Cortico–reticulo–spinal circuit reorganization enables functional recovery after severe spinal cord contusion

Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex–dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico–reticulo–spinal circuit reorganization may also improve recovery in humans

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

A brain-spine interface alleviating gait deficits after spinal cord injury in primates

Quentin Barraud, Jocelyne Bloch, David Allenson Borton, Marco Capogrosso, Grégoire Courtine, Simone Ellen Joze Duis, Jérôme Gandar, Eduardo Martin Moraud, Silvestro Micera, Jean-Baptiste Mignardot, Tomislav Milekovic, Elodie Rey, Fabien Bertrand Paul Wagner

Spinal cord injury disrupts the communication between the brain and the spinal circuits that orchestrate movement. To bypass the lesion, brain-computer interfaces(1-3) have directly linked cortical activity to electrical stimulation of muscles, and have thus restored grasping abilities after hand paralysis(1,4). Theoretically, this strategy could also restore control over leg muscle activity for walking(5). However, replicating the complex sequence of individual muscle activation patterns underlying natural and adaptive locomotor movements poses formidable conceptual and technological challenges(6,7). 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(8-10). 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 realtime 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.

Nature Publishing Group2016

Brain-controlled neuroprosthetic interventions to restore locomotion after contusion spinal cord injury in the rat

Marco Bonizzato

Spinal cord injury (SCI), second only to stroke, is the leading cause of paralysis. Therapies based on electrical stimulation of the spinal cord and other locomotor areas of the Nervous System improve motor control in people with neurotrauma. Neuromodulation of the sensorimotor systems can indeed reactivate circuitries that are left dormant after SCI and turn them into an active locomotor state. These results have been found in animal models and translated to clinical fruition. Recent medical research has demonstrated that the involvement of volition and motor intent is a decisive factor for success of rehabilitation therapies that involve functional electrical stimulation of spinal cord and muscles. A key brain area that encodes information related to the conscious processing and execution of movement is the primary sensory-motor cortex. In this thesis I present two novel neuroprosthetic systems for neuromodulation based on cortical population activity in rats with SCI. We tested the hypotheses that neurons in the motor cortex could provide a reliable input for closed-loop neuroprosthetic systems designed to electrically stimulate different locomotor areas of the nervous system in a locomotor-phase-specific manner and thus enhance the locomotor output. During the experiments, we connected cortical correlates of intended movements with patterns of stimulation delivered either at the midbrain or at the sublesional spinal cord. Our brain-controlled functional stimulation reduced locomotor deficits caused by spinal cord injury and restored voluntary control of foot movement. These findings and the control policies we developed could be applied to clinical trials to improve the results of neurorehabilitation, for the benefit of people living with SCI.

EPFL2017

A brain-spine interface alleviating gait deficits after spinal cord injury in primates

Nature Publishing Group2016

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

Léonie Asboth

EPFL2017