Stimulation magnétique transcrânienne et inhibition intra-corticale (variabilité liée au recrutement des motoneurones spinaux et des neurones corticaux)

L activation "transynaptique" des neurones pyramidaux du cortex moteur primaire par stimulation magnétique transcrânienne (TMS) induit des volées corticospinales (CSP) transmises aux motoneurones spinaux. Leur activation entraîne une contraction traduite par un potentiel (PEM) dans l activité électromyographique du muscle cible. L amplitude du PEM en mV sert à évaluer l état d excitabilité des neurones de la voie CSP. Si une TMS conditionnante précède de 2 à 5 ms une TMS test, le PEM évoqué par le double choc de TMS est plus petit que le PEM induit par la TMS test seule. Cette inhibition, la SICI, vient de l activation d interneurones inhibiteurs qui modifient la réponse des neurones pyramidaux à la TMS test. La variabilité des résultats remet en cause la fiabilité de cette méthode. Plusieurs paramètres ont été testés, mais jamais les propriétés des neurones corticaux et spinaux n ont été suspectées. L objectif du projet doctoral était de vérifier si les propriétés de ces neurones influencent l évaluation de la SICI chez l Homme. Le PEM test a été exprimé en % de la réponse motrice maximale (Mmax), plutôt qu en mV, pour évaluer la fraction de MNs recrutés par la TMS test. Des unités motrices isolées ont été testées pour explorer les réponses des neurones corticaux à la TMS. Les résultats ont révélé que i) la sommation des volées CSP au niveau des MNs n est pas linéaire ce qui influence l évaluation de la SICI, ii) l intégration des entrées synaptiques inhibitrices au niveau des réseaux corticaux afférents aux cellules pyramidales n est pas linéaire. Ce travail a permis de proposer une nouvelle méthode d évaluation des mécanismes corticaux révélés avec la TMS.PARIS-BIUP (751062107) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS)

International audienceTranscranial magnetic stimulation (TMS) and repetitive TMS (rTMS) are indirect and non-invasive methods used to induce excitability changes in the motor cortex via a wire coil generating a magnetic field that passes through the scalp. Today, TMS has become a key method to investigate brain functioning in humans. Moreover, because rTMS can lead to long-lasting after-effects in the brain, it is thought to be able to induce plasticity. This tool appears to be a potential therapy for neurological and psychiatric diseases. However, the physiological mechanisms underlying the effects induced by TMS and rTMS have not yet been clearly identified. The purpose of the present review is to summarize the main knowledge available for TMS and rTMS to allow for understanding their mode of action and to specify the different parameters that influence their effects. This review takes an inventory of the most-used rTMS paradigms in clinical research and exhibits the hypotheses commonly assumed to explain rTMS after-effects

Modulation of recurrent inhibition from knee extensors to ankle motoneurones during human walking

The neural control for muscle coordination during human locomotion involves spinal and supraspinal networks, but little is known about the exact mechanisms implicated. The present study focused on modulation of heteronymous recurrent inhibition from knee extensors to ankle motoneurones at different times in the gait cycle, when quadriceps (Quad) muscle activity overlaps that in tibialis anterior (TA) and soleus (Sol). The effects of femoral nerve stimulation on ankle motoneurones were investigated during treadmill walking and during tonic co-contraction of Quad and TA/Sol while standing. Recurrent inhibition of TA motoneurones depended on the level of background EMG, and was similar during walking and standing for matched background EMG levels. On the other hand, recurrent inhibition in Sol was reduced in early stance, with respect to standing, and enhanced in late stance. Reduced inhibition in Sol was also observed when Quad was coactivated with TA around the time of heel contact, compared to standing at matched background EMG levels in the two muscles. The modulation of recurrent inhibition of Sol during walking might reflect central and/or peripheral control of the Renshaw cells. These modulations could be implicated in the transition phases, from swing to stance to assist Sol activation during the stance phase, and from stance to swing, for its deactivation

Transient increase in recurrent inhibition in amyotrophic lateral sclerosis as a putative protection from neurodegeneration

International audienceAim: Adaptive mechanisms in spinal circuits are likely involved in homeostatic responses to maintain motor output in amyotrophic lateral sclerosis. Given the role of Renshaw cells in regulating the motoneuron input/output gain, we investigated the modulation of heteronymous recurrent inhibition.Methods: Electrical stimulations were used to activate recurrent collaterals resulting in the Hoffmann reflex depression. Inhibitions from soleus motor axons to quadriceps motoneurons, and vice versa, were tested in 38 patients and matched group of 42 controls.Results: Compared to controls, the mean depression of quadriceps reflex was larger in patients while that of soleus was smaller suggesting that heteronymous recurrent inhibition was enhanced in quadriceps but reduced in soleus. The modulation of recurrent inhibition was linked to the size of maximal direct motor response and lower limb dysfunctions suggesting a significant relationship with the integrity of the target motoneuron pool and functional abilities. No significant link was found between the integrity of motor axons activating Renshaw cells and the level of inhibition. Enhanced inhibition was particularly observed in patients within the first year after symptom onset and with slow progression of lower limb dysfunctions. Normal or reduced inhibitions were mainly observed in patients with motor weakness first in lower limbs and greater dysfunctions in lower limbs.Conclusion: We provide the first evidence for enhanced recurrent inhibition and speculate that Renshaw cells might have transient protective role on motoneuron by counteracting hyperexcitability at early stages. Several mechanisms likely participate including cortical influence on Renshaw cell and reinnervation by slow motoneurons

