Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth.

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.

Omistus, kontrolli ja päämies-agentti- ongelmat osakeyhtiössä

Tutkielman tavoitteena on selvittää osakeyhtiön määräysvaltasuhteet ja miten päämies-agentti- ongelmat vaikeuttavat määräysvallan käyttöä. Tutkimusmetodi on lainopillinen ja lähestyminen aiheeseen tapahtuu sekä yhtiöoikeudellisesta, että oikeustaloustieteellisestä näkökulmasta. Aineistona tutkielmassa käytetään lähinnä voimassa olevaa lainsäädäntöä ja oikeuskirjallisuutta. Päämies-agentti- ongelmalla tarkoitetaan osakeyhtiössä määräysvallan osittaista luisumista omistajalta (päämies) yritysjohdolle (agentti) tai vähemmistöomistajalta (päämies) kontrolloivalle omistajalle (agentti). Tärkeimpiä ongelman lähteitä ovat epäsymmetrinen informaatio ja intressiristiriidat yhtiön johdon ja omistajien välillä tai toisaalta yhtiötä lähellä olevien omistajien ja muiden omistajien välillä. Epäsymmetrinen informaatio luo osaltaan puitteet agenttitahojen opportunistiselle käyttäytymiselle. Ratkaisuja päämies-agentti- ongelmiin ovat ennen kaikkea päämiestahoja suojaava lainsäädäntö ja ulkoiset yritysjohtajien käyttäytymistä ohjaavat keinot, kuten erilaiset kannustinjärjestelmät ja hyvät hallintotavat. Kontrolloivien omistajien käyttäytymistä on puolestaan vaikea ohjata ja erilaisilla määräysvaltaa keskittävillä omistusrakenteilla onkin taipumus voimistaa päämies-agentti- ongelmien vaikutusta. Erityisiä tilanteita osaltaan luovat myös luonteiltaan erilaiset omistajatahot, kuten institutionaaliset omistajat.

Microstructure of the superior longitudinal fasciculus predicts stimulation-induced interference with on-line motor control.

A cortical visuomotor network, comprising the medial intraparietal sulcus (mIPS) and the dorsal premotor area (PMd), encodes the sensorimotor transformations required for the on-line control of reaching movements. How information is transmitted between these two regions and which pathways are involved, are less clear. Here, we use a multimodal approach combining repetitive transcranial magnetic stimulation (rTMS) and diffusion tensor imaging (DTI) to investigate whether structural connectivity in the 'reaching' circuit is associated to variations in the ability to control and update a movement. We induced a transient disruption of the neural processes underlying on-line motor adjustments by applying 1Hz rTMS over the mIPS. After the stimulation protocol, participants globally showed a reduction of the number of corrective trajectories during a reaching task that included unexpected visual perturbations. A voxel-based analysis revealed that participants exhibiting higher fractional anisotropy (FA) in the second branch of the superior longitudinal fasciculus (SLF II) suffered less rTMS-induced behavioral impact. These results indicate that the microstructural features of the white matter bundles within the parieto-frontal 'reaching' circuit play a prominent role when action reprogramming is interfered. Moreover, our study suggests that the structural alignment and cohesion of the white matter tracts might be used as a predictor to characterize the extent of motor impairments.

Las reglas de la mayoría y Borda: un ejercicio de simulación

En el presente documento se describe un ejercicio de simulación orientado a facilitar la comprensión y asimilación del funcionamiento de la votación por mayoría y la regla de Borda. El ejercicio consiste en proponer a los alumnos que escojan entre dos proyectos (un programa de becas y una ampliación de las aulas de estudio) que presuntamente se van a realizar en la facultad en la que estudian. Para determinar qué proyecto se debería llevar a cabo se utiliza las reglas de la mayoría y Borda. Los alumnos deben responder a diversas rondas de votaciones donde el orden de la votación o agenda ha sido determinada por el instructor. El ejercicio es útil para exponer y debatir las cuestiones que se explican en un curso estándar de Hacienda Pública sobre el uso de la regla de la mayoría y la regla de Borda, como por ejemplo, la existencia de ciclos en los resultados de una votación, la posibilidad de condicionar el resultado de las votaciones mediante la manipulación de la agenda, el comportamiento estratégico, la formación de coaliciones, las propiedades del teorema de Arrow y la eficiencia de la(s) diferentes alternativas escogidas. El ejercicio se enmarca como parte de las actividades realizadas por el Grupo de Innovación Docente (GID-HAL) de la Universidad de Barcelona.

