Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2017-02-02T17:18:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Mayara Campêlo_Dissertação de mestrado_pós banca_versão Mônica_04.09.16.pdf: 2549632 bytes, checksum: 64ce0b1fe03a64305e5570dde8abb4e0 (MD5) / Made available in DSpace on 2017-02-02T17:18:33Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Mayara Campêlo_Dissertação de mestrado_pós banca_versão Mônica_04.09.16.pdf: 2549632 bytes, checksum: 64ce0b1fe03a64305e5570dde8abb4e0 (MD5) Previous issue date: 2016-03-07 / CNPQ / O exercício físico e as estimulações não invasivas do sistema nervoso central (SNC) são capazes de promover neuroplasticidade do SNC. Dentre as estimulações não invasivas destaca-se a estimulação transcraniana magnética repetitiva (EMTr) e, mais recentemente, a estimulação transcutânea medular por corrente contínua (ETMCC). O uso associado do exercício físico com a EMT ou com a ETMCC parece modular reflexos medulares. Contudo, não há evidência sistemática quanto aos efeitos da ETMCC sobre a excitabilidade da medula espinal, nem evidência comparativa das associações da ETMCC e da EMTr com o exercício físico. Portanto, essa dissertação apresenta dois artigos originais. O primeiro estudo é uma revisão sistemática com meta-análise que teve por objetivo sumarizar e avaliar o nível de evidência da eficácia da ETMCC em modificar a atividade medular. Dos sete estudos da revisão sistemática, cinco foram incluídos na meta-análise do efeito da ETMCC anódica e quatro na meta-análise do efeito da ETMCC catódica. Não houve efeito significante da ETMCC anódica e catódica, quando comparadas à ETMCC sham. Com isso, o estudo 1 conclui que não há evidência da eficácia da ETMCC em modular a excitabilidade medular. O segundo estudo é um crossover, triplo-cego, sham controlado, randomizado e contrabalanceado realizado com adultos saudáveis. Seu objetivo foi investigar as repercussões, nas excitabilidades medular e cortical, da associação da EMTr e da ETMCC com o exercício físico. Doze voluntários (24,75±2,77) foram submetidos a seis sessões experimentais, intercaladas por um período de 5 a 7 dias. Em cada sessão, um tipo de estimulação não invasiva do SNC (ETMCC anódica, ETMCC catódica, ETMCC sham, EMTr 20 Hz, EMTr1 Hz e EMTr sham) foi isoladamente associado a 20 minutos de exercício físico na esteira (EFE), em intensidade moderada. As repercussões das associações foram investigadas por meio de dois desfechos, avaliados antes (baseline), imediatamente (T0), 30 (T1) e 60 minutos (T2) após as intervenções. A excitabilidade medular (desfecho primário) e a excitabilidade cortical (desfecho secundário) foram mensuradas, respectivamente, por meio do componente doloroso do reflexo de retirada da perna (RIII) e de potenciais evocados motores (PEM). O estudo dois revelou que as intervenções ETMCC catódica/EFE (baseline/T0) e ETMr 20Hz/EFE (baseline/T0) aumentaram a excitabilidade medular, enquanto a aplicação da ETMr 1Hz/EFE (baseline/T2) e da ETMr 20Hz/EFE (baseline/T0, baseline/T1, e baseline/T2 ) aumentaram os níveis de excitabilidade cortical. Com isso, o estudo crossover demonstra que as associações EMTr/EFE e ETMCC/EFE podem interferir na atividade do SNC, mas apenas a ETMr 20Hz/EFE foi capaz de, simultaneamente, modular as excitabilidades cortical e medular. Portanto, a associação de estimulações não invasivas/EFE é capaz de modular o SNC e os efeitos decorrentes parecem depender do tipo de estimulação não invasiva aplicada. / Physical exercise and central nervous system (CNS) non invasive stimulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcutaneous spinal direct current stimulation (tsDCS), are able to promote CNS plasticity. Furthermore, the association between physical exercise and rTMS or tsDCS appears to promote spinal reflexes modulation. However, there are not systematic evidence about tsDCS effects on spinal reflexes. Similarly, there are no comparative study about an associative intervention of physical exercise and rTMS or tsDCS.Thus, this masters dissertation presents two originals articles. The first one is a systematic review with meta-analysis aimed to summarize and evaluate the level of evidence of tsDCS efficacy to modify spinal cord excitability. Seven studies were included on this systematic review. From these, five using anodal tsDCS and four using cathodal tsDCS were included on meta-analysis. The results indicated that there were not significant effects of anodal and cathodal tsDCS, when compared to sham tsDCS. Therefore, the first article concluded that there are not evidence of tsDCS efficacy to modulate spinal cord excitability. The second article is a crossover, triple-blind, sham controlled, randomized and counterbalanced study with healthy individuals. The aim of this study was to investigate the repercussions of the association between rTMS or tsDCS and physical exercise over CNS excitability. Twelve volunteers performed six experimental sessions. On each session, one type of CNS non invasive stimulation technique (anodal tsDCS, cathodal tsDCS, sham tsDCS, rTMS 20 Hz, rTMS 1 Hz or rTMS sham) was