Thèse présentée en vue de l’obtention du grade de Ph. D. recherche et intervention en psychologie, option neuropsychologie clinique / L’aphasie survient le plus souvent à la suite d’un accident vasculaire cérébral (AVC) ischémique touchant l’artère cérébrale moyenne (ACM) gauche et représente l’une des conséquences les plus dévastatrices d’un AVC. La présente thèse vise à répondre à deux lacunes scientifiques importantes dans le domaine de l’aphasie secondaire à l’AVC impliquant l’ACM gauche, la première, plus fondamentale, et la seconde, plus clinique. Dans un premier temps, alors que les effets de l’AVC ischémique sur la matière grise ont été largement documentés dans les études précédentes, les mécanismes sous-tendant les dommages à la matière blanche cérébrale demeurent peu étudiés. Ainsi, le premier article inclus dans cette thèse vise à décrire le patron d’évolution longitudinale des propriétés microstructurelles de la matière blanche ipsilésionnelle après un AVC ischémique impliquant l’ACM gauche, en utilisant l’imagerie par résonance magnétique de diffusion. Nos résultats suggèrent que différents mécanismes pathophysiologiques s’opèrent pendant les stades aigu, subaigu précoce et chronique de l’AVC, avec la matière blanche lésionnelle et la matière blanche périlésionnelle affectée par l’ischémie à différents degrés et selon un décours temporel différent. Nous montrons que la considération d’une combinaison de mesures de diffusion à différents temps de mesure peut nous informer par rapport à la nature des différents mécanismes pathophysiologiques en cours, incluant l’oedème cellulaire, les dommages axonaux et la dégradation de la gaine de myéline. Une autre question qui demeure peu explorée dans la littérature sur l’aphasie post-AVC concerne la façon dont l’anomie, son symptôme cardinal, est reflétée dans la production de discours aux stades précoces du trouble. Le second article de cette thèse vise donc à évaluer la relation entre les mesures quantitatives de la production de discours et la performance dans le contexte de tâches de dénomination d’images au stade subaigu précoce de l’aphasie post-AVC impliquant l’ACM gauche (8-14 jours post-AVC). Nos résultats montrent la présence d’atteintes pour plusieurs mesures micro- et macrolinguistiques du discours chez les personnes avec aphasie et indiquent que l’informativité du discours (unités de contenu sémantique) est la mesure discursive la plus fortement corrélée aux capacités de dénomination. Nos résultats contribuent à une meilleure compréhension de la façon dont l’anomie est reflétée dans le contexte de la production de discours continu chez les personnes avec aphasie post-AVC dans la phase précoce du trouble. Ils suggèrent également que l’évaluation quantitative du discours peut offrir de l’information unique et potentiellement plus complexe à propos des atteintes langagières précoces, laquelle ne peut être entièrement captée par une tâche de dénomination d’images. / Post-stroke aphasia most frequently occurs after an ischemic stroke involving the left middle cerebral artery (MCA) and represents one of the most devastating consequences of a stroke. This thesis aims to address two major scientific gaps in the field of post-stroke aphasia: the first one is more fundamental, and the second one, more clinical. First, while the effects of ischemic stroke on cerebral grey matter have been thoroughly described in previous literature, the mechanisms of ischemic white matter injury remain far less understood. The first article of this thesis aims to characterize the longitudinal evolution of the microstructural properties of ipsilesional white matter after an ischemic stroke involving the left MCA, using diffusion magnetic resonance imaging. Our findings suggest that various pathophysiological mechanisms are at play after the ischemic stroke, with the lesional white matter and perilesional white matter tissue affected by ischemia at different rates and to different extents. We show that the examination of multiple diffusivity metrics may inform us about the mechanisms occurring at different time points, including cellular edema, axonal damage, and myelin loss. Another scientific gap in the post-stroke aphasia literature is that we do not know how anomia, its cardinal feature, is reflected in connected speech production during the early stages of the disease. The second article included in the thesis aims to assess the relationship between quantitative measures of connected speech production and performance in confrontation naming in people with aphasia in the early subacute stage following an ischemic stroke involving the left MCA (8–14 days post-stroke). We provide evidence for the presence of impairments in an array of micro- and macrolinguistic measures of speech in individuals with post-stroke aphasia and we show that confrontation naming abilities most strongly relate to informativeness in a picture description task. Our findings contribute to a better understanding of how anomia impacts connected speech production in the first days after stroke onset and suggest that quantitative discourse analysis may provide unique, possibly more complex information that isn’t entirely captured by picture naming tasks.

