Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: An update

AbstractStroke is a leading cause of adult motor disability. The number of stroke survivors is increasing in industrialized countries, and despite available treatments used in rehabilitation, the recovery of motor functions after stroke is often incomplete. Studies in the 1980s showed that non-invasive brain stimulation (mainly repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]) could modulate cortical excitability and induce plasticity in healthy humans. These findings have opened the way to the therapeutic use of the 2 techniques for stroke. The mechanisms underlying the cortical effect of rTMS and tDCS differ. This paper summarizes data obtained in healthy subjects and gives a general review of the use of rTMS and tDCS in stroke patients with altered motor functions. From 1988 to 2012, approximately 1400 publications were devoted to the study of non-invasive brain stimulation in humans. However, for stroke patients with limb motor deficit, only 141 publications have been devoted to the effects of rTMS and 132 to those of tDCS. The Cochrane review devoted to the effects of rTMS found 19 randomized controlled trials involving 588 patients, and that devoted to tDCS found 18 randomized controlled trials involving 450 patients. Without doubt, rTMS and tDCS contribute to physiological and pathophysiological studies in motor control. However, despite the increasing number of studies devoted to the possible therapeutic use of non-invasive brain stimulation to improve motor recovery after stroke, further studies will be necessary to specify their use in rehabilitation

Modifications of excitability of spinal networks in healthy subjects and patients with central nervous system lesions

