Rozprawy doktorskie na temat „Stimulation corticale directe”

Les recherches sur l'appropriation corporelle sont essentielles pour le développement des prothèses. En effet, l'incapacité à s’approprier une prothèse entraîne inconfort et douleurs fantômes chez de nombreux patients. Pour améliorer l'acceptation et l'utilisation des prothèses, il est donc crucial de comprendre et de pouvoir manipuler ce sens d’appropriation. Le modèle souris présente de nombreux avantages pour ces recherches grâce à ses comportements riches de membres supérieurs ainsi qu’aux technologies optogénétiques disponibles d’abord chez ce modèle. Ces techniques permettent une exploration précise du rôle du retour tactile dans l’appropriation des prothèses, et constituent une approche novatrice pour étudier ce phénomène. Dans le cadre de cette thèse j’ai participé à la construction d’un prototype d’une prothèse motorisée à l’échelle de la souris qui peut être contrôlé par l’activité neuronale enregistrée à l’aide d’électrodes chroniques implantées dans le cortex moteur des animaux. L'étude de l’appropriation est particulièrement importante dans le cadre du développement de notre modèle de neuroprothèse, pour comprendre l’interaction de différents éléments sensoriels ou moteurs sur l’intégration d’un membre artificiel. Pour étudier cette question ma thèse s’est focalisée sur l’utilisation de méthodes comportementales exploitant des illusions perceptives pour manipuler l’appropriation de membres. Ainsi, dans l'illusion de la main en caoutchouc, grâce à des stimulations visuelles et tactiles synchrones, les participants s’approprient comme faisant partie de leur corps une fausse main placée devant eux, tandis que leur vraie main reste cachée. Nous avons adapté cette illusion au modèle souris pour explorer le rôle du retour tactile dans l’appropriation des prothèses. Nous avons exposé des souris à ce paradigme, en les plaçant devant une prothèse ressemblant à leur patte, pendant que cette dernière est cachée. Après 2 minutes de stimulations, nous menaçons la patte et observons les réactions des animaux à cette menace avec une analyse automatisée de différents points d’intérêt de la face de l’animal. Les animaux montrent des signes d’appropriation envers la prothèse, démontrant que ce sens peut être étudié à ce niveau chez la souris. Dans le contexte du développement de neuroprothèses, il est nécessaire de pouvoir fournir un retour tactile artificiel aux patients quand le membre en périphérie a été perdu. C’est dans cette optique que nous avons exploré la possibilité d’induire cette illusion via des stimulations corticales des régions sensorielles de la patte par optogénétique. Nous avons d’abord mené une étude d’observation des dynamiques corticales générées par des stimulations de la patte en périphérie en utilisant de l’imagerie calcique. Cela nous a permis d’adapter nos stimulations optogénétiques pour mimer l’entrée sensorielle en périphérie. Nous avons ensuite reproduit notre premier protocole de l’illusion classique en replaçant les stimulations tactiles de la patte par des stimulations directes corticales. Les résultats préliminaires de ces expériences montrent un effet similaire à ce qui a été observé auparavant avec l’illusion classique, montrant la possibilité d’induire l’appropriation d’une prothèse à travers un retour tactile cortical. À terme, ces travaux ont permis de développer une plateforme de recherche chez le modèle souris pour le développement de neuroprothèses et permettront de développer de meilleures stratégies de retour sensoriel, pour un meilleur contrôle et une meilleure appropriation des prothèses chez des patients<br>Research on bodily embodiment is necessary for the development of prostheses. Indeed, the inability to embody a prosthesis is a source of discomfort and is accompanied by phantom pain in the residual limbs of many amputees. The mouse model offers many advantages for this type of research due to its rich upper limb behaviours and the availability of optogenetic technologies in this model. These techniques allow for precise exploration of the role of tactile feedback in prosthesis embodiment and represent an innovative approach to studying this phenomenon. As part of this thesis, I contributed to the construction of a motorized prosthesis prototype at the mouse scale, controllable by neuronal activity recorded using chronic electrodes implanted in the animals' motor cortex. The study of embodiment is particularly important in the context of developing a neuroprosthesis model to understand the interaction of various sensory or motor elements on the integration of an artificial limb. To investigate this question, my thesis focused on using behavioural methods, exploiting perceptual illusions to manipulate limb embodiment. For instance, in the rubber hand illusion, synchronous visual and tactile stimulations cause participants to perceive a fake hand placed in front of them as part of their body, while their real hand remains hidden. We adapted this illusion in the mouse model to explore the role of tactile feedback in prosthesis embodiment. We exposed mice to this paradigm by placing them in front of a prosthesis resembling their paw while hiding their actual paw. After 2 minutes of stimulations, we threatened the paw and observed the animals' reactions to this threat using an automated analysis of various points of interest on the animal's face. The animals showed signs of embodiment towards the prosthesis, demonstrating that this sense can be studied at this level in mice. In the context of neuroprosthesis development, it is necessary to provide artificial tactile feedback to patients when the peripheral limb is lost. With this goal in mind, we explored the possibility of inducing this illusion through cortical stimulations of the sensory regions of the paw using optogenetics. We first conducted an observational study of the cortical dynamics generated by peripheral paw stimulations using calcium imaging. This allowed us to adapt our optogenetic stimulations to mimic peripheral sensory input. We then replicated our initial classical illusion protocol by replacing the tactile stimulations of the paw with direct cortical stimulations. The preliminary results of these experiments showed a similar effect to what was previously observed with the classical illusion, indicating the possibility of inducing prosthesis embodiment through cortical tactile feedback. Ultimately, this work led to the creation of a research platform using the mouse model for neuroprosthetic development which could help in providing better sensory feedback strategies for improved control and embodiment of prostheses in patients

