Autisme, Sillon Temporal Supérieur (STS) Et Perception Sociale: Études

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Autisme, Sillon Temporal Supérieur (STS) Et Perception Sociale: Études Université Pierre et Marie Curie Ecole Doctorale : Cerveau, Cognition, Comportement Autisme, sillon temporal supérieur (STS) et perception sociale : Études en imagerie cérébrale et en TMS Par Ana Riva BAGGIO SAITOVITCH Thèse de doctorat de Neurosciences Dirigée par le Dr. Monica ZILBOVICIUS Présentée et soutenue publiquement le 15/12/2014 Devant un jury composé de : Pr. Frédérique Bonnet-Brilhault (PU-PH - Rapporteur) Pr. Isabelle Desguerre (PU-PH - Rapporteur) Pr. David Cohen (PU-PH - Examinateur) Dr. Nathalie George (DR - Examinateur) Pr. Lionel Naccache (PU-PH - Examinateur) « Moça, olha so o que eu te escrevi E preciso força, pra sonhar E perceber que a estrada vai além do que se vê » Remerciements Je commence par remercier ma directrice de thèse Monica Zilbovicius. J’ai le plaisir et l’honneur de travailler avec Monica depuis 5 ans. En regardant d’où nous sommes parties, c’est avec une grande fierté et une note d’incrédulité que je réalise où nous sommes aujourd’hui. Nous nous sommes lancées vers l’inconnu, avec très peu de moyens et tout le chemin a dû être construit au fur et à mesure. C’est grâce à sa force incroyable, à sa ténacité et à sa compétence que nous sommes où nous en sommes aujourd’hui. Je la remercie d’avoir partagé avec moi son enthousiasme, ses connaissances et sa façon de vivre le travail de recherche scientifique. Il est impossible de travailler avec Monica et de ne pas se donner à 100%... et elle offre le double en retour. Au cours de ces 5 dernières années Monica m’a guidé dans cette aventure, faisant preuve d’une grande confiance en moi, tout en étant toujours présente. J’ai l’impression qu’ensemble nous sommes allées au bout du monde… ou en tout cas au bout du Brésil ! Je ne pourrai jamais la remercier suffisamment pour la place qu’elle m’a accordée dans sa vie et dans son travail et l’affection avec laquelle elle m’a accueillie. Ma vie a pris une nouvelle voie le jour où j’ai rencontré Monica et je lui en serai toujours très reconnaissante. Je tiens à remercier chaleureusement le Pr. Nathalie Boddaert de m’avoir reçue à bras ouverts sur ce projet TMS si innovant, pour lequel elle est investigateur principal. L’énergie de Nathalie nous motive tous et fonctionne comme un moteur inarrêtable qui ne fait qu’avancer. Je la remercie également, ainsi que le Pr. Francis Brunelle, de nous avoir ouvert les portes du Service de Radiologique Pédiatrique de l’Hôpital Necker. Ce travail de thèse n’aurait pas été possible sans cet accueil et sans leur soutien. Je remercie le Pr. Yves Samson pour ses conseils, sa rigueur scientifique et son orientation dans la mise en place de ce projet de thèse, ainsi que pour son implication tout au long du processus. Je remercie le Pr. David Cohen, le Dr. Nathalie George et le Pr. Lionel Naccache d’avoir accepté de faire partie de mon jury de thèse. Je remercie particulièrement le Pr. Frédérique Bonnet-Brilhault et le Pr. Isabelle Desguerre d’avoir accepté, par ailleurs, d’être rapporteurs de cette thèse. Je suis extrêmement honorée de la qualité scientifique de ce jury. La réalisation de la recherche chez des patients repose obligatoirement sur le recrutement des cliniciens impliqués. Je tiens à remercier le Dr. Nadia Chabane et son équipe au Service de Pédopsychiatrie de l’hôpital Robert-Debré, ainsi que le Dr. Anne Philippe au Service de génétique à l’hôpital Necker, de nous avoir adressé les patients qui ont intégré ces études. Je remercie également l’équipe du Pr. Marie-Odile Krebs, au Centre Hospitalier Sainte-Anne, en particulier le Dr. Gilles Martinez et le Dr. Isabelle Amado, ainsi que l’équipe du Pr. Frédérique Bonnet-Brilhault au CHU de Tours. Ce travail de thèse a été réalisé au sein de l’unité INSERM 1000. Je remercie le Dr. Jean-Luc Martinot, de m’avoir reçue au sein de l’unité. Je dois également un grand merci à Hervé Lemaitre, ingénieur de recherche dans l’unité, pour tout ce qu’il m’a appris et pour son aide précieuse dans le traitement des données issues de ces études, avec une gentillesse et une patience sans égales. Toujours au sein de l’unité, je tiens à remercier notre chère secrétaire, Chantal Gourlan, pour tout le soutien logistique qu’elle nous a apporté au cours de ces années, toujours avec une grande amabilité. Je remercie ma collègue Elza Rechtman pour l’aide et le soutien qu’elle m’a apporté, notamment au cours de la phase de rédaction de ce travail. J’ai pu retrouver chez Elza un grand esprit d’équipe et une énergie qui ont été essentiels pour les dernières étapes de la réalisation de cette thèse. Je manifeste ici ma gratitude et mon souhait de pouvoir faire autant pour elle qu’elle a fait pour moi au cours de ces derniers mois. Les études en TMS ont