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La découverte dans le cerveau du singe macaque de cellules visuo-motrices qui répondent de façon identique à la production et la perception d’actes moteurs soutient l’idée que ces cellules, connues sous le nom de neurones-miroirs, encoderaient la représentation d’actes moteurs. Ces neurones, et le système qu’ils forment, constitueraient un système de compréhension moteur; par delà la simple représentation motrice, il est également possible que ce système participe à des processus de haut niveau en lien avec la cognition sociale. Chez l’humain adulte, des études d’imagerie récentes montrent d’importants chevauchements entre les patrons d’activité liés à l’exécution d’actes moteurs et ceux associés à la perception d’actions. Cependant, malgré le nombre important d’études sur ce système de résonance motrice, étonnamment peu se sont penchées sur les aspects développementaux de ce mécanisme, de même que sa relation avec certaines habiletés sociales dans la population neurotypique. De plus, malgré l’utilisation répandue de certaines techniques neurophysiologiques pour quantifier l’activité de ce système, notamment l’électroencéphalographie et la stimulation magnétique transcrânienne, on ignore en grande partie la spécificité et la convergence de ces mesures dans l’étude des processus de résonance motrice. Les études rassemblées ici visent à combler ces lacunes, c'est-à-dire (1) définir l’existence et les propriétés fonctionnelles du système de résonance motrice chez l’enfant humain, (2) établir le lien entre ce système et certaines habiletés sociales spécifiques et (3) déterminer la validité des outils d’investigation couramment utilisés pour mesurer son activité. Dans l’article 1, l’électroencéphalographie quantitative est utilisée afin de mesurer l’activité des régions sensorimotrices chez un groupe d’enfants d’âge scolaire durant la perception d’actions de la main. On y démontre une modulation de l’activité du rythme mu aux sites centraux non seulement lors de l’exécution de tâches motrices, mais également lors de l’observation passive d’actions. Ces résultats soutiennent l’hypothèse de l’existence d’un système de résonance motrice sensible aux représentations visuelles d’actes moteurs dans le cerveau immature. L’article 2 constitue une étude de cas réalisée chez une jeune fille de 12 ans opérée pour épilepsie réfractaire aux médicaments. L’électroencéphalographie intracrânienne est utilisée afin d’évaluer le recrutement du cortex moteur lors de la perception de sons d’actions. On y montre une modulation de l’activité du cortex moteur, visible dans deux périodes distinctes, qui se reflètent par une diminution de la puissance spectrale des fréquences beta et alpha. Ces résultats soutiennent l’hypothèse de l’existence d’un système de résonance motrice sensible aux représentations auditives d’actions chez l’enfant. L’article 3 constitue une recension des écrits portant sur les données comportementales et neurophysiologiques qui suggèrent la présence d’un système de compréhension d’action fonctionnel dès la naissance. On y propose un modèle théorique où les comportements d’imitation néonataux sont vus comme la résultante de mécanismes d’appariement moteurs non inhibés. Afin de mesurer adéquatement la présence de traits empathiques et autistique dans le but de les mettre en relation avec l’activité du système de résonance motrice, l’article 4 consiste en une validation de versions françaises des échelles Empathy Quotient (Baron-Cohen & Wheelwright, 2004) et Autism Spectrum Quotient (Baron-Cohen et al., 2001) qui seront utilisées dans l’article 5. Les versions traduites de ces échelles ont été administrées à 100 individus sains et 23 personnes avec un trouble du spectre autistique. Les résultats répliquent fidèlement ceux obtenus avec les questionnaires en version anglaise, ce qui suggère la validité des versions françaises. Dans l’article 5, on utilise la stimulation magnétique transcrânienne afin d’investiguer le décours temporel de l’activité du cortex moteur durant la perception d’action et le lien de cette activité avec la présence de traits autistiques et empathiques chez des individus normaux. On y montre que le cortex moteur est rapidement activé suivant la perception d’un mouvement moteur, et que cette activité est corrélée avec les mesures sociocognitives utilisées. Ces résultats suggèrent l’existence d’un système d’appariement moteur rapide dans le cerveau humain dont l’activité est associée aux aptitudes sociales. L’article 6 porte sur la spécificité des outils d’investigation neurophysiologique utilisés dans les études précédentes : la stimulation magnétique transcrânienne et l’électroencéphalographie quantitative. En utilisant ces deux techniques simultanément lors d’observation, d’imagination et d’exécution d’actions, on montre qu’elles évaluent possiblement des processus distincts au sein du système de résonance motrice. En résumé, cette thèse vise à documenter l’existence d’un système de résonance motrice chez l’enfant, d’établir le lien entre son fonctionnement et certaines aptitudes sociales et d’évaluer la validité et la spécificité des outils utilisés pour mesurer l’activité au sein de ce système. Bien que des recherches subséquentes s’avèrent nécessaires afin de compléter le travail entamé ici, les études présentées constituent une avancée significative dans la compréhension du développement et du fonctionnement du système de résonance motrice, et pourraient éventuellement contribuer à l’élaboration d’outils diagnostiques et/ou de thérapeutiques chez des populations où des anomalies de ce système ont été répertoriées. / The discovery of cells in the macaque brain that respond both to action production and perception brings support to the hypothesis that these mirror-neurons (MN) code for the representation of action. These cells, and the system they form (the so-called mirror neuron system; MNS), appear to underlie action understanding by simulating the perceived action into the observer’s brain. Beyond simple action understanding, it has been suggested that this system contributes to higher-order processes related to social cognition. In human adults, recent imaging studies have shown important ovelaps in the activity patterns during both action production and execution, supporting the existence of a system similar to that shown in monkeys. However, surprisingly few studies have investigated the presence and the development of the MNS in the human child, and its relationship with socio-cognitive abilities in healthy individuals. Moreover, we still ignore the specificity of measures widely used to assess this system. The studies that follow aim at clarifying these issues. More specifically, the main objectives of this work are to : (1) establish the existence and the properties of motor resonance mechanisms in children; (2) clarify the relationship between activity of the MNS and social abilities in healthy individuals; and (3) determine the specificity of neurophysiological tools widely used to measure MNS activity in humans. In the first article, quantitative electroencephalography is used to assess the activity of sensorimotor regions in a group of school-age children during the observation of simple hand movements. We show a modulation of mu rhtyhm activity at central sites not only during motor production, but also during passive action observation. These results support the existence of an action-execution pairing system sensitive to visual actions in the immature brain. In the second article, we present an experiment conducted in a 12 year-old child undergoing presurgical monitoring for intractable epilepsy. Intracranial electroencephalography is used to assess motor cortex involvement in the perception of action-related sounds. We show a modulation of motor cortex activity at two distinct time-periods in the alpha and beta bands. These results suggest the presence of a motor matching system sensitive to auditory stimuli in the child’s brain. In the third article, we present an overview of behavioral and neurophysiological data supporting the idea that an action-understanding system is present from birth in humans. We propose a theoretical model whereby neonatal imitation is the result on an uninhibited motor resonance system. In order to adequatly measure the presence of empathic and autistic traits in healhy individuals to assess their link with motor resonance, article 4 consists of a french validation of questionnaires used in the fifth article, the Empathy Quotient (Baron-Cohen & Wheelwright, 2004) and the Autism Spectrum Quotient (Baron-Cohen et al., 2001). Translated versions of these scales were administered to 100 healthy adults and 23 individuals with autistic spectrum disorders. Our results replicate faithfully those obtained with the original version of the scales. In the fifth article, transcranial magnetic stimulation is used to assess the timecourse of motor cortex activity during action observation, as well as its relationship with empthic and autistic traits in healthy individuals. We show that the motor cortex is rapidly modulated following movement onset, and that its activity correlates with specific socio-cognitives measures. These results suggest the presence of a rapid mechanism taking place in the motor resonance system that is related to social ability. The sixth acticle aims at clarifying the specificity of the neurophysiological tools used in the preceeding studies to quantify MNS, namely transcranial magnetic stimulation and quantitative electroencephalography. Using both techniques simultaneously during action observation, imagination and execution, we show that these measures capture different aspects of motor resonance. In summary, this thesis aims at documenting the existence of a motor resonance mechanism in children, establishing the relationship between MNS activity and socio-cognitive traits and assessing the specificity of the measures used to quantify activity within this system. Although further studies are needed to complete the task begun here, these studies contribute significantly to our understanding of the development and function of motor resonance mechanism is humans. In the long run, they could contribute to the elaboration of diagnostic markers, and ultimately therapeutic targets, in clinical populations where abnormalities of this system have been documented.

