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

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

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

Soft multimodal neural interfaces for unravelling sensory neurological circuits

Frédéric Pierre Gérald Michoud

Diseases or injuries affecting the nervous system can dramatically disrupt the quality of life. Despite extensive efforts towards treating dysfunctional nervous systems, the pharmacological and electrical approaches generally involved lack the temporal and spatial resolutions needed to selectively modulate neural activity. The somatosensory system intertwines numerous neural populations with distinct functionalities, whose specific neuromodulation would be beneficial for the alleviation of chronic pain and the restoration of locomotion after spinal cord injury. This thesis aims to develop a new generation of electrical and optical neural interfaces to selectively parse the somatosensory system. At the peripheral nerve level, we proposed an optical cuff and a wireless optoelectronic system to deliver epineural optogenetic stimulations in freely-behaving mice. The former consists of a soft elastomeric cuff wrapped around the sciatic nerve and integrated into a thin optic fiber. We demonstrated consistent orderly recruitment of motor units with optical stimulations in Thy1::ChR2 mice. This optocuff represents a simple, yet efficient, solution to probe the peripheral nervous system using optogenetics. However, untethered experimentation offers more versatility for fine neuromodulation applications. Within this framework, we developed a system comprising an ultra-miniaturized wireless stimulator and a soft circumneural ÎŒ-LED array to deliver optogenetic stimulations to the sciatic nerve. This optoelectronic implant conformed to the nerveâs morphology and complied with its dynamic motion. We demonstrated the systemâs efficacy via optogenetic activation of nociceptors in TRPV1::ChR2 mice. Both the optocuff and the wireless optoelectronic system exhibited seamless bio-integration after chronic implantation, thus highlighting the benefits of soft neurotechnology for interfacing with peripheral nerves. At the spinal level, we introduced a transversal electrode array for multipolar epidural stimulation of the spinal cord. The silicone materials used for its fabrication conferred this implant with mechanical properties matching the dura mater, allowing for remarkable biocompatibility following long-term implantation. Based on the spinal cord anatomy, this implant displayed a wide distribution of neural electrodes at a single spinal level, which enabled selective recruit- ment of posterior spinal roots. This novel paradigm was implemented to a spatio-temporal stimulation protocol and demonstrated potential in restoring locomotion after spinal cord injury. Finally, we reported a soft ÎŒ-LED array to deliver optogenetic stimulations in deep spinal structures. Insertion of this thin (< 100 ÎŒm) optoelectronic implant in the mouse epidural space did not provoke tissue damages while maintaining its functionality with normal dynamic motion. As a proof-of-principle, we showed concomitant electromyographic activity with epidural optical stimulations in Thy1::ChR2 mice. This premise offers a large range of opportunities to probe the spinal circuits involved in sensory processing and locomotion. In conclusion, these selective neural interfaces are proposed as innovative tools to unravel peripheral and spinal neural circuits. This venue will support the development of relevant clinical treatments for tackling dysfunctional neural systems. Eventually, these implant concepts pave the way for the translation of fine neuromodulation therapies in humans.

EPFL2019

Closed-loop neuromodulation of spinal sensorimotor circuits controls refined locomotion after complete spinal cord injury

Marco Bonizzato, Grégoire Courtine, Eduardo Martin Moraud, Silvestro Micera, Pavel Musienko, Stanisa Raspopovic, Nikolaus Wenger

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with spinal cord injury. With common neuromodulation devices, electrical stimulation parameters are tuned manually and remain constant during movement. We developed a mechanistic framework to optimize neuromodulation in real time to achieve high-fidelity control of leg kinematics during locomotion in rats. We first uncovered relationships between neuromodulation parameters and recruitment of distinct sensorimotor circuits, resulting in predictive adjustments of leg kinematics. Second, we established a technological platform with embedded control policies that integrated robust movement feedback and feed-forward control loops in real time. These developments allowed us to conceive a neuroprosthetic system that controlled a broad range of foot trajectories during continuous locomotion in paralyzed rats. Animals with complete spinal cord injury performed more than 1000 successive steps without failure, and were able to climb staircases of various heights and lengths with precision and fluidity. Beyond therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders.

American Association for the Advancement of Science2014

Soft multimodal neural interfaces for unravelling sensory neurological circuits

Frédéric Pierre Gérald Michoud

EPFL2019

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

Jérôme Gandar

EPFL2019