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.

L’aphasie est un symptôme fréquent après un AVC et a un impact majeur social, économique, médical et psychologique sur les patients. Des études récentes ont tenté avec peu de succès de rechercher des critères pronostiques cliniques précoces de récupération d’une aphasie. L’enjeu de cette possibilité de prédiction est un enjeu majeur clinique et scientifique et peut influencer la prise en charge ré-éducative décidée dès les premiers jours après l’AVC. De plus, l’étude clinico-physiologique de la récupération du langage permettrait de mieux comprendre les mécanismes de plasticité cérébrale mis en jeux. Tout d’abord, nous allons nous intéresser chez le sujet sain à l’implication du cortex moteur dans des tâches de perception, renforçant l’idée que cette structure anatomique jouerait un rôle plus étendu que celui auquel elle a été reléguée pendant de nombreuses années, puis nous allons explorer des facteurs prédictifs de la récupération de l’aphasie, les facteurs langagiers dans un premier temps et des facteurs électrophysiologiques, notamment via la TMS explorant l’intégrité du cortex moteur, et leur contribution dans la prédiction de la récupération. / Considering the high incidence of post-stroke aphasia and its significant social and economic impact, better understanding the mechanisms of language recovery in order to predict patient’s outcome and to optimize rehabilitation is a clinical and scientific challenge. Here we aimed to study whether the motor cortex is involved in speech and language perception, suggesting this structure could play a crucial role. Then, we investigated whether some language features could contribute to the prognosis of aphasia recovery. Finally, we investigated whether the anatomofunctional evaluation of the corticomotor pathway using TMS could improve the prediction of post stroke aphasia recovery.

Using functional magnetic resonance imaging in humans, Brodmann's area 5 (BA5) is observed to be activated during the suppression of motor output in the context of a NO-GO task. In monkeys, BA5 is associated with somatosensation and specifically linked with motor preparation. The goal of this thesis is to investigate BA5 influences on corticospinal excitability prior to the onset of movement, in the context of a GO/NO-GO paradigm. To achieve this goal, paired-pulse TMS is used to probe the functional connectivity between BA5 and ipsilateral primary motor cortex (M1) for a muscle specific to the hand. Three experiments are performed that investigate the differences in corticospinal output to the hand in a GO task versus a NO-GO task and the stimulation parameters that reveal such differences. Results indicate that BA5 is able to condition M1 prior to movement in a task-specific manner. Further, motor evoked potentials (MEPs) are suppressed in the context of a NO-GO task relative to a GO task, and task-specific differences rely on the intensity and direction of induced current in the cortex. In conclusion, data from this thesis contribute to our understanding of the role of BA5 in motor control. / Thesis / Master of Science in Kinesiology

<p> Clinical diagnosis, classification of injury and the reliable and detailed description of a patient's neurological status are key factors in determining intervention, rehabilitation programs and predicting recovery. The American Spinal Injury Association (ASIA) impairment scale (AIS) is a standardized method for spinal cord injury (SCI) classification and neurologic status examination. Studies have revealed the AIS classification to be a general assessment tool that fails to explain the varying degrees and patterns of neurological damage, especially in individuals with incomplete injuries. In addition, intragroup variability can be attributed to inaccuracies in examinations and improper assessment tools that have limited research findings. Transcranial Magnetic Stimulation (TMS) has been used as a non-invasive method of evaluating the integrity of the motor nervous system. The primary purpose of this study was to evaluate TMS as an assessment tool to describe motor impairment of SCI individuals. A second purpose of this study was to assess AIS accuracy and sensitivity to muscle activation by using surface electromyographic (sEMG) techniques during clinical examinations. Six incomplete SCI participants were clinically assessed to obtain their individual motor scores from key muscles following AIS assessment criteria. TMS was then used to stimulate the motor cortex to elicit motor evoked potentials (MEPs) in 4 key muscles. MEPs correlated with motor scores, where significantly higher and lower MEPs corresponded to the highest and lowest motor scores, respectively. Of the 48 muscles analyzed, 18 received a motor score of zero; however MEPs were obtained in 7 of these 18 muscles. In general, MEPs paralleled motor function as assessed by the AIS. Results suggest that TMS may provide information on the relationship between corticospinal integrity and the quality of motor function. In addition, TMS demonstrated adequate validity and sensitivity to SCI individual differences. MEPs provided additional information regarding the existence of spared neuronal pathways not identified by standard clinical evaluations. The therapeutic potential of these motor pathways has yet to be explored. EMG activity was significantly correlated to motor scores and MEPs however; EMG analysis revealed some inaccuracies in muscle examinations and supported MEP data. Results suggest that the implementation of electrophysiological assessment tools may be more sensitive to detect motor damage, adaptive movement patterns and overall muscle activation that may be misinterpreted during clinical examinations.</p> / Thesis / Master of Science (MSc)

