Unbiased interrogation of whole brain circuits in spinal cord injury leading to the design of a clinically relevant therapy to improve locomotion

Spinal cord injury (SCI) remains a global problem, and despite decades of research there currently is no cure for this disease. Recently, significant advances in the use of neuroprosthetic rehabilitation to improve locomotor outcomes after SCI have been made both in preclinical models and in humans. More specifically, the administration of lumbar epidural electrical stimulation (EES) has been shown to improve lower limb function after SCI with long-term improvements when combined with locomotor training. There have been important strides in understanding the mechanisms of this strategy and the role of the spinal cord, but there remains a significant gap in understanding the role of the brain in the recovery of locomotion after SCI. The purpose of this thesis was to address this gap and to elucidate the circuits in the brain that potentially, when modulated, could improve functional recovery after SCI and augment current therapeutic paradigms.

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

Biomaterials. Electronic dura mater for long-term multimodal neural interfaces

Léonie Asboth, Quentin Barraud, Marco Capogrosso, Grégoire Courtine, Simone Ellen Joze Duis, Jérôme Gandar, Arthur Edouard Hirsch, Stéphanie Lacour, Eduardo Martin Moraud, Silvestro Micera, Tomislav Milekovic, Ivan Rusev Minev, Pavel Musienko, Natalia Pavlova, Nicolas Vachicouras, Nikolaus Wenger

The mechanical mismatch between soft neural tissues and stiff neural implants hinders the long-term performance of implantable neuroprostheses. Here, we designed and fabricated soft neural implants with the shape and elasticity of dura mater, the protective membrane of the brain and spinal cord. The electronic dura mater, which we call e-dura, embeds interconnects, electrodes, and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. The soft implants extracted cortical states in freely behaving animals for brain-machine interface and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury.

American Association for the Advancement of Science2015

Brain-Controlled Neuroprosthetic Therapies And Mechanisms Of Recovery After Spinal Cord Injury

Galyna Pidpruzhnykova

Spinal cord injury (SCI) is the second leading cause of paralysis, which induces abrupt impairments with devastating consequences for the quality of life of patients. Despite significant progress in SCI treatment through neurorehabilitation training and spinal cord stimulation (SCS) techniques, there is still no cure for SCI and the mechanisms of recovery are poorly understood. My thesis represents a series of studies which investigate the neural mechanisms underlying locomotor recovery after SCI and leverage these findings for the development of brain-controlled neuroprosthetic therapies to enhance the potential of neurorehabilitation therapies. The first study focused on investigating neural mechanisms underlying locomotor recovery after clinically relevant contusion SCI. During this study, we assessed changes in over a hundred kinematic parameters using gait pattern extraction and principal component analysis. Our results show that the animals learned to step even in the absence of electrochemical enabling factors. Remarkably, we observed a carryover effect of locomotor recovery to the previously unpracticed swimming task. Afterwards, we dissected the neural mechanisms underlying the observed behavioral effect using viral tracing techniques and a double-virus construct allowing targeted pathway inactivation. As a result, we were able to reversibly abolish stepping capacity of rehabilitated rats, suggesting the critical importance of the reticulospinal tract for the recovery from contusion SCI. These findings gave us the rationale for the second study in which we developed a novel rehabilitation paradigm of brain-controlled stimulation of the mesencephalic locomotor region (MLR). The MLR sends excitatory descending input to reticulospinal neurons in the brainstem, which relay the descending locomotor command through the tissue bridge spared after contusion SCI. Thus, we hypothesized that MLR stimulation may lead to improved locomotion in rats after SCI when combined with neurorehabilitation training and electrochemical SCS. We found that brain-controlled MLR stimulation was able to improve kinematic output in rehabilitated animals and to significantly reduce side effects of non brain-controlled MLR stimulation. Thus, this novel neuroprosthetic paradigm is capable of enhancing existing rehabilitation techniques. However, the long-term effectiveness of this intervention during SCI rehabilitation needs to be further investigated to evaluate its full therapeutic benefit. Finally, after evaluating the possible beneficial and adverse effects of MLR stimulation in a translational context, we proposed another type of brain-controlled stimulation that directly bypasses the lesion site through an electronic bridge between the brain and the spinal cord. For this, we created a neuroprosthetic system allowing for direct cortical control of spinal cord neuromodulation during gait rehabilitation. This refinement of SCS delivery significantly improved both immediate locomotor output and the long-term recovery of rats after SCI. In conclusion, this thesis uncovers mechanisms of recovery from SCI and demonstrates the therapeutic potential of brain-controlled neuroprosthetic therapies. Furthermore, it raises important questions and identifies challenges in translating these therapies from the bench to the bedside. Hence, this work constitutes a valuable input for both basic science and the development of clinically relevant interventions.