Les commotions cérébrales ont longtemps été considérées comme une blessure ne comportant que peu ou pas de conséquences. Cependant, la mise à la retraite forcée de plusieurs athlètes de haut niveau, liée au fait d'avoir subi des commotions cérébrales multiples, a porté cette question au premier plan de la culture scientifique et sportive. Malgré la sensibilisation croissante du public et la compréhension scientifique accrue des commotions cérébrales, il reste encore beaucoup d’inconnus au sujet de ces blessures. En effet, il est difficile de comprendre comment cette atteinte peut avoir des effets si profonds malgré le fait qu’elle n’entraîne apparemment pas de conséquences physiques apparentes lorsque les techniques traditionnelles d’imagerie cérébrale sont utilisées. Les techniques de neuroimagerie fonctionnelle ont cependant contribué à répondre aux nombreuses questions entourant les conséquences des commotions cérébrales ainsi qu'à accroître la compréhension générale de la physiopathologie de commotions cérébrales. Bien que les techniques de base telles que l'imagerie structurelle comme les scans TC et IRM soient incapables de détecter des changements structurels dans la grande majorité des cas (Ellemberg, Henry, Macciocchi, Guskiewicz, & Broglio, 2009; Johnston, Ptito, Chankowsky, & Chen, 2001), d'autres techniques plus précises et plus sensibles ont été en mesure de détecter avec succès des changements dans le cerveau commotionné. Des études d’IRM fonctionelle ont entre autres établi une solide relation entre les altérations fonctionnelles et les symptômes post-commotionels (Chen, Johnston, Collie, McCrory, & Ptito, 2007; Chen et al., 2004; Chen, Johnston, Petrides, & Ptito, 2008; Fazio, Lovell, Pardini, & Collins, 2007). Les mesures électrophysiologiques telles que les potentiels évoqués cognitifs (ERP) (Gaetz, Goodman, & Weinberg, 2000; Gaetz & Weinberg, 2000; Theriault, De Beaumont, Gosselin, Filipinni, & Lassonde, 2009; Theriault, De Beaumont, Tremblay, Lassonde, & Jolicoeur, 2010) et la stimulation magnétique transcrânienne ou SMT (De Beaumont, Brisson, Lassonde, & Jolicoeur, 2007; De Beaumont, Lassonde, Leclerc, & Theoret, 2007; De Beaumont et al., 2009) ont systématiquement démontré des altérations fonctionnelles chez les athlètes commotionnés. Cependant, très peu de recherches ont tenté d'explorer davantage certaines conséquences spécifiques des commotions cérébrales, entre autres sur les plans structural et métabolique. La première étude de cette thèse a évalué les changements structurels chez les athlètes commotionnés à l’aide de l'imagerie en tenseur de diffusion (DTI) qui mesure la diffusion de l'eau dans la matière blanche, permettant ainsi de visualiser des altérations des fibres nerveuses. Nous avons comparé les athlètes commotionnés à des athlètes de contrôle non-commotionnés quelques jours après la commotion et de nouveau six mois plus tard. Nos résultats indiquent un patron constant de diffusion accrue le long des voies cortico-spinales et dans la partie du corps calleux reliant les régions motrices. De plus, ces changements étaient encore présents six mois après la commotion, ce qui suggère que les effets de la commotion cérébrale persistent bien après la phase aiguë. Les deuxième et troisième études ont employé la spectroscopie par résonance magnétique afin d'étudier les changements neurométaboliques qui se produisent dans le cerveau commotionné. La première de ces études a évalué les changements neurométaboliques, les aspects neuropsychologiques, et la symptomatologie dans la phase aiguë post-commotion. Bien que les tests neuropsychologiques aient été incapables de démontrer des différences entre les athlètes commotionnés et non-commotionnés, des altérations neurométaboliques ont été notées dans le cortex préfrontal dorsolatéral ainsi que dans le cortex moteur primaire, lesquelles se sont avérées corréler avec les symptômes rapportés. La deuxième de ces études a comparé les changements neurométaboliques immédiatement après une commotion cérébrale et de nouveau six mois après l’atteinte. Les résultats ont démontré des altérations dans le cortex préfrontal dorsolatéral et moteur primaire dans la phase aiguë post-traumatique, mais seules les altérations du cortex moteur primaire ont persisté six mois après la commotion. Ces résultats indiquent que les commotions cérébrales peuvent affecter les propriétés physiques du cerveau, spécialement au niveau moteur. Il importe donc de mener davantage de recherches afin de mieux caractériser les effets moteurs des commotions cérébrales sur le plan fonctionnel. / Concussions had long been considered an injury of little to no consequence. However, the forced retirement of several high profile athletes due to the impact of having suffered multiple concussions has pushed the issue to the forefront of scientific and sports culture alike. Despite the growing public awareness and the ever-expanding scientific understanding of concussions there is still much that remains unknown about these injuries. Indeed, understanding how an injury can have such profound effects, though mostly transient, without any apparent physical consequence continues to confound how concussions are conceptualized in research. Neuroimaging techniques have helped answer many of the questions surrounding