Scholarly article on topic 'Non-invasive brain stimulation (NIBS) and motor recovery after stroke'

Non-invasive brain stimulation (NIBS) and motor recovery after stroke Academic research paper on "Clinical medicine"

CC BY-NC-ND
0
0
Share paper
OECD Field of science
Keywords
{Stroke / "Motor recovery" / rTMS / TBS / tDCS / PAS / "Brain plasticity" / AVC / "Récupération motrice" / rTMS / TBS / tDCS / PAS / "Plasticité cérébrale"}

Abstract of research paper on Clinical medicine, author of scientific article — M. Simonetta-Moreau

Abstract Recovery of motor function after stroke occurs largely on the basis of a sustained capacity of the adult brain for plastic changes. This brain plasticity has been validated by functional imaging and electrophysiological studies. Various concepts of how to enhance beneficial plasticity and in turn improve functional recovery are emerging based on the concept of functional interhemispheric balance between the two motor cortices. Besides conventional rehabilitation interventions and the most recent neuropharmacological approaches, non-invasive brain stimulation (NIBS) has recently been proposed as an add-on method to promote motor function recovery after stroke. Several methods can be used based either on transcranial magnetic stimulation (repetitive mode: rTMS, TBS) via a coil, or small electric current via larges electrodes placed on the scalp, (transcranial direct current stimulation tDCS). Depending on the different electrophysiological parameters of stimulation used, NIBS can induce a transient modulation of the excitability of the stimulated motor cortex (facilitation or inhibition) via a probable LTP-LTD-like mechanism. Several small studies have shown feasible and positive treatment effects for most of these strategies and their potential clinical relevance to help restoring the disruption of interhemispheric imbalance after stroke. Results of these studies are encouraging but many questions remain unsolved: what are the optimal stimulation parameters? What is the best NIBS intervention? Which cortex, injured or intact, should be stimulated? What is the best window of intervention? Is there a special subgroup of stroke patients who could strongly benefit from these interventions? Finally is it possible to boost NIBS treatment effect by motor training of the paretic hand or by additional neuropharmacological interventions? There is clearly a need for large-scale, controlled, multicenter trials to answer these questions before proposing their routine use in the management of stroke patients.

Academic research paper on topic "Non-invasive brain stimulation (NIBS) and motor recovery after stroke"

Available online at

ScienceDirect

Elsevier Masson France

EM consulte

www.sciencedirect.comwww.em-consulte.com

Annals of Physical and Rehabilitation Medicine xxx (2014) xxx-xxx

Literature review/Revue de la litterature

Non-invasive brain stimulation (NIBS) and motor recovery after stroke

Neuromodulation corticale non invasive (NIBS) et récupération motrice post-AVC

M. Simonetta-Moreau

a,b,c,*

a Centre hospitalier universitaire de Toulouse, pôle neurosciences, CHU Purpan, place du Dr Baylac, 31059 Toulouse cedex 9, France Imagerie cérébrale et handicaps neurologiques UMR 825, université de Toulouse, UPS, CHU Purpan, place du Dr Baylac, 31059 Toulouse cedex 9, France c Inserm, imagerie cerébrale et handicaps neurologiques UMR 825, CHU Purpan, Pavillon Baudot, place du Dr Baylac, 31024 Toulouse cedex 3, France *Correspondence. Centre hospitalier universitaire de Toulouse, pole neurosciences, CHU Purpan, place du Dr Baylac, 31059 Toulouse cedex 9, France.

Received 6 August 2014; accepted 6 August 2014

Abstract

Recovery of motor function after stroke occurs largely on the basis of a sustained capacity of the adult brain for plastic changes. This brain plasticity has been validated by functional imaging and electrophysiological studies. Various concepts of how to enhance beneficial plasticity and in turn improve functional recovery are emerging based on the concept of functional interhemispheric balance between the two motor cortices. Besides conventional rehabilitation interventions and the most recent neuropharmacological approaches, non-invasive brain stimulation (NIBS) has recently been proposed as an add-on method to promote motor function recovery after stroke. Several methods can be used based either on transcranial magnetic stimulation (repetitive mode: rTMS, TBS) via a coil, or small electric current via larges electrodes placed on the scalp, (transcranial direct current stimulation tDCS). Depending on the different electrophysiological parameters of stimulation used, NIBS can induce a transient modulation of the excitability of the stimulated motor cortex (facilitation or inhibition) via a probable LTP-LTD-like mechanism. Several small studies have shown feasible and positive treatment effects for most of these strategies and their potential clinical relevance to help restoring the disruption of interhemispheric imbalance after stroke. Results of these studies are encouraging but many questions remain unsolved: what are the optimal stimulation parameters? What is the best NIBS intervention? Which cortex, injured or intact, should be stimulated? What is the best window of intervention? Is there a special subgroup of stroke patients who could strongly benefit from these interventions? Finally is it possible to boost NIBS treatment effect by motor training of the paretic hand or by additional neuropharmacological interventions? There is clearly a need for large-scale, controlled, multicenter trials to answer these questions before proposing their routine use in the management of stroke patients. © 2014 Published by Elsevier Masson SAS.

Keywords: Stroke; Motor recovery; rTMS; TBS; tDCS; PAS; Brain plasticity Résumé

Le cerveau d'un patient victime d'un accident vasculaire cerébral (AVC) a les capacites de reconfigurer son activite dans les suites de l'infarctus. Cette plasticité; cerébrale spontanee, substrat de la récuperation fonctionnelle, a fait l'objet de nombreux travaux de recherche en imagerie fonctionnelle et en electrophysiologie aboutissant au concept de balance interhemispherique et au developpement de techniques de neuromodulation corticale, visant a faciliter les processus naturels de plasticite corticale. Ces methodes non invasives utilisent soit, l'application sur le scalp a travers un coil d'un courant magntîtique en mode répetitif, (stimulation magnetique transcrânienne répetitive rTMS, TBS), soit l'application d'un courant electrique continu de faible intensite a travers deux larges electrodes placees sur le scalp, (stimulation electrique directe transcrânienne, tDCS). Elles permettent d'induire une modulation de l'excitabilite du cortex moteur sous-jacent transitoire et focale, (facilitation ou inhibition en fonction des parametres de stimulation), par un mecanisme de type LTP/LTD. Ces methodes visent principalement a restaurer l'equilibre de la balance interhemispherique entre le cortex moteur du cote lese et du cote sain. Plusieurs etudes ont souligne leur interêt potentiel dans la récuperation motrice post-AVC en montrant des amtîliorations sensibles des performances motrices de la main parétique comparativement a des stimulations placebo, ainsi que leur bonne tolerance. Cependant, de nombreuses questions demeurent encore en suspens avant de pouvoir les utiliser en routine, concernant les parametres de stimulation optimaux, les cibles potentielles, le choix des techniques, la meilleure periode de leur

E-mail addresses: simonetta.m@chu-toulouse.fr, philippe.marque@gmail.com.

http://dx.doi.Org/10.1016/j.rehab.2014.08.003 1877-0657/© 2014 Published by Elsevier Masson SAS.

application (phase aiguë, chronique), les critères de sélection des patients susceptibles d'en bénéficier et finalement leur place par rapport aux techniques conventionnelles de reeducation et les approches neuropharmacologiques. © 2014 Publie par Elsevier Masson SAS.

Mots clés : AVC ; Recuperation motrice ; rTMS ; TBS ; tDCS ; PAS ; Plasticite cerébrale

1. English version

1.1. Brain plasticity and cortical reorganization mechanisms after stroke

The brain has the ability to reconfigure its activity in the aftermath of an ischemic stroke thanks to its natural plasticity. The latter expresses itself via the basic brain metabolism, changes in cortical mapping (overactivation of the damaged cortices, changes in motor and sensitive somatotopies [1,2]), and recruitment of brain areas at a distance from the lesion which will be involved in functional recovery [3]. During the motor recovery phase, functional imaging studies (PET scan and functional MRI) have underlined the involvement of areas adjacent to the lesion [4] and the recruitment of areas in the healthy hemisphere [5,6]. It has been largely validated that adequate motor recovery of the paretic hand in stroke patients is correlated to a reorganization of the brain activity within the injured hemisphere [7-9]. If at first, the recovery relies on neuronal networks involving at the same time ispilesional and contralesional secondary sensorimotor areas, the return to a more classic network would promote a quality recovery [10,11]. In fact the greater the asymmetry between both hemispheres is, the worse the recovery will be [12,13]. Longitudinal studies have validated the existence of dynamic changes in the balance of activation between the healthy and injured hemispheres (interhemispheric balance) during recovery, with an initial hyperactivity of the healthy hemisphere during a movement of the paretic hand [4,11,14]. In the dynamic evolution of recovery, it seems that patients exhibiting a poor recovery will continue to show an activation of the contralesional hemisphere [7,15]. However, imaging studies cannot refine if this bilateral activation is the consequence of poor motor performances of the paretic hand (epiphenomenon), or the indication of a disruption in the interhemispheric balance interfering secondarily with motor performances. This is why electrophysiology studies are relevant. Results from the study by Werhahn et al. [16] suggest that the role of the contralesional motor cortex in the recovery of performances of the paretic hand would be minor during the chronic phase since the reaction time of finger movements of the paretic hand is only disrupted by the application of interferential TMS on the ispilesional motor cortex but not by TMS applied on the contralesional motor cortex. However, a more recent study [17] showed that the application of interferential TMS on contralesional motor areas disrupts more the simple reaction time of a finger movement performed with the paretic hand when patients exhibit a poor recovery, thus suggesting on the contrary, a functional role of contralesional motor areas in recovery, even more so when patients have severe impairments.