associated with 20 minutes of treadmill. An interval between five and seven days was assumed as washout period. The physical exercise (treadmill) was perfomed on moderate intensity and the CNS excitability was investigated by two outcomes measures, assessed at four different time points: before (baseline), immediately (T0), 30 (T1) and 60 (T2) minutes after the interventions. Spinal cord (primary outcome) and cortical (secondary outcome) excitabilities were assessed by the painful component of withdrawal reflex (RIII) and by motor evoked potentials (MEP), respectively. The result reveled that cathodal tsDCS/treadmill (baseline/T0) and rTMS 20HZ/treadmill (baseline/T0) increased spinal cord excitability. Additionally, rTMS1 Hz/treadmill (baseline/T2) and rTMS 20Hz/treadmill (baseline/T0, baseline/T1 and baseline/T2) increased cortical excitability. Thereby, the crossover study demonstrated that rTMS/treadmill and TsDCS/treadmill associative intervention are able to interfere on CNS excitability. However, only rTMS 20Hz/treadmill was able to modulate cortical and spinal cord activity. Therefore, CNS non invasive technique and physical exercise associative intervention can modify CNS excitability and the after effects seems to be dependent on the type of stimulation.

INTRODUÇÃO: Há evidências de modulação da excitabilidade do córtex motor por informações cerebelares, em animais e humanos. O objetivo deste estudo foi comparar a assimetria inter-hemisférica de excitabilidade cortical entre indivíduos com infarto cerebelar na fase crônica e controles saudáveis, através de estimulação magnética transcraniana. MÉTODOS: Foram incluídos sete indivíduos com infarto cerebelar (> 4 meses pós-infarto) e sete controles saudáveis. Cada participante foi submetido a uma sessão de estimulação magnética transcraniana do córtex motor no hemisfério direito e no hemisfério esquerdo, para a realização de medidas de excitabilidade e a determinação de assimetrias entre os hemisférios cerebrais. Os seguintes parâmetros de excitabilidade cortical foram avaliados: limiar motor de repouso, facilitação intracortical, inibição intracortical, relação entre amplitudes de potenciais evocados motores e amplitudes de ondas M, com intensidade de estimulação correspondendo ao limiar motor de repouso, a 130% do limiar motor de repouso, e a 100% da capacidade máxima do estimulador. RESULTADOS: Houve diferença significante na assimetria inter-hemisférica da inibição intracortical entre os grupos (teste de Mann-Whitney, p=0,048). Em todos os indivíduos com infartos cerebelares, a inibição intracortical foi menor no córtex motor primário contralateral ao infarto cerebelar, em comparação ao córtex motor ipsilateral. Houve ainda correlação significante entre o tempo de ocorrência do infarto cerebelar e a assimetria da inibição intracortical (r=0,91, p=0,004). Os demais parâmetros avaliados não apresentaram diferença significante entre os dois hemisférios em ambos os grupos. CONCLUSÕES: Estes resultados indicam que, em indivíduos com infarto cerebelar na fase crônica, ocorre desinibição do córtex motor contralateral. Avaliados em conjunto com estudos realizados em indivíduos com infartos cerebelares na fase subaguda, apoiam a hipótese de que alterações na inibição intracortical passam por modificações dinâmicas em diversas fases após um infarto cerebelar / INTRODUCTION: There is evidence of modulation of excitability of the motor cortex by cerebellar and somatosensory input in animals and humans. The goal of this study was to compare the inter-hemispheric asymmetry of cortical excitability in humans with cerebellar infarcts and healthy controls. METHODS: In order to evaluate inter-hemispheric asymmetry, seven individuals with cerebellar infarcts (> 4 months post-infarct) and seven healthy subjects were evaluated. There were no significant differences in age or gender between the groups. Each participant was submitted to one session of transcranial magnetic stimulation of the motor cortex of the right and left hemispheres, to determine asymmetries in excitability between the cerebral hemispheres. The following parameters of cortical excitability were evaluated: resting motor threshold, intracortical facilitation, intracortical inhibition, the relationship between motor evoked potential amplitudes and M-wave amplitudes. Three stimulation intensities were used: resting motor threshold, 130% of the resting motor threshold, and the stimulator\'s maximum output. RESULTS: There was a significant difference in inter-hemispheric asymmetry of intracortical inhibition between the groups (Mann-Whitney test, p=0.048). For all individuals with cerebellar infarcts, intracortical inhibition was lower in the primary motor cortex contralateral to the cerebellar infarction, compared to the ipsilateral motor cortex. There was also a significant correlation between the time elapsed since the cerebellar infarction and asymmetry of intracortical inhibition (r=0.91, p=0.004). The other variables evaluated were not significantly different between the two hemispheres in either group. CONCLUSIONS: These results indicate that disinhibition of the contralateral motor cortex occurs in individuals with chronic cerebellar infarcts. Taken together with studies performed in individuals with cerebellar infarcts in the subacute phase, these results support the hypothesis that changes in intracortical inhibition undergo dynamic changes over time, after a cerebellar infarct

