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Computational methods in neuroscience have advanced our understanding of neuronal regulation of motor behavior and locomotion and have been applied to identify encoding of behavioral features in circuits. The cerebellum has an established role in sensorimotor processing during coordinated movements, referred to as the “head ganglion of the proprioceptive system” (Sherrington, 1906). Increasing evidence also highlights its role in the processing of behaviorally meaningful stimuli that have the potential of guiding adaptative movements relevant to the task and priming downstream targets for action. Yet the extent to which these diverse encodings of signals in complex motor tasks are present in the cerebellar nuclei and their influence on behavior remains unknown. To shed new light on the role of this subcortical region using computational approaches, this thesis begins with an introduction that reviews the circuity of the mammalian cerebellum, highlights its proposed functions in motor behavior, and explores our understanding of its role in locomotion. In the first chapter, I analyze electrophysiological recordings from cerebellar nuclei in a locomotor obstacle avoidance task in mice that involves a rich and diverse set of task relevant features. Given the complexity of and correlations between the behavioral features, statistical modeling is required to attribute the firing rates to the correct combinations. This model enables identifying the encoding of these signals and reporting on the prevalence and degree to which they are present across individual cells in the nuclei. Additionally, this model allows investigation into the encoding of groups of cells that are selective for specific features. Chapter 2 uses network modeling to generate hypotheses about population level activity in two cortical areas, the primary and supplementary motor areas, and differentiate their computations in monkeys performing a cycling task. Finally, in chapter 3 I concentrate on a specific class of recurrent network models in the balanced state and investigate the linkage between connectivity distribution and firing sparsity, which has the potential to further our understanding on the emergence of feature selectivity in excitatory/inhibitory circuits.

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.

Le système vestibulaire et le cortex moteur participent au contrôle de la posture, mais la nature de leurs interactions est peu documentée. Afin de caractériser les interactions vestibulo-corticales qui sous-tendent le contrôle de l’équilibre en position debout, l’activité électromyographique (EMG) du soléaire (SOL), du tibial antérieur (TA) et du péronier long (PERL) de la jambe droite a été enregistrée chez 14 sujets sains. La stimulation galvanique vestibulaire (GVS) a été appliquée avec la cathode derrière l’oreille droite ou gauche à différents intervalles inter-stimulus (ISIs) avant ou après la stimulation magnétique transcrânienne induisant des potentiels moteurs évoqués (MEPs) au niveau des muscles enregistrés. Lorsque que la cathode était à droite, une inhibition des MEPs a été observée au niveau du SOL à un ISI de 40 et 130 ms et une facilitation des MEPS a été observée au niveau TA à un ISI de 110 ms. Lorsque la cathode était à gauche, une facilitation des MEPs a été observée au niveau du SOL, du TA et du PERL à un ISI de 50, -10 et 0 ms respectivement. L’emplacement de ces interactions sur l’axe neural a été estimé en fonction des ISIs et en comparant l’effet de la GVS sur les MEPs à son effet sur l’EMG de base et sur le réflexe-H. Selon ces analyses, les modulations observées peuvent avoir lieu au niveau spinal ou au niveau supraspinal. Ces résultats suggèrent que les commandes de la voie corticospinale peuvent être modulées par le système vestibulaire à différents niveaux de l’axe neuronal. / The vestibular system and the motor cortex are involved in the control of posture but the nature of their interactions is poorly documented. To characterize vestibulo-cortical interactions underlying the control of balance during quiet standing, the electromyographic activity (EMG) of the soleus (SOL), tibialis anterior (TA) and peroneus longus (PERL) of the right leg was recorded in 14 healthy subjects. Bipolar galvanic vestibular stimulation (GVS) was applied with the cathode behind the right or left ear at various inter-stimulus intervals (ISI) before and after transcranial magnetic stimulation eliciting motor evoked potentials (MEP) in the muscles recorded. When the cathode was on the right, MEP in the SOL were inhibited at 40 and 130 ms while MEP were facilitated in TA at 110 ms. When the cathode was on the left, MEP were facilitated in the SOL at 50 ms, in TA at -10 ms and in PERL at 0 ms. The localization of these interactions along the neural axis was estimated according to the ISI and by comparing the effect of the GVS on the MEP to its effect on the background EMG and on the SOL H-reflex. Based on these analyses, the observed modulations of MEP observed could have occurred at spinal or supraspinal level. These results suggest that the corticospinal output may be modulated by the vestibular system at different levels of the neural axis.

