In vivo Structural Imaging of the Cerebellum, the Contribution of Ultra-High Fields.

This review covers some of the contributions to date from cerebellar imaging studies performed at ultra-high magnetic fields. A short overview of the general advantages and drawbacks of the use of such high field systems for imaging is given. One of the biggest advantages of imaging at high magnetic fields is the improved spatial resolution, achievable thanks to the increased available signal-to-noise ratio. This high spatial resolution better matches the dimensions of the cerebellar substructures, allowing a better definition of such structures in the images. The implications of the use of high field systems is discussed for several imaging sequences and image contrast mechanisms. This review covers studies which were performed in vivo in both rodents and humans, with a special focus on studies that were directed towards the observation of the different cerebellar layers.

Local alignment refinement using structural assessment.

Homology modeling is the most commonly used technique to build a three-dimensional model for a protein sequence. It heavily relies on the quality of the sequence alignment between the protein to model and related proteins with a known three dimensional structure. Alignment quality can be assessed according to the physico-chemical properties of the three dimensional models it produces.In this work, we introduce fifteen predictors designed to evaluate the properties of the models obtained for various alignments. They consist of an energy value obtained from different force fields (CHARMM, ProsaII or ANOLEA) computed on residue selected around misaligned regions. These predictors were evaluated on ten challenging test cases. For each target, all possible ungapped alignments are generated and their corresponding models are computed and evaluated.The best predictor, retrieving the structural alignment for 9 out of 10 test cases, is based on the ANOLEA atomistic mean force potential and takes into account residues around misaligned secondary structure elements. The performance of the other predictors is significantly lower. This work shows that substantial improvement in local alignments can be obtained by careful assessment of the local structure of the resulting models.

Developmental critical period in genetic redox dysregulation: animal and human studies in schizophrenia

Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the major cellular antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Importantly, abnormal GSH synthesis of genetic origin was observed: Two case-control studies showed an association with a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease associated genotypes (35% of patients) correlated with decreased GCLC protein, GCL activity and GSH content. Similar GSH system anomalies were observed in early psychosis patients. Such redox dysregulation combined with environmental stressors at specific developmental stages could underlie structural and functional connectivity anomalies. In pharmacological and knock-out (KO) models, GSH deficit induces anomalies analogous to those reported in patients. (a) morphology: spine density and GABA-parvalbumine immunoreactivity (PV-I) were decreased in anterior cingulate cortex. KO mice showed delayed cortical PV-I at PD10. This effect is exacerbated in mice with increased DA from PD5-10. KO mice exhibit cortical impairment in myelin and perineuronal net known to modulate PV connectivity. (b) physiology: In cultured neurons, NMDA response are depressed by D2 activation. In hippocampus, NMDA-dependent synaptic plasticity is impaired and kainate induced g-oscillations are reduced in parallel to PV-I. (c) cognition: low GSH models show increased sensitivity to stress, hyperactivity, abnormal object recognition, olfactory integration and social behavior. In a clinical study, GSH precursor N-acetyl cysteine (NAC) as add on therapy, improves the negative symptoms and decreases the side effects of antipsychotics. In an auditory oddball paradigm, NAC improves the mismatched negativity, an evoked potential related to pre-attention and to NMDA receptors function. In summary, clinical and experimental evidence converge to demonstrate that a genetically induced dysregulation of GSH synthesis combined with environmental insults in early development represent a major risk factor contributing to the development of schizophrenia

Predicting human resting-state functional connectivity from structural connectivity

In the cerebral cortex, the activity levels of neuronal populations are continuously fluctuating. When neuronal activity, as measured using functional MRI (fMRI), is temporally coherent across 2 populations, those populations are said to be functionally connected. Functional connectivity has previously been shown to correlate with structural (anatomical) connectivity patterns at an aggregate level. In the present study we investigate, with the aid of computational modeling, whether systems-level properties of functional networks-including their spatial statistics and their persistence across time-can be accounted for by properties of the underlying anatomical network. We measured resting state functional connectivity (using fMRI) and structural connectivity (using diffusion spectrum imaging tractography) in the same individuals at high resolution. Structural connectivity then provided the couplings for a model of macroscopic cortical dynamics. In both model and data, we observed (i) that strong functional connections commonly exist between regions with no direct structural connection, rendering the inference of structural connectivity from functional connectivity impractical; (ii) that indirect connections and interregional distance accounted for some of the variance in functional connectivity that was unexplained by direct structural connectivity; and (iii) that resting-state functional connectivity exhibits variability within and across both scanning sessions and model runs. These empirical and modeling results demonstrate that although resting state functional connectivity is variable and is frequently present between regions without direct structural linkage, its strength, persistence, and spatial statistics are nevertheless constrained by the large-scale anatomical structure of the human cerebral cortex.

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Structural connectomics in brain diseases.