The process of movement execution can be separated into two sections; the foreperiod and the response time. The foreperiod represents the time between the warning signal (WS) and the presentation of the imperative “go” signal, and the response time incorporates both the reaction time (RT) and the movement time (Schmidt & Lee, 2011). Transcranial magnetic stimulation (TMS) was used to probe corticospinal excitability (CE) which has been measured in a variety of RT tasks during both the foreperiod and the response time periods. The purpose of the two studies in this thesis was to measure when and at what rate changes in CE occur in both simple and complex tasks. The results of the first experiment indicated that CE levels quickly increased from baseline with the presentation of the WS. This was followed by a holding period in which CE was held constant until a decline in CE occurred prior to the presentation of the IS. This decline was followed by a rapid increase in CE as the movement was initiated and released. Importantly, even though levels of CE were decreasing relative to the start of the decline, participants were still in a heightened state as they prepared to release their movements. Furthermore, it is suggested that selective inhibitory control mechanisms were at least partly responsible for the decline prior to the IS. The results of the second experiment indicated that MEP amplitudes in a simple task were significantly larger compared to those in a complex task relative to both the IS and the onset of electromyography. These findings suggest that simple and complex tasks achieve differing levels of corticospinal excitability, and it is suggested that the complex requires the use of the cerebellum, which suppresses excitatory projections to the thalamus, and consequently to the motor cortex.

The corpus callosum provides a physical and functional connection between the two hemispheres of the brain allowing interactions between homologous cognitive, sensory and motor areas. In humans, the integrity of transcallosal connections between motor cortices can be evaluated quickly and non-invasively using transcranial magnetic stimulation (TMS) via the ipsilateral silent period (iSP). While the technique has been known for 20 years, many issues remain unsolved regarding which methods are best to elicit the iSP as an index of transcallosal inhibition. In addition, there is still limited information regarding the influence of individualized factors such as age on iSP measurements. This thesis investigates how common physiological and methodological factors influence the iSP in order to establish this method as a reliable index to assess the integrity of the transcallosal pathway linking primary motor cortices. In the first series of experiments, we used a previously described TMS protocol to elicit iSPs [1] to investigate changes in motor transcallosal inhibition in relation to individual factors linked to age, hand preference and history of concussions. A second series of methodological experiments examined the effects of stimulation intensity on the iSP and to determine its inter-session reliability. Our first series of experiments provided evidence that advancing age and history of concussions in young athletes were each independently associated with alterations in transcallosal inhibition. This was evidenced by changes in the duration of transcallosal inhibition (DTI) and in the latency of transcallosal inhibition (LTI) derived from iSP measurements. These experiments also revealed that the degree of hand preference in young adults was reflected in measures of transcallosal inhibition, so that mixed-handed individuals (i.e., ambidextrous) exhibited evidence of more efficient transcallosal transmission than either strong right or left handed individuals. The second series of experiments focusing on methodological aspects showed that the iSP duration (though not its onset) was influenced by stimulation intensity, increasing linearly with intensity up to 140% of the resting motor threshold (RMT). Our analysis further revealed that the probability of eliciting detectable iSP also increased with increasing intensity up to 130% RMT before reaching a plateau. A stimulation intensity of 130% of RMT appears to be optimal to elicit iSPs in healthy participants. In a subsequent study, we showed that iSP elicited at this stimulation intensity (i.e., 130% RMT) had good inter-session reliability. In light of these investigations, we recommend for future studies that, in addition to contraction of the homologous muscles of the opposite hand as proposed by Giovannelli et al 2009, that an intensity of 130% RMT should be used to elicit the iSP when assessing transcallosal inhibition between motor cortices.