Los pacientes con epilepsia son bien conocidos por tener un mayor riesgo de muerte súbita inesperada. El riesgo de muerte súbita inesperada en pacientes con epilepsia (SUDEP) varía de 0,35 a 2,3 por cada 1000 personas por año en las poblaciones de base comunitaria, a 6,3 a 9,3 en los candidatos a cirugía para la epilepsia. Los mecanismos agónicos precisos que desencadenan SUDEP son desconocidos, aunque la evidencia reciente del estudio de unidades de monitoreo de Epilepsia (MORTEMUS) apunta al colapso combinado respiratorio y cardiovascular que conduce al fatal evento. Los signos adversos del sistema nervioso autónomo son prominentes durante las convulsiones. Arritmias cardíacas (bradicardia, asistolia, taquiarritmias) en aproximadamente el 72% de los pacientes con epilepsia, hipotensión post ictal, sensibilidad barorrefleja alterada (que puede comprometer el flujo sanguíneo cerebral), incremento del tono simpático, expresado como aumento de la sudoración y disminución de la variabilidad inter-ictal del ritmo cardíaco nocturno (HRV) son comunes. La alteración severa de la respiración se ve típicamente en las convulsiones clónicas tónicas generalizadas (GTCS). Las características del electroencefalograma (EEG), incluida la supresión generalizada post-ictal en el EEG (PGES), sugieren un alto riesgo de SUDEP, se correlacionan fuertemente con un aumento de la sudoración y una disminución de la HRV y pueden ir acompañadas de hipotensión profunda. Los mecanismos neuronales subyacentes a estos patrones necesitan ser definidos. La epilepsia es un trastorno cortical prototípico, donde la mayoría de los síntomas se producen por la activación o inhibición de regiones específicas en la corteza. Las descargas epileptiformes que involucran un área específica en el cerebro pueden inducir síntomas relacionados con la funcionalidad de ese área. De manera similar, la estimulación eléctrica del cerebro se puede usar para mapear funciones cerebrales. Aunque varios estudios que usan estimulación eléctrica cerebral han sugerido el posible papel de estructuras corticales en la respiración y el control autonómico, los informes de algunos investigadores han indicado hallazgos mixtos, de tal manera que no hay consenso sobre las áreas precisas de la corteza involucrada. Nuestro objetivo fue identificar los sitios corticales con funciones en el control respiratorio y/o autonómico y correlacionar la activación inducida por las crisis epilepticas o la inhibición de estas estructuras, con particulares patrones autonómicos y respiratorios peri-ictales reconocidos como posibles índices de riesgo de muerte. Este estudio describe el papel de varias estructuras límbicas/paralímbicas en la respiración y el control de la presión arterial humana, y los mecanismos patogénicos de la respiración y las respuestas autonómicas durante las crisis epilépticas, proporcionando información sobre los mecanismos que pueden desencadenan la muerte súbita inesperada en los pacientes con epilepsia (SUDEP).<br>Patients with epilepsy are well known to be at increased risk of sudden unexpected death. The risk of Sudden Unexpected Death in Epilepsy Patients (SUDEP) ranges from 0.35 to 2.3 per 1000 people per year in community-based populations, to 6.3 to 9.3 in epilepsy surgery candidates. SUDEP’s precise agonal mechanisms are unknown, although recent evidence from the Mortality in Epilepsy Monitoring Units Study (MORTEMUS) points to combined respiratory and cardiovascular collapse driving the fatal event. Adverse autonomic nervous system signs are prominent during seizures. Cardiac arrhythmias (bradycardia, asystole, tachyarrhythmias) in approximately 72% of epilepsy patients, post-ictal hypotension, impaired baroreflex sensitivity (potentially compromising cerebral blood flow), enhanced sympathetic outflow, expressed as increased sweating and decreased inter-ictal nocturnal heart rate variability (HRV) are common. Severe alteration of breathing is typically seen in generalized tonic clonic seizures (GTCS). Electroencephalogram (EEG) characteristics, including post-ictal generalized EEG suppression (PGES), are suggestive of high SUDEP-risk, strongly correlate with increased sweating and decreased HRV, and may be accompanied by profound hypotension. Neural mechanisms underlying these patterns need to be defined. Epilepsy is a prototypic cortical disorder, where most of the symptoms are produced by the activation or inhibition of specific regions in the cortex. Epileptiform discharges involving a specific area in the brain may induce symptoms related with that area’s functionality. In a similar manner, electrical brain stimulation can be used to map brain functions. Although several studies using brain electrical stimulation have suggested the possible role of cortical structures in respiration and autonomic control, reports from some investigators have indicated mixed findings, such that there is no consensus on the precise areas of cortex concerned. We aimed to identify cortical sites with roles in respiratory and/or autonomic control and to correlate seizure induced activation or inhibition of these structures to particular peri-ictal autonomic and breathing patterns recognized as potential indices of risk for death. This study describes the role of several limbic/paralimbic structures in respiration and human blood pressure control, and pathomechanisms of breathing and autonomic responses during epileptic seizures, providing insights into mechanisms of failure in SUDEP.

