L'épilepsie affecte en France environ 500 000 personnes, parmi lesquelles environ un tiers présente une pharmaco-résistance. Pour ces patients, une chirurgie peut être envisagée, qui consiste en la résection de la région cérébrale à l'origine des crises, également appelée « zone épileptogène » (ZE). Le succès du traitement chirurgical repose à la fois sur la possibilité de bien circonscrire la zone nécessaire et suffisante à la survenue des crises, mais aussi sur l'identification du potentiel rôle fonctionnel du tissu cérébral situé dans ou à proximité de cette zone, afin d'éviter que l'intervention engendre des déficits cognitifs.Dans ce travail de thèse, nous nous sommes penchés sur des signaux électrophysiologiques entre 80 et 500 Hz, appelés oscillations haute fréquence (HFO), qui ont été récemment désignés comme pouvant être de nouveaux marqueurs de la ZE, et sur leurs analogues, les HFO physiologiques, qui semblent quant à eux être impliqués dans des processus cognitifs. Nous avons tenté d'identifier des paramètres permettant de distinguer ces deux classes de HFO. Alors que ces signaux sont à l'heure actuelle essentiellement enregistrés en EEG intracérébral (SEEG pour stéréo-électro-encéphalographie), nous avons également exploré la possibilité de les étudier en Imagerie par Résonnance Magnétique fonctionnelle simultanément à la SEEG, ce qui pourrait permettre à l'avenir d'en obtenir une cartographie sur l'ensemble du cerveau. La vocation générale de ces travaux est de participer à la compréhension et l'amélioration de l'étude des HFO pathologiques et physiologique, afin d'optimiser leur utilisation pour la chirurgie des épilepsies pharmaco-résistantes / Epilepsy affects 500 000 persons in France, among which about 30% will continue to have seizure despite medication. For those patients, a surgical treatment can be proposed, that consists in removing the brain region causing seizures, namely the “epileptogenic zone” (EZ). To achieve a good surgical outcome, it is necessary to identify the zone that is both necessary and sufficient for seizure start, but also, to identify the function of the brain tissue that is located close to this zone, to avoid eventual cognitive deficits.In this thesis, we were interested in the electrophysiological activities between 80 and 500 Hz called high frequency oscillations (HFO), that were recently identified as new markers of the EZ, and the analogous physiological HFO that seem to be implicated in cognitive processes. We tried to identify features that could enable to distinguish between this to class of HFO. While these activities are still mainly recorded with intra-cerebral electro-encephalography (icEEG), we also explored the possibility to study them with functional Magnetic Resonance Imaging, simultaneously with icEEG. This method could, in the future, enable to get a HFO mapping over the whole brain. The aim of this work is to participate in the comprehension and exploration improvement of pathological and physiological HFO, to enhance their use in intractable epilepsy surgery

This dissertation introduces a new approach for assessing the effects of pediatric epilepsy on the language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI data. An auditory description decision task (ADDT) paradigm was used to activate the language network for 29 patients and 30 controls recruited from three major pediatric hospitals. Empirical evaluations illustrated that pediatric epilepsy can cause, or is associated with, a network efficiency reduction. Patients showed a propensity to inefficiently employ the whole brain network to perform the ADDT language task; on the contrary, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was carried out. The analysis revealed no substantial global network feature differences between the patient and control groups. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient’s extent of activation network showed a tendency towards more random networks. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. The left hemispheric hubs displayed greater centrality values for patients, whereas the right hemispheric hubs displayed greater centrality values for controls. This hub hemispheric disparity was not correlated with a right atypical language laterality found in six patients. Finally it was shown that a multi-level unsupervised clustering scheme based on self-organizing maps, a type of artificial neural network, and k-means was able to fairly and blindly separate the subjects into their respective patient or control groups. The clustering was initiated using the local nodal centrality measurements only. Compared to the extent of activation network, the intensity of activation network clustering demonstrated better precision. This outcome supports the assertion that the local centrality differences presented by the intensity of activation network can be associated with focal epilepsy.

No description available.

