<p>Temporal order judgment (TOJ) refers to one’s ability to successively report the temporal order of two tactile stimuli delivered to independent skin sites. The brain regions involved in processing TOJ remain unclear. Research has shown that TOJ performance can be impaired with a conditioning background stimuli and this phenomenon, known as TOJ synchronization (TOJ-S), is suggested to be mediated by inhibitory neural mechanisms within the primary somatosensory cortex (SI) that create perceptual binding across the two skin sites. Continuous theta-burst stimulation (cTBS) over SI impairs tactile spatial and temporal acuity. This dissertation examines the effects of cTBS on TOJ and TOJ-S performance on the hand. In Experiment 1, TOJ and TOJ-S were measured from the right hand before and for up to 34 minutes following 50 Hz cTBS over SI. In Experiment 2, same measurements were obtained bilaterally for up to 42 minutes following 30 Hz cTBS over SI. Compared to pre-cTBS values, TOJ was impaired for up to 42 minutes on the right hand following 30 Hz cTBS. TOJ-S performance was improved for up to 18 minutes on the right hand following 50 Hz cTBS. These experiments reveal two major findings. First, cTBS act upon different inhibitory circuits that are suggested to mediate TOJ and TOJ-S. Second, cTBS parameters may dictate cTBS effects over SI excitability. The findings of this work not only emphasize the significant contributions of SI on tactile temporal perception, it provides novel insight of the underlying neural mechanisms of cTBS effects on SI cortical excitability.</p> / Master of Science in Kinesiology

Résumé : L’interaction entre la douleur et le système moteur est bien connue en clinique et en réadaptation. Il est sans surprise que la douleur est un phénomène considérablement invalidant, affectant la qualité de vie de ceux et celles qui en souffrent. Toutefois, les bases neurophysiologiques qui sous-tendent cette interaction demeurent, encore aujourd’hui, mal comprises. Le but de la présente étude était de mieux comprendre les mécanismes corticaux impliqués dans l’interaction entre la douleur et le système moteur. Pour ce faire, une douleur expérimentale a été induite à l’aide d’une crème à base de capsaïcine au niveau de l’avant-bras gauche des participants. L'effet de la douleur sur la force des projections corticospinales ainsi que sur l’activité cérébrale a été mesuré à l’aide de la stimulation magnétique transcrânienne (TMS) et de l’électroencéphalographie (EEG), respectivement. L’analyse des données EEG a permis de révéler qu'en présence de douleur aiguë, il y a une augmentation de l’activité cérébrale au niveau du cuneus central (fréquence têta), du cortex dorsolatéral préfrontal gauche (fréquence alpha) ainsi que du cuneus gauche et de l'insula droite (toutes deux fréquence bêta), lorsque comparée à la condition initiale (sans douleur). Également, les analyses démontrent une augmentation de l'activité du cortex moteur primaire droit en présence de douleur, mais seulement chez les participants qui présentaient simultanément une diminution de leur force de projections corticales (mesurée avec la TMS t=4,45, p<0,05). Ces participants ont également montré une plus grande connectivité entre M1 et le cuneus que les participants dont la douleur n’a pas affecté la force des projections corticospinales (t=3,58, p<0,05). Ces résultats suggèrent qu’une douleur expérimentale induit, chez certains individus, une altération au niveau des forces de projections corticomotrices. Les connexions entre M1 et le cuneus seraient possiblement impliquées dans la survenue de ces changements corticomoteurs. / Abstract : The interaction between pain and the motor system is well-known in clinic. For instance, it is well documented that pain significantly complicates the rehabilitation of the patients. The aim of the present study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Nineteen healthy adults participated in the study. The effect of pain (induced with a capsaicin cream) on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. For EEG, 15 non-overlapping, 2-seconds artifacts were randomly selected for each participant. Intracranial source current density and functional connectivity was determined using sLORETA software. When participants experienced experimentally-induced inflammatory pain, their resting state brain activity increased significantly in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and both left cuneus and right insula (beta frequency; all ts >3.66; all ps<0.01). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a simultaneous reduction in the strength of the corticospinal projections (quantified using the recruitment curves obtained with TMS; t=4.45, p<0.05). These participants further showed greater beta motor-cuneus connectivity than participants for whom pain did not affect M1 somatotopy (t=3.58, p<0.05). These results suggest that pain-evoked increases in M1 beta power are intimately tied to alterations in corticospinal system. Moreover, we provide evidence that beta motor-cuneus connectivity is related to the corticomotor alterations induced by pain.