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<br>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"

Introduction : La stimulation électrique directe basse fréquence est pratiquée sur des patients épileptiques pharmaco-résistants implantés avec des électrodes profondes. Elle induit de potentiels évoqués cortico-corticaux (PECC) qui permettent d’estimer la connectivité in vivo et ont permis de caractériser des réseaux locaux. Pour estimer la connectivité à l’échelle du cortex, le projet multicentrique F-TRACT vise à rassembler plusieurs centaines de patients dans une base de données pour proposer un atlas probabiliste de tractographie fonctionnelle.Méthodes : La construction de la base de données à nécessité la mise en place technique de pipelines de traitement semi-automatiques pour faciliter la gestion du nombre important de données de stéréo-électroencéphalographie (SEEG) et d’imagerie. Ces pipelines incluent des nouvelles méthodes de traitement du signal et d’apprentissage automatique, qui ont été développées pour identifier automatiquement les mauvais contacts et corriger l’artefact induit par la stimulation. Les analyses de groupe se sont basées sur des métriques des PECC et des cartes temps-fréquences des réponses à la stimulation.Résultats : La performance des méthodes développées pour le projet a été validée sur des données hétérogènes, en termes de paramètres d’acquisition et de stimulation, provenant de différents centres hospitaliers. L’atlas a été généré à partir d’un échantillon de 173 patients, fournissant une mesure de probabilité de connectivité pour 79% des connexions et d’estimer des propriétés biophysiques des fibres pour 46% d’entre elles. Son application à une sous-population de patients a permis d’étudier les réseaux impliqués dans la génération de symptômes auditifs. L’analyse de groupe oscillatoire a mis en avant l’influence de l’anatomie sur la réponse à la stimulation.Discussion : Cette thèse présente une méthodologie d’étude des PECC à l’échelle du cortex cérébral, utilisant des données hétérogènes en termes d’acquisition, de paramètres de stimulation et spatialement. L’incrémentation du nombre de patients dans l’atlas généré permettra d’étudier les interactions cortico-corticales de manière causale<br>Introduction: Low-frequency direct electrical stimulation is performed in drug-resistant epileptic patients, implanted with depth electrodes. It induces cortico-cortical evoked potentials (CCEP) that allow in vivo connectivity mapping of local networks. The multicentric project F-TRACT aims at gathering data of several hundred patients in a database to build a propabilistic functional tractography atlas that estimates connectivity at the cortex level.Methods: Semi-automatic processing pipelines have been developed to handle the amount of stereo-electroencephalography (SEEG) and imaging data and store them in a database. New signal processing and machine-learning methods have been developed and included in the pipelines, in order to automatically identify bad channels and correct the stimulation artifact. Group analyses have been performed using CCEP features and time-frequency maps of the stimulation responses.Results: The new methods performance has been assessed on heterogeneous data, coming from different hospital center recording and stimulating using variable parameters. The atlas was generated from a sample of 173 patients, providing a connectivity probability value for 79% of the possible connections and estimating biophysical properties of fibers for 46% of them. The methodology was applied on patients who experienced auditory symptoms that allowed the identification of different networks involved in hallucination or illusion generation. Oscillatory group analysis showed that anatomy was driving the stimulation response pattern.Discussion: A methodology for CCEP study at the cerebral cortex scale is presented in this thesis. Heterogeneous data in terms of acquisition and stimulation parameters and spatially were used and handled. An increasing number of patients’ data will allow the maximization of the statistical power of the atlas in order to study causal cortico-cortical interactions

