Electrical spinal cord stimulation protocols to regulate neurological functions after spinal cord injury

Spinal cord injury (SCI) is a life-changing event. People who suffer from it lose their abilityto move normally and are subject to life-threatening symptoms. When the insult is not toosevere, partial recovery is possible. Otherwise, for severely affected people, the perspectives toever retrieve normal functions is almost non-existent. A critically important window to promoteplasticity is in the acute phase after the trauma (weeks to months). However, at this stage,people cannot take active part in rehabilitation programs due to their incapacity to activate theirlimbs and to the apparition of severe autonomic symptoms such as orthostatic hypotension.Hence, current activity-based treatments are of little help for this population. Consequently, SCIdramatically affects their autonomy and quality of life on the life-long term.Continuous Epidural Electrical Stimulation (EES) of the spinal cord has been proposed as amethod to reactivate dormant neural networks innervated below the site of injury. It enablesrobust control over locomotion and autonomic functions. In animal models of severe lesion,continuous EES promoted long lasting recovery of motor abilities when coupled with an intensivetraining. In human, its recent application indeed supported overground walking in chronicallyand severely injured people, but only showed limited plastic effects when compared to animals.Why? Recent advances support that continuous EES abolishes proprioceptive feedback thatis essential to promote recovery. Moreover, late treatment of severe injuries consistently fail apromoting recuperation of functions. Alternatively, over the last decade, our laboratory developeda spatio-temporally patterned approach to EES. In addition to restore fine control over motorfunctions, this technique avoids the caveats of continuous EES, and hypothetically opens a windowof opportunity for plasticity to happen. In this thesis, we propose a translation of this concept tohumans. We first demonstrate that spatio-temporal EES restores robust and versatile locomotorcontrol in people with chronic incomplete, though severe, SCI. Furthermore, the results supportan aptitude of this approach to promote long lasting recovery of functions without stimulationafter 5 months of intensive training. We then report on a patient-tailored technology, thatincludes personalized computational models enabling precise pre-operative planning strategies, anew electrode-lead and control softwares. This technology enables restoration of various motorfunctions in people with chronic and motor-complete injuries within few hours after beginningof therapy. Finally, we transfer this targeted approach to the control of blood pressure. Wedemonstrate that closed-loop stimulation protocols support a precise control over arterial bloodpressure in rodents, non-humane primates and humans with severe SCI submitted to challengingcardiovascular conditions. Combined, the results presented in this manuscript open a clinicallyrealistic perspective for the application of EES acutely after injury and to potentially promoterobust recovery in severe SCI.

Electrical spinal cord stimulation protocols to regulate motor and autonomic functions in people with neurological disorders

Robin Jonathan Demesmaeker

Neurological disorders such as spinal cord injury (SCI) massively reduce independence and quality of life. Most often, the majority of the nervous system is still fully or partially spared, but dysfunctional due to aberrant or absent descending input from the brain. Neuromodulation techniques restore function by artificially engaging these neuronal circuits. Given its central position and multi- functional role, the spinal cord provides an excellent gateway for such therapies.Epidural Electrical Stimulation (EES) of the spinal cord has been put forward as a potential therapy to restore motor and autonomic function after SCI. Throughout the last decade, our laboratory developed the concept of biomimetic EES. Spatiotemporal stimulation parameters are optimized to re-establish the natural dynamics of the underlying spinal circuitry. Strong evidence in rodent and non- human primate models suggests that biomimetic EES could promote locomotion and haemodynamic stability after severe SCI, leading to a push for rapid clinical translation of this potentially game-changing therapy. This clinical translation is the pivot of my thesis.The first part focuses on the recovery of leg motor control after SCI. The results of a first-in-human clinical trial in 9 participants with chronic SCI are presented. We developed a set of targeted neurotechnologies that include a new epidurally implanted electrode array, real-time communication and tailormade software systems that enable the precise delivery of biomimetic EES. We demon- strate that biomimetic EES can be optimized to immediately restore a vast number of leg motor functions such as walking and cycling, as well as trunk posture. Furthermore, after 5 months of intensive EES-enabled volitional training, participants did not only all improve their motor performance while using EES, they moreover regained volitional control over previously paralyzed muscles. This neuro- logical recovery correlated with a reduced metabolic activity in the spinal cord, suggesting spinal remodeling. A systematic pre-clinical approach identified a specific neuronal population mediating these effects.The second part of my thesis considers another critically important body function: haemodynamic management. Orthostatic hypo- tension is a major health issue after severe SCI and stems from a disconnection between the vasomotor regulatory centres in the brainstem and the sympathetic circuitry that adjusts peripheral vascular resistance. Preclinical work in rodents showed that EES ap- plied to the low-thoracic spinal cord could restore haemodynamic stability after SCI. On the path towards clinical translation, we implemented closed-loop control of EES in a non-human primate model of SCI to maintain haemodynamic stability during orthostatic challenge. I moreover present a case-study that demonstrates the transferability of thoracic EES to improve haemodynamic manage- ment in a patient with Multiple System Atrophy (MSA). A marked reduction of orthostatic hypotension led to a clinically relevant decrease in fainting episodes and considerably improved quality of life.My thesis demonstrates the prosthetic and therapeutic effects of biomimetic EES and highlights its ability to immediately restore body functions and boost neurological recovery after SCI and in MSA. These results strengthen the belief that EES holds the potential to evolve into a relevant and efficient therapeutic intervention in a plentitude of neurological disorders.

