SUMMARY Non Rapid Eye Movement (NREM) sleep in humans is defined by spontaneous neural activities organized by specific rhythms or oscillations. The aim of this thesis is to characterize, by means of neuroimaging techniques, the shaping of brain function by these physiological rhythms. The studied oscillations are sleep spindles, delta waves and slow oscillation, representing the main identifiable neurophysiological events of human NREM sleep. Sleep spindles are a hallmark of light NREM sleep. They are commonly described on electroencephalographic (EEG) recordings as 11-15 Hz oscillations, lasting more than 0.5 sec and with a typical waxing-and-waning waveform. During deeper stages of NREM sleep, spindles are progressively replaced by a slow wave activity (SWA; 0.5-4 Hz), which encompasses delta waves (1-4 Hz) and slow oscillations (0.5-1 Hz). In combination with EEG, we studied these rhythms using two different functional brain imaging techniques : positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These studies originally contribute to the understanding of the generating mechanisms and functional roles of NREM sleep oscillations, which are a hallmark of sleep architecture in healthy humans. Neural correlates of NREM sleep oscillations assessed by EEG / PET In this section, we report the analyses of PET data devoted to the study of NREM sleep oscillations. We characterized the brain areas in which activity, measured in terms of regional cerebral blood flow (rCBF), was correlated with EEG spectral power in the spindle (11-15 Hz), delta waves (1-4 Hz) and slow oscillation (0.5-1 Hz) frequency bands, in 23 non-sleep-deprived young healthy volunteers. EEG activity in the spindle frequency band was negatively correlated with rCBF in the thalamus. This result was in agreement with data suggesting the generation of spindles within cortico-thalamo-cortical loops (Steriade, 2006). Spectral power in the delta band was negatively correlated with rCBF in the medial prefrontal cortex, striatum, insula, anterior cingulate cortex, precuneus and basal forebrain, which are structures potentially involved in the modulation of cortical delta waves (Dang-Vu et al., 2005b). The functional brain mapping of slow oscillations was highly similar to the one of delta waves, in keeping with the hypothesis that both types of oscillations share common physiological mechanisms. These results consisted in negative correlations, which means that the cerebral blood flow in these areas was lower when the power in the corresponding frequency band was higher. The different rhythms of NREM sleep are synchronized by the slow oscillation, which alternates a hyperpolarization phase during which cortical neurons remain silent, and a depolarization phase associated with important neuronal firing. The prominent effect of hyperpolarization phases could account for the decrease in blood flow found in PET studies. Indeed, PET has a limited temporal resolution, around one minute, and therefore averages brain activity over relatively long periods, during which hyperpolarization phases predominate. Thus PET imaging does not allow to directly study brief events, lasting one second or so, such as NREM sleep oscillations. Besides, the spectral power values used in PET studies are just an indirect reflection of the appearance of these rhythms during sleep. These considerations justify the use of fMRI because, together with improved spatial resolution, its temporal resolution around one second allows to assess brain responses associated to the occurrence of NREM sleep oscillations, taken as identifiable events. Neural correlates of NREM sleep oscillations assessed by EEG / fMRI The largest section of the thesis is devoted to the use of fMRI in the study of NREM sleep oscillations. We characterized the brain areas in which activity, measured in terms of blood oxygen level dependent (BOLD) signal, was correlated with the occurrence of NREM sleep oscillations. Compared to EEG with PET, EEG recording with simultaneous fMRI was technically much more challenging. In particular, the analysis of EEG data acquired simultaneously with fMRI required a complex signal processing in order to remove all artefacts induced during the scanning procedure. After clean EEG data had been obtained, automatic detection of spindles (Molle et al., 2002), delta waves and slow oscillations (Massimini et al., 2004) was performed according to published criteria, and provided the series of events to be used as regressors in the statistical analysis of fMRI data. The latter assessed the main effects of spindles, delta waves and slow oscillations on BOLD signal changes across the 14 non-sleep-deprived young healthy volunteers selected for this study. Spindles were analysed considering 2 potential subtypes. Indeed, in humans, while most spindles are recorded in central and parietal regions and display a frequency around 14 Hz (fast spindles), others are prominent on frontal derivations with a frequency around 12 Hz (slow spindles). Previous data also show differences between both subtypes in their modulation by age, circadian and homeostatic factors, menstrual cycle, pregnancy and drugs (De Gennaro and Ferrara, 2003). However, no clear evidence of a distinct neurobiological basis for these two subtypes of spindles has been demonstrated so far. After automatic detection of spindles and their differentiation as fast and slow, we showed that the two subtypes were associated with activation of partially distinct thalamo-cortical networks. These data further support the existence of 2 subtypes of sleep spindles modulated by segregated neural networks (Schabus et al., 2007). Slow oscillation has initially been described at the cellular level in animals as an oscillation <1 Hz of membrane potential, alternating a hyperpolarization phase (down) during which cortical neurons are silent and a depolarization phase (up) associated with intense neuronal firing (Steriade, 2006). At the macroscopic level, this slow rhythm is found on human EEG recordings as high amplitude slow waves, defined by a peak-to-peak amplitude of more than 140 µV (Massimini et al., 2004). The slow oscillation also synchronizes other NREM sleep rhythms such as spindles (Molle et al., 2002) and delta waves (defined here as waves of lower peak-to-peak amplitude : between 75 and 140 µV). The organization of NREM sleep by the slow oscillation suggests that NREM sleep should be characterized by increased brain activities associated with the up state of slow oscillation. Indeed, we observed significant BOLD signal changes in relation to both slow waves and delta waves in specific brain areas including inferior and medial frontal gyrus, parahippocampal gyrus, precuneus, posterior