Les Troubles Obsessionnels et Compulsifs (TOC) sont un trouble mental sévère et fréquemment résistant. La physiopathologie du trouble se caractérise par des anomalies au sein des boucle cortico-striato-thalamo-cortical entrainant une hyper-activité du cortex orbito-frontal, du cortex cingulaire antérieur, du putamen. Au cours des dernières années, des anomalies structurales et fonctionnelles du cervelet ont de plus été mise en évidence dans les TOC venant compléter le modèle existant.Nous avons mise au point un protocole de traitement par tDCS ciblant le cortex orbito-frontal gauche et le cervelet droit pour les TOC résistants. Dans une première étude, nous avons étudié la faisabilité de ce protocole de traitement dans une étude ouverte. Cette étude a mis en évidence une réduction significative des symptômes dans une population de patient à haut niveau de résistance. Dans une deuxième étude, nous avons évaluer l’effet de ce traitement dans un protocole randomisé, contrôlé et parallèle contre placebo. Cette étude n’a pas confirmé l’efficacité de ce protocole de traitement. Dans cette même population, nous avons au cours du protocole mesuré les paramètres d’excitabilité corticale au niveau du cortex moteur par stimulation magnétique transrânienne. Nous avons ainsi mis en évidence que la tDCS provoquait une augmentation significative des processus d’inhibition (Short Interval Cortical Inhibition : SICI ) et une diminution non significative des processus de facilitation (Intra Cortical Facilitation : ICF). L’étude des effets cliniques et électro-physiologiques de cette approche thérapeutique novatrice dans les TOC résistants n’a pas permis de confirmer son intérêt clinique malgré un impact de ce protocole sur les modifications de l’excitabilité corticale inhérentes aux troubles. Ces données ont été mise en relation avec la littérature afin de proposer des perspectives d’évolution dans l’utilisation de la tDCS dans les TOC résistants<br>Obsessive-compulsive disorder (OCD) is a severe mental illness. OCD symptoms are often resistant to available treatments. Neurobiological models of OCD are based on an imbalance between the direct (excitatory) and indirect (inhibitory) pathway within this cortico-striato-thalamo-cortical loops, which causes hyperactivation in the orbito-frontal cortex, the cingular anterior cortex, the putamen. More recently, the role of cerebellum in the OCD physiopathology has been brought to light by studies showing structural and functional abnormalities. We proposed to use tDCS as a therapeutic tool for resistant OCD by targeting the hyperactive left orbito-frontal cortex with cathodal tDCS (assumed to decrease cortical excitability) coupled with anodal cerebellar tDCS. In a first study, we studied the feasibility of this treatment protocol in an open-trial. This study found a significant reduction in symptoms in a population with a high level of resistance. In a second study, we evaluated the effect of this treatment in a randomized-controlled trial. This study did not confirm the effectiveness of this intervention. We have assessed motor cortex cortical excitability parameters by transcranial magnetic stimulation. We thus demonstrated that the tDCS caused a significant increase of inhibition processes (Short Interval Cortical Inhibition: SICI) and a nonsignificant decrease in the facilitation processes (Intra Cortical Facilitation (ICF)). In addition, clinical improvement assessed by Clinical Global Impression at the end of the follow-up period (3 months) was positively correlated with SICI at baseline.tDCS with the cathode placed over the left OFC combined with the anode placed over the right cerebellum decreased hyper-excitability in the motor cortex but was not significantly effective in SSRI- resistant OCD patients. These works were discussed in light of the available literature to create future prospect in the field of tDCS treatment for OCD resistant patients

<p> The dissertation consists of three parts. The first part is a systematic review of the literature regarding transcranial direct current stimulation (tDCS) and its effects on lower extremity motor behaviors and corticospinal excitability of the lower extremity representation of the motor cortex in healthy subjects. The second part investigates how different electrode montages and electrode conductance mediums affect corticospinal excitability of the tibialis anterior (TA) representation of the motor cortex in healthy subjects. The third part studies how different electrode montage and electrode conductance medium combinations affect ankle tracking accuracy in healthy subjects regarding the dominant lower extremity.</p><p>

This thesis investigated transcranial direct current stimulation (tDCS) as applied to the motor system, and its ability to modulate underlying cortical processes and resultant motor behaviours. Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) were employed to assess the extent to which tDCS induces quantifiable changes in neural structure and function in controls and stroke patients. Modifications in the connectivity of intrinsic functional networks following tDCS application were examined using resting state fMRI. Polarity-specific changes were found: cathodal (inhibitory) tDCS increased the strength of the default mode network and increased functional coupling between major nodes within the motor network. No significant effects were found following anodal (excitatory) tDCS. Although anodal tDCS elicited only subtle changes in resting activity, it is known to produce robust modifications of behaviour. Single and paired-pulse TMS were used to investigate the neurophysiological underpinnings of these changes. Consistent with the theory of homeostatic plasticity, anodal tDCS applied prior to task performance increased GABAA-mediated cortical inhibition and worsened behaviour. The specificity of these changes suggests a central role for the mechanism of surround inhibition. A longitudinal clinical trial in chronic stroke patients was conducted to determine the utility of tDCS as an adjunct in motor rehabilitation. Serial MRI scans revealed that, when combined with motor training, anodal tDCS increased functional activity and grey matter in primarily ipsilesional motor areas. These brain changes were correlated with behavioural improvements in the stroke-affected upper limb. The laterality of connectivity at baseline, as measured by resting state activity and corticospinal tract integrity, was predictive of response to the rehabilitation program, particularly in those stroke patients who received tDCS. Asymmetry favouring the contralesional hemisphere predicted greater behavioural gains. Such results underscore the importance of re-normalisation of structure and functional activity toward the lesioned hemisphere in stroke rehabilitation.

Tinnitus is the perception of sound in the absence of an actual sound stimulus. Recent developments have shifted the focus to the central nervous system and the neural correlate of tinnitus. Broadly, tinnitus involves cortical map rearrangement, pathological neural synchrony, and increased spontaneous firing rates. Various cortical regions, such as Heschl’s gyrus in the auditory cortex, have been found to be associated with different aspects of tinnitus, such as perception and loudness. I propose a cortical stimulation mapping study of Heschl’s gyrus using a depth and subdural electrode montage to conduct electrocorticography. This study would provide high-resolution data on abnormal frequency band oscillations characteristic of tinnitus and pinpoint regions where they occur. The validity of the neural synchrony model would also be tested in this study.