Conversely, Lotze et al. [18,19] showed that inhibitory rTMS applied on the contralesional motor cortex of chronic stroke patients with a good recovery induces disruptions in movement precision when performing a complex sequencing gesture with the paretic hand, thus suggesting that the hyperactivity or recruiting of contralesional motor areas during complex motor tasks could have a beneficial effect on the performances of the paretic hand. To sum up, these results underline the difficulties in apprehending the exact role played by the contralateral hemisphere in motor recovery after stroke. It most certainly relies on several factors including time elapsed since stroke (acute or chronic phase), importance and site of the lesion and complexity of the motor task to be performed.

1.2. Modulation of intra- and interhemispheric cortical excitability after stroke

TMS has enabled teams to study the changes in the excitability of the primary motor cortices of the injured and healthy hemispheres during the recovery phase as well as the modulation of interhemispheric inhibition at rest and when planning and executing a voluntary movement. The first studies in this field reported results in favor of an hyperactivity of the healthy hemisphere during motor recovery of the paretic hand [20,21], which tends to decrease over time, especially in patients with a satisfactory recovery [22]. With double-shock TMS [23], authors reported a decrease in the mechanisms of the GABAergic inhibitory interneurons (GABA-A, short intra-cortical inhibition [SICI]) of the motor networks for the injured and healthy hemispheres, during the acute or subacute phase [24-27]. This SICI modulation might reflect a recovery strategy promoting the use of the usual or compensatory motor areas, but its measurement only seems reliable after 3 months of recovery [28].

Each motor cortex exerts a mutual influence on its opposite counterpart via glutamatergic transcallosal fibers projecting onto the GABAergic inhibitory interneurons of the opposite motor cortex [29-31]. These interhemispheric connections (interhemispheric inhibition [IHI]) can be indirectly studied via double-shock TMS [29,30]. These interhemispheric interactions are useful in the voluntary control of unimanual and bimanual movements [32]. According to the concept of interhemispheric balance, after brain damage (M1, language areas, parietal areas), there is a decreased excitability of the ispilesional motor cortex and a hyperexcitability of the contralesional motor cortex. After an ischemic stroke, we can observe an increased IHI from the contralesional M1, exerting an action on the ispilesional M1, when preparing for a voluntary movement, which would be inversely correlated with a good

recovery of the paretic hand: a higher IHI disruption would lead to a poorer motor recovery [33,34]. The recovery of the damaged area might be disrupted by an excessive inhibitory input via the transcallosal pathways, coming from the contralesional area of the healthy hemisphere in a state of hyperactivity due to the decreased reciprocal inhibitory input of the damaged hemisphere onto the healthy one. This hypothesis represents one of the "detrimental" brain plasticity models of the healthy hemisphere onto the damaged hemisphere, which might disrupt motor recovery after stroke. This model is the origin of the development of brain neuromodulation techniques aimed at restoring physiological interhemispheric balance.

1.3. Non-invasive brain stimulation methods: NIBS

Based on functional imaging and electrophysiological data leading to the concept of disruption of the interhemispheric balance after stroke (see review [35]), in the past 12 years, noninvasive brain stimulation (NIBS) techniques have been developed to optimize functional recovery by modulating natural brain plasticity. The many objectives of using NIBS in motor recovery post-stroke are:

• increase the excitability of the motor cortex on the damaged side;

• limit the development of maladaptive compensatory strategies (hyperexcitability of the contralesional motor cortex);

• restore the integrity of the interhemispheric balance between the motor cortices of the damaged and healthy sides;

• enhance the response of the motor system to common rehabilitation techniques and facilitate motor learning ("addon" therapy);

• reduce residual impairments.

1.3.1. Repetitive transcranial magnetic stimulation (rTMS) and theta burst stimulation (TBS)

rTMS consists in the application of trains of magnetic pulses at a frequency ranging from 1 to 50 Hz, during 1 to 30 minutes on the brain, via a coil placed on the scalp over the area to be stimulated [36]. The effects induced by one or more rTMS sessions depend on the stimulation frequency, (< to 1 Hz: decreased excitability [37]; > 5 Hz: increased excitability [38]); number of stimuli (600-2000), train length, stimulation intensity, stimulation duration, number of sessions (single session/multiple sessions).

In theta burst stimulation (TBS), [39], pulses are applied in bursts of three, delivered at a frequency of 50 Hz (Theta frequency). Each burst of 3 pulses is delivered at a frequency of 5 Hz. When it is applied in continuous manner, for 40 to 60 seconds, cTBS induces inhibiting after-effects. When used in an intermittent manner, (trains of 10 bursts for 2 seconds followed by an 8-second pause, repeated every 10 seconds), for 20 to 60 seconds, intermittent TBS (iTBS) induces facilitating after-effects.

The relevance of this method compared to rTMS lies in its very short stimulation duration, under 60 seconds, its main drawback is the high cost of TBS equipment.

Regardless of its application mode, rTMS or TBS, the neuromodulation effects are related to the induction of aftereffects involving LTP-LTD synaptic plasticity mechanisms, i.e. long-term potentiation (LTP) or long-term depression (LTD). Studies on animal models have shown that the repetitive presynaptic stimulation of an afferent fiber is necessary and sufficient to induce a sustainable depression of the synaptic activity (low-frequency LTD), or a sustainable potentiation of the synaptic activity (LTP with high frequencies of 50-100 Hz) [40]. Thus, low-frequency rTMS (1 Hz) or cTBS will induce sustainable LTD-type synaptic after-effects and high-frequency rTMS (> 5 Hz) or iTBS will induce inhibiting LTP-type synaptic after-effects.

The duration of these after-effects is at least equivalent to the duration of the stimulation for rTMS (20 to 30 minutes), and from 30 minutes to 1 hour for TBS. The application of 5 or 10 daily sessions (multiple sessions) could increase the sustainability of the effects over time [41,42].

The contraindications for using cortical TMS are similar to the ones for MRI, in addition to a history of epilepsy. The latter is a relative contraindication since the risk of seizures during or around rTMS sessions only increases when using stimulation frequency above 10 Hz and when stimulating the damaged side.

The choice of stimulation parameters (frequency, intensity, duration) must abide by security criteria [43,44]. This neuromodulation method does not exhibit major risks if one avoids using lengthy and continuous trains at a high intensity. It is generally well-tolerated by patients, yet quite difficult to use in clinical practice due to the cumbersome and costly equipment.

1.3.2. Transcranial direct stimulation: tDCS

tDCS consists in applying continuous electrical current stimulation on the scalp between 2 non-metallic electrodes surrounded by a sponge soaked in NaCL solution. A continuous constant low-intensity current, from 1 to 2 mA, is applied during 10 to 20 minutes via a small galvanic stimulator, easy to transport and which can be pre-programmed in advance [45,46]. The mechanism of action for tDCS is very well-known [47]. Contrarily to rTMS, it never induces muscle contractions when applied above the motor cortex. During stimulation, the continuous current induces changes in membrane polarity by modulating the conductivity of sodium and calcic channels. After stimulation, according to the direction of the current, it can induce excitatory (anodal tDCS), or inhibitory (cathodal tDCS) after-effects, via a LTP/LTD-type synaptic plasticity mechanism, NMDA receptor-dependent [47].

This technique is well-tolerated. There is a slight tingling sensation under the active electrode upon stimulation, which usually disappears after a few minutes. This particularity makes it an excellent placebo, much better than using a placebo rTMS coil. No severe adverse event has been reported with this technique, when respecting the usual recommended usage parameters, i.e. 1 to 2 mA intensity, with stimulation duration < 25 minutes. If these parameters are not respected (stimulation duration > 25 minutes and stimulation intensity > 2 mA or using water instead of NaCL), it can lead

to a transient local irritation under the active electrode. Scalp burns have been described [48].

To sum up, the advantages of rTMS and TBS consist in the focal nature of the stimulation (figure-8 coil), and the very short stimulation duration (< 1 minute), for TBS. The drawbacks are the costly equipment, difficulty to use in clinical practice, potential risk of triggering seizures on a damaged brain, the imperfect nature of the placebo coil for clinical trials that evaluate its efficacy. The major inconvenient of tDCS is the fact that the stimulation is not completely focal in nature. Its numerous advantages (low cost, simple use, easy application, quality of the placebo, excellent tolerance even for underlying brain lesion), make it the method of choice compared to rTMS because it can potentially be performed in rehabilitation centers or even at home.

1.3.3. Paired associative stimulation (PAS)

PAS consists of a combined peripheral repetitive low-frequency median nerve stimulation at wrist level combined with single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex, repeated for 30 minutes at a frequency of 0.05 Hz. According to the time interval between the cortical stimulation and peripheral stimulation, PAS can induce sustainable excitatory (25ms interstimulus interval) or inhibitory (10ms interval) after-effects [49-51]. The duration of after-effects is at least similar to the duration of combined stimulation (30 to 60 minutes). It involves a LTP/LTD-type associative synaptic plasticity mechanism entirely based on the temporal sequence between cortical stimulation and peripheral stimulation. It has been largely less used than rTMS or tDCS for therapeutic neuromodulation [52,53].

To sum up, to decrease the excitability of the primary motor cortex, there are 4 NIBS techniques: TMS 1 Hz, cTBS, PAS 10 and cathodal tDCS. Conversely, to increase the excitability of the motor cortex, the methods are: high-frequency rTMS (5-1020 Hz), iTBS, PAS 25 and anodal tDCS.

The LTP/LTD-type after-effects induced can be measured by electrophysiological methods and functional imaging correlated to the study of motor performances.

