Apesar dos numerosos estudos enfocando a compreensão da esquizofrenia, sua etiologia permanece desconhecida. Atualmente, as medicações antipsicóticas disponíveis são baseadas principalmente na hipótese dopaminérgica, porém, apresentam eficácia parcial no tratamento dos sintomas. Diante disso, outros sistemas neurais têm sido investigados e, nesse contexto, a hipótese glutamatérgica conquistou grande importância. Essa hipótese postula a presença de uma hipoatividade do receptor glutamatérgico N-metil-D-aspartato na esquizofrenia e, consequentemente, de uma desregulação na neurotransmissão do óxido nítrico. Um ensaio clínico recente com a administração de nitroprussiato de sódio, um doador de óxido nítrico, mostrou resultados significativos na melhora da sintomatologia de pacientes esquizofrênicos, entretanto, nenhum estudo de neuroimagem investigou quais são os efeitos dessa droga no sistema nervoso central. No crescente campo de estudo da neuroimagem funcional as redes neurais foram descobertas, sendo a default mode network uma das mais estudadas na esquizofrenia. Os recentes estudos de neuroimagem funcional têm evidenciado alterações do funcionamento dessa rede neural nos pacientes portadores da doença, evidenciando assim, a importância da default mode network na compreensão da esquizofrenia. Nesse caminho, o presente estudo investigou os efeitos agudos da administração de nitroprussiato de sódio na conectividade funcional da rede default mode network através da ressonância magnética funcional mediada pelo contraste BOLD (blood oxygen level dependent) em pacientes portadores de esquizofrenia e em voluntários saudáveis. Os pacientes portadores de esquizofrenia foram divididos em dois grupos de acordo com a medicação antipsicótica em uso: grupo sem clozapina (n=13) e grupo com clozapina (n=13). Os voluntários saudáveis também foram divididos em grupo controle (n=14) e grupo controle com tarefa de escuta passiva (n=5). Todos os pacientes portadores de esquizofrenia e o grupo controle foram submetidos a um protocolo de infusão de nitroprussiato de sódio com aquisição simultânea de imagens funcionais. Nossos resultados mostraram um aumento da conectividade funcional da default mode network com a infusão da medicação nos pacientes portadores de esquizofrenia, especialmente no hemisfério direito, enquanto esse mesmo padrão não foi encontrado nos controles saudáveis. Além disso, o aumento na conectividade se mostrou distinto entres os grupos de pacientes avaliados, sendo mais precoce e amplo no grupo de pacientes que não estava em uso do antipsicótico clozapina. Observamos também que o efeito modulatório da droga ocorreu sobre regiões da default mode network já estudadas e fortemente implicadas na fisiopatogenia da esquizofrenia. Assim, nossa investigação neurofuncional contribuiu para a compreensão dos efeitos terapêuticos do nitroprussiato de sódio na sintomatologia de pacientes portadores de esquizofrenia. Nossos achados também reforçam a importância do nitroprussiato de sódio como uma nova ferramenta farmacológica adjuvante no tratamento da esquizofrenia / Despite numerous studies focusing on the understanding of schizophrenia, its etiology remains unknown. Currently, available antipsychotic medications are mainly based on dopamine hypothesis, however, they exhibit partial efficacy in the treatment of the symptoms. Therefore, other neural systems have been investigated and, in this context, the glutamatergic hypothesis gained great importance. This hypothesis postulates the presence of a hypoactivity of the N-methyl-D-aspartate glutamate receptor in schizophrenia and, consequently, a deregulation of nitric oxide neurotransmission. A recent clinical trial with the administration of sodium nitroprusside, a nitric oxide donor, showed significant results in improving the symptoms of schizophrenic patients, however, no neuroimaging study investigated what are the effects of this drug on the central nervous system. The neural networks were discovered from the growing field of functional neuroimaging study and the default mode network is one of the most studied in schizophrenia. The recent functional neuroimaging studies have shown alterations in the functioning of this neural network in patients with the disease, highlighting the importance of the default mode network in the understanding of schizophrenia. In this way, the present study investigated the acute effects of sodium nitroprusside administration in the functional connectivity of the default mode network using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in patients with schizophrenia and healthy volunteers. Schizophrenic patients are divided into two groups according to antipsychotic medication used: group treated without clozapine (n = 13) and group treated with clozapine (n = 13). Healthy volunteers were also divided into control group (n = 14) and control group with passive listening task (n = 5). All schizophrenic patients and healthy volunteers were subjected to a sodium nitroprusside infusion protocol simultaneously to acquisition of functional images. Our results showed