Ce travail de thèse porte sur la modélisation des potentiels évoqués cortico-corticaux (PECCs) induits par stimulation électrique intracérébrale lors de procédures de chirurgie de l’épilepsie en stéréo-électroencéphalographie. Nous utilisons pour cela des modèles de masse neurale de type modèles causaux dynamiques (Dynamic causal modeling, DCM).Dans un premier temps, nous démontrons l'importance d'utiliser une technique d'intégration précise pour résoudre le système d'équations différentielles formalisant la dynamique du modèle (Lemaréchal et al., 2018), en particulier pour une estimation précise des paramètres neuronaux du modèle.Dans une seconde étude, nous développons cette méthodologie pour l'appliquer aux PECCs de la base de données du projet F-TRACT. Les délais et les vitesses de propagation axonale entre régions cérébrales ainsi que les constantes de temps synaptiques locales sont estimés et projetés sur des parcellisations corticales validées par la communauté internationale en neuroimagerie. Le nombre important de jeux de données utilisés dans cette étude (&gt;300) permet en particulier de mettre en évidence des différences de propriétés dynamiques de connectivité en fonction de l'âge des populations considérées (Lemaréchal et al., soumis).Enfin, le dernier travail montre comment, dans le contexte Bayésien de DCM, un atlas de connectivité peut servir à améliorer la spécification et l'estimation d'un modèle de masse neurale pour l’explication de données électrophysiologiques de surface de type électroencéphalographique ou magnétoencéphalographique, en fournissant des distributions a priori sur ses paramètres de connectivité.Dans l'ensemble, cette thèse propose de nouvelles estimations des propriétés dynamiques des interactions cortico-corticales. Grâce à la publication et à la mise à disposition de nouveaux atlas regroupant ces propriétés neuronales, les résultats générés peuvent dès à présent servir à une meilleure spécification et une estimation plus précise de modèles neuronaux de cerveau entier<br>This thesis work aims at modeling cortico-cortical evoked potentials (CCEPs) induced by intracortical direct electrical stimulation in epileptic patients being recorded with stereo-electroencephalography during epilepsy surgery. Neural mass models implemented within the dynamic causal modeling (DCM) framework are used for this purpose.We first demonstrate the importance of using an accurate integration scheme to solve the system of differential equations governing the global dynamics of the model, in particular to obtain precise estimates of the neuronal parameters of the model (Lemaréchal et al., 2018).In a second study, this methodology is applied to a large dataset from the F-TRACT project. The axonal conduction delays and speeds between brain regions, as well as the local synaptic time constants are estimated and their spatial mapping is obtained based on validated cortical parcellation schemes. Interestingly, the large amount of data included in this study allow to highlight brain dynamics differences between the young and the older populations (Lemaréchal et al., submitted).Finally, in the Bayesian context of DCM, we show that an atlas of connectivity can improve the specification and the estimation of a neural mass model, for electroencephalographic and magnetoencephalographic studies, by providing a priori distributions on the connectivity parameters of the model.To sum up, this work provides novel insights on dynamical properties of cortico-cortical interactions. The publication of our results in the form of an atlas of neuronal properties already provides an effective tool for a better specification of whole brain neuronal models