The body of work hereby presented aims at better defining the specific mechanisms underlying cognitive control and flexibility, and to investigate the neural substrates that might support these dynamics. More specifically, the anterior cingulate (ACC), dorsolateral prefrontal (dlPFC) and frontopolar (FPC) cortices have been proposed to play a fundamental role in monitoring and detecting the presence of environmental contingencies that require the recruitment of cognitive control (such as competition between responses in the presence of conflicting information), implementing cognitive control, and supporting higher-order cognitive processing, respectively. This thesis investigates the effects of damage to these regions, and of interference with their activity, on these processes. It also argues for the importance of dissociating possible separate cognitive control components that might differently contribute to behavioural adjustments (such as caution and attention/task-relevant processing), and provides one of the first attempts to quantify them within the parameters of a mathematical model of choice response-time, the Linear Ballistic Accumulator (LBA). The results confirm the crucial role of the dlPFC in modulating behavioural adjustments, as both damage and interference with this region’s activity significantly affect measures of conflict-induced behavioural adaptation. It is hypothesized that dlPFC might drive behavioural adjustments by encoding recent conflict history and/or supporting the automatization of a newly advantageous behavioural strategy during the early stages after a change in conflict levels. When a task does not involve competition between a habit and instructed behaviour, lesions or interference with ACC’s activity do not appear to affect behaviour in a manner that is consistent with the classic conflict-monitoring framework. It is suggested that its role might be better described as a more general monitoring and confirmatory mechanism that evaluates both actual and potential outcomes of an action, in order to proactively guide adjustments away from contextually disadvantageous responses. Finally, lesions to the FPC do not affect abstract-rule integration, but do impair the early stages of acquisition of a new abstract rule, when a previously rewarded rule stops being rewarded, and specifically when acquisition is dependent on self-initiated exploration. This suggests a role for FPC in the evaluation of multiple concurrent options in order to aid the development of new behavioural strategies.

In everyday life we regularly update our expectations about the locations at which sensory events may occur, and about the motor responses that are appropriate in a given situation. The experiments in this thesis investigated the neural correlates of perceptual processes and motor preparation during human decision making, and the regions that causally contribute to decision making in the human brain. In Chapter 3, I used electroencephalography (EEG) to investigate whether alpha-band (~8-14 Hz) oscillations provide a graded index of participants’ preparatory attentional states. Time-frequency analysis revealed that manipulating spatial certainty regarding the location of an upcoming visual target led to parametric changes in the lateralization of preparatory occipito-parietal alpha oscillations, and to parametric modulation of parieto-central beta-band (~15-25 Hz) power typically associated with response preparation. In Chapter 4, I used EEG to investigate whether evolution of lateralization of sensorimotor alpha- and beta-band activity reflected participants’ evolving expectations about an upcoming motor response. Lateralization of activity in both frequency bands varied parametrically with the available evidence, suggesting such lateralized activity correlates with participants’ internal decision variables. Further analysis identified unique contributions to lateralized and non-lateralized oscillatory activity due to the prior evidence, evidence update, and surprise related to the observed information at each stage of the task. In Chapter 5, I extended the paradigm developed in Chapter 4 for use with online repetitive transcranial magnetic stimulation (TMS) and concurrent EEG recording. Delivery of TMS during decision making allowed investigation of the causal role played by a left hemisphere medial intraparietal region that is the putative human homologue of the macaque medial intraparietal cortex (MIP). MIP stimulation disrupted decision-making behaviour by biasing participants’ decisions against contralateral-to-stimulation (i.e., right-handed) responses. Comparison of the magnitude of TMS-induced changes in behaviour and beta-band activity demonstrated that the intraparietal cortex plays a causal role both in decision making and in the appearance of beta-band activity over the motor cortex. In Chapter 6, the broader consequences of the experimental work presented in this thesis are discussed, in addition to promising directions for future research.