cingulate cortex, ponto-mesencephalic tegmentum and cerebellum. All these responses consisted in brain activity increases. These results stand in sharp contrast with earlier sleep studies, in particular PET studies, reporting decreases in brain activity during NREM sleep. Here we showed that NREM sleep cannot be reduced to a state of global and regional brain activity decrease, but is actually an active state during which phasic increases in brain activity are synchronized to the slow oscillation. We then compared brain responses to delta and slow waves respectively and found no significant difference. In agreement with our PET data, this result suggests that slow waves and delta waves share common neurobiological mechanisms. However, when effects of slow and delta waves were tested separately, we observed that slow waves were specifically associated with activation of brainstem and mesio-temporal areas, while delta waves were associated with activation of inferior and medial frontal areas. This result is important in regard to the potential role of slow oscillation in memory consolidation during sleep (Marshall et al., 2006). Indeed, the preferential activation of mesio-temporal areas with high amplitude slow waves suggests that the amplitude of the wave is a crucial factor in the recruitment during sleep of brain structures involved in the processing of memory traces. RESUME Le sommeil lent de lhomme est défini par la présence dactivités neuronales spontanées, organisées sous forme de rythmes ou oscillations spécifiques. Lobjectif des travaux réalisés dans le cadre de cette thèse est de caractériser, par des méthodes de neuroimagerie, le fonctionnement cérébral au cours de ces rythmes physiologiques. Les oscillations que nous avons étudiées sont les fuseaux du sommeil, les ondes delta et les oscillations lentes, représentant les principales activités neurophysiologiques identifiables chez lhomme au cours du sommeil lent. Les fuseaux du sommeil constituent un élément essentiel du sommeil lent léger. Ils sont communément décrits sur les enregistrements électroencéphalographiques (EEG) comme des oscillations de fréquence comprise entre 11 et 15 Hz, dune durée dau moins 0,5 sec, et de morphologie caractéristique daugmentation puis de diminution damplitude. Au cours des stades plus profonds de sommeil lent, les fuseaux sont en grande partie remplacés par une activité donde lente (SWA; 0,5-4 Hz) qui recouvre les ondes delta (1-4 Hz) et les oscillations lentes (0,5-1 Hz). En combinaison à lEEG, nous avons utilisé deux techniques dimagerie fonctionnelle différentes pour étudier ces rythmes: la tomographie par émission de positons (PET) et limagerie en résonance magnétique fonctionnelle (fMRI). Ces études apportent une contribution originale à notre compréhension du sommeil lent chez lhomme sain, par lexploration des mécanismes générationnels de ces oscillations, piliers de larchitecture du sommeil. Corrélats cérébraux des rythmes du sommeil lent en EEG / PET Dans cette section, nous décrivons lutilisation de la PET dans létude des rythmes du sommeil lent. Nous avons caractérisé les régions cérébrales dans lesquelles lactivité, mesurée en terme de débit sanguin cérébral régional (rCBF), était corrélée à la puissance spectrale EEG dans la bande de fréquence des fuseaux (11-15 Hz), des ondes delta (1-4 Hz) et des oscillations lentes (0.5-1 Hz), chez 23 jeunes volontaires sains et non privés de sommeil. Lactivité EEG dans la bande des fuseaux était corrélée négativement avec le rCBF dans le thalamus. Ce résultat est en accord avec les données suggérant la genèse des fuseaux par des boucles dinteraction cortico-thalamo-corticale (Steriade, 2006). La puissance spectrale dans la bande delta était négativement corrélée avec le rCBF au niveau du cortex préfrontal médial, du striatum, de linsula, du cortex cingulaire antérieur, du précuneus et du télencéphale basal, régions potentiellement impliquées dans la modulation des ondes delta corticales (Dang-Vu et al., 2005b). La carte des oscillations lentes était superposable à celle des ondes delta, ce qui suggère que ces deux types doscillations relèvent chez lhomme de mécanismes physiologiques communs. Ces résultats démontraient donc des corrélations négatives, ce qui signifie que le débit sanguin cérébral dans ces régions était dautant plus faible que la puissance dans la bande de fréquence correspondante était élevée. Linterprétation de ce phénomène doit intégrer le fait que les différents rythmes du sommeil lent sont sculptés par loscillation lente, laquelle alterne une phase dhyperpolarisation au cours de laquelle les neurones corticaux sont silencieux, et une phase de dépolarisation au cours de laquelle ils déchargent en bouffées. Leffet prépondérant des phases dhyperpolarisation pourrait expliquer la baisse de débit cérébral démontrée en PET. En effet, cette dernière présente une résolution temporelle limitée, de lordre de la minute, ce qui a pour effet dintégrer lactivité cérébrale sur des périodes de temps relativement longues, au cours desquelles les phases dhyperpolarisation corticale prédominent. Limagerie en PET ne permet pas donc pas détudier directement des événements brefs de lordre de la seconde, tels que les oscillations du sommeil lent. En outre, les valeurs de puissance spectrale utilisées pour caractériser ces rythmes en PET ne reflètent quindirectement leur survenue au cours du sommeil. Ces considérations justifient le recours à limagerie en fMRI, dont la résolution temporelle de lordre de la seconde permet dévaluer les réponses cérébrales associées à la survenue des oscillations du sommeil lent, considérées cette fois comme des événements identifiables. Corrélats cérébraux des rythmes du sommeil lent en EEG / fMRI Dans cette partie, la plus importante, nous décrivons lanalyse en fMRI des rythmes du sommeil lent. Nous avons caractérisé les régions cérébrales dont l'activité, mesurée par le signal BOLD, était corrélée à la survenue des oscillations du sommeil lent. Par rapport à la situation rencontrée en PET, lenregistrement des données EEG nécessaire à la détection des rythmes du sommeil lent, simultanément à lacquisition fMRI, a posé des difficultés techniques considérablement plus grandes. En particulier, linterprétation de lEEG dans ces conditions a nécessité un traitement précis du signal afin den éliminer les éléments artéfactuels qui le contaminent. Ce nest quaprès ce processus que la détection automatique des fuseaux (Molle et al., 2002), des ondes delta et des oscillations lentes (Massimini et al., 2004) selon des critères publiés a pu seffectuer, permettant dobtenir les séries dévénements qui furent entrés comme régresseurs dans lanalyse statistique des données fMRI. Cette