Les progrès dans le domaine de la neuroimagerie cérébrale ont permis une certaine compréhension des maladies mentales comme la schizophrénie. Cependant, peu de résultats sont cohérents et ils sont souvent contradictoires, ce qui rend difficile de tirer des conclusions concrètes par rapport à la maladie. Plusieurs facteurs jouent un rôle dans les résultats divergents et convergents : Les différentes techniques d'imagerie et les analyses, le nombre de patients inclus dans les études, l'âge des patients, l'âge de l’'apparition de la maladie, les critères de diagnostic, les effets du traitement antipsychotique, le statut social, ainsi que les comorbidités, font partie de ces facteurs. Bien que les différences cérébrales entre femmes et hommes « normaux » sont bien établies, ce n’est que ces dernières années que des études en neuroimagerie de la schizophrénie ont abordé les différences homme-femme comme une explication potentielle des résultats discordants de l’imagerie cérébrale. L'objectif de cette thèse est de comprendre le rôle du sexe (genre féminin et masculin) dans les anomalies anatomiques observées dans la schizophrénie; ceci, en réalisant des études qui contrôlent, autant que possible, l'effet de différentes variables confondantes et en utilisant des analyses d’IRM automatisées chez des patients et des sujets sains de même âge et du même sexe. Une brève revue globale des résultats actuels dans le domaine de la schizophrénie ainsi que des résultats liés aux différences entre les sexes dans la schizophrénie vont être présentés. La première étude visait à étudier l'influence des différences de sexe sur des mesures de la gyrification corticale de la schizophrénie. Étant donné que la schizophrénie est une maladie dont les «symptômes cliniques » ont un impact négatif sur la qualité de vie des patients qui en souffrent, nous avons exploré la relation entre la gyrification corticale et les différents symptômes de la schizophrénie chez les hommes et les femmes atteints de ce trouble psychiatrique. Le rôle du sexe sur la gyrification corticale et son association aux symptômes a été à peine étudié chez les patients atteints de schizophrénie ; c’est pour cette raison que, nous croyons que cette étude est d’une importante valeur. Dans cette première étude, des images 3T T1 ont été acquises auprès de 48 patients atteints de schizophrénie (24 hommes [SZ-M] et 24 femmes [SZ-F]) et 48 volontaires sains (24 hommes [NC-M] et 24 femmes [NC-F]), appariés en fonction de l'âge et du sexe. Des mesures d’indice de gyrification (IG) pour chaque hémisphère et les quatre lobes cérébraux (frontaux, temporal, pariétal, et occipital) ont été effectuées en utilisant le pipeline de CIVET, lequel est entièrement automatisé. Plusieurs résultats intéressants ont émergé: les patients avaient des valeurs inférieures importantes de l’IG global par rapport aux témoins; SZ-M avaient des valeurs d'IG hémisphériques significativement inférieurs par rapport à NC-M, cela n'a pas été observé dans les groupes de femmes. Aucune différence entre les sexes dans les valeurs de diminution de l’IG avec l'âge n’a été observés chez les témoins sains par contre, une diminution de la valeur de l’IG avec l’âge chez les patients était plus importante chez les patients homme que les patients femmes. Une détérioration plus progressive dans l'hémisphère droit dans les deux groupes de patients a été observée, tout comme des réductions significatives des valeurs d’IG en relation avec la durée de la maladie chez SZ-M, mais pas chez SZ-F. Dans les groupes de patients, on observe des diminutions des valeurs d’IG dans les lobes frontaux bilatéraux et, le lobe occipital droit; le groupe SZ-M a montré une valeur d’IG significativement plus élevée par rapport à NC-M dans le lobe temporal droit; SZ-F a montré des valeurs d’IG significativement plus faibles dans les lobes bilatéraux frontaux, temporaux, pariétaux et le lobe occipital droit, par rapport à NC-F. Aucune corrélation significative n'a été trouvée entre les valeurs de l'IG et le profil de la symptomatologique dans les deux groupes de patients. Etant donné que l’IG reflète, en partie, des altérations dans le développement et la connectivité cérébrale, la diminution de l’IG observée chez les patients est en accord avec le modèle de développement neurobiologique de disconnectivité dans la schizophrénie. De plus, nous soulignons l'importance de l'âge ainsi que la durée de la maladie lorsque nous comparons les hommes et les femmes atteints de schizophrénie. Cependant, nous n'avons pas observé de corrélation significative n'a été trouvée entre les valeurs de l'IG et les symptômes, ce qui est d'un intérêt particulier et inattendu compte tenu des résultats de la neuroimagerie montrant par exemple certaines corrélations entre les symptômes positifs et certaines anomalies du lobe temporal dans la schizophrénie. Considérant