Le trouble bipolaire est un trouble de l’humeur chronique marqué par l'alternance de dépressions, d'épisodes maniaques et de rémissions. La neuroimagerie permet l'étude de l'anatomie et du fonctionnement cérébral des patients bipolaires. Des études existantes avaient ainsi retrouvé des anomalies dans les aires du traitement des émotions chez les patients bipolaires. L'IRM anatomique avait permis de mettre en évidence certaines modifications morphométriques des régions associées (amygdale, gyrus cingulaire, thalamus) ainsi que des hypersignaux de la substance blanche. En imagerie fonctionnelle, lors du traitement d'informations émotionnelles, les patients bipolaires présentaient une hyperactivation d'un réseau ventro-limbique et une hypoactivation d'un réseau dorsal cognitif. Nous avons tout d’abord utilisé l'IRM de diffusion pour étudier la connectivité anatomique dans le trouble bipolaire. Dans une première étude, nous avons reconstruit le faisceau uncine, reliant le réseau dorsal cognitif au réseau ventro-limbique, chez 16 patients bipolaires et 16 contrôles en utilisant les techniques de suivi de fibres dites de tractographie exploitant les données d'IRM de diffusion. Les patients bipolaires avaient plus de fibres reconstruites dans le faisceau uncine gauche. Dans le même échantillon, en étudiant l'anisotropie du processus de diffusion dans tout le cerveau, nous avons également identifié une augmentation diffuse de la connectivité anatomique chez les patients. Enfin, nous avons réalisé une étude multicentrique internationale d’IRM de diffusion incluant 118 patients 10 bipolaires et 86 contrôles. Nous avons alors montré une diminution significative de l'anisotropie le long du corps calleux, du cingulum gauche et du faisceau arqué gauche chez les patients. Les patients bipolaires avec caractéristiques psychotiques avaient une anisotropie du corps calleux plus basse que les patients sans caractéristiques psychotiques. Dans une seconde partie de notre travail, nous avons étudié l'interférence produite par une information émotionnelle sur un traitement cognitif chez les patients. Nous avons comparé 17 patients bipolaires euthymiques à 17 sujets contrôles en IRM fonctionnelle lors d'un paradigme de type go/no-go émotionnel. Notre étude apporte des arguments tendant à démontrer l'existence d'une altération de la modulation par une information émotionnelle d’un traitement cognitif chez les patients avec une hyperactivation d’un réseau fronto-cingulo-striatal. Enfin, nous avons réalisé une synthèse quantitative de la littérature s'intéressant à l'imagerie anatomique, fonctionnelle et de diffusion dans le trouble bipolaire. Nous avons retrouvé chez les patients une diminution d’activation dans les tâches émotionnelles et une diminution du volume de substance grise dans des régions frontales et dorsales, tandis que sont présentes des hyperactivations dans des régions limbiques. L'ensemble de ces résultats a permis de préciser le modèle neural du trouble bipolaire avec les anomalies les plus importantes au niveau des zones impliquées dans la régulation automatique des émotions. Nos travaux ont significativement contribué à faire envisager le trouble bipolaire comme lié à des anomalies de la connectivité préfronto-limbique. Ils ouvrent aussi des perspectives de travail pour progresser dans la compréhension de sa physiopathologie. En particulier, le suivi prospectif d'une cohorte de patients permettra d'évaluer l'influence de l'évolution de la maladie bipolaire sur la structure cérébrale. Les techniques récentes d'IRM de diffusion permettront de mieux comprendre la signification physiopathologique des anomalies identifiées. Enfin, la reconceptualisation dimensionnelle proposée par le DSM-5 et le NIMH permettra probablement d'identifier des dimensions plus pertinentes que les catégories