increased default mode network functional connectivity with the drug infusion in patients with schizophrenia, mainly in the right hemisphere, while this same pattern was not found in healthy controls. In addition, the increase in connectivity was distinct between groups of patients because it was earlier and more extensive in the group of patients that was not in use of clozapine antipsychotic. We also note that the drug modulatory effect occurred on default mode network regions already studied and strongly implicated in the schizophrenia pathogenesis. Thus, our neurofunctional research contributed to the understanding of the sodium nitroprusside therapeutic effects on the schizophrenia symptoms. Our findings also underline the importance of sodium nitroprusside as a new adjuvant pharmacological tool in the treatment of schizophrenia

Esta tese apresenta um novo método para analisar dados de ressonância magnética funcional (FMRI) durante o estado de repouso denominado Análise de Componentes Esparsos Locais (LSCA). A LSCA é uma especialização da Análise de Componentes Esparsos (SCA) que leva em consideração a informação espacial dos dados para reconstruir a informação temporal de fontes bem localizadas, ou seja, fontes que representam a atividade de regiões corticais conectadas. Este estudo contém dados de simulação e dados reais. Os dados simulados foram preparados para avaliar a LSCA em diferentes cenários. Em um primeiro cenário, a LSCA é comparada com a Análise de Componentes Principais (PCA) em relação a capacidade de detectar fontes locais sob ruído branco e gaussiano. Em seguida, a LSCA é comparada com o algoritmo de Maximização da Expectativa (EM) no quesito detecção de fontes dinâmicas locais. Os dados reais foram coletados para fins comparativos e ilustrativos. Imagens de FMRI de onze voluntários sadios foram adquiridas utilizando um equipamento de ressonância magnética de 3T durante um protocolo de estado de repouso. As imagens foram pré-processadas e analisadas por dois métodos: a LSCA e a Análise de Componentes Independentes (ICA). Os componentes identificados pela LSCA foram comparados com componentes comumente reportados na literatura utilizando a ICA. Além da comparação direta com a ICA, a LSCA foi aplicada com o propósito único de caracterizar a dinâmica das redes de estado de repouso. Resultados simulados mostram que a LSCA é apropriada para identificar fontes esparsas locais. Em dados de FMRI no estado de repouso, a LSCA é capaz de identificar as mesmas fontes que são identificadas pela ICA, permitindo uma análise mais detalhada das relações entre regiões dentro de e entre componentes e sugerindo que muitos componentes identificados pela ICA em FMRI durante o estado de repouso representam um conjunto de componentes esparsos locais. Utilizando a LSCA, grande parte das fontes identificadas pela ICA podem ser decompostas em um conjunto de fontes esparsas locais que não são necessariamente independentes entre si. Além disso, as fontes identificadas pela LSCA aproximam muito melhor o sinal temporal observado nas regiões representadas por seus componentes do que as fontes identificadas pela ICA. Finalmente, uma análise mais elaborada utilizando a LSCA permite estimar também relações dinâmicas entre os componentes previamente identificados. Assim, a LSCA permite identificar relações clássicas bem como relações causais entre componentes do estado de repouso. As principais implicações desse resultado são que diferentes premissas permitem decomposições aproximadamente equivalentes, entretanto, critérios menos restritivos tais como esparsidade e localização permitem construir modelos mais compactos e biologicamente mais plausíveis. / This thesis presents Local Sparse Component Analysis (LSCA), a new method for analyzing resting state functional magnetic resonance imaging (fMRI) datasets. LSCA, a extension of Sparse Component Analysis (SCA), takes into account data spatial information to reconstruct temporal sources representing connected regions of significant activity. This study contains simulation data and real data. The simulated data were prepared to evaluate the LSCA in different scenarios. In the first scenario, the LSCA is compared with Principal Component Analysis (PCA) for detecting local sources under Gaussian white noise. Then, LSCA is compared with the expectation maximization algorithm (EM) for detecting the dynamics of local sources. Real data were collected for comparative and illustrative purposes. FMRI images from eleven healthy volunteers were acquired using a 3T MRI scanner during a resting state protocol. Images were preprocessed and analyzed using LSCA and Independent Components Analysis (ICA). LSCA components were compared with commonly reported ICA components. In addition, LSCA was applied for characterizing the dynamics of resting state networks. Simulated results have shown that LSCA is suitable for identifying local sparse sources.For real resting state FMRI data, LSCA is able to identify the same sources that are identified using ICA, allowing detailed functional connectivity analysis of the identified regions within and between components. This suggests that ICA resting state networks can be further decomposed into local sparse components that are not necessarily independent from each other. Moreover, LSCA sources better represent local FMRI signal oscillations than ISCA sources. Finally, brain connectivity analysis shows that LSCA can identify both instantaneous and causal relationships between resting state components. The main implication of this study is that independence and sparsity are equivalent assumptions in resting state FMRI. However, less restrictive criteria such as sparsity and source localization allow building much more compact and biologically plausible brain connectivity models.