1.4. Results of NIBS controlled clinical studies in motor recovery post-stroke

We will first report the results of two fundamental studies, one electrophysiology study and one functional imaging study, which evaluated the effect of a rTMS session at the frequency of 1 Hz applied on the contralesional motor cortex (M1) in chronic stroke patients. These two studies showed an improvement of motor performances of the paretic hand after the real rTMS session and not the placebo one. In one case, it was correlated to the decreased excitability of the healthy motor cortex [54], whereas in the other case, it was not correlated to fMRI results that did however show a normalization of the motor network activation during a grasping movement performed with the paretic hand, with a decreased activity in the motor areas on the healthy side [55]. We also reported in a PET scan study, that rTMS at the frequency of 1 Hz applied on the right M1 in

healthy subjects induced an increase of the blood flow on the left M1 during a right hand movement and validated that this type of transient neuromodulation could also be observed in patients recruited in the first month after ischemic stroke [56]. Another electrophysiology study validated that one unique session of cTBS on the contralesional M1 in 12 patients included between D1 and D45 after stroke led to an increased PEM amplitude measured on a muscle of the paretic hand, probably caused by the suppression of excessive transcallosal inhibition exerted by the contralesional M1 on the ispilesional M1 [57].

Two other studies, one with inhibitory rTMS at 1 Hz [58,59], the other with cathodal tDCS [58,59], evaluated the effect of inhibitory NIBS vs placebo applied on the contralesional M1 for 5 days in a row in chronic stroke patients, and reported an improvement of motor performances of the paretic hand. This 15% improvement in the time needed to complete the Jebsen and Taylor Test (JTT) was the object of a 15-day follow-up.

Three other studies published between 2007 and 2012 reported a moderate improvement of the motor performances of the paretic hand after one [55,60] or 10 [61] sessions of rTMS at

I Hz on the contralesional M1 in acute or chronic stroke patients.

Studies in 2006 and 2007 reported the first results on a session of excitatory NIBS (rTMS 10 Hz [62], anodal tDCS [63,64] and iTBS [65] applied on the ispilesional M1 of chronic stroke patients. All these results showed moderate improvement yet superior to placebo for the motor performances of the paretic hand evaluated by the JTT or other motor tests. The Ameli study in 2009 [66] included a larger number of patients compared to former studies (16 sub-cortical lesions and 13 cortical + sub-cortical lesions) with a very large inclusion period between week 1 and week 88 post-stroke. Its relevance lies in the beneficial effect of a single session of excitatory rTMS at 10 Hz applied on the ipsilesional M1 which depends on the extension of the ischemic lesion: an increased frequency of the beating of the index finger of the paretic hand was observed post-intervention in 14 out of the 16 patients with a sub-cortical lesion, whereas the same beating frequency was decreased in 7 patients with a more spread-out cortical-sub-cortical lesion. At the fMRI, this study also showed a reduced activity of the contralesional motor cortex, induced by rTMS, in

II of the sub-cortical patients. There was also a positive correlation between the improvement of motor performances of the paretic hand post rTMS and the activity of the ipsilesional M1 as seen on the fMRI measured in basal conditions before the intervention and conversely a large bilateral recruitment of the primary and secondary motor areas in 7 of the 13 patients with spread-out lesions.

Two studies in 2007 and two other ones in 2012 reported negative results for NIBS: the application of one session of anodal tDCS daily on the ipsilesional M1 for 6 weeks, (6 x 5 days), associated with an intensive robot-assisted motor training of the paretic limb, in 10 patients, with severe initial impairments in the subacute stroke phase (4 to 8 weeks post-stroke) was only correlated to an improvement of the Fugl-Meyer score in 3 out of the 10 patients included [67]. It was an

open study. The application of excitatory rTMS sessions at 20 Hz, or placebo, on the ipsilesional M1 repeated 10 days in a row coupled with constraint-induced movement therapy in two parallel groups of 19 chronic patients, did not yield a significant difference between both groups on the scores of the global motor indexes (wolf motor function and motor activity log)

[68]. More recently, a two-center British study on 41 chronic stroke patients followed for 3 months, distributed into 3 parallel groups and evaluated on the Nine-Hole Peg Test (NHPT), the JTT and grip test did not show a significant difference between the three groups regardless of the type of NIBS used, i.e. cTBS, iTBS or placebo applied daily for 10 days, and in all cases associated with intensive standardized rehabilitation training

[69]. The authors suggest a probable ceiling effect related to the association of NIBS and rehabilitation training to explain this absence of effects. Finally Rossi et al. in 2012 [70] did not observe a significant difference on the Fugl-Meyer score and the NIHSS conducted at 5 days and at 3 months, between two parallel groups of 25 patients each, recruited in the acute phase, 2 days after the onset of stroke, after application on the ipsilesional M1 of a daily session of anodal tDCS or placebo repeated 5 days in a row. In this series, the patients exhibited severe impairments upon inclusion.

To sum up, between 2005 and 2012, there were about 25 controlled studies that evaluated the effectiveness of NIBS in motor recovery post-stroke. These first studies demonstrated its excellent tolerance. The reported results depend on the stroke stage when the NIBS is applied (acute, subacute and chronic), application site (healthy or damaged hemisphere), lesion area (cortical or sub-cortical), NIBS method, number of sessions, and association or not with standard or intensive rehabilitation.

The duration of the follow-up was rather short and criteria were not standardized, see review [71,72].

The size of the positive effects of NIBS on motor performances of the paretic hand compared to the placebo effect of the intervention remains overall modest ranging with a 10 to 20% improvement. Most of these studies focused on small cohorts (6-50 patients). The effects of NIBS seemed better for sub-cortical lesions compared to more spread-out lesions. Most studies did not benefit from a longitudinal follow-up. The application of successive sessions vs one single session did not seem to increase significantly the size of the effects, but might consolidate them on the long-term. This remains to be validated in future multicenter studies on large sample of patients. These sessions do seem to be easier to implement with tDCS than with rTMS, which requires a more cumbersome and costly equipment for the rehabilitation centers.

In a meta-analysis, Hsu et al. [73], evaluated the effect of rTMS on motor recovery, based on 18 studies for a total of 392 patients. The mean positive effect size of rTMS on motor function was 0.55 (95% CI, 0.37-0.72) with P < 0.01. Effect size increased in case of sub-cortical lesion (0.73-95% CI, 0.44-1.02). It was greater for low-frequency rTMS (0.69-95% CI, 0.42-0.95) vs high-frequency rTMS (0.41-95% CI, 0.14-0.68) and quite similar between rtMS application in the acute (0.79-95% CI, 0.42-1.16) or chronic (0.66-95% CI, 0.31-1.00) phase.

In 2013, several questions still remain unanswered. Which method should be privileged? What would be the ideal NIBS dose (optimal stimulation parameters)? What would be the optimal number of sessions? Time window for NIBS application: acute phase, chronic phase or both? Where should it be applied: healthy side, damaged side or both sides at the same time? Who should benefit from it: patient with moderate or heavy impairments or rather solely patients with sub-cortical lesions rather than cortical ones? How should it be applied: alone or as adjuvant therapy? Before or after rehabilitation? What type of influence do synaptic plasticity regulation factors have? What evaluation criteria should be used, those that evaluate motor performances of the paretic hand or rather those focusing on improving quality of life and autonomy?

Progressively, some answers to these questions have been brought forward. Regarding the choice of the application site, four studies with three parallel groups of patients, in the acute or subacute stroke phase, compared the effects of multisession excitatory NIBS (5-10 days), applied on the damaged M1 side, (rTMS 3-5 Hz, [74-76], to anodal tDCS [77] to inhibitory NIBS on the healthy M1 side (rTMS 1 Hz or cathodal tDCS) and to placebo stimulation. Results of these studies are controversial and it is impossible to draw any conclusion. However, the simultaneous application of anodal tDCS on the ipsilesional M1 and cathodal tDCS on the contralesional M1, repeated for 5 days in a row showed a mean increase of 6 points, i.e. 21% improvement, on the Fugl-Meyer score of the upper limb, vs 5% for the placebo group, on 2 groups of 10 patients, each in the chronic recovery phase [78]. An additional study from the same team showed that a two-fold increase in the number of bihemispheric tDCS sessions, (2 sessions for 5 days total), allowed a mean increase of 8.2 ± 2.2 on the Fugl-Meyer score, yet the improvement was not linear over time: it was greater the first week than the second week of treatment [78].

Regarding the potentiating effect of associating NIBS to intensive rehabilitation, results are also controversial in this case with two negative studies previously mentioned, [68,69], and a more recent one with 14 chronic stroke patients, which showed that associating bihemispheric tDCS to constraint-induced movement therapy (CIMT) decreased more significantly the time required to complete the JTT than CIMT [79]. Cohen's team [80] in their study on 9 chronic stroke patients showed that combining peripheral nerve stimulation of the median and cubital nerve of the paretic hand for 2 hours followed by a 20-minute anodal tDCS session on the ipsilesional M1 yielded a 41.3% improvement in the performances of the paretic hand in a sequential motor task of the fingers, compared to placebo. The improvement was 22.7% when tDCS was combined to peripheral stimulation, compared to tDCS alone and 15.4% when compared to peripheral stimulation alone.

Regarding the optimization of stimulation parameters (see review [81]), the comparison of the different techniques of a tDCS session in a cross-over study on 10 patients showed that in average, bihemispheric tDCS yielded the best improvements regarding the time needed to complete the JTT, followed by anodal then cathodal tDCS [82]. Two recent studies underlined

the relevance of using tDCS in chronic stroke patients to promote and improve the learning capacity of a motor task performed with the paretic hand [83,84].