the physical consequences of concussions on the brain as well as increasing the general understanding of the pathophysiology of concussions. While basic structural imaging techniques such as CT scans and MRI are unable to detect any structural changes in the vast majority of cases (Ellemberg, et al., 2009; Johnston, et al., 2001), other more precise and sensitive techniques have been able to successfully detect changes in the concussed brain. Functional MRI studies have further established a strong relationship between functional alterations and post-concussion symptoms (Chen, et al., 2007; Chen, et al., 2004; Chen, et al., 2008; Fazio, et al., 2007). Electrophysiological measures such as ERP (Gaetz, et al., 2000; Gaetz & Weinberg, 2000; Theriault, et al., 2009; Theriault, et al., 2010) and TMS (De Beaumont, Brisson, et al., 2007; De Beaumont, Lassonde, et al., 2007; De Beaumont, et al., 2009) have consistently demonstrated alterations in concussed athletes. However, there has been very little research that has attempted to further explore the specific structural and metabolic aspects of concussion. The first study assessed structural changes in concussed athletes using diffusion tensor imaging which measures water diffusion in white matter. We compared concussed athletes with non-concussed control athletes in the days immediately after injury and again six months later. Our results indicated a consistent pattern of increased diffusion along neural tracts of the cortical spinal tract and in the corpus callosum underlying motor cortex. Furthermore, these changes were still present six months after injury suggesting that the effects of concussion are persistent past the acute phase. The second and third studies employed magnetic resonance spectroscopy as a means of investigating the neurometabolic changes that occur in the concussed brain. The first of these studies investigated the neurometabolic changes, neuropsychological aspects, and symptomatology in the acute post-injury phase. While neuropsychological testing was unable to show differences between concussed and non-concussed athletes, neurometabolic alterations were noted in the dorsal lateral prefrontal cortex as well as in primary motor cortex which correlated with reported symptoms. The second study investigated neurometabolic changes immediately after concussion and again six months after injury. Results indicated alterations in the dorsolateral prefrontal and primary motor cortices in the acute post-injury phase, but only those in primary motor cortex persisted to the six month time point.

Regular aerobic exercise has a wide range of positive effects on health and cognition. Exercise has been demonstrated to provide a particularly powerful and replicable method of triggering a wide range of structural changes within both human and animal brains. However, the details and mechanisms of these changes remain poorly understood. This thesis undertakes a comprehensive examination of the relationship between brain plasticity and aerobic exercise. A large, longitudinal experiment was conducted in which healthy but sedentary participants were scanned before and after six-weeks of monitored aerobic exercise. Increases in the volume of the anterior hippocampus were observed, as previously reported in an older cohort after a longer exercise intervention. Multimodal imaging methods allowed an in-depth exploration of the mechanisms underlying this volume change, which proved to be dominated by white matter changes rather than the vascular changes that have been previously reported. A surprising global change in the balance of CSF, blood, and brain tissue within the cranial cavity was also observed. Cross-sectional differences in memory and brain structure associated with fitness were also observed. The volume of the anterior hippocampus was shown to correlate with a measure of working memory. Higher cerebral blood volume throughout the brain was found to correlate with greater fitness and better working memory. Focal associations between fitness and magnetic susceptibility, a measure of iron content, were also observed in the basal ganglia. These findings demonstrate that aerobic fitness is associated with improved cognition and brain structure throughout the lifespan rather than simply acting to mitigate age related brain atrophy or accelerate brain development. Finally, a new pipeline was developed for analysing hippocampal morphometry using high-resolution, 7 Tesla scans. Striking variability in the convolution of the hippocampal surface is reported. This technique shows promise for imaging the precise nature of the change in hippocampal volume associated with aerobic exercise. This thesis adds to the evidence that aerobic exercise is a potent catalyst for behavioural and brain plasticity while also demonstrating that the mechanisms for those plastic changes are likely different than previously supposed. Future work will refine these measurement techniques, perhaps to a point where brain changes can be monitored on a single subject level. This work will provide an important tool to understand how best to utilize aerobic exercise to facilitate adaptive behavioural changes, mitigate the negative effects of ageing and disease on the brain, and maximize the benefits of active lifestyles.