La perception de mouvements est associée à une augmentation de l’excitabilité du cortex moteur humain. Ce système appelé « miroir » sous-tendrait notre habileté à comprendre les gestes posés par une tierce personne puisqu’il est impliqué dans la reconnaissance, la compréhension et l’imitation de ces gestes. Dans cette étude, nous examinons de quelle façon ce système miroir s’implique et se latéralise dans la perception du chant et de la parole. Une stimulation magnétique transcrânienne (TMS) à impulsion unique a été appliquée sur la représentation de la bouche du cortex moteur de 11 participants. La réponse motrice engendrée a été mesurée sous la forme de potentiels évoqués moteurs (PÉMs), enregistrés à partir du muscle de la bouche. Ceux-ci ont été comparés lors de la perception de chant et de parole, dans chaque hémisphère cérébral. Afin d’examiner l’activation de ce système moteur dans le temps, les impulsions de la TMS ont été envoyées aléatoirement à l’intérieur de 7 fenêtres temporelles (500-3500 ms). Les stimuli pour la tâche de perception du chant correspondaient à des vidéos de 4 secondes dans lesquelles une chanteuse produisait un intervalle ascendant de deux notes que les participants devaient juger comme correspondant ou non à un intervalle écrit. Pour la tâche de perception de la parole, les participants regardaient des vidéos de 4 secondes montrant une personne expliquant un proverbe et devaient juger si cette explication correspondait bien à un proverbe écrit. Les résultats de cette étude montrent que les amplitudes des PÉMs recueillis dans la tâche de perception de chant étaient plus grandes après stimulation de l’hémisphère droit que de l’hémisphère gauche, surtout lorsque l’impulsion était envoyée entre 1000 et 1500 ms. Aucun effet significatif n’est ressorti de la condition de perception de la parole. Ces résultats suggèrent que le système miroir de l’hémisphère droit s’active davantage après une présentation motrice audio-visuelle, en comparaison de l’hémisphère gauche. / The perception of movements is associated with increased activity in the human motor cortex. This system underlies our ability to understand one’s actions, as it is implicated in the recognition, understanding and imitation of actions. In this study, we investigated the involvement and lateralization of this “mirror neuron” system (MNS) in the perception of singing and speech. Transcranial magnetic stimulation (TMS) was applied over the mouth representation of the motor cortex in 11 participants. The generated motor response was measured in the form of motor evoked potentials (MEPs), recorded from the mouth muscle. The MEPs were compared for the singing and speech conditions in each cerebral hemisphere. Furthermore, to investigate the time course of the MNS activation, TMS pulses were randomly emitted in 7 time windows (ranging from 500 to 3500 milliseconds after stimulus onset). The stimuli for the singing condition consisted in 4-second videos of singers producing a 2-note ascending interval. Participants had to judge whether the sung interval matched a written interval, previously presented on the screen. For the speech condition, 4-second videos of a person explaining a proverb were shown. Participants had to decide whether this explanation matched a written proverb previously displayed on the screen. Results show that the MEP amplitudes were higher after stimulation of the right hemisphere in the singing condition. More specifically, sending TMS pulses between 1000 and 1500 milliseconds over the right hemisphere yielded higher MEPs as compared to the left hemisphere. No effect was found in the speech condition. These results suggest that the right MNS is more activated after an audiovisual motor presentation compared to the left hemisphere.

L’expérience subjective accompagnant un mouvement se construit a posteriori en intégrant différentes sources d’informations qui s’inter-influencent à différents moments tant avant qu’après le mouvement. Cette expérience subjective est interprétée par un modèle d’attribution bayésien afin de créer une expérience d’agentivité et de contrôle sur les mouvements de son propre corps. Afin de déterminer l’apport de l’interaction entre les paramètres considérés par le modèle d’attribution et d’investiguer la présence de disparités inter-individuelles dans la formation de l’expérience subjective du mouvement, une série de 90 pulsations simples de stimulation magnétique transcrânienne (SMT) sur le cortex moteur primaire (M1) suivi de multiples questions sur l’expérience subjective reliée au mouvement provoqué a été effectuée chez 20 participants normaux. Les données objectives du mouvement ont été recueillies par électromyographie (EMG) et capture du mouvement. Un modèle de régression a entre autres été effectué pour chaque participant afin de voir quelle proportion du jugement subjectif pouvait être expliqué par des indices objectifs et cette proportion variait grandement entre les participants. Les résultats de la présente étude indiquent la présence d’une capacité individuelle à se former des jugements subjectifs reflétant adéquatement la réalité comme en témoigne la cohérence entre les différentes mesures d’acuité et plusieurs variables mesurant l’expérience subjective. / Subjective experience is built after the fact by integrating different sources of information that interact with each other at different moments (before, during and after the movement). In order to create subjective experience of agency and control, the characteristics of the movement are interpreted by a Bayesian model. To determine the impact of the interaction between the parameters that enter in that Bayesian attribution model and to investigate possible disparities in the formation of subjective experience of movement between individuals, a series of 90 pulses of single-pulse transcranial magnetic stimulation (TMS) followed by four questions on the subjective experience relative to the movement was conducted on 20 normal subjects. Objective data about the movement was gathered using electromyography (EMG) and motion capture. Individual regression models have been conducted to determine the proportion of the subjective judgements that varied accordingly to the objective parameters of the movement; this proportion varied greatly between participants. The present study proposes that there is an individual capacity to form subjective judgements that adequately represent the reality, as suggested by coherence between different accuracy measures and different variables measuring the subjective experience.