Corticospinal control from M1 and PMv areas on inhibitory cervical propriospinal neurons in humans

International audienceInhibitory propriospinal neurons with diffuse projections onto upper limb motoneurons have been revealed in humans using peripheral nerve stimulation. This system is supposed to mediate descending inhibition to motoneu-rons, to prevent unwilling muscle activity. However, the corticospinal control onto inhibitory propriospinal neurons has never been investigated so far in humans. We addressed the question whether inhibitory cervical propriospinal neurons receive corticospinal inputs from primary motor (M1) and ventral premotor areas (PMv) using spatial facilitation method. We have stimulated M1 or PMv using transcranial magnetic stimulation (TMS) and/or median nerve whose afferents are known to activate inhibitory propriospinal neurons. Potential input convergence was evaluated by studying the change in monosy-naptic reflexes produced in wrist extensor electromyogram (EMG) after isolated and combined stimuli in 17 healthy subjects. Then, to determine whether PMv controlled propriospinal neurons directly or through PMv-M1 interaction, we tested the connectivity between PMv and propriospinal neu-rons after a functional disruption of M1 produced by paired continuous theta burst stimulation (cTBS). TMS over M1 or PMv produced reflex inhibition significantly stronger on combined stimulations, compared to the algebraic sum of effects induced by isolated stimuli. The extra-inhibition induced by PMv stimulation remained even after cTBS which depressed M1 excitability. The extra-inhibition suggests the existence of input convergence between peripheral afferents and corticospinal inputs onto inhibitory propriospinal neurons. Our results support the existence of direct descending influence from M1 and PMv onto inhibitory propriospinal neurons in humans, possibly though direct corticospinal or via reticulospinal inputs

Corticospinal control from M1 and PMv areas on inhibitory cervical propriospinal neurons in humans

International audienceInhibitory propriospinal neurons with diffuse projections onto upper limb motoneurons have been revealed in humans using peripheral nerve stimulation. This system is supposed to mediate descending inhibition to motoneu-rons, to prevent unwilling muscle activity. However, the corticospinal control onto inhibitory propriospinal neurons has never been investigated so far in humans. We addressed the question whether inhibitory cervical propriospinal neurons receive corticospinal inputs from primary motor (M1) and ventral premotor areas (PMv) using spatial facilitation method. We have stimulated M1 or PMv using transcranial magnetic stimulation (TMS) and/or median nerve whose afferents are known to activate inhibitory propriospinal neurons. Potential input convergence was evaluated by studying the change in monosy-naptic reflexes produced in wrist extensor electromyogram (EMG) after isolated and combined stimuli in 17 healthy subjects. Then, to determine whether PMv controlled propriospinal neurons directly or through PMv-M1 interaction, we tested the connectivity between PMv and propriospinal neu-rons after a functional disruption of M1 produced by paired continuous theta burst stimulation (cTBS). TMS over M1 or PMv produced reflex inhibition significantly stronger on combined stimulations, compared to the algebraic sum of effects induced by isolated stimuli. The extra-inhibition induced by PMv stimulation remained even after cTBS which depressed M1 excitability. The extra-inhibition suggests the existence of input convergence between peripheral afferents and corticospinal inputs onto inhibitory propriospinal neurons. Our results support the existence of direct descending influence from M1 and PMv onto inhibitory propriospinal neurons in humans, possibly though direct corticospinal or via reticulospinal inputs

Furosemide unmasks inhibitory dysfunction following spinal cord injury in humans: implications for spasticity

International audienceSpasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and necessitates long-term multi-disciplinary pharmacological and non-pharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies consistently have demonstrated a downregulation of KCC2 activity after spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. Furosemide, a recognized KCC2 antagonist in animals, blocks the formation of inhibitory post-synaptic potentials in spinal motoneurons without affecting excitatory post-synaptic potentials. Based on observations in animals studies, we hypothesized that furosemide may be used to unmask KCC2 downregulation after spinal cord injury in humans, which contributes to reflex hyperexcitability. We have shown previously that furosemide reduces both pre-synaptic and post-synaptic inhibition in healthy subjects without altering monosynaptic excitatory transmission. These findings provide evidence that furosemide may be used in humans to evaluate inhibitory synapses in the spinal cord. In this present study, we show that furosemide fails to modulate both pre- and post-synaptic inhibitions relayed to soleus spinal motor neurons in persons with spinal cord injury. The lack of furosemide effect after spinal cord injury suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important etiological factor in hyperreflexia after spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centered on chloride homeostasis

The PAI-1 swing: Microenvironment and Cancer cell migration

International audienceCancer is a complex and dynamic process caused by a cellular dysfunction leading to a whole organ or even organism vital perturbation. To better understand this process we need to study each of the levels involved, what allows the scale change, and to integrate this knowledge. A matricellular protein, PAI-1, is able to induce in vitro cell behaviour modifications, morphological changes, and to promote cell migration. PAI-1 influences the mesenchymoamaeboid transition. This matricellular protein should be considered as a potential launcher of the metastatic process acting at the molecular, cellular, tissular levels and, as a consequence, at the organism's level