To optimize the modest positive effects of NIBS on motor recovery, it seems necessary to better select the patients that could benefit from this technique and validate the markers predictive of a good response to NIBS. In the acute phase, these selection criteria could be clinical (age, importance of the initial motor improvements evaluated by standardized scales, presence of comorbid affections), morphological (integrity of the corticospinal tract in diffusion imaging [85]), cortical or sub-cortical site as well as spreading of the ischemic lesion. In the chronic phase, we could add functional imaging data by asking the patient who has recovered enough in order to perform, during PET scan or fMRI, a simple or complex movement with the paretic hand. In fact, because of their great inter-individual variability, TMS electrophysiological data (measure of the motor thresholds at rest and under movement, intensity curve, measure of the intra-cortical inhibition), yield a lesser predictive value than imaging data, especially during the acute phase in the first 3 weeks post stroke, yet there is a good correlation between the motor function of the hand and the mean measures of the integrity of cortico-spinal tract, especially in the first three months of the recovery [28]. Stinear et al. [86] integrated electrophysiological data (presence or not of evoked motor potential in the acute phase) to the PREP algorithm predictive of the potential for upper limb recovery after stroke, which they proposed alongside clinical (''SAFE'' score) and diffusion MRI data (fractional anisotropy asymmetry index measured on the posterior limb of the internal capsules). The potential relevance of a brain plasticity genetic marker (polymorphism in the BDNF gene) remains to be validated.

1.5. Conclusion

These past few years, the use of functional imaging and TMS allowed for a better understanding of the underlying mechanisms of motor recovery after stroke in order to develop new therapeutic strategies based on NIBS which have demonstrated their potential relevance in motor function recovery. However, the individual response to neuromodulation varies and depends on several biological and technical factors which have not been completely mastered. The choice of the ideal NIBS still needs to be refined. Using imaging data as early as possible should enable teams to better select patients who could benefit from this technique in the acute or subacute phase and use it to "boost" the natural capacities of brain plasticity and recovery after stroke. During the chronic phase, these neuromodulation techniques certainly bear a potential relevance especially for improving learning capacities during rehabilitation care, but in that case also, it concerns patients preselected according to imaging and electrophysiology data. Its future use in common clinical practice will require additional large-scale, multicenter longitudinal studies on bigger cohorts of patients in order to determine its place against other conventional rehabilitation techniques and neurophar-macological approaches as well as its eventual relevance as an "add-on" therapy.

Disclosure of interest

The author declares that he has no conflicts of interest concerning this article.

2. Version française

2.1. Plasticité cérébrale et mécanismes de la réorganisation corticale apms un AVC

Le cerveau d'un patient victime d'un accident vasculaire cerebral (AVC) a les capacites de reconfigurer son activite dans les suites de l'infarctus grace a sa plasticite naturelle. Celle-ci s'exprime par une redistribution du metabolisme cerebral de base, une modification des cartographies corticales (suractiva-tion des cortex leses, modification des somatotopies motrices et sensitives [1,2], et un recrutement d'aires cerebrales a distance de la lesion, qui vont participer a la recuperation fonctionnelle [3]. Pendant la phase de la recuperation motrice, les etudes d'imagerie fonctionnelle (TEP scan et IRM fonctionnelle), ont montre l'implication des aires adjacentes a la lesion [4] et le recrutement des aires de l'hemisphere non lesé [5,6]. Il est actuellement admis qu'une bonne recuperation motrice de la main paretique chez des patients ayant presente un AVC est liee a une reorganisation de l'activite au sein de l'hemisphere leese [7-9]. Si dans un premier temps la recuperation fait appel a des reseaux neuronaux impliquant a la fois des aires sensori-motrices secondaires ipsilesionnelles et des aires controtésion-nelles, c'est le retour a un reseau plus classique qui permettrait une recuperation de qualite [10,11]. En effet, plus l'asymetrie entre les deux hemispheres est grande, moins bonne est la recuperation [12,13]. Les etudes longitudinales ont confirme l'existence de changements dynamiques d'equilibre dans l'activation entre hemisphere sain et lese (balance interhemis-pherique) au cours de la recuperation avec une hyperactivite initiale de l'hemisphere intact lors du mouvement de la main paretique [4,11,14]. Dans la progression dynamique de la recuperation, il semble que les patients qui ont une mauvaise recuperation continuent d'avoir une activation de l'hemisphere sain [7,15]. Cependant, les etudes d'imagerie ne permettent pas de savoir si cette activation bilaterale est une consequence des mauvaises performances motrices de la main paretique, (epiphenomene), ou bien le reflet d'une perturbation de la balance interhemispherique qui interfere secondairement avec les performances motrices. C'est tout l'interêt des etudes d'electrophysiologie. Les résultats de l'etude de Werhahn et al. [16] suggerent que le role du cortex moteur controlesionnel dans la recuperation des performances de la main paretique serait mineur a la phase chronique puisque le temps de reaction d'un mouvement des doigts execute avec la main paretique n'est perturbe que par l'application d'une TMS interferentielle sur le cortex moteur ipsilesionnel mais pas par une TMS appliquee sur le cortex moteur controlesionnel. Cependant, une etude ulterieure [17] montre que l' application d'une TMS interferentielle sur les aires motrices controlesionnelles perturbe d'autant plus le temps de reaction simple d'un mouvement des doigts de la main paretique que les patients ont

une mauvaise recuperation suggérant, au contraire, un role fonctionnel des aires motrices controlesionnelles dans la recuperation, d'autant plus important que les patients ont un deficit résiduel lourd. A l'inverse, Lotze et al. [18,19] ont montre qu'une rTMS inhibitrice, appliquee sur le cortex moteur controlesionnel de patients ayant bien récuperé a la phase chronique, induit des perturbations dans la precision de realisation d'un geste sequentiel complexe effectue avec la main parétique, suggerant que l'hyperactivite ou recrutement des aires motrices controlesionnelles lors de la realisation de taches motrices complexes pourrait avoir un effet benefique sur les performances de la main parétique. En synthese, ces résultats soulignent la difficulte de connaître le role exact de l'hemisphere sain dans la recuperation motrice post-AVC. Il depend très certainement de nombreux facteurs dont le temps ecoule depuis l'AVC (phase aigue, chronique), l'importance et le site de la lesion et la complexite de la tache motrice a réaliser.

2.2. Modulation de l'excitabilité corticale intra- et interhémisphérique aprns un AVC

L'utilisation de la TMS a permis d'etudier les changements d'excitabilite des cortex moteurs primaires de l'hemisphere lese et sain au cours de la phase de recuperation, ainsi que les modulations de l'inhibition interhemispherique au repos et lors de la preparation et l'execution d'un mouvement volontaire. Les premieres etudes TMS dans ce domaine ont montre des résultats en faveur d'une hyperactivite de l'hemisphere sain au cours de la recuperation motrice de la main parétique [20,21] qui a tendance a diminuer au cours du temps surtout chez les patients qui récuperent bien [22]. En TMS double choc [23], il a ete montre du cote lese comme du cote sain, en phase aigue ou subaigue, une diminution des mecanismes inhibiteurs inter-neuronaux gabaergiques (GABA-A, short intra-cortical inhibition, SICI) des circuits moteurs [24-27]. Cette modulation de la SICI pourrait refleter une strategie de recuperation visant a favoriser l'utilisation des aires motrices habituelles ou compensatrices mais sa mesure ne serait fiable qu'après 3 mois de recuperation [28].

Chaque cortex moteur exerce une influence mutuelle sur son homologue oppose via les fibres transcallosales glutamatergi-ques se projetant sur des interneurones inhibiteurs gabaergiques du cortex moteur oppose [29-31]. Ces connexions interhemis-pheriques (inhibition interhemispherique ; IHI) peuvent etre indirectement etudiees par la TMS double choc [29,30]. Ces interactions interhemispheriques sont utiles dans le contrôle volontaire des mouvements uni- et bi-manuels [32]. Selon le concept de balance interhemispherique, après une lesion du cerveau, (M1, aires du langage, aires parietales), il existerait une diminution d'excitabilite du cortex moteur ipsilesionnel et une hyperexcitabilite du cortex moteur controlesionnel. Apres un AVC, on observe une augmentation du niveau d'IHI provenant de M1 controlesionnel et s'exerçant sur M1 ispilesionnel, lors de la preparation d'un mouvement volontaire, qui serait inversement corrèlee a une bonne recuperation de la main parétique : plus l'IHI serait perturbee, moins bonne serait la recuperation motrice [33,34]. La recuperation de la

zone lesee serait perturbee par un input inhibiteur excessif via les voies transcallosales, provenant de l'aire contralesionnelle de l'hemisphere sain en etat d'hyperactivite, du fait de la diminution de l'input inhibiteur réciproque de l'aire lesee sur l'aire saine. Cette hypothese représente un des modeles de plasticite corticale « nefaste » de l'hemisphere sain s'exerçant sur l'hemisphere lese et pouvant perturber la recuperation motrice post-AVC. Il est a la base du developpement des techniques de neuromodulation corticale visant a rétablir la balance interhemispherique physiologique.