La voix humaine constitue la partie dominante de notre environnement auditif. Non seulement les humains utilisent-ils la voix pour la parole, mais ils sont tout aussi habiles pour en extraire une multitude d’informations pertinentes sur le locuteur. Cette expertise universelle pour la voix humaine se reflète dans la présence d’aires préférentielles à celle-ci le long des sillons temporaux supérieurs. À ce jour, peu de données nous informent sur la nature et le développement de cette réponse sélective à la voix. Dans le domaine visuel, une vaste littérature aborde une problématique semblable en ce qui a trait à la perception des visages. L’étude d’experts visuels a permis de dégager les processus et régions impliqués dans leur expertise et a démontré une forte ressemblance avec ceux utilisés pour les visages. Dans le domaine auditif, très peu d’études se sont penchées sur la comparaison entre l’expertise pour la voix et d’autres catégories auditives, alors que ces comparaisons pourraient contribuer à une meilleure compréhension de la perception vocale et auditive. La présente thèse a pour dessein de préciser la spécificité des processus et régions impliqués dans le traitement de la voix. Pour ce faire, le recrutement de différents types d’experts ainsi que l’utilisation de différentes méthodes expérimentales ont été préconisés. La première étude a évalué l’influence d’une expertise musicale sur le traitement de la voix humaine, à l’aide de tâches comportementales de discrimination de voix et d’instruments de musique. Les résultats ont démontré que les musiciens amateurs étaient meilleurs que les non-musiciens pour discriminer des timbres d’instruments de musique mais aussi les voix humaines, suggérant une généralisation des apprentissages perceptifs causés par la pratique musicale. La seconde étude avait pour but de comparer les potentiels évoqués auditifs liés aux chants d’oiseaux entre des ornithologues amateurs et des participants novices. L’observation d’une distribution topographique différente chez les ornithologues à la présentation des trois catégories sonores (voix, chants d’oiseaux, sons de l’environnement) a rendu les résultats difficiles à interpréter. Dans la troisième étude, il était question de préciser le rôle des aires temporales de la voix dans le traitement de catégories d’expertise chez deux groupes d’experts auditifs, soit des ornithologues amateurs et des luthiers. Les données comportementales ont démontré une interaction entre les deux groupes d’experts et leur catégorie d’expertise respective pour des tâches de discrimination et de mémorisation. Les résultats obtenus en imagerie par résonance magnétique fonctionnelle ont démontré une interaction du même type dans le sillon temporal supérieur gauche et le gyrus cingulaire postérieur gauche. Ainsi, les aires de la voix sont impliquées dans le traitement de stimuli d’expertise dans deux groupes d’experts auditifs différents. Ce résultat suggère que la sélectivité à la voix humaine, telle que retrouvée dans les sillons temporaux supérieurs, pourrait être expliquée par une exposition prolongée à ces stimuli. Les données présentées démontrent plusieurs similitudes comportementales et anatomo-fonctionnelles entre le traitement de la voix et d’autres catégories d’expertise. Ces aspects communs sont explicables par une organisation à la fois fonctionnelle et économique du cerveau. Par conséquent, le traitement de la voix et d’autres catégories sonores se baserait sur les mêmes réseaux neuronaux, sauf en cas de traitement plus poussé. Cette interprétation s’avère particulièrement importante pour proposer une approche intégrative quant à la spécificité du traitement de la voix. / The human voice is the most meaningful sound category of our auditory environment. Not only is the human voice the carrier of speech, but it is also used to extract a wealth of relevant information on the speaker. Voice-sensitive areas have been identified along the superior temporal sulci of normal adult listeners. Yet little data is available on the nature and development of this selective response to voice. In the visual domain, a vast literature focuses on a similar problem regarding face perception. Several studies have identified processes and regions involved in visual expertise, demonstrating a strong resemblance to those used for faces. In the auditory domain, very few studies have compared voice expertise to expertise for other sound categories. Such comparisons could contribute to a better understanding of voice perception and