ces résultats, nous avons décidé d'investiguer, dans notre deuxième étude, l'association entre les symptômes et les densités de matière grise (DMG) et de matière blanche (DMB) à la place des mesures de gyrification corticale. Nous avons utilisé la morphométrie basée sur le voxel "Voxel Based Morphometry (VBM8.0 with Diffeomorphic Anatomical Registration (Through Exponentiated Lie Algebra [DARTEL])" et la modélisation linéaire automatique (SPSS21.0 ALM) sur les images 3T T1 MPRAGE acquises auprès de 40 patients atteints de schizophrénie (SZ) et 41 témoins sains (NC). Nous avons trouvé que les patients atteints de schizophrénie avaient une DMG réduite dans le cortex cingulaire antérieur, le cortex temporal médian gauche et une DMG plus élevée dans le cortex cingulaire postérieur gauche par rapport aux sujets sains. Une diminution significative de DMB dans la région fronto-rectal inférieure gauche et la région pariétale postérieure gauche a été observée chez les patients comparés aux sujets sains. Nous avons trouvé des corrélations positives entre les symptômes positifs et la DMG dans l'insula gauche et le noyau caudé droit; et entre les symptômes négatifs et la DMG dans le cortex frontal médian droite et le lobe postérieur de cervelet droit. Nous avons aussi trouvé des corrélations négatives de DMG dans la région pariétale droite (précuneus), le lobe postérieur du cervelet gauche et les symptômes positifs; ainsi qu'entre la DMG du lobe antérieur du cervelet gauche et les symptômes négatifs. En outre, des corrélations positives ont été trouvées entre la DMB dans le cortex frontal médian droit et les symptômes positifs et entre le DMB dans la région frontale supérieure droite et les symptômes négatifs. Des corrélations négatives ont été trouvées entre les symptômes positifs et la DMB dans la région occipitale inférieure droite et le cunéus occipital droit, tandis que des corrélations négatives ont été trouvées entre la DMB et la région frontale supérieure gauche. Il est intéressant de noter que lorsque les symptômes ont été analysés par regroupement, nous avons trouvé que le symptôme de la désorganisation conceptuelle corrélait positivement avec la DMG totale et la DMB totale. L’augmentation de DMG a été associée à une diminution de la gravité des hallucinations et du manque de spontanéité; tandis que l'augmentation de DMB totale a été associée à la diminution de la sévérité de l'hostilité et des idées de grandeur. Une comparaison entre les groupes d'hommes a montré une diminution de la DMG chez les patients schizophrènes, tandis qu’aucune différences n’a été observée dans les groupes de femmes. Nous n’avons trouvé aucune corrélation entre la DMG, la DMB, le liquide cérébro-spinal, le volume total du cerveau, les symptômes individuels et la schizophrénie chez les sujets féminins. Chez les hommes atteints de schizophrénie, on observe des corrélations négatives importantes entre les idées de grandeur et la DMB; des corrélations positives entre la désorientation et la DMB. De plus on observe des corrélations entre et les déficits d'attention et de DMG et DMB. Nos résultats montrent que ces associations sont différentes chez les hommes et les femmes atteints de la schizophrénie. La symptomatologie de schizophrénie est un mélange de déficits cognitifs et socio-affectifs. Dans ce contexte, le but de notre troisième étude est d'étudier chez les patients atteints de la schizophrénie des DMG et DMB et leur relation avec l’acuité mnésique avec des contenus émotionnelles (négatives, positives et neutres) ainsi que étudier l'effet des différences de sexe sur nos résultats. Quarante et un patients droitiers, traités par antipsychotique, souffrant de schizophrénie (SZ) et 40 témoins sains (NC), tous droitiers, ont participé à l’étude. Nous avons utilisé des images de l'International Affective Picture System (IAPS), une banque d'images émotionnelles, et de l’IRM. On observe chez les témoins sains des corrélations entre les valeurs élevées de DMG du cortex pariétal postérieur, du lentiform, du putamen, noyau caudé, le cortex orbitofrontal inférieur gauche et la reconnaissance des images négatives. On observe des corrélations entre la DMG dans la région temporale gauche, fusiforme et la reconnaissance des images positives ; et également dans le cervelet antérieur gauche et l’acuité des images neutres. Chez les patients on observe des valeurs élevées des DMG dans le cortex occipital inférieur gauche et la reconnaissance des images négatives, mais aucune corrélation entre la capacité de reconnaissance des images positives ou neutres. Nous avons observé chez les témoins sains: des relations significatives entre la DMB dans le cortex pariétal postcentral gauche et la capacité de reconnaître des images négatives; dans le cortex temporal inferieur gauche, le cortex pariétal gauche (précuneus), le cortex frontal gauche et la capacité de