Durant les dernières décennies, le système moteur a été largement étudié. Pourtant, bien des zones d'incertitudes persistent concernant d'une part la nature des circuits neuronaux de haut niveau impliqués dans l'émergence des sentiments d'intention ou de conscience motrice et d'autre part l'organisation des structures cérébrales de bas-niveau impliquées dans l'expression de ces sentiments. Il a été suggéré que le cortex pariétal et l'aire motrice supplémentaire pourraient jouer un rôle dans la génération des intentions motrices, alors que le cortex prémoteur pourrait plutôt sous-tendre la conscience du geste. Cela étant, les processus exacts implémentés dans chacune de ces régions, la façon dont elles interagissent fonctionnellement et la nature des signaux qu'elles échangent avec les structures sensorimotrices considérées de bas-niveau demeurent méconnus. Il est établi que ces structures bas-niveau, dont le cortex moteur primaire et le cervelet, contiennent des cartes sensorimotrices organisées de manière topographique. Cependant, l'organisation fine de cette topographie et la nature des interactions entre les différentes cartes restent à définir. Dans ce travail de thèse, j'ai utilisé la stimulation électrique directe chez des patients opérés de tumeurs et malformations cérébrales pour explorer la manière dont les multiples représentations motrices sont organisées et pour identifier les régions responsables de l'émergence des sentiments d'intention et de conscience motrice. J'ai alors pu montrer, en particulier, l'existence de cartes motrices multiples au sein des cortex moteur primaire et cérébelleux. Par ailleurs, j'ai pu identifier le rôle critique du cortex pariétal pour l'émergence du sentiment d'intention motrice et -sur la base de processus prédictifs- de la conscience d'agir. Par rapport à ce point, j'ai aussi pu mettre en évidence que le cortex prémoteur était impliqué, à travers un contrôle continu des prédictions pariétales, dans l'émergence d'une conscience d'agir non plus inférée mais véritable / During the last five decades, the motor system has been widely studied. Yet, little is known about the neural substrate of high-level aspects of movement such as intention and awareness and how these functions are related to low-level movement execution processes. It has been suggested that the parietal cortex and supplementary motor area are involved in generating motor intentions, while premotor cortex may play a role in the emergence of motor awareness. However, the precise mechanisms implemented within each of these areas, the way they interact functionally and the nature of the signals conveyed to primary sensory and motor regions is far from being understood. Furthermore, intention and awareness of movement are also influenced by peripheral information coming from the skin, muscles and joints, and this information must be integrated to produce smooth, accurate and coordinated motor actions. Cortical and subcortical structures such as the primary motor cortex and the cerebellum are known to contain motor maps thought to contribute to motor control, learning and plasticity, but the intrinsic organization of these maps and the nature of their reciprocal relations are still unknown. In this thesis I used Direct Electrical Stimulation in patients undergoing brain surgeries to investigate how multiple motor representations are organized and identify the regions responsible for the emergence of conscious motor intention and awareness. I showed, in particular, the existence of multiple efferent maps within the cerebellum and the precentral gyrus. Furthermore, I identified the critical role of the parietal cortex for the emergence of conscious intention and -based on predictive processes- motor awareness. I also provided evidence that the premotor cortex is involved in "checking" parietal estimations, thus leading to a sense of "veridical awareness"

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.