diagnostiques actuelles. / [Summary made by the web site Reverso] The bipolar disorder is a confusion of the chronic humor marked by the alternation of depressions, manic episodes and forgiveness. The neuroimaging allows the study of the anatomy and the cerebral functioning of the bipolar patients. Existing studies had so found anomalies in the areas of the treatment of the feelings at the bipolar patients. The anatomical MRI had allowed to highlight certain morphométriques modifications of the regions associated (tonsil, gyrus cingulaire, thalamus) as well as hypersignals of the white material. In functional imaging, during the processing of emotional information, the bipolar patients presented a hyperactivation of a network ventro-limbique and a hypoactivation of a cognitive dorsal network. We used first of all the MRI of distribution to study the anatomical connectivity in the bipolar disorder. In a first study, we reconstructed the beam uncine, connecting(binding) the cognitive dorsal network with the ventro-limbique network, at 16 bipolar patients and 16 controls by using the techniques of follow-up of said fibers of tractographie exploiting the data of MRI of distribution. The bipolar patients had more fibers reconstructed in the beam left uncine. In the same sample, by studying the anisotropie of the process of distribution in all the brain, we also identified a diffuse increase of the anatomical connectivity at the patients. In the same sample, by studying the anisotropie of the process of distribution in all the brain, we also identified a diffuse increase of the anatomical connectivity at the patients. Finally, we realized a study international multicentrique of MRI of distribution including 118 bipolar patients 10 and 86 controls. We then showed a significant decrease of the anisotropie along the corpus callusum, along the left(awkward) cingulum and along the left hooked beam at the patients. The bipolar patients with psychotic characteristics had an anisotropie of the corpus callusum lower than the patients without psychotic characteristics. In a second part of our work, we studied the interference produced by an emotional information about a cognitive treatment at the patients. We compared 17 bipolar patients euthymiques on 17 subjects controls in functional MRI during one paradigm of type emotional go / no-go. Our study brings arguments tending to demonstrate the existence of a change of the modulation by an emotional information of a cognitive treatment at the patients with a hyperactivation of a fronto-cingulo-striatal network. Finally, we realized a quantitative synthesis of the literature being interested in the anatomical, functional imaging and of distribution in the bipolar disorder. We found at the patient's a decrease of activation in the emotional tasks and a decrease of the volume of grey matter in frontal and dorsal regions, whereas are present hyperactivations in limbiques regions. All these results allowed to specify the neural model of the bipolar disorder with the most important anomalies at the level of zones implied in the self-regulation of the feelings. Our works significantly contributed to make envisage the bipolar disorder as bound to anomalies of the préfronto-limbique connectivity. They also open working perspectives to progress in the understanding of its physiopathology. In particular, the forward-looking follow-up of patients' troop will allow to estimate the influence of the evolution of the bipolar disease on the intellectual structure. The recent techniques of MRI of distribution will allow to understand better the physiopathological meaning of the identified anomalies. Finally, the dimensional reconceptualisation proposed by the DSM-5 and the NIMH will probably allow to identify dimensions more relevant than the current diagnostic categories.