hearing. This thesis aims to clarify the nature of the processes and regions involved in voice perception. Different types of experts and different experimental methods were used in three separate studies. The first study assessed the influence of musical expertise on timbre voice processing, by using using behavioral voice and musical instrument discrimination tasks. The results showed that amateur musicians performed better than non-musicians in both tasks, suggesting a generalization of auditory abilities associated with musical practice. The second study compared event related potentials evoked by birdsongs in bird experts and non-expert participants. Because a different topographical distribution was observed among bird experts in all sound categories, a definitive interpretation was difficult to make. In the third study, we asked whether the voice-sensitive areas would be recruited by different categories of sounds of expertise in guitar makers, bird experts and non-experts. The behavioral data showed an interaction between the two groups of experts and their respective category of expertise for memory and discrimination tasks. The functional magnetic resonance imaging results showed an interaction of the same type in the left superior temporal sulcus and the left posterior cingulate gyrus. The results show that the voice selective areas do not exclusively process voice stimuli but could also contribute to expert-level processing of other sound categories. Therefore, cortical selectivity to human voice could be due to a prolonged exposure to voice. The data presented demonstrate several behavioral and anatomo-functional similarities between cerebral voice processing and other types of auditory expertise. These common aspects can be explained by a functional and economical brain organization. Consequently, sound processing would rely on shared neural networks unless necessary. This interpretation is particularly important to suggest an integrative approach for studying voice processing specificity.

Understanding the causes of individual differences in brain structure may give clues about the etiology of cognition, personality, and psychopathology, and also may identify endophenotypes for molecular genetic studies on brain development. We performed a comprehensive statistical genetic study of anatomic neuroimaging data from a large pediatric sample (N=600+) of twins and family members from the Child Psychiatry Branch at the NIMH. These analyses included variance decomposition of structural volumetric endophenotypes at several levels of resolution, voxel-level analysis of cortical thickness, assessment of gene by age interaction, several multivariate genetic analyses, and a search for genetically-mediated brain-behavioral relationships. These analyses found strong evidence for a genetic role in the generation of individual differences in brain volumes, with the exception of the cerebellum and the lateral ventricles. Subsequent multivariate analyses demonstrated that most of the genetic variance in large volumes shares a common source. More subtle analyses suggest that although this global genetic factor is the principal determinant of neuroanatomic variability, genetic factors also mediate regional variability in cortical thickness and are different for gray and white matter volumes. Models using graph theory show that brain structure follows small-world architectural rules, and that these relationships are genetically-determined. Structural homologues appeared to be strongly related genetically, which was further confirmed using novel methods for semi-multivariate quantitative genetic analysis at the voxel level. Studies on interactions with age were mixed. We found evidence of gene by age interaction on frontal and temporal lobar volumes, indicating that the role of genetic factors on these structures is dynamic during childhood. Analyses on cortical thickness at a finer scale, however, showed that environmental factors are more important in childhood, and environmental changes were responsible for most of the changes in heritability over this age range. When assessing the relationship between brain and behavior, we found weak negative genetic correlations and positive environmental correlations between IQ and cortical thickness, which appear to partially cancel each other out. More complex models allowing for age interactions suggest that high and low IQ groups have different patterns of gene by age interactions in concordance with prior literature on cortical phenotypes.