Observing others performing actions is a common way to learn new motor skills. Such ability appears to be linked with one’s ability to imagine actions (motor imagery) (Wang et al. 2014). While motor imagery has been widely used in the context of athletic performance, the same approach has also been advocated in rehabilitation settings, where they often target populations with chronic pain using mobile health applications (de la Vega and Miro 2014). However, we still have very limited information as to how the ability to perform motor imagery addresses this rehabilitation application (Johnson et al. 2012). In the present study, we examined this question by looking at modulation in corticospinal excitability in the context of a motor imagery task. The imagery task itself consisted of judging whether images depicting hands in different postures represented either right or left hands. Based on prior neuroimaging and chronometric studies, such laterality judgments about hand postures are thought to involve mental rotations of one’s own hand (i.e., a form of implicit motor imagery) and thus provided an ideal context to evaluate if advocating such strategy is a valid approach to elicit motor activation in rehabilitation patients (Butson et al. 2014; Goble and Brown 2008; Parsons 1987). To this end, we used non-invasive transcranial magnetic stimulation (TMS) to probe the excitability of the motor system while young healthy participants performed mental rotations in the hand judgment task. Corticospinal excitability was tested in both hemispheres separately (target muscle: first dorsal interosseous) with participants (n=18) seated in front of a computer screen while they performed hand laterality judgments using a commercial set of pictures depicting bare hands in different postures. Excitability was tested also under two other conditions to contrast with variations measured during the hand laterality task, i.e. a mental counting task and a control task (looking at the image of a static foot). In all conditions, TMS (110% resting motor threshold) was set to trigger at ~half of the mean response time in the hand laterality task measured prior to testing with TMS. Comparison of task-related variations in MEP amplitude revealed no significant hemispheric main effect or interaction, although MEPs tended to be larger in general in response to left TMS. A “task condition” effect was observed owing to the large MEP facilitation elicited during the mental counting task, which was significantly different (p<0.001) from either the control “Foot” task or the hand rotation task. In fact, the latter task tended to be associated with MEP depression. A secondary experiment involving a subset of participants (n=6) to examine the influence of image contents (i.e. hand performing actions instead of bare hands) and probing more proximal muscles produced similar results as the main experiment. These results indicate that the general assumption that laterality tasks involving body parts will lead to internal mental rotation and motor activation and enhanced excitability is not necessarily true. In fact, our observations suggest that participants may rely on non-motor strategies based on visual cues when making laterality judgments about body parts. As well, no evidence for hemispheric asymmetry was found with the hand laterality task which is in line with other recent reports. Collectively, these results highlight the need to exert caution when using laterality tasks for rehabilitation purposes. One cannot simply assume that such tasks will translate into motor simulation and facilitation of the motor system. More research should be undertaken before recommending the hand mental rotation task as a viable rehabilitation option for chronic pain.