reconnaissance des images positives; des valeurs de DMB du cortex temporel médian et l’acuité des images neutres. Les patients atteints de schizophrénie ont montré des relations significatives entre de DMB dans le cortex occipito-lingual gauche et la reconnaissance des images négatives ; dans le cortex pariétal angulaire gauche et la reconnaissance des images positives ; et dans le cortex temporal supérieur droit et les images neutres. Les différences de sexe dans la schizophrénie ont été observées : chez les patients de sexe masculin, des corrélations négatives ont été trouvées entre les DMB et la capacité de reconnaître des images négatives et positives. Chez les hommes sains, nous avons trouvé des corrélations positives entre des valeurs totales de DMG et la capacité de reconnaître des images négatives. Nous n’avons pas observé de corrélations dans les groupes de femmes. Ces résultats soutiennent l'hypothèse de l'atrophie fronto-temporale régionale chez les patients schizophrènes. Toutefois, nous notons qu’ils ont des augmentations relatives des valeurs de DMB dans le cortex occipito-pariétal. Nous avançons l'hypothèse que les déficits mnésiques chez les patients sont liés à des perturbations dans la coordination des réseaux cérébraux, ce qui peut être affecté par des déficits structuraux plus évidents chez les patients masculins. Par conséquent, nous préconisons que les futures études devraient utiliser le connectome ou l’approche « réseaux cérébraux » pour étudier l’impact du sexe (genre masculin-féminin) sur les déficits cognitifs et symptomatologiques dans la schizophrénie. Nos résultats globaux soulignent l'importance de la différence entre homme et femme dans la modulation de manifestations cliniques et fonctionnelles de la schizophrénie. Ainsi, nous croyons que le contrôle des covariables comme l'âge, la durée de la maladie et le statut social est insuffisant et que les études futures sur la schizophrénie devraient systématiquement séparer les hommes des femmes, afin de mieux comprendre cette maladie mentale complexe et dévastatrice. / Advances in cerebral neuroimaging techniques have helped our understanding of mental illnesses, such as schizophrenia. Few findings remain consistent and are often contradictory, making it difficult to draw informative conclusions about the disease. Several factors play a role in both diverging and converging results. Imaging technique and analyses, number of patients involved, age of patients, age at onset of the disease, diagnostic criteria, antipsychotic treatment effects, social status, comorbidities, are among some of the reasons. Despite well established cerebral sex differences in healthy population, it is only in recent years that neuroimaging studies in schizophrenia have addressed sex differences as a major possible explanation for discrepant neuroimaging finding. The aim of this thesis is to help understand the role of sex on brain structures in schizophrenia, by conducting studies that control as much as possible for other variables and by using MRI automated analyses for patients and controls matched for age and sex. This work will briefly present findings in schizophrenia in general, and then an extensive review of the literature on sex differences in schizophrenia will be presented. From it, we are able to conclude that sex differences have been reported with rare exception in almost all aspects involved in the life of patients with schizophrenia. Chapters 1. The first study investigated sex differences in cortical gyrification in schizophrenia patients (SZ). In addition, considering that schizophrenia is a disease of “clinical symptoms” that determine the quality of life of patients afflicted by it, we explored the relation between cortical gyrification and symptoms in males and females with schizophrenia. The role of sex on cortical gyrification and its association with symptoms has been scarcely investigated in patients with schizophrenia. In this study, 3T T1 images were acquired from 48 schizophrenia patients (24 males [SZ-M] and 24 females [SZ-F]) and 48 normal controls [NC] (24 males [NC-M] and 24 females [NC-F]) matched for age, sex, and handedness. Gyrification Index (GI) analyses for each hemisphere and four cerebral regions (frontal, temporal, parietal, and occipital) were performed using the fully automated CIVET pipeline. Patients had significant lower values of the overall GI relative to normal controls and SZ-M had significant lower right hemispheric GI values compared to NC-M. This was not observed in either NC-F or in SZ. No gender difference in GI values decreases with age were observed in NC. In patients, GI decreases with age were greater in SZ-M than SZ-F, with a more progressive deterioration in the right hemisphere in both patient groups. Significant GI value reductions in association with duration of illness were observed in SZ-M