Orientadores: Marilisa Mantovani Guerreiro, Maria Augusta Santos Montenegro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T12:19:41Z (GMT). No. of bitstreams: 1 Teixeira_KarineCoutoSarmento_D.pdf: 1935380 bytes, checksum: f49a9408e7247c9252440fae53c691c3 (MD5) Previous issue date: 2013 / Resumo: A cefaléia é uma condição extremamente prevalente em crianças e gera transtorno na vida familiar e escolar do seu portador. O objetivo geral do presente estudo foi caracterizar a frequência e tipos de cefaléia na infância, além de responder a algumas perguntas organizadas em subprojetos expostos abaixo. Foi realizada avaliação retrospectiva de prontuários, visando analisar os dados clínicos e de neuroimagem. As informações obtidas por análise de prontuários e complementadas em visitas de rotina. Os 674 pacientes estudados integraram um banco de dados, a partir do qual os resultados foram analisados e distribuídos em subprojetos. No subprojeto 1, verificamos o papel da investigação por neuroimagem nas cefaléias na infância. Foram incluídos 646 pacientes que apresentavam queixa de cefaléia e exame neurológico normal, a fim de avaliar o benefício da neuroimagem no diagnóstico e tratamento dessa patologia. Achados anormais de neuroimagem foram encontrados em 60 pacientes, classificados em três grupos: a) 9 pacientes com alterações relacionadas à patologia de base; b) 43 pacientes com alterações radiológicas benignas; e c) 8 pacientes com alterações radiológicas que mudaram a conduta médica. Desse último grupo, quatro pacientes tiveram lesões potencialmente cirúrgicas: hematoma subdural, tumor temporal de baixo grau, cisto colóide do terceiro ventrículo e papiloma do plexo coróide. No subprojeto 2, analisamos o papel da sinusopatia diagnosticada por imagem como etiologia das cefaléias. Os pacientes foram incluídos de forma prospectiva, comparando-se um grupo de 62 pacientes com cefaléia com um grupo controle de 41 pacientes, todos sem sintomas agudos de sinusite. Não encontramos diferença significativa entre os dois grupos em relação ao diagnóstico de sinusopatia por neuroimagem. No subprojeto 3, foram estudadas as características das síndromes periódicas da infância em 38 pacientes: 2 pacientes com torcicolo paroxístico benigno da infância; 12 com vertigem paroxística benigna da infância; 15 com migrânea abdominal; 1 com vômitos cíclicos; 3 com auras em migrânea; e 5 pacientes com migrânea confusional. Todos tinham exame neurológico normal e 25 pacientes tinham história familiar de migrânea. Os dois subtipos mais prevalentes na infância foram vertigem paroxística benigna da infância e migrânea abdominal. A profilaxia foi instituída em 23 pacientes (13 com ciproeptadina e 10 com flunarizina), todos tiveram boa evolução. No subprojeto 4 foi avaliado qual porcentagem dos pacientes com migrânea necessita de profilaxia e qual a sua eficácia. Dos 430 pacientes com migrânea, a terapia profilática foi instituída em 168 pacientes e 90% destes obtiveram boa resposta terapêutica. A droga mais utilizada foi a flunarizina em 90 pacientes, seguida pela ciproheptadina em 34 pacientes. Com os dados acima descritos foi possível concluir que: A história clínica de pacientes pediátricos não permite boa caracterização do tipo de cefaléia em muitas crianças, a maioria dos pacientes com cefaléia apresenta exame neurológico normal; migrânea sem aura é o tipo de cefaléia mais prevalente entre os pacientes acompanhados em nosso serviço; exame neurológico normal em pacientes pediátricos com cefaléia primária do tipo migrânea e tensional não exclui alteração de neuroimagem; cefaléia secundária mais frequentemente está associada a exame neurológico e neuroimagem alterados; este estudo sugere que a neuroimagem seja indicada na infância, após atendimento de serviço terciário, pois pode alterar conduta; sinusopatia diagnosticada pela neuroimagem em pacientes com cefaléia não exclui o diagnóstico de cefaléias primárias; os equivalentes de migrânea apresentam exame neurológico normal e boa resposta ao tratamento profilático; sugerimos que flunarizina e ciproheptadina são eficazes na profilaxia medicamentosa da migrânea / Abstract: Headache is an extremely prevalent condition in children and causes distress in their families and school life. The general aim of this study was to characterize the frequency and types of headache in childhood. This was a retrospective study conducted at an outpatient pediatric neurology clinic. Our database included 674 patients. Our data showed that most patients with headache had a normal neurological examination and migraine without aura was the most prevalent type of headache. Further results were subdivided in four subprojects. In subproject 1, we verified the role of neuroimaging in the diagnosis and treatment of headache in childhood. We included 646 patients with headache as a main complain and normal neurological examination. The