Ziel der Arbeit war es beim Menschen die Pathophysiologie neuronaler Funktion bei zerebraler Ischämie näher zu charakterisieren sowie Kenntnisse über Umorganisationsprozesse des motorischen Systems nach einem Schlaganfall zu gewinnen. Als Untersuchungsinstrument wurde die transkranielle Magnetstimulation (TMS) eingesetzt, die basierend auf der Analyse exzitatorischer und inhibitorischer Reizeffekte (kortikospinal vermittelte exzitatorische Reizantworten, postexzitatorische Inhibition, transkallosale Inhibition, intrakortikale Inhibition und Fazilitierung) einen nicht-invasiven Zugang zur Funktion kortikaler Neurone und ihrer Efferenzen ermöglicht. An Patienten mit einer Okklusion der A. carotis interna wurden die Auswirkungen einer Ischämie auf die neuronale Funktion des motorischen Kortex untersucht. Es konnte erstmals in vivo nachgewiesen werden, dass eine zerebrale Perfusionsminderung eine selektive Funktionsstörung kortikaler inhibitorischer Interneurone in der betroffenen Hemisphäre und eine Beeinträchtigung interhemisphärischer Hemmmechanismen induziert. An Patienten mit unterschiedlich lokalisierten ischämischen Läsionen wurde der Einfluss des interhemisphärischen Informationstransfers auf Reorganisationsprozesse in der kontralateralen Hemisphäre untersucht. Es zeigte sich, dass bei Schlaganfallpatienten die kortikale Erregbarkeit der nicht-geschädigten Hemisphäre durch eine über das Corpus callosum vermittelte Inhibition signifikant moduliert wird. In zukünftigen Studien ist zu klären, inwieweit sich die Veränderungen der kortikalen Erregbarkeit positiv auf die Funktionsrestitution auswirken und dies durch den Einsatz rehabilitativer Verfahren unterstützt werden kann. / The study was performed to investigate the pathophysiology of motoneuronal function in cerebral ischemia tand mechanisms of motor cortex reoganisation following stroke. The function of cortical neurons was assessed using transcranial magnetic stimulation of the motor cortex and by analysing the excitatory and inhibitory stimulation effects (corticospinally mediated excitatory response, postexcitatory inhibition, transcallosal inhibition, intracortical inhibition and facilitation). In patients with carotid occlusive disease we investigated the influence of hemispheric ischemia on motor cortex function. Patients with differently localised monohemispheric lesions served as a clinical model to investigate the impact of interhemispheric interaction on motor cortex reorganisation in the non-lesioned hemisphere. The present study is the first to demonstrate that hemispheric ischemia preferentially induces an impairment of trancallosally mediated interhemispheric inhibition and intracortical inhibitory processes. It could be further shown that in acute stroke interhemispheric interaction via callosal fibres significantly influences cortex excitability in the nonlesioned hemisphere e.g. loss of transcallosal inhibition induces hyperexcitability of the contralateral undamaged motor cortex. In the future it has to be elucidated what role excitability changes play for functional recovery and rehabilitation in stroke.

Introdução. A estimulação do córtex motor (ECM) tem sido utilizada para o tratamento de pacientes com síndromes neuropáticas dolorosas crônicas e resistentes a tratamentos farmacológicos convencionais. O córtex motor primário pode ser a estrutura mais rostral do neuroeixo relacionada ao sistema de modulação da dor, e a ECM provoca ativação neuronal na substância cinzenta periaquedutal (PAG). A PAG é um dos principais centros do sistema descendente supressor de dor e recebe aferências de diferentes regiões do encéfalo. Esse estudo investiga o efeito da estimulação do córtex motor sobre a liberação de neurotransmissores na PAG em modelo de dor neuropática, com o objetivo de investigar os mecanismos neuroquímicos responsáveis pelo feito terapêutico. Métodos. No primeiro experimento, ratos Wistar machos foram aleatoriamente divididos em três grupos. No primeiro grupo, os animais foram submetidos à indução de dor neuropática através da constrição crônica do nervo ciático, no segundo grupo, os animais foram submetidos apenas à exposição do nervo ciático e no terceiro grupo, nenhuma intervenção para indução de dor neuropática foi realizada. Todos os animais foram submetidos a implante unilateral epidural de eletródios de estimulação sobre a área do córtex motor correspondente a pata posterior e implante de cânula guia direcionada à PAG utilizando coordenadas estereotáxicas. Os animais foram avaliados no teste de hiperalgesia mecânica e uma sonda de microdiálise foi introduzida em direção a PAG. As amotras de microdiálise foram coletadas e a análise dos neurotransmissores foi feita em um sistema de cromatografia líquida de alta eficiência (HPLC). No segundo experimento, ratos Wistar machos com dor neuropática induzida na pata posterior foram submetidos a implante estereotáxico de cânula guia direcionada à PAG, e foi realizada micro-injeção de antagonista de glicina e/ou GABA na PAG, previamente a ECM, para avaliar a influência desses antagonistas no efeito analgésico induzido pela estimulação