but not in SZ-F. Patient groups had lower GI in bilateral frontal, temporal, and parietal lobes than controls. SZ-F had significant lower GI values in left frontal, bilateral temporal and left parietal lobe compared to NC-F. No significant correlations were found between GI values and symptom scores in either group of patients. Since GI reflects, in part, alterations in cerebral development and connectivity, the decrease in GI observed in patients is in agreement with the neurodevelopmental model of disconnectivity in schizophrenia, and may explain the worse prognosis and social outcome observed in male patients. Furthermore, we emphasize the importance of age and duration of illness when comparing males and females with schizophrenia. Observed differences between male and female patients may reflect a more diffuse and generalized cortical loss in males. Female patients had cortical loss in specific regions, while preserving cortical gyrification in compensatory regions. Our latter finding -no significant correlation between GI values and symptom scores- was of particular interest and was unexpected in view of neuroimaging findings of correlations between positive symptoms and temporal lobe abnormalities. 2. In the second study, we examined the association between symptoms and brain structure using gray (GMD) and white matter (WMD) densities. Voxel-based morphometry (VBM8.0 with Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra [DARTEL]) and Automatic Linear Modeling (SPSS21.0 ALM) were used on 3T T1 MPRAGE images acquired from 40 schizophrenia patients (SZ) and 41 normal controls (NC). We found that SZ had lower GMD in the anterior cingulate cortex and left middle temporal gyrus, and higher GMD in the left posterior cingulate in comparison to NC. SZ had significantly lower WMD in the left inferior fronto-rectal and the left posterior parietal regions in comparison to NC. Significant positive correlations were found between positive symptoms and GMD in the left insula and right caudate, and between negative symptoms and GMD in the right middle frontal and the posterior lobe of the right cerebellum (uvula). Inverse relationships between GMD in the right parietal (precuneus), the left posterior lobe of the cerebellum (uvula) and positive symptoms, and between GMD in the left anterior lobe of the cerebellum and negative symptoms were observed in SZ. In addition, positive correlations were found between WMD in the right middle frontal lobe, and between positive symptoms and WMD in the right superior frontal region with negative symptoms. Negative correlations were found between positive symptoms and WMD in the right inferior occipital and the right occipital cuneus, while negative symptoms correlated negatively with the WMD of the left superior frontal. When symptom clusters were analyzed, conceptual disorganization symptom positively correlated with both total GMD and WMD. While increases in GMD were associated with decreased severity of lack of spontaneity and hallucinations symptom, increases in total WMD were associated with decreased severity of hostility and grandiosity symptoms. Comparison between male subjects revealed decreased GMD in male schizophrenia patients, while no differences were observed between females across groups. No correlations were found in female groups between GMD, WMD, CSF, or total brain volume and individual symptoms. In males with schizophrenia, significant negative correlation between ideas of grandiosity and WMD, a positive correlation between disorientation and WMD, and attention deficits and GMD and WMD were found. The current data suggest region-specific GMD and WMD association with negative and positive symptoms. In addition, it reveals that such associations are different in male and female schizophrenia patients. 3. The third study investigated the relationships of GMD and WMD with memory accuracy for emotionally negative, positive, and neutral pictures in schizophrenia patients relative to normal controls. Schizophrenia is characterized by an amalgam of cognitivo-socio-emotional deficits. The relationship between emotion processing on cognition and neurobiological underpinnings merit more attention than it has received so far. Memory deficits are among the most common deficits in schizophrenia and have a widespread impact on cognition in general. Additionally, consistently with the major theme of the present thesis, we investigated the effect of gender on the observed effect. Forty one, right-handed medicated patients with schizophrenia (SZ) and 40 right-handed normal controls (NC) matched by age and sex were assessed for memory accuracy using negative, positive and neutral pictures taken from the International Affective Picture System (IAPS). Imaging methods and analyses were similar to our second study. Fifteen minutes after presentation of selected IAPS images (incidental encoding), subjects were asked to recognize the previously seen images among other images. We found higher GMD in NC in the right posterior parietal cortex, lentiform, putamen, and caudate, as well as the left inferior orbitofrontal cortex, in relation with the negative images accuracy. NC had higher GMD in the left temporal and fusiform regions in relation with the positive images accuracy, and higher GMD in the left anterior cerebellum in relation with neutral images. Schizophrenia subjects had higher GMD in the left inferior occipital cortex in relation with the negative images accuracy, but GMD was not correlated with positive or neutral images accuracy in this group. WMDs correlations were higher in NC in the left postcentral parietal region for negative images; in the left inferior temporal, left precuneus parietal, and left frontal regions for positive images; and in the left middle temporal region for neutral images. Schizophrenia patients had higher WMD in the left lingual occipital for negative images; in the left angular parietal for positive images; and in the right superior temporal region for neutral images. While examining the two sexes separately, we observed inverse correlations between WMD and both negative and positive pictures in male patients. In addition, only in male controls, GMD positively correlated with negative pictures and this correlation was absent in female SZ subjects and NC females. These findings support the hypothesis of fronto-temporal regional atrophy in schizophrenia. Schizophrenia patients have relatively increased occipito-parietal WMD, advancing the hypothesis that the core pathophysiological problem underlying recall memory in SZ may be related to disruptive alterations in the coordination of large-scale brain networks, and this may be affected by structural deficits that are more evident in male patients. It is recommended that future studies should use the connectomes or the brain networks approach to investigate the effect of sex on memory deficits in schizophrenia. Our overall findings point out to the importance of sex in modulating the clinical and functional manifestations of schizophrenia. We believe that controlling for covariates as age, duration of illness, social status, etc. is insufficient and that future studies in schizophrenia should systematically separate male and female findings, if we wish to understand this complex and devastating mental illness.

L’IRM de diffusion (IRMd) est l’unique technique non invasive qui permet l’exploration de la microstructure cérébrale. En plus d’une large utilisation pour les applications médicales, l’IRMd est aussi utilisée en neuroscience pour comprendre l’organisation et le fonctionnement du cerveau. Toutefois, sa faible résolution spatiale et sa sensibilité aux artéfacts limitent son utilisation chez le primate non humain.L’objectif de cette étude est de développer une nouvelle approche qui permette d’acquérir des données d’IRMd à très haute résolution spatiale sur des cerveaux de macaques anesthésiés. Cette méthode est basée sur un balayage 3D de l’espace de Fourier avec un module de lecture d’Echo Planar-segmenté.Cette méthode a été tout d’abord implémentée sur une machine IRM 3 Tesla (Prisma, Siemens), puis validée et optimisée in-vitro et in-vivo. Par rapport à la méthode d’acquisition classique, un gain de sensibilité de l’ordre de 3 pour la substance grise cérébrale et de 4.7 pour la substance blanche cérébrale a été obtenu grâce à la méthode développée.Cette méthode a permis de réaliser l’IRMd du cerveau de Macaque avec une résolution spatiale isotrope de 0.5 mm jamais atteinte auparavant. L’intérêt de réaliser des données d’IRMd à une telle résolution pour visualiser et analyser in-vivo des structures fines non détectables avec la méthode d’acquisition classique comme les sous-champs de l’hippocampe ou encore la substance blanche superficielle, a été démontré dans cette étude. Des résultats préliminaires très encourageants ont également été obtenus chez l’homme / Diffusion MRI (dMRI) is the unique non-invasive technique that allows exploring the cerebral microstructure. Besides a wide use for medical applications, dMRI is also employed in neuroscience to understand the brain organization and connectivity. However, the low spatial resolution and the sensitivity to artefacts limit its application to non-human primates.This work aims to develop a new approach that allows to acquire dMRI at very high spatial resolution on anesthetized macaque brains. This method is based on a 3D sampling of Fourier space with a segmented Echo Planar imaging readout module. This method has been firstly implemented on a 3 Tesla MR scanner (Prisma, Siemens), validated and optimized in-vitro and in-vivo. Compared to the conventional acquisition method, a gain of sensitivity of 3 for the cerebral grey matter and of 4.7 for the white matter was obtained with the proposed approach.This method allowed us to acquire dMRI data on the macaque brain with a spatial isotropic resolution of 0.5 mm ever reached before. The interest to acquire dMRI data with such a spatial resolution to visualize and analyze in-vivo fine structures not detectable with the classical acquisition method, like the sub-fields of hippocampus and the superficial white matter, has also illustrated in this study. Finally, very encouraging preliminary results were also obtained in humans

INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentados / INTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herein

INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentados / INTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herein

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This thesis is focused on the human brain microstructure mapping using quantitative and diffusion MRI. The T1/T2 quantitative imaging relies on sequences dedicated to the mapping of T1 and T2 relaxation times. Their variations within the tissue are linked to the presence of different water compartments defined by a specific organization of the tissue at the cell scale. Measuring these parameters can help, therefore, to better characterize the brain microstructure. The dMRI, on the other hand, explores the brownian motion of water molecules in the brain tissue, where the water molecules' movement is constrained by natural barriers, such as cell membranes. Thus, the information on their displacement carried by the dMRI signal gives access to the underlying cytoarchitecture. Combination of these two modalities is, therefore, a promising way to probe the brain tissue microstructure. The main goal of the present thesis is to set up the methodology to study the microstructure of the white matter of the human brain in vivo. The first part includes the acquisition of a unique MRI database of 79 healthy subjects (the Archi/CONNECT), which includes anatomical high resolution data, relaxometry data, diffusion-weighted data at high spatio-angular resolution and functional data. This database has allowed us to build the first atlas of the anatomical connectivity of the healthy brain through the automatic segmentation of the major white matter bundles, providing an appropriate anatomical reference for the white matter to study individually the quantitative parameters along each fascicle, characterizing its microstructure organization. Emphasis was placed on the construction of the first atlas of the T1/T2 profiles along the major white matter pathways. The profiles of the T1 and T2 relaxation times were then correlated to the quantitative profiles computed from the diffusion MRI data (fractional anisotropy, radial and longitudinal diffusivities, apparent diffusion coefficient), in order to better understand their relations and to explain the observed variability along the fascicles and the interhemispheric asymmetries. The second part was focused on the brain tissue modeling at the cell scale to extract the quantitative parameters characterizing the geometry of the cellular membranes, such as the axonal diameter and the axonal density. A diffusion MRI sequence was developed on the 3 Teslas and 7 Teslas Siemens clinical systems of NeuroSpin which is able to apply any kind of gradient waveforms to fall within an approach where the gradient waveform results from an optimization under the hypothesis of a geometrical tissue model, hardware and time constraints induced by clinical applications. This sequence was applied in the study of fourteen healthy subjects in order to build the first quantitative atlas of the axonal diameter and the local axonal density at 7T. We also proposed a new geometrical model to model the axon, dividing the axonal compartment, usually modelled using a simple cylinder, into two compartments: one being near the membranes with low diffusivity and one farer from the membranes, less restricted and with higher diffusivity. We conducted a theoretical study showing that under clinical conditions, this new model allows, in part, to overcome the bias induced by the simple cylindrical model leading to a systematic overestimation of the smallest diameters. Finally, in the aim of going further in the physiopathology of the autism, we added to the current 3T imaging protocol the dMRI sequence developed in the framework of this thesis in order to map the axonal diameter and density. This study is ongoing and should validate shortly the contribution of these new quantitative measures of the microstructure in the comprehension of the atrophies of the corpus callosum, initially observed using less specific diffusion parameters such as the generalized fractional anisotropy. There will be other clinical applications in the future.

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