2.3. Methodes de neuromodulation corticale non invasives : NIBS

Sur la base de ces donnees d'imagerie fonctionnelle et d'electrophysiologie aboutissant au concept de perturbation de la balance interhemispherique au decours d'un AVC (voir revue [35]), se sont developpees dans les 12 dernieres annees des techniques de neuromodulation corticale, (non-invasive brain stimulation: NIBS), visant a faciliter, optimiser la recuperation fonctionnelle en modulant la plasticite naturelle du cerveau. Les objectifs de la NIBS dans la recuperation motrice post-AVC sont multiples :

• augmenter l'excitabilite du cortex moteur du cote lese ;

• limiter le developpement de strategies compensatrices non adaptees (hyperexcitabilite du cortex moteur controlesionnel) ;

• rétablir l'equilibre de la balance interhemispherique entre les cortex moteurs cote lese et sain ;

• potentialiser la réponse du systeme moteur aux techniques de reeducation classiques en faciliter le reapprentissage moteur (add-on therapie) ;

• diminuer le handicap résiduel

2.3.1. Stimulation magnetique transcrânienne repetitive (rTMS) et theta burst stimulation (TBS)

La rTMS consiste en l'application d'un train de stimulis magnetiques a une frequence allant de 1 a 50 Hz, pendant 1 a 30 minutes, sur une zone du cerveau, au moyen d'une sonde (ou coil) posee sur le scalp en regard de la zone a stimuler [36]. Les post-effets induits par l'application d'une ou plusieurs sessions de rTMS dependent de la frequence de stimulation, (< a 1 Hz : diminution de l'excitabilite [37] ; > 5 Hz : augmentation de l'excitabilite [38]) du nombre de chocs (600-2000), de la longueur du train, de l'intensite de stimulation, du site de stimulation, de la durée de la stimulation, du nombre de seances (session uniques/multisessions).

La theta burst stimulation (TBS) [39] consiste en l'application de bursts de 3 pulses magnetiques pulsant a 50 Hz, (frequence theta). Chaque burst de 3 pulses est delivré a une frequence de 5 Hz. Lorsqu'elle est appliquee de faç;on continue, pendant 40 a 60 secondes, la TBS (cTBS) induit des post-effets inhibiteurs. Lorsqu'elle est appliquee de faç;on intermittente, (trains de10 bursts pendant 2 secondes suivis d'une pause de 8 secondes, répetes toutes les 10 secondes), pendant 20 a 60 secondes, la TBS intermittente (iTBS) induit des post-effets facilitateurs.

L'interêt de cette methode, par rapport a la rTMS est sa durée de stimulation très courte inferieure a 60 secondes ; son inconvenient majeur etant celui du cout eieve de l'appareillage.

Quel que soit son mode d'application, rTMS classique ou TBS, ses effets neuromodulateurs sont lies a l'induction de post-effets mettant en jeu les mecanismes de plasticité synaptique de type LTP-LTD, c'est-a-dire potentiation ou depression a long terme. Les travaux chez l'animal ont montre que la stimulation presynaptique repetitive d'une fibre afférente est necessaire et suffisante pour induire une depression durable de l'activite de la synapse, (basses frequences LTD), ou une potentiation durable de l'activite de la synapse, (hautes frequences 50-100 Hz LTP) [40]. Ainsi, la rTMS a basse frequence (1 Hz) ou la cTBS vont pouvoir induire des posteffets synaptiques durables de type LTD et la rTMS a haute frequence (superieure a 5 Hz) ou la iTBS vont pouvoir induire des post-effets synaptiques inhibiteurs de type LTP.

La durée de ces post-effets est au moins equivalente a la durée de la stimulation pour la rTMS, (20 a 30 minutes), et de 30 minutes a 1 heure pour la TBS. L'application de 5 ou 10 seances quotidiennes, (multisessions), permettrait d'augmenter la durée des effets dans le temps [41,42].

Les contre-indications a l'utilisation de la stimulation magnetique corticale sont les memes que celles de l'IRM a laquelle il faut rajouter la presence d'une epilepsie. Cette derniere est une contre-indication relative car le risque de survenue d'une crise comitiale au cours ou au decours de la seance de rTMS n'augmente que si on utilise des frequences de stimulation superieures a 10 Hz et que l'on stimule du côté lesionnel.

Le choix des parametres de stimulation (frequence, intensité, durée) doit respecter les critères de securité d'utilisation [43,44]. Cette methode de neuromodulation ne présente pas de risque majeur a condition dtéviter de stimuler avec des trains continus de longue durée et a forte intensité. Elle est generalement bien tolerée par les patients, mais contraignante en pratique de par la lourdeur du materiel et son cout

eleve.

2.3.2. Transcranial direct stimulation: tDCS

Elle consiste en l'application de courants electriques continus sur le scalp entre 2 electrodes non metalliques entourées d'une eponge imprégnee d'une solution de NaCL. Un courant constant continu de faible intensité de l'ordre de 1 a 2 mA est applique pendant 10 a 20 minutes au moyen d'un stimulateur galvanique de petite taille, facile a transporter et programmable a l'avance [45,46]. Le mecanisme d'action de tDCS est bien connu [47]. Contrairement a la rTMS, il n'induit jamais de contraction musculaire pendant la stimulation lorsqu'il est applique en regard du cortex moteur. Pendant la stimulation, le courant continu induit des changements de polarité membranaire en modulant la conductance des canaux sodium et calciques. Apres la simulation, en fonction du sens du courant, il peut induire des post-effets durables excitateurs, (tDCS anodale), ou inhibiteurs, (tDCS cathodale), par un mecanisme de plasticité synaptique de type LTP/LTD, récepteur NMDA - dependant [47].

Cette methode est très bien tolerée. Elle induit une legere sensation de picotements sous l'electrode active à l'induction de la stimulation qui disparaît generalement en quelques minutes. Cette particularité en fait un excellent placebo, bien meilleur que l'utilisation d'une sonde rTMS placebo. Aucun evenement grave n'a eté rapporte après son utilisation a condition de respecter les parametres usuels de stimulation recommandee, c'est-a-dire, a l'intensité de 1 a 2 mA et avec une durée de simulation inferieure a 25 minutes. Dans le cas contraire, (durée de stimulation superieure a 25 minutes et intensité de simulation superieure a 2 mA ou encore utilisation d'eau a la place du NaCL), elle peut entraîner une irritation locale transitoire sous l'electrode active. Des bnilures cutanees du scalp ont eté decrites [48].

En synthese, les avantages de la rTMS et de la TBS sont représentés par le caractère focal de la stimulation, (sonde en 8), et la durée très courte de la stimulation, (< 1 minute), pour la TBS. Ses inconvenients sont représentés par le cout eleve de l'appareillage, sa lourdeur d'utilisation pratique clinique, le risque potentiel de declencher une crise d'epilepsie sur un cerveau lese, le caractère imparfait de la sonde placebo pour les etudes d'efficacité clinique. Le principal inconvenient de la tDCS est représenté par le caractère peu focal de la stimulation. Ses nombreux avantages (faible cout, simplicité d'utilisation, facilite d'application, qualité du placebo, excellente tolerance y compris avec une lesion cerébrale sous-jacente), en font la methode privilegiee actuellement par rapport a la rTMS car potentiellement réalisable en centre de réeducation ou a domicile.

2.3.3. Paired associative stimulation (PAS)

La PAS consiste en l'application combinee d'une stimulation magnetique simple choc sur le cortex moteur primaire et d'une stimulation electrique peripherique du nerf median au poignet, répetée pendant 30 minutes, a 1 frequence de 0,05 Hz. En fonction de l'intervalle de temps entre la stimulation corticale et la simulation peripherique, elle est capable d'induire des post-effets excitateurs durables (intervalle interstimulus de 25 ms) ou inhibiteurs (intervalle de 10 ms) [49-51]. La durée des post-effets est au moins egale a la durée de la stimulation combinee (30 a 60 minutes). Elle met en jeu un mecanisme de plasticité synaptique associative de type « LTP/LTD » qui repose entièrement sur la sequence temporelle entre la stimulation corticale et la simulation peripherique. Elle a ete beaucoup moins utilisee que la rTMS ou la tDCS dans un but de neuromodulation therapeutique [52,53].

Pour résumer, si on souhaite diminuer l'excitabilité du cortex moteur primaire, on dispose de 4 methodes de NIBS : rTMS 1 Hz, cTBS, PAS 10 et tDCS cathodale. Si on souhaite au contraire augmenter l'excitabilité du cortex moteur, on dispose de la rTMS a haute frequence (5-10-20 Hz), la iTBS, la PAS 25 et la tDCS anodale.

Les post-effets induits de type LTP/LTD sont mesurables par des methodes electrophysiologiques et d'imagerie fonctionnelle corrélees a l'etude des performances motrices.

2.4. Résultats des études cliniques contrôlées de NIBS dans la recuperation motrice post-AVC

Nous citerons d'abord les résultats de deux etudes princeps, l'une d'electrophysiologie et l'autre d'imagerie fonctionnelle qui ont evalue l'effet d'une session de rTMS a 1 Hz appliquee sur le cortex moteur (M1) controlesionnel chez des patients en phase chronique post-AVC. Ces deux etudes montraient une amelioration des performances motrices de la main parétique après la session de rTMS vraie et pas après la session placebo. Dans un cas, elle etait corrèlee a la diminution d'excitabilite du cortex moteur sain [54], alors que dans l'autre, elle n'etait pas corrèlee aux résultats d'IRMf qui montraient pourtant une normalisation de l'activation du reseau moteur pendant un mouvement de grasping realise avec la main parétique, avec une diminution d'activite dans les zones motrices du cote sain [55]. Nous avions aussi montre en TEP qu'une rTMS 1 Hz appliquee sur M1 droit chez des sujets normaux induisait une augmentation du debit sanguin cerebral sur M1 gauche pendant un mouvement de la main droite et verifie que ce type de neuromodulation transitoire pouvait aussi etre observee chez des patients inclus dans le premier mois après leur AVC ischemique [56]. Une autre etude d'electrophysiologie a confirme que l'application d'une session unique de cTBS sur M1 controlesionnel chez 12 patients inclus entre le 1er et le 45e jour après la survenue de l'AVC entraînait une augmentation d'amplitude du PEM mesure sur un muscle de la main parétique, probablement due a une levee de l'inhibition transcallosale excessive exercee par M1 controlesionnel sur M1 ipsilesionnel [57].