findings were subdivided into three groups: 9 patients had abnormalities related to an underlying disease; 43 had radiological benign findings; and, eight had radiological findings that influenced clinical care. Of this latter group, four patients had potentially surgical lesions: subdural hematoma, low-grade temporal lobe tumor, colloid cyst of the third ventricle and choroid plexus papilloma. In subproject 2, we verified the role of sinus disease as a cause of headache when sinus disease is diagnosed by neuroimaging. Patients were included prospectively, comparing the group of 62 patients with headache with a control group of 41 patients with other neurological conditions and without headache, all without symptoms of acute sinusitis. There was no significant difference among them. In subproject 3, we included 38 patients with childhood periodic syndromes: 15 children had abdominal migraine, 12 had benign paroxysmal vertigo of childhood, five had confusional migraine, three had aura without migraine, two had benign paroxysmal torticollis of infancy, and one had cyclic vomiting. All had normal neurological examination and 25 patients had a family history of migraine. The two most prevalent subtypes in childhood were benign paroxysmal vertigo of infancy and abdominal migraine. Prophylaxis was recommended to 23 patients (13 cyproheptadine and 10 flunarizine), all had a good outcome. In subgroup 4, we verified the percentage of patients with migraine that need prophylaxis and its effectiveness. The prophylactic therapy was introduced in 168 patients and was effective in 90% of them. Flunarizine was the most used drug in 90 patients, followed by cyproheptadine in 34 patients. Our data allowed the following conclusions: clinical history of pediatric patients does not allow a good characterization of type headache in many children, most patients present with headache normal neurological examination; migraine without aura is the most prevalent type of headache among patients followed in our service; normal neurological examination in pediatric patients with primary headache of migraine and tension-type does not exclude changes in neuroimaging, secondary headache is most often associated with neurological examination and neuroimaging changed, this study suggests that neuroimaging is indicated in childhood after tertiary care, as it can alter conduct; sinusitis diagnosed by neuroimaging in patients with headache does not exclude the diagnosis of primary headaches, migraine equivalents have normal neurological examination and a good response to prophylactic treatment, we suggest that flunarizine and cyproheptadine are effective in the prophylaxis of migraine medication / Doutorado / Neurologia / Doutora em Ciências Médicas

Plusieurs fonctions cognitives sont latéralisées dans le cerveau humain adulte. Nous avons étudié l’origine des asymétries fonctionnelles chez les nourrissons, en évaluant les substrats neuronaux de reconnaissance des visages et des traitements du langage imbriqués dans les réseaux visuels et auditifs, grâce à la neuroimagerie non invasive (EEG et l’IRM de diffusion). Pour cela, nous avons étudié le développement fonctionnel et structurel de ces deux systèmes cérébraux au cours des six premiers mois postnataux. Nous avons observé que la vitesse des réponses visuelles était liée à la maturation des faisceaux de fibres de la matière blanche conduisant ces réponses, plus que l’âge des bébés, alors que la vitesse des réponses auditives doit dépendre d’un réseau de faisceaux de fibres et de régions corticales plus vaste. Parallèlement, nous avons étudié la latéralisation de la reconnaissance des visages grâce à un paradigme de discrimination des visages présentés dans chaque hémichamp. Nous avons observé que seul l'hémisphère droit pouvait discriminer les visages et que les informations pertinentes étaient transférées entre les deux hémisphères. Pour cibler la latéralisation du traitement du langage, nous avons étudié les réponses à des stimuli de la parole présentés de manière monaurale. Une comparaison entre un groupe de nourrissons avec une agénésie du corps calleux et un groupe contrôle a montré que les réponses à ces stimuli étaient transférées de façon asymétrique via le corps calleux. Cette asymétrie, facilitée vers l’hémisphère gauche, intervient probablement dans la latéralisation précoce du réseau du langage. L’ensemble de ces études mettent bien en évidence le potentiel de la neuroimagerie pour étudier le développement du cerveau et ces asymétries précoces. / Several cognitive functions such as face and speech processing are lateralized in the adult human brain. The ontogeny of these functional asymmetries is yet poorly understood. We aimed to evaluate the neural substrates of face and speech processing, nested in the visual and auditory networks using non-invasive neuroimaging techniques in infants. First, we studied