La stimulation magnétique répétitive transcrânienne (rTMS) du cortex moteur à visée antalgique réunit deux conditions extrêmement intéressantes: un accès non invasif à une cible corticale éloquente et, par la modulation de son activité, la possibilité d'influencer le transfert et l'intégration du message nociceptif. L'objectif de cette thèse est d'évaluer comment une approche de recherche clinique permet à la fois de progresser dans la compréhension des mécanismes qui sous-tendent l'effet antalgique de la rTMS et d'optimiser cet effet chez le patient. Une première étude paramétrique, concernant la technique de stimulation, a montré que l'orientation du courant était cruciale pour le développement d'un effet antalgique, l'orientation la plus favorable étant celle activant des interneurones corticaux. Nous n'avons toutefois pas objectivé de modification spécifique d'une composante sensorielle de la douleur en rapport avec cet effet local, ni une influence liée au caractère somatotopique de la stimulation. Ainsi, l'efficacité de la stimulation ne semble pas tributaire de sa localisation en regard de la représentation corticale du territoire douloureux. L'action sur la composante sensorielle de la douleur n'expliquant pas à elle seule l'effet antalgique de la rTMS, nous avons analysé les interactions entre effet antalgique et effet placebo : la rTMS a une efficacité propre, indépendante de l'effet placebo et lorsqu'elle est efficace, elle majore l'effet d'une séance placebo réalisée par la suite, par un phénomène de conditionnement. La rTMS active facilite les mécanismes de contrôle central de la douleur grâce à ses connexions à distance et à son action sur les systèmes endorphiniques, également impliqués dans l'effet antalgique du placebo. A la lumière de ces résultats, nous avons analysé les critères cliniques sur lesquels reposent l'efficacité à long terme des procédures de stimulation épidurale antalgique du cortex moteur et la valeur prédictive de la rTMS: l'efficacité de la rTMS apparaît comme un marqueur utile pour prédire l'efficacité au long cours de la stimulation corticale épidurale, lorsque la douleur est évaluée non seulement dans sa dimension sensorielle pure mais également à travers son retentissement psychologique global. L'ensemble de ces travaux suggère une action multiple de la rTMS s'exerçant probablement dans les 3 sphères (sensori-discriminative, affective et cognitive) qui sous- tendent la perception et le vécu de la douleur chronique / Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex allows a non- invasive access to an eloquent cortical area and, by the modulation of its activity, the possible interference with central integration of pain. ln this thesis we have applied clinical research methods to enhance the understanding of the mechanisms of pain relief by rTMS and to optimize its clinical effect in chronic pain patients. A first parametrical study, concerning technical aspects of the stimulation, showed the crucial role of current orientation to increase the magnitude of analgesic effects, a postero-anterior orientation promoting interneuronal activation being superior to a latero-medial direction. We found neither a selective modification of sensorial component of pain nor a somatotopic effect of the stimulation: indeed, rTMS analgesic efficacy was not dependent upon stimulation being applied to the cortical representation of the painful territory. The impossibility to explain the whole analgesic effect of rTMS by an isolated modulation of sensory components of pain prompted us to study the interactions between real and placebo rTMS analgesic effects. Active rTMS has a specific analgesic effect, and, when efficacious, it was able to enhance the placebo effect of subsequent sham stimulation. The value of rTMS to adequately predict the long-term efficacy of invasive motor cortex epidural stimulation (surgically implanted MCS) was assessed in a further study. The analgesic efficacy of single-point rTMS proved to be useful to predict the long-term outcome of surgically implanted MCS, provided that such outcome assessment was not exclusively founded on pain intensity but also on the psychological consequences of chronic pain. These results suggest that rTMS exerts its analgesic effects at multiple levels, and probably modifies the 3 different spheres (sensori-discriminative, affective and cognitive) at the origin of perception and consequences of chronic pain in daily life

