Step training reinforces specific spinal locomotor circuitry in adult spinal rats

Locomotor training improves function after a spinal cord injury both in experimental and clinical settings. The activity-dependent mechanisms underlying such improvement, however, are sparsely understood. Adult rats received a complete spinal cord transection (T9), and epidural stimulation (ES) electrodes were secured to the dura matter at L2. EMG electrodes were implanted bilaterally in selected muscles. Using a servo-controlled body weight support system for bipedal stepping, five rats were trained 7 d/week for 6 weeks (30 min/d) under quipazine (0.3 mg/kg) and ES (L2; 40 Hz). Nontrained rats were handled as trained rats but did not receive quipazine or ES. At the end of the experiment, a subset of rats was used for c-fos immunohistochemistry. Three trained and three nontrained rats stepped for 1 h (ES; no quipazine) and were returned to their cages for 1 h before intracardiac perfusion. All rats could step with ES and quipazine administration. The trained rats had higher and longer steps, narrower base of support at stance, and lower variability in EMG parameters than nontrained rats, and these properties approached that of noninjured controls. After 1 h of stepping, the number of FOS+ neurons was significantly lower in trained than nontrained rats throughout the extent of the lumbosacral segments. These results suggest that training reinforces the efficacy of specific sensorimotor pathways, resulting in a more selective and stable network of neurons that controls locomotion.

Neuroprosthetic system to restore locomotion after neuromotor disorder

Nikolaus Wenger

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with Spinal Cord Injury (SCI) and Parkinson disease. Stimulation parameters are tuned manually and remain constant during motor execution which is suboptimal to mediate maximum therapeutic effects. Here, I present a novel neuroprosthetic system that enabled adaptive changes of neuromodulation parameters during locomotion and allowed to restore high-fidelity control over leg movements in paralyzed rats. Beyond the therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders. Several limitations have restricted the development of neuroprosthetic systems for closed loop neuromodulation. (1) First, it required a mechanistic understanding of the relationships between stimulation features and the recruitment of specific sensorimotor circuits. I found that electrical neuromodulation primarily recruits afferent reflex pathways that lead to coordinated activity of leg muscles during stepping. Moreover, the specific electrode location on the spinal cord could activate distinct reflex pathways and activate specific leg muscle groups of paralyzed rats. These results have been leveraged for the design of flexible and stretchable multi-electrode arrays for electrical and chemical spinal cord stimulation. (2) Second, it was necessary to perform comprehensive mapping experiments to characterize the effect of neuromodulation parameters on hind limb kinematics in order to establish stable and robust feedback signals for real time control. Step height and ground reaction forces emerged as the primary targets for the control of closed loop neuromodulation after spinal cord injury. (3) Third, implementation and optimization of closed-loop neuromodulation strategies necessitated the development of an advanced technological platform that combined feedback and feed-forward loops that match the natural flow of information in the modulated neural systems. These integrated developments allowed animals with complete spinal cord injury to perform over 1000 successive steps without failure, and to climb staircases of various heights and lengths with precision and fluidity. Moreover, the neuroprosthetic system was able to alleviate locomotor deficits in an alpha-synuclein rodent model of Parkinsonâs disease. Current knowledge of human spinal cord properties in response to electrical neuromodulation suggests that the developed control policies can translate into clinical applications to improve neurorehabilitation therapies. Moreover, the developed neuroprosthetic system can readily be interfaced with control signals from the brain to establish cortico-spinal neuroprostheses that are intended to promote activity-dependent plasticity during recovery from spinal cord injury.

EPFL2014

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

Corticolumbar dynamics during recovery after spinal cord injury

Selin Anil

In humans, a severe spinal cord contusion interrupts the vast majority of supraspinal projections to the spinal cord below the lesion. Permanent paralysis results from the chronic failure of these spared projections to engage lumbar circuits producing leg movement. We modeled these injuries in rodents, and showed the immediate access of cortical circuits onto the electrochemically-enabled lumbar spinal cord. Neuroprosthetic rehabilitation leveraged spared motor circuits elements, ultimately leading to the establishment of a cortico-reticulo-spinal relay that mediated the recovery of voluntary control over the legs. Cortical fibers underwent a drastic anatomical remodeling, contacting glutamatergic reticulospinal neurons in the brainstem which, despite lesion variability, consistently retained synaptic connections onto lumbar circuits. This circuit-level reorganization mediated a cortex-dependent recovery of natural locomotor behaviors. In the aim of refining our understanding of the cortical contribution to the restoration of leg motor control with neuroprosthetic rehabilitation, we established a methodology to translate to rats a technique of endoscopic calcium imaging in freely-moving animals. We increased the stability of the implant, reaching unprecedented chronic degrees of longevity. Using this newly implemented technology, we tracked the activity of single corticolumbar cells during natural walking in intact rats, showing a strong representation of motor behavioral features in the population. We additionally highlighted the stability of locomotion-related classifications of individual neurons, suggesting a segregation of movement-related representations. The contusion was accompanied by important anatomical changes of corticolumbar cell bodies, preventing the longitudinal identification of single neurons across injury. However, population-level analyses highlighted a maintained strong representation of locomotion at late stages after injury and training. We did not find any dynamic change in corticolumbar population activity correlating with the recovery of voluntary leg motor control, which reflected in a stability of the fractions of movement-related neurons. These early results start shedding light on possible mechanisms of functional plasticity accompanying recovery after spinal cord injury, as a peculiar form of motor learning. Concurrently to the functional reorganization of corticolumbar neurons, we investigated the anatomical plasticity of this specific population with contusion and training. Neuroprosthetic rehabilitation led to a strengthening of collateral connections onto the thoracic spinal segments above the lesion. However, we found no effect of training on the anatomical remodeling throughout the brain and brainstem. Notably, the absence of sprouting of corticolumbar collaterals in the brainstem reticular formation leads us to question the identity of the cortical population involved in the formation of the cortico-reticulo-spinal relay.

EPFL2020