Le but de cette thèse était d’étudier les mécanismes cérébraux sous-tendant la prise de décision sociale chez des sujets sains, l’influence des hormones stéroïdiennes gonadiques sur la flexibilité cognitive et les dysfonctionnements cérébraux sous-tendant la dévaluation de récompenses dans la maladie de Parkinson. Lors de notre premier protocole, nous avons étudié comment le fait de prendre une décision pour soi ou pour un groupe auquel nous appartenons, et lorsque nous faisons face à un seul individu ou à un groupe, influence notre aversion à l’iniquité et les régions cérébrales engagées. Nos résultats ont montré l’influence de deux réseaux cérébraux distincts dans l’aversion à l’iniquité lors de ces interactions sociales, définissant une signature cérébrale à l’effet de « discontinuité interpersonnelle/intergroupe». Notre seconde étude visait à déterminer l’influence d’un traitement hormonal substitutif sur la flexibilité cognitive, chez les femmes récemment ménopausées. De nombreuses études ont montré un effet délétère d’une supplémentation hormonale sur les fonctions cognitives, si celle-ci débute tardivement après la ménopause. Cependant, une récente hypothèse a proposé que le traitement hormonal puisse être bénéfique et neuroprotecteur contre des maladies psychiatriques, s‘il débute lors d’une courte durée à la suite du début de ménopause. Dans une étude combinant pharmacologie et IRMf, nous avons démontré une modulation par traitement hormonal sur les régions impliquées dans le contrôle cognitif chez des femmes récemment ménopausées. Notre dernière étude évalue l’effet d’un traitement dopaminergique et la présence d’un trouble du contrôle des impulsions particulier (i.e., l’hypersexualité) chez des patients atteints par la maladie de Parkinson. Nos résultats préliminaires ont montré l’influence de ces facteurs sur des régions frontales et sous-corticales spécifiques impliquées dans des choix, nécessitant l’évaluation de différents coûts (i.e., effort/attente) menant à des récompenses plus ou moins importantes. Notre thèse démontre l’intérêt de combiner les études de pharmacologie et d’IRMf pour comprendre comment les traitements hormonaux et dopaminergiques influencent les mécanismes cérébraux de la décision individuelle et sociale / The aim core of this thesis is to investigate different aspects of decision-making and flexibility in healthy and clinical populations. Specifically, we investigated the neural correlates of social decision-making in young healthy individuals, the influence of steroid hormones on cognitive flexibility in early menopausal women and cerebral dysfunctions involved in reward devaluation during decision-making process in individuals suffering of Parkinson disease. First, we studied the neural correlates of iniquity aversion when making a decision for oneself or on behalf of his own group and when facing a single individual or another group. Our results highlight influence of two distinct neural network involved in iniquity aversion during complex social exchange, outlining a neuronal explanation to interindividualintergroup discontinuity effect. Our second study, described the influence of hormone replacement therapy (i.e., HRT) on cognitive flexibility in early menopausal women. Many studies described a deleterious effect of steroid supplementation on executive cognitive functions, if it delayed after the onset of the menopause. However, “windows of opportunity” hypothesis suggests a benefic and neuroprotective effect against psychiatric disorders, if hormonal replacement therapy starts close to the beginning of menopause. Combining pharmacological and neuroimaging approaches, we showed a neuroprotective effect in brain structures involved in cognitive flexibility, in young menopausal women. Finally, our last study highlights the effect of dopaminergic treatment in Parkinsonians patients developing impulsive control disorder (i.e., hypersexuality). Preliminary results showed influence of these two factors on distinct subsystems involved in evaluation of different types of costs (i.e., effort/delay) associated with subsequent rewards. This thesis demonstrates the value of combining pharmacology studies and fMRI in order to better understand to which extent hormonal and dopaminergic treatments affect the brain mechanisms during individual and social decision-making

In neuroscience and biomedical engineering fields, one of the most important issues nowadays is finding a relationship between different brain regions when it is stimulated. Connectivity is an important research area in neuroscience which tries to determine the relationship between different brain region when the brain is stimulated externally or internally. Three main type of connectivity are discussed in this field: Anatomical, Functional and Effective connectivity. Importance of effective connectivity is its ability to detect brain disorders in early stages. Some brain disorders are Schizophrenia, MS and Major Depression disease. Comparing the effective connectivity between a healthy and unhealthy brain will help to diagnose brain disorder. In this master study, two methods named Dynamic Causal Modeling (DCM) and Psychophysiological Interaction (PPI) are used to compare effective connectivity and neuronal activity between different regions of brain when there are three different stimulations. Since the neural activity is latent in fMRI data, there is a need to a model which is able to transfer data from neuronal level to a visible data like Blood-Oxygen level dependent (BOLD) signal. DCM uses a haemodynamic balloon model (HD) to represent this data transfer. The hemodynamic model must be so that the parameters of neural and BOLD signal be the same. It should be noted that what is looked for is not the BOLD signal but the neuronal activity. In this study, as the first step, we did preprocessing of MR images and after ROI`s are created using the program MARSBAR. Ten ROIs, which are thought to have connections between them are selected by considering the stimulations used in the experiments in obtaining the data used in this thesis. The data used contains fMRI images of 11 healthy subjects. Stimulations of experiment are applied to images got from group analysis of 11 healthy subjects. These Stimulations are then used in preparing the design matrix and the parameters related to DCM. These parameters are the values related to connection matrices defining bilinear dynamic model on ROI. Bayesian method is used to select best model between all these models. Another method of PPI is also applied to analyze effective connectivity between 10 ROIs. This method considers two issues of physiological and psychological effects. Like DCM, the preprocessing steps and ROI selection is done for PPI and hemodynamic model is designed for this method. Neural and hemodynamic responses of ROIs are compared using this method.

