Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders

Central nervous system (CNS) disorders distinctly impair locomotor pattern generation and balance, but technical limitations prevent independent assessment and rehabilitation of these subfunctions. Here we introduce a versatile robotic interface to evaluate, enable and train pattern generation and balance independently during natural walking behaviors in rats. In evaluation mode, the robotic interface affords detailed assessments of pattern generation and dynamic equilibrium after spinal cord injury (SCI) and stroke. In enabling mode, the robot acts as a propulsive or postural neuroprosthesis that instantly promotes unexpected locomotor capacities including overground walking after complete SCI, stair climbing following partial SCI and precise paw placement shortly after stroke. In training mode, robot-enabled rehabilitation, epidural electrical stimulation and monoamine agonists reestablish weight-supported locomotion, coordinated steering and balance in rats with a paralyzing SCI. This new robotic technology and associated concepts have broad implications for both assessing and restoring motor functions after CNS disorders, both in animals and in humans. © 2012 Nature America, Inc. All rights reserved.

Cortico-reticulo-spinal circuits mediate functional recovery after spinal cord contusion

Léonie Asboth

After a spinal cord injury (SCI), only half of affected individuals regain voluntary control of leg movements below the level of the lesion. Anatomical, electrophysiological and imaging data revealed that even the most severe forms of SCI usually spare a small bridge of tissue in the surrounding of the lesion cavity. These bridges contain residual fibers from brain projections that maintain a physical connection with the lumbar spinal cord, where the circuits coordinating leg movements reside. However, without therapeutic interventions, these spared fibers will fail to conduct nervous information from brain centers to the spinal circuits below injury, leading to permanent paralysis. It is accepted that spontaneous regeneration of lesioned fibers is limited in the adult nervous system, but hope for motor recovery lies in the capacity of the spared neural motor network to readapt and find compensational routes. In the past, a neuroprosthetic rehabilitation strategy combining electrochemical neuromodulation of the spinal cord during robot-assisted overground locomotion was developed for rats to restore volitional control of the paralyzed legs. Such rehabilitation platforms was developed for rats, enabling large-scale studies prior to pre-clinical trials in non-human primates. However, most innovative tools for the manipulation of specific populations of neurons are currently designed for mice, and these techniques are essential to establish causality between the anatomical reorganization and the observed functional recovery. In the first part of this thesis, we developed a robotic interface with end-effector modules that can be rapidly exchanged between experiments with rats or mice. The functionalities of the robot are tailored to the size and weight of the animal, to the personalized need of assistance and to the type of performed task. Using this platform, the next part of the thesis uncovers the mechanisms enabling motor recovery after a clinically relevant injury model â a severe spinal cord contusion. Such injury leads to permanent leg motor deficits with very little spontaneous recovery. Similar to humans, the modelled contusion injury induce highly variable white matter damage with undefined neural pathway sparing. For the first time, we show that the rehabilitation strategy enabled rats to regain supraspinal control of leg movements that persisted without any neuromodulation even during unpracticed motor tasks. We then investigated the reorganization of the spared circuitry that mediated this functional recovery after contusion. Despite interruption of direct corticospinal projections, we showed that the motor cortex regained adaptive control over the paralyzed legs during neuromodulation of lumbar circuits. We found that the cortical command was relayed through spared glutamatergic projection neurons in the reticular formation. Indeed, due to the distributed spatial topography of reticulospinal projections, the contusion systematically spares a subset of these projections. Extensive training promoted plasticity of the identified cortico-reticulo-spinal pathway mediating a motor cortex dependent recovery of voluntary leg movements. As the anatomy and function of reticulospinal pathways are well-conserved across mammals, this pathway may be recruited by similar therapeutic interventions to improve recovery in humans.