Deux autres etudes, l'une avec de la rTMS inhibitrice a 1 Hz [58,59], l'autre avec la tDCS cathodale [58,59] ont evalue l'effet d'une NIBS inhibitrice contre placebo appliquee sur M1 controlesionnel 5 jours de suite chez des patients AVC en phase chronique et ont rapporte une amelioration des performances de la main parétique dans le temps de realisation du test de Jebsen et Taylor (JTT) de l' ordre de 15 % avec un suivi de 15 jours.

Trois autres etudes publiees entre 2007 et 2012 ont rapporte une amelioration moderée des performances motrices de la main parétique après l'application d'une [55,60] ou de dix sessions [61] de rTMS a 1 Hz surM1 controlesionnel chez des patients inclus en phase aigue ou subaigue après l'AVC.

En 2006 et 2007, etaient rapportes les premiers résultats de l'application d'une session de NIBS excitatrice (rTMS 10 Hz [62], tDCS anodale [63,64], et iTBS [65] appliquee sur M1 ipsilesionnel chez des patients en phase chronique post-AVC. Toutes montraient des ameliorations moderées mais superieures au placebo des performances motrices de la main parétique evaluees par le JTT ou d'autres tests moteurs. L'étude d'Ameli et al. en 2009 [66], réalisee sur un nombre de patients plus important que les précedentes (16 sous-corticaux et 13 corticaux + sous-corticaux) mais, avec une très large periode d'inclusion entre la 1re et la 88e semaine post-AVC), a eu l'interêt de montrer que l'effet benefique de la session unique de rTMS excitatrice a 10 Hz appliquee sur M1 ipsilesionnel dependait de l'extension de la lesion ischemique : une augmentation de la frequence de battement de l'index de la

main pareétique eétait observeée en post-intervention chez 14 des 16 patients avec une leésion sous-corticale alors qu'elle eétait diminueée chez 7 des patients avec une leésion plus eétendue cortico-sous-corticale. Cette eétude montrait eégalement une diminution de l'activite du cortex moteur controlesionnel en IRMf, induite par la rTMS, chez 11 des patients sous-corticaux. Il existait egalement une correlation positive entre l'amelioration des performances motrices de la main pareétique post rTMS et l'activite de M1 ispilesionnel en IRMf mesurée dans les conditions basales avant l'intervention et au contraire un large recrutement bilateéral des aires motrices primaires et secondaires chez 7 des 13 patients avec leésions eétendues.

Deux etudes en 2007 et deux en 2012 rapportent des résultats negatifs de la NIBS : l'application d'une session de tDCS anodale quotidienne sur M1 ipsileésionnel pendant 6 semaines, (6 x 5 jours), couplee a un entraînement moteur intensif assiste par robot du membre pareétique, chez 10 patients, avec un deéficit initial lourd, en phase subaigue de recuperation, (4 a 8 semaines post-AVC), n'etait suivie d'une amelioration du score de Fugl-Meyer que chez 3 des 10 patients inclus [67]. Il s'agissait d'une etude en ouvert. L'application de sessions de rTMS excitatrice a 20 Hz ou d'un placebo sur M1 ispileésionnel reépeéteées 10 jours de suite et couplees a une therapie contrainte induite chez deux groupes paralleles de 19 patients, en phase chronique n'entraînait aucune difference significative entre les deux groupes sur les scores des echelles motrices globales (Wolf Motor Function et Motor Activity Log) [68]. Plus récemment, une eétude bi-centrique anglaise portant sur 41 patients chroniques, suivis pendant 3 mois, reépartis en 3 groupes paralleles et evalues sur le test des 9 chevilles, le JTT et le griptest ne montraient pas de diffeérence significative entre les 3 groupes quel que soit le type de NIBS appliqueée quotidiennement pendant 10 jours, cTBS, iTBS ou placebo mais, dans tous les cas, coupleée une reéeéducation intensive standardisee [69]. Les auteurs suggeraient un probable effet plafond lie a l'association de la NIBS et de la reeducation pour expliquer ce manque d'effet de la NIBS. Enfin Rossi et al., en 2012 [70], n'ont pas observe de difference significative sur le score de Fugl-Meyer et le NIHSS, realise a 5 jours et a 3 mois, entre les deux groupes paralleles de 25 patients chacun, inclus en phase aigue 2 jours après la survenue de l'AVC, après l'application sur M1 ispilesionnel d'une session quotidienne de tDCS anodale ou de placebo reépeéteée 5 jours de suite. Il s'agissait dans cette seérie de patients preésentant un deéficit assez lourd a l'inclusion.

En synthese, entre 2005 et 2012, il y a eu environ 25 eétudes controîleées eévaluant l'efficaciteé de la NIBS dans la recuperation motrice post-AVC. Ces premieres etudes ont demontre son excellente tolerance. Les résultats rapportes sont variables en fonction de la peériode d'application de la NIBS (aigue, subaigue chronique), du site d'application (hemisphere sain ou lese), du site de la lesion, (cortical ou sous-cortical), du choix de la meéthode de NIBS, du nombre de sessions, du couplage ou non a une reeducation standard ou intensive. La dureée de la peériode de suivi est le plus souvent courte et le choix des criteres dévaluation non standardises, voir revue [71,72].

La taille des effets positifs de la NIBS sur la motricité de la main paretique par rapport a l'effet placebo de l'intervention reste globalement modeste de l'ordre de 10 a 20 % d'amelioration. La plupart de ces etudes portent sur de petits effectifs (6-50 patients). Les effets de la NIBS semblent meilleurs pour des lesions sous-corticales par rapport a des lesions corticales etendues. La majorite de ces etudes n'ont pas suivi longitudinal. L'application de multisessions successives par rapport a l'application d'une seule session ne semble pas augmenter de facon importante la taille des effets mais, peut-etre, permet de les consolider en durée. Cela reste a confirmer sur des etudes longitudinales multicentriques avec de larges echantillons de patients. Ces etudes semblent maintenant plus faciles a mettre en place avec la tDCS qu'avec la rTMS, qui necessite un appareillage beaucoup plus lourd et coûteux pour les centres.

Dans une meta-analyse, Hsu et al. [73] evaluant l'effet de la rTMS sur la recuperation motrice, réalisee a partir de 18 etudes portant sur un total de 392 patients, la taille moyenne de l'effet positif de la rTMS sur la fonction motrice etait de 0,55 95 % CI, 0,37-0,72) p < 0,01). La taille de l'effet augmente en cas de lesion sous-corticale (0,73 95 % CI, 0,44-1,02). Il est plus grand pour la rTMS basse frequence (0,69 95 % CI, 0,42-0,95) par rapport a la rTMS a haute frequence (0,41 95 % CI 0,140,68) et assez proche entre une application de la rTMS en phase aigue (0,79 95 % CI 0,42-1,16) ou en phase chronique (0,66 95 % CI 0,31-1,00).

En 2013, il reste encore de nombreuses questions en suspens. Quelle methode privilegier ? A quelle dose appliquer la NIBS (parametres de stimulation optimaux) ? Quel est le nombre optimal de session ? Quand faut-il l'appliquer ; en phase aigue, chronique, ou les deux ?

Où faut-il appliquer ; du cote sain, lese, ou des 2 côtés en meme temps ? A qui faut-il la proposer ; a des patients qui présentent un deficit modere ou lourd ou bien uniquement a des patients qui présentent des lesions sous-corticales plutot qu'a des lesions corticales ? Comment l'appliquer ; seule ou en traitement adjuvant ? Pendant ou avant la reeducation ? Quelle est l'influence des facteurs de regulation de la plasticité synaptique ? Quels critères dévaluation choisir, ceux qui evaluent les performances motrices de la main paretique ou bien ceux qui s'intéressent a l'amelioration de la qualité de vie et de l'autonomie ?

Quelques réponses commencent progressivement a etre apportées. En ce qui concerne le site d'application a privilegier entre M1 lesionnel et controlesionnel, quatre etudes ont compare sur trois groupes paralleles de patients, en phase aigue ou subaigue de la recuperation, les effets d'une NIBS excitatrice multisession, (5-0 jours), appliquee sur M1 cote lese, (rTMS 3-5 Hz, [74-76], ou d'une tDCS anodale [77] aune NIBS inhibitrice sur M1 cote sain (rTMS 1 Hz ou tDCS cathodale) et a une stimulation placebo. Les résultats de ces etudes sont controverses et ne permettent pas de repondre a cette question. En revanche, l'application simultanee d'une seance de tDCS anodale sur M1 ipsilesionnel et d'une tDCS cathodale sur M1 controlesionnel répetée 5 jours de suite fait gagner en moyenne 6 points, soit 21 % d'amelioration, sur le

score de Fugl-Meyer membre supérieur, contre 5 % pour le groupe placebo, sur deux groupes de 10 patients, chacun en phase chronique de recuperation [78]. Une etude comptémen-taire de la meme equipe a montre que la multiplication par deux du nombre de sessions de tDCS bi-hemispherique, (2 x 5 jours) permettait un gain moyen de 8,2 ± 2,2 du score de Fugl-Meyer mais l'amelioration n'etait pas lineaire dans le temps : elle etait plus importante la premiere semaine que la deuxieme semaine de traitement [78].