Transcranial magnetic stimulation (TMS) is commonly used to measure corticospinal and intracortical excitability in basic and clinical neuroscience. However, the effect of glucose on TMS-based measures is not well defined, despite a potentially impactful influence on precision and reliability. Here, a double-blinded placebo-controlled study was used to test the effects of glucose on two commonly used TMS measures: short-interval intracortical inhibition (SICI), and the area under the motor evoked potential recruitment curves (AURC). SICI and AURC are thought to reflect inhibitory (GABAergic) and excitatory (glutamatergic) neurotransmission respectively. Healthy males (N=18) each participated in four sessions. Session 1 involved TMS familiarization and acquisition of an individualized blood glucose response curve. During sessions 2, 3 and 4, dependent measures were taken before (T0) and twice after (T1 & T2) drinking 300 mL of solution containing glucose (75 g), sucralose-sweetened placebo (control for sweetness) or plain water (control for time). The T1 and T2 measurements were started 5 minutes prior to the blood glucose peak observed during Session 1. Blood glucose and mean arterial pressure (MAP) were also monitored. Sucralose, but not water or glucose increased AURC and none of the treatments altered SICI. There was no association between blood glucose level and TMS measures, but in all three conditions MAP rose after consumption of the drink. There was a positive correlation between the rise in blood pressure and the relative increase in AURC at the higher stimulus intensities. Eleven participants returned for a fifth session to quantify the smallest detectible change in the AURC measurements and it was confirmed that significant changes were real while non-significant differences in measurement means fell within the range of expected measurement error. This study also suggests a relationship between corticospinal excitability and autonomic tone. Additional investigation is required to understand the mediating factors of this association. / Thesis / Master of Science (MSc)

Previous research has established that observing another in pain activates both affective and sensorimotor cortical activity that is also present during the first-hand experience of pain. Some researchers have taken this “mirroring” response as indicative of empathic processing. However, very little work has explored the downstream behavioral effects of empathic pain observation. The aim of this dissertation is to begin to fill this gap in the literature by exploring the relationship between empathic pain observation, overt motor behaviours, and sensorimotor activity. In chapters 2-4, I provide robust evidence that observing pain inflicted on another person leads to faster reaction time responses. This effect is shown to be temporally extended (by at least 500ms after pain observation), effector-general (affecting both finger and foot responses), influenced by top-down (i.e., instructions to explicitly empathize) but not bottom-up (i.e., the perceived level of pain) factors, and is not influenced by adaptive (approach/withdraw) behaviours. In chapter 5, I show that sensorimotor activity, measured via TMS-induced Motor Evoked Potentials, increases while observing another in pain regardless whether the observer is preparing to make an action vs. passively observing the stimuli. These results run counter to the literature, and I provide several explanations for why these results were found. Lastly, in chapter 6, I show that sensorimotor activity, measured via Mu and Beta suppression, also increases while observing another in pain regardless whether the observer is preparing to make an action vs. passively observing the stimuli. Interestingly, I do not find significant correlations between sensorimotor activity during pain observation and faster reaction times after pain observation. I embed these findings in relation to the wider social neuroscience of empathy literature and discuss several limitations and challenges in empirically measuring “empathy” as a psychological construct. Overall, this dissertation furthers our understanding of empathy for pain by highlighting the behavioural consequences of pain observation and its connection (or rather, lack thereof) to sensorimotor activity during pain observation. / Thesis / Doctor of Philosophy (PhD) / Past research suggests that overlapping brain activity during the first-hand experience of pain and pain observation may be indicative of empathy. However, very little work has been done to explore how pain observation influences overt behaviours. This thesis investigates this issue by having participants complete a reaction time task while watching videos of needles stabbing a person’s hand. The findings reported in this thesis suggests that observing another in pain facilitates motor behaviours (i.e., faster reaction times); this facilitation extends 500ms after pain observation, affects both the hand and feet, is accentuated by instructing participants to explicitly empathize, and is not influenced by approach vs. withdraw movements. Brain activity in the motor system was also found to increase during pain observation. Overall, this thesis begins the discussion of how empathic pain observation influences explicit motor behaviours, and how such behaviours may be related to brain activity.