été réalisées au sein de la plateforme TMS, à l’ICM. Depuis la conception du projet, nous avons pu compter sur le soutien du Dr. Sabine Meunier et du Dr. Traian Popa et je les en remercie. Par ailleurs, je tiens à remercier particulièrement Traian Popa pour son aide et son grand engagement dans la mise en place de ce projet. Enfin, je remercie également le Dr. Jean Charles Lamy et Sophien Medhi pour l’enthousiasme avec lequel ils se sont lancés sur ce projet. Les examens d’IRMs ont été effectués au sein du Service de Radiologie Pédiatrique de l’hôpital Necker. Je remercie le Dr. David Grévent et le Dr. Raphael Calmon pour leur soin dans la réalisation de chaque examen. Par ailleurs, la réalisation de tous ces examens, pas toujours évidente, n’a été possible que grâce à une équipe formidable, avec qui ça a été un grand plaisir de travailler. Un grand merci aux très chères manips IRM, Stéphanie, Céline, Martine, Julie, Catherine, ainsi qu’à Laurent, Nelly, Hayet, Nicole, Isabelle, Chantal, Charles pour le soutien logistique apporté. Pour toutes les études en eye-tracking, nous avons pu compter sur l’aide constante de l’équipe de Tobii. Je remercie Antoine, Léopoldine et Jerôme pour leur assistance permanente, toujours avec enthousiasme, gentillesse et une grande bonne volonté. Je tiens à remercier l’équipe du Service de Pédopsychiatrie de l’Université de Sao Paulo au Brésil, en particulier à Helena, Mirian et Caia, pour tous les échanges et pour les nouvelles possibilités de riches collaborations qui s’annoncent. Je remercie Marie Danigo pour la révision et correction de ce texte en un temps record. Je remercie la Fondation Orange pour le financement de cette thèse. Je suis consciente et très honorée de la confiance qui m’a été accordée. Je remercie chaleureusement les parents et les enfants et jeunes avec autisme qui ont intégré ces études. Au cours des années, ces familles font preuve d’une grande confiance dans notre travail et elles sont et seront toujours au cœur de nos motivations. Nous en sommes extrêmement reconnaissants. Enfin, et ce n’est pas le moins important, je tiens à remercier mes parents, Henrique et Elisa Saitovitch, pour la porte qu’ils ont toujours laissé ouverte pour que je trouve mon chemin, ainsi que pour leurs encouragements permanents et leur confiance dans mes capacités de faire toujours plus que je pensais possible. Je remercie également tous mes amis et mes proches, qui m’ont encouragé et soutenu dans un contexte qui n’a pas forcément été le plus simple et qui, prés ou loin, ont toujours su être présents : Marianna, Carla, Ado, Flora, Simone, Claudio, Silvana, Raphael, Camila, Thiago, Adriana, Mathieu, Mathilde, Céline, Gaëtan. Je remercie Elyas pour avoir été là et pour les nouvelles aventures dans lesquels nous nous lançons ensemble. Résumé Les troubles du spectre autistique sont vraisemblablement liés à des altérations des circuits neuronaux au cours du développement. Des études en imagerie cérébrale ont mis en évidence des anomalies anatomo-fonctionnelles localisées notamment au niveau du sillon temporal supérieur (STS) dans l’autisme. Chez le sujet sain, le STS est impliqué dans la perception et la cognition sociale, dont les dysfonctionnements sont au cœur des symptômes autistiques. En effet, des anomalies de la perception sociale, notamment un manque de préférence par les yeux, ont été mises en évidence dans l’autisme. Dans cette thèse nous avons montré qu’il est possible de moduler l’activité neuronale du STS droit à l’aide de la stimulation magnétique transcranienne (TMS) avec un impact significatif sur la perception sociale, mesurée par l’eye- tracking. En effet, suite à une inhibition du STS, des jeunes volontaires sains regardent moins les yeux des personnages dans les scènes sociales. Par ailleurs, cette perception sociale a été corrélée au débit sanguin cérébral (DSC) au repos, mesuré en IRM avec la séquence arterial spin labelling. Ainsi, les volontaires sains qui regardaient le plus les yeux des personnages étaient ceux chez qui le DSC au repos était plus élevé au niveau des régions temporales droites. De plus, cette corrélation a été également observée chez des enfants avec autisme: les enfants qui regardaient le plus les yeux des personnages étaient ceux chez qui le DSC au repos était plus important au niveau des régions temporales droites. Enfin, les résultats préliminaires concernant l’application de la TMS chez des adultes avec autisme ouvrent des nouvelles perspectives thérapeutiques. Mots clés : autisme, STS, perception sociale, TMS, IRM-ASL, eye-tracking ___________________________________________________________________________ Autism, superior temporal sulcus (STS) and social perception: brain imaging and TMS studies Abstract Autism is a pervasive developmental disorder associated with alterations of neural circuits.
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