Le but de cette thèse est d’investiguer l’organisation fonctionnelle du contrôle cognitif au sein du cortex préfrontal latéral dans la schizophrénie. Chez le sujet sain, Koechlin et coll. (Science, 2003) ont montré que le cortex préfrontal latéral était structuré en une cascade de processus de contrôle allant des régions antérieures aux régions postérieures, intégrant respectivement les informations épisodiques (événements antérieurs) et contextuelles (le contexte immédiat de l’action) au choix de l’action en réponse à un stimulus externe. En utilisant le paradigme expérimental de Koechlin et coll. en IRM fonctionnelle, nous avons investigué l’architecture fonctionnelle du contrôle cognitif au sein du cortex latéral préfrontal chez 15 patients schizophrènes et 14 sujets contrôles appariés. Dans une première étude, nous avons trouvé que les patients schizophrènes présentaient un déficit sélectif du contrôle contextuel associé à une hypoactivation des régions postérieures préfrontales, expliquant la désorganisation du discours et du comportement observés chez ces patients. Par ailleurs, les patients schizophrènes hyperactivaient leurs régions rostrales du cortex préfrontal latéral pendant le contrôle des informations de nature épisodique, ce que nous avons interprété comme une tentative de compensation infructueuse des dysfonctions du contrôle contextuel. Dans une seconde étude, nous avons montré que les patients schizophrènes présentaient également une perturbation du traitement top-down des informations de nature épisodique, liée à une dysconnectivité des régions rostrales vers les régions caudales du cortex préfrontal latéral. / The goal of this thesis is to investigate the functional organization of cognitive control within the LPFC in schizophrenia. We used a model postulating that cognitive control is functionally organized within the lateral prefrontal cortex (LPFC) as a cascade of representations ranging from premotor to anterior LPFC regions according to stimuli, the present perceptual context, and the temporal episode in which stimuli occur. Using functional magnetic resonance imaging, we investigated the functional architecture of cognitive control within the LPFC in 15 schizophrenic patients and 14 matched healthy controls. In a first study, we found that immediate contextual signals insufficiently bias the caudal LPFC activity required to select the appropriate behavioral representation. This specific deficit could thus alter the internal consistency of schizophrenic patients’ behavior. To compensate for this weakening of contextual influence, schizophrenic patients may inefficiently use temporal episodic information through higher activation in rostral LPFC regions. In a second study, we showed that schizophrenic patients inappropriately process episodic information flow along a rostro-caudal axis within the LPFC. This top-down episodic control dysfunction could lead to a disruption of episodic memory that could account for the patients’ difficulties in organizing their behavior across time. All the results argue in favor of both dysfunctional specialization and integration within the LPFC in schizophrenia.

L'objectif de cette thèse est d'identifier les bases neurales de la représentation de soi chez le primate non-humain, par une approche d'imagerie par résonnance magnétique fonctionnelle. Nous avons pour cela étudié la convergence multimodale 1) à l'échelle de l'aire par la description de la cartographie du sillon intraparietal dans un contexte de stimulations auditives, tactiles et visuelles et 2) à l'échelle du cerveau entier où nous décrivons précisément les sites de convergence visuo-tactile au niveau cortical. Nous avons également étudié le phénomène d'intégration multisensorielle dans un contexte visuo-tactile dynamique, pour lequel nous montrons que les effets comportementaux (étude psychophysique menée chez l'homme) et le réseau d'activations cortical sont maximisés quand le stimulus visuel prédit le stimulus tactile plutôt que lors de leur présentation simultanée. Enfin, nous avons étudié la représentation de l'espace en caractérisant les bases neurales de l'espace proche et de l'espace lointain à partir d'un dispositif expérimental naturaliste et nous montrons l'existence de deux réseaux corticaux qui traitent séparément les informations appartenant à l'espace proche et à l'espace lointain / The aim of this thesis is to investigate the neural basis of self-representation in the non human primate. We studied the multimodal convergence both 1) at the area level precisely mapping auditory, tactile and visual convergence in the intraparietal sulcus and 2) at the whole brain level capturing the spatial pattern of visuo-tactile cortical convergence. We also investigated the neural network subserving multisensory integration in a dynamical visuo tactile context, showing that the strongest behavioral and cortical are obtained when the visual stimuli is predictive of the tactile stimulus rather than during simultaneous presentations. Finally, we studied the representation of space by characterizing the neural bases of near space and far space in a real naturalistic environment, thus providing the neural grounds for the observed behavioral and neuropsychological dissociation between near and far space processing