En ce qui concerne l'effet potentialisateur de l'association de la NIBS a une reeducation intensive, les résultats sont la aussi controverses avec deux etudes negatives précedemment citées, [68,69], et une etude plus récente montrant que l'association de la tDCS bi-hemispherique a une therapie contrainte induite chez 14 patients en phase chronique diminue de facon plus importante le temps de realisation du test de Jebsen Taylor que la therapie contrainte induite seule [79]. L'équipe de Cohen [80] a montre chez 9 patients, en phase chronique post-AVC, que la combinaison d'une stimulation nerveuse peéripheérique eélectrique du nerf meédian et cubital du cote de la main paretique appliquee pendant 2 heures, suivie d'une seance de tDCS anodale de 20 minutes appliquee sur M1 ispilesionnel amelioraient de 41,3 % les performances de la main paretique, dans une tache d'apprentissage moteur sequentiel des doigts, comparativement au placebo. L'amelioration etait de 22,7 % quand on comparait la tDCS combinee a la stimulation peripherique a l'application de la tDCS seule et de 15,4 % quand on la comparait a l'application d'une stimulation peéripheérique seule.

En ce qui concerne l'optimisation des parametres de stimulation, (voir revue [81], la comparaison des différents montages d'une session de tDCS chez 10 patients en cross-over montre qu'en moyenne, c'est la tDCS bi-hemispherque qui permet la meilleure ameélioration dans le temps de reéalisation du JTT suivie de la tDCS anodale, puis cathodale [82]. Deux etudes récentes soulignent l'intérêt de l'utilisation de la TDCS chez des patients AVC en phase chronique pour favoriser, ameliorer leur capacité d'apprentissage d'une tache motrice réalisee avec la main paretique [83,84].

Pour optimiser les effets positifs modestes de la NIBS sur la recuperation motrice, il paraît necessaire de mieux selectionner les patients qui peuvent en tirer benefice et de valider des marqueurs prédictifs de bonne réponse a la NIBS. En phase aigue, ces critères pourraient etre cliniques (age, importance du deéficit moteur initial eévalueé par des eéchelles standardiseées, existence de comorbiditeés), morphologiques (inteégriteé du faisceau cortico-spinal en imagerie de diffusion [85], et site cortical ou sous-cortical et eétendue de la leésion ischeémique. En phase chronique, on pourrait y rajouter les donneées d'imagerie fonctionnelle en demandant au patient qui a deja un peu récuperé d'executer, pendant l'acquisition des images en TEP ou IRMf, un mouvement simple et complexe avec la main pareétique. Du fait d'une grande variabiliteé interindividuelle, les donneées d'eélectrophysiologie apporteées par la TMS (mesure des seuils moteurs au repos et sous mouvement, courbe en intensiteé, mesure de l'inhibition intracorticale) semblent avoir une moins bonne valeur preédictive que les donneées de

l'imagerie, surtout en phase aigue dans les 3 premieres semaines post-AVC, mais il existe une bonne correlation entre la fonction motrice de la main et les mesures moyennes de l'integrite du faisceau cortico-spinal, surtout dans les trois premiers mois de recuperation [28]. Stinear et al. [86] integrent des donnees electrophysiolgiques, (presence ou pas d'un potentiel evoque moteur en phase aigue), a l'algoritme prédictif du pronostic de recuperation du membre superieur, (PREP), qu'ils proposent a cote des donnees cliniques, (score « SAFE »), et d'IRM de diffusion, (asymetrie de l'index d'anisotropie fractionnelle mesure sur le bras posterieur de la capsule interne). L'interêt potentiel d'un marqueur genetique de plasticite corticale (polymorphisme BDNF) reste a demontrer.

2.5. Conclusion

L'utilisation de l'imagerie fonctionnelle et de la TMS nous ont permis ces dernieres annees de mieux comprendre les mecanismes qui sous-tendent la recuperation motrice après la survenue d'un AVC et de developper de nouvelles strategies therapeutiques basees sur la NIBS qui ont demontré leur potentiel interét dans la recuperation de la fonction motrice. Cependant, la réponse individuelle a la neuromodulation est variable et elle depend de nombreux facteurs biologiques et techniques non encore parfaitement contrôles. Le choix de la NIBS ideale reste a definir. L'utilisation des donnees de l'imagerie réalisee le plus précocement possible devrait permettre de mieux selectionner les patients qui peuvent en beneficier en phase aigue ou subaigue et de l'utiliser pour « booster » les capacites naturelles de plasticite et de reparation du cerveau après une lesion vasculaire. En phase chronique, ces techniques de neuromodulation ont très certainement un interèt potentiel en particulier pour ameliorer les capacites d'apprentissage au cours de la prise en charge rèeducative mais la encore, sur des patients préalablement selectionnes en fonction des donnees de l'imagerie fonctionnelle et de l'electro-physiologie. Son utilisation en pratique clinique courante ne pourra se faire qu'après avoir realise des etudes longitudinales a grande echelle, multicentriques sur de larges echantillons de patients qui permettront de determiner sa place par rapport aux techniques conventionnelles de reeducation et les approches neuropharmacologiques et son interèt eventuel en add-on therapie.

Declaration d'interets

L'auteur declare ne pas avoir de conflits d'interèts en relation avec cet article.

References

[1] Donoghue JP. Plasticity of adult sensorimotor representations. Curr Opin Neurobiol 1995;5:749-54.

[2] Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol 1984;224:591-605.

[3] Rossini PM, Altamura C, Ferreri F, Melgari JM, Tecchio F, Tombini M, et al. Neuroimaging experimental studies on brain plasticity in recovery from stroke. Eura Medicophys 2007;43:241-54.

[4] Cramer SC, Nelles G, Benson RR, Kaplan JD, Parker RA, Kwong KK, et al. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 1997;28:2518-27.

[5] Chollet F, DiPiero V, Wise RJ, Brooks DJ, Dolan RJ, Frackowiak RS. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 1991;29:63-71.

[6] Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RS. Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol 1992;31:463-72.

[7] Loubinoux I, Carel C, Pariente J, Dechaumont S, Albucher JF, Marque P, et al. Correlation between cerebral reorganization and motor recovery after subcortical infarcts. Neuroimage 2003;20:2166-80.

[8] Tombari D, Loubinoux I, Pariente J, Gerdelat A, Albucher JF, Tardy J, et al. A longitudinal fMRI study: in recovering and then in clinically stable sub-cortical stroke patients. Neuroimage 2004;23:827-39.

[9] Ward NS, Cohen LG. Mechanisms underlying recovery of motor function after stroke. Arch Neurol 2004;61:1844-8.

[10] Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke 2003;34:1553-66.

[11] Ward NS, Brown MM, Thompson AJ, Frackowiak RS. Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 2003;126: 2476-96.

[12] Rossini PM, Tecchio F, Pizzella V, Lupoi D, Cassetta E, Pasqualetti P. Interhemispheric differences of sensory hand areas after monohemi-spheric stroke: MEG/MRI integrative study. Neuroimage 2001;14: 474-85.

[13] Rossini PM, Tecchio F, Pizzella V, Lupoi D, Cassetta E, Pasqualetti P, et al. On the reorganization of sensory hand areas after mono-hemispheric lesion: a functional (MEG)/anatomical (MRI) integrative study. Brain Res 1998;26:153-66.

[14] Calautti C, Leroy F, Guincestre JY, Baron JC. Displacement of primary sensorimotor cortex activation after subcortical stroke: a longitudinal PET study with clinical correlation. Neuroimage 2003;19:1650-4.

[15] Calautti C, Naccarato M, Jones PS, Sharma N, Day DD, Carpenter AT, et al. The relationship between motor deficit and hemisphere activation balance after stroke: a 3T fMRI study. Neuroimage 2007;34:322-31.

[16] Werhahn KJ, Conforto AB, KadomN, Hallett M, CohenLG. Contribution of the ipsilateral motor cortex to recovery after chronic stroke. Ann Neurol 2003;54:464-72.

[17] Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wima-laratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A 2002;29:14518-23.

[18] Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain 2006;129:791-808.

[19] Lotze M, Markert J, Sauseng P, Hoppe J, Plewnia C, Gerloff C. The role of multiple contralesional motor areas for complex hand movements after internal capsular lesion. J Neurosci 2006;31:6096-102.

[20] Cicinelli P, Traversa R, Rossini PM. Post-stroke reorganization of brain motor output to the hand: a 2-4 month follow-up with focal magnetic transcranial stimulation. Electroencephalogr Clin Neurophysiol 1997;105:438-50.

[21] Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM. Follow-up of interhemispheric differences of motor evoked potentials from the ''affected'' and ''unaffected'' hemispheres in human stroke. Brain Res 1998;24803:1-8.

[22] Manganotti P, Acler M, Zanette GP, Smania N, Fiaschi A. Motor cortical disinhibition during early and late recovery after stroke. Neurorehabil Neural Repair 2008;22:396-403.

[23] Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501-19.

[24] Butefisch CM, Wessling M, Netz J, Seitz RJ, Homberg V. Relationship between interhemispheric inhibition and motor cortex excitability in subacute stroke patients. Neurorehabil Neural Repair 2008;22:4-21.

[25] Cicinelli P, Pasqualetti P, Zaccagnini M, Traversa R, Oliveri M, Rossini PM. Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study. Stroke 2003;34:2653-8.

[26] Liepert J, Storch P, Fritsch A, Weiller C. Motor cortex disinhibition in acute stroke. Clin Neurophysiol 2000;111:671-6.

[27] Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002;113:936-43.

[28] Swayne OB, Rothwell JC, Ward NS, Greenwood RJ. Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology. Cereb Cortex 2008;18:1909-22.

[29] Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol 1992;453:525-46.

[30] Gerloff C, Cohen LG, Floeter MK, Chen R, Corwell B, Hallett M. Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract. J Physiol 1998;510:249-59.