Ma thèse est consacrée à l’étude des réseaux neuronaux spinaux impliqués dans la motricité chez l’Homme est comprend deux chapitres. Des travaux récents effectués sur la moelle épinière du rat ont mis en évidence qu’au cours du développement chez les mammifères, les synapses GABAergiques et glycinergiques sont tout d’abord excitatrices avant de devenir inhibitrices et qu’une section de la moelle épinière ne permet pas cette transformation. Cette transition développementale semble due à l’action d’un transporteur transmembranaire (KCC2) au cours de développement qui diminue après section de la moelle épinière. La diminution de l’expression du KCC2 dépolarise l’action du GABA et de la glycine, ce qui conduit donc à une réduction de l'efficacité de synapse inhibitrice. Le but de ce projet est d’explorer si chez l’Homme une section traumatique de la moelle épinière qui prive les neurones inhibiteurs de leur contrôle suprasegmentaire a pour conséquence de modifier leur comportement synaptique, voire de les ramener à un fonctionnement « immature », c’est-à-dire de transformer des synapses inhibitrices en synapses facilitatrices. Pour tester cette hypothèse, nous avons étudié l’effet sur des synapses inhibitrices de la moelle épinière d’une prise per os de furosémide, un antagoniste de KCC2, et comparé ses effets chez des sujets sains et chez des patients porteurs d’une section de la moelle épinière. L’étude sur les sujets sains suggère que le furosémide (40 mg) a pour effet une réduction du fonctionnement des synapses inhibitrices. Cet effet du furosémide sur les synapses inhibitrices semble être réduit chez des patients. Les résultats obtenus chez les sujets sains indiquent que furosémide administré per os à des dose largement utilisé en clinique humain modifie sélectivement le fonctionnement des synapses inhibitrices et permet donc de disposer d’un mesure non-invasive de fonctionnement intrinsèque de la synapse inhibitrice. Les résultats préliminaires obtenus chez les patients porteurs d’une section de la moelle épinière suggèrent une réduction de l’efficacité de synapses inhibitrices qui probablement contribue à la spasticité. La stimulation électrique transcrânienne de courant continu encore appelée « transcranial direct current stimulation (tDCS) » par les anglo-saxons, a connu un essor considérable et constitue aujourd’hui une technique de référence pour moduler l’excitabilité du cortex chez l’Homme. En 2009, Roche et al. ont montré dans notre laboratoire, que la tDCS anodale appliquée sur l’hémisphère contralateral pouvait également modifier l’excitabilité des réseaux neuronaux spinaux (i.e. l’inhibition réciproque au niveau du poignet) enregistrée sur le côté dominant chez les sujets sains. L’existence de projection corticale ipsilatérale sur les réseaux neuronaux spinaux de la moelle épinière et leurs éventuelles modifications après lésion cortico-sous-corticale reste très controversée. Dans ce projet, nous avons testé les effets de la tDCS ipsi- et contralarérale du cortex non-lésé sur l’inhibition réciproque chez des patients AVC. La tDCS ipsilatérale n’induit pas de modifications de l’inhibition réciproque chez les sujets sains. Des résultats similaires enregistrés sur le membre supérieur lésé ont été observés chez des patients AVC, mais ces résultats mériteraient d’être confortés avec un plus grand nombre de sujets. La tDCS contralatérale chez les sujets sains n’induit pas de modifications de l’inhibition réciproque enregistrées sur le membre supérieur non-dominant. Ce résultat est différent de celui observé sur le membre supérieur dominant par Roche et al. (2009). Ce contrôle asymétrique sur l'inhibition réciproque est argument en faveur de l'hypothèse que l'inhibition inter-hémisphérique (IHI) entre les deux cortex moteurs est asymétrique. L’IHI à partir de l'hémisphère «dominant» est probablement plus importante.My thesis is devoted to the study of the spinal circuitry involved in motor functions using non-invasive electrophysiological methods in humans. It comprises two research projects.Studies in animals have shown that during neural development, GABAergic and glycinergic neurons are first excitatory, and then become inhibitory during maturation. This developmental transition is mainly due to the activation of co-transporter KCC2 at the mature state. A down-regulation of KCC2 was reported after spinal cord transection in the rat that leads to the depolarising (excitatory) action of GABA and glycine and thus results in a reduction of inhibitory synaptic efficiency. The aim of this project was to explore if spinal cord injury (SCI) in human reverses the pattern of GABAergic and glycinergic neurons back towards the immature state (primarily excitatory). To test this hypothesis, we studied the effects of furosemide (a KCC2 antagonist) on spinal inhibitory synaptic function, and compared the results obtained in healthy subjects and SCI patients. Results in healthy subjects suggest that furosemide (40 mg, orally-administrated) induces a reduction of inhibitory synapse functions. This effect of furosemide on inhibitory synapses seems to be reduced in SCI patients. Our results suggest that furosemide has the potential to test functions of inhibitory synapses in humans. The difference of furosemide effects on spinal inhibitory synapse excitability in healthy subjects and SCI patients favours the hypothesis of a decrease in inhibitory neuronal activity induced by down-regulation of KCC2 after SCI in humans that likely contributes to spasticity. Transcranial direct current stimulation (tDCS) has emerged as a method for exploring cortex excitability in humans. Roche et al. (2009) have shown in our laboratory that using anodal tDCS over contralateral motor cortex can also induce changes in spinal network excitability (i.e. reciprocal inhibition between forearm muscles) in the dominant limb in healthy subjects. It is unknown whether motor activity from the unaffected cerebral hemisphere could be employed after semi-brain damage in patients with hemiplegia. Moreover, little is known about the non-affected limb if it always functions like 'normal' after unilateral stroke. In this project, the ipsi- and contralateral corticospinal controls on reciprocal inhibition between forearm muscles were explored using anodal tDCS applied over the unaffected motor cortex of stroke patients and then compared to the results obtained in healthy subjects. Ipsilateral tDCS induces no change in reciprocal inhibition in healthy subjects. Similar results recorded on the affected upper limb are observed in stoke patients. However a larger number of patients is required to confirm the results. Contralateral anodal tDCS in healthy subjects shows no changes of reciprocal inhibition recorded in the non-dominant upper limb. This result is different from that observed in the dominant upper limb by Roche et al. (2009). This asymmetrical control on reciprocal inhibition would favour the hypothesis that the inter-hemispheric inhibition (IHI) between both motor cortices is asymmetric, with prominent IHI projections originating in the “dominant” left hemisphere. Contralateral anodal tDCS of the unaffected motor cortex induces a strong decrease in reciprocal inhibition in non-affected upper limb in stoke patients.This is different from that observed in both dominant and non-dominant upper limb in healthy subjects suggesting that the pathophysiological changes after unilateral stroke would probably not occur only on the hemiparesis side, but may also the non-affected side. A larger number of patients is still required to confirm the results

Modifications d'excitabilité des réseaux neuronaux de la moelle épinière chez des sujets sains et des patients porteurs de lésions du système nerveux central