Cette thèse vise à répondre à trois questions fondamentales: 1) La diminution de l’excitabilité corticospinale et le manque d’inhibition intracorticale observés suite à la stimulation magnétique transcrânienne (SMT) du cortex moteur de la main atteinte de sujets hémiparétiques sont-ils aussi présents suite à la SMT du cortex moteur de la jambe atteinte? 2) Est-ce que les altérations dans l’excitabilité corticomotrice sont corrélées aux déficits et incapacités motrices des personnes ayant subi un accident vasculaire cérébral depuis plus de 6 mois? 3) La vibration musculaire, étant la source d’une forte afférence sensorielle, peut-elle moduler l’excitabilité corticomotrice et améliorer la performance motrice de ces personnes? Premièrement, afin d’appuyer notre choix d’intervention et d’évaluer le potentiel de la vibration mécanique locale pour favoriser la réadaptation des personnes ayant une atteinte neurologique, nous avons réalisé une révision en profondeur de ses applications et intérêts cliniques à partir d’informations trouvées dans la littérature scientifique (article 1). La quantité importante d’information sur les effets physiologiques de la vibration contraste avec la pauvreté des études qui ont évalué son effet thérapeutique. Nous avons trouvé que, malgré le manque d’études, les résultats sur son utilisation sont encourageants et positifs et aucun effet adverse n’a été rapporté. Dans les trois autres articles qui composent cette thèse, l’excitabilité des circuits corticospinaux et intracorticaux a été étudiée chez 27 sujets hémiparétiques et 20 sujets sains sans atteintes neurologiques. Les fonctions sensorimotrices ont aussi été évaluées par des tests cliniques valides et fidèles. Tel qu’observé à la main chez les sujets hémiparétiques, nous avons trouvé, par rapport aux sujets sains, une diminution de l’excitabilité corticospinale ainsi qu’un manque d’inhibition intracorticale suite à la SMT du cortex moteur de la jambe atteinte (article 2). Les sujets hémiparétiques ont également montré un manque de focus de la commande motrice lors de l’activation volontaire des fléchisseurs plantaires. Ceci était caractérisé par une augmentation de l’excitabilité nerveuse des muscles agonistes, mais aussi généralisée aux synergistes et même aux antagonistes. De plus, ces altérations ont été corrélées aux déficits moteurs au membre parétique. Le but principal de cette thèse était de tester les effets potentiels de la vibration des muscles de la main (article 3) et de la cuisse (article 4) sur les mécanismes neuronaux qui contrôlent ces muscles. Nous avons trouvé que la vibration augmente l’amplitude de la réponse motrice des muscles vibrés, même chez des personnes n’ayant pas de réponse motrice au repos ou lors d’une contraction volontaire. La vibration a également diminué l’inhibition intracorticale enregistrée au quadriceps parétique (muscle vibré). La diminution n’a cependant pas été significative au niveau de la main. Finalement, lors d’un devis d’investigation croisé, la vibration de la main ou de la jambe parétique a résulté en une amélioration spécifique de la dextérité manuelle ou de la coordination de la jambe, respectivement. Au membre inférieur, la vibration du quadriceps a également diminuée la spasticité des patients. Les résultats obtenus dans cette thèse sont très prometteurs pour la rééducation de la personne hémiparétique car avec une seule séance de vibration, nous avons obtenu des améliorations neurophysiologiques et cliniques. / This thesis aims to answer three basic questions: 1) Are the decrease in corticospinal excitability and the lack of intracortical inhibition observed following transcranial magnetic stimulation (TMS) of the affected hand motor cortex of stroke patients present after TMS of the affected leg motor cortex? 2) Are the alterations in corticomotor excitability correlated with motor impairments and disabilities of subjects who have suffered a stroke for over six months? 3) Can muscle vibration, as a source of strong sensory afference modulate corticomotor excitability and improve motor performance of these subjects? First of all, to support our choice of intervention and to assess the potential of local mechanical vibration to promote the recovery of persons with neurological impairment, we conducted a thorough review of its physiological effects and clinical applications in the scientific literature (article 1). The wealth of information on the physiological effects of vibration contrasts with the lack of studies that have evaluated its therapeutic effects. Nevertheless, we found that, despite the paucity of studies, the results on its clinical use are encouraging and positive and no adverse effects were reported. In the other three articles included in this thesis, the excitability of corticospinal and intracortical circuits has been studied in 27 hemiparetic patients and in 20 healthy subjects without neurological disease or injury. Sensorimotor functions were also evaluated with valid and reliable clinical tests. Similar to that observed in the hand of hemiparetic patients, we found, compared to the healthy subjects, a decrease of corticospinal excitability and a lack of intracortical inhibition following TMS of the affected leg motor cortex (Article 2). The hemiparetic patients also showed a lack of focus of the motor output during voluntary activation of plantar flexors. This was characterized by an increase in the neural excitability not only of the agonist muscles, but also of the synergists and even the antagonist muscles. The main goal of this thesis was to test the potential effects of vibrating hand (Article 3) and thigh (Article 4) muscles on the neural mechanisms that control these muscles. We found that vibration increases the amplitude of motor responses in the vibrated muscles and even produces a response in subjects with no motor response at rest or during a voluntary contraction. The vibration also decreased the intracortical inhibition recorded in the paretic quadriceps muscle (vibrated muscle). The decrease was however not significant at the hand. Finally, using a cross-over design study, the vibration of the paretic hand or leg resulted in specific improvements in hand dexterity or leg coordination, respectively. In the lower limb, quadriceps vibration also reduced the spasticity in patients. The results obtained in this thesis are very promising for stroke rehabilitation because with a single session of vibration, we obtained neurophysiological and clinical improvements.

