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

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.

Neuroprosthetic rehabilitation and translational mechanism after severe spinal cord injury

Lucia Florinda Friedli Wittler

Traumatic SCIs have long-term health, economic and social consequences, stressing the urgency to develop interventions to improve recovery after such injuries. Today, the only proven effective interventions to enhance recovery after SCI are activity-based rehabilitation therapies, such as locomotor training. However, locomotor training shows no or very limited efficacy to improve function after a severe SCI that induces paralysis of the limbs. To mimic the outcome of severe but incomplete SCI in rodents, we developed a model of double opposite-side lateral hemisections termed staggered hemisection in adult rats. This model induced permanent paralysis below the level of injury but leaves an intervening gap of intact neural tissue that provides a substrate for recovery. We showed that this SCI leads to degradation of motor functions, which correlates with the formation of aberrant neuronal connections below the lesion. Robotic devices with a rehabilitative purpose should act as propulsive or postural neuroprosthesis allowing training under natural conditions. Our versatile robotic interface provides multidirectional bodyweight support during overground locomotion in rats. We next evaluated the effects of robot-assisted gait training enabled by electrochemical stimulation of spinal circuits to restore locomotion after staggered hemisection SCI. We found that after two months of daily training, paralyzed rats recovered the ability to initiate, sustain and adjust bipedal locomotion while supported in the robot under electrochemical stimulation. This recovery correlated with ubiquitous reorganization of corticospinal, brainstem, and intraspinal fibers. We next evaluated whether this treatment was capable of restoring supraspinal control of locomotion after a clinically relevant SCI. Rats received a severe contusion of the spinal cord that spared less than 10% of intact tissue. Robot-assisted rehabilitation restored weight-bearing locomotion in all the trained rats when stimulated electrochemicallay and in a subset of rats in the absence of any enabling factors which paralelled with the reorganization of axonal projections of reticulospinal fibers below the contusion. Virus-mediated silencing of reticulospinal neurons projecting to lumbar segments demonstrated that these inputs were necessary to initiate and sustain walking after training. When delaying the onset of training by two months, in the chronic stage, all the rats regained voluntary locomotor movements but the extent of the recovery was reduced compared to rats trained early after SCI. The results provide a strong rationale to evaluate the impact of neuroprosthetic training to improve motor functions in human patients with incomplete SCI. Translation of treatment paradigms developed in rodent models into effective clinical applications remains a major challenge in biomedical research. Here, we studied recovery of motor functions in more than 400 quadriplegic patients who presented various degree of spinal cord damage laterality. We found that recovery increases with the asymmetry of early motor deficits. We conclude that emergence of spinal cord decussating corticospinal fibers and bilateral motor cortex projections during mammalian evolution supports greater recovery after lateralized SCI primates compared to rodents. Novel experimental models and dedicated therapeutic strategies are necessary to take advantage of this powerful neuronal substrate for recovery after SCI.

EPFL2014

Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord

Marco Capogrosso, Grégoire Courtine, Jérôme Gandar, Nathan Antoine Greiner, Stéphanie Lacour, Eduardo Martin Moraud, Ivan Rusev Minev, Pavel Musienko, Polina Shkorbatova, Nikolaus Wenger

Objective. We recently developed soft neural interfaces enabling the delivery of electrical and chemical stimulation to the spinal cord. These stimulations restored locomotion in animal models of paralysis. Soft interfaces can be placed either below or above the dura mater. Theoretically, the subdural location combines many advantages, including increased selectivity of electrical stimulation, lower stimulation thresholds, and targeted chemical stimulation through local drug delivery. However, these advantages have not been documented, nor have their functional impact been studied in silico or in a relevant animal model of neurological disorders using a multimodal neural interface. Approach. We characterized the recruitment properties of subdural interfaces using a realistic computational model of the rat spinal cord that included explicit representation of the spinal roots. We then validated and complemented computer simulations with electrophysiological experiments in rats. We additionally performed behavioral experiments in rats that received a lateral spinal cord hemisection and were implanted with a soft interface. Main results. In silico and in vivo experiments showed that the subdural location decreased stimulation thresholds compared to the epidural location while retaining high specificity. This feature reduces power consumption and risks of long-term damage in the tissues, thus increasing the clinical safety profile of this approach. The hemisection induced a transient paralysis of the leg ipsilateral to the injury. During this period, the delivery of electrical stimulation restricted to the injured side combined with local chemical modulation enabled coordinated locomotor movements of the paralyzed leg without affecting the non-impaired leg in all tested rats. Electrode properties remained stable over time, while anatomical examinations revealed excellent bio-integration properties. Significance. Soft neural interfaces inserted subdurally provide the opportunity to deliver electrical and chemical neuromodulation therapies using a single, bio-compatible and mechanically compliant device that effectively alleviates locomotor deficits after spinal cord injury

2018

Neuroprosthetic Technologies to Evaluate and Train Leg Motor Control in Neurologically Impaired Individuals

Camille Georgette Marie Le Goff-Mignardot

Spinal cord injury (SCI) disrupts many essential sensorimotor and autonomic functions. Consequently, individuals with SCI can face decades with permanent disabilities. Advances in clinical management have decreased morbidity, but no clinical trial has yet demonstrated the efficacy of a repair strategy. In the past decade, Courtine lab has developed neurotechnologies that restored volitional control of locomotion in animal models of SCI. The intervention acts over two-time windows. In the short-term, the delivery of epidural electrical stimulation (EES) targeting the posterior lumbar roots with timing that mimics the natural activation of the spinal cord enables stepping in otherwise paralyzed rats. In the long-term, this targeted EES with intensive robot-assisted overground training triggers a reorganization of descending pathways that reestablished voluntary control of the paralyzed legs, even without EES. These results in animal models encouraged the transfer of these technologies and concepts to clinical applications. My contribution to this translational research program forms the core of my thesis. The first section presents a software that I developed in order to enable a comprehensive yet semi-automated analysis of kinematics and muscle activity underlying locomotor functions in humans. This toolbox allows to evaluate gait features of people with neuromotor deficits, quantify locomotor performance compared to healthy people or to monitor changes in different experimental conditions or over the time course of interventions, and automatically generate comprehensive gait reports directly understandable by scientists and clinicians. The second section introduces a paradigm shift in robotic postural assistance: the gravity-assist. We demonstrated the detrimental impact of high levels of body weight support on gravity-dependent interactions during standing and walking. We developed a gravity-assist algorithm that fine-tunes the forward and upward body weight support to reestablish these interactions based on each patientâs residual capacities. We validated the personalized gravity-assist in 30 individuals with SCI or stroke. Compared to other conditions of support, the gravity-assist enabled all the patients to improve their locomotion performance. This platform establishes refined conditions to empower and train overground locomotion in a safe yet ecological environment. The third section reports the development of targeted EES in patients with chronic SCI, and the impact of an intensive 5-month rehabilitation with gravity-assist and targeted EES on the recovery of motor functions. The key findings can be summarized as follows: We established procedures to configure targeted EES that immediately enabled voluntary control of weak or paralyzed muscles; Targeted EES boosts the residual supraspinal inputs to the lumbar spinal cord, enabling all the patients to adapt their gait to specific tasks; Locomotor performance improved during the rehabilitation; All the patients regained voluntary control over previously paralyzed muscles without EES. These combined results establish the proof-of-concept on the therapeutic potential of targeted EES and intensive, robot-assisted rehabilitation to restore locomotion after SCI. Together with similar results obtained in the US in patients with severe SCI, our findings are establishing a pathway towards the development of a viable treatment to support motor functions and improve recovery after SCI.

EPFL2019