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

Introdução: Embora alterações estruturais cerebrais na esquizofrenia venham sendo repetidamente demonstradas em estudos de ressonância magnética (RM), ainda permanece incerto se tais alterações são estáticas ou progressivas. Enquanto estudos longitudinais são tradicionalmente utilizados na avaliação da questão da progressão, estudos transversais de neuroimagem comparando diretamente pacientes com esquizofrenia crônica e de primeiro episódio a controles saudáveis têm sido bastante raros até o presente. Com o recente interesse em meganálises combinando dados multicêntricos de RM visando-se a maior poder estatístico, o presente estudo multicêntrico de morfometria baseada no voxel (VBM) foi realizado para avaliar os padrões de alterações estruturais cerebrais segundo os diferentes estágios da doença, bem como para avaliar quais (se alguma) dessas alterações se correlacionariam especificamente a moderadores clínicos potenciais, tais como exposição cumulativa a antipsicóticos, tempo de doença e gravidade da doença. Métodos: Selecionou-se uma ampla amostra de pacientes com esquizofrenia (161, sendo 99 crônicos e 62 de primeiro episódio) e controles (151) a partir de quatro estudos prévios de RM (1,5T) realizados na mesma região do Brasil. O processamento e análise das imagens foi realizado usando-se o software Statistical Parametric Mapping (SPM8) com emprego do algoritmo DARTEL (diffeomorphic anatomical registration through exponentiated Lie algebra). Os efeitos de grupo sobre os volumes regionais de substância cinzenta (SC) foram analisados através de comparações voxel-a-voxel por análises de covariância em modelos lineares gerais, inserindo-se, em todas as análises, o volume total de SC, protocolo do scanner, idade e sexo como variáveis de confusão. Por fim, foram realizadas análises de correlação entre os aludidos moderadores clínicos potenciais e os volumes cerebrais globais e regionais. Resultados: Os pacientes com esquizofrenia de primeiro episódio apresentaram reduções volumétricas sutis em comparação aos controles, em um circuito neural circunscrito e identificável apenas em análises SVC (small volume correction) [p < 0.05, com correção family-wise error (FWE)], incluindo a ínsula, estruturas têmporo-límbicas e corpo estriado. Os pacientes crônicos, por outro lado, apresentaram um padrão de alterações extensas comparativamente aos controles, envolvendo os córtices frontais orbitais, superiores e inferiores bilateralmente, córtex frontal médio direito, ambos os córtices cingulados anteriores, ambas as ínsulas, e os córtices temporais superior e médio direitos (p < 0.05, análises whole-brain com correção FWE). Foram encontradas correlações negativas significantes entre exposição cumulativa a antipsicóticos e volumes globais de SC e substância branca nos pacientes com esquizofrenia, embora as correlações com reduções regionais não tenham sido significantes. Detectaram-se, ainda, correlações negativas significantes entre tempo de doença e volumes regionais relativos da ínsula esquerda, córtex cingulado anterior direito e córtices pré-frontais dorsolaterais nas análises SVC para os grupos conjuntos (esquizofrenia crônica e de primeiro episódio). Conclusão: Os achados supracitados indicam que: a) as alterações estruturais associadas com o diagnóstico de esquizofrenia são mais disseminadas na forma crônica em comparação à de primeiro episódio; b) reduções volumétricas regionais em áreas específicas do cérebro podem variar em função do tempo de doença; c) a exposição cumulativa a antipsicóticos associou-se a alterações volumétricas globais, e não regionais / Introduction: Although structural brain changes in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression, cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls have been very scarce to date. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, illness duration and overall illness severity. Methods: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses ]p < 0.05, family-wise error (FWE)-corrected], including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). Significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. There were also significant negative correlations between duration of illness and relative GM volumes of the left insula, and right anterior cingulate and dorsolateral prefrontal cortices on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. Conclusion: The above data indicate that: a) brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients; b) relative GM volume deficits in specific brain regions may vary as a function of duration of illness; c) cumulative doses of antipsychotics usage were associated with brain volumes globally rather than regionally

