Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury

Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.

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

A Computational Approach for the Design of Epidural Electrical Spinal Cord Stimulation Strategies to Enable Locomotion after Spinal Cord Injury

Emanuele Formento

Spinal cord injury (SCI) is a major cause of paralysis with currently no effective treatment. Epidural electrical stimulation (EES) of the lumbar spinal cord has been shown to restore locomotion in animal models of SCI, but has not yet reached the same level of efficacy in humans. The mechanisms through which EES promotes locomotion, and the causes underlying these inter-species differences remain largely unknown, although essential to fully exploit the therapeutic potential of this neuromodulation strategy. Here, we addressed these questions using a deductive approach based on computer simulations and hypothesis-driven experiments, and proposed complementary strategies to enhance the current efficacy of EES-based therapies. In the first part of this thesis, we studied the mechanisms through which EES enables locomotion in rat models of SCI. Performing simulations and behavioral experiments, we provided evidence that EES modulates proprioceptive afferents activity, without interfering with the ongoing sensory signals. We showed that this synergistic interaction allows muscle spindle feedback circuits to steer the unspecific excitation delivered by EES to functionally relevant pathways, thus allowing the formation of locomotor patterns. By leveraging this understanding, we developed a stimulation strategy that allowed adjusting lesion-specific gait deficits, hence increasing the therapeutic efficacy of EES. In the second part of this thesis, we evaluated the influence of trunk posture on proprioceptive feedback circuits during locomotion, and thus on the effect of EES, in rat models of SCI. By combining modeling and experiments, we showed that trunk orientation regulates leg proprioceptive signals, as well as the motor patterns produced during EES-induced stepping. We exploited these results to develop a control policy that by automatically regulating trunk orientation significantly enhanced locomotor performance. In the last part of this thesis, we investigated the causes underlying species-specific effects of EES. Hypothesis-driven simulations suggested that in humans continuous EES blocks the proprioceptive signals traveling along the recruited fibers. We corroborated this prediction by performing experiments in rats and people with SCI. In particular, we showed that EES disrupts the conscious perception of leg movements, as well as the afferent modulation of sensorimotor circuits in humans, but not in rats. We provide evidence that in humans, due to this phenomenon, continuous EES can only facilitate locomotion to a limited extent. This was insufficient to provide clinically relevant improvements in the tested participants. Finally, we proposed two sensory-compliant stimulation strategies that might overcome these limitations, and thus augment the therapeutic efficacy of EES. In this thesis we elucidated key mechanisms through which EES promotes locomotion, we exposed critical limitations of continuous EES strategies when applied to humans, and we introduced complementary strategies to maximize the efficacy of EES therapies. These findings have far-reaching implications in the development of future strategies and technologies supporting the recovery of locomotion in people with SCI using EES.

EPFL2018

Personalizable computational models of electrical spinal cord stimulation to restore function after neurological disorders

Andreas Rowald

Spinal Cord Injury (SCI) disrupts the communication between the brain and spinal circuits below the lesion, leading to a plethora of neurological impairments, including the loss of motor function. At present, the only medical practices to enhance recovery after paralysis are activity-based therapies. In severe cases, SCI-patients fail to produce active movements voluntarily and are therefore unable to fully benefit from these therapies. Epidural Electrical Stimulation (EES) applied over the lumbosacral spinal cord has demonstrated to enable locomotion in preclinical animal models and humans with SCI. EES may therefore play a pivotal role in the recovery of locomotion after SCI.However, neither has EES reached the same level of efficacy in humans as in preclinical animal models, nor is there consensus on the definition of clinically meaningful stimulation protocols. In the absence of clear understanding on how EES promotes the formation of motor patterns, stimulation protocols have been largely based on empirical observations. Instead, hypothesis-driven definition of stimulation parameters has demonstrated superior efficacy in other neuromodulation therapies, such as deep brain stimulation.In this thesis, I outline a computational approach to inform EES strategies for the recovery of neurological function after SCI. For this purpose, I leveraged a combination of finite element methods, neurophysical and neuromusculoskeletal models to refine our understanding on how EES promotes locomotion after SCI, inform the design of neuromodulation technologies and develop personalized EES treatments in humans with SCI.In the first part of this thesis, I provide evidence that EES recruits proprioceptive and cutaneous afferents in the dorsal roots. I suggest that the recruitment of proprioceptive feedback circuits promotes the formation of motor patterns. In contrary, the continuous recruitment of cutaneous afferents may disrupt the production of locomotion. In the next chapter, I study interspecies difference of EES. I argue that these differences necessitate the adaption of stimulation protocols to enable translation of EES as a therapy from preclinical models to humans. I propose the application of spatiotemporal protocols with low-amplitude, high-frequency bursts to improve the efficacy of EES in humans. In the following chapter, I describe a technological framework that enables the implementation of such stimulation paradigms in people with SCI. I outline how personalized computational modeling can be used for treatment planning. I then summarize how I advanced this rudimentary computational tool into a computational framework for the rapid elaboration of highly realistic personalizable computational models. I explain how I leveraged this framework to inform the arrangements of electrodes on a paddle lead to enable locomotion in large and diversified patient-cohorts, perform preoperative treatment planning and validate the efficacy of both the lead and treatment planning protocol in individuals with severe, chronic SCI. Finally, I summarize how I translated my computational framework for other use-cases including the control of hemodynamics and the evaluation of an optoelectronic system to enable locomotion in preclinical models.

EPFL2021