Oportunidades estratégicas para la implementación del voto electrónico remoto

A partir d"una anàlisi comparada de diferents experiències d"implementació del vot electrònic remot a Espanya i de dades sociopolítiques de valoració d"aquestes votacions, es discuteixen els diferents arguments justificadors de la seva implementació. S"analitzen així els arguments estructurals que incentiven l"adopció del vot electrònic en el context del funcionament dels sistemes polítics democràtics, sense oblidar, però, la percepció i l"avaluació dels ciutadans davant l"ús de les NTIC per a l"emissió del vot. L"anàlisi se centra en la presa en consideració de les debilitats i les amenaces potencials associades a la introducció del vot electrònic, per a concloure que la seva implementació haurà d"ésser progressiva i complementària als sistemes tradicionals de votació.

Eduskuntaryhmien äänestyskoheesio vuosien 1991-2006 valtiopäivillä

Abstract: Voting cohesion in the Finnish Parliament during 1991-2006

An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a genetic disease known to lead to cerebral structural alterations, which we study using the framework of the macroscopic white-matter connectome. We create weighted connectomes of 44 patients with 22q11DS and 44 healthy controls using diffusion tensor magnetic resonance imaging, and perform a weighted graph theoretical analysis. After confirming global network integration deficits in 22q11DS (previously identified using binary connectomes), we identify the spatial distribution of regions responsible for global deficits. Next, we further characterize the dysconnectivity of the deficient regions in terms of sub-network properties, and investigate their relevance with respect to clinical profiles. We define the subset of regions with decreased nodal integration (evaluated using the closeness centrality measure) as the affected core (A-core) of the 22q11DS structural connectome. A-core regions are broadly bilaterally symmetric and consist of numerous network hubs - chiefly parietal and frontal cortical, as well as subcortical regions. Using a simulated lesion approach, we demonstrate that these core regions and their connections are particularly important to efficient network communication. Moreover, these regions are generally densely connected, but less so in 22q11DS. These specific disturbances are associated to a rerouting of shortest network paths that circumvent the A-core in 22q11DS, "de-centralizing" the network. Finally, the efficiency and mean connectivity strength of an orbito-frontal/cingulate circuit, included in the affected regions, correlate negatively with the extent of negative symptoms in 22q11DS patients, revealing the clinical relevance of present findings. The identified A-core overlaps numerous regions previously identified as affected in 22q11DS as well as in schizophrenia, which approximately 30-40% of 22q11DS patients develop.

Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging.

Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

Abstenció diferencial, vot dual i vot diferencial a L'Hospitalet de Llobregat : Estudi sobre el comportament electoral a L'Hospitalet de Llobregat entre 1979 i 2014

Aquest treball presenta un anàlisi sobre el comportament electoral a L'Hospitalet de Llobregat entre 1979 i 2014, en relació als diferents nivells de participació electoral i les diferències en el vot a partits que es produeixen segons l'àmbit de la convocatòria electoral.

Redox dysregulation in schizophrenia : effect on myelination of cortical structures and connectivity