how the functional and structural characteristics of these two brain systems change over the first postnatal semester. With EEG, we showed age-related decreases in the latency of brain responses and demonstrated that the speed of early visual responses is related to the maturation of underlying white matter tracts conducting them, as assessed with diffusion MRI. For the auditory system, our results suggested that the speed of responses may rely on maturation of more pathways and cortical regions. In parallel, we studied face processing lateralization using a discrimination paradigm of faces presented in each hemifield and observed that only the right hemisphere was able to discriminate between faces. Further evidence also suggested a transfer of face-relevant information across hemispheres. To study speech processing lateralization, we used a paradigm with monaural presentation of speech stimuli. A comparison between typical infants and infants with callosal agenesis, suggested an asymmetric transfer of auditory information across hemispheres, facilitated toward the left hemisphere, that might contribute to the lateralization of language early on. This thesis highlights the potential of neuroimaging techniques for the study of brain’s structural and functional development and of hemispheric asymmetries early on.

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings.

Visuomotor behaviour – from handling simple objects to operating complex devices – is of fundamental importance in our everyday lives, yet there is relatively little evidence as to how healthy ageing affects these processes. A central role is played by the human capacity for reaching and grasping. Grasping an object requires complex visuomotor transformations, including processing of the object’s extrinsic features (it’s spatial location) and intrinsic features (such as size and shape). It has been documented that action relevant intrinsic object properties automatically facilitate specific motor actions despite being task-irrelevant, the so-called object affordance effect. These effects have been demonstrated for (1) grasp type (precision and power grips being facilitated by small and large objects) and (2) object-orientation (whereby right and left handed grasps are facilitated by object-orientation), and might underlie the effortlessness with which humans can interact with objects. Yet, these paradigms have not previously been employed in the study of healthy ageing, and little is known concerning how these processes change over the life span. Elucidating these changes is of particular importance as age-related degeneration of white matter integrity is well documented. Consequently, if successful visuomotor behaviour relies on white matter integrity, age-related reductions in affordance effects should be observed. This prediction was tested in a series of experiments. Experiment 1 investigated age-differences in object-size compatibility effects, and results corroborated our prediction of age-related reductions in object-size effects. Experiment 2 investigated age-differences in (1) spatial compatibility effects versus object-orientation effects, and (2) the locus of the effects (facilitation versus interference effects). Results revealed (1) some evidence of larger affordance than spatial effects in both age-groups, and (2) interference effects in the younger group and both facilitation and interference effects in the older group, showing a potential change in processing modes or strategies. Experiments 3 and 4 addressed the main competing account, the attention-directing hypothesis (according to which attentional shifts are responsible for the generation of automatic response codes, rather than the affects arising from afforded actions), by using a novel stimulus set in which such attentional differences can be ruled out. Results provided strong evidence in favour of the object-size affordance hypothesis. A final neuroimaging experiment investigated age-differences in the object-size effect and its neural correlates by combining behavioural, functional MRI and diffusion tensor imaging (DTI) data. Results revealed evidence of age-differences, both on the behavioural and functional level. For the DTI data, we investigated all four diffusion metrics (something which is not frequently reported in the healthy ageing literature), and found widespread age-related differences in white matter integrity. The empirical findings presented in this thesis offer a significant contribution to ageing research, by further elucidating the relationship between age-related neurophysiological changes and visuomotor behaviour. The overall picture which emerged from this series of experiments was consistent with our prediction of age-related reductions in affordance effects. Furthermore, it is likely that these age-differences may have, at least in part, a neurophysiological basis.