EPFL2021

Corticospinal neuroprostheses to restore locomotion after spinal cord injury

Janine Beauparlant, Marco Bonizzato, David Allenson Borton, Grégoire Courtine, Stéphanie Lacour, Eduardo Martin Moraud, Silvestro Micera, Ivan Rusev Minev, Pavel Musienko, Nikolaus Wenger

In this conceptual review, we highlight our strategy for, and progress in the development of corticospinal neuroprostheses for restoring locomotor functions and promoting neural repair after thoracic spinal cord injury in experimental animal models. We specifically focus on recent developments in recording and stimulating neural interfaces, decoding algorithms, extraction of real-time feedback information, and closed-loop control systems. Each of these complex neurotechnologies plays a significant role for the design of corticospinal neuroprostheses. Even more challenging is the coordinated integration of such multifaceted technologies into effective and practical neuroprosthetic systems to improve movement execution, and augment neural plasticity after injury. In this review we address our progress in rodent animal models to explore the viability of a technology-intensive strategy for recovery and repair of the damaged nervous system. The technical, practical, and regulatory hurdles that lie ahead along the path toward clinical applications are enormous - and their resolution is uncertain at this stage. However, it is imperative that the discoveries and technological developments being made across the field of neuroprosthetics do not stay in the lab, but instead reach clinical fruition at the fastest pace possible.. (C) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Elsevier2014

Neurorehabilitation and neuroprosthetic technologies to regain motor function following spinal cord injury

