No description available.

No description available.

La gravité terrestre est une contrainte mécanique fondamentale exercée sur les organismes vivants et contre laquelle nous avons adapté nos stratégies de posture et de locomotion ainsi que toutes les régulations métaboliques et cardiovasculaires. Outre le stimulus mécanique direct, la gravité est mesurée par l'organe vestibulaire, premier système sensoriel à émerger chez les protochordés il y a environ 500 millions d'années, aussi précocement que le système visuel. Le système vestibulaire a alors été asservi aux fonctions d'équilibre et de stabilisation du regard, par des réflexes posturaux et oculaires, fonctions récemment enrichies d’un rôle clé dans la cognition spatiale et sociale chez l’adulte. Ses capacités d’encodage des mouvements de la tête, des accélérations du corps et de la gravité terrestre font de ce système un acteur majeur dans la perception de la verticalité, la navigation, l’orientation et la mémorisation spatiale. Nous avons émis l'hypothèse que la perception sensorielle vestibulaire de la gravité via les otolithes pourrait jouer un rôle crucial non seulement chez l’adulte mais également dans les premières étapes du développement des fonctions sensorimotrices et cognitives. Pour la première fois, nous avons étudié un modèle de souris original (souris Head-tilt, B6Ei.GL-Nox3Het / J) présentant une absence congénitale sélective de gravisenseurs vestibulaires. Les souris présentaient un retard dans l'acquisition des réflexes sensorimoteurs, des capacités d’orientation spatiale par guidage olfactif, d'une communication mère-petits par ultrasons alors que les soins maternels étaient normaux. Un retard dans la locomotion et des troubles hyperactifs avec stéréotypies ont également été montré. Nous démontrons ainsi que le développement des individus sur Terre possède une période critique dépendante de la perception sensorielle vestibulaire de la gravité, au moins entre les jours post-nataux 6 à 10 chez les rongeurs. Les informations otolithiques jouent également un rôle clé chez l’adulte dans les fonctions motrices, les processus mnésiques spatiaux et non spatiaux et dans la régulation émotionnelle. Une corrélation entre ces troubles et le retard développemental a été mis en évidence. Nous travaillons actuellement sur les effets de stimulations sensorielles précoces sur le développement et les fonctions adultes chez la souris Het ainsi que sur la caractérisation structurale et fonctionnelle au niveau cérébral des atteintes développementales et comportementales observées. Les observations chez les souris Het corroborent les symptômes rapportés chez les enfants vestibulo-déficients, soutenant le besoin d'un meilleur dépistage des maladies vestibulaires pendant l'enfance. De manière intéressante, les symptômes de ces souris correspondent à ceux présentés par des modèles murins validés d'autisme et réactualiseraient l’importance de la graviception vestibulaire dans la physiopathologie et la thérapie des troubles du spectre autistique (TSA) et autres maladies neurodégénératives au cours du développement. / Earth’s gravity is a fundamental mechanical constraint for living organisms against which we have adapted our strategies of posture and locomotion as well as all metabolic and cardiovascular regulations. Beyond the mechanical stimulus, the vestibular organ is the first sensory system to emerge in protochordates about 500 million years ago, as early as the visual system, encoding the gravity strength into the brain. The vestibular system has since then been devoted to balance and gaze stabilization supported by postural and ocular reflexes, recently fortified with a key role in spatial and social cognition in adults. Its encoding abilities of head movements, body accelerations and Earth's gravity make this system a major player in the perception of verticality, navigation, orientation and spatial memorization. We have hypothesized that vestibular sensory perception of gravity might play a crucial role not only in adults, but also during the first stages of development in both sensorimotor and cognitive functions. For the first time, we have investigated an original mouse model (Head-Tilt mice, B6Ei.GL-Nox3Het/J) with selective congenital absence of vestibular gravisensors. Our data highlights that mouse pups suffered from a delay in the acquisition of sensorimotor reflexes, spatial olfactive guidance, path integration and ultrasonic communication while maternal care remained normal. In addition, a delay in locomotor development and the appearance of were observed during the late stage of development. We demonstrate that development on Earth has a critical period dependent on the vestibular sensory perception of gravity, at least between postnatal days 6 to 10 in rodents. We have shown that otolithic information plays a key role in the adult motor functions, spatial and non-spatial memory processes, reference frames choice but also in emotional regulation. These disorders have been correlated with early developmental delay. We are currently working on the effects of early sensory stimulation on development and adult functions in our Het mouse model as well as on the structural and functional characterization at the cerebral level of observed developmental and behavioral impairments. Observations in Het mice corroborate with symptoms reported in vestibulo-deficient children, supporting the need for better screening of vestibular diseases during childhood. Remarkably, the symptoms of our vestibulo-congenital deficient mice investigated here matched with the profile of validated mouse models of autism and re-update the significance of vestibular graviception in the physiopathology and therapy of autism spectrum disorders during its development.