Il a été suggéré que la similarité physique entre un observateur et une action observée facilite la perception et la compréhension d’action. Par exemple, l’observation d’un acteur exécutant des gestes de la main ayant une signification culturelle est associée à une augmentation de l’excitabilité corticospinale lorsque les deux individus sont de la même ethnicité (Molnar-Szakacs et al., 2007). La perception tactile serait également facilitée lorsqu’un individu regarde un modèle de sa propre race être touché (Serino et al., 2009), tandis que des études en imagerie cérébrale fonctionnelle suggèrent la présence d’activations plus importantes dans le cortex cingulaire lorsqu’un sujet observe une personne de son propre groupe racial ressentir de la douleur (Xu et al., 2009). Certaines études ont lié ces résultats à un mécanisme de résonance motrice, possiblement associé au système des neurones miroirs (SNM), suggérant que la représentation de l’action dans les aires motrices est facilitée par la similarité physique. Toutefois, la grande majorité des stimuli utilisés dans ces études comportent une composante émotionnelle ou culturelle pouvant masquer les effets purement moteurs liant la similarité physique à un mécanisme de résonance motrice. De plus, la sélectivité de l’activation du SNM face à des stimuli biologiques a récemment été remise en question en raison de biais méthodologiques. La présente thèse présente trois études visant à évaluer l’effet de la similarité physique et des caractéristiques biologiques d’un mouvement sur la résonance motrice à l’aide de mesures comportementales et neurophysiologiques. À cet effet, l’imitation automatique de mouvements de la main, l’excitabilité corticospinale et la désynchronisation du rythme électroencéphalographique mu ont servi de marqueurs de l’activité du SNM. Dans les trois études présentées, la couleur de la peau et l’aspect biologique du stimulus observé ou imité ont été systématiquement manipulés. Nos données confirment la sélectivité du SNM pour le mouvement biologique en démontrant une réponse imitative plus rapide et une désynchronisation du rythme mu plus prononcée lors de la présentation de stimuli biologiques comparativement à des stimuli non-biologiques répliquant les aspects physiques du mouvement humain. Les deux mêmes mesures montrent une réponse neurophysiologique et comportementale équivalente lorsque l’action est exécutée par un agent de couleur similaire ou dissimilaire au participant. Nous rapportons aussi un effet surprenant de la similarité physique sur l’excitabilité corticospinale, où l’observation d’une action exécutée par un agent de couleur différente est associée à une activation plus grande du cortex moteur primaire droit de participants de sexe féminin. Prises dans leur ensemble, ces données suggèrent que la similarité physique avec une action observée ne module généralement pas l’activité du SNM au niveau des aires sensorimotrices en l’absence de composantes culturelles et émotionnelles. De plus, les résultats présentés suggèrent que le SNM est sélectif au mouvement biologique plutôt qu’à l’aspect kinématique du mouvement. / It has been suggested that physical similarity with an observed model facilitates action perception and understanding. For example, increased corticospinal excitability is found in participants observing actors of their own ethnicity performing culture-specific hand movements (Molnar-Szakacs et al., 2007). Tactile perception is also said to be increased when individuals watch a model of the same race being touched (Serino et al., 2009). Moreover, imaging data suggest that stronger activations are observed in the cingulate cortex when a subject observes a person of their own race feeling pain (Xu et al., 2009). Some studies have linked these findings with a motor resonance mechanism, possibly associated with the mirror neuron system (MNS), suggesting that action representation in motor areas is facilitated by physical similarity. However, most of the observed stimuli in those studies include emotional or cultural components, which may blur the link between physical similarity and motor resonance per se. The present thesis is comprised of three studies that aimed at evaluating the effect of physical similarity on motor resonance using stimuli that are purely motor in nature. The effect of physical similarity on motor responses during action observation was assessed with behavioral and electrophysiological measures. To this end, imitation of simple finger movements, as well as corticospinal excitability and mu rhythm desynchronization during passive observation of simple finger movements was evaluated, using stimuli that were similar or dissimilar to the participant in terms of skin color. In line with previous results, observation of biological movement resulted in faster reaction times and greater mu desynchronization compared to non-biological movement. Physical similarity with the imitated or observed hand did not affect imitation speed or mu desynchronization. It did, however, have a surprising effect on corticospinal excitability, where the amplitude of transcranial magnetic stimulation-induced motor evoked potentials was greater in the right hemisphere of female participants observing hand movement executed by hands of a different color. These data suggest that physical similarity with an observed action in terms of skin color does not modulate MNS activity in sensorimotor cortex when cultural and emotional components are absent. The present results also strengthen the notion that the motor cortex node of the MNS is tuned to the biological nature of an observed action.

Die transkranielle Magnetstimulation (TMS) ist ein nichtinvasives Hirnstimulationsverfahren, mit welchem sowohl die funktionelle Untersuchung umschriebener kortikaler Regionen als auch die Modulation der Erregbarkeit ebendieser sowie die Induktion neuroplastischer Phänomene möglich ist. Sie wurde in der Vergangenheit insbesondere bei der Erforschung des humanen zentralmotorischen Systems angewandt. Dabei zeigte sich, dass ein einzelner über dem primärmotorischen Areal (M1) applizierter TMS-Puls multiple deszendierende Erregungswellen im Kortikospinaltrakt induzieren kann. Von diesen Undulationen besitzt die D-Welle (direkte Welle) die kürzeste Latenz und sie rekurriert auf eine direkte Aktivierung kortikospinaler Neurone, wohingegen I-Wellen (indirekte Wellen) längere Latenzen besitzen und durch transsynaptische Aktivierung dieser Zellen entstehen. Bemerkenswert ist das periodische Auftreten der letztgenannten Erregungswellen mit einer Periodendauer von etwa 1,5 ms. Zwar sind die genauen Mechanismen noch unbekannt, welche der Entstehung dieser I-Wellen sowie dem Phänomen der I-Wellen-Fazilitierung, das sich in geeigneten TMS-Doppelpulsprotokollen offenbart, zugrunde liegen, jedoch existieren hierzu verschiedene Erklärungsmodelle. Im Mittelpunkt der vorliegenden Arbeit steht die repetitive Anwendung eines TMS-Doppelpulsprotokolls, bei dem das Interpulsintervall (IPI) im Bereich der I-Wellen-Periodizität liegt (iTMS) und das gleichsam durch eine Implementierung der I-Wellen-Fazilitierung in der repetitiven TMS charakterisiert ist. Da gezeigt werden konnte, dass iTMS mit einem IPI von 1,5 ms (iTMS_1,5ms) die kortikospinale Erregbarkeit signifikant intra- und postinterventionell zu steigern vermag, und die I-Wellen-Periodizität interindividuellen Schwankungen unterliegt, wurde in der hier vorgestellten Studie an Normalprobanden der Einfluss einer individuellen Anpassung des IPIs (resultierend in der iTMS_adj) auf die intrainterventionelle kortikospinale Erregbarkeit untersucht. In der Tat stellte sich heraus, dass die iTMS_adj der iTMS_1,5ms diesbezüglich überlegen ist. Dieses Ergebnis unterstreicht das Potential einer Individualisierung der interventionellen TMS für erregbarkeitsmodulierende Effekte und macht dasjenige der ohnehin auf physiologische Prozesse abgestimmten iTMS explizit, was insbesondere für klinische Anwendungen relevant sein mag.