Although the hazards of prenatal exposure to addictive substances have been documented for decades, it continues to be a prevalent social and health concern today. Alcohol and cocaine are two commonly abused substances during pregnancy, often leading to behavioral and cognitive disorders in exposed children. At present, the relationship between teratogenic effects of prenatal alcohol exposure (PAE) and prenatal cocaine exposure (PCE) on the brain and observed behavioral outcomes is still unclear. A primary reason for this incomplete understanding is the lack of information regarding neuronal functioning in these populations. Functional MRI, which measures real-time brain activation in response to certain stimuli, can be utilized to bridge the gap between known structural damage and observed behavioral outcomes. This thesis aims to examine structural and functional alterations in PAE and PCE populations as compared to unexposed, socio-economic status-matched populations. As the PAE population is highly affected by structural dysmorphology, the applicability of a newly developed diffeomorphic image registration method to this population is examined. Additionally, task-positive and task-negative functional connectivity and activity are investigated in the PAE population, and related to underlying structural alterations. Neural correlates of global arousal and emotional regulation are investigated in the PCE population, as these behavioral outcomes are most notable. Similarly, functional connectivity and activation in task-positive and task-negative networks, as well as correlated structural measures, are examined in the PCE population. The diffeomorphic image registration algorithm was found to improve both structural and functional image registration for the PAE population. In the examination of specific deficits in arithmetic processing, poorer performance in the PAE group was attributed to a multi-level effect produced by altered structural and functional connectivity and functional activity in calculation and default mode networks. Baseline arousal levels were found to be higher in adolescents with PCE as compared to healthy controls (by altered default mode network functioning); emotional regulation also appeared to be affected in the PCE group by a prefrontal-amygdala structural and functional disconnect. The findings of this thesis give insights into the relationship between task-positive and task-negative duality and cognitive impairment, and contribute to a more comprehensive understanding of the spectrum of clinical disorders caused by prenatal exposure to alcohol and cocaine.

Dans ce mémoire, nous décrivons le travail effectué pour étendre nos connaissances sur les sources d’instabilité instrumentales en imagerie de résonance magnétique, en particulier dans le domaine anatomique par une étude où cinq adultes ont été scannés quatre fois dans la même plate-forme IRM, deux fois avant et deux fois après une mise à niveau importante d’un scanner 3T de Siemens. Les volumes de l’hippocampe droit et gauche de chaque sujet ont été mesurés avec une segmentation manuelle. Nous avons analysé la fiabilité test-retest avant et après la mise à niveau du système d’IRM. Dans le domaine fonctionnel, cinq adultes ont été scannés quatre fois dans la même plate forme IRM deux fois avant et deux fois après la même mise à niveau du scanneur. Les acquisitions du signal BOLD sont faites dans deux différentes résolutions spatiales (2x2x2mm et 4x4x4mm) pour évaluer la sensibilité du signal BOLD sous conditions de haute et basse SNR. Une dernière étude fonctionnelle sur fantôme avait pour but d’étudier la stabilité de la machine pour les images fonctionnelles et détecter les sources de bruit de type machine. La séquence EPI (Echo Planar Imaging) d’écho de gradient à deux dimensions a été utilisée. Des analyses comme le pourcentage des fluctuations et l’analyse de Fourier des résidus ont également été réalisées. Nous résultats indiquent que les différences dans le matériel provenant d’une importante mise à niveau ne peuvent pas compromettre la validité des études structurelles et fonctionnelles faites à travers la mise à niveau du scanneur. Les acquisitions quotidiennes ont permis de suivre l’évolution de la stabilité et de détecter toute source de bruit qui peut détériorer la détection des activations dans les images fonctionnelles. / In this thesis, we describe work we carried out to extend our knowledge on instrumental sources of MRI variability, in both anatomical and functional imaging. The anatomical study involved five adults