dernière évalue leffet principal des fuseaux, ondes delta et oscillations lentes sur les variations du signal BOLD chez lensemble des 14 jeunes volontaires sains et non privés de sommeil sélectionnés pour létude. En ce qui concerne les fuseaux, ils furent subdivisés en 2 sous-types. Chez lhomme en effet, alors que la grande majorité des fuseaux sont enregistrés dans les régions centrales et pariétales, avec une fréquence denviron 14 Hz (fuseaux rapides), dautres fuseaux dits lents (environ 12 Hz) prédominent dans les régions frontales. Des données antérieures rapportent également des différences entre ces deux sous-types en ce qui concerne leur modulation par des paramètres comme lâge, les facteurs circadiens et homéostatiques, la phase du cycle menstruel, la grossesse et certains agents pharmacologiques (De Gennaro and Ferrara, 2003). Cependant, aucune description formelle dun substrat biologique distinct navait encore été établie pour ces 2 sous-types de fuseaux. Après détection automatique des fuseaux et leur ségrégation en fuseaux rapides et lents, nous avons pu démontrer que les 2 sous-types de fuseaux étaient associés à des activations dans des réseaux thalamo-corticaux partiellement distincts. Ces données apportent donc des arguments pour établir lexistence de 2 sous-types biologiquement différenciés de fuseaux du sommeil (Schabus et al., 2007). Loscillation lente du sommeil lent a été décrite initialement au niveau cellulaire chez lanimal comme une oscillation de fréquence <1Hz et qui alterne une phase dhyperpolarisation (ou down), au cours de laquelle les neurones corticaux sont silencieux, et une phase de dépolarisation (ou up) qui correspond à une période de décharges neuronales intenses (Steriade, 2006). Chez lhomme, cette oscillation lente est également retrouvée sur les enregistrements EEG de surface sous forme dondes lentes de haute amplitude, définies par une amplitude pic-à-pic de plus de 140 µV (Massimini et al., 2004). Loscillation lente synchronise aussi dautres rythmes du sommeil lent tels les fuseaux (Molle et al., 2002) et les ondes delta (définies ici par des ondes de plus basse amplitude pic-à-pic : entre 75 et 140 µV). Lorganisation du sommeil lent par ces oscillations lentes suggère que le sommeil lent devrait être marqué par des activations cérébrales survenant en synchronie avec les phases up des oscillations lentes. De fait, nous avons observé des variations significatives de signal BOLD en association avec les ondes lentes et delta dans des régions cérébrales spécifiques incluant le gyrus frontal inférieur et médial, le gyrus parahippocampique, le precuneus, le cortex cingulaire postérieur, le tegmentum ponto-mésencéphalique et le cervelet. Ces variations étaient positives dans toutes les régions mises en évidence, ce qui traduit une augmentation dactivité. Ces résultats sont originaux en ce quils suggèrent que le sommeil lent, contrairement à ce qui était conclu des précédentes études du sommeil chez lhomme (particulièrement en PET), ne se réduit pas à une hypoactivation cérébrale globale et régionale. Au contraire, nos données montrent que le sommeil lent saccompagne dune activation cérébrale phasique rythmée par la phase de dépolarisation des oscillations lentes. Nous avons ensuite comparé les réponses cérébrales aux ondes delta et celles aux ondes lentes. Aucune région cérébrale ne présentait dactivité significativement différente en fonction des 2 types dondes. En accord avec nos données PET, ce résultat suggère quil ny a pas de différence formelle sur le plan des mécanismes neurobiologiques entre ondes lentes et ondes delta. Toutefois, lorsque les effets des ondes lentes et delta furent testés séparément, nous avons observé que les ondes lentes activaient spécifiquement le tronc cérébral et le cortex mésio-temporal alors que les ondes delta activaient les aires frontales inférieure et médiale. Cet résultat est important si lon considère en particulier le rôle potentiel des oscillations lentes dans la consolidation des traces mnésiques au cours du sommeil (Marshall et al., 2006). Lactivation préférentielle des aires mésio-temporales avec les ondes lentes de haute amplitude suggère en effet que lamplitude de londe est un paramètre déterminant dans le recrutement au cours du sommeil de structures cérébrales impliquées dans le traitement des traces mnésiques.

Theory of Mind (ToM) is the ability to infer others’ mental states and thus to predict their behavior (Perner, 1991). Therefore, ToM is essential for the adequate adjustment of behavior in social situations. ToM can be divided into: 1) cognitive ToM encompassing inferences about intentions and beliefs and 2) affective ToM encompassing inferences about emotions (Shamay-Tsoory, Harari, Aharon-Peretz, & Levkovitz, 2010). Well-functioning skills of both ToM aspects are much-needed in the developmental period of adolescence because in this age phase peer relationships become more important and romantic relationships arise (Steinberg & Morris, 2001). Importantly, affective psychopathological disorders often have their onset in adolescence. ToM development in adolescence might be based on underlying cognitive mechanisms such as the ability to inhibit one’s own thoughts in order to understand another person’s thoughts (Carlson & Moses, 2001). Another possible mechanism relates to functional brain development across adolescence (Blakemore, 2008). Therefore, neurocognitive mechanisms may underlie ongoing ToM development in adolescence. First studies indicate an ongoing behavioral and functional brain development of ToM (e.g. Blakemore, 2008). However, ToM development in adolescence and how this might relate to underlying (neuro)cognitive functions remains largely underexamined. The major aims of the current thesis were first to answer the overall question whether there is an ongoing development of ToM in adolescence. This question relates to both behavioral and functional brain development. As a second major aim, the present work sought to elucidate possible (neuro)cognitive mechanisms of ongoing ToM development across adolescence. Specifically, these cognitive mechanisms might be basic cognitive functions as well as executive functions. Additionally, the present work aimed at exploring potential (neuro)cognitive mechanisms through an integration of both behavioral and functional brain studies. The current experimental work spans three cross-sectional studies investigating adolescents (aged around 12-15 years) and young adults (aged around 18-22 years) to examine for the first time both the behavioral (studies I and II) and functional brain development of ToM (study III) in adolescence and its underlying (neuro)cognitive mechanisms. In all three studies, more