Skolvägran hos barn med autism är vanligare än hos neurotypiska barn (Munkhaugen et al.,2017) och barn med ADHD riskerar att inte nå godkänt betyg i skolan (Jangmo et al., 2019). Lärares bristande kunskaper om NPF samt otillräckliga anpassningar i skolan har lyfts somorsaker till detta (Anderson, 2020). Denna kvantitativa studie hade som syfte att få svar på hur föräldrar till elever medautism och/eller ADHD i mellanstadieåldern uppfattar att skolan fungerar överlag för derasbarn, samt vilka faktorer som har störst inverkan och korrelation med denna upplevelse.Däribland frånvaro, lärares- och skollednings kunskap om NPF, förståelse från skolpersonal,andra elevers bemötande samt anpassningar i skolan. Kön, skolform, medicinering och typ avdiagnos har också funnits med som variabler och kunnat kontrolleras för eventuell inverkanpå hur skolan upplevs fungera överlag. Studien har gjorts via en webbaserad enkät där deltagarna (n=144) rekryterats medbekvämlighetsurval. Resultaten visar att lärares- och skollednings kunskap om NPF, samt frånvarosignifikant korrelerar med hur skolan bedöms fungera överlag. Detta ger en indikation på attflera lärare saknar adekvat kunskap om autism och ADHD och att en kunskapshöjning inomdessa områden behövs. / School absenteeism is more common for children with autism than neurotypical developingchildren (Munkhaugen et al., 2017) and children with ADHD risk not reaching a passinggrade (Jangmo et al., 2019). Teacher’s lack of knowledge about neurodevelopmentaldisorders and insufficient adaptation strategies in school have been highlighted as a reason(Anderson, 2020). The purpose of this quantitative study was to obtain answers to how parents ofchildren with autism and/or ADHD perceive how school works in general, and what factorshave the greatest impact and correlation with that experience. Factors examined areabsenteeism, teacher and school management knowledge of autism and/or ADHD,understanding from school staff, attitude from other pupils and adaptations in school. Gender,type of school, medical treatment and type of diagnosis (autism/ADHD) are additionalvariables that have been able to be examined on their impact on the overall schoolexperience. The data was collected through an online survey where the participants (n=144) wererecruited with a convenience sample. The results show that teacher and school management's knowledge of autism and/orADHD, as well as absence, significantly correlates with how the school is judged to functionoverall. This indicates that an increase in knowledge among existing teachers who lackadequate knowledge about autism and ADHD is required.

Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans. Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences. Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts. Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function. Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.

No description available.

No description available.

