Altered Gaba And Somatostatin Modulation Of Proprioceptive Feedback After Spinal Cord Injury In Lamprey

While various changes occur after spinal cord lesions, their influence on functional recovery is generally unclear. We have shown changes in proprioceptor and locomotor network properties below lesion sites in the lamprey spinal cord. The proprioceptive system offers a particularly tractable model for analyzing these changes. Here, we have sought evidence for changes in neuromodulatory effects below lesion sites by comparing the effects of gamma-aminobutyric acid (GABA) and somatostatin, both of which are located around the edge cells, on proprioceptive responses in lesioned and unlesioned spinal cords. Exogenously applied GABA significantly reduced or abolished bending-evoked responses in unlesioned animals. In lesioned animals bending-evoked responses were stronger and certain of the effects of exogenously applied GABA were reduced. However, blocking endogenous GABA with bicuculline significantly potentiated responses in lesioned but not unlesioned animals. This suggested that the potentiated responses in lesioned animals were nevertheless associated with stronger tonic GABAergic inhibition. There were significant differences in these effects when lesioned animals were separated on the basis of their degree of recovery: notably, bicuculline only potentiated responses in animals that recovered good locomotor function, suggesting a need for raised endogenous GABA levels. Somatostatin alone did not affect edge cell responses in lesioned or unlesioned animals, but in lesioned animals it reduced and thus further weakened the inhibitory effects of GABA. There are thus multiple changes in sensory modulation in the lesioned spinal cord, and differences in these effects may influence the degree of recovery. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

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

From lamprey to salamander: an exploratory modeling study on the architecture of the spinal locomotor networks in the salamander

Andrej Bicanski, Auke Ijspeert

The evolutionary transition from water to land required new locomotor modes and corresponding adjustments of the spinal "central pattern generators" for locomotion. Salamanders resemble the first terrestrial tetrapods and represent a key animal for the study of these changes. Based on recent physiological data from salamanders, and previous work on the swimming, limbless lamprey, we present a model of the basic oscillatory network in the salamander spinal cord, the spinal segment. Model neurons are of the Hodgkin-Huxley type. Spinal hemisegments contain sparsely connected excitatory and inhibitory neuron populations, and are coupled to a contralateral hemisegment. The model yields a large range of experimental findings, especially the NMDA-induced oscillations observed in isolated axial hemisegments and segments of the salamander Pleurodeles waltlii. The model reproduces most of the effects of the blockade of AMPA synapses, glycinergic synapses, calcium-activated potassium current, persistent sodium current, and -current. Driving segments with a population of brainstem neurons yields fast oscillations in the in vivo swimming frequency range. A minimal modification to the conductances involved in burst-termination yields the slower stepping frequency range. Slow oscillators can impose their frequency on fast oscillators, as is likely the case during gait transitions from swimming to stepping. Our study shows that a lamprey-like network can potentially serve as a building block of axial and limb oscillators for swimming and stepping in salamanders.

Springer Berlin Heidelberg2013

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury

Léonie Asboth, Quentin Barraud, Laetitia Danielle Philippine Baud, Jocelyne Bloch, Marco Capogrosso, Grégoire Courtine, Simone Ellen Joze Duis, Jérôme Gandar, Arthur Edouard Hirsch, Julie Kreider, Stéphanie Lacour, Eduardo Martin Moraud, Silvestro Micera, Ivan Rusev Minev, Andrea Mortera, Pavel Musienko, Natalia Pavlova, Rubia van den Brand, Nikolaus Wenger

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Nature Publishing Group2016

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

Jérôme Gandar

EPFL2019