There is growing evidence to suggest that vascular disease plays an important role in late life depressive disorder. The aim of this study was to characterize vascular impairment in late life depression. Assessment of endothelial function, arterial stiffness, and atherosclerosis in a variety of vessel beds was carried out in 25 subjects with late life depression and 21 nondepressed control subjects. All study subjects underwent wave velocity, pulse wave analysis, carotid intima media thickness analysis, and magnetic resonance imaging of the brain and a subset gluteal fat biopsy and direct assessment of small artery endothelial function. There were no baseline differences in demographics or a range of vascular risk factors between the groups. There was a generalised vascular dysfunction in depressed subjects with significantly more atherosclerosis, poorer endothelial function and increased arterial stiffness. On neuroimaging, depressed subjects had significantly more dilated Virchow-Robin spaces in the basal ganglia. White matter lesion volumes in all regions were higher in depressed subjects but not significantly so. Furthermore, subjects with late onset depression (onset >60years) had greater vascular impairment when compared to those with early onset illness. Lastly, depressed subjects who did not respond to antidepressant monotherapy showed more vascular dysfunction compared to responders. The study has a number of limitations including the small sample size and as the study was cross sectional, the observed relationship between vascular dysfunction and depression is associative rather than causal. Further research in larger samples is required to address the methodological limitations of this study. If the study results are confirmed, the use of vasoprotective drugs to improve vascular function or retard atherosclerosis as diasease modifying agents in late life depression would be a rational development.

Les travaux en psychologie ont mis en évidence que les jeunes et âgés utilisent différentes stratégies pour accomplir des tâches cognitives. La question qui se pose alors est comment nous choisissons une stratégie parmi plusieurs stratégies disponibles. Afin de mieux comprendre la sélection stratégique, l’objectif de cette thèse était d’étudier le phénomène de changement stratégique intra-item et son évolution au cours du vieillissement, d’une part, et de mettre en évidence les mécanismes impliqués lors du choix d’une stratégie, d’autre part. Nos données montrent que différentes variables, intrinsèques et extrinsèques aux problèmes, influencent la capacité de changement stratégique intra-item au cours du vieillissement. Les jeunes et les âgés interrompent une stratégie en cours d’exécution et choisissent une stratégie différente que celle précédemment exécutée. Les participants changeaient plus fréquemment de stratégies afin de choisir la meilleure stratégie, et ce d’autant plus que la stratégie était facile à exécuter. Les âgés avaient de plus difficultés que les jeunes à changer de stratégies et par conséquent, ils choisissaient moins fréquemment la meilleure stratégie. Nous montrons aussi que la sélection stratégique est associée à une augmentation de l’activité cérébrale dans des régions préfrontales bien connues pour être le siège des fonctions exécutives. Enfin, nous discutons en quoi ces résultats ont d’importantes implications concernant, les modèles théoriques de la sélection stratégique, et concernant le vieillissement cognitif. / Psychology research has shown that young and older adults used different strategies to accomplish a cognitive task. Thus, the issue of how we choose a strategy among several available strategies is raised. In order to further understand strategy selection, the goal of this thesis was to investigate the within-item strategy switching and its evolution with age, on one hand, and to highlight mechanisms involved in the selection strategy, on other hand. Our data show that different variables, intrinsic and extrinsic to the problems, affect the ability of switching strategies within item during aging. Young and older adults interrupt a mid-execution strategy and choose a different strategy than previously executed. Participants switched strategies more frequently to choose the best strategy, and especially when the strategy was easy to execute. Older adults had more difficulties than young adults to switch strategies and therefore, they chose less frequently the best strategy. We also show that the strategy selection is associated with increased brain activities in prefrontal regions, well known to be the seat of executive functions. Finally, we discuss how these results have important implications for theoretical models of strategy selection, and for cognitive aging.