Les mouvements sont le résultat de contractions musculaires dont l’organisation spatio-temporelle est régie par des structures cérébrales et médullaires. Etudier les circuits qui les sous-tendent est une étape indispensable pour renforcer nos connaissances des mécanismes à l’origine de la commande des mouvements volontaires et pour mieux comprendre la pathophysiologie des mouvements anormaux. Les muscles squelettiques sont innervés par les motoneurones alpha de la moelle épinière qui à leur out sont influencés par des neurones des aires corticales motrices. Cette voie descendante constitue la voie corticomotoneuronale (CM) et est responsable de l’exécution des mouvements volontaires. Le cortex moteur primaire est considéré comme une structure clé, au cœur du système, permettant l’intégration complexe de nombreuses influences multi-régions pour conduire aux comportements moteurs adéquats. Les interactions qui existent entre les différents groupes de neurones au sein de M1 influent en dernier lieu sur la sortie motrice. De la balance complexe entre ces influences inhibitrices et excitatrices, locales ou à distance va dépendre l’état d’excitabilité des cellules CM contrôlant les différents muscles. L'objectif de ce travail de thèse était d'étudier comment évoluent certains de ces mécanismes excitateurs ou inhibiteurs du cortex moteur primaire lorsque la commande motrice volontaire d’un muscle de l’index est modifiée. Nous avons étudié le rôle de ces mécanismes dans les changements d’excitabilité de la voie CM qui accompagnent la contraction tonique volontaire du muscle premier interosseus dorsalis (FDI) en comparant une tâche simple mais peu naturelle : l’abduction de l'index, une tâche naturelle plus complexe: la pince pouce-index et la condition de repos musculaire. Nous avons également étudié l’effet de la commande motrice sur l’interaction entre deux de ces mécanismes inhibiteurs l’un à longue latence, la LICI, l’autre à courte latence, la SICI. Enfin nous avons souhaité évaluer le décours temporel de ces mécanismes dans un cadre pathologique tâche-dépendant: la crampe de l’écrivain. Pour cela, nous avons utilisé la technique d’electromyographie de surface pour enregistrer les potentiels moteurs évoqués par la Stimulation Magnétique Transcrânienne. Nous avons mis en évidence une modulation tâche-dépendante de la LICI. Par rapport à la tâche d’abduction simple, la LICI s’estompait plus tôt lors de la tâche de pince pouce-index, traduisant une désinhibition plus précoce lors d’un mouvement plus complexe. Nous avons observé, et ce pour la première fois dans la littérature, une phase de facilitation nette qui suivait cette désinhibition, et qui était absente lorsque le muscle était au repos. Ces résultats sont également visibles dans un muscle voisin du FDI, non engagé dans la tâche; cela suggère que les mécanismes à l’origine de la facilitation sont impliqués dans l’activité volontaire sans spécificité topographique. L’interaction entre la LICI et la SICI n’a pas été modifiée par la tâche effectuée, laissant penser qu’elle n’est pas impliquée dans les changements d’excitabilité tâche-dépendants. Enfin, il apparaît que la désinhibition est retardée chez les sujets dystoniques quand le muscle est engagé dans un mouvement complexe de pince pouce-index mais pas dans une tâche simple d’abduction de l’index en comparaison à des sujets contrôles. Ces résultats illustrent le fait que lors d’un mouvement plus complexe, l’efficacité des circuits inhibiteurs du cortex moteur primaire est modifiée, ce qui permet de réguler l’activité des cellules CM, afin d’adapter la commande motrice au mouvement souhaité. Le fait que cette désinhibition soit retardée dans une tâche complexe (proche de la tâche affectée) mais pas dans une tâche simple chez les patients atteints d’une crampe de l’écrivain suggère que les mécanismes à l’origine de la désinhibition pourraient participer aux troubles moteurs qui caractérisent la maladie. / Movements are evoked by muscles contractions whose spatial organization is mediated by both spinal and cortical components. It is important to investigate the underlying circuitry of movements to extend our knowledge on how voluntary movement are controlled and to better understand the pathophysiology of movements disorders. The spinal alpha motoneurons innervating distal muscles are controlled at least in parts by corticomotoneuronal neurons located in the motor cortical areas. Among them, the primary motor cortex is considered as a key structure, performing a complex integration of multi-regional influences leading to appropriate motor behaviors. Axons from corticomotoneuronal (CM) cells of the primary motor cortex reach the spinal cord via descending motor pathway. CM neurons are influenced by local or distant, inhibitory and excitatory components which determine the balance of excitability. The aim of this thesis was to explore changes of some of the excitatory and inhibitory mechanisms of motor cortex as a function of the task being performed. We assessed the time course of Long-interval Intracortical Inhibition (LICI), Late