O desenvolvimento da estimulação magnética transcraniana (EMT) permitiu o estudo de potenciais evocados motores eliciados pela estimulação direta do córtex cerebral de forma não-invasiva. Foi observado que diferentes paradigmas de estimulação cortical por EMT apresentam diferentes padrões de resposta, que posteriormente foram associados ao funcionamento de circuitos corticais GABAérgicos e glutamatérgicos do córtex motor, compondo assim índices de excitabilidade cortical motora (ECM). Ademais, desvios da normalidade de tais índices foram encontrados em diversas condições clínicas, incluindo transtornos mentais como a esquizofrenia. O uso dessas medidas também auxiliou o desenvolvimento da estimulação transcraniana por corrente contínua (ETCC), técnica que se mostrou capaz de produzir efeitos neuromodulatórios no sistema nervoso central de forma segura e com mínimos efeitos adversos. Tal técnica vem apresentando possibilidades terapêuticas promissoras, como por exemplo, tendo sido observado sua eficácia no alívio de alucinações auditivas de indivíduos com esquizofrenia. O uso de ETCC para tratamento de sintomas negativos da esquizofrenia também pode vir a se mostrar uma abordagem eficaz, e a análise da ECM pode auxiliar no entendimento dos seus mecanismos de ação e atuar como possível preditor de resposta terapêutica. O objetivo do presente estudo é avaliar o perfil de ECM em um grupo de indivíduos com esquizofrenia, e as possíveis influências de um protocolo terapêutico utilizando ETCC sobre essas medidas. Com esse objetivo, foi selecionada uma coorte de sujeitos com esquizofrenia que participou em ensaio clínico randomizado e controlado com placebo (estimulação sham), tendo a ETCC como intervenção ativa alvo. A ECM foi mensurada na avaliação inicial dos sujeitos, assim como após a primeira sessão de ETCC, e quando da avaliação de desfecho primário. O protocolo terapêutico de ETCC envolveu a colocação de 2 eletrodos de área 5x7 cm, pólo anódico aplicado sobre região correspondente ao córtex pré-frontal dorsolateral esquerdo e pólo catódico aplicado sobre córtex de transição temporoparietal esquerdo; com intensidade de corrente de 2 mA, aplicada por 20 minutos. Cada sujeito foi submetido a 10 sessões no total. Encontramos que idade se correlacionou com diminuição da inibição intracortical, reproduzindo resultado previamente encontrado em indivíduos saudáveis. Acerca da modulação da ECM após sessão de ETCC, observamos que sujeitos submetidos à intervenção ativa apresentaram aumento da inibição intracortical no hemisfério estimulado, em oposição à ausência de mudança significativa da ECM nos sujeitos que receberam estimulação placebo. Os resultados sugerem que sessão de ETCC, utilizando os parâmetros aplicados neste estudo, levou ao aumento da inibição intracortical. Devido a evidências prévias de déficit de inibição intracortical em pessoas com esquizofrenia, é possível que o fenômeno observado represente mecanismo terapêutico da ETCC. É necessário verificar se tal efeito sobre a ECM acompanha medidas objetivas de resposta clinica. Caso isto se comprove, a ECM pode se tornar um valioso marcador de resposta terapêutica e evolução clinica em pacientes com esquizofrenia<br>The development of transcranial magnetic stimulation allowed the study of motor evoked potentials by applying direct stimuli to the brain cortex in a non-invasive fashion. Different stimulation protocols were observed to yield different response patterns, which were later associated with the functioning of cortical GABAergic and glutamatergic circuits, assembled as motor cortex excitability indices. Also, deviations from normality of such indices were observed in several clinical conditions, including mental disorders such as schizophrenia. The use of these measurements also helped the development of transcranial direct current stimulation (tDCS), a technique which was shown to promote neuromodulatory effects in central nervous system, with potential treatment applications. This technique has been used with success in the treatment of auditory hallucinations in patients with schizophrenia. The use of tDCS might also be effective in the treatment of negative symptoms of schizophrenia, and motor cortex excitability analysis might be used to clarify its physiological effects and act as a possible treatment response predictor. The aim of the present study is to evaluate the motor cortical excitability profile of individuals with schizophrenia, as well as possible influences of tDCS over these measurements. With this aim, we selected a cohort of subjects with schizophrenia who participated in a randomized placebo controlled clinical trial using transcranial direct current stimulation (and sham stimulation for placebo), and measuring motor cortical excitability during baseline evaluation, after the first stimulation session, and at the time of the primary outcome evaluation. The transcranial direct current stimulation protocol used in the present study involved the use of 2 electrodes of area 5x7 cm, anode placed over the region corresponding to the left dorsolateral prefrontal cortex, and cathode over the left cortical temporoparietal juntion. A current of 2 mA intensity was applied for 20 minutes. Each subject underwent a total of 10 sessions. We found that age was correlated to reduced intracortical inhibition, as has been previously found in healthy subjects. Regarding changes of motor cortical excitability following a transcranial direct current stimulation session, we observed that subjects that received the active stimulation displayed an increase in intracortical inhibition, as opposed to those who received sham stimulation, which did not present with any significant change. Results suggest that transcranial direct current stimulation session, using the parameters described in this study, led to an increase in intracortical inhibition. Given previous evidence of intracortical inhibition deficit in individuals with schizophrenia, it is possible that the observed phenomenon corresponds to a treatment mechanism of the electrical stimulation in this population. This need to be confirmed by comparing such changes in cortical excitability to objective measurements of clinical improvement. In case that is confirmed, measurement of motor cortical excitability may have a valuable application as a marker of treatment response and clinical outcome for patients with schizophrenia

The present study investigated the effects of transcranial direct current stimulation (tDCS) on maximal voluntary contraction strength (MVC) and the time to failure (TTF) of an isometric muscle endurance test of the elbow flexors. Prior to the main study, the test-retest reliability of MVC and TTF measures was investigated using 10 men (33.2 ± 9.4 y) for the measurements separated by 60 min (within-day) and one week (between-day). Coefficient of variation (CV), Intraclass correlation (ICC, R), a paired t-test and the Bland-Altman plots revealed that TTF at 30% MVC task was reliable, and was able to detect a possible effect of tDCS on TTF, if the magnitude of effect was greater than 11%. Based on the reliability study results, it was hypothesised that tDCS would increase TTF from the first test to the second test separated by 60 min, when a tDCS treatment was administered immediately before the second test. Fifteen men (27.7 ± 8.4 y) were tested for MVC and TTF at 30%-MVC before and immediately after tDCS or sham intervention (10 min) in three separate sessions. In two sessions direct current (2 mA) was delivered through saline-soaked sponge electrodes, with the anode placed on the scalp overlying the right motor cortical representation of the left arm and the cathode secured over the right shoulder. One session was a sham intervention (current delivery for the first 30s). The order of the intervention sessions was randomised and counterbalanced amongst the subjects and subjects who were blinded to intervention type. Changes in MVC strength and TTF from pre to post intervention were compared between the interventions by a two-way repeated measures ANOVA. No significant differences were evident for the two tDCS sessions. MVC strength (baseline: 66.0 ± 11.4 Nm) decreased by 5.9 ± 4.2 % (P

Numerical cognition has been shown to share many aspects of spatial cognition, both behavioural and neurological. However, it is unclear whether a particular type of spatial cognition, visuospatial mental imagery (VSMI), may play a role in symbolic numerical representation. In this thesis, I first show that mental rotation, a form of VSMI, is related to two measures of basic numerical representation. I then show that number-space synaesthesia (NSS), a rare type of VSMI involving visualised spatial layouts for numbers, does not show an advantage in mental rotation, but shows interference in number line mapping. I next present a study investigating links between NSS and the ability to learn novel numerical symbols. I demonstrate that NSS shows an advantage at learning novel numerals, and that transcranial random noise stimulation, which increases cortical excitability, confers broadly similar advantages that nonetheless differ in subtle ways. I present a study of transcranial alternating current stimulation on the same symbol learning paradigm, which fails to demonstrate effects. Lastly, I present data showing that strength of numerical representation in these newly-learnt symbols is correlated with a measure of mental rotation, and also with visual recognition ability for the symbols after, but not before, training. All together, these findings suggest that VSMI does indeed play a role in numerical cognition, and that it may do so from an early stage of learning symbolic numbers.