Introdução: Embora alterações estruturais cerebrais na esquizofrenia venham sendo repetidamente demonstradas em estudos de ressonância magnética (RM), ainda permanece incerto se tais alterações são estáticas ou progressivas. Enquanto estudos longitudinais são tradicionalmente utilizados na avaliação da questão da progressão, estudos transversais de neuroimagem comparando diretamente pacientes com esquizofrenia crônica e de primeiro episódio a controles saudáveis têm sido bastante raros até o presente. Com o recente interesse em meganálises combinando dados multicêntricos de RM visando-se a maior poder estatístico, o presente estudo multicêntrico de morfometria baseada no voxel (VBM) foi realizado para avaliar os padrões de alterações estruturais cerebrais segundo os diferentes estágios da doença, bem como para avaliar quais (se alguma) dessas alterações se correlacionariam especificamente a moderadores clínicos potenciais, tais como exposição cumulativa a antipsicóticos, tempo de doença e gravidade da doença. Métodos: Selecionou-se uma ampla amostra de pacientes com esquizofrenia (161, sendo 99 crônicos e 62 de primeiro episódio) e controles (151) a partir de quatro estudos prévios de RM (1,5T) realizados na mesma região do Brasil. O processamento e análise das imagens foi realizado usando-se o software Statistical Parametric Mapping (SPM8) com emprego do algoritmo DARTEL (diffeomorphic anatomical registration through exponentiated Lie algebra). Os efeitos de grupo sobre os volumes regionais de substância cinzenta (SC) foram analisados através de comparações voxel-a-voxel por análises de covariância em modelos lineares gerais, inserindo-se, em todas as análises, o volume total de SC, protocolo do scanner, idade e sexo como variáveis de confusão. Por fim, foram realizadas análises de correlação entre os aludidos moderadores clínicos potenciais e os volumes cerebrais globais e regionais. Resultados: Os pacientes com esquizofrenia de primeiro episódio apresentaram reduções volumétricas sutis em comparação aos controles, em um circuito neural circunscrito e identificável apenas em análises SVC (small volume correction) [p < 0.05, com correção family-wise error (FWE)], incluindo a ínsula, estruturas têmporo-límbicas e corpo estriado. Os pacientes crônicos, por outro lado, apresentaram um padrão de alterações extensas comparativamente aos controles, envolvendo os córtices frontais orbitais, superiores e inferiores bilateralmente, córtex frontal médio direito, ambos os córtices cingulados anteriores, ambas as ínsulas, e os córtices temporais superior e médio direitos (p < 0.05, análises whole-brain com correção FWE). Foram encontradas correlações negativas significantes entre exposição cumulativa a antipsicóticos e volumes globais de SC e substância branca nos pacientes com esquizofrenia, embora as correlações com reduções regionais não tenham sido significantes. Detectaram-se, ainda, correlações negativas significantes entre tempo de doença e volumes regionais relativos da ínsula esquerda, córtex cingulado anterior direito e córtices pré-frontais dorsolaterais nas análises SVC para os grupos conjuntos (esquizofrenia crônica e de primeiro episódio). Conclusão: Os achados supracitados indicam que: a) as alterações estruturais associadas com o diagnóstico de esquizofrenia são mais disseminadas na forma crônica em comparação à de primeiro episódio; b) reduções volumétricas regionais em áreas específicas do cérebro podem variar em função do tempo de doença; c) a exposição cumulativa a antipsicóticos associou-se a alterações volumétricas globais, e não regionais / Introduction: Although structural brain changes in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression, cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls have been very scarce to date. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, illness duration and overall illness severity. Methods: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses ]p < 0.05, family-wise error (FWE)-corrected], including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). Significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. There were also significant negative correlations between duration of illness and relative GM volumes of the left insula, and right anterior cingulate and dorsolateral prefrontal cortices on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. Conclusion: The above data indicate that: a) brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients; b) relative GM volume deficits in specific brain regions may vary as a function of duration of illness; c) cumulative doses of antipsychotics usage were associated with brain volumes globally rather than regionally

Introdução: Os glicocorticoides (GCs) estão envolvidos na regulação e adaptação da resposta ao estresse, exercendo seus efeitos através de seus receptores. Variações polimórficas no gene do receptor de glicocorticoide (GR) têm sido caracterizadas funcionalmente. O polimorfismo A3669G do gene do GR está relacionado a modificações na sensibilidade aos GCs e mudanças no perfil metabólico. Concentrações fisiológicas de GCs estimulam a ingestão calórica e, na presença de insulina, modificam a preferência alimentar. A variante A3669G do gene do GR parece levar a um menor risco para diabetes, em pacientes com Síndrome de Cushing, e para o tabagismo, quando associado a um polimorfismo do gene do receptor de mineralocorticoide, sugerindo uma modulação na via de recompensa. O objetivo deste trabalho é avaliar a associação de variantes do polimorfismo A3669G do gene do GR com o comportamento alimentar e parâmetros metabólicos em uma amostra de estudantes, correlacionando com dados de neuroimagem funcional. Métodos: A amostra