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

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.

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

Lentiviral Transgenesis as a Tool to Study the Role of Uncoupling Protein Isoforms in the Nervous System

Hélène Danielle Perreten Lambert

A tight coupling exists between synaptic activity and glucose utilization by astrocytes. Metabolic cooperation between neurons and astrocytes mediates this coupling. During synaptic activation, glutamate that is released in the synaptic cleft as a neurotransmitter by neurons is rapidly cleared by an active uptake into astrocytes. One glutamate is co-transported with three Na+. Intracellular astrocytic Na+ homeostasis is re-established by the Na+/K+-ATPase which requires ATP provided mainly by glycolysis. The resulting lactate is released in extracellular space and contributes to the energetic balance of activated neurons. This coupling between astrocytes and neurons is known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). The role of mitochondria in this coupling remains to be determined and more specifically the role of uncoupling proteins (UCP) which have been recently identified in neural tissues. UCPs belong to a family of mitochondrial carriers which are present in the inner mitochondrial membrane. There are five isoforms named UCP1 to UCP5. The well-known characterized is UCP1, also named thermogenin, which is present in the brown adipose tissue (BAT) of the small rodents and is responsible of non-shivering thermogenesis. It dissipates the proton gradient across the inner mitochondrial membrane, thereby producing heat instead of ATP. UCP2 is ubiquitous and is implicated in protection against excessive reactive oxygen (ROS) production. The expression of UCP3 is restricted to skeletal muscle where it is linked to fatty acid metabolism. The role of the brain isoforms UCP4 and UCP5 is still poorly understood. Initially, we set out to evaluate their function in energy metabolism of astrocytes and neurons. We used the lentiviral strategy to overexpress or silence the UCPs isoforms in primary cultures of astrocytes and neurons. We found that only UCP4 and UCP5 had an uncoupling activity in brain cells. Indeed, we observed a reduced mitochondrial potential and a reduced ATP/ADP ratio in astrocytes as well as in neurons overexpressing UCP4 or UCP5. UCP4 reduced the oxidative pathway of astrocytes without modifying the basal glucose metabolism and without having a lethal effect on the cell. Oxygen consumption rate (OCR) of brain cells ovexpressing UCPs was reduced. Moreover, UCP4 increased lactate release by astrocytes, suggesting an implication in the astrocyte-neuron coupling. We also brought evidence that both UCP4 and UCP5 partially protect brain cells from oxidative damage. All these results were confirmed by experiments on UCPs silencing. In a second step, we used a co-culture model to study the impact of astrocytic uncoupling protein on neuronal survival and we demonstrated that the presence of uncoupling protein in astrocytes prevents neuronal death after glutamate excitotoxicity. Taken together, all these results support an important role of uncoupling proteins in the regulation of astrocytic energy production, thus promoting local export of lactate which can be used by neurons.

EPFL2011

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

Quentin Barraud, Grégoire Courtine, Lucia Florinda Friedli Wittler, Pavel Musienko, Rubia van den Brand

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species have not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than did rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys but nearly absent in rats. Our results uncover pronounced interspecies differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury reemphasizes the importance of primate models for designing clinically relevant treatments.

American Association for the Advancement of Science2015