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.<br>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.

The purpose of this study was to examine the effects of cathodal transcranial direct current stimulation (tDCS) on cortical spreading depression (CSD) in the rat cerebral cortex. CSD is a propagating wave of hyperexcitability that occurs in a number of neurological disorders characterized by excess cerebral excitability such as migraine, acute brain injury, or stroke. Since tDCS is a non-invasive method capable of inducing polarity-dependent changes in cortical excitability, we hypothesized that cathodal stimulation would prevent, attenuate, or change the characteristics of CSD. Forty Sprague-Dawley male rats were randomly divided into two stimulation condition groups: sham tDCS and cathodal tDCS. In both experimental groups, CSD was induced by applying potassium chloride onto cortical surface. Electroencephalogram (EEG) data was recorded during each experiment and subjected to analysis. CSD incidence was compared between the sham and cathodal tDCS group. We observed that significantly fewer CSD events were exhibited during cathodal tDCS relative to sham stimulation. Evaluation of CSD wave characteristics between experimental groups revealed no differences in propagation velocity, amplitude, or waveform of CSD, nor in the presence of neuronal silencing. The results of this study lend support for the use of cathodal tDCS as an effective method for reducing cortical excitability and provides the groundwork for future study of the mechanisms of tDCS and its treatment targets in neurological disorders whose symptoms are created or exacerbated by CSD.

Cortical spreading depression (CSD) is a depolarizing wave that travels through the cerebral cortex, and is followed by an inhibition of cortical activity. The propagation of CSD elicits metabolic challenges in tissue that may be irrecoverable in an ischemic brain, and thus has implications in neurological disease. Limiting the incidence of CSD may be instrumental in limiting the extent of neuronal damage following brain injury. Transcranial direct current stimulation (tDCS) is a form of brain stimulation that alters the level of cortical activity. Anodal tDCS, which increases cortical excitability, is used to treat a variety of neurological syndromes but may have the potential to exacerbate certain pathologies. This contention has never been evaluated using in vivo brain recordings. This study seeks to determine the effects of anodal tDCS on CSD, a phenomenon common to many neurological disorders. CSD was induced in the rat cortex by administration of potassium chloride. Animals were subjected to either anodal tDCS or sham stimulation. Cortical electrical activity was monitored using an intracortical multielectrode array, and data was analyzed to measure the effects of anodal tDCS versus sham on CSD incidence, velocity, amplitude, and several other characteristics of the wave. The hypothesis of the study was that anodal tDCS would increase the incidence, velocity, and amplitude of the CSD wave. No significant effects of anodal tDCS on CSD were observed in this study. Results indicate that anodal tDCS does not increase the velocity, amplitude, or frequency of the spreading depression wave, nor does it interrupt the wave. These data have implications for the use of anodal tDCS in the treatment of neurological disorders associated with spreading depression.

Transcranial direct current stimulation (TDCS) allows for the noninvasive modulation of cortical activity. In this study, the effects of cathodal and anodal TDCS treatment on baseline activity in the motor cortex of rats were investigated via translaminar electroencephalogram (EEG) recording and power spectral density analysis. Treatment with low intensity anodal TDCS for five minutes was found to increase delta and theta frequency cortical activity during and for up to five minutes following treatment. This study also assessed the interaction of TDCS with the phenomenon of cortical spreading depression (CoSD), which has been implicated in numerous disease states, including migraine and stroke. TDCS treatment was given concurrently with induction of CoSD via administration of potassium chloride to the surface of the dura. The presence of the spreading depression event, a characteristic low frequency wave observed to travel outwards from the point of CoSD induction and downwards through the cortex, was used as a proxy measure for the occurrence of CoSD. It was observed that animals treated with cathodal TDCS exhibited fewer spreading depression events relative to those treated with anodal TDCS or those receiving sham treatment. In this study, animals were segregated into groups that exhibited stimulus artifact during TDCS treatment and those that did not. Stimulus artifact was defined as a characteristic alpha and/or beta frequency activity spike lasting throughout and not longer than the period of stimulation. Those animals receiving TDCS without exhibiting stimulus artifact were considered for the purposes of this study to not have received proper TDCS treatment, and acted as a sham treatment group. Because salient differences emerged between the stimulus artifact positive and stimulus artifact negative groups, this study suggests that the presence of stimulus artifact could be used as a proxy measure for successful TDCS dosage.