Il existe plusieurs théories du contrôle moteur, chacune présumant qu’une différente variable du mouvement est réglée par le cortex moteur. On trouve parmi elles la théorie du modèle interne qui a émis l’hypothèse que le cortex moteur programme la trajectoire du mouvement et l’activité électromyographique (EMG) d’une action motrice. Une autre, appelée l’hypothèse du point d’équilibre, suggère que le cortex moteur établisse et rétablisse des seuils spatiaux; les positions des segments du corps auxquelles les muscles et les réflexes commencent à s’activer. Selon ce dernier, les paramètres du mouvement sont dérivés sans pré-programmation, en fonction de la différence entre la position actuelle et la position seuil des segments du corps. Pour examiner de plus près ces deux théories, nous avons examiné l’effet d’un changement volontaire de l’angle du coude sur les influences cortico-spinales chez des sujets sains en employant la stimulation magnétique transcrânienne (TMS) par-dessus le site du cortex moteur projetant aux motoneurones des muscles du coude. L’état de cette aire du cerveau a été évalué à un angle de flexion du coude activement établi par les sujets, ainsi qu’à un angle d’extension, représentant un déplacement dans le plan horizontal de 100°. L’EMG de deux fléchisseurs du coude (le biceps et le muscle brachio-radial) et de deux extenseurs (les chefs médial et latéral du triceps) a été enregistrée. L’état d’excitabilité des motoneurones peut influer sur les amplitudes des potentiels évoqués moteurs (MEPs) élicitées par la TMS. Deux techniques ont été entreprises dans le but de réduire l’effet de cette variable. La première était une perturbation mécanique qui raccourcissait les muscles à l'étude, produisant ainsi une période de silence EMG. La TMS a été envoyée avec un retard après la perturbation qui entraînait la production du MEP pendant la période de silence. La deuxième technique avait également le but d’équilibrer l’EMG des muscles aux deux angles du coude. Des forces assistantes ont été appliquées au bras par un moteur externe afin de compenser les forces produites par les muscles lorsqu’ils étaient actifs comme agonistes d’un mouvement. Les résultats des deux séries étaient analogues. Un muscle était facilité quand il prenait le rôle d’agoniste d’un mouvement, de manière à ce que les MEPs observés dans le biceps fussent de plus grandes amplitudes quand le coude était à la position de flexion, et ceux obtenus des deux extenseurs étaient plus grands à l’angle d’extension. Les MEPs examinés dans le muscle brachio-radial n'étaient pas significativement différents aux deux emplacements de l’articulation. Ces résultats démontrent que les influences cortico-spinales et l’activité EMG peuvent être dissociées, ce qui permet de conclure que la voie cortico-spinale ne programme pas l’EMG à être générée par les muscles. Ils suggèrent aussi que le système cortico-spinal établit les seuils spatiaux d’activation des muscles lorsqu’un segment se déplace d’une position à une autre. Cette idée suggère que des déficiences dans le contrôle des seuils spatiaux soient à la base de certains troubles moteurs d’origines neurologiques tels que l’hypotonie et la spasticité. / According to a dominant theory, the motor cortex is directly involved in pre-programming motor outcome in terms of movement trajectories and electromyographic (EMG) patterns. In contrast, the equilibrium point theory suggests that the motor cortex sets and resets the spatial thresholds, i.e., the positions of body segments at which muscles and reflexes begin to act. Movement parameters thereby emerge without pre-programming, depending on the difference between the actual and the threshold position of the body segments. To choose between these two theories of motor control, we investigated corticospinal influences associated with voluntary changes in elbow joint angle in healthy individuals using transcranial magnetic stimulation (TMS) of the brain site projecting to motoneurons of the elbow muscles. In order to minimize the influence of motoneuronal excitability on the evaluation of corticospinal influences, motor evoked potentials (MEPs) elicited by TMS were obtained during the EMG silent period produced by a brief muscle shortening prior to the TMS pulse. MEPs were obtained at a flexion and an extension elbow angle actively established by subjects. MEPs were recorded from 2 elbow flexors (biceps and brachioradialis) and 2 extensors (medial and lateral heads of triceps). Flexor MEP amplitude was bigger at the elbow flexion position in the case of the biceps and extensor MEPs were bigger at the extension position in both extensors studied (reciprocal pattern). MEPs observed in the brachioradialis did not differ at the two elbow orientations. A similar difference in corticospinal influences at the two elbow positions was often preserved when the tonic activity of elbow muscles was equalized by compensating the passive muscle forces at the two positions with a torque motor. Thus, corticospinal influences and EMG activity were de-correlated and it can be concluded that the corticospinal system is not involved in pre-determining the magnitude of motor commands to muscles. Results suggest that the corticospinal system resets the spatial thresholds for muscle activation when segments move from one position to another. This implies that deficits in spatial threshold control may underlie different neurological motor problems (e.g., hypotonia and spasticity).

Introdução: A osteoartrite de joelhos (KOA) apresenta alta prevalência, principalmente em mulheres. Com o envelhecimento da população esta prevalência irá aumentar. Os tratamentos conservadores apresentam limitada eficácia em expressivo número de pacientes no curso do tratamento . A cirurgia de protetização apresenta altos custos, possibilidade de complicações pós-operatórias graves e ainda que a correção anatômica seja perfeita, em torno de 20% dos pacientes persistem com dor crônica pós-operatória. Portanto, é preciso avançar no conhecimento dos mecanismos fisiopatológicos e estudar novas abordagens terapêuticas para agregar às existentes, visando melhor manejo da dor e para restabelecer a função de maneira mais efetiva. Estas questões motivaram três questões centrais que origiram os três estudos que compõem esta tese. Estudo I: No primeiro estudo avaliamos os mecanismos pelos quais há perpetuação da dor na KOA. Para responder a esta questão buscou respostas aos seguintes objetivos: I) Comparar se a função da via da dor inibitório descendente está associada com o estado de inibição no sistema corticospinal, indexado pelo potencial evocado motor (MEP) e o período de silêncio cortical (CSP) em pacientes com KOA e controles saudáveis. II) Determinar se há correlação entre as medidas de inibição intracortical (CSP, MEP) com alterações na escala de dor numérica (NPS 0-10) na KOA durante a tarefa de modulação condicionada de dor (CPM-task) considerando o efeito da capacidade funcional auto-relatada avaliada pelo Western Ontário and McMaster Universities Index (WOMAC) e uso de analgésicos. Métodos: Estudo transversal, foram incluídas 21 pacientes femininas com KOA e 10 controles saudáveis com idade entre 19 a 75 anos. Os parâmetros de excitabilidade do córtex motor (MEP e CSP) foram avaliados utilizando a estimulação magnética trasncraniana (EMT). Avaliação de dor e a incapacidade pelo WOMAC e a NPS (0-10) durante a CPM-task. Resultados: A média ajustada (DP) do CSP observada em pacientes com OA foi 23,43% menor do que em indivíduos saudáveis [54,54 (16,10) vs. 70,94 (22,87)], respectivamente (P = 0,01). A função do sistema modulador descendente de dor avaliado pela alteração do NPS (0-10) durante o CPM-task foi negativamente correlacionada com o parâmetro de excitabilidade cortical indexado pelo CSP (P = 0,001). O CSP foi negativamente correlacionado com a dor e incapacidade avaliada pelo índice WOMAC. Conclusão: Foi observado um sistema inibitório descendente de dor enfraquecido, corroborando com os achados em outras patologias de dor crônica. Estudo II O segundo estudo buscou determinar se na KOA, uma sessão de IMS (eletroestimulação intramuscular) ativa comparada com sham promove um efeito nos parâmetros de excitabilidade do córtex motor [MEP, inibição intracortical curta - SICI, facilitação intracortical (ICF) e CSP] e nas medidas de dor [limiar de dor a pressão (PPT); escala visual analógica de dor (VAS) e mudança na escala de dor numérica (NPS0-10) durante a CPM-task]. Esse estudo também se propôs a determinar se o fator neurotrófico derivado do cérebro (BDNF) sérico medeia o efeito desta estimulação no sistema