cortical. Resultados. Animais submetidos à indução de dor neuropática apresentaram reversão da hiperalgesia mecânica após ECM. A estimulação cortical induziu um aumento significativo nos níveis de glicina durante (aumento de 153%) e após MCS (134%). A concentração de GABA aumentou 145% durante a estimulação epidural. Os níveis de glutamato não mostraram alteração no microdialisado da PAG após ECM. Houve uma correlação estatisticamente significativa entre o posicionamento da sonda de microdiálise nas colunas lateral e dorsolateral da PAG e o aumento na liberação do neurotransmissor glicina nos animais do grupo CCI. A administração de antagonista de glicina na PAG reverteu o efeito antinociceptivo da estimulação cortical. A micro-injeção de antagonista de GABA na PAG reverteu parcialmente o efeito da ECM. Conclusões. Nossos resultados sugerem que os neutransmissores glicina e GABA, liberados na PAG durante ECM, contribuem para o efeito antinociceptivo da via analgésica descendente. Os resultados desse projeto poderão contribuir para a elucidação dos mecanismos do efeito antinociceptivo da ECM / Introduction. Motor cortex stimulation (MCS) has been used for the treatment of patients with chronic neuropathic pain syndromes that are resistant to conventional pharmacological treatment. The motor cortex may be the most rostral structure in the neuroaxis responsible for pain modulation, and MCS increase the neuronal activation of periaqueductal gray (PAG). The PAG is one of the main subcortical centers of the descending pain suppressor system, and receives inputs from several brain areas. This study investigates the effects of MCS on the release of neurotransmitters in the PAG in neuropathic pain model, in order to investigate the possible neurochemical mechanisms responsible for this effect. Methods. In the first experiment, Wistar male rats were randomly subdivided into three surgical groups. In the first group, induction of neuropathic pain was performed through chronic constriction injury of the right sciatic nerve, in the second group, the animals were submitted just to exposure of the sciatic nerve and in the third group, no intervention for induction of neuropathic pain was performed. All the rats underwent implantation of unilateral epidural electrodes on the motor area corresponding to the right hind paw. The animals were evaluated for mechanical hyperalgesia test and a microdialysis guide cannula was stereotaxically implanted into the PAG. The microdialysate samples were collected and the neurotransmitters analysis was performed by a high- performance (HPLC). In the second experiment, animals with induced neuropathic pain in the hind paw were submitted to a stereotaxic implantation of a guidewire directed to PAG, and a microinjection of glycine and/or GABA antagonist in the PAG before the ECM was performed, to evaluate the influence of these antagonists on the analgesic effect induced by the cortical stimulation. Results. Animals subjected to induction of neuropathic pain showed reversal of mechanical hyperalgesia after motor cortex stimulation. Cortical stimulation induced a significant increase in glycine levels during (153 % increase) and after MCS (134%). The GABA concentration increases 145 % during transdural stimulation. Glutamate levels showed no change in PAG microdialysate after MCS. There was a statistically significant correlation between the positioning of the microdialysis probe in the lateral and dorsolateral columns of the PAG and the increase in the release of the neurotransmitter glycine in the animals of the CCI group. Administration of glycine antagonist in PAG reversed the antinociceptive effect of cortical stimulation. Microinjection of GABA antagonist in PAG partially reversed the effect of MCS. Conclusions. Our results suggest that the neurotransmitters glycine and GABA, released in PAG during MCS, contribute to descending antinociceptive actions. The results of this project will contribute for the elucidation of the mechanisms of the antinociceptive effect of MCS, a phenomenon that has not been fully understood currently

A recuperação motora da mão é importante para a independência funcional de pacientes com acidente vascular cerebral (AVC). A estimulação magnética transcraniana (EMT) é uma técnica não invasiva que pode ser usada para avaliar a excitabilidade do córtex motor. O objetivo principal deste estudo foi avaliar a correlação entre as medidas de EMT (inibição intracortical, IIC; facilitação intracortical, FIC; período silente ipsilateral, Psil) e o desempenho motor em atividades relevantes para as atividades de vida diária, em indivíduos com AVC (grupo AVC) e boa recuperação motora, assim como em sujeitos sem AVC (grupo controle). As medidas foram realizadas no hemisfério afetado (HA) dos indivíduos com AVC e no hemisfério homólogo dos sujeitos do grupo controle. Os objetivos secundários foram: confirmar que a as medidas de EMT do grupo AVC seriam comparáveis às do grupo controle; investigar a relação entre as medidas de IIC ou FIC e o Psil nos dois grupos. Após avaliação de elegibilidade de 2298 sujeitos, 12 pacientes (seis homens) foram incluídos