Cette thèse traite du rôle qu'un facteur de risque génétique développé chez les patients souffrant de schizophrénie, à savoir un déficit de la synthèse du glutathion, peut jouer dans les anomalies de la connectivité cérébrale trouvées chez ces patients. L'essentiel du travail a été consacré à évaluer la structure de la substance blanche dans l'ensemble du cerveau chez un modèle animal par une méthode similaire à celle utilisée en recherche clinique avec l'imagerie par résonance magnétique (IRM). Cette approche de translation inverse chez la souris knock-out de glutamate-cystéine ligase modulateur sous-unité (Gclm KO), avait l'objectif d'étudier l'effet des défenses redox déficientes sur le développement des connexions cérébrales, tout en excluant celui des facteurs non liés au génotype. Après avoir établi le protocole de recherche, l'influence d'une manipulation environnementale a également été étudiée. Pour effectuer une analyse statistique fiable des données d'IRM obtenues, nous .avons d'abord créé un atlas du cerveau de la souris afin de l'utiliser comme modèle pour une segmentation précise des différentes régions du cerveau sur les images IRM obtenues in vivo. Les données provenant de chaque région d'intérêt ont ensuite été étudiées séparément. La qualité de cette méthode a été évaluée dans une expérience de simulation pour déduire la puissance statistique réalisable dans chaque région en fonction du nombre d'animaux utilisés. Ces outils d'analyse nous ont permis d'évaluer l'intégrité de la substance blanche dans le cerveau des souris durant le développement grâce à une expérience longitudinale, en utilisant l'imagerie du tenseur de diffusion (DTI). Nous avons ainsi observé des anomalies dans les paramètres dérivés du tenseur (diffusivité et anisotropie) dans la Commissure Antérieure et le Fimbria/Fornix des souris Gclm KO, par rapport aux animaux contrôles. Ces résultats suggèrent une substance blanche endommagée dans ces régions. Dans une expérience électrophysiologique, Pascal Steullet a montré que ces anomalies ont des conséquences fonctionnelles caractérisées par une réduction de la vitesse de conduction dans les fibres nerveuses. Ces données renforcent les conclusions des analyses d'imagerie. Le mécanisme par lequel une dérégulation redox affecte la structure de la substance blanche reste encore à définir, car une analyse immunohistochimique des protéines constituantes de la couche de myéline des fibres concernées n'a pas donné de résultats concluants. Nous avons également constaté un élargissement des ventricules dans les jeunes souris Gclm KO, mais pas chez les adultes et des anomalies neurochimiques déjà connues chez ces animaux (Duarte et al. 2011), à savoir une réduction du Glutathion et une augmentation de l'acide N-acétylaspartique, de l'Alanine et du ratio Glutamine/Glutamate. Nous avons ensuite testé l'effet d'un stress environnemental supplémentaire, l'élevage en isolement social, sur le phénotype. Ce stress n'a eu aucun effet sur la structure de la substance blanche évaluée par DTI, mais a réduit la concentration de myo-Inositol et augmenté le ratio de Glutamine/Glutamate dans le cortex frontal. Nous avons aussi reproduit dans ce groupe indépendant d'animaux les effets du génotype sur le profil neurochimique, sur la taille des ventricules et aussi sur les paramètres dérivés du tenseur de diffusion dans le Fimbria/Fornix, mais pas dans la Commissure Antérieure. Nos résultats montrent qu'une dérégulation redox d'origine génétique perturbe la structure et la fonction de la substance blanche dans des régions spécifiques, causant ainsi l'élargissement des ventricules. Ces phénotypes rassemblent certaines caractéristiques neuro-anatomiques de la schizophrénie, mais les mécanismes qui en sont responsables demeurent encore inconnus. L'isolement social n'a pas d'effet sur la structure de la substance blanche évaluée par DTI, alors qu'il est prouvé qu'il affecte la maturation des oligodendrocytes. La neurochimie corticale et en particulier le rapport Glutamine/Glutamate a été affecté par le dérèglement redox ainsi que par l'isolement social. En conséquence, ce ratio représente un indice prometteur dans la recherche sur l'interaction du stress environnemental avec le déséquilibre redox dans le domaine de la schizophrénie. -- The present doctoral thesis is concerned with the role that a genetic risk factor for the development of schizophrenia, namely a deficit in Glutathione synthesis, may play in the anomalies of brain connectivity found in patients. Most of the effort was devoted to perform a whole-brain assessment of white matter structure in the Glutamate-Cysteine ligase modulatory knockout mouse model (Gclm KO) using Magnetic Resonance Imaging (MRI) techniques similar to those used in state-of-the-art clinical research. Such reverse translational approach taking brain imaging from the bedside to the bench aimed to investigate the role that deficient redox defenses may play in the development of brain connections while excluding all influencing factors beside the genotype. After establishing the protocol, the influence of further environmental manipulations was also studied. Analysis of MRI images acquired in vivo was one of the main challenges of the project. Our strategy consisted in creating an atlas of the mouse brain to use as segmentation guide and then analyze the data from each region of interest separately. The quality of the method was assessed in a simulation experiment by calculating the statistical power achievable in each brain region at different sample sizes. This analysis tool enabled us to assess white matter integrity in the mouse brain along development in a longitudinal experiment using Diffusion Tensor Imaging (DTI). We discovered anomalies in diffusivity parameters derived from the tensor in the Anterior Commissure and Fimbria/Fornix of Gclm KO mice when compared to wild-type animals, which suggest that the structure of these tracts is compromised in the KO mice. In an elegant electrophysiological experiment, Pascal Steullet has provided evidence that these anomalies have functional consequences in form of reduced conduction velocity in the concerned tracts, thus supporting the DTI findings. The mechanism by which redox dysregulation affects WM structure remains unknown, for the immunohistochemical analysis of myelin constituent proteins in the concerned tracts produced inconclusive results. Our experiments also detected an enlargement of the lateral ventricles in young but not adult Gclm KO mice and confirmed neurochemical anomalies already known to affect this animals (Duarte et al. 2011), namely a reduction in Glutathione and an increase in Glutamine/Glutamate ratio, N-acetylaspartate and Alanine. Using the same methods, we tested the effect of an additional environmental stress on the observed phenotype: rearing in social isolation had no effect on white matter structure as assessed by DTI, but it reduced the concentration of myo-Inositol and increased the Glutamine/Glutamate ratio in the frontal cortex. We could also replicate in this separate group of animals the effects of genotype on the frontal neurochemical profile, ventricular size and diffusivity parameters in the Fimbria/Fornix but not in the Anterior Commissure. Our data show that a redox dysregulation of genetic origin may disrupt white matter structure and function in specific tracts and cause a ventricular enlargement, phenotypes that resemble some neuroanatomical features of schizophrenia. The mechanism responsible remains however unknown. We have also demonstrated that environmental stress in form of social isolation does not affect white matter structure as assessed by DTI even though it is known to affect oligodendrocyte maturation. Cortical neurochemistry, and specifically the Glutamine to Glutamate balance was affected both by redox dysregulation and social isolation, and is thus a good target for further research on the interaction of redox imbalance and environmental stress in schizophrenia.