Cortical Disinhibition (LCD) and Long interval Intracortical Facilitation (LICF), which are mechanisms that potentially act to modulate the output of CM controlling the first dorsal interosseus (FDI) muscle. We compared three conditions : index finger abduction (a simple but not natural task), precision grip between index and thumb ( amore natural and complex task), and rest. We also evaluated the effect of task on interaction between LICI and Short Interval Intracortical Inhibition (SICI). Finally, we assessed the time course of LICI in patients suffering from writer’s cramp. For this purpose, we used surface electromyography to record motor potentials evoked by Transcranial Magnetic Stimulation.We showed a task-dependent change in late inhibitory and disinhibitory components. Compared with abduction task, the LICI induced during precision grip was shorter, suggesting an early disinhibition in more complex task. The disinhibition was followed by a period of facilitation only during the active tasks, i.e. facilitation was not observed when all muscles were at restat rest. However, long interval intracortical facilitation can be observed in a muscle at rest not engaged in an active task if a neighboring muscle is activated. It is therefore likely that mechanisms underlying facilitation are associated with voluntary contraction albeit with lack of topographic specificity. Interaction between LICI and SICI was not modified between tasks, suggesting that it was not involved in task-dependent changes of cortical excitability. Lastly, disinhibition was shown to be delayed in dystonic patients when the FDI was actively engaged in a precision grip but not in index abduction, compared with control subjects. An explanation might be that mechanisms underlying disinhibition are impaired in thumb-index precision grip (a task similar to that inducing unwanted contractions in writer’s cramp). Task-specidic disruption of LICI and late cortical disinhibition may therefore be at least in part responsible for pathophysiology of dystonia. It is likely that during complex task, the efficacy of LICI, and more generally of motor cortex inhibitory mechanisms, is modified to allow adaptation of CM neurons activity to the functional requirements of the motor task being performed.

O circuito neuronal relacionado à depressão na doença de Parkinson (DP), assim como os efeitos da terapia antidepressiva nestes pacientes, não é bem estabelecido. Os métodos de neuroimagem podem levar ao melhor conhecimento da patogênese e também dos mecanismos de ação relacionados a um tipo específico de tratamento. Para avaliar as diferenças da atividade neuronal, comparamos 21 pacientes com DP e diagnóstico de depressão e 16 sem depressão através de ressonância magnética funcional (RMf) em uma tarefa cognitiva que inclui percepção emocional e escolha forçada com duas opções. Estes 21 pacientes deprimidos foram aleatorizados em dois grupos de tratamento por 4 semanas: estimulação magnética transcraniana (EMT) ativa sobre o córtex pré-frontal dorsolateral esquerdo ( 5 Hz EMT - 120% do limiar motor) com pílula placebo e EMT placebo com 20 mg diária de fluoxetina. Os pacientes foram submetidos a um experimento de RMf cujo paradigma foi relacionado a eventos apresentação visual de faces de conteúdo emocional. Os pacientes sem depressão realizaram RMf duas vezes (teste reteste) e os deprimidos quatro vezes (duas vezes antes e duas depois do tratamento). As imagens dos pacientes com DP e depressão demonstraram menor atividade no córtex pré-frontal medial quando comparados aos pacientes com DP sem depressão. Ambos os subgrupos de pacientes com DP e depressão apresentaram melhora significativa e similar dos sintomas da depressão. Após o tratamento com EMT ativa observou-se menor atividade do giro fusiforme esquerdo, do cerebelo e do córtex pré-frontal dorsolateral direito e maior atividade do córtex pré-frontal dorsolateral esquerdo e do cíngulo anterior nas imagens de RMf quando comparados àquelas antes do tratamento. Por outro lado a fluoxetina determinou aumento da atividade do córtex pré-motor direito e do córtex pré-frontal medial direito em imagens de RMf realizadas após o tratamento. Observou-se efeito de interação entre os grupos (tempo (pré x pós) versus tipo de tratamento (fluoxetina x EMT)) no córtex préfrontal medial esquerdo sendo maior o aumento no grupo tratado com EMT. Nossos achados mostraram: 1) padrão diferente de atividade cerebral em pacientes com DP com e sem depressão; 2) efeitos antidepressivos da EMT e da fluoxetina foram semelhantes e significativos;e 3) em pacientes com DP e depressão os efeitos da EMT e fluoxetina são associados a diferentes mudanças da atividade cerebral, e em ambos as áreas encontradas são parte da rede neural relacionada