no grupo AVC com média (+- desvio-padrão) de idade 52,9 (+- 11,8) anos, pontuações na escala de AVC do National Institutes of Health de 2,6 (+- 1,8) e na subescala de avaliação do membro superior de Fugl-Meyer de 57,5 (+- 4,6). No grupo controle foram incluídos 10 indivíduos (seis homens) com média de idade 53,3 (+- 12,0) anos. Nos dois grupos, foram avaliados: desempenho no teste de Jebsen Taylor, força de preensão, limiar motor, IIC, FIC e Psil. O coeficiente de correlação de Spearman foi utilizado para avaliar a correlação entre medidas de desempenho motor e medidas de EMT, assim como para associações entre medidas de excitabilidade intracortical e Psil. Para comparação das medidas entre o grupo AVC e o grupo controle, foi utilizado o teste de Mann-Whitney. Foi encontrada uma correlação significativa (r = 0,68; p = 0,014) entre a força de preensão e a IIC no Grupo AVC, mas não no grupo controle (r= 0,16; p= 0,47). Não foram encontradas correlações estatisticamente significativas entre o desempenho no teste de Jebsen-Taylor e qualquer outra medida de excitabilidade nos dois grupos. Não houve diferenças estatisticamente significativas entre as medidas de EMT nos dois grupos (p > 0,05). Não houve correlação significativa entre as medidas de excitabilidade intracortical e o Psil no grupo AVC, mas houve correlação significativa entre aumento da IIC e maior duração do Psil no grupo controle (r=-0,8; p= 0,008). A FIC não teve correlação significativa com o Psil em quaisquer dos grupos. Esses resultados sugerem que a atividade gabaérgica no córtex motor primário do HA seja relevante para a força da mão parética em indivíduos com AVC. Além disso, confirmam a hipótese de que pacientes com boa recuperação motora apresentem padrões de excitabilidade cortical semelhante aos de indivíduos saudáveis. Finalmente, os resultados não corroboram a hipótese de que um mesmo grupo de interneurônios medeie a IIC do HA e a inibição inter hemisférica do hemisfério afetado para o hemisfério não afetado em indivíduos com AVC e bom desempenho motor, na fase crônica / Recovery of hand motor function is important for the functional independence of patients with stroke. Transcranial magnetic stimulation (TMS) is a non-invasive technique for assessment of motor cortex excitability. The main objective of this study was to evaluate the correlation between TMS measures (short-interval intracortical inhibition, SICI; intracortical facilitation, ICF and ipsilateral silent period, ISP) and motor performance in subjects with stroke and good motor recovery (stroke group) as well as in subjects without stroke (control group). Measurements were performed in the affected hemisphere of stroke subjects and in the homologous hemisphere of subjects in the control group. The secondary objectives were: to confirm that the SICI, ICF and ISP of the stroke group would be comparable to those of the control group; to investigate the relation between SICI or ICF and the ISP in the two groups. After assessment of eligibility in 2298 subjects, 12 patients (six men) were included in the stroke group. Mean (+- standard deviation) age was 52.9 (+- 11.8) years, National Institutes of Health Stroke Scale score was 2.6 (+- 1.8) and Fugl-Meyer upper limb subscale score was 57.5 (+- 4.6) in the stroke group. In the control group, 10 subjects (six men) were included with a mean age of 53.3 (+- 12.0) years. In the two groups, the Jebsen-Taylor test, grip strength, motor threshold, SICI or ICF and ISP were evaluated. The Spearman\'s correlation coefficient was used to assess the correlation between motor performance measures and TMS measures, as well as the associations between intracortical excitability measures and the ISP. The Mann-Whitney test was used to compare the measures between the stroke group and the control group. A significant correlation (r = 0.68, p = 0.014) was found between grip strength and SICI in the stroke group, but not in the control group (r = 0.16, p = 0.47). No statistically significant correlations were found between performance in the Jebsen-Taylor test and any other measures of excitability in the two groups. There were no statistically significant differences between the TMS measurements between the two groups (p > 0.05). There was no significant correlation between the SICI measures and the ISP in the stroke group, but there was a significant correlation between increased SICI and longer duration of the ISP in the control group (r=-0.8; p=0.008). ICF had no significant correlation with the ISP in any of the groups. These results suggest that increased gabergic activity in the motor cortex of the affected hemisphere is relevant for strength of the paretic hand in patients with stroke. Also, they confirm the hypothesis that patients with good motor recovery present patterns of cortical excitability similar to those of healthy subjects. Finally, the results do not support the hypothesis that the same group of interneurons mediate intracortical inhibition and interhemispheric inhibition of the unaffected hemisphere by the affected hemisphere in subjects with stroke and good motor performance in the chronic phase