cortico-espinhal, tal como avaliado pelo MEP e pelo PPT. Métodos: Foram incluídas 26 mulheres com KOA, com idade entre 50 a 75 anos. Elas foram divididas randomicamente para receber uma sessão de 30 minutos de IMS ativa (n = 13) ou IMS sham (n = 13) por meio de eletroestimulação com frequência de 2 Hz. As agulhas foram inseridas paravertebrais em nível da saída das raízes lombares de L1 a S2 e nos músculos cuja inervação corresponde a essas raízes e que sustentam a articulação do joelho (vasto medial, reto anterior, vasto lateral, tibial anterior e inserção da pata anserina). Os desfechos foram as medidas de dor (VAS, PPT, NPS durante CPM-task) e parâmetros de excitabilidade (MEP, CSP, SICI, ICF) realizados antes e imediatamente após a intervenção. Resultados: a IMS ativa comparado com sham diminuiu o MEP em 31,61% [intervalo de confiança (IC) 95%, 2,34-60,98]. Para os resultados secundários, IMS reduziu o ICF e aumentou o CSP. A IMS melhorou a dor relatada no VAS, o PPT e a pontuação do NPS (0-10) durante a CPM-task. O BDNF foi negativamente correlacionado com o PPT (r = 20,56). Conclusão: Obtivemos resultados demonstrando melhora da dor e reforço do sistema cortico-espinhal inibitório comparado ao tratamento sham com IMS. Estudo III O terceiro estudo buscou: 1) Avaliar se a utilização da ETCC (estimulação transcraniana de corrente contínua) combinada a IMS pode promover um resultado melhor de modulação da via cortico-espinhal de dor através da potenciação dos efeitos dos dois tratamentos; comparado a cada um deles isoladamente e ao tratamento sham. 2) Avaliar a capacidade da ETCC em reforçar o sistema inibitório descendente de dor e modular a excitabilidade neuronal através da VAS, PPT e NPS durante CPM-task. Além disso, avaliamos se o BDNF sérico poderia prever o efeito da terapia no final do tratamento. Métodos: 60 mulheres de 50 a 75 anos. Randomizadas em um de quatro grupos: ETCC+IMS, ETCC+IMS sham, ETCC sham+IMS, ETCC sham+IMS sham. Receberam 5 sessões de tratamento: ETCC anodal, lado contrário ao joelho acometido, 2mA, 30 min. IMS: estimulação com freqüência de 2Hz, 30 min; agulhas colocadas a 2cm de L1 á S2, nos músculos vasto medial, vasto lateral, reto anterior, tibial anterior e na inserção da pata anserina. Resultados: O a-tDCS + a-IMS mostrou os melhores resultados com diferença significativa na dor (VAS) [média (DP) relacionadas ao tratamento (pós e pré): 0.46 (0.04) vs. 6.32 (1.97); 95%CI -5.42 (-8.24 to -4.36), p=.003] e funcionalidade. Esse resultado iniciou na primeira sessão e manteve-se ao longo do estudo. A-tDCS+a-IMS foi o único capaz de modificar o sistema inibitório descendente de dor. Conclusão: Obtivemos melhora da dor e capacidade funcional com IMS, ETCC e ETCC+IMS. Mas somente o grupo de tratamento ETCC+IMS demonstrou capacidade de modificação do sistema inibitório descendente de dor. / Background: Knee osteoarthritis (KOA) has a high prevalence, especially in women. With the aging of the population this prevalence will increase. Conservative treatments have limited efficacy in expressive number of patients in the course of the treatment. The total knee replacement surgery presents high costs, possibility of serious postoperative complications and although the anatomical correction is perfect, around 20% persist with chronic postoperative pain. Therefore, it’s necessary to advance in the knowledge of pathophysiological mechanisms and to study new therapeutic approaches to add to the existing ones, aiming to better manage pain and to restore function more effectively. These questions motivated three central questions that originated the three studies that compose this thesis. Study I In the first study we evaluated the mechanisms by which there is perpetuation of pain in knee osteoarthritis and to answer this question sought to answer the following objectives: I) To compare if the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system, indexed by the motor evoked potential (MEP) and the cortical silent period (CSP) in patients with KOA and healthy controls. II) To determine if there is a correlation between the intracortical inhibition measures (CSP, MEP) with changes in the numerical pain scale (NPS 0-10) in the KOA during the task of conditioned pain modulation (CPM-task) considering the effect of the self-reported function evaluated by the Western Ontario and McMaster Universities Index (WOMAC) and the use of analgesics. Methods: A cross-sectional study included 21 female patients with KOA and 10 healthy controls aged 19-75 years old. Motor cortex excitability parameters (MEP and CSP) were assessed using transcranial magnetic stimulation (TMS). Pain assessment and disability by WOMAC and NPS (0-10) during the CPM-task. Results: The adjusted mean (SD) of CSP observed in patients with OA was 23.43% lower than in healthy subjects [54,54 (16,10) vs 70.94 (22.87)], respectively (P = 0.01). The function of the descending pain modulatory system evaluated by the NPS (0-10) change during the CPM-task was negatively correlated with the cortical excitability parameter indexed by CSP (P = 0.001). CSP was negatively correlated with pain and disability assessed by the WOMAC index. Conclusion: It was observed a descending pain inhibitory system weakened, corroborating the findings of other chronic pain conditions. Study II The second study sought to determine if one active IMS session compared to sham promoted an effect on motor cortex excitability (MEP, short intracortical inhibition - SICI, intracortical facilitation (ICF) and CSP and in the pain measures [pressure pain threshold (PPT); Visual analogue pain scale (VAS) and numerical pain scale change (NPS0-10) during the CPM-task]. This study also aimed to determine whether serum brain-derived neurotrophic factor (BDNF) mediates the effect of this stimulation on the cortico-spinal system, as assessed by MEP and PPT. Methods: Twenty-six women with KOA, aged 50-75 years old, were included. They were randomly divided to receive a 30-minute session of active IMS (n = 13) or IMS sham (n = 13) by electrostimulation with a frequency of 2 Hz. The needles were inserted paravertebral at the level of the lumbar roots exit from L1 to S2 and in the muscles whose innervation corresponds to these roots and which support the knee joint (vastus medialis, rectus anterior, vastus lateral, tibialis anterior and insertion of the anserine paw). The outcomes were pain measures (VAS, PPT, NPS during CPM-task) and excitability parameters (MEP, CSP, SICI, ICF) performed before and immediately after the intervention. Results: the active IMS compared with sham decreased the MEP by 31.61% [confidence interval (CI) 95%, 2.34-60.98]. For the secondary outcomes, IMS reduced ICF and increased CSP. IMS improved pain reported in VAS, PPT, and NPS score (0-10) during the CPM-task. BDNF was negatively correlated with PPT (r = 20.56). Conclusion: We obtained results demonstrating improvement of pain and enhancement of the inhibitory corticospinal system compared to sham treatment with IMS. Study III The third study aimed to: 1) Evaluate if the use of the combined tDCS (transcranial direct current stimulation) to IMS can promote a better result of modulation of the corticospinal pain pathway through the potentiation of the effects of the two treatments; compared to each of them alone, and with the sham treatment. 2) To evaluate the ability of the tDCS to strengthen the descending inhibitory pain system and to modulate neuronal excitability through VAS, PPT and NPS during CPM-task. In addition, we evaluated whether serum BDNF could predict the effect of therapy at the end of treatment. Methods: 60 women aged 50 to 75 years old. Randomized in one of four groups: tDCS + IMS, tDCS + IMS sham, tDCS sham + IMS, tDCS sham + IMS sham. They received 5 sessions of treatment: anodal tDCS, opposite side to affected knee, 2mA, 30 min. IMS: stimulation with frequency of 2Hz, 30 min; needles placed at 2 cm from L1 to S2, in the vastus medialis, vastus lateralis, rectus anterior, tibialis anterior and insertion of the anserine paw. Results: a-tDCS + a-IMS showed the best results with significant difference in pain (VAS) [mean (SD) related to treatment (post and pre): 0.46 (0.04) vs. 6.32 (1.97); 95% CI -5.42 (-8.24 to -4.36), p = .003] and functionality. This result started in the first session and was maintained throughout the study. A-tDCS + a-IMS was the only one able to modify the descending inhibitory pain system. Conclusion: We achieved improved pain and functional capacity with IMS, tDCS and tDCS + IMS. But only the tDCS + IMS treatment group demonstrated ability to modify the descending inhibitory pain system.