Despite the interest in the neuroimaging of working memory, little is still known about the neurobiology of complex working memory in tasks that require simultaneous manipulation and storage of information. In addition to the central executive network, we assumed that the recently described salience network [involving the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC)] might be of particular importance to working memory tasks that require complex, effortful processing. Method: Healthy participants (n = 26) and participants suffering from working memory problems related to the Kleine–Levin syndrome (KLS) (a specific form of periodic idiopathic hypersomnia; n = 18) participated in the study. Participants were further divided into a high- and low-capacity group, according to performance on a working memory task (listening span). In a functional magnetic resonance imaging (fMRI) study, participants were administered the reading span complex working memory task tapping cognitive effort. Principal findings: The fMRI-derived blood oxygen level dependent (BOLD) signal was modulated by (1) effort in both the central executive and the salience network and (2) capacity in the salience network in that high performers evidenced a weaker BOLD signal than low performers. In the salience network there was a dichotomy between the left and the right hemisphere; the right hemisphere elicited a steeper increase of the BOLD signal as a function of increasing effort. There was also a stronger functional connectivity within the central executive network because of increased task difficulty. Conclusion: The ability to allocate cognitive effort in complex working memory is contingent upon focused resources in the executive and in particular the salience network. Individual capacity during the complex working memory task is related to activity in the salience (but not the executive) network so that high-capacity participants evidence a lower signal and possibly hence a larger dynamic response.

This dissertation is composed of three studies that use statistical, behavioral, and neuroimaging methods to investigate Chinese and English speakers’ semantic interpretations of four types of visual information including icons, single Chinese characters, single English words, and pictures. The goal is to examine whether people cognitively process icons as logographical words. By collecting survey data from 211 participants, the first study investigated how differently these four types of visual information can express specific meanings without ambiguity on a quantitative scale. In the second study, 78 subjects participated in a behavioral experiment that measured how fast people could correctly interpret the meaning of these four types of visual information in order to estimate the differences in reaction times needed to process these stimuli. The third study employed functional magnetic resonance imaging (fMRI) with 20 participants selected from the second study to identify brain regions that were needed to process these four types of visual information in order to determine if the same or different neural networks were required to process these stimuli. Findings suggest that 1) similar to pictures, icons are statistically more ambiguous than English words and Chinese characters to convey the immediate semantics of objects and concepts; 2) English words and Chinese characters are more effective and efficient than icons and pictures to convey the immediate semantics of objects and concepts in terms of people’s behavioral responses, and 3) according to the neuroimaging data, icons and pictures require more resources of the brain than texts, and the pattern of neural correlates under the condition of reading icons is different from the condition of reading Chinese characters. In conclusion, icons are not cognitively processed as logographical words like Chinese characters although they both stimulate the semantic system in the brain that is needed for language processing. Chinese characters and English words are more evolved and advanced symbols that are less ambiguous, more efficient and easier for a literate brain to understand, whereas graphical representations of objects and concepts such as icons and pictures do not always provide immediate and unambiguous access to meanings and are prone to various interpretations. / text

No description available.