à depressão. / The neural circuitry underlying depression in patients with Parkinson\'s disease (PD) is unknown, let alone the treatment effects of antidepressant therapy. Neuroimaging methods can give insights into the pathogenesis of depression and also in the mechanisms of action related to specific treatment choice. In order to evaluate differences between PD patients with and without concomitant depression we studied 21 patients with PD and depression and 16 PD patients without depression using fMRI. All patients were examined using an event-related fMRI paradigm based on visual presentation of faces with emotional content in a two options forced choice task. Furthermore the twenty-one PD depressed patients were randomized in two active treatment groups for 4 weeks: active rTMS over left dorsolateral prefrontal cortex (5 Hz rTMS - 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/day. Event-related fMRI with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time point. The same test-retest approach was adopted in the group of non-depressed PD patients. The analysis showed significant differences between depressed and non-depressed PD patients in the medial pre-frontal cortex, with reduced activation as detected by BOLD effect in the later group. The two groups of depressed PD patients showed a had a significant treatment effect, and with similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right dorsolateral prefrontal cortex (DLPFC) and brain activity increases in left DLPFC and anterior cingulate gyrus as compared to baseline. In contrast, after fluoxetine treatment, there was brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups versus time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that medial prefrontal cortex is a critical area in the depression neural circuitry in PD. Antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.

INTRODUÇÃO: O comprometimento cognitivo observado na lesão axonial difusa (LAD) é considerado uma das mais debilitantes sequelas neurológicas nesta população. A estimulação magnética transcraniana (EMT), uma técnica de estimulação encefálica não-invasiva, tem sido utilizada com sucesso no tratamento de doenças neuropsiquiátricas. Os resultados pouco satisfatórios dos tratamentos convencionais dos distúrbios cognitivos vistos no traumatismo cranioencefálico (TCE) motivaram a investigação por novas estratégias terapêuticas, dentre elas a EMT. Entretanto, até o presente momento, não há estudos Sham-controlados investigando os efeitos cognitivos induzidos pela EMT nessa população. Assim, o presente estudo avaliou a segurança, tolerabilidade e eficácia da EMT na reabilitação cognitiva de pacientes com LAD crônica. MÉTODOS: Trata-se de um ensaio clínico prospectivo aleatorizado, duplamente encoberto, que incluiu 37 participantes com o diagnóstico de LAD crônica, em dois grupos de intervenção: Ativo e Sham. A EMT repetitiva (EMTr) de alta frequência (10 Hz) foi aplicada no córtex pré-frontal dorsolateral (CPFDL) esquerdo em um total de 10 sessões, com intensidade de 110% do limiar motor de repouso. Todos os participantes realizaram avaliação neuropsicológica (ANP), composta por sete testes neuropsicológicos [1: TMT Partes A e B; 2: Brief Visuospatial Memory Test (BVMT); 3: Hopkins Verbal Learning Test (HVLT); 4: Grooved Pegboard Test; 5: teste de Fluência Verbal semântica e fonêmica; 6: teste dos Dígitos e 7: teste dos Cinco Pontos], e avaliação da excitabilidade cortical (AEC), por meio da EMT de pulsos simples e pareados, ambas realizadas em três momentos distintos: antes da intervenção (E1 - pré-intervenção), até uma semana (E2 - pós-intervenção precoce) e 90 dias (E3 - pós-intervenção tardio) após o término da EMTr. O participante desconhecia em qual grupo de intervenção havia sido alocado, assim como o avaliador que realizou as ANPs. A medida de desfecho primário foi o escore no Trail Making Test (TMT) Parte B, um teste robusto que avalia funções executivas e atenção. RESULTADOS: Trinta participantes foram submetidos à EMTr e concluíram o seguimento, sendo 17 deles presentes no grupo Ativo e 13 no grupo Sham. Os dados demográficos pesquisados na linha de base, bem como os escores da ANP e valores aferidos na AEC, não foram diferentes entre os grupos. Com relação à performance no TMT Parte B, os tempos medianos aferidos no grupo Ativo foram 141 (100 - 209,5), 85 (67 - 274) e 161 (73 - 223) segundos nos momentos E1, E2 e E3, respectivamente, enquanto que no grupo Sham foram 97 (83 - 269), 70 (60 - 212) e 96 (59,5 - 171,5) segundos. Não houve interação tempo x grupo significativa entre as condições testadas (Ativo vs. Sham) durante os três momentos de avaliação (análise de variância ANOVA; P = 0,450), denotando não ter havido diferença no desempenho do TMT