A dor crônica musculoesquelética é um importante problema de saúde pública, pois, além de ter alta prevalência, suas consequências são nefastas à condição física, psicológica e comportamental, levando ao afastamento do trabalho e aposentadoria precoce. Considerando que quadros de dor crônica são relacionados a alterações biológicas em importantes sistemas endógenos, a busca de biomarcadores sistêmicos interrelacionados com este processo podeser útil para o entendimento dos possíveis efeitos terapêuticos e adversos de técnicas de neuromodulacão, tanto centrais quanto periféricas. Baseado nisto, o objetivo principal deste estudo foi avaliar o efeito dos tratamentos com estimulação magnética transcraniana repetitiva (rTMS) e eletroestimulação intramuscular (DIMST) na intensidade da dor e em parâmetros bioquímicos e neurofisiológicos em pacientes com dor crônica musculoesquelética,e, secundariamente, buscar possíveis biomarcadores em quadros de dor crônica musculoesquelética. Este estudo foi dividido em dois experimentos. No experimento 1, comparou-se o efeito das técnicas de neuromodulação periférica (DIMST) e central (rTMS) sobre os parâmetros de excitabilidade cortical e níveis séricos de BDNF, S100β, citocinas e parâmetros de estresse oxidativo em pacientes com SDM. Foram recrutadas 46 mulheres, com idade entre 19 e 75 anos e diagnóstico de síndrome dolorosa miofascial (SDM). Trata-se de um ensaio clínico randomizado, cego, em paralelo, controlado com placebo-sham. As pacientes foram randomizadas em 4 grupos: (1) rTMS+DIMST, (2) rTMS +sham-DIMST, (3) sham-rTMS+DIMST e (4) sham-rTMS + sham-DIMST. No experimento 2, avaliou-se parâmetros neurofisiológicos de excitabilidade cortical e níveis séricos de BDNF como marcadores de dor crônica musculoesquelética. Foram recrutadas 72 mulheres, com idade entre 19 e 75 anos e diagnóstico de osteoartrite (OA) e SDM. Os parâmetros mensurados foram: dor pela escala análogo-visual (EAV), limiar de dor por algometria (PPT) e excitabilidade cortical pelo TMS. No experimento 1, as pacientes mostrarem-se iguais entre os grupos no basal. Houve uma redução na dor mensurada pela EAV nos grupos 1, 2 e 3 em relação ao grupo 4. O parâmetro de excitabilidade, potencial evocado motor (MEP), apresentou um aumento de amplitude ao final da intervenção 2. Não foram observadas mudanças nos parâmetros bioquímicos analisados durante e ao final das intervenções, seja entre as intervenções e dentro das intervenções. No experimento 2, observou-se que o PPT apresenta uma correlação positiva com inibição intracortical (ICI) e negativa com a facilitação intracortical (ICF). As pacientes com SDM apresentam o período silente (CSP) mais longo que pacientes com OA. O BDNF e estradiol apresentam relação positiva com PPT; no entanto, quando foi avaliada a interação destes fatores, o efeito sobre o PPT foi em direção oposta. Em resumo, os tratamentos ativos, central e/ou periférico, mostraram-se eficazes no alívio da dor, porém, dentre os parâmetros bioquímicos analisados, não se observouum biomarcador responsivo a estas técnicas. Sugere-se uma relação entre dor crônica musculoesquelética e alterações na excitabilidade cortical do córtex motor. Além disto, é importante ressaltar que estes tratamentos não alteraram nenhum dos parâmetros de avaliação de dano celular, como, por exemplo, o aumento de proteína glial (S100β), sugerindo que são técnicas seguras no que se refere aos parâmetros avaliados nesta tese. Posteriores estudos são necessários buscando novos biomarcadores que permitam um melhor diagnóstico, prognóstico e avaliação da resposta ao tratamento com técnicas de neuromodulação na dor crônica musculoesquelética. / Chronic musculoskeletal pain is a major public health problem with high prevalence, because, besides its high prevalences, its consequences are harmful to the physical, psychological and behavioral condition, leading to absence from work and early retirement. Taking into account that chronic pain processes are related to biological changes in endogenous systems, searching systemic biomarkers interconnected with this process can be useful to understand the potential therapeutic and adverse effects of the neuromodulation techniques, both central and peripheral. Based on that, the aim of this study was to evaluate the effect of treatment with repetitive transcranial magnetic stimulation (rTMS) and intramuscular electrical stimulation (DIMST) on pain intensity, biochemical and neurophysiological parameters in chronic musculoskeletal pain patients. Secondly, the aim was to find possible biomarkers in chronic musculoskeletal pain conditions. This study was divided into two protocols. Protocol 1, it was compared the effect of central (rTMS) and peripheral (DIMST) neuromodulation techniques on pain intensity, cortical excitability parameters and serum levels of BDNF, S100β, cytokines and oxidative stress parameters in patients with myofascial pain syndrome (MPS.) Fourty women, aged between 19 and 75 years, MPS diagnosis were recruited. This is a randomized, blind, parallel, placebo - sham clinical trial. The patients were randomized into four groups: (1) rTMS + DIMST, (2) rTMS + sham-DIMST, (3) sham-rTMS + DIMST, and (4) sham-rTMS + sham-DIMST. Protocol 2, we assessed the neurophysiological parameters of cortical excitability and BDNF serum levels as markers of chronic musculoskeletal pain. Seventy-two women, aged between 19 and 75 years diagnosed with osteoarthritis (OA) and MPS were recruited. The measured parameters were: pain intensity by visual analogue scale (VAS), pain pressure threshold (PPT) and cortical excitability by TMS. In protocol 1, the patients presented similarities in the baseline between the four groups. The patients presented a reduction in painintensity measured by VAS in the groups 1, 2 and 3 in relation to group 4. After rTMS intervention, there was an increase in the MEP amplitude. There were no changes in biochemical parameters analyzed during and after the interventions. In protocol 2, it was observed that PPT has a positive correlation with intracortical inhibition (ICI) and negative correlation with intracortical facilitation (ICF). Patients with MPS exhibit longer silent period (CSP) than OA patients. BDNF and estradiol serum levels presented a positive correlation with PPT; however, when their interaction was assessed, the effect on the PPT was in the opposite direction. In summary, the active, central and/ or peripheral treatments were effective in relieving the pain; however, among the biochemical parameters analyzed, there was no biomarker responsive to these techniques. It is suggested a relationship between chronic musculoskeletal pain and changes in cortical excitability of the motor cortex. Furthermore, it is important to note that these treatments did not alter any of the parameters of cellular damage assessment, such as the increase of glial protein (S100β), suggesting that they are safe as to the parameters evaluated in these techniques. Further studies are needed to find new biomarkers that allow better diagnosis, prognosis and assessment of treatment response with neuromodulation techniques in chronic musculoskeletal pain.

