abstract: The human hand is a complex biological system. Humans have evolved a unique ability to use the hand for a wide range of tasks, including activities of daily living such as successfully grasping and manipulating objects, i.e., lifting a cup of coffee without spilling. Despite the ubiquitous nature of hand use in everyday activities involving object manipulations, there is currently an incomplete understanding of the cortical sensorimotor mechanisms underlying this important behavior. One critical aspect of natural object grasping is the coordination of where the fingers make contact with an object and how much force is applied following contact. Such force-to-position modulation is critical for successful manipulation. However, the neural mechanisms underlying these motor processes remain less understood, as previous experiments have utilized protocols with fixed contact points which likely rely on different neural mechanisms from those involved in grasping at unconstrained contacts. To address this gap in the motor neuroscience field, transcranial magnetic stimulation (TMS) and electroencephalography (EEG) were used to investigate the role of primary motor cortex (M1), as well as other important cortical regions in the grasping network, during the planning and execution of object grasping and manipulation. The results of virtual lesions induced by TMS and EEG revealed grasp context-specific cortical mechanisms underlying digit force-to-position coordination, as well as the spatial and temporal dynamics of cortical activity during planning and execution. Together, the present findings provide the foundation for a novel framework accounting for how the central nervous system controls dexterous manipulation. This new knowledge can potentially benefit research in neuroprosthetics and improve the efficacy of neurorehabilitation techniques for patients affected by sensorimotor impairments. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

abstract: The activation of the primary motor cortex (M1) is common in speech perception tasks that involve difficult listening conditions. Although the challenge of recognizing and discriminating non-native speech sounds appears to be an instantiation of listening under difficult circumstances, it is still unknown if M1 recruitment is facilitatory of second language speech perception. The purpose of this study was to investigate the role of M1 associated with speech motor centers in processing acoustic inputs in the native (L1) and second language (L2), using repetitive Transcranial Magnetic Stimulation (rTMS) to selectively alter neural activity in M1. Thirty-six healthy English/Spanish bilingual subjects participated in the experiment. The performance on a listening word-to-picture matching task was measured before and after real- and sham-rTMS to the orbicularis oris (lip muscle) associated M1. Vowel Space Area (VSA) obtained from recordings of participants reading a passage in L2 before and after real-rTMS, was calculated to determine its utility as an rTMS aftereffect measure. There was high variability in the aftereffect of the rTMS protocol to the lip muscle among the participants. Approximately 50% of participants showed an inhibitory effect of rTMS, evidenced by smaller motor evoked potentials (MEPs) area, whereas the other 50% had a facilitatory effect, with larger MEPs. This suggests that rTMS has a complex influence on M1 excitability, and relying on grand-average results can obscure important individual differences in rTMS physiological and functional outcomes. Evidence of motor support to word recognition in the L2 was found. Participants showing an inhibitory aftereffect of rTMS on M1 produced slower and less accurate responses in the L2 task, whereas those showing a facilitatory aftereffect of rTMS on M1 produced more accurate responses in L2. In contrast, no effect of rTMS was found on the L1, where accuracy and speed were very similar after sham- and real-rTMS. The L2 VSA measure was indicative of the aftereffect of rTMS to M1 associated with speech production, supporting its utility as an rTMS aftereffect measure. This result revealed an interesting and novel relation between cerebral motor cortex activation and speech measures. / Dissertation/Thesis / Doctoral Dissertation Speech and Hearing Science 2018

Em pacientes com esquizofrenia, sintomas obsessivo-compulsivos (SOC) são associados com taxas mais baixas de qualidade de vida e polifarmácia. Não há estudos controlados anteriores testando a eficácia da estimulação magnética transcraniana repetitiva (EMTr) para o tratamento de SOC nesta população. Este trabalho examinou os efeitos terapêuticos da EMTr aplicadas à Área Motora Suplementar (1 Hz, 20 min, 20 sessões) em SOC e sintomas gerais em pacientes com esquizofrenia ou transtorno esquizoafetivo, e se esta intervenção pode produzir alterações nos níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF). Inicialmente, foi realizado um relato de três casos, com o objetivo de fornecer uma evidência inicial de eficácia. Dois dos três pacientes que participaram apresentaram redução da Escala de Sintomas Obsessivo-Compulsivos de Yale-Brown (Y-BOCS), com retorno aos valores iniciais 4 semanas após o término do tratamento. Foi realizado então um estudo duplo-cego randomizado controlado por placebo para confirmação dos efeitos terapêuticos. EMTr ativa e placebo foram entregues para 12 pacientes (6 em cada grupo). Os escores da Escala de Sintomas Obsessivo-Compulsivos de Yale-Brown (Y-BOCS) e da Escala Breve de Avaliação Psiquiátrica (BPRS), bem como os níveis de BDNF, foram avaliados antes, depois, e 4 semanas após as intervenções. A EMTr não alterou significativamente os resultados após o tratamento e no follow-up (Y-BOCS: Χ2 = 3,172; p = 0,205; BPRS: X2 = 1.629; p = 0,443; BDNF: X2 = 2.930; p = 0,231). Parece haver uma tendência para a melhoria da pontuação BPRS 4 semanas após o tratamento no grupo ativo comparando com placebo (d de Cohen = 0,875, com 32,9% de poder estatístico). Não foram relatados efeitos colaterais. São necessários estudos futuros com amostras maiores. / In patients with schizophrenia, obsessive-compulsive symptoms (OCS) are associated with lower rates of quality of life and polypharmacy. No previous controlled studies have tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the treatment of OCS in this population. The present study examined the therapeutic effects of rTMS applied to the supplementary motor area (1 Hz, 20 min, 20 sessions) on OCS and general symptoms in patients with schizophrenia or schizoaffective disorder, and whether this intervention can produce changes in plasma levels of brain-derived neurotrophic factor (BDNF). Initially, there was a report of three cases with the aim of providing initial evidence of efficacy. Two patients showed a reduction on the Yale-Brown Obsessive-Compulsive Symptoms Scale (Y-BOCS) scores, with return to baseline 4 weeks after completion of treatment. Then, a double-blind randomized controlled trial was conducted. Active and sham rTMS were delivered to 12 patients (6 on each group). Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Brief Psychiatric Rating Scale (BPRS) scores, as well as BDNF levels, were assessed before, after, and 4 weeks after treatment. rTMS did not significantly change the outcomes after treatment and on the follow-up (Y-BOCS: Wald’s Χ2=3.172; p=0.205; BPRS: X2=1.629; p=0.443; BDNF: X2=2.930; p=0.231). There seemed to be a trend towards improvement of BPRS scores 4 weeks after rTMS treatment comparing with sham (Cohen’s d=0.875, with 32.9% statistical power). No side effects were reported. Future studies with larger sample sizes are needed.

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 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.

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).