Le toucher a un rôle critique dans notre vie quotidienne pour saisir, manipuler des objets, ou simplement marcher. Les aires primaires somatosensorielles présentent la particularité d'être organisées somatotopiquement, donnant lieu au dénommé Homunculus. Alors que la plupart de notre surface corporelle est représentée suivant un ordre similaire à sa continuité physique, l'Homunculus présente une discontinuité majeure, la main et le visage étant représentés côte à côte. La frontière main-visage a été souvent utilisée comme un repère pour étudier l'une des particularités les plus fascinantes de notre cerveau, sa capacité de réorganisation. En particulier, la plasticité somatosensorielle a été trouvée capable de traverser la frontière main-visage suite à une privation d'afférences. Alors qu'il est connu depuis longtemps que l'augmentation des afférences conduit également à des changements corticaux souvent associés à des bénéfices perceptifs, la possibilité qu'une telle plasticité puisse traverser la frontière main-visage reste inexplorée. Le travail de ma thèse a pour but d'examiner cette question. Une première étude comportementale a révélé que le fait d'augmenter les afférences d'un doigt améliore non seulement l'acuité tactile de ce doigt, mais aussi du visage, suggérant un transfert de changements plastiques au travers de la frontière main-visage. Afin d'examiner ceci, deux études supplémentaires ont été réalisées en utilisant deux techniques complémentaires d'imagerie cérébrales, à savoir l'IRMf et la MEG. En adéquation avec nos hypothèses, une réorganisation des représentations de la main et du visage a été trouvée. Dans l'ensemble, ce travail révèle qu'une plasticité adaptative menant à des bénéfices perceptifs peut se propager sur de larges distances corticales, en particulier au-delà de la frontière main-visage, et par conséquent ouvre une nouvelle fenêtre d'investigation pouvant avoir un réel impact dans la promotion de rééducation / Touch plays a critical role in our daily life to grasp and manipulate objects, or simply walk. The primary somatosensory areas exhibit the striking feature of being somatotopically organized, giving rise to the so-called Homunculus. While most of our body surface is represented following an order similar to its physical continuity, the Homunculus displays a major discontinuity, the hand and the face being represented next to each other. The hand-face border has been widely used as a somatotopic hallmark to study one of the most fascinating features of our brain, its capacity for reorganization. Particularly, somatosensory plasticity was found to cross the hand-face border following deprivation of inputs. While it has long been known that increasing inputs also leads to cortical changes typically associated with perceptual benefits, whether such plasticity can cross the hand-face border remains unknown. My thesis work aimed to investigate this question. A first behavioural study revealed that increasing inputs to a finger improves not only the tactile acuity at this finger, but also at the face, suggesting a transfer of plastic changes across the hand-face border. To investigate this, two additional studies were performed using two complementary brain imaging techniques, namely high-field fMRI and MEG. In agreement with our hypotheses a reorganization of both hand and face representations was found. Altogether, this work reveals that adaptive plasticity leading to perceptual benefits can spread over large cortical distances, in particular across the hand-face border, and thus opens up a new window of investigation that may have a real impact in promoting rehabilitation