In addition to low mood, major depressive disorder (MDD) is characterized by persistent cognitive deficits that impair daily functioning and resist improvement with conventional pharmacotherapies. Repetitive transcranial magnetic stimulation (rTMS) holds promise as an efficacious alternative, offering better outcomes than medication for patients with treatment-resistant depression (TRD). Yet, current rTMS protocols that administer sinusoidal biphasic pulses achieve remission in less than the majority. However, monophasic pulses may yield higher success rates based on greater cortical excitation/neuromodulation strength. MDD is associated with altered P300 event-related potentials (ERPs), indexing decreased attentional resource allocation and slower cortical processing speed. Using a cohort of 20 TRD patients who received high-frequency rTMS, this study aimed to assess the impact of monophasic and biphasic stimulation on attention-related P300 measures and their utility as correlates of clinical/cognitive response. Based on baseline and post-treatment change in P300 components, rTMS-induced increases in automatic attention/passive information processing differed by pulse type and predicted greater clinical improvement in depressed individuals. This study represents an important step towards identifying cognitive changes and underlying cortical mechanisms associated with rTMS response and targeted MDD treatment.

La compréhension des effets cérébraux sous-tendant l’impact de la stimulation magnétique transcrânienne répétée (rTMS) est un a priori nécessaire à la connaissance de la prise en charge thérapeutique des patients bénéficiant de ces traitements. A posteriori, elle permet en plus de comprendre les processus physiopathologiques responsables des symptômes cliniques propres aux troubles mentaux. Nous nous sommes ici intéressés aux effets de la rTMS sur le cerveau des patients souffrant de schizophrénie (SZ), au travers des deux principes fondamentaux du fonctionnement cérébral que sont la ségrégation et l’intégration fonctionnelle. En premier lieu, nous avons analysé l’effet de la rTMS visant le cortex préfrontal médian (CPM) sur le principe de ségrégation fonctionnelle chez des SZ avec trouble de la cognition sociale. Pour ce faire nous avons développé un paradigme d’imagerie par résonance magnétique fonctionnelle (IRMf) écologique et novateur de cognition sociale. Un prérequis aux études longitudinales en IRMf est la reproductibilité du signal d’activation. Nous avons alors démontré la fiabilité de notre paradigme entre deux sessions, puis à l’aide de ce paradigme, nous avons étudié l’effet de la rTMS sur la ségrégation à partir de la variation du signal BOLD et des taux de N-AcetylAspartate et de glutamate. Puis nous avons étudié l’impact de la rTMS ciblant le sillon temporal supérieur gauche (STSg) sur les hallucinations auditivo-verbales (AVH) en termes de connectivité fonctionnelle statique (intégration fonctionnelle). Nous avons ainsi mis en évidence l’effet bénéfique de la rTMS sur le trouble de cognition sociale et sur les AVH. En outre, quand la rTMS cible le STSg, il ne semble pas avoir d’effet sur la connectivité fonctionnelle statique du réseau cérébral du langage observé. Cependant, focalisé au niveau du CPM, elle permettrait d’augmenter la concentration de N-acétylaspartate des SZ. L’absence d’effet de la rTMS illustrerait plutôt des profils d’organisation cérébrale différents des SZ, et ce par des variabilités interindividuelles, suggérant qu’il serait à l’avenir bénéfique de déterminer les caractéristiques optimales de la stimulation sur une base individuelle afin de mieux moduler les processus anormaux du cerveau dans les schizophrénies. / The understanding of the brain effects underlying the impact of repeated transcranial magnetic stimulation (rTMS) is a necessary a priori necessary concerning patients treatments. A posteriori, it also helps to understand the pathophysiological processes responsible for the clinical symptoms of mental disorders. Hither, we are interested in the effects of rTMS on the brain of patients with schizophrenia (SZ), through the two fundamental principles of cerebral functioning: segregation and functional integration. First, we have analyzed the effect of rTMS on the medial prefrontal cortex (MPFC) according to functional segregation in SZ with social cognition disorder. To do this we have developed an ecological and innovative social cognition paradigm for functional magnetic resonance imaging (fMRI). A prerequisite for longitudinal studies in fMRI is the reproducibility of the activation signal, we have then demonstrated the reliability of our paradigm between two sessions. Using this paradigm, we have studied the effect of rTMS on segregation from the variation of the BOLD signal and the levels of N-Acetyl Aspartate and glutamate. Then, we studied the impact of rTMS targeting the left temporal sulcus (STS) on auditory-verbal hallucinations (AVH) in terms of functional connectivity (functional integration). We have thus demonstrated the beneficial effect of rTMS on social cognition disorder and on AVH. Moreover, when the rTMS targets the STS, it does not seem to have an effect on the static functional connectivity within the listening language network. However, focused on the MPFC, it would increase the N-acetylaspartate concentration of SZ. The absence of the effect of the rTMS would rather illustrate different brain organization patterns of the SZ, due to inter-individual variability, suggesting that it would be in the future beneficial to determine optimal characteristics of stimulation on an individual basis in order to best modulate abnormal processes of the brain in schizophrenias.