Contexte Malgré les conséquences néfastes bien connues de la consommation de cannabis chez les patients souffrant de schizophrénie (SCZ), ces derniers en font usage dans une proportion atteignant 40%. Plusieurs études ont tenté d’éclaircir la nature du lien qui existe entre ces deux problématiques, mais cela demeure à ce jour un sujet d’incertitude. Des études précédentes, dont certaines de notre groupe, ont montré que les patients souffrant de schizophrénie et d’un trouble d’abus de cannabis (SCZCAN) présentaient moins de symptômes négatifs, de meilleures capacités cognitives et un processus de traitement des émotions se rapprochant davantage de la normale. Objectif La présente étude vise à évaluer la mémoire émotionnelle ainsi que ses corrélats neurobiologiques par imagerie par résonance magnétique fonctionnelle (IRMf) chez les SCZCAN en comparaison avec les SCZ. Notre hypothèse est que les SCZCAN vont mieux performer lors d’une tâche de mémoire émotionnelle en comparaison avec les SCZ et qu’ils démontreront des activités dans des régions cérébrales plus étendues et impliquées dans la mémoire et le traitement émotionnel. Méthode Trois groupes de sujets, soit un groupe de SCZ (N=14), un groupe de SCZCAN (N=14) et un groupe contrôle (N=21) ont participé à une tâche de mémoire émotionnelle lors d’une imagerie par IRMf. Résultats Les résultats de notre étude ont montré que les SCZCAN performaient mieux que les SCZ dans une tâche de mémoire émotionnelle et montraient des activations dans des régions cérébrales plus étendues à l’IRMf, en particulier celles impliquées dans mémoire et dans le traitement des émotions (cortex orbitofrontal et temporal, hippocampe). Conclusion Les SCZCAN ont une préservation relative de leur mémoire émotionnelle en comparaison aux SCZ, ce qui est corrélé avec de plus grandes activations cérébrales dans les régions qui jouent un rôle dans la mémoire et le traitement émotionnel. / Context In spite of well-known adverse consequences of cannabis consumption in patients with schizophrenia (SCZ), it is recognized that cannabis use reaches levels as high as 40 % in this population. Recently, a number of studies have attempted to get a better grasp of the relationship between these two conditions, which remains unclear to this day. Previous studies, including some from our group, have shown that cannabis abusing patients (SCZCAN) tend to have less prominent negative symptoms, better cognitive abilities, and that their emotion processing is closer to normal. Aim The present study aims to compare emotional memory in patients with schizophrenia with or without cannabis abuse, our hypothesis being that SCZCAN will perform better on an emotional memory task and will activate larger brain regions during functional imaging, as compared to SCZ. Method Three groups of subjects, namely SCZ (N=14), SCZCAN (N=14) and control subjects (N=21) underwent an emotional memory task during a functional magnetic resonance imaging session. Results Our study showed that the group of SCZCAN performed better than SCZ in a functional memory task and activated larger brain regions during functional imaging, in particular those linked to memory and emotional processing (orbitofrontal and temporal cortex, hippocampus). Conclusion The group of SCZCAN demonstrated a relative preservation of their emotional memory as compared to SCZ and activated larger brain regions during functional imaging.