A esquizofrenia continua sendo um dos transtornos mais desafiadores para a clínica psiquiátrica, apesar dos estudos atuais que tentam elucidar sua fisiopatologia e buscar novas opções de tratamento. A n-acetilcisteína (NAC) é uma droga utilizada há mais de 30 anos na clínica médica no tratamento da intoxicação por acetaminofeno e como mucolítico na DPOC, entre outros. Evidências recentes apoiam o seu uso no tratamento de diversos transtornos neuropsiquiátricos, como depressão, transtorno afetivo bipolar, dependência química e esquizofrenia. A droga tem como provável mecanismo de ação um aumento na atividade antioxidante através do aumento nos níveis de glutationa (GSH) e modulação da neurotransmissão glutamatérgica. Nas duas últimas décadas, o estudo dos mecanismos neurobiológicos subjacentes aos transtornos psiquiátricos, bem como a investigação dos possíveis mecanismos e regiões cerebrais influenciados por substâncias psicofarmacológicas, recebeu importante contribuição das técnicas de neuroimagem funcional. Apesar disto, até o momento existem poucos estudos que avaliaram os mecanismos centrais relacionados às propriedades antipsicóticas da NAC em humanos. Este estudo tem o objetivo de investigar os efeitos da NAC em indivíduos portadores de esquizofrenia refratária em uso exclusivo de clozapina através de medidas de sintomas positivos e negativos e da avaliação da perfusão cerebral através de ressonância magnética nuclear utilizando a técnica de arterial spin labeling (ASL). Foram avaliados 20 sujeitos com esquizofrenia refratária em uso de clozapina em um estudo com distribuição aleatória, duplo-cego e controlado por placebo, utilizando a dose de 2000mg por dia de NAC. Do total da amostra, 14 tiveram as imagens perfusão sanguínea cerebral analisadas. O estudo teve a duração de oito semanas, com avaliações a cada quatro semanas e realização das RMN no início e ao final do período. Não foram observadas diferenças estatisticamente significativas entre os grupos placebo e NAC nas escalas BPRS e PANSS-N. O grupo que recebeuNAC apresentou mais efeitos colaterais, porém no geral a medicação foi bem tolerada. Também não se observou diferenças no FSC das diversas ROI analisadas. A NAC não produziu mudanças estatisticamente significativas nas escalas de sintomas e no FSC nesta amostra, apesar de outros estudos mostrarem diferenças significativas favorecendo a NAC. O presente estudo não mostrou melhora do FSC, mesmo após oito semanas, o que pode significar que a ASL pode não ser um método adequado para avaliar os efeitos cerebrais desta droga / Schizophrenia continues to be one of the most challenging psychiatric disorders in the clinical practice, despite recent studies that attempt to elucidate its pathophysiology and search for new treatment options. N-acetylcysteine (NAC) is a drug that has been used for more than 30 years in clinical medicine, in situations like acetaminophen intoxication and as mucolytic in COPD, among others. Recent studies support its therapeutic use in neuropsychiatric disorders such as depression, bipolar disorder, substance abuse and schizophrenia. The mechanism of action of NAC seems to occur in antioxidant activity, through the increase of glutathione levels (GSH) and in the modulation of glutamatergic neurotransmission. In the last two decades, the study of the neurobiological mechanisms underlying psychiatric disorders, as well as the investigation of the possible mechanisms and brain areas influenced by psychopharmacological substances received a significant contribution of functional neuroimaging techniques. Despite this, there are few studies that have evaluated the central mechanisms related to the antipsychotic properties of NAC in humans. This study aims to investigate the effects of NAC in subjects with refractory schizophrenia, exclusively on clozapine use, through measure of positive and negative symptoms and the evaluation of cerebral perfusion by magnetic resonance imaging, using the arterial spin labeling technique (ASL) . Twenty subjects with refractory schizophrenia were evaluated in a randomized, double-blind, placebo-controlled study using a dose of 2000mg per day of NAC. From the total sample, 14 had cerebral perfusion images analyzed. The study had a duration of eight weeks, with evaluations at each four weeks and MRI sessions before the beginning of NAC and at the end of the period. The results did not show statistically significant differences between placebo and NAC groups onthe BPRS and PANSS-N scales. The NAC group presented more side effects, although the medication was well tolerated in general. There were also no differences in the cerebral blood flow (CBF) among the regions of interest analyzed. Although there was no difference regarding symptoms scales the CBF in this sample, other studies found differences favoring NAC. The present study did not show changes of the CBF, which might mean that ASL is not an adequate technic to evaluate neurochemical effects of this drug

The brain; complex system people want to know about but still they are at the beginning of understanding it. There has been a lot of neuroimaging systems since developement of modern technologies and magnetic resonance imaging is one of them. In last days it isn't enough to examine only structural character of brain, the scientists are dealing with functional states more and more; the functional magnetic resonance imaging is perfectly good tool for this. There is a big amount of researches concerning individual brain regions but also a lot of them dealing with communication across the brain to clear up the causes of human behavior and functional failures. This thesis introduces the brain connectivity exploration, it uses the parcellation by anatomical atlases and it tries to use the knowledge of graph theory as one of the options to determine relations between brain centres and regions. The thesis introduces the software created for extraction of connectivity matrix resulting in graph processing and visualization.