Previous research and current models have proposed that the right temporoparietal junction (rTPJ) is crucially involved in the control and distinction of shared representations of action. Hitherto, this assumption has mainly been based on neuroimaging work ( (Spengler, von Cramon, & Brass, 2009); (Spengler, von Cramon, & Brass, 2010)) We tested this hypothesis, that the rTPJ is causally involved in managing shared representations by using repetitive transcranial magnetic stimulation in an offline paradigm to disrupt neural activity in this region. Using a simple imitation-inhibition task we showed that stimulation of the rTPJ led to increased reaction times when participants had to control automatic imitation of a perceived hand movement, as they had to concurrently plan and execute an opposite movement. Our study provides the first empirical evidence that the rTPJ is necessary for managing and navigating within a shared representational system. These results may also have important implications for future theorizing about the role of the TPJ region in controlling shared representations also in other domains, such as somatosensation or emotional experiences.:1 Bibliografische Beschreibung 2 Introduction 2.1 Imitation 2.1.1 Automatic imitation and mirroring 2.1.2 Control of automatic imitation 2.2 Functional Neuroanatomy 2.2.1 Temporo-parietal junction (TPJ) 2.2.2 Function of the right TPJ 2.3 Transcranial magnetic stimulation (TMS) 2.3.1 History 2.3.2 Physical Basis of TMS 2.3.3 TMS stimulatore 2.3.4 rTMS 2.3.5 Medical Use 3 Own Study: Aims and research questions 3.1 Research Questions 4 Materials and Methods 4.1 Participants 4.2 General procedure 4.3 Imitation-Inhibition task 4.4 TMS- protocol 4.5 Data analysis 5 Results 6 Discussion 7 Conclusion 8 Literatur directory 9 Figures and Table 10 Curriculum Vitae 12 Erklärung über die eigenständige Abfassung der Arbeit

La douleur neuropathique est fréquente, invalidante et souvent difficile à traiter avec les médicaments dont nous disposons actuellement. Une meilleure compréhension de la physiopathologie de ces douleurs et le développement de nouvelles thérapeutiques sont nécessaires. La stimulation magnétique transcrânienne (TMS) est une technique permettant d’évaluer l’excitabilité corticale et de moduler la douleur et pourrait ainsi constituer une piste intéressante. La sclérose en plaques (SEP) engendre fréquemment des douleurs neuropathiques et constitue la pathologie sur laquelle s’est focalisé ce travail. L’objectif de ce dernier était tout d’abord de définir précisément les caractéristiques des douleurs dans la SEP, ensuite de tester chez des sujets sains de nouvelles fréquences de TMS répétitives (rTMS) pour tenter d’améliorer et de mieux comprendre les effets antalgiques de cette technique et enfin, de réaliser une étude thérapeutique de l’effet de la rTMS chez des patients présentant des douleurs neuropathiques centrales en rapport avec une SEP. Durant la première partie de ce travail, nous avons conduit une enquête postale adressée à 1300 patients SEP qui a permis de montrer que 51% des patients présentaient des douleurs aux caractéristiques neuropathiques, 46% des migraines et que ces deux symptômes n’étaient pas indépendants mais semblaient médiés par des mécanismes distincts. La seconde partie de ce travail a débuté par une revue de la littérature concernant les mécanismes d’action de la rTMS utilisée à visée antalgique. Nous avons ensuite réalisé une étude impliquant 14 sujets sains, qui a permis de montrer qu’une nouvelle fréquence de rTMS, la stimulation theta burst prolongée continue (pcTBS), permettait d’obtenir une antalgie au froid plus importante que la rTMS classique à 10Hz après stimulation du cortex moteur primaire (M1) gauche. Chez ces sujets sains, l’effet antalgique n’était pas lié à une modulation de l’excitabilité du cortex moteur primaire ou à une majoration de la modulation de la douleur induite par une stimulation conditionnante. La dernière partie du travail est en cours. Elle correspond à un essai contrôlé, randomisé, en double aveugle, impliquant 3 groupes parallèles (rTMS à 10Hz, pcTBS et rTMS placebo ciblant le M1 gauche). Soixante-six patients SEP présentant des douleurs neuropathiques réfractaires seront inclus (22 par groupe). Ils bénéficieront d’une séance de rTMS par jour durant cinq jours consécutifs et seront suivis durant un mois. Le critère principal de jugement porte sur la variation de la douleur entre la semaine précédant les rTMS et le huitième jour après la première rTMS. Des