碩士<br>高雄醫學大學<br>物理治療學系碩士班<br>106<br>Background and purpose：Previous studies have demonstrated the transcranial direct current stimulation (tDCS) and neuromuscular electrical stimulation (NMES) intervention on motor recovery of upper extremity (UE) of stroke patients are evident, but changes of cortical excitability by combination of two neuromodulation instruments are still unknown. The aim of this study was to investigate the effects of tDCS combined with NMES on excitability of motor cortex in patients with stroke. Methods：Twenty three patients with first-ever ischemic stroke for more than six months were recruited and assigned into one of three groups (tDCS combined with NMES, tDCS combined with sham NMES, or sham tDCS combined with sham NMES) by block randomization. All participants received an intervention protocol with a total of 15 sessions for 3 weeks (5 times per week, 30 minutes daily). The tDCS intensity was set at 2mA with dual stimulation mode, the two electrodes were placed on the bilateral primary motor cortex. Two active electrodes of the NMES with intensity of 10 ~ 20mA were placed on the motor points of the extensor carpi radialis muscle and the extensor digitorum muscle. Transcranial magnetic stimulation was used to assess the changes in corticomotor excitability before and after the first and 15 interventions. Results：A total of twenty subjects completed the interventions and assessments. No significant changes in corticomotor excitability among three groups were found after the first and 15 interventions. Conclusion：Our preliminary findings did not support that the tDCS combined with NMES might increase effect in cortical excitability in lesioned hemisphere. Future studies need to recruit more subjects and identify the optimal settings of intervention mode.

La stimulation électrique transcrânienne à courant direct (tDCS) est une technique non invasive de neuromodulation qui modifie l’excitabilité corticale via deux grosses électrodes de surface. Les effets dépendent de la polarité du courant, anodique = augmentation de l’excitabilité corticale et cathodique = diminution. Chez l’humain, il n’existe pas de consensus sur des effets de la tDCS appliquée au cortex somatosensoriel primaire (S1) sur la perception somesthésique. Nous avons étudié la perception vibrotactile (20 Hz, amplitudes variées) sur le majeur avant, pendant et après la tDCS appliquée au S1 controlatéral (anodale, a; cathodale, c; sham, s). Notre hypothèse « shift-gain » a prédit une diminution des seuils de détection et de discrimination pour la tDCS-a (déplacement vers la gauche de la courbe stimulus-réponse et une augmentation de sa pente). On attendait les effets opposés avec la tDCS-c, soit une augmentation des seuils (déplacement à droite et diminution de la pente). Chez la majorité des participants, des diminutions des seuils ont été observées pendant et immédiatement suivant la tDCS-a (1 mA, 20 min) en comparaison à la stimulation sham. Les effets n’étaient plus présents 30 min plus tard. Une diminution du seuil de discrimination a également été observée pendant, mais non après la tDCS-c (aucun effet pour détection). Nos résultats supportent notre hypothèse, uniquement pour la tDCS-a. Une suite logique serait d’étudier si des séances répétées de tDCS-a mènent à des améliorations durables sur la perception tactile. Ceci serait bénéfique pour la réadaptation sensorielle (ex. suite à un accident vasculaire cérébral).<br>Transcranial direct-current stimulation (tDCS) is a non-invasive neuromodulation technique which aims to modify cortical excitability using large surface-area electrodes. tDCS is thought to increase (anodal, a-tDCS) or decrease (cathodal, c-tDCS) cortical excitability. At present, there is no consensus as to whether tDCS to primary somatosensory cortex (S1) modifies somatosensory perception. This study examined vibrotactile perception (frequency, 20 Hz, various amplitude) on the middle finger before, during and after contralateral S1 tDCS (a-, c- and sham, s-). The experiments tested our shift-gain hypothesis which predicted that a-tDCS would decrease vibrotactile detection and discrimination thresholds (leftward shift of the stimulus-response function with increased gain/slope), while c-tDCS would increase thresholds (shift to right; decreased gain). The results showed that weak, a-tDCS (1 mA, 20 min), compared to sham, led to a reduction in both thresholds during the application of the stimulation in a majority of subjects. These effects persisted after the end of a-tDCS, but were absent 30 min later. Cathodal tDCS, vs sham, had no effect on detection thresholds; in contrast, there was a decrease in discrimination threshold during but not after c-tDCS. The results thus supported our hypothesis, but only for anodal stimulation. Our observation that enhanced vibrotactile perception outlasts, albeit briefly, the period of a-tDCS is encouraging. Future experiments should determine whether repeated sessions of a-tDCS can produce longer lasting improvements. If yes, clinical applications could be envisaged, e.g. to apply a-tDCS to S1 in conjunction with retraining of sensory function post-stroke.

Spreading depression (SD) is a slow propagating wave of depolarization that can spread throughout the cortex in the event of brain injury or any general energy failure of the brain. Massive cellular depolarization causes enormous ionic and water shifts and silences synaptic transmission in the affected tissue. Large amounts of energy are required to restore ionic gradients and are not always met. When these energetic demands are not met, brain tissue damage can occur. The exact mechanism behind initiation and propagation of SD are unknown, but a general model is known. It may be possible to prevent or delay the onset of SD using non-invasive electromagnetic techniques. Transcranial magnetic stimulation (TMS), electrical stimulation (ES), and transcranial direct coupled stimulation (tDCS) could be used to decrease neuronal excitability in different ways. In theory, any technique that can reduce cortical excitability could suppress SD initiating or propagating.