complex, advanced ToM tasks were employed to avoid ceiling effects. Study I was aimed at investigating if cognitive and affective ToM continues to develop in adolescence and at exploring if basic cognitive variables such as verbal ability, speed of processing, and working memory capacity underlie such development. Hence, two groups of adolescents and young adults completed tasks of ToM and basic cognitive abilities. Large age effects were revealed on both measures of ToM: adolescents performed lower than adults. These age differences remained significant after controlling for basic cognitive variables. However, verbal ability covaried with performance in affective ToM. Overall, results support the hypothesis of an ongoing development of ToM from adolescence to adulthood on both cognitive and affective aspects. Results may further indicate verbal ability being a basic cognitive mechanism of affective ToM. Study II was designed to further explore if affective ToM, as measured with a dynamic realistic task, continues to develop across adolescence. Importantly, this study sought to explore executive functions as higher cognitive mechanisms of developing affective ToM across adolescence. A large group spanning adolescents and young adults evaluated affective mental states depicted by actors in video clips. Additionally, participants were examined with three subcomponents of executive functions, inhibition, updating, and shifting following the classification of Miyake et al. (2000). Affective ToM performance was positively related to age and all three executive functions. Specifically, inhibition explained the largest amount of variance in age related differences of affective ToM performance. Overall, these results indicate the importance of inhibition as key underlying mechanism of developing an advanced affective ToM in adolescence. Study III set out to explore the functional brain development of affective ToM in adolescence by using functional magnetic resonance imaging (fMRI). The affective ToM measure was the behavioral developmentally sensitive task from study II. An additional control condition consisted of the same emotional stimuli with the instruction to focus on physical information. This study faced methodical challenges of developmental fMRI studies by matching performance of groups. The ventromedial prefrontal cortex (vMPFC) was significantly less deactivated in adolescents in comparison to adults, which might suggest that adolescents seem to rely more on self-referential processes for affective ToM. Furthermore, adolescents compared to adults showed greater activation in the dorsolateral prefrontal cortex (DLPFC) in the control condition, indicating that adolescents might be distracted by the emotional content and therefore needed to focus more on the physical content of the stimulus. These findings suggest affective ToM continues to develop on the functional brain level and reveals different underlying neurocognitive strategies for adolescents in contrast to adults. In summary, the current thesis investigated whether ToM continues to develop in adolescence until young adulthood and explored underlying (neuro)cognitive mechanisms. Findings suggest that there is indeed an ongoing development of both the cognitive and affective aspect of ToM, which importantly contributes to the conceptual debate. Moreover, the second benefit to the debate is to demonstrate how this change may occur. As a basic cognitive mechanism verbal ability and as an executive functioning mechanism inhibition was revealed. Furthermore, neurocognitive mechanisms in form of different underlying neurocognitive strategies of adolescents compared to adults were shown. Taken together, ToM development in adolescence seems to mirror a different adaptive cognitive style in adolescence (Crone & Dahl, 2012). This seems to be important for solving the wealth of socio-emotional developmental tasks that are relevant for this age span.

L'application de classifieurs linéaires à l'analyse des données d'imagerie cérébrale (fMRI) a mené à plusieurs percées intéressantes au cours des dernières années. Ces classifieurs combinent linéairement les réponses des voxels pour détecter et catégoriser différents états du cerveau. Ils sont plus agnostics que les méthodes d'analyses conventionnelles qui traitent systématiquement les patterns faibles et distribués comme du bruit. Dans le présent projet, nous utilisons ces classifieurs pour valider une hypothèse portant sur l'encodage des sons dans le cerveau humain. Plus précisément, nous cherchons à localiser des neurones, dans le cortex auditif primaire, qui détecteraient les modulations spectrales et temporelles présentes dans les sons. Nous utilisons les enregistrements fMRI de sujets soumis à 49 modulations spectro-temporelles différentes. L'analyse fMRI au moyen de classifieurs linéaires n'est pas standard, jusqu'à maintenant, dans ce domaine. De plus, à long terme, nous avons aussi pour objectif le développement de nouveaux algorithmes d'apprentissage automatique spécialisés pour les données fMRI. Pour ces raisons, une bonne partie des expériences vise surtout à étudier le comportement des classifieurs. Nous nous intéressons principalement à 3 classifieurs linéaires standards, soient l'algorithme machine à vecteurs de support (linéaire), l'algorithme régression logistique (régularisée) et le modèle bayésien gaussien naïf (variances partagées). / The application of linear machine learning classifiers to the analysis of brain imaging data (fMRI) has led to several interesting breakthroughs in recent years. These classifiers combine the responses of the voxels to detect and categorize different brain states. They allow a more agnostic analysis than conventional fMRI analysis that systematically treats weak and distributed patterns as unwanted noise. In this project, we use such classifiers to validate an hypothesis concerning the encoding of sounds in the human brain. More precisely, we attempt to locate neurons tuned to spectral and temporal modulations in sound. We use fMRI recordings of brain responses of subjects listening to 49 different spectro-temporal modulations. The analysis of fMRI data through linear classifiers is not yet a standard procedure in this field. Thus, an important objective of this project, in the long term, is the development of new machine learning algorithms specialized for neuroimaging data. For these reasons, an important part of the experiments is dedicated to studying the behaviour of the classifiers. We are mainly interested in 3 standard linear classifiers, namely the support vectors machine algorithm (linear), the logistic regression algorithm (regularized) and the naïve bayesian gaussian model (shared variances).