scanned four times in the same platform MRI twice before and twice after a major update of a 3T Siemens scanner. The volumes of left and right hippocampus of each subject were measured with a manual segmentation. We then analyzed the test-retest reliability before and after updating the MRI system. In the functional study, five adults were scanned four times on the same MRI system twice before and twice after a major hardware update. Blood oxygenation level- dependent (BOLD) acquisitions were made at two different spatial resolutions (2x2x2mm and 4x4x4mm) to assess the reproducibility of BOLD measurements under conditions of high and low SNR. A final functional study using a gel phantom was used to study the stability of the machine for functional images and isolate the sources of noise arising from hardware. Two-dimensional gradient-echo EPI (Echo Planar Imaging) signals were analyzed to assess the percentage variability and Fourier analysis of residual error performed. Our results indicate that the differences in hardware from a major upgrade do not significantly affect the reliability of structural and functional studies spanning a major hardware upgrade. Daily quality assurance acquisitions on phantoms can be used to monitor the stability of the machine, which may aid in the early detection of hardware faults.

L’étude des réseaux cérébraux en IRM fonctionnelle au repos est de plus en plus utilisée chez les patients victimes d’accidents vasculaires cérébraux. La majorité des études se sont focalisés sur les déficits moteurs, attentionnels ou phasiques. Dans ce travail, nous avons étudié l’impact du handicap global sur la connectivité fonctionnelle de grands réseaux corticaux à la phase subaiguë d’infarctus cérébraux. Ce travail a porté sur 50 patients ayant subi un premier infarctus sus-tentoriel (29 hommes, 22 AIC gauche, 57 ± 14 ans, délai médian après l’AIC = 4.5 semaines) et 75 témoins (27 hommes, 55 ± 15 ans). Sept réseaux de repos ont été étudiés à partir d’une analyse en graine et nous avons distingué pour chacun les connectivités fonctionnelles interhémisphérique, ipsi et contralésionnelle. Les 22 patients sans handicap (mRS = 0/1) avaient une connectivité normale alors qu’une diminution diffuse et bilatérale était observée chez les 28 patients avec handicap, expliquant 22% de la variance. Les analyses post-hoc ont montré que ces différences s’observaient essentiellement entre les patients sans handicap et ceux avec handicap léger et portaient surtout sur le mode par défaut et un réseau exécutif. Nous avons calculé pour chacun un score d’intégrité de la connectivité fonctionnelle permettant de résumer l’ensemble de ces altérations. Cet outil simple permettait de prédire le handicap résiduel avec une spécificité de 91% et une sensibilité de 86%. Nous avons donc observé une diminution diffuse de la connectivité fonctionnelle des réseaux de repos chez les patients ayant un handicap résiduel, alors qu’une connectivité normale marquait un excellent pronostic fonctionnel. / Resting-state functional MRI is increasingly used to investigate brain networks in stroke patients. Most studies focused specifically on motor, attentional and language deficits. Here we have investigated the relationships between global post-stroke disability and functional connectivity of seven major cortical networks in subacute ischemic stroke patients. We have studied 50 patients with first-ever unilateral hemispheric stroke (29 men, 22 left strokes, 57 ± 14 years) with a median post-stroke delay of 4.5 weeks and 75 healthy volunteers (27 men, 55 ± 15 years). Seven cortical networks were characterized with a seed-based approach and for each network we distinguished inter-hemispheric, ipsi- and contra-lesional functional connectivity. The 22 patients without disability (modified Rankin’s scale 0-1) had normal functional connectivity in all networks whereas the 28 disabled patients had widespread and bilateral decreases in functional connectivity explaining 22 % of the variance. Secondary analyses showed that abnormalities mainly differentiate no disability from mild disability and may predominate in default-mode and top-down control networks. We have computed for each subject a functional connectivity index that summarizes all these abnormalities. This simple tool was strongly predictive of residual disability with a specificity of 91% and a sensitivity of 86%. In conclusion, widespread and bilateral alterations in cortical connectivity occur in disabled subacute stroke patients, whereas normal indicate excellent global outcome.

