Moelle spinale | EPFL Graph Search

La moelle spinale (selon la nouvelle nomenclature), ou moelle épinière (dans l’ancienne nomenclature), désigne la partie du système nerveux central qui prolonge la moelle allongée appartenant au tronc cérébral. Elle est contenue dans le canal rachidien (canal formé par la superposition des foramens vertébraux), qui la soutient et la protège. Elle est constituée de neurones et de cellules gliales. Sa fonction principale est la transmission des messages nerveux entre le cerveau et le reste du corps. Elle contient également des circuits neuronaux indépendants qui contrôlent certains réflexes. Embryologie La moelle spinale dérive du tube neural mis en place chez l'humain à la de développement grâce à la neurulation, en arrière du rhombencéphale. Lorsque le tube neural se développe, la notochorde sous-jacente produit un facteur connu sous le nom de sonic hedgehog ou SHH. En réaction, la partie inférieure du tube se met également à sécréter du SHH et induit le développem

Axon regeneration and circuit reorganization after complete spinal cord injury

Sabry Leonardo Barlatey

First human trials involving neuroprosthetic rehabilitation demonstrated recently that significant functional benefits can be achieved with lumbosacral neuromodulation and reorganized spared projections. However, complete spinal cord injuries (SCI) wholly isolate infralesional circuits from any supraspinal control, leading to irreversible motor deficits that neuroprosthetics still fails to address. As axons fail to regrow across the lesion site, neuroregenerative research after SCI has been dogmatically focusing attention on minimizing the environmental inhibitions to axon regeneration. In the present work, we demonstrate that spontaneous axon regeneration failure can be reversed, and that propriospinal axons are able to grow across complete non-neural lesion cores when the required facilitators are provided. We identified three mechanisms needed for propriospinal regrowth : i) enhancing neuronal intrinsic growth capacities using viral technologies, ii) remodeling the lesion core with growth factors, in order to densify permissive substrates, and iii) guiding axons chemically across the SCI site. Propriospinal neurons - that coordinate different spinal segments in healthy conditions - are known to support recovery of locomotion in incomplete models of spinal cord injury. However, restoring a robust descending bridge of propriospinal axons does not by itself promote any functional benefit. We hypothesize that a lack of somatosensory feedback to the motor cortex (M1), together with insufficient descending motor control, may prevent coherent exchange of information between lumbosacral and cortical motor centers. Therefore, we explored the neuroregenerative potential of reticulospinal axons - which are projected from the brainstem to the spinal cord - as a second relay for the descending motor cortical command. Together with axon guidance and lesion remodeling, our viral manipulation of intrinsic growth programs induced limited yet significant reticulospinal regeneration into the lesion core. In order to enhance this reticulospinal regrowth, we explored activity-dependent mechanisms of neurite growth control. As we observed that activity does not recruit growth programs after SCI, we revealed a possible divergence between the mechanisms that underly reticulospinal axon regrowth and neurite sprouting. In the mean time, we are developing a somatosensory interface that aims at restoring sensory feedback to the motor cortex after complete SCI. Based on hindlimb electromyographic activity, we linked locomotion to optogenetic neuromodulation of the motor thalamus, and were able to evoke responses in M1 by selectively activating thalamocortical projections, both before and after complete spinal lesion. Such technology enables a direct recruitment of thalamic nuclei that gate motor learning and motor planning at a cortical level. Coming experiments will test wether a strategy combining propriospinal regeneration with locomotion-dependent thalamocortical modulation is sufficient to restore voluntary stepping after complete SCI.

EPFL2019

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

Unbiased interrogation of whole brain circuits in spinal cord injury leading to the design of a clinically relevant therapy to improve locomotion

Newton Cho

Spinal cord injury (SCI) remains a global problem, and despite decades of research there currently is no cure for this disease. Recently, significant advances in the use of neuroprosthetic rehabilitation to improve locomotor outcomes after SCI have been made both in preclinical models and in humans. More specifically, the administration of lumbar epidural electrical stimulation (EES) has been shown to improve lower limb function after SCI with long-term improvements when combined with locomotor training. There have been important strides in understanding the mechanisms of this strategy and the role of the spinal cord, but there remains a significant gap in understanding the role of the brain in the recovery of locomotion after SCI. The purpose of this thesis was to address this gap and to elucidate the circuits in the brain that potentially, when modulated, could improve functional recovery after SCI and augment current therapeutic paradigms.

EPFL2021

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

Flavio Raschella

EPFL2019

Axon regeneration and circuit reorganization after complete spinal cord injury

Sabry Leonardo Barlatey

EPFL2019