Positron emission tomography (PET) is a functional imaging method that allows studying physiological, biochemical or pharmacological processes in vivo. PET is being used in both research and clinical practice. In the brain, it has been used to investigate metabolism, receptor binding, and alterations in regional blood flow. This thesis involves both preclinical and clinical dual-tracer PET imaging studies of different neurological disorders. In this way, different radiotracers were used along the projects. The first project focused on the implementation and in vivo validation of the simultaneous dual-tracer PET imaging technique on the rat brain and its applications in the study of cerebral ischemia. In particular, in this project two biological processes were studied at the same time: cerebral blood flow and cerebral glucose metabolism. The second project consisted in a clinical correlation study of the GABAergic and serotonin systems in a population with Essential Tremor (ET), the most commonly movement disorders. / La tomografia per emissió de positrons (PET) és un mètode d'imatge funcional que permet l'estudi in vivo de processos fisiològics, bioquímics i farmacològics. La PET s'utilitza tant en la pràctica clínica com en la recerca. Al cervell, s'ha utilitzat per investigar el metabolisme, la neurotransmissió, i les alteracions en el flux sanguini regional. Aquesta tesi implica estudis preclínics i clínics de la tècnica PET en diversos trastorns neurològics. D'aquesta manera, es van utilitzar diferents radiotraçadors al llarg dels projectes. El primer projecte es va centrar en la implementació i validació in vivo de la tècnica PET del doble-marcador simultani en el cervell de rata i les seves aplicacions en l'estudi de la isquèmia cerebral. En particular, en aquest projecte es van estudiar en el mateix moment dos processos biològics: el flux sanguini cerebral i el metabolisme cerebral de la glucosa. El segon projecte va consistir en un estudi clínic de correlació dels sistemes GABAèrgic i serotoninèrgic en una població amb tremolor essencial (TE), el trastorn del moviment més comú

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Introdução: A esclerodermia é rara doença do tecido conectivo que se manifesta através da esclerose cutânea e variável acometimento sistêmico. Duas categorias de esclerodermia são conhecidas: esclerose sistêmica, caracterizada por esclerose cutânea e acometimento visceral e a esclerodermia localizada ou morfeia que classicamente apresenta evolução benigna e autolimitada, confinada a pele e/ou tecidos subjacentes. Estudos recentes demonstram que a forma localizada possa eventualmente apresentar acometimento de órgãos internos e morbidade variável. Objetivo: Neste estudo objetivamos determinar as características demográficas, a prevalência de manifestações sistêmicas e alterações laboratoriais, bem como a associação com doenças autoimunes, em pacientes com esclerodermia da face. Métodos: Pacientes com esclerodermia localizada, incluindo os casos de esclerodermia em golpe de sabre, síndrome de Parry-Romberg e morfeia em placas com acometimento facial, foram avaliados e submetidos à investigação neurológica, incluindo exame clínico neurológico e ressonância magnética de crânio, e avaliação oftalmológica. Após 3 anos, o subgrupo de pacientes disponível para seguimento foi ressubmetido à ressonância magnética. Resultados: Foram estudados 34 pacientes com esclerodermia localizada da face. Deste total, 64,7% apresentavam uma ou mais manifestações extracutâneas, sendo cefaleia a queixa mais frequente, encontrada em 61,8% dos pacientes. Dos 23 pacientes submetidos à avaliação neurológica, 56,5% apresentaram alterações neurológicas possivelmente associadas à esclerodermia. Alterações à ressonância magnética foram observadas em 50% dos casos. O achado mais frequente foi a presença de lesões parenquimatosas com alteração de sinal em 50% dos pacientes. Dos pacientes que apresentavam alteração neurológica, 80% também apresentavam alguma alteração à ressonância magnética. Doze pacientes foram ressubmetidos a novo exame após 3 anos. Em todos os pacientes os achados de imagem se mantiveram inalterados. Durante esse intervalo de 3 anos, 25% dos pacientes apresentaram sinais de atividade da esclerodermia. Quanto à avaliação oftalmológica, 67,9% dos pacientes avaliados apresentaram alteração, sendo os achados mais frequentes a ocorrência de alterações orbiculares da esclerodermia (20,6%) e xeroftalmia (10,7%). Conclusão: Pacientes com esclerodermia localizada da face apresentam alta prevalência de alterações neurológicas e oftalmológicas. Baseado nestes achados, sugerimos que todos os casos de esclerodermia localizada da face devam ser detalhadamente examinados quanto à presença de alterações sistêmicas / Introduction: Scleroderma is a rare connective tissue disease that manifests as skin sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement and localized scleroderma or morphea which classically presents benign evolution and selflimited, confined to the skin and / or underlying tissue. Recent studies show that the localized form may possibly course with involvement of internal organs and variable morbidity. Objective: This study aimed to determine the demographic characteristics, the prevalence of systemic manifestations and laboratory findings, as well as the association with autoimmune diseases, in patients with scleroderma of the face. Methods: Patients with localized scleroderma, including cases of scleroderma en coup de sabre, Parry-Romberg syndrome and morphea plaque with facial involvement were evaluated and underwent neurological examination, including neurologic examination and magnetic resonance imaging, and ophthalmology evaluation. After 3 years, the subgroup of patients available for follow-up was subjected again to MRI. Results: We studied 34 patients with localized scleroderma of the face. Of this total, 64,7% had one or more extracutaneous manifestation, headache being the most frequent complaint found in 61,8% of patients. Of the 23 patients undergoing neurological evaluation, 56,5% had neurological changes possibly associated with scleroderma. MRI changes were observed in 50% of cases. The most frequent was the presence of parenchymal lesions with signal alteration in 50% of patients. Of the patients who had neurological deficits, 80% also had a change to MRI. Twelve patients were subjected again to another MRI scan after 3 years. In all patients, imaging findings were unchanged. During this interval of 3 years, 25% of patients showed signs of activity of scleroderma. As for ophthalmologic evaluation, 67,9% of patients showed abnormalities, with the most frequent findings being the occurrence of orbicular changes of scleroderma (20.6%) and xerophthalmia (10.7%). Conclusion: Patients with localized scleroderma face have a high prevalence of neurological and ophthalmological changes. Based on these findings, we suggest that all cases of localized scleroderma of the face should be thoroughly examined for the presence of systemic changes