Rubia van den Brand

Spinal cord injury (SCI) leads to a range of disabilities, including locomotor impairments that seriously diminish the patients’ quality of life. Strategies to promote functional recovery after severe SCI will undoubtedly include approaches to regenerate injured pathways. The present work pursues a less ambitious, but potentially more rapidly applicable approach to improve function after SCI by applying neurorehabilitation augmented with neuroprosthetic technologies. In an intact situation, the production of standing and walking results from the integration of information within spinal neuronal networks that receive signals from supraspinal centers and afferent pathways. In the majority of cases, the spinal neuronal networks that coordinate leg movements are located below the injury. Due to the interruption of supraspinal signals, these networks are in a non-functional state. Over the past decades multiple research groups have developed interventions to access dormant spinal networks in order to enable functional states during rehabilitation. The underlying objective is to promote activity-dependent plasticity in the trained sensorimotor pathways. During my thesis, I contributed to the development of neuroprosthetic technologies that provide a powerful means to reanimate non-functional networks. The aim of these paradigms is to mimic the supraspinal signals that are normally delivered to spinal locomotor circuits to generate hindlimb motor function. These technologies include: (i) An electrical spinal neuroprosthesis that replaces the supraspinal excitatory drive to augment the central state of excitability, and thus increase the susceptibility of spinal circuits to respond to afferent input. (ii) A chemical spinal neuroprosthesis mimicking the supraspinal source of monoaminergic neuromodulation that promotes locomotor permissive states of spinal circuits. (iii) A robotic postural neuroprosthesis that provides optimal conditions of posture and balance, which enable sensory feedback to become a source of motor control after severe SCI. Multifactorial statistical analyses revealed that each sub-system of the developed neuroprosthetic technologies mediates distinct influences on the production of gait performance, suggesting targeting of selective spinal circuits. Optimal combinations of neuroprosthetic technologies transformed lumbosacral locomotor circuits from dormant to highly functional states, which enabled paralyzed rats with complete SCI to perform weight-bearing stepping with plantar placement for extended periods of time. After 8-weeks of locomotor training enabled by an electrochemical neuroprosthesis, rats with complete SCI exhibited significantly improved gait performance, which was associated with activity-dependent plasticity in lumbosacral circuits. Trained rats were able to instantaneously adapt hindlimb locomotor patterns to changes in speed, load and direction of stepping in the complete absence of brain input. Under these conditions, ‘the smart spinal brain’ interprets multifaceted afferent information to generate motor outputs that meet both internal and external requirements for maintaining successful locomotor states despite dramatic changes in environmental conditions. Non-ambulatory individuals with severe SCI typically exhibit progressive neuronal dysfunction in the chronic stage of injury. To investigate the underlying mechanisms, we developed a new model of severe SCI that consists of 7 two opposite side, staggered lateral hemisections. This SCI completely interrupts direct supraspinal input to spinal locomotor circuits, but spares a bridge of intact neural tissue through which intraspinal remodeling could occur. This SCI not only led to permanent paralysis but also triggered various functional alterations that resembled the signature characteristics of neuronal dysfunction seen in human individuals. Anatomical analyses revealed that undirected compensatory plasticity of sub-lesional spinal circuits was in part responsible for neuronal dysfunction in the chronic stage of severe SCI. This aberrant sprouting led to a chaotic recruitment of sensorimotor circuits that contributed to the emergence of abnormal reflex properties and deterioration of gait performance. We next investigated whether neurorehabilitation augmented with neuroprosthetic technologies was able to prevent the development of neuronal dysfunction, and instead improve functional recovery, in rats with two opposite side, staggered lateral hemisections. For this aim, we developed a rehabilitation program combining (i) automated treadmill-based training to induce beneficial activity-dependent plasticity of sub-lesional spinal circuits and (ii) overground active training encouraging the rat to engage its paralyzed hindlimbs in order to promote remodeling of descending neuronal pathways. After eight weeks of active training, paralyzed rats recovered the capacity to initiate and sustain full-weight bearing bipedal locomotion overground, and even to climb staircases and avoid obstacles. Combinations of anatomical and complementary experiments demonstrated that training promoted multi-level plasticity of spared neuronal pathways above and across the lesion, which restored supraspinal control of lumbosacral locomotor circuits. Rats that were exclusively trained on the treadmill showed improved stepping capacities, but plasticity was restricted to the trained spinal circuits. They failed to initiate or sustain locomotion overground. These results demonstrate the importance of active training under highly functional states to promote reorganization of spared neuronal systems through activity-dependent mechanisms after a severe SCI. Activity-based approaches have become common medical practices to improve functional recovery following incomplete SCI in humans. However, after more severe SCI these interventions show limited efficacy, possibly due to the non-functional state of the spinal cord during training. A recent case study tested this hypothesis in a paraplegic man who suffered chronic motor paralysis. Epidural electrical spinal cord stimulation was applied during stand training to enable functional states of spinal circuits. After several months of rehabilitation, the chronically paralyzed individual regained supraspinal control over specific leg joint movements in a supine position. However, this capacity was only present when stimulation was applied. These results suggest that the therapeutic paradigms that we developed and demonstrated in rats may also apply to human patients. While challenges lie ahead, neurorehabilitation augmented with neuroprosthetic technologies may progressively become a new treatment option to improve functional recovery of spinal-cord-injured human patients. The present work emphasizes the importance of fostering bridges between neuroscience, technology and medicine to develop neurotechnologies and rehabilitation paradigms that have the potential to translate into clinical practices.