A computational modeling approach to study the neuromechanics of terrestrial locomotion

Shravan Tata Ramalingasetty
EPFL, 2022
Thèse EPFL

Résumé

The main theme of my thesis will be to use neuro-muscular modeling techniques to study locomotion of terrestrial mammals. Locomotion is the ability of animals to interact with the environment to propel themselves in space. It involves co-ordination and precise timing of tens of muscles and multiple joints to produce rhythmic, efficient and robust gaits. It is now understood that it is a complex interaction of brain, spinal cord, the musculo-skeletal system and the environment. During my thesis I plan to develop models of rodents to non-human primates to humans to study the interactions between these components. I will be carrying out my research at BioRob lab and funded by the Human Brain Project. After spending an year on this subject currently I have developed a neuro-muscular hind limb model of a mouse. I am using this model to study different locomotion theories ranging from reflex based abstraction methods to Central Patter Generator networks and spiking neuron based spinal circuits. The closed loop approach seems promising and I am now able to generate stable locomotion on a forward dynamics model using all the mentioned frameworks. The future plan will be to further improve the rodent model with more degrees of freedom in the forelimb and extend the same modeling approach to develop non-human primate and human models to carry out similar experiments.

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https://infoscience.epfl.ch/record/295141?ln=fr

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Publications associées (45)

Brain-spine interface technologies to alleviate gait deficits after Parkinson's disease

Flavio Raschella

Gait and balance deficits are motor disabilities that typically develop late in the progression of Parkinson's disease (PD). These deficits are thought to be the result of dysregulated neural activity in the cortico-basal ganglia-thalamic-cortical motor loop, caused by the depletion of dopaminergic and cholinergic circuits. PD patients exhibit gait abnormalities characterized by postural instability and reduced locomotor control, which diminish their functional independence and strongly affect their quality of life. This is further aggravated by the onset of falling events. These deficits represent a therapeutic challenge as they typically respond poorly or not at all to standard therapies, such as dopaminergic medication and deep brain stimulation (DBS). Whereas the efficacy of DBS in treating cardinal symptoms of PD, such as tremor, rigidity and bradykinesia is well established, effects on gait and balance deficits are still controversial. With disease progression the majority of PD patients develop a resistance to DBS treatment, which results in a significant worsening of gait and postural stability, while cardinal symptoms remain partially stable. In the last decade, Epidural Electrical Stimulation (EES) of the spinal cord has been proposed as a possible solution for improving locomotor performance in people with PD. Initial results on rodent and marmoset models of PD were promising. In these studies, EES was delivered continuously at the thoracic level of the spinal cord, without taking into consideration the locomotor state. However, translation to human patients led to conflicting results. In parallel, studies in spinal cord injury (SCI), in both animal models and patients, have drawn attention to the use of spatially and temporally specific stimulation protocols that independently engage flexion and extension muscles synergies. This strategy has allowed unprecedented progress, enabling full weight-bearing and restoration of locomotion after only a few days of application. In order to promote voluntary control of locomotion after SCI, a first brain-spine interface (BSI) was engineered to link the intended motor state to the EES protocols, re-establishing the altered communication between the brain and the spinal cord. In this thesis, I show that gait and balance deficits developed in the non-human primate (NHP) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD are similar to those observed in PD patients. Next, I describe the design of spatiotemporal EES protocols using the activation of the spinal motor neurons. I subsequently show that, although MPTP treatment drastically reduces the number of dopaminergic neurons in the substantia nigra, it has no detectable impact on the cortical dynamics underlying locomotion. Furthermore, I demonstrate that a BSI immediately alleviates gait and balance deficits in an NHP MPTP model of PD. Finally, I investigate the interaction between DBS and BSI in a MPTP-treated NHP. Although DBS increases the alertness and locomotor activity of the NHP, it has no effect on kinematic parameters during gait. The BSI, instead, alone or in combination with DBS, improves locomotor performance such that it approaches healthy locomotion. Therefore, I demonstrate that the BSI and DBS can be simultaneously applied, opening up the possibility of a combined therapeutic approach in human patients. As such, the subsequent step should be to test the efficacy of the BSI in treating PD patients.

EPFL2019

Chargement

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

Chargement

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

Chargement

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Brain-spine interface technologies to alleviate gait deficits after Parkinson's disease

Flavio Raschella

EPFL2019

Neuroprosthetic rehabilitation and translational mechanism after severe spinal cord injury

Lucia Florinda Friedli Wittler

EPFL2014

EPFL2019