objectifs secondaires physiopathologiques (imagerie et excitabilité corticale) impliquent l’inclusion de 40 patients SEP ne présentant pas de douleur (STIMASEP, NCT02059096). / Neuropathic pain is common, debilitating and often difficult to treat with the drugs we currently have. A better understanding of the pathophysiology of these pains and the development of new therapeutics are needed. Transcranial Magnetic Stimulation (TMS) is a technique for evaluating cortical excitability and modulating pain, and could be an interesting avenue. Multiple sclerosis (MS) frequently causes neuropathic pain and is the pathology on which this work has focused. The aim of the latter was first of all to precisely define the characteristics of pain in MS, then to test in healthy subjects new frequencies of repetitive TMS (rTMS) in an attempt to improve and better understand the analgesic effects of this technique and finally, to perform a therapeutic study of the effect of rTMS in patients with central neuropathic pain related to MS.During the first part of this work, we conducted a postal survey addressed to 1300 MS patients, which showed that 51% of patients had pain with neuropathic features, 46% of migraine headaches and that these two symptoms were not independent. but seemed to be mediated by distinct mechanisms.The second part of this work started with a review of the literature concerning the mechanisms of action of rTMS used for analgesic purposes. We then conducted a study involving 14 healthy subjects, which showed that a new frequency of rTMS, prolonged continuous theta-burst stimulation (pcTBS), made it possible to obtain a more important cold-pain treatment than the conventional 10 Hz rTMS. after stimulation of the left primary motor cortex (M1). In these healthy subjects, the analgesic effect was not related to a modulation of the excitability of the primary motor cortex or to an increase in the modulation of pain induced by conditioning stimulation.The last part of the work is in progress. It consists of a randomized, double-blind controlled trial involving 3 parallel groups (10 Hz rTMS, pcTBS and placebo rTMS targeting the left M1). Sixty-six MS patients with refractory neuropathic pain will be included (22 per group). They will receive one rTMS session per day for five consecutive days and will be followed for one month. The primary endpoint is variation in pain between the week prior to rTMS and the eighth day after the first rTMS. Secondary physiopathological objectives (imaging and cortical excitability) imply the inclusion of 40 MS patients presenting no pain (STIMASEP, NCT02059096).

When exploring movement production, motor control researchers have been interested in investigating the relative contributions to different types of movement. In a research setting, a startling acoustic stimulus (SAS) can be used as a tool to explore the neural processes that are occurring when preparing and initiating a movement. Additionally, suprathreshold TMS is another tool which can induce a suppression of the cortical region of the brain, resulting in RT delays which provides us with the ability to assess the corticospinal contributions to a particular movement. The aim of the current study was to investigate potential differences in the planning and execution of bimanual versus unimanual wrist extension movements. It was of particular interest as to whether bimanual coupling occurs at the cortical level or in lower parts of the output pathway (reticulospinal). Participants (N=6) were instructed to complete a unimanual or bimanual wrist extension following a control go-signal or a SAS. For subset of trials, in order to explore the level of corticospinal excitability of the movement, suprathreshold TMS was applied over the left M1 during the task to induce a cortical silent period (CSP). Results revealed that theimpact of TMS on response initiation was not significantly different for unimanual task versus a bimanual task. Furthermore, the SP (silent period) only had an impact on the right limb and not the left during the bilateral task. Lastly, SAS did lead to shorter RTs for both the unimanual and bimanual wrist extension task, but the RT delay induced by TMS in the right limb was not shorter in SAS trials compared to control. The findings of the present study suggest that bimanual coupling may be occurring at the cortical level and in lower parts of the output pathway as there may be correlated neural activity in the two hemispheres occurring during bimanual wrist extension movements.