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico que acomete cerca de 1 a 3,1% das pessoas ao longo da vida. Embora o seu modelo neurobiológico ainda não esteja completamente estabelecido, inúmeras evidências apontam para áreas relacionadas ao circuito córtico-estriado-pálido-talâmico-cortical (CEPTC). Em especial, o córtex órbito-frontal (COF) é uma região que desempenha um papel fundamental dentro da hipótese fisiopatológica do TOC. Paralelamente, esta região já foi associada, em sujeitos saudáveis, com a habilidade de utilização espontânea da estratégia de agrupamento semântico na memorização de palavras - o que facilita sua evocação posterior. Ao mesmo tempo, estudos neuropsicológicos evidenciaram que pacientes com TOC apresentam déficits na memória episódica verbal (MEV) e que tais déficits poderiam ser mediados por dificuldades em funções executivas ligadas ao planejamento, como utilização de estratégias. Portanto, para testar a hipótese de que há diferenças no correlato neural da codificação da MEV entre pacientes com TOC e controles saudáveis, foi utilizado um teste neuropsicológico adaptado para ressonância magnética funcional (RMf): o paradigma tinha apresentação em bloco. O objetivo do presente estudo foi investigar a etapa de codificação da MEV e a capacidade de agrupamento semântico espontâneo em crianças e adolescentes com TOC. Assim, o paradigma foi constituído por duas listas de palavras: uma, semanticamente relacionada (SR), na qual as palavras eram divididas em categorias semânticas e outra, não relacionada (NR), na qual não havia relação aparente entre as palavras. O contraste de maior interesse do estudo foi a diferença entre essas duas condições (SR > NR). O nível de agrupamento semântico foi quantificado por um índice semântico. Os grupos foram formados por 25 crianças e adolescentes com TOC e 25 controles saudáveis, pareados por sexo, idade, escolaridade, preferência manual e QI. Embora os grupos estivessem pareados por essas características, eles se diferiram em sintomas clínicos, tais como sintomas de depressão, ansiedade e necessidade de rotina por parte da criança/adolescente. Os resultados comportamentais do teste de MEV mostraram que os grupos não se diferenciaram: ambos evocaram a mesma quantidade de palavras e não apresentaram diferenças no índice semântico. Apesar disso, a comparação entre os grupos - controlada para variáveis clínicas - revelou menor ativação (sinal BOLD) nos pacientes em diversas regiões cerebrais: frontais, parietais e occipito-temporais. Por outro lado, a análise de interação psicofisiológica (PPI) revelou que os pacientes apresentaram um aumento da conectividade do COF com regiões temporais em relação aos controles. Isso ocorreu para três das quatro regiões de interesse que foram posicionadas no COF: lateral e medial de ambos os hemisférios. Além disso, o grupo de pacientes apresentou uma correlação positiva entre o índice semântico e o efeito BOLD no COF, o que não ocorreu para o grupo controle. Esses resultados indicam diferenças no funcionamento cerebral de crianças e adolescentes com TOC tanto em regiões que estão dentro do modelo neurobiológico proposto para o TOC (circuito CEPTC), como fora dele também. De acordo com os resultados do presente estudo, as diferenças de ativação e de conectividade poderiam ser consideradas como um déficit latente, uma vez que ambos os grupos apresentaram o mesmo desempenho no paradigma / The obsessive-compulsive disorder (OCD) is a psychiatric disorder that affects 1-3.1% of the general population (lifetime rate). Although its neurobiological model has not been completely establish, numerous evidences indicate that areas of the cortico-striatalpale- thalamic-cortical (CSPTC) circuit are engaged in the disease. In particular, the orbitofrontal cortex (OFC) is a region that plays a key role in the pathophysiological hypothesis of OCD. In parallel to this, in healthy controls this region has been associated with the ability of using spontaneous strategies of semantic clustering at the encoding of related words - in a way that facilitates the posterior retrieval of these words. At the same time, neuropsychological studies showed that OCD patients present verbal episodic memory (VEM) deficits, and that these deficits could be mediated by executive dysfunction - like planing and utilization of strategies. Thus, to investigate the hypothesis that there are differences at the neural correlates of VEM encoding between children and adolescents with OCD and healthy controls, we used a blocked design functional Magnetic Resonance Imaging (fMRI) paradigm to evaluate both groups. The main objective of the study was to investigate the VEM encoding and the ability to spontaneously organize words according to their semantic categories. In order to do this, the fMRI paradigm consisted of two kinds of word lists: a semantically related list (SR), in which words were divided into semantic categories and a unrelated list (UR), were there was no apparent relationship between the words. However, the contrast of most interest of this study, was the difference between the conditions (\'SR > UR\'). The semantic clustering level was quantified by a semantic clustering index. Groups were constituted by 25 children and adolescents with OCD and 25 healthy controls paired by gender, age, educational level, handedness and IQ. Although both groups were matched for these characteristics, they differed in clinical symptoms such as depression, anxiety and routines. Behavioral results showed that the groups were similar in terms of retrieved words and semantic index. Nevertheless, the comparison between groups - controlled for clinical variables - showed less activation (BOLD signal) in patients in several brain regions: frontal, parietal and occipito-temporal. On the other hand, the psychophysiological interaction analysis (PPI) revealed that patients have had an increase in the OFC connectivity with the temporal regions. This has occurred in three of the four regions of interest that were placed in the OFC: lateral and medial of both hemispheres. Also, the patients showed a positive correlation between the semantic index and the BOLD effect in the OFC, which was not observed in the control group. These results suggest that there are differences in brain functioning of children and adolescents with OCD in regions that are inside/outside of the neurobiological model for OCD (CSPTC circuit). In accordance with the present results, these differences in brain activation and connectivity could be regarded as a latent deficit, since both groups presented the same behavioral performance