Muitas das interações que temos com o ambiente envolvem situações dinâmicas. Raramente estas situações são realizadas de maneira isolada. Em ações interceptativas, por exemplo, o sistema nervoso precisa estimar quando um alvo irá atingir uma determinada posição e constantemente ajustar os movimentos para diferentes contextos. Apesar de estudos psicofísicos terem investigado possíveis variáveis ópticas e modulações do contexto envolvidas na integração visuomotora, pouca atenção foi direcionada para compreender os mecanismos cerebrais da integração de informação visual de movimento e ações motoras em cenários dinâmicos. O objetivo geral desta tese foi investigar estes mecanismos e entender como o contexto modula a atividade cerebral em ações interceptativas em adultos jovens saudáveis. No primeiro experimento, foram investigadas quais áreas estão associadas com a integração entre informação visual de movimento e ação motora sincronizatória. Foi utilizado desenho relacionado à eventos em ressonância magnética funcional avaliando a atividade cerebral em tarefa de timing coincidente. Foi identificada uma rede fronto-parietal bilateral dorsal e ativação bilateral do braço ascendente do sulco temporal inferior, região funcionalmente definida como hV5+, e giro angular. No segundo experimento, foi testada a influência causal da área hV5+ e córtex pré-motor dorsal no viés comportamental que tentativa prévia exerce sobre a tentativa atual usando estimulação magnética transcraniana. Os resultados deste experimento sugerem que o efeito da tentativa prévia depende fortemente de um mecanismo de memória de curto prazo implícito no córtex pré-motor dorsal e moderadamente da área hV5+. No terceiro experimento, o objetivo foi verificar o efeito da repetição e expectativa de repetição da velocidade do estímulo nas áreas associadas com ações interceptativas. Para isso, os participantes interceptaram pares de alvos móveis com velocidade igual ou diferente em experimento relacionado à eventos em ressonância magnética funcional. A expectativa sobre a repetição da velocidade do estímulo foi manipulada pela probabilidade de repetição da velocidade do alvo em diferentes blocos. Os resultados comportamentais indicaram que a velocidade do primeiro estímulo enviesou o erro temporal dos participantes para responder ao segundo estímulo e que a manipulação da expectativa dos participantes não resultou em diferença no erro temporal. Não houve modulação da amplitude do sinal BOLD pela repetição do estímulo ou pela manipulação da expectativa sobre a repetição de velocidade. No quarto experimento, foram investigados os mecanismos cerebrais que permitem que a expectativa influencie o comportamento em uma tarefa de timing coincidente. Para isso, a expectativa sobre a velocidade do alvo foi manipulada a cada tentativa por meio de dicas em um experimento relacionado à eventos em ressonância magnética funcional. Os resultados deste experimento mostraram que a expectativa sobre a velocidade do alvo aumenta o sinal BOLD para expectativa válida em hV5+ e córtex pré-motor dorsal. Em geral, os resultados desta tese mostram que a integração visuomotora em ações interceptativas está associada com atividade em uma rede fronto-parietal dorsal e da área hV5+. Destas áreas, foi verificado que o córtex pré-motor dorsal e área hV5+ tem papel de armazenar informação da tentativa prévia que enviesa o comportamento na tentativa atual. Por fim, foi mostrado que a expectativa sobre a velocidade do alvo modula o sinal BOLD em áreas iniciais do processamento sensorial e de planejamento motor. Estes resultados avançam o conhecimento sobre os mecanismos neurais associados à integração visuomotora em ações interceptativas e mostram como o contexto em que a tarefa é realizada modula essa integração / Many of our interactions with the environment happen in dynamic situations. These situations are rarely experienced in isolation. In interceptive actions, for example, the nervous system needs to estimate when a target will arrive at a certain position and constantly adjust movements for different contexts. Although psychophysical studies have investigated the putative optical variables and contextual modulations in visuomotor integration, less attention has been devoted to understand brain mechanisms underlying the integration of visual motion information and motor actions in dynamic scenarios. The main goal of the present thesis was to investigate the brain mechanisms involved in visuomotor integration of interceptive actions in healthy young adults. In the first experiment, it was investigated which brain areas are associated with integration of visual motion information and timed motor action in an event-related functional magnetic resonance imaging experiment. Results showed greater BOLD signal in a bilateral dorsal fronto-parietal network, as well as hV5+ and angular gyrus. In the second experiment, it was tested the causal influence of area hV5+ and dorsal premotor cortex on the behavioral bias that previous trial exerts on the current trial using transcranial magnetic stimulation. The results of this experiment provide causal evidence that the previous trial effect is mediated to a large extent by an implicit shortterm memory mechanism in the dorsal premotor cortex, and to a lesser extent by hV5 +, in a visuomotor integration task with moving objects. In the third experiment, the goal was to verify the effect of repetition and expectation about repetition of speed in brain areas associated with visuomotor integration in interceptive actions. To that end, participants intercepted pairs of moving targets with either same or different speed in an event-related functional magnetic resonance experiment. Expectation about speed repetition of target speed was manipulated through the probability of speed repetition in different blocks. Behavioral results indicate that speed from the first stimulus biased participants\' temporal error for the second stimulus. However, manipulation of participants\' expectation did not affect temporal error. In addition, BOLD signal amplitude was modulated by neither stimulus speed repetition nor expectation. In the forth experiment, brain mechanisms that allow expectation to influence behavior in a coincident timing task were investigated. Participant\'s expectation about target speed was manipulated on a trial-by-trial basis by means of cues in an event-related functional magnetic resonance experiment. The results of this experiment showed that expectation about target speed increases BOLD signal for valid expectations in hV5+ and dorsal premotor cortex. Overall, the results in this thesis show that visuomotor integration in interceptive actions is associated with activity in a dorsal fronto-parietal network and hV5+. In addition, it was verified that dorsal premotor cortex and hV5+ have a role in storing information from previous trial that bias behavior on the current trial. Lastly, it was shown that expectation about upcoming target speed modulates BOLD signal in early stage visual motion processing as well as motor planning areas. These results advance knowledge about the brain mechanisms associated with visuomotor integration in interceptive actions and show how context modulates this integration process

Introdução: A osteoartrite de joelhos (KOA) apresenta alta prevalência, principalmente em mulheres. Com o envelhecimento da população esta prevalência irá aumentar. Os tratamentos conservadores apresentam limitada eficácia em expressivo número de pacientes no curso do tratamento . A cirurgia de protetização apresenta altos custos, possibilidade de complicações pós-operatórias graves e ainda que a correção anatômica seja perfeita, em torno de 20% dos pacientes persistem com dor crônica pós-operatória. Portanto, é preciso avançar no conhecimento dos mecanismos fisiopatológicos e estudar novas abordagens terapêuticas para agregar às existentes, visando melhor manejo da dor e para restabelecer a função de maneira mais efetiva. Estas questões motivaram três questões centrais que origiram os três estudos que compõem esta tese. Estudo I: No primeiro estudo avaliamos os mecanismos pelos quais há perpetuação da dor na KOA. Para responder a esta questão buscou respostas aos seguintes objetivos: I) Comparar se a função da via da dor inibitório descendente está associada com o estado de inibição no sistema corticospinal, indexado pelo potencial evocado motor (MEP) e o período de silêncio cortical (CSP) em pacientes com KOA e controles saudáveis. II) Determinar se há correlação entre as medidas de inibição intracortical (CSP, MEP) com alterações na escala de dor numérica (NPS 0-10) na KOA durante a tarefa de modulação condicionada de dor (CPM-task) considerando o efeito da capacidade funcional auto-relatada avaliada pelo Western Ontário and McMaster Universities Index (WOMAC) e uso de analgésicos. Métodos: Estudo transversal, foram incluídas 21 pacientes femininas com KOA e 10 controles saudáveis com idade entre 19 a 75 anos. Os parâmetros de excitabilidade do córtex motor (MEP e CSP) foram avaliados utilizando a estimulação magnética trasncraniana (EMT). Avaliação de dor e a incapacidade pelo WOMAC e a NPS (0-10) durante a CPM-task. Resultados: A média ajustada (DP) do CSP observada em pacientes com OA foi 23,43% menor do que em indivíduos saudáveis [54,54 (16,10) vs. 70,94 (22,87)], respectivamente (P = 0,01). A função do sistema modulador descendente de dor avaliado pela alteração do NPS (0-10) durante o CPM-task foi negativamente correlacionada com