An MRI’s superior soft tissue contrast and ability to perform parametric scanning make it a powerful tool for use during medical procedures; from surgery to rehabilitation. However, the MRI’s strong static magnetic field, fast switching gradients and constrained space make accomplishing procedures within it difficult. Recent advances in the field of robotics have enabled the creation of devices capable of assisting medical practitioners in this environment. In this work, technologies to enable the use and control of robotic assistive devices for MRI interventions are presented. This includes a modular controller that is designed, built and used to control two surgical systems with minimal effect on image quality. Progressive improvements to an MRI conditional actuator including the construction of a first of a kind plastic piezoelectric resonant motor stator that improves the motor’s compatibility with the MRI is presented. Finally, control algorithms are evaluated for real-time functional MRI based control of a rehabilitation robot which includes the use of a robot for controlling brain activity of a subject in an online experiment.

付記する学位プログラム名: 京都大学卓越大学院プログラム「先端光・電子デバイス創成学」 / 京都大学 / 新制・課程博士 / 博士(工学) / 甲第23205号 / 工博第4849号 / 新制||工||1757(附属図書館) / 京都大学大学院工学研究科電気工学専攻 / (主査)教授 小林 哲生, 教授 松尾 哲司, 特定教授 中村 武恒 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

An MRI’s superior soft tissue contrast and ability to perform parametric scanning make it a powerful tool for use during medical procedures; from surgery to rehabilitation. However, the MRI’s strong static magnetic field, fast switching gradients and constrained space make accomplishing procedures within it difficult. Recent advances in the field of robotics have enabled the creation of devices capable of assisting medical practitioners in this environment. In this work, technologies to enable the use and control of robotic assistive devices for MRI interventions are presented. This includes a modular controller that is designed, built and used to control two surgical systems with minimal effect on image quality. Progressive improvements to an MRI conditional actuator including the construction of a first of a kind plastic piezoelectric resonant motor stator that improves the motor’s compatibility with the MRI is presented. Finally, control algorithms are evaluated for real-time functional MRI based control of a rehabilitation robot which includes the use of a robot for controlling brain activity of a subject in an online experiment.

The research performed in this thesis aims to improve our understanding about one of the most malignant tumors of the human brain – glioma. From the early stages of my career I was confronted with the cruel reality of losing patients due to this devastating disease. The studies performed over the last four years involve extensive data analysis in different clinical and laboratory settings. The direct application of different analysis methods and tools in order to investigate the glioma infiltration delineation has potentially lead to direct applications of our results in the clinical setting. The overall approach of the study is based on three primary outcome measures, i.e., neuronal, electrophysiological and genetic/molecular features for distinguishing infiltrated and non-infiltrated zones within specifically peritumoral tissue (PT) and, more extensively, across the radiologically-defined boundaries of healthy, peritumoral and tumoral tissues. As such, we propose for the first time an objective demarcation and characterization of the PT and we detail how the genetic and epigenetic alterations within the tumoral and peritumoral area are linked with macroscopic functional MRI results. We also describe scale-free features (power law exponent) as well as distinct spectral features and reactivity to external stimulus in the tumoral and adjacent tissue of patients and provide novel insights in terms of glioma’s electrophysiology. The insights gained from these empirical studies further improve our understanding about the pathophysiology of this disease at micro- and macroscopic scales allowing us to envisage novel management methods for patients affected by glioma.