My thesis is devoted to the study of the spinal circuitry involved in motor functions using non-invasive electrophysiological methods in humans. It comprises two research projects.Studies in animals have shown that during neural development, GABAergic and glycinergic neurons are first excitatory, and then become inhibitory during maturation. This developmental transition is mainly due to the activation of co-transporter KCC2 at the mature state. A down-regulation of KCC2 was reported after spinal cord transection in the rat that leads to the depolarising (excitatory) action of GABA and glycine and thus results in a reduction of inhibitory synaptic efficiency. The aim of this project was to explore if spinal cord injury (SCI) in human reverses the pattern of GABAergic and glycinergic neurons back towards the immature state (primarily excitatory). To test this hypothesis, we studied the effects of furosemide (a KCC2 antagonist) on spinal inhibitory synaptic function, and compared the results obtained in healthy subjects and SCI patients. Results in healthy subjects suggest that furosemide (40 mg, orally-administrated) induces a reduction of inhibitory synapse functions. This effect of furosemide on inhibitory synapses seems to be reduced in SCI patients. Our results suggest that furosemide has the potential to test functions of inhibitory synapses in humans. The difference of furosemide effects on spinal inhibitory synapse excitability in healthy subjects and SCI patients favours the hypothesis of a decrease in inhibitory neuronal activity induced by down-regulation of KCC2 after SCI in humans that likely contributes to spasticity. Transcranial direct current stimulation (tDCS) has emerged as a method for exploring cortex excitability in humans. Roche et al. (2009) have shown in our laboratory that using anodal tDCS over contralateral motor cortex can also induce changes in spinal network excitability (i.e. reciprocal inhibition between forearm muscles) in the dominant limb in healthy subjects. It is unknown whether motor activity from the unaffected cerebral hemisphere could be employed after semi-brain damage in patients with hemiplegia. Moreover, little is known about the non-affected limb if it always functions like 'normal' after unilateral stroke. In this project, the ipsi- and contralateral corticospinal controls on reciprocal inhibition between forearm muscles were explored using anodal tDCS applied over the unaffected motor cortex of stroke patients and then compared to the results obtained in healthy subjects. Ipsilateral tDCS induces no change in reciprocal inhibition in healthy subjects. Similar results recorded on the affected upper limb are observed in stoke patients. However a larger number of patients is required to confirm the results. Contralateral anodal tDCS in healthy subjects shows no changes of reciprocal inhibition recorded in the non-dominant upper limb. This result is different from that observed in the dominant upper limb by Roche et al. (2009). This asymmetrical control on reciprocal inhibition would favour the hypothesis that the inter-hemispheric inhibition (IHI) between both motor cortices is asymmetric, with prominent IHI projections originating in the “dominant” left hemisphere. Contralateral anodal tDCS of the unaffected motor cortex induces a strong decrease in reciprocal inhibition in non-affected upper limb in stoke patients.This is different from that observed in both dominant and non-dominant upper limb in healthy subjects suggesting that the pathophysiological changes after unilateral stroke would probably not occur only on the hemiparesis side, but may also the non-affected side. A larger number of patients is still required to confirm the results.Ma thèse est consacrée à l’étude des réseaux neuronaux spinaux impliqués dans la motricité chez l’Homme est comprend deux chapitres. Des travaux récents effectués sur la moelle épinière du rat ont mis en évidence qu’au cours du développement chez les mammifères, les synapses GABAergiques et glycinergiques sont tout d’abord excitatrices avant de devenir inhibitrices et qu’une section de la moelle épinière ne permet pas cette transformation. Cette transition développementale semble due à l’action d’un transporteur transmembranaire (KCC2) au cours de développement qui diminue après section de la moelle épinière. La diminution de l’expression du KCC2 dépolarise l’action du GABA et de la glycine, ce qui conduit donc à une réduction de l'efficacité de synapse inhibitrice. Le but de ce projet est d’explorer si chez l’Homme une section traumatique de la moelle épinière qui prive les neurones inhibiteurs de leur contrôle suprasegmentaire a pour conséquence de modifier leur comportement synaptique, voire de les ramener à un fonctionnement « immature », c’est-à-dire de transformer des synapses inhibitrices en synapses facilitatrices. Pour tester cette hypothèse, nous avons étudié l’effet sur des synapses inhibitrices de la moelle épinière d’une prise per os de furosémide, un antagoniste de KCC2, et comparé ses effets chez des sujets sains et chez des patients porteurs d’une section de la moelle épinière. L’étude sur les sujets sains suggère que le furosémide (40 mg) a pour effet une réduction du fonctionnement des synapses inhibitrices. Cet effet du furosémide sur les synapses inhibitrices semble être réduit chez des patients. Les résultats obtenus chez les sujets sains indiquent que furosémide administré per os à des dose largement utilisé en clinique humain modifie sélectivement le fonctionnement des synapses inhibitrices et permet donc de disposer d’un mesure non-invasive de fonctionnement intrinsèque de la synapse inhibitrice. Les résultats préliminaires obtenus chez les patients porteurs d’une section de la moelle épinière suggèrent une réduction de l’efficacité de synapses inhibitrices qui probablement contribue à la spasticité. La stimulation électrique transcrânienne de courant continu encore appelée « transcranial direct current stimulation (tDCS) » par les anglo-saxons, a connu un essor considérable et constitue aujourd’hui une technique de référence pour moduler l’excitabilité du cortex chez l’Homme. En 2009, Roche et al. ont montré dans notre laboratoire, que la tDCS anodale appliquée sur l’hémisphère contralateral pouvait également modifier l’excitabilité des réseaux neuronaux spinaux (i.e. l’inhibition réciproque au niveau du poignet) enregistrée sur le côté dominant chez les sujets sains. L’existence de projection corticale ipsilatérale sur les réseaux neuronaux spinaux de la moelle épinière et leurs éventuelles modifications après lésion cortico-sous-corticale reste très controversée. Dans ce projet, nous avons testé les effets de la tDCS ipsi- et contralarérale du cortex non-lésé sur l’inhibition réciproque chez des patients AVC. La tDCS ipsilatérale n’induit pas de modifications de l’inhibition réciproque chez les sujets sains. Des résultats similaires enregistrés sur le membre supérieur lésé ont été observés chez des patients AVC, mais ces résultats mériteraient d’être confortés avec un plus grand nombre de sujets. La tDCS contralatérale chez les sujets sains n’induit pas de modifications de l’inhibition réciproque enregistrées sur le membre supérieur non-dominant. Ce résultat est différent de celui observé sur le membre supérieur dominant par Roche et al. (2009). Ce contrôle asymétrique sur l'inhibition réciproque est argument en faveur de l'hypothèse que l'inhibition inter-hémisphérique (IHI) entre les deux cortex moteurs est asymétrique. L’IHI à partir de l'hémisphère «dominant» est probablement plus importante