o parâmetro de excitabilidade cortical indexado pelo CSP (P = 0,001). O CSP foi negativamente correlacionado com a dor e incapacidade avaliada pelo índice WOMAC. Conclusão: Foi observado um sistema inibitório descendente de dor enfraquecido, corroborando com os achados em outras patologias de dor crônica. Estudo II O segundo estudo buscou determinar se na KOA, uma sessão de IMS (eletroestimulação intramuscular) ativa comparada com sham promove um efeito nos parâmetros de excitabilidade do córtex motor [MEP, inibição intracortical curta - SICI, facilitação intracortical (ICF) e CSP] e nas medidas de dor [limiar de dor a pressão (PPT); escala visual analógica de dor (VAS) e mudança na escala de dor numérica (NPS0-10) durante a CPM-task]. Esse estudo também se propôs a determinar se o fator neurotrófico derivado do cérebro (BDNF) sérico medeia o efeito desta estimulação no sistema cortico-espinhal, tal como avaliado pelo MEP e pelo PPT. Métodos: Foram incluídas 26 mulheres com KOA, com idade entre 50 a 75 anos. Elas foram divididas randomicamente para receber uma sessão de 30 minutos de IMS ativa (n = 13) ou IMS sham (n = 13) por meio de eletroestimulação com frequência de 2 Hz. As agulhas foram inseridas paravertebrais em nível da saída das raízes lombares de L1 a S2 e nos músculos cuja inervação corresponde a essas raízes e que sustentam a articulação do joelho (vasto medial, reto anterior, vasto lateral, tibial anterior e inserção da pata anserina). Os desfechos foram as medidas de dor (VAS, PPT, NPS durante CPM-task) e parâmetros de excitabilidade (MEP, CSP, SICI, ICF) realizados antes e imediatamente após a intervenção. Resultados: a IMS ativa comparado com sham diminuiu o MEP em 31,61% [intervalo de confiança (IC) 95%, 2,34-60,98]. Para os resultados secundários, IMS reduziu o ICF e aumentou o CSP. A IMS melhorou a dor relatada no VAS, o PPT e a pontuação do NPS (0-10) durante a CPM-task. O BDNF foi negativamente correlacionado com o PPT (r = 20,56). Conclusão: Obtivemos resultados demonstrando melhora da dor e reforço do sistema cortico-espinhal inibitório comparado ao tratamento sham com IMS. Estudo III O terceiro estudo buscou: 1) Avaliar se a utilização da ETCC (estimulação transcraniana de corrente contínua) combinada a IMS pode promover um resultado melhor de modulação da via cortico-espinhal de dor através da potenciação dos efeitos dos dois tratamentos; comparado a cada um deles isoladamente e ao tratamento sham. 2) Avaliar a capacidade da ETCC em reforçar o sistema inibitório descendente de dor e modular a excitabilidade neuronal através da VAS, PPT e NPS durante CPM-task. Além disso, avaliamos se o BDNF sérico poderia prever o efeito da terapia no final do tratamento. Métodos: 60 mulheres de 50 a 75 anos. Randomizadas em um de quatro grupos: ETCC+IMS, ETCC+IMS sham, ETCC sham+IMS, ETCC sham+IMS sham. Receberam 5 sessões de tratamento: ETCC anodal, lado contrário ao joelho acometido, 2mA, 30 min. IMS: estimulação com freqüência de 2Hz, 30 min; agulhas colocadas a 2cm de L1 á S2, nos músculos vasto medial, vasto lateral, reto anterior, tibial anterior e na inserção da pata anserina. Resultados: O a-tDCS + a-IMS mostrou os melhores resultados com diferença significativa na dor (VAS) [média (DP) relacionadas ao tratamento (pós e pré): 0.46 (0.04) vs. 6.32 (1.97); 95%CI -5.42 (-8.24 to -4.36), p=.003] e funcionalidade. Esse resultado iniciou na primeira sessão e manteve-se ao longo do estudo. A-tDCS+a-IMS foi o único capaz de modificar o sistema inibitório descendente de dor. Conclusão: Obtivemos melhora da dor e capacidade funcional com IMS, ETCC e ETCC+IMS. Mas somente o grupo de tratamento ETCC+IMS demonstrou capacidade de modificação do sistema inibitório descendente de dor. / Background: Knee osteoarthritis (KOA) has a high prevalence, especially in women. With the aging of the population this prevalence will increase. Conservative treatments have limited efficacy in expressive number of patients in the course of the treatment. The total knee replacement surgery presents high costs, possibility of serious postoperative complications and although the anatomical correction is perfect, around 20% persist with chronic postoperative pain. Therefore, it’s necessary to advance in the knowledge of pathophysiological mechanisms and to study new therapeutic approaches to add to the existing ones, aiming to better manage pain and to restore function more effectively. These questions motivated three central questions that originated the three studies that compose this thesis. Study I In the first study we evaluated the mechanisms by which there is perpetuation of pain in knee osteoarthritis and to answer this question sought to answer the following objectives: I) To compare if the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system, indexed by the motor evoked potential (MEP) and the cortical silent period (CSP) in patients with KOA and healthy controls. II) To determine if there is a correlation between the intracortical inhibition measures (CSP, MEP) with changes in the numerical pain scale (NPS 0-10) in the KOA during the task of conditioned pain modulation (CPM-task) considering the effect of the self-reported function evaluated by the Western Ontario and McMaster Universities Index (WOMAC) and the use of analgesics. Methods: A cross-sectional study included 21 female patients with KOA and 10 healthy controls aged 19-75 years old. Motor cortex excitability parameters (MEP and CSP) were assessed using transcranial magnetic stimulation (TMS). Pain assessment and disability by WOMAC and NPS (0-10) during the CPM-task. Results: The adjusted mean (SD) of CSP observed in patients with OA was 23.43% lower than in healthy subjects [54,54 (16,10) vs 70.94 (22.87)], respectively (P = 0.01). The function of the descending pain modulatory system evaluated by the NPS (0-10) change during the CPM-task was negatively correlated with the cortical excitability parameter indexed by CSP (P = 0.001). CSP was negatively correlated with pain and disability assessed by the WOMAC index. Conclusion: It was observed a descending pain inhibitory system weakened, corroborating the findings of other chronic pain conditions. Study II The second study sought to determine if one active IMS session compared to sham promoted an effect on motor cortex excitability (MEP, short intracortical inhibition - SICI, intracortical facilitation (ICF) and CSP and in the pain measures [pressure pain threshold (PPT); Visual analogue pain scale (VAS) and numerical pain scale change (NPS0-10) during the CPM-task]. This study also aimed to determine whether serum brain-derived neurotrophic factor (BDNF) mediates the effect of this stimulation on the cortico-spinal system, as assessed by MEP and PPT. Methods: Twenty-six women with KOA, aged 50-75 years old, were included. They were randomly divided to receive a 30-minute session of active IMS (n = 13) or IMS sham (n = 13) by electrostimulation with a frequency of 2 Hz. The needles were inserted paravertebral at the level of the lumbar roots exit from L1 to S2 and in the muscles whose innervation corresponds to these roots and which support the knee joint (vastus medialis, rectus anterior, vastus lateral, tibialis anterior and insertion of the anserine paw). The outcomes were pain measures (VAS, PPT, NPS during CPM-task) and excitability parameters (MEP, CSP, SICI, ICF) performed before and immediately after the intervention. Results: the active IMS compared with sham decreased the MEP by 31.61% [confidence interval (CI) 95%, 2.34-60.98]. For the secondary outcomes, IMS reduced ICF and increased CSP. IMS improved pain reported in VAS, PPT, and NPS score (0-10) during the CPM-task. BDNF was negatively correlated with PPT (r = 20.56). Conclusion: We obtained results demonstrating improvement of pain and enhancement of the inhibitory corticospinal system compared to sham treatment with IMS. Study III The third study aimed to: 1) Evaluate if the use of the combined tDCS (transcranial direct current stimulation) to IMS can promote a better result of modulation of the corticospinal pain pathway through the potentiation of the effects of the two treatments; compared to each of them alone, and with the sham treatment. 2) To evaluate the ability of the tDCS to strengthen the descending inhibitory pain system and to modulate neuronal excitability through VAS, PPT and NPS during CPM-task. In addition, we evaluated whether serum BDNF could predict the effect of therapy at the end of treatment. Methods: 60 women aged 50 to 75 years old. Randomized in one of four groups: tDCS + IMS, tDCS + IMS sham, tDCS sham + IMS, tDCS sham + IMS sham. They received 5 sessions of treatment: anodal tDCS, opposite side to affected knee, 2mA, 30 min. IMS: stimulation with frequency of 2Hz, 30 min; needles placed at 2 cm from L1 to S2, in the vastus medialis, vastus lateralis, rectus anterior, tibialis anterior and insertion of the anserine paw. Results: a-tDCS + a-IMS showed the best results with significant difference in pain (VAS) [mean (SD) related to treatment (post and pre): 0.46 (0.04) vs. 6.32 (1.97); 95% CI -5.42 (-8.24 to -4.36), p = .003] and functionality. This result started in the first session and was maintained throughout the study. A-tDCS + a-IMS was the only one able to modify the descending inhibitory pain system. Conclusion: We achieved improved pain and functional capacity with IMS, tDCS and tDCS + IMS. But only the tDCS + IMS treatment group demonstrated ability to modify the descending inhibitory pain system.