Le langage demeure préservé des effets du vieillissement mais précocement atteint dans la Maladie d'Alzheimer (MA). Le discours, en mobilisant l'ensemble des fonctions cognitives, pourrait mettre en évidence davantage de difficultés. Ce travail vise à analyser des productions de patients et de participants âgés typiques en lien avec les changements cognitifs et cérébraux. Une étude s'est intéressée à la production de discours portant sur des événements personnellement vécus. Une deuxième visait à comparer ce type de discours à un discours sur support imagé. Les résultats montrent que les difficultés rencontrées lors d'un discours d'événements vécus seraient corrélées à l'atteinte mnésique des patients. A l'inverse, elles seraient associées à l'atteinte exécutive et lexicale dans un discours imagé. Une dernière étude s'est focalisée sur la variabilité existant chez les participants âgés "typiques". Une analyse en cluster a montré quatre profils de locuteurs, dont un profil "hors-sujet" qui pourrait refléter une zone ambiguë entre vieillissement normal et pathologique. Ce travail pointe des marqueurs de MA prodromale, en lien avec les modifications cognitives et cérébrales. Certaines difficultés seraient liées à une atteinte mnésique ou exécutive indépendamment de l'altération langagière. / Language is the most preserved cognitive function from the effects of aging. Unlike typical aging, Alzheimer's disease (AD) is characterized by an early impairment. Analysis of discourse may reveal more difficulties than other tests since it mobilizes a large set of cognitive functions. This work aims to analyze various discourses in AD patients and participants with typical aging, in relation to various cognitive tests as well as neuroimaging data. One study focused on a memory-based discourse. A second study compared a memory-based and in a picture-based discourse. Patients' difficulties were correlated on one hand with memory impairment in the memory-based discourse and on the second hand with lexical-executive impairment in the picture-based discourse. A final study focused on discourse variability in the general aging population. A cluster analysis revealed four profiles of speakers. Among them, an "off-topic" profile could reflect a grey zone between normal and pathological aging. This work allowed us to shed light on deficit markers and compensatory strategies in prodromal AD, in relation with cognitive and cerebral changes. In particular, many difficulties may actually be related to memory or executive impairment, regardless of a language alteration.

The brain consists of spatially distinct areas, which underlie different aspects of human behavior. Using advanced neuroimaging technology and neurocomputational analysis methods, researchers have been able to uncover the functional roles of many of these areas and how they are interconnected both structurally and functionally to produce actions, sensations and cognitions which allow us to navigate our lives. In more recent years, it has been discovered that these brain networks also underlie the healthy functioning of the brain while it is at rest, i.e. awake but not performing any explicit or goal-directed tasks. Changes in these resting-state networks (RSNs) have been implicated in a number of neurological and psychiatric disorders, indicating that their degradation may play a role in the diverse loss of sensory, motor or cognitive functions associated with these.In this thesis, we introduce some new guidelines for capturing the electrophysiology of RSN structures using magnetoencephalography (MEG), a non-invasive neuroimaging technique which directly measures the magnetic fields associated with the synchronized electrical neural activity underlying these connections. Using MEG, we are able to consider these complex communication structures with great spatial and temporal resolution and probe how they are altered in multiple sclerosis (MS), a disease defined in part by both the degradation of the structures connecting different brain areas and by impairments across a wide spectrum of cognitive functions. However, in order to achieve this, there are methodological and analytical issues that must be dealt with.This thesis is separated into three introductory chapters and three research chapters. The introductory chapters outline the relevant theoretical bases that are not covered in the specific research chapters, while each of the research chapters contain a study undertaken as part of the thesis. Additionally, some research chapters start with an additional introductory prologue which expands on relevant ideas or concepts that are used but not fully explained in the corresponding papers.This thesis contains three empirical studies. In the