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

Anodal tDCS of contralateral hemisphere modulates ipsilateral control of spinal motor networks targeting the paretic arm post-stroke

International audienceObjectiveThe role of ipsilateral motor cortex efferent pathways in the transmission of voluntary command to spinal motor nuclei remains controversial in humans. In healthy subjects, their implication in cortical control is hidden by predominant role of crossed corticospinal tract. However, evidence from electrophysiological and imaging studies suggest that ipsilateral tracts may contribute to functional recovery after unilateral brain damage. This randomized-sham control study aims to explore to what extent ipsilateral tracts from the undamaged hemisphere may strengthen corticospinal control onto spinal motor networks following stroke.MethodsAnodal transcranial direct current stimulation (tDCS) was combined with monosynaptic H-reflex method to evaluate the variations of reciprocal inhibition (RI) in wrist flexors in 21 stroke participants.ResultsAnodal tDCS decreased RI in wrist flexors in stroke participants in both arms. tDCS unmasks an ipsilateral control from the undamaged hemisphere onto spinal motor networks controlling affected arm muscles in stroke participants. In the unaffected (contralateral) arm, effects in stroke participants were opposite to those induced in healthy subjects.ConclusionsStimulation of the undamaged cortex in stroke participants induces modulation of ipsilateral motor networks controlling the hemiparetic side.SignificanceRehabilitation could leverage stimulation of the undamaged hemisphere to enhance motor recovery post stroke

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