Die funktionelle Magnetresonanztomographie (fMRT) mit einer Feldstärke von 3 T ist in der prächirurgischen Nutzen-Risiko-Evaluation von Patienten mit Hirntumoren in bzw. im Bereich funktionell bedeutsamer Regionen, wie beispielsweise in Nachbarschaft zum Sulcus centralis, gut etabliert. Das Konzept der Neuroplastizität umfasst unter anderem Mechanismen zur zerebralen kortikalen Reorganisation nach Hirnschädigung. Ziel der vorliegenden prospektiven fMRT-Verlaufsstudie ist die Evaluation der noch wenig bekannten längerfristigen funktionellen Veränderungen des Gehirns nach neurochirurgischer Intervention. Zu diesem Zwecke wurden 14 Patienten mit Hirntumoren innerhalb oder in der Nähe des primären motorischen Cortex (MI) in die Studie eingeschlossen, welche sich einer neurochirurgischen Behandlung unterzogen. Bei 12 der Patienten wurde sowohl prä- als auch postoperativ eine funktionelle Bildgebung (fMRT) anhand des motorischen Paradigmas des unimanuellen und bimanuellen Fingertappens in einem 3 T MRT-Scanner durchgeführt. Wegen Bewegungsartefakten konnten lediglich 9 der Patienten in die weitere Auswertung eingeschlossen werden. Als Kontrollgruppe diente eine einmalige Untersuchung von neun gesunden Probanden. An längerfristigen Reorganisationsmustern konnten bei Patienten ohne Handparese sowohl die Rekrutierung der geschädigten als auch der intakten Hemisphäre des kortikalen motorischen Netzwerkes aufgezeigt werden. Tumorwachstum im Bereich des supplementär-motorischen Areals (SMA) ging mit einer bilateralen Rekrutierung der rostralen Portion des SMA (SMAr) einher. Die postoperative Reorganisation des motorischen Netzwerkes umfasste unter kontraläsionalen Fingertappen eine Lateralisierung der Aktivierung der SMAr zur nicht betroffenen Hemisphäre. Diese war umso ausgeprägter je größer das Tumorvolumen oder je näher der Tumor zur SMAr gelegen war. Demnach kann eine Dysfunktion der ipsilateralen SMAr präoperativ durch eine bilaterale und postoperativ durch eine kontraläsionale Rekrutierung kompensiert werden.

Background: Serotonin has been implicated in impulsive behaviours such as temporal discounting. While animal studies and theoretical approaches suggest that reduced tonic serotonin levels increase temporal discounting rates and vice versa, evidence from human studies is scarce and inconclusive. Furthermore, an important modulator of serotonin signalling, a genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR), has not been investigated for temporal discounting so far. Objective: First, the purpose of this study was to test for a significant association between 5-HTTLPR and temporal discounting. Second, we wished to investigate the effect of high/low tonic serotonin levels on intertemporal choice and blood oxygen-level-dependent response, controlling for 5-HTTLPR. Methods: We tested the association of 5-HTTLPR with temporal discounting rates using an intertemporal choice task in 611 individuals. We then manipulated tonic serotonin levels with acute tryptophan interventions (depletion, loading, balanced) in a subsample of 45 short (S)-allele and 45 long (L)/L-allele carriers in a randomised double-blind crossover design using functional magnetic resonance imaging and an intertemporal choice task. Results: Overall, we did not find any effect of serotonin and 5-HTTLPR on temporal discounting rates or the brain networks associated with valuation and cognitive control. Conclusion: Our findings indicate that serotonin may not be directly involved in choices including delays on longer timescales such as days, weeks or months. We speculate that serotonin plays a stronger role in dynamic intertemporal choice tasks where the delays are on a timescale of seconds and hence are therefore directly experienced during the experiment.