Functional magnetic resonance imaging (fMRI) is a widely used, noninvasive technique to map brain activation, and has provided considerable insight into human brain function over the past two decades. Until recently, fMRI studies have focused on gray matter; however, reports of fMRI activation in white matter are mounting. White matter fMRI activation has the potential to greatly expand the breadth of brain connectivity research, as well as improve the assessment and diagnosis of white matter and connectivity disorders. Despite these potential benefits, white matter fMRI activation remains controversial. The controversy is partially due to the existence of incompletely understood facets of fMRI signals in white matter. This thesis describes three experiments that aim to refine what is currently known about white matter fMRI activation. In the first experiment, one of the main concerns about fMRI activation in white matter was addressed; namely, whether white matter has sufficient cerebrovascular reactivity to support hemodynamic changes that can be measured with fMRI. It was demonstrated that white matter has the capacity to support detectable hemodynamic changes in the absence of partial volume effects. In the second experiment, the effect of static magnetic field strength on sensitivity to white matter fMRI activation was explored as a possible cause of the relative paucity of reports of white matter fMRI activation. The results showed greater sensitivity to white matter fMRI activation at 4 T relative to 1.5 T MRI. In the third experiment, the relationship between white matter activation and the activated network of gray matter regions was explored. This was accomplished using fMRI-guided tractography in which structural connections between activated clusters are evaluated. Structural connectivity between white matter fMRI activation and regions of gray matter activation was demonstrated, providing evidence of the functional significance of fMRI activation in white matter. These experiments provide important insights, which will allow for improved investigations of white matter fMRI activation in the future. In addition, it is posited that experimenter bias, via selective reporting of activation clusters, has contributed to the slow acceptance of fMRI activation in white matter.

La perception est décrite comme l’ensemble des processus permettant au cerveau de recueillir et de traiter l’information sensorielle. Un traitement perceptif atypique se retrouve souvent associé au phénotype autistique habituellement décrit en termes de déficits des habilités sociales et de communication ainsi que par des comportements stéréotypés et intérêts restreints. Les particularités perceptives des autistes se manifestent à différents niveaux de traitement de l’information; les autistes obtiennent des performances supérieures à celles des non autistes pour discriminer des stimuli simples, comme des sons purs, ou encore pour des tâches de plus haut niveau comme la détection de formes enchevêtrées dans une figure complexe. Spécifiquement pour le traitement perceptif de bas niveau, on rapporte une dissociation de performance en vision. En effet, les autistes obtiennent des performances supérieures pour discriminer les stimuli définis par la luminance et inférieures pour les stimuli définis par la texture en comparaison à des non autistes. Ce pattern dichotomique a mené à l’élaboration d’une hypothèse suggérant que l’étendue (ou complexité) du réseau de régions corticales impliquées dans le traitement des stimuli pourrait sous-tendre ces différences comportementales. En effet, les autistes obtiennent des performances supérieures pour traiter les stimuli visuels entièrement décodés au niveau d’une seule région corticale (simples) et inférieures pour les stimuli dont l’analyse requiert l’implication de plusieurs régions corticales (complexes). Un traitement perceptif atypique représente une caractéristique générale associée au phénotype autistique, avec de particularités rapportées tant dans la modalité visuelle qu’auditive. Étant donné les parallèles entre ces deux modalités sensorielles, cette thèse vise à vérifier si l’hypothèse proposée pour expliquer certaines particularités du traitement de l’information visuelle peut possiblement aussi caractériser le traitement de l’information auditive dans l’autisme. Le premier article (Chapitre 2) expose le niveau de performance des autistes, parfois supérieur, parfois inférieur à celui des non autistes lors du traitement de l’information auditive et suggère que la complexité du matériel auditif à traiter pourrait être en lien avec certaines des différences observées. Le deuxième article (Chapitre 3) présente une méta-analyse quantitative investiguant la représentation au niveau cortical de la complexité acoustique chez les non autistes. Ce travail confirme l’organisation fonctionnelle hiérarchique du cortex auditif et permet d’identifier, comme en vision, des stimuli auditifs pouvant être définis comme simples et complexes selon l’étendue du réseau de régions corticales requises pour les traiter. Le troisième article (Chapitre 4) vérifie l’extension des prédictions de l’hypothèse proposée en vision au traitement de l’information auditive. Spécifiquement, ce projet compare les activations cérébrales sous-tendant le traitement des sons simples et complexes chez des autistes et des non autistes. Tel qu’attendu, les autistes montrent un patron d’activité atypique en réponse aux stimuli complexes, c’est-à-dire ceux dont le traitement nécessitent l’implication de plusieurs régions