Parte B antes e após o tratamento. Consoante aos resultados do TMT Parte B, as pontuações obtidas nos outros testes incluídos na ANP não demonstraram diferenças em relação aos grupos de intervenção. Não foram observadas mudanças significativas, ou interação entre os grupos nos parâmetros avaliados na AEC. Em uma análise exploratória, observou-se alteração da inibição intracortical de intervalo curto, um dos parâmetros medidos na AEC, na linha de base do estudo em comparação com dados disponíveis na literatura em indivíduos saudáveis, sugerindo a existência de um comprometimento de circuitos corticais inibitórios nos pacientes com LAD crônica. CONCLUSÃO: Apesar de a EMT repetitiva de alta frequência no CPFDL esquerdo ter sido segura e relativamente bem tolerada, os achados deste estudo não forneceram evidências de efeito terapêutico cognitivo desta técnica em pacientes com LAD crônica. A AEC na linha de base demonstrou a presença de alteração da inibição cortical, o que amplia o conhecimento sobre os processos neurofisiológicos envolvidos neste tipo de lesão encefálica. Registro do ensaio clínico no Clinicaltrials.gov - NCT02167971 / INTRODUCTION: Cognitive impairment typically observed in diffuse axonal injury (DAI) is considered one of the main causes of disability in this population. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, has been successfully used in the treatment of various neuropsychiatric disorders. The mixed results of the conventional treatments used for cognitive rehabilitation motivated the investigation of new therapeutic strategies, such as TMS. However, to the best of our knowledge, there are no sham-controlled studies addressing the cognitive effects induced by TMS in these victims. Thus, the present study aimed to evaluate the safety, tolerability and efficacy of TMS for cognitive rehabilitation in chronic DAI. METHODS: This is a prospective double-blind clinical trial that randomly included 37 participants with the diagnosis of chronic DAI in two intervention groups: Active and Sham. High frequency (10 Hz) repetitive TMS (rTMS) was applied over the left dorsolateral prefrontal cortex (DLPFC) in a total of ten sessions, at 110% intensity of the resting motor threshold. All participants underwent neuropsychological evaluation (NPE) that included 7 different neuropsychological tests [1: TMT Parts A and B; 2: Brief Visuospatial Memory Test (BVMT); 3: Hopkins Verbal Learning Test (HVLT); 4: Grooved Pegboard Test, 5: Controlled Oral Word Association Test; 6: Digit Span Test e 7: Five-Point Test], and cortical excitability assessment (CEA) with single and paired-pulse TMS, both performed at three different times: before the intervention (E1 - preintervention) , up to one week (E2 - early post-intervention) and 90 days (E3 - late post-intervention) after rTMS completion. The participant was unaware of which intervention group had been allocated, as well as the evaluator who carried out the NPEs. The primary outcome measure was the Trail Making Test (TMT) Part B, a robust test that assesses executive functions and attention. RESULTS: Thirty participants underwent rTMS and completed follow-up, 17 of them in the Active group and 13 in the Sham group. The demographic data at the baseline (E1), as well as the NPE scores and CEA values were not different between the groups. Regarding the performance in TMT Part B, the median times measured in the Active group were 141 (100 - 209.5), 85 (67 - 274) and 161 (73 - 223) seconds at evaluations E1, E2 and E3 respectively, while in the Sham group the values were 97 (83 - 269), 70 (60 - 212) and 96 (59.5 - 171.5) seconds. There was no significant interaction between the conditions tested (Active vs Sham) during the three assessments (analysis of variance ANOVA; P = 0.450), indicating that there was no difference in the performance of TMT Part B before and after treatment. As observed in the TMT Part B, no significant differences between the groups were seen in other tests included in NPE. Regarding the CEA, the parameters evaluated showed no time x group interaction. An exploratory analysis at the baseline of the study revealed alteration of short interval intracortical inhibition, one of the variables measured in CEA, when compared with data available in the literature in healthy individuals, suggesting impairment of cortical inhibitory circuits in patients with chronic LAD. CONCLUSION: rTMS was safe and well tolerated in this study. Findings did not provide evidence of therapeutic effect of 10 Hz rTMS over the left DLPFC for cognitive rehabilitation in chronic DAI. Alteration of short interval intracortical inhibition was demonstrated in this population, which expands knowledge about the neurophysiological processes involved in this type of brain injury