[31] Daskalakis ZJ, Christensen BK, Fitzgerald PB, Roshan L, Chen R. The mechanisms of interhemispheric inhibition in the human motor cortex. J Physiol 2002;543:317-26.

[32] Duque J, Murase N, Celnik P, Hummel F, Harris-Love M, Mazzocchio R, et al. Intermanual differences in movement-related interhemispheric inhibition. J Cogn Neurosci 2007;19:204-13.

[33] Duque J, Hummel F, Celnik P, Murase N, Mazzocchio R, Cohen LG. Transcallosal inhibition in chronic subcortical stroke. Neuroimage 2005;28:940-6.

[34] Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemi-spheric interactions on motor function in chronic stroke. Ann Neurol 2004;55:400-9.

[35] Nowak DA, Grefkes C, Ameli M, Fink GR. Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair 2009;23:641-56.

[36] Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Canete C, Catala MD. Study and modulation of human cortical excitability with transcra-nial magnetic stimulation. J Clin Neurophysiol 1998;15:333-43.

[37] Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997;48:1398-403.

[38] Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation. Clin Neurophysiol 2000;111:800-5.

[39] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201-6.

[40] Buonomano DV, Merzenich MM. Cortical plasticity: from synapses to maps. Annu Rev Neurosci 1998;21:149-86.

[41] Baumer T, Lange R, Liepert J, Weiller C, Siebner HR, Rothwell JC, et al. Repeated premotor rTMS leads to cumulative plastic changes of motor cortex excitability in humans. Neuroimage 2003;20:550-60.

[42] Valero-Cabre A, Pascual-Leone A, Rushmore RJ. Cumulative sessions of repetitive transcranial magnetic stimulation (rTMS) build-up facilitation to subsequent TMS-mediated behavioural disruptions. Eur J Neurosci 2008;27:765-74.

[43] Lefaucheur JP, Andre-Obadia N, Poulet E, Devanne H, Haffen E, Londero A, et al. [French guidelines on the use of repetitive transcranial magnetic stimulation (rTMS): safety and therapeutic indications]. Neurophysiol Clin 2011;41:221-95.

[44] Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation. Electroencephalogr Clin Neurophysiol 1998;108:1-16.

[45] Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000;15:633-9.

[46] Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 2001;27:1899-901.

[47] Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 2010;66:198-204.

[48] Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull 2007;72:208-14.

[49] Ridding MC, Uy J. Changes in motor cortical excitability induced by paired associative stimulation. Clin Neurophysiol 2003;114:1437-44.

[50] Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 2000;3:572-84.

[51] Ridding MC, Taylor JL. Mechanisms of motor-evoked potential facilitation following prolonged dual peripheral and central stimulation in humans. J Physiol 2001;537:623-31.

[52] Uy J, Ridding MC, Hillier S, Thompson PD, Miles TS. Does induction of plastic change in motor cortex improve leg function after stroke? Neurology 2003;61:982-4.

[53] Castel-Lacanal E, Marque P, Tardy J, de Boissezon X, Guiraud V, Chollet F, et al. Induction of cortical plastic changes in wrist muscles by paired associative stimulation in the recovery phase of stroke patients. Neuror-ehabil Neural Repair 2009;23:366-72.

[54] Takeuchi N, Chuma T, Matsuo Y, Watanabe I, Ikoma K. Repetitive transcranial magnetic stimulation of contralesional primary motor cortex improves hand function after stroke. Stroke 2005;36:2681-6.

[55] Nowak DA, Grefkes C, Dafotakis M, Eickhoff S, Kust J, Karbe H, et al. Effects of low-frequency repetitive transcranial magnetic stimulation of the contralesional primary motor cortex on movement kinematics and neural activity in subcortical stroke. Arch Neurol 2008;65:741-7.

[56] Conchou F, Loubinoux I, Castel-Lacanal E, Le Tinnier A, Gerdelat-Mas A, Faure-Marie N, et al. Neural substrates of low-frequency repetitive transcranial magnetic stimulation during movement in healthy subjects and acute stroke patients. A PET study. Hum Brain Mapp 2008.

[57] Di Lazzaro V, Pilato F, Dileone M, Profice P, Capone F, Ranieri F, et al. Modulating cortical excitability in acute stroke: a repetitive TMS study. Clin Neurophysiol 2008;119:715-23.

[58] Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, Pascual-Leone A, Fregni F. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci 2007;25:123-9.

[59] Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006.

[60] Liepert J, Zittel S, Weiller C. Improvement of dexterity by single session low-frequency repetitive transcranial magnetic stimulation over the con-tralesional motor cortex in acute stroke: a double-blind placebo-controlled crossover trial. Restor Neurol Neurosci 2007;25:461-5.

[61] Conforto AB, Anjos SM, Saposnik G, Mello EA, Nagaya EM, Santos Jr W, et al. Transcranial magnetic stimulation in mild to severe hemiparesis early after stroke: a proof of principle and novel approach to improve motor function. J Neurol 2012;259:1399-405.

[62] Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, et al. Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke 2006;37: 1471-6.

[63] Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke 2006;37:2115-22.

[64] Hummel FC, Voller B, Celnik P, Floel A, Giraux P, Gerloff C, et al. Effects of brain polarization on reaction times and pinch force in chronic stroke. BMC Neurosci 2006;7:73.

[65] Talelli P, Greenwood RJ, Rothwell JC. Exploring theta burst stimulation as an intervention to improve motor recovery in chronic stroke. Clin Neu-rophysiol 2007;118:333-42.

[66] Ameli M, Grefkes C, Kemper F, Riegg FP, Rehme AK, Karbe H, et al. Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol 2009;66:298-309.

[67] Hesse S, Werner C, Schonhardt EM, Bardeleben A, Jenrich W, Kirker SG. Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: a pilot study. Restor Neurol Neurosci 2007;25:9-15.

[68] Malcolm MP, Triggs WJ, Light KE, Gonzalez Rothi LJ, Wu S, Reid K, et al. Repetitive transcranial magnetic stimulation as an adjunct to constraint-induced therapy: an exploratory randomized controlled trial. Am J Phys Med Rehabil 2007;86:707-15.

[69] Talelli P, Wallace A, Dileone M, Hoad D, Cheeran B, Oliver R, et al. Theta burst stimulation in the rehabilitation of the upper limb: a semirando-mized, placebo-controlled trial in chronic stroke patients. Neurorehabil Neural Repair 2012;26:976-87.

[70] Rossi C, Sallustio F, Di Legge S, Stanzione P, Koch G. Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients. Eur J Neurol 2012;20:202-4.

[71] Grefkes C, Fink GR. Disruption of motor network connectivity post-stroke and its noninvasive neuromodulation. Curr Opin Neurol 2012;25:670-5.

[72] Kandel M, Beis JM, Le Chapelain L, Guesdon H, Paysant J. Non-invasive cerebral stimulation for the upper limb rehabilitation after stroke: a review. Ann Phys Rehabil Med 2012;55:657-80.

[73] Hsu WY, Cheng CH, Liao KK, Lee IH, Lin YY. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. Stroke 2012;43:1849-57.

[74] Emara TH, Moustafa RR, Elnahas NM, Elganzoury AM, Abdo TA, Mohamed SA, et al. Repetitive transcranial magnetic stimulation at 1 Hz and 5 Hz produces sustained improvement in motor function and disability after ischaemic stroke. Eur J Neurol 2010;17:1203-9.

[75] Khedr EM, Abdel-Fadeil MR, Farghali A, Qaid M. Role of 1 and 3 Hz repetitive transcranial magnetic stimulation on motor function recovery after acute ischaemic stroke. Eur J Neurol 2009;16:1323-30.

[76] Sasaki N, Mizutani S, Kakuda W, Abo M. Comparison of the effects of high- and low-frequency repetitive transcranial magnetic stimulation on upper limb hemiparesis in the early phase of stroke. J Stroke Cerebrovasc Dis 2011;22:413-8.

[77] Kim DY, Lim JY, Kang EK, You DS, Oh MK, Oh BM, et al. Effect of transcranial direct current stimulation on motor recovery in patients with subacute stroke. Am J Phys Med Rehabil 2010;89:879-86.

[78] Lindenberg R, Zhu LL, Schlaug G. Combined central and peripheral stimulation to facilitate motor recovery after stroke: the effect of number of sessions on outcome. Neurorehabil Neural Repair 2012;26:479-83.

[79] Bolognini N, Pascual-Leone A, Fregni F. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil 2009;6:8.

[80] Celnik P, Paik NJ, Vandermeeren Y, Dimyan M, Cohen LG. Effects of combined peripheral nerve stimulation and brain polarization on performance of a motor sequence task after chronic stroke. Stroke 2009;40: 1764-71.

[81] Hiscock A, Miller S, Rothwell J, Tallis RC, Pomeroy VM. Informing dose-finding studies of repetitive transcranial magnetic stimulation to enhance motor function: a qualitative systematic review. Neurorehabil Neural Repair 2008;22:228-49.

[82] Mahmoudi H, Borhani Haghighi A, Petramfar P, Jahanshahi S, Salehi Z, Fregni F. Transcranial direct current stimulation: electrode montage in stroke. Disabil Rehabil 2011;33:1383-8.

[83] Lefebvre S, Laloux P, Peeters A, Desfontaines P, Jamart J, Vandermeeren Y. Dual-tDCS enhances online motor skill learning and long-term retention in chronic stroke patients. Front Hum Neurosci 2013;6:343.

[84] Zimerman M, Heise KF, Hoppe J, Cohen LG, Gerloff C, Hummel FC. Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke 2012;43:2185-91.

[85] Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain 2007;130:170-80.

[86] Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD. The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 2012;135:2527-35.