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

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.

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

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

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.