Classifier combination for in vivo magnetic resonance spectra of brain tumours

In this paper we present a multi-stage classifier for magnetic resonance spectra of human brain tumours which is being developed as part of a decision support system for radiologists. The basic idea is to decompose a complex classification scheme into a sequence of classifiers, each specialising in different classes of tumours and trying to reproducepart of the WHO classification hierarchy. Each stage uses a particular set of classification features, which are selected using a combination of classical statistical analysis, splitting performance and previous knowledge.Classifiers with different behaviour are combined using a simple voting scheme in order to extract different error patterns: LDA, decision trees and the k-NN classifier. A special label named "unknown¿ is used when the outcomes of the different classifiers disagree. Cascading is alsoused to incorporate class distances computed using LDA into decision trees. Both cascading and voting are effective tools to improve classification accuracy. Experiments also show that it is possible to extract useful information from the classification process itself in order to helpusers (clinicians and radiologists) to make more accurate predictions and reduce the number of possible classification mistakes.

Microstructural Brain Differences Predict Functional Hemodynamic Responses in a Reward Processing Task

Many aspects of human behavior are driven by rewards, yet different people are differentially sensitive to rewards and punishment. In this study, we showthat white matter microstructure inthe uncinate/inferiorfronto-occipitalfasciculus, defined byfractional anisotropy values derived from diffusion tensor magnetic resonance images, correlates with both short-term (indexed by the fMRI blood oxygenation level-dependent response to reward in the nucleus accumbens) and long-term (indexed by the trait measure sensitivity to punishment) reactivityto rewards.Moreover,traitmeasures of reward processingwere also correlatedwith reward-relatedfunctional activation in the nucleus accumbens. The white matter tract revealed by the correlational analysis connects the anterior temporal lobe with the medial and lateral orbitofrontal cortex and also supplies the ventral striatum. The pattern of strong correlations suggests an intimate relationship betweenwhitematter structure and reward-related behaviorthatmay also play a rolein a number of pathological conditions, such as addiction and pathological gambling.

Individual Differences in True and False Memory Retrieval Are Related to White Matter Brain Microstructure

We sometimes vividly remember things that did not happen, a phenomenon with general relevance, not only in the courtroom. It is unclear to what extent individual differences in false memories are driven by anatomical differences in memory-relevant brain regions. Here we show in humans that microstructural properties of different white matter tracts as quantified using diffusion tensor imaging are strongly correlated with true and false memory retrieval. To investigate these hypotheses, we tested a large group of participants in a version of the Deese-Roediger-McDermott paradigm (recall and recognition) and subsequently obtained diffusion tensor images. A voxel-based whole-brain level linear regression analysis was performedto relatefractional anisotropyto indices oftrue andfalse memory recall and recognition. True memory was correlated to diffusion anisotropy in the inferior longitudinal fascicle, the major connective pathway of the medial temporal lobe, whereas a greater proneness to retrieve false items was related to the superior longitudinal fascicle connecting frontoparietal structures. Our results show that individual differences in white matter microstructure underlie true and false memory performance.