Imaging the connectome in vivo has become feasible through the integration of several rapidly developing fields of science and engineering, namely magnetic resonance imaging and in particular diffusion MRI on one side, image processing and network theory on the other side. This framework brings in vivo brain imaging closer to the real topology of the brain, contributing to narrow the existing gap between our understanding of brain structural organization on one side and of human behavior and cognition on the other side. Given the seminal technical progresses achieved in the last few years, it may be ready to tackle even greater challenges, namely exploring disease mechanisms. In this review we analyze the current situation from the technical and biological perspectives. First, we critically review the technical solutions proposed in the literature to perform clinical studies. We analyze for each step (i.e. MRI acquisition, network building and network statistical analysis) the advantages and potential limitations. In the second part we review the current literature available on a selected subset of diseases, namely, dementia, schizophrenia, multiple sclerosis and others, and try to extract for each disease the common findings and main differences between reports.

Justification du système économique et perception du travail en groupe

L'étude classique des attributions de responsabilité instiguée par Heider en psychologie sociale s'est principalement bornée à aborder ce processus psychosocial dans une perspective individualiste qui se cantonne aux niveaux intra-individuel et interpersonnel (selon la distinction opérée par Doise). Les réflexions et les travaux empiriques présentés dans cette thèse ont deux objectifs. Dans un premier temps, il s?agit d'élargir cette perspective aux autres niveaux sociologique et idéologique (en faisant notamment recours à l'approche des attributions sociales et aux propositions de Fauconnet sur les règles de responsabilité). Deuxièmement, il s?agit d'éprouver la pertinence d'une telle approche dans un contexte particulier : celui du travail en groupe dont la nature des rapports sociaux qui y étaient présentés ont été manipulés à l'aide de scénarii chez des étudiant-e-s de l?Université de Lausanne. L?objectif principal de cette thèse est donc de tester un modèle d?ancrage des attributions de responsabilité qui permette de souligner les dynamiques représentationnelles sous-jacentes en termes de légitimation ou de remise en cause de l?organisation des groupes. Dans l?ensemble les résultats indiquent que si la nature des rapports sociaux (re)présentés dans un groupe sont de puissants déterminants de la manière de légitimer ou de remettre en cause l?organisation des groupes, le niveau individuel d'adhésion à des croyances idéologiques dominantes, comme la justification du système économique, représente un modérateur des prises de position des répondant-e-s interrogé-e-s. De plus, il semble que ces processus évoluent dans le temps, faisant ainsi apparaître l'existence de phénomènes de socialisation relativement plus complexes que ne le laissent entendre les recherches actuellement effectuées dans ce domaine. En effet, si des connaissances idéologiques sur le monde sont acquises dans les filières universitaires et n?interviennent pas toujours dans les processus de formation des représentations du travail en groupe, des connaissances spécifiques aux disciplines et à la politique de sélection universitaire semblent intervenir dans le processus de légitimation des rapports sociaux dans les groupes au niveau des attributions. En tentant une articulation entre les concepts d?ancrage des représentations sociales, d?attribution et de socialisation, cette thèse permet ainsi de souligner la pertinence qu?il y a à insérer une problématique en termes de croyances idéologiques dans l?étude des groupes sociaux.<br/><br/>Heider?s approach of responsibility attributions almost exclusively emphasized on an individualistic point of view ; i.e. focusing at an intraindividual and interpersonnal level of analysis according to Doise?s distinction. The reflexions and empirical studies presented here firstly aim at broaden this perspective by taking socio-structural as well as societal levels of analysis into account. Secondly, it is to test this approach in the particular domain of organized groups. Manipulation of the structure of social relations in work groups on screenplays were undertaken (in a population of students from the Lausanne University). Hence, the main goal of these studies is to test the impact of the social ancoring of social representations in the responsibility processes in terms of legitimation or opposition to the group organization. All in all, the results show that social structures are powerfull predictors of the formation of social representations of a work situation and so forth of the attribution process. Nevertheless hegemonic ideological beliefs, such as Economical System Justification, do play a substantial moderating role in this process. It also proves to be evolving through time. The present findings show that a complexe process of socialization is occuring during the student?s university life. Indeed, the results let us believe that ideological beliefs may not interact anytime in the group?s perception and in the construction of the representation of the situation. In the same time, it seems that more discipline specific oriented knowledge and the impact of selection policy at the Lausanne University also predict the groupe legimation process and interfer with the ideological beliefs. Trying to articulate concepts of fields of research like social representations, attribution and socialization, the present thesis allows to underline the heuristic potential of reabilitating ideological beliefs at a dispositional level in the study of group process.

Atypical coordination of cortical oscillations in response to speech in autism.

Subjects with autism often show language difficulties, but it is unclear how they relate to neurophysiological anomalies of cortical speech processing. We used combined EEG and fMRI in 13 subjects with autism and 13 control participants and show that in autism, gamma and theta cortical activity do not engage synergistically in response to speech. Theta activity in left auditory cortex fails to track speech modulations, and to down-regulate gamma oscillations in the group with autism. This deficit predicts the severity of both verbal impairment and autism symptoms in the affected sample. Finally, we found that oscillation-based connectivity between auditory and other language cortices is altered in autism. These results suggest that the verbal disorder in autism could be associated with an altered balance of slow and fast auditory oscillations, and that this anomaly could compromise the mapping between sensory input and higher-level cognitive representations.