first, we investigated the differential impact of source reconstruction methods and MEG system type on resting state functional connectivity (rsFC). The results showed that the choice of source reconstruction algorithm has a substantial impact on the uncovered rsFC in the posterior default mode network (DMN). Specifically, this was shown to be due to a suppression of the source activity in this region when using a Beamformer rather than minimum norm estimation (MNE) for source reconstruction. Through exploring this effect this we also made a novel discovery about a linear synchronization structure within the posterior DMN. This also led us to recommend the use of MNE when conducting MEG rsFC studies involving the DMN, representing a novel and important result regarding best practice recommendations for the field as a whole and for the subsequent studies in this thesis.In the second study, we set out to distinguish intrinsic, i.e. task-invariant, and extrinsic, i.e. task-dependent, functional connectivity (FC) using a large data set containing MEG data from more than a hundred participants acquired during several different tasks with multiple task levels, as well as during rest, We were able to demonstrate that the human brain operates using two distinct modes of neuronal integration in parallel, i.e. intrinsic FC in the form of amplitude FC and extrinsic FC in the form of phase FC. These results are important both in that they establish a new conceptual framework for functional integration in the human brain and in that they highlight a potentially fuzzy distinction between resting-state and task-related FC, which can be better approached using this novel intrinsic/extrinsic formulation. Having established the existence of an intrinsic functional integration structure in amplitude FC among brain regions, in the third study we investigated how amplitude rsFC is altered in brain disease, here represented by patients with MS. We showed that patients with MS display specific alterations in amplitude FC, particularly involving the DMN and sensorimotor (SMN) networks, compared to healthy participants. Additionally, we showed that the degree of disease-related physical disability was associated with specific motor-related amplitude rsFC changes, and that variations in cognitive task performance and neuropsychological scores were different between patients and healthy subjects on scores which were significantly different between the groups. These results demonstrate the ability of intrinsic/amplitude FC to characterize functional changes in clinical populations that are associated with specific disability-related and neuropsychological outcomes. / Le cerveau se compose de différentes zones fonctionnelles spatialement distinctes, qui sous-tendent différents aspects du comportement humain. En utilisant une technologie avancée de neuroimagerie et des méthodes d'analyse neurocomputationnelle, les neuroscientifiques ont caractérisé les rôles fonctionnels d’un bon nombre de structures cérébrales (i.e. la spécialisation fonctionnelle) et comment elles sont interconnectées à la fois structurellement et fonctionnellement (i.e. l’intégration fonctionnelle) pour produire les actions motrices, les sensations et les fonctions cognitives qui nous permettent de naviguer dans nos vies. Ces dernières années, les techniques de neuroimagerie ont également démontré que ces réseaux cérébraux fonctionnels sous-tendent également le bon fonctionnement du cerveau lorsqu'il est « au repos », c'est-à-dire qu'il n'effectue aucune tâche explicite ou ciblée. Des modifications de ces réseaux « de l’état de repos » (RSN) ont été impliquées dans un certain nombre de pathologies neurologiques ou psychiatriques, indiquant que leur altération peut jouer un rôle dans les déficits de fonctions sensorielles, motrices ou cognitives présentées par les patients.Dans cette thèse, nous introduisons de nouvelles lignes directrices pour investiguer l'électrophysiologie des RSN à l'aide de la magnétoencéphalographie (MEG), une technique de neuroimagerie non invasive qui mesure directement les champs magnétiques associés à l'activité neuronale électrique. Nous avons premièrement déterminé comment les choix méthodologiques au niveau de la reconstruction de sources en MEG influence les résultats de l’estimation de l’intégration fonctionnelle cérébrale. Ensuite, nous avons été en mesure d’étudier l’intégration fonctionnelle au sein des RSNs avec une grande résolution spatiale et temporelle, et ainsi, de déterminer les processus neurophysiologiques à l’origine de l’intégration fonctionnelle « intrinsèque » (i.e. indépendante d’une tâche ou de ce que le sujet fait) et « extrinsèque » (i.e. influencée ou modulée par une tâche). Nous avons démontré que l’intégration fonctionnelle intrinsèque repose sur le couplage de l’enveloppe (ou amplitude) de l’activité rythmique cérébrale alors que l’extrinsèque repose sur le couplage de phase de cette activité. Enfin, nous avons déterminé comment l’intégration fonctionnelle intrinsèque est altérée dans la sclérose en plaques (SEP), une maladie caractérisée en partie par la dégradation des connexions reliant différentes zones cérébrales et par des altérations variables des fonctions cognitive. Nous avons pu démontrer que le handicap moteur et certains troubles cognitifs (fatigue, cognitiven fluence verbale) sont associés à des altérations de l’intégration fonctionnelle intrinsèque de RSNs spécifiques. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

Neurological abnormalities are associated with emotion processing deficits seen in children with neurodevelopmental disorders. Research suggests that inflammatory mechanisms can negatively impact brain structure and function and are thought to play a role in these processing atypicalities. Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit emotion processing impairments and associated neural abnormalities. We investigated the roles of inflammatory factors and structural connectivity in relation to emotion processing deficits in 28 children with 22q11.2DS and 33 typically developing children (M = 11.12 years old; SD = 2.17). Results indicate poorer social skills and significantly lower emotion recognition scores in children with 22q11.2DS compared to controls. Additionally, children with 22q11.2DS had higher anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways and lower serum IL-3 concentrations than their typically developing peers. Right amygdala to fusiform gyrus FA values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. However, there was no indication that IL-3 mediated the relationship between diagnosis and abnormal connectivity. Future studies should employ longitudinal methods to characterize how these connectivity patterns influence social-emotional development as the child ages.

La schizophrénie est un trouble mental, chronique et invalidant caractérisé par divers symptômes tels que des hallucinations, des épisodes délirants ainsi que des déficiences dans les fonctions cognitives. Au fil des ans, l'Imagerie par Résonance Magnétique (IRM) a été de plus en plus utilisée pour mieux comprendre les anomalies structurelles et fonctionnelles inhérentes à ce trouble. Les progrès récents en apprentissage automatique et l'apparition de larges bases de données ouvrent maintenant la voie vers la découverte de biomarqueurs pour le diagnostic/ pronostic assisté par ordinateur. Compte tenu des limitations des algorithmes actuels à produire des signatures prédictives stables et interprétables, nous avons prolongé les approches classiques de régularisation avec des contraintes structurelles provenant de la structure spatiale du cerveau afin de: forcer la solution à adhérer aux hypothèses biologiques, produisant des solutions interprétables et plausibles. De telles contraintes structurelles ont été utilisées pour d'abord identifier une signature neuroanatomique de la schizophrénie et ensuite une signature fonctionnelle des hallucinations chez les patients atteints de schizophrénie. / Schizophrenia is a disabling chronic mental disorder characterized by various symptoms such as hallucinations, delusions as well as impairments in high-order cognitive functions. Over the years, Magnetic Resonance Imaging (MRI) has been increasingly used to gain insights on the structural and functional abnormalities inherent to the disorder. Recent progress in machine learning together with the availability of large datasets now pave the way to capture complex relationships to make inferences at an individual level in the perspective of computer-aided diagnosis/prognosis or biomarkers discovery. Given the limitations of state-of-the-art sparse algorithms to produce stable and interpretable predictive signatures, we have pushed forward the regularization approaches extending classical algorithms with structural constraints issued from the known biological structure (spatial structure of the brain) in order to force the solution to adhere to biological priors, producing more plausible interpretable solutions. Such structured sparsity constraints have been leveraged to identify first, a neuroanatomical signature of schizophrenia and second a neuroimaging functional signature of hallucinations in patients with schizophrenia. Additionally, we also extended the popular PCA (Principal Component Analysis) with spatial regularization to identify interpretable patterns of the neuroimaging variability in either functional or anatomical meshes of the cortical surface.