Le vieillissement des sociétés dans le monde s’accompagne d’immenses possibilités en même temps que de nombreux défis en matière de santé et de bien-être. Comme en témoignent les aînés, la qualité de vie lors du vieillissement dépend fortement de l’état de santé cognitive. Une meilleure compréhension des constituants de la santé cognitive constitue donc un élément central dans le défi qui attend les neuroscientifiques. Pour accomplir efficacement les activités cognitives quotidiennes, les régions du cerveau synchronisent leur activité l’une avec l’autre, tel que mesuré par la connectivité fonctionnelle basée sur les données de l’imagerie cérébrale. Les méthodes utilisant la connectivité fonctionnelle ont permis de mettre en avant une architecture relativement stable en soutien aux processus cognitifs. Cette organisation fonctionnelle serait en grande partie déterminée par l’architecture présente au « repos » (l’activité spontanée non contrôlée), mais serait également modulée par le type et le niveau d’activité dans les réseaux spécifiques à la tâche. À ce jour, il n’est pas clair si l’activité cognitive module l’association entre les mesures de connectivité fonctionnelle et l’âge, ou encore les expériences de vie, suspectées de soutenir le maintien des performances cognitives à travers un phénomène de réserve neurocognitive. Cette question est particulièrement d’intérêt dans le cadre des habiletés lexico-sémantiques, qui apparaissent -de manière générale- exceptionnellement bien préservées avec l’âge. Cette thèse, articulée en trois études, vise donc à décrire et comparer l’effet de l’âge sur les patrons de connectivité fonctionnelle lors de tâches lexico-sémantiques et au repos, ainsi qu’à caractériser l’influence de la complexité de la tâche et des expériences de vie sur les relations unissant âge et performance cognitive. Une première étude -grâce à l’imagerie cérébrale- décrit les interactions fonctionnelles entre régions lors de diverses tâches de vocabulaire. L’objectif de cette première étude est de décrire les changements de connectivité fonctionnelle liés à l’âge en utilisant trois tâches langagières et de comparer ces changements avec ceux observés dans un état de repos, et ce, dans une cohorte de 300 adultes âgés entre 18 et 85 ans. Il faut en effet rappeler que la compréhension de la réorganisation du cerveau dans le vieillissement repose principalement sur des études au repos; ou sur un plus petit nombre d’études ayant exploré les capacités cognitives qui, typiquement, déclinent avec l’âge. Cette littérature a mené à l’élaboration de concepts et de modèles du vieillissement cognitif qui semblent transversaux aux domaines cognitifs. Toutefois, certaines habiletés, comme les capacités langagières lexico-sémantiques, sont caractérisées par la préservation générale de la performance dans le vieillissement, offrant ainsi une potentielle fenêtre privilégiée pour observer des mécanismes cognitifs efficaces. L’exploration des caractéristiques spécifiques à une activité pourrait donc offrir un nouveau regard sur les mécanismes qui sous-tendent un vieillissement cognitif optimal. Les résultats indiquent que les différences de connectivité fonctionnelles liées à l’âge varient d’un paradigme à l’autre et que l’état de repos présente des caractéristiques très distinctes des tâches. En particulier, les régions du réseau du langage montrent des augmentations de la connectivité au cours du vieillissement, tandis que seules des diminutions de connectivité caractérisent l’état de repos. Ces résultats ont été reproduits en manipulant différentes variables du modèle, suggérant une certaine robustesse. Une seconde étude s’attarde à décrire les différences d’architecture fonctionnelle entre jeunes et aînés dans le contexte de la réalisation de tâches de dénomination. La connectivité fonctionnelle induite par une tâche offre le potentiel de révéler des processus neurofonctionnels particulièrement adaptés à l’état cognitif. La manipulation méthodologique de la tâche devait donc permettre d’étudier avec précision les mécanismes neurofonctionnels qui soutiennent la préservation de la performance pour une activité cognitive donnée. Par exemple, l’utilisation d’un paradigme de tâche permet l’utilisation d’un atlas propre à la tâche et à l’échantillon au lieu des atlas génériques issus d’un état de repos, ou la manipulation du niveau de complexité. Le but de la deuxième étude est de décrire les changements de connectivité fonctionnelle liés à l’âge pendant l’accomplissement d’une tâche cognitive qui est typiquement préservée dans le vieillissement sain, ainsi que de comparer les différences liées à une complexité plus élevée, tel que défini par la fréquence lexicale. Les résultats suggèrent des mécanismes propres à l’âge et à la tâche. Les adultes plus âgés présentent une gamme complexe de différences dans l’architecture fonctionnelle, en particulier dans les régions motrices de la parole, mais aussi sous la forme d’une ségrégation accrue des régions classiquement attribuée au traitement sémantique. Seules quelques régions présentent un effet d’interaction significatif entre la demande intrinsèque de la tâche et les différences liées à l’âge, ce qui suggère des mécanismes spécifiques à la tâche plutôt que transversaux aux domaines cognitifs. Dans l’ensemble, les résultats de ces deux études confirment donc l’intérêt complémentaire des analyses en connectivité fonctionnelle induite par une tâche pour comprendre l’organisation cérébrale qui sous-tend le maintien de la performance cognitive au cours du vieillissement sain. Une troisième étude se focalise en conséquence sur les liens entre les expériences de vie cognitivement stimulantes et la performance comportementale durant l’accomplissement d’une tâche cognitive en décrivant l’architecture neurofonctionnelle d’adultes jeunes et âgés. Dans l’étude des facteurs sous-tendant la préservation cognitive dans le vieillissement, l’impact des expériences de vie cognitivement stimulantes (p.ex.: niveau d’éducation, activité professionnelle, activités quotidiennes) a attiré l’intérêt de nombreux chercheurs au cours des 20 dernières années. Il est par exemple suggéré que les expériences de vie cumulées contribuent à la préservation cognitive dans le vieillissement sain ainsi qu’aux premiers stades d’une maladie neurodégénérative. Une relation indirecte est soupçonnée entre les expériences de vie et l’activité cognitive, à travers l’activité neuronale. Toutefois, l’impact des expériences de vie sur les capacités de dénomination – une activité cognitive parmi les mieux conservées avec l’âge -- est encore inconnu. L’objectif de la troisième étude est de décrire les relations directes et indirectes entre la connectivité fonctionnelle, la performance aux tâches et les activités cognitivement stimulantes (éducation, profession, activités quotidiennes) chez les personnes âgées. Les résultats montrent que le niveau de performance est associé à des patrons distincts de connectivité fonctionnelle chez les personnes jeunes et âgées pendant la dénomination de mots. Dans le contexte d’une tâche généralement réussie, il n’existe toutefois pas de relation entre le niveau de participation à des activités stimulantes (p.ex. : éducation, profession, activités de loisirs) et la performance à la tâche chez les ainés, contrairement à ce qui est observé chez les adultes jeunes. En somme, les travaux de cette thèse supportent l’hypothèse selon laquelle les mesures de connectivité fonctionnelle s’avèrent sensibles à l’état cognitif, offrant ainsi un appui à l’utilisation de paradigmes soigneusement conçus pour répondre à des questions spécifiques sur le vieillissement cognitif. Lors de l’exécution réussie d’une tâche de dénomination de mots, les adultes plus âgés font preuve d’une synchronisation spécifique à la tâche entre régions cérébrales, en association avec le niveau de performance. Bien que les expériences de vie cognitivement stimulantes interagissent avec la connectivité fonctionnelle chez les personnes âgées, celles-ci semblent peu corrélées à la performance dans le contexte d’une habileté préservée. Ces résultats offrent une perspective alternative aux rapports sur les mécanismes neuronaux de domaine général dans le vieillissement et suggèrent que l’utilisation d’une méthodologie propre à l’échantillon et à la tâche