corticales. En bref, l’ensemble des résultats suggèrent que les prédictions de l’hypothèse formulée en vision peuvent aussi s’appliquer en audition et possiblement expliquer certaines particularités du traitement de l’information auditive dans l’autisme. Ce travail met en lumière des différences fondamentales du traitement perceptif contribuant à une meilleure compréhension des mécanismes d’acquisition de l’information dans cette population. / Perception involves the processes allowing the brain to extract and understand sensory information. Atypical perceptual processing has been associated with the autistic phenotype usually described in terms of impairments in social and communication abilities, as well as restricted interests and repetitive behaviours. Perceptual atypicalities are reported across a range of tasks. For instance, superior performance in autistics compared to non autistics is observed for pure tone discrimination as well as for complex figure disembodying tasks. One particular study reported atypical low-level visual processing in autism. In this experiment, autistics displayed enhanced performance for identifying the orientation of luminance-defined gratings and inferior performance for texture-defined gratings in comparison to non autistics. This dichotomous pattern led to the formulation of a hypothesis suggesting an inverse relation between the level of performance and the extent (or complexity) of the cortical network required for processing the stimuli. Specifically, autistics would perform better than non autistics during processing visual stimuli involving one cortical region (luminance-defined or simple stimuli), while they would show decreased performance for processing stimuli involving a network of cortical region (texture-defined or complex stimuli). Atypical perceptual processing is described as a general feature associated with the autistic phenotype and is reported for both the visual and the auditory modalities. Considering the existing parallels between the two sensory modalities, the principal purpose of the presented doctoral dissertation it to verify whether the hypothesis proposed to explain atypical visual processing in autism could also apply to audition. The first article (Chapter 2) is an exhaustive literature review of studies on autistics’ auditory processing abilities. Taken together, the results suggest that the level of performance of autistics on auditory tasks could be related to the acoustic complexity of the stimuli. The second article (Chapter 3) uses quantitative meta-analysis to investigate how auditory complexity is represented at the cortical level in non autistics. This study confirms the hierarchical functional organization of the auditory cortex and allows defining simple and complex auditory stimuli based on the extent of the cortical network involved in their processing, as it was done in vision. The third article (Chapter 4) verifies if the predictions of the hypothesis proposed in vision could also apply in audition. Specifically, this study examines the cortical auditory response to simple and complex sounds in autistics and non autistics. As expected, autistics display atypical cortical activity in response to complex auditory material that is stimuli involving a network of multiple cortical regions to be processed. In sum, the studies in this dissertation indicate that the predictions of the hypothesis proposed in vision could extend to audition and possibly explain some of the atypical behaviours related to auditory processing in autism. This thesis demonstrates fundamentally different auditory cortical processing in autistics that could help define a general model of perceptual differences in autism which could represent a key factor in the understanding of information acquisition.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Although most odorants we encounter in daily life are mixtures of several chemical substances, we still lack significant information on how we perceive and how the brain processes mixtures of odorants. We aimed to investigate the processing of odor mixtures using behavioral measures and functional magnetic resonance imaging (fMRI). The odor mixture contained a target odor (ambroxan) in a concentration at which it could be perceived by half of the subjects (sensitive group); the other half could not perceive the odor (insensitive group). In line with previous findings on multi-component odor mixtures, both groups of subjects were not able to distinguish a complex odor mixture containing or not containing the target odor. However, sensitive subjects had stronger activations than insensitive subjects in chemosensory processing areas such as the insula when exposed to the mixture containing the target odor. Furthermore, the sensitive group exhibited larger brain activations when presented with the odor mixture containing the target odor compared to the odor mixture without the target odor; this difference was smaller, though present for the insensitive group. In conclusion, we show that a target odor presented within a mixture of odors can influence brain activations although on a psychophysical level subjects are not able to distinguish the mixture with and without the target. On the practical side these results suggest that the addition of a certain compound to a mixture of odors may not be detected on a cognitive level; however, this additional odor may significantly change the cerebral processing of this mixture. In this context, FMRI offers unique possibilities to look at the subliminal effects of odors.