provém de alunos de 6 escolas de Porto Alegre, avaliados em 2008 e em 2013. Em 2008, 131 indivíduos apresentavam o protocolo completo de avaliação e, destes, 74 retornaram em 2013. A avaliação incluiu genotipagem, antropometria, exames laboratoriais, comportamento alimentar e um paradigma avaliando a ativação cerebral em resposta a visualização de imagens de alimentos palatáveis, não palatáveis e de objetos neutros. A análise da associação com os fenótipos foi realizada através do teste t de Student e Chi quadrado; os dados do estudo longitudinal foram analisados por meio de Equações de Estimatição Generalizada. Resultados: A variante G do polimorfismo A3669G do gene do GR foi encontrado em 17,6% em 2008 e em 14,9% da amostra em 2013. Não houve diferença entre os grupos de carreadores do alelo G e não carreadores quanto a diferentes confundidores; a comparação entre as médias dos dois grupos sobre o consumo calórico proveniente de proteínas, carboidratos e gorduras em 2008 não revelou diferenças significativas; nesta etapa, as análises evidenciaram maior consumo de açúcares e de calorias totais no grupo não carreador do alelo G. Em 2013, estes indivíduos não carreadores do alelo G do polimorfismo A3669G apresentaram maior insulinemia e além de aumento no índice de resistência à insulina, sem diferenças no consumo alimentar. Os dados de neuroimagem funcional indicaram que a visualização de imagens de alimentos palatáveis pelo grupo não carreador do alelo G ativou o giro occipital médio, uma região implicada no processamento visual, mostrando menor ativação em giro pré central e nas áreas de Brodmann 4 e 6, relacionadas ao planejamento motor e sensibilidade ao sabor. Conclusão: Os resultados mostram que os indivíduos não carreadores da variante G do polimorfismo A3669G do gene do GR apresentaram menor sensibilidade à insulina, precedidos pela modulação na preferência alimentar. Os achados em neuroimagem funcional indicam maior saliência de incentivo aos alimentos palatáveis e predisposição à impulsividade no grupo não carreador do alelo G. Sugere-se que a redução na sensibilidade em nível celular aos GCs relacionada à presença do alelo G, afete a ingestão alimentar, reduzindo o consumo de alimentos palatáveis, diminuindo o risco para doenças metabólicas. / Introduction: Glucocorticoids are involved in regulation and adaptation of the stress response, exerting effects through its receptors. Variations on the glucocorticoid receptors genes have been characterized functionally. The A3669G polymorphism of the glucocorticoid receptor gene is related to a change in the tissue sensitivity to glucocorticoids and altered metabolic profile. Physiological concentrations of glucocorticoids stimulate food intake and in the presence of insulin affect food preferences. The G variant of the A3669G polymorphism appears to lead to a lower risk for diabetes, in patients with Cushing's syndrome, and smoking, when associated with a polymorphism of the mineralocorticoid receptor gene, suggesting a modulation in reward pathways. The objective of this study is to evaluate the association of A3669G polymorphism variants with feeding behavior and metabolic parameters in a sample of students correlating with functional neuroimaging data. Methods: The sample includes students of 6 schools in Porto Alegre, evaluated at two occasions 2008 and in 2013. In 2008, 131 individuals had complete protocol assessment and, from these, 74 returned in for re- evaluation in 2013. The evaluation included genotyping, anthropometry, laboratory tests, feeding behavior and a functional MRI paradigm to verify brain activation in response to the visualization of palatable, non- palatable foods and neutral items. The association with phenotypes was performed using Student's t test and Chi-square; longitudinal study data were evaluated using Generalized Estimating Equations. Results: The variant of the A3669G polymorphism was found in 17.6% of the students in 2008 and 14.9% of the sample in 2013. There was no difference between groups in the sample composition; the comparison between groups of the mean caloric intake originating from proteins, carbohydrates and fats in 2008 revealed no significant differences; at this time, analysis showed lower consumption of sugars and total calories in the G carrier group. In 2013, these individuals showed a reduction in insulin level and resistance, with no differences in food intake. The fMRI data indicated that viewing a food palatable image by the wild-type allele carrier group activated a region involved in visual processing (middle occipital gyrus) and deactivated an area related to motor planning and sensitivity to taste (pre central gyrus). Conclusion: The results showed that G carriers of the A3669G polymorphism of glucocorticoid receptor gene had lower insulin resistance levels, preceded by modulation of their food preference. The findings in functional neuroimaging showed increased incentive salience on viewing palatable food images and a predisposition for impulsivity in noncarriers. Data suggest that reduction in glucocorticoids sensitivity at a cellular level affects food intake, by reducing consumption of palatable foods, possibly decreasing the risk for metabolic diseases.