EPFL2017

Spatiotemporal stimulation strategies in neuroprostheses to improve locomotion after spinal cord injury

Jérôme Gandar

Spinal cord injury (SCI) disrupts communication within central nervous system and lead to range of neurological disorders including paralysis. Current rehabilitation strategies to restore locomotion are poorly effective in people with severe SCI. Epidural electrical stimulation (EES) showed promising results in animal models and humans to improve recovery. However, EES protocols have remained empirical, which has limited the efficacy of this paradigm. In this thesis, I report my contribution to the development of EES related software and hardware that were driven by the under- standing of the mechanisms underlying EES. These neurotechnologies showed a remarkable efficacy to reestablish locomotion in animal models of leg paralysis. EES protocols have primarily been delivered with continuous stimulations applied over the middle of the spinal cord, independently of current limb positions. However the natural activity of the spinal cord does not correspond to this limited monotone modulation. In the first part of this thesis, we developed spatiotemporal stimulation protocols that seek to reproduce the natural activity of the spinal cord during walking. Using computational models, we identified optimal electrode locations that target individual posterior roots. These simulations steered the design of spatially selective spinal implants. Control software triggered stimulation trains in real-time to engage extensor and flexor synergies according to limb positions. This spatiotemporal neuro- modulation therapy enhanced locomotor performances in rats with severe SCI. However, these spatiotemporal neuromodulation protocols were controlled via an external computer. The animal had no control over the occurrence of the stimulation. To remedy this limitation, we designed a brain-spine interface. We linked motor states decoded from leg motor cortex activity to spinal cord stimulation protocols to elicited the intended movements. We implemented this brain-spine interface in a nonhuman primate models of transient unilateral leg paralysis. All the animals immediately regained movements of the paralyzed leg. There is often a mechanical mismatch between current stiff implants and the soft neural tissues of the host. The third part of this thesis is dedicated to the design and fabrication of soft neural implants that present the same elasticity as the dura mater. These implants maintain the ability to deliver electrochemical stimulation while being stretched. Such interfaces can be applied to multiple neuroprosthetic applications, including the restoration of locomotion in paralyzed rats. In the last part of this thesis, I addressed the current limitations of spinal implant specificity. We found that EES activates the large afferent fibers within the dorsal rots and developed novel implants that take advantage of the known trajectories of the dorsal roots to increase the specificity of EES. First, we built a precise anatomical computational model of the lumbosacral roots. We then ran simulations that identi- fied multipolar electrode configurations capable of steering the current specifcally. These results drove the fabrication of soft neural implants that we inserted chronically in rat models of severe SCI. Experiments showed that multipolar EES increases the specificity of the stimulation compared to conventional protocols. All the concepts developed and validated in my thesis are already applied or are steering applications in humans with SCI.

EPFL2019

Corticospinal neuroprostheses to restore locomotion after spinal cord injury

Janine Beauparlant, Marco Bonizzato, David Allenson Borton, Grégoire Courtine, Stéphanie Lacour, Eduardo Martin Moraud, Silvestro Micera, Ivan Rusev Minev, Pavel Musienko, Nikolaus Wenger

In this conceptual review, we highlight our strategy for, and progress in the development of corticospinal neuroprostheses for restoring locomotor functions and promoting neural repair after thoracic spinal cord injury in experimental animal models. We specifically focus on recent developments in recording and stimulating neural interfaces, decoding algorithms, extraction of real-time feedback information, and closed-loop control systems. Each of these complex neurotechnologies plays a significant role for the design of corticospinal neuroprostheses. Even more challenging is the coordinated integration of such multifaceted technologies into effective and practical neuroprosthetic systems to improve movement execution, and augment neural plasticity after injury. In this review we address our progress in rodent animal models to explore the viability of a technology-intensive strategy for recovery and repair of the damaged nervous system. The technical, practical, and regulatory hurdles that lie ahead along the path toward clinical applications are enormous - and their resolution is uncertain at this stage. However, it is imperative that the discoveries and technological developments being made across the field of neuroprosthetics do not stay in the lab, but instead reach clinical fruition at the fastest pace possible.. (C) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.