orientation and consequent improvement of the piezoelectric effects of fibroin.

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Bien que la plasticité ipsilesionnelle suite à un accident vasculo-cérébral (AVC) soit bien établie, la réorganisation du cortex contralésionnel et son effet sur la récupération fonctionnelle restent toujours non élucidés. Les études publiées présentent des points de vue contradictoires sur le rôle du cortex contralésionnel dans la récupération fonctionnelle. La taille de lésion pourrait être le facteur déterminant la réorganisation de ce dernier. Le but principal de cette étude fut donc d’évaluer l’effet des AVC de tailles différentes dans la région caudal forelimb area (CFA) du rat sur la réorganisation physiologique et la récupération comportementale de la main. Suite à une période de récupération spontanée pendant laquelle la performance motrice des deux membres antérieurs fut observée, les cartes motrices bilatérales du CFA et du rostral forelimb area (RFA) furent obtenues. Nous avons trouvé que le volume de lésion était en corrélation avec le niveau de récupération comportementale et l’étendue de la réorganisation des RFA bilatéraux. Aussi, les rats ayant de grandes lésions avaient des plus grandes représentations de la main dans le RFA de l’hémisphère ipsilésionnel et un déficit de fonctionnement plus persistant de la main parétique. Dans l’hémisphère contralésionnel nous avons trouvé que les rats avec des plus grandes représentations de la main dans le RFA avaient des lésions plus grandes et une récupération incomplète de la main parétique. Nos résultats confirment l’effet du volume de lésion sur la réorganisation du cortex contralésionnel et soulignent que le RFA est l’aire motrice la plus influencée dans le cortex contralésionnel. / While our understanding of ipsilesional plasticity and its role in recovery of hand function following ischemic stroke has increased dramatically, the reorganization of the contralesional motor cortex and its effect on recovery remain unclear. Currently published studies offer contradictory views on the role of contralesional motor cortex in recovery. Lesion extent has been suggested as the factor determining the type of reorganization of the contralesional motor cortex. The primary goal of this study was thus to evaluate the effect of unilateral strokes of different sizes in caudal forelimb area (CFA) of the rat on both physiological reorganization and behavioral recovery. At the end of a period of spontaneous recovery during which we monitored motor performance of both limbs, we obtained bilateral maps of the CFA and the putative premotor area of the rat – rostral forelimb area (RFA). We found that lesion volume in the CFA correlates with both the extent of behavioral recovery of the paretic hand and the extent of both ipsi and contralesional cortical reorganization. We found that rats with bigger lesions had larger hand representations in the ipsilesional hemisphere and more persistent deficits of the paretic hand. In the contralesional hemisphere we found that rats with larger hand representation in the RFA had bigger lesions and incomplete recovery of the paretic hand. Our results confirm the effect of lesion volume on the reorganization of the contralesional motor cortex and highlight contralesional RFA as the motor cortical area most influenced by lesion volume for future investigations.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Undulatory locomotion is a common and powerful strategy used in nature at different biological scales by a broad range of living organisms, from flagellated bacteria to prehistoric snakes, which have overcome the complexity of living in ”flowable” media. By taking inspiration from this evolution-induced strategy, we aim at modelling the locomotion in a granular and viscous environment with the objective to provide more insights for designing robots for soil-like media exploration. Moreover, in contrast to common types of movement, the granular locomotion is still not well understood and is an open and challenging field. We approached this phenomenon with several tools: (i.) numerically, via coupling the Finite Element Method (FEM) with the Discrete Element Method (DEM) using ABAQUS; (ii.) analytically, by employing the Lagrangian formalism to derive the equations of motion of a discrete and continuous system subject to non-conservative forces, and (iii.) experimentally, by creating an ad-hoc set up in order to observe the migration of microfibres used for the treatment of spinal cord injuries. The computational attempts to model the motion in a granular medium involved the simulation of the dynamics of an elastic beam (FEM) surrounded by rigid spherical particles (DEM). A propulsion mechanism was introduced by sinusoidally forcing the beam’s tip normally to the longitudinal axis, while the performance of the locomotion was evaluated by means of a parametric study. Depending on the parameters of the external excitation, after a transient phase, the slender body reached a steady-state with a constant translational velocity. In order to gain physical insights, we studied a simplified version of the previous continuous beam by introducing a discrete multi-bar system. The dynamics of the latter was analytically derived, by taking into account the forces exchanged between the locomotor and the environment, according to the Resistive Force Theory. By numerically solving the equations of motion and evaluating the input energy and dissipations, we were able to define the efficiency and thus provide an effective tool to optimise the locomotion. It is worth mentioning that the two approaches, despite the different physical hypothesis, show a qualitatively and quantitatively good accordance. The numerical and analytical models previously analysed have shown promising results for the interpretation of "ad-hoc" experiments that demonstrate the migration of a microfibre embedded in a spinal cord-like matrix. This migration needs to be avoided, once the regenerative microfibre is implanted in the lesioned spinal cord, for the sake of the patients health.

Pour comprendre comment le cortex cérébral extrait du sens et produit des actions à partir des informations sensorielles, il est nécessaire de comprendre à la fois son architecture et ses états dynamiques. Dans la présente thèse nous avons abordé cette relation structure-fonction au niveau des aires cérébrales, leurs connections et leurs interactions au sein du réseau cortical. Les aires sont connectées entre elles par deux grands types de projections axonales. D'une part, les connections « feedforward » (littéralement « antéroactives ») transmettent l'information des aires sensorielles aux aires de plus haut niveau dans la hiérarchie corticale et dont l'activité sous-tend des représentations plus abstraites. À l'inverse, les connections feedback (rétroactives) relient des aires dans la direction descendante de la hiérarchie corticale, vers les aires sensorielles primaires. Pour explorer les rôles respectifs des connections feedforward et feedback nous avons utilisé une triple approche. Premièrement, nous avons mis en évidence une asymétrie fonctionnelle très nette entre propagation feedforward et feedback grâce à des enregistrements et de la microstimulation électrique dans les aires V1 et V4 de macaques en comportement. D'autre part, nous avons étudié les propriétés globales du réseau cortical grâce à une riche base de données de connectivité basée sur des injections de traceurs fluorescents, et décrit une propriété générale et fondamentale de l'organisation corticale. Enfin, nous avons combiné des propriétés anatomiques des aires corticales et les données de connectivité dans un modèle dynamique à grande échelle du cortex / To understand how the cerebral cortex does what it does, it is necessary to elucidate both how its dynamic states are correlated with the functions it performs, and how it is organised. Many functional and anatomical gradients have been described that reflect the hierarchical abstraction at the heart of cortical computation. It was showed that two flavours of cortical connections exist, and that in the visual cortex they happen to transport information in opposite directions along this gradient. It was also hypothesised that other modalities exhibit the same type of gradient in their respective domains. However, studying requires knowledge of the architecture at different levels (such as the cortical column) and a causal understanding of the functional properties of these types of connections. First, we have studied the dynamics of both feedforward and feedback propagation in the visual system of awake, behaving macaque monkeys. Using the causal method of electrical microstimulation and recording, we have found a dynamic signature of each type of projections and an asymmetry in the way each type of input interacts with ongoing activity in a given visual area. Secondly, thanks to a rich and systematic data set in the macaque, we have found a fundamental organisational principle of the embedded and weighted cortical network that holds also in the more detailed level of neuronal connections inside an area. Finally, we have combined known anatomical gradients with actual inter-areal connectivity into a dynamic model, and here we show how it relates to both the ordering of areas along a hierarchical gradient and the wiring diagram of the cortical network