Submitted by Fernanda Furlanetto Bellentani null (fernandafbelle@gmail.com) on 2017-03-07T01:02:32Z No. of bitstreams: 1 Tese Bellentani FF.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-03-10T16:53:16Z (GMT) No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Made available in DSpace on 2017-03-10T16:53:16Z (GMT). No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) Previous issue date: 2017-02-17 / A conectividade funcional é anormal na epilepsia do lobo temporal mesial (ELTm). O objetivo deste estudo foi investigar os efeitos de fármacos antiepilépticos (FAES) na conectividade funcional de pacientes com ELTm. Para isso, 31 pacientes com ELTm (16 à direita e 15 à esquerda) e 36 controles foram investigados. Sequências 3D volumétricas T1 e imagens funcionais a partir de sinal BOLD foram adquiridas em um equipamento 3T. Os dados da ressonância magnética funcional (RMf) em repouso foram processados e analisados utilizando o programa CONN. Para cada sujeito, duas formas de análise foram realizadas: uma de correlação entre as várias regiões de interesse e outra de região interesse para todos os voxels. A análise de grupos foi feita utilizando um modelo linear geral com nível de significância de p < 0,05 corrigido para múltiplas comparações. Foram realizadas comparações entre pacientes com ELTm (direita ou esquerda) e controles, seguidas de comparações de acordo com a carga de FAEs. A partir dessas análises, foi constatado uma redução de conectividade com volume total de 9092 mm3 (p<0,0001), em pacientes com ELTm esquerda e 5234 mm3 (p<0,0001), em pacientes com ELTm direita . Quando considerada a carga de medicação, pacientes com ELTm esquerda, recebendo doses altas, apresentaram redução de conectividade nas regiões temporais. Nos pacientes que recebiam doses baixas, essa redução atingiu uma área total mais extensa, no córtex frontal medial, na região posterior do cíngulo e pré-cúneo. Para o lado direito, em pacientes recebendo doses altas, a redução de conectividade foi observada apenas na área do cótex frontal medial. Nos que receberam doses baixas, 2 áreas com redução foram observadas (córtex frontal medial e região posterior do cíngulo) e com uma extensão maior. A análise de correlação envolvendo regiões de interesse mostrou, para ambos os lados, que o circuito amígdalo-hipocampal e a rede de modo padrão apresentaram maior conectividade quando utilizadas maiores doses de FAEs. Com base nesses resultados, foram confirmadas áreas de conectividade funcional anormal em pacientes com ELTm e que se apresentam mais difusas em pacientes com ELTm esquerda. Conclui-se também que as doses de medicamentos podem influenciar nestas observações, uma vez que o aumento de dose tende a normalizar a conectividade funcional cerebral. / The functional connectivity is abnormal in mesial temporal lobe epilepsy (MTLE). The objective of this study was to investigate the effects of antiepileptic drugs (AED) laterality and medication effect in the functional connectivity of MTLE. For this, 31 patients with MTLE (16 right and 15 left) and 36 controls were investigated. 3D volumetric sequences T1 and functional images from BOLD signal were acquired in a 3T equipment. Functional magnetic resonance imaging (fMRI) data were processed and analyzed using the CONN program. Two forms of analysis were performed for each patient: one of correlation between the various regions of interest and other of region of interest for all the voxels. The group analyzes was done following a general linear model with a level of significance of p < 0,05 corrected for the multiple comparisons. Comparisons were made between patients with MTLE (right or left) and controls, following of comparisons according to the AED. From these analysis, it was observed that in patients with left MTLE, there was a reduction in connectivity with total volume of 9092 mm³ (p<0,0001) and in patients with right MTLE, the areas of decreased connectivity totaled 5234 mm³ (p<0,0001). When considering the medication load, patients with left MTLE receiving high doses presented reduced connectivity in the temporal regions and in patients receiving low doses, this reduction reached a more extensive total area, in the medial frontal cortex, in the posterior region of the cingulate and pre-cuneous. To the right side, in patients receiving high doses, a reduced connectivity was observed only in the area of the medial frontal cortex, whereas in those receiving low doses, 2 areas with reduction were observed (medial frontal cortex and posterior cingulate region). The analysis of correlation involving regions of interest showed, to both sides that the amygdalo-hippocampal circuit and the network pattern mode presented greater connectivity when higher doses of AED. Based on these results were confirmed areas of abnormal functional connectivity in patients with MTLE and are more difuse in patients with left MTLE. It was also concluded that drug doses can influence these observations, once the doses increase tends to normalize functional brain connectivity.

This lecture takes a dual-targeted approach in: 1) acquainting the audience with newer neuroimaging techniques applied to the consequences of vestibular dysregulation following noise or blast-induced mild traumatic brain injury (mTBI); and 2) considers treatment and rehabilitation modalities of vestibular and balance dysfunction in order to help veteran’s resume normal activities-of-daily-living. Relevant examples from each targeted lecture will be provided. Intended Audience: Professionals interested in the area of vestibular and balance assessment, neuroimaging, and rehabilitation.