peut s’avérer utile pour parvenir à un portrait complet des processus cognitifs sains en matière de vieillissement. / The aging of societies worldwide comes with both immense opportunities as well as numerous challenges regarding health and wellness. As reported by older adults, quality of life in aging is heavily dependent upon cognitive health. A better understanding of the constituents of cognitive health is thus a central piece of the scientific challenge that awaits neuroscientists. For a cost-effective functioning in everyday cognitive activities, brain regions synchronize their activity one with another, as is measured by functional connectivity using neuroimaging. Functional connectivity has allowed for the recognition of a relatively stable architecture in charge of cognitive processes. This functional organization would be in large part determined by the architecture present at “rest” (the unconstrained spontaneous activity), but would also be modulated by the cognitive activity and by the cognitive demand in task-specific networks. The current understanding of the brain reorganization in aging relies mostly on either resting-state studies, or on a smaller number of studies that explored cognitive abilities typically declining with age. This literature led to the development of domain-general models and concepts regarding cognitive aging. Yet, little is known about task-specific patterns in functional connectivity with age. For example, lexical-semantic abilities are characterized by general preservation of performance in aging, therefore offering a potentially privileged window to observe efficient cognitive mechanisms. The exploration of task-specific characteristics could thus offer a new insight on neurofunctional mechanisms that define healthy aging, including potential reserve phenomenon. The general aim of this thesis, articulated in three studies, is to describe and compare the effect of age on functional connectivity patterns during lexico-semantic tasks and at rest, as well as to characterize the influence of task complexity and life experiences on the relationship between age and cognitive performance. The goal of the first study was to describe the age-related changes in functional connectivity using three language tasks in a large cohort of aging adults [18-85 years old] and to compare these changes with those observed in a resting state. Results show that age-related differences vary from one paradigm to another and that resting-state present very distinct pattern when compared with tasks. Notably, regions of the language network show age-related increases in connectivity while only age-related decreases characterize resting-state. These results remained stable even after manipulation of the model’s confounding variables, suggesting a certain robustness. Task-induced functional connectivity thus holds a potential to reveal neurofunctional processes that are distinctly adapted to the cognitive state. In consequence, a precise neurofunctional characterization for a given cognitive activity may benefit from a methodological fine-tuning. Such manipulation of the task may reveal neurofunctional mechanisms that support preserved cognitive abilities. For example, task paradigm allows the use of a sample and task-specific template instead of generic -resting-state- atlases, or the manipulation of the cognitive demand level. The goal of the second study was to describe the age-related changes of the functional connectivity patterns during the accomplishment of a cognitive task that is typically preserved in healthy aging, as well as to compare age-related differences under higher task demand, defined by lexical frequency. Results suggest both age and task-specific mechanisms. Older adults show a complex array of differences in functional connectivity architecture, especially so in speech motor regions, but also in the form of increased segregation of regions classically attributed to semantic processing. Only a few regions show a significant interaction effect between intrinsic task demand and age-related differences in functional connectivity. Altogether, the findings from the first two studies confirm the complementary interest of task-induced functional connectivity analysis to uncover the brain organization that subserves lexico-semantic abilities during healthy aging. Yet, little is known about what processes underly inter-individual differences in performance. In the investigation of preserved performance in aging, the impact of cognitively stimulating life experiences has drawn many interests in the past 20 years. Life experiences were indeed demonstrated to contribute to the preservation of cognitive performance in healthy aging and in the early stages of neurodegenerative diseases. This mechanism is suspected of operating through an indirect relationship between life experiences and cognitive activity via neural activity. It may also be mediated by the individual capacity to cope with the demand of the task. The impact of such lifetime experience on naming abilities --- amongst the best-preserved with age --- is still unknown. The goal of the third study was thus to describe the direct and indirect relationships between lifelong activities (i.e., education, occupation, everyday activities), functional connectivity, and task performance in older individuals. Results show that life experiences interact with functional connectivity during successful word naming among older individuals. An interaction with task demand was also noted in some brain regions, suggesting demand-dependent neural mechanisms. In conclusion, functional connectivity proves to be sensitive to the actual cognitive state, supporting the use of carefully designed paradigms to answer specific questions about cognitive aging. During the successful performance of a word naming task, older adults show a task-specific use of the brain connectome. While cognitively stimulating life experiences interact with functional connectivity in older adults, it appears poorly related to task performance in the context of preserved naming abilities. These findings offer an alternative perspective to previous reports of domain-general neural mechanisms in aging. Task and sample-specific designs may reveal useful to reach a complete characterization of successful cognitive processes in healthy aging.

Functional magnetic resonance imaging (fMRI) is recent important method, used in neuroimaging. The aim of this thesis is to develop software tool for comparison of two methods for functional and effective connectivity estimation. In this thesis are described the basics of magnetic resonance imaging, fMRI, basic terms of fMRI experiments and generally are described methods of functional and effective connectivity. Then are more detailed mentioned methods of dynamic causal modeling (DCM), Granger causal modeling (GCM) and independent component analysis (ICA). Practical implementation of DCM in toolbox SMP and ICA in toolbox GIFT is also mentioned. In purpose to describe behavior of DCM and GCM in dependence on several parameters are performed Monte Carlo simulations. Then the concept and realization of software tool for simulating connectivity and comparison of DCM and GCM are described. Finally results of DCM and GCM comparison and results of Monte Carlo simulations are discussed.