Langues et identités culturelles: oscillations de l'école du monolinguisme au plurilinguisme et des discours aux pratiques.

Pourquoi traiter de l'école pour aborder le rapport entre langue et culture ? Car, dans mon parcours personnel, l'institution scolaire a tenu un rôle prédominant dans la construction du lien entre mes langues - l'italien et le français - et mes appartenances culturelles. Ainsi, la première partie du mémoire porte sur cette histoire-là d'une part, et sur l'élaboration du travail de recherche de l'autre. La deuxième et la troisième partie du mémoire affrontent les oscillations de l'école quant à la question linguistique. Le terme école comprend ici tout ce qui touche, conceptuellement ou pragmatiquement, au monde scolaire. En effet, les discours sur l'école et les pratiques au sein de l'école sont les deux facettes d'une même médaille. Plus précisément, la deuxième partie expose les rhétoriques émanant des sciences humaines d'un côté, et des discours politiques de l'autre. Nous verrons comment ces deux sphères sont étroitement liées. D'une même voix, elles affirment le lien entre la langue et l'identité culturelle et exhortent l'institution scolaire à la valorisation du multilinguisme. Comme annoncé, la troisième partie constitue un retour au singulier et entre dans la pratique de l'école. A travers les entretiens réalisés avec des enseignants de l'école vaudoise, il s'agit d'appréhender le lien entre les discours et les pratiques, l'universel et le particulier. Nous constaterons qu'à ce niveau-là, les credo du monolinguisme et du multilinguisme combattent encore l'un contre l'autre. Expliciter le sous-titre du mémoire permet de réduire les malentendus. Celui-ci annonce deux types d'oscillations, étroitement articulées l'une à l'autre. Premièrement, les oscillations du monolinguisme au plurilinguisme observables dans deux dimensions. Une diachronique - qui n'est pas traitée dans ce travail - mettrait en lumière le passage d'une conception strictement monolingue de l'école à une conception plurilingue qui se diffuse depuis quelques années. La dimension synchronique, retenue dans ce mémoire, révèle comment, au sein du corps enseignant vaudois d'aujourd'hui, la perception monolingue des uns résiste aux assauts du paradigme plurilingue des autres. Deuxièmement, les oscillations de l'école prise entre les discours et les pratiques. Tantôt dans un rapport de force, tantôt dans une réciprocité créatrice, ces deux pôles négocient constamment les conditions d'existence de l'école. L'actualité de l'école vaudoise, avec la réintroduction des notes au niveau secondaire à la rentrée scolaire d'août 2005, est un exemple concret de cette oscillation de l'institution scolaire qui résulte de la négociation entre les discours et les pratiques.

Refractory intraretinal or subretinal fluid in neovascular age-related macular degeneration treated with intravitreal ranizubimab: Functional and Structural Outcome.

PURPOSE: To investigate the visual acuity results of eyes with neovascular age-related macular degeneration and refractory fluid despite monthly treatment with ranibizumab, and to investigate differences between refractory subretinal fluid and intraretinal cystic changes. METHODS: Retrospective chart review of consecutive treatment-refractory neovascular age-related macular degeneration, defined as persistent intraretinal or subretinal fluid despite monthly ranibizumab injections during 12 months or more. Data were evaluated for baseline characteristics, type and location of the refractory fluid, mean visual acuity change, number of injections, and the time point of first complete disappearance of all fluid on spectral domain optical coherence tomography. RESULTS: Seventy-six eyes (74 patients, mean age, 76.8 years) were identified. The mean follow-up was 33.6 months (range, 12-73 months). The mean number of injections was 11.4 in the first year and 27.7 over follow-up. The refractory fluid was located subfoveally in 61.8%. In 27 eyes (35.5%), the fluid resolved after a mean of 21.8 months (range, 13-49 months). Mean visual acuity increased by 9.0, 7.9, and 7.9 letters by Month 12, Month 24, and Month 36, respectively. Subgroup analysis revealed a higher risk for fibrosis (odds ratio, 3.30) or atrophy (odds ratio, 3.34) in patients with refractory cysts as compared with refractory subretinal fluid. Furthermore, refractory cysts showed a higher risk for a 10-letter visual acuity loss (P = 0.018). CONCLUSION: Fluid refractory to monthly treatment with ranibizumab for neovascular age-related macular degeneration still allowed for well-maintained visual improvement, even in subfoveal location. Late fluid resolution may occur. However, refractory cysts were associated with poorer anatomical and functional outcome than subretinal fluid.

Basal ganglia-cortical structural connectivity in Huntington's disease.

Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia-cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia-cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3-Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel-based analyses of probabilistic tractography were used to quantify basal ganglia-cortical structural connections. Canonical variate analysis was used to demonstrate disease-associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia-cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728-1740, 2015. © 2015 Wiley Periodicals, Inc.