The emergence of statistical and predictive methods able to analyse genomic data has revolutionised the field of medical genetics, allowing the identification of disease-causing gene variants (i.e. mutations) for several human genetic diseases. Although these approaches have greatly improved our understanding of Mendelian «one gene – one phenotype» genetic models, studying diseases related to more intricate models that involve causative variants in several genes (i.e. oligogenic diseases) still remains a challenge, either due to the lack of sufficient methodologies and disease-specific cohorts to study or the phenotypic complexity associated with such diseases. This situation makes it difficult to not only understand the genetic mechanisms of the disease, but to also offer proper counseling and support to the patient. Until recently, no specialized predictive methods existed to directly predict causative variant combinations for oligogenic diseases. However, with the advent of data on variant combinations in gene pairs (i.e. bilocus variant combinations) leading to disease, collected at the Digenic Diseases Database (DIDA), we hypothesized that the transition from single to variant combination pathogenicity predictors is now possible.To investigate this hypothesis, we organised our research on two main routes. At first, we developed an interpretable variant combination pathogenicity predictor, called VarCoPP, for gene pairs. For this goal, we trained multiple Random Forest algorithms on pathogenic bilocus variant combinations from DIDA against neutral data from the 1000 Genomes Project and investigated the contribution of the incorporated variant, gene and gene pair features to the prediction outcome. In the second part, we explored the usefulness of different gene pair burden scores based on this novel predictive method, in discovering oligogenic signatures in neurodevelopmental diseases, which involve a spectrum of monogenic to polygenic cases. We performed a preliminary analysis on the Deciphering Developmental Diseases (DDD) project containing exome data of 4195 families and assessed the capability of our scores in supporting already diagnosed monogenic cases, discovering significant pairs compared to control cases and linking patients in communities based on the genetic burden they share, using the Leiden community detection algorithm.The performance of VarCoPP shows that it is possible to predict disease-causing bilocus variant combinations with good accuracy both during cross-validation and when testing on new cases. We also show its relevance for disease-related gene panels, and enhanced its clinical applicability by defining confidence zones that guarantee with 95\% or 99\% probability that a prediction is indeed a true positive, guiding clinical researchers towards the most relevant results. This method and additional biological annotations are incorporated in an online platform called ORVAL that allows the prediction and exploration of candidate disease-causing oligogenic variant combinations with predicted gene networks, based on patient variant data. Our preliminary analysis on the DDD cohort shows that - although all bi-locus burden scores show advantages, disadvantages and certain types of biases - taking the maximum pathogenicity score present inside a gene pair seems to provide, at the moment, the most unbiased results. We also show that our predictive methods enable us to detect patient communities inside DDD, based exclusively on the shared pathogenic bi-locus burden between patients, with more than half of these communities containing enriched phenotypic and molecular pathway information. Our predictive method is also able to bring to the surface genes not officially known to be involved in disease, but nevertheless, with a biological relevance, as well as a few examples of potential oligogenicity inside the network, paving the way for further exploration of oligogenic signatures for neurodevelopmental diseases. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Elever med neuropsykiatriska funktionsvariationer (NPF) upplever en försämrad skolgång på grund av att den är dåligt anpassad efter deras behov. Grundskolelärare har ett ansvar att anpassa sin undervisning så den passar alla, men deras ökade belastning lämnar lite tid över till att kommunicera med sina elever på individnivå för att ta reda på deras behov. Den bristande kommunikationen mellan grundskolelärare och elever med NPF blir problematisk då parternas behov missförstås av varandra. Denna studie undersökte hur man genom produktdesign kan skapa en bättre kommunikation mellan elever med NPF och deras lärare. Studien genomfördes med teorier och metoder från forskningsfältet användarcentrerad design. Genom intervjuer, observationer, dokumentanalys, en ökad empatisk förståelse och marknadsundersökning skaffade studien en förståelse av användarnas behov och önskemål. En koncept- och produktutvecklingsfas möjliggjorde skapandet av ett slutgiltigt produktförslag. Studiens slutsats visar hur produktdesign i en användarcentrerad designprocess skapar en förståelse för en användargrupp och möjliggör ett produktförslag som tillfredsställer deras behov. Studien resulterade i ett produktförslag som kan förbättra kommunikationen mellan grundskoleelever med NPF och deras lärare. Produktförslaget kan förhoppningsvis leda till en bättre skolgång för elever med NPF om läraren gör anpassningar i sitt klassrum och/eller undervisning som tar hänsyn till elevens behov. Produktförslaget är endast ett förslag på hur en produktlösning kan se ut bland många andra möjliga lösningar. Studiens kunskapsbidrag bidrar med insikt i hur man genom produktdesign och en användarcentrerad designprocess kan utforska en användargrupp för att tillgodose deras behov. / Students with cognitive disabilities are unsatisfied with their lower school education because of poor adaption to their needs. Lower school teachers have a responsibility to adjust their way of teaching and classroom environment in order to fulfill everyone’s needs. But the abundant workload teachers experience leaves little time for individual communication with their students to find out their needs. This study examined how product design can create a better communication between lower school students with cognitive disabilities and their teachers. The study used theories and methods from the research field of user-centered design. The methods used were interviews, observations, analysis of documents, improvement of empathetic understanding and a market analysis. These enabled a better understanding of the users’ needs and desires. The study’s conclusion shows how product design in a user-centered design process can create a better understanding of a user group and a design-proposal that satisfies the users’ needs and desires. The study resulted in a design-proposal that can improve communication between lower school students and their teachers. The design proposal can potentially lead to an improved education for students with cognitive disabilities if the teacher adjusts their classroom environment and/or way of teaching with regards to their students’ needs. The design-proposal is merely a proposal among many other solutions of how a product solution could be made. The study contributes with research about how product design and a user-centered design process can examine a user group in order to satisfy their needs.

Background: Fetal alcohol spectrum disorders (FASD), which are caused by prenatal alcohol exposure (PAE), affects people around the world. Certain communities in South Africa have among the highest reported incidences of fetal alcohol syndrome (FAS) in the world. Although PAE-related brain alterations have been widely documented, the mechanisms whereby alcohol affects the brain are not clearly understood. MRI relaxation parameters T1, T2, T2* and proton density (PD), are basic tissue properties that reflect the underlying biology. The present study aims to advance our understanding of how PAE alters the microstructural properties of tissue by examining PAE-related changes in these tissue parameters in adolescents with FASD. Methods: The final sample used in this study consisted of 53 children from a previously studied longitudinal cohort (Jacobson et al., 2008) and 12 additionally recruited subjects. Of the 65 participants, 18 were diagnosed with FAS or partial FAS (PFAS) and made up the FAS/PFAS group, 18 were diagnosed as heavily exposed non-syndromal (HE) and 29 were age matched controls. Subjects were scanned at the Cape Universities Body Imaging Centre (CUBIC) located at Groote Schuur Hospital on a 3T Siemens Skyra MRI. Structural images were obtained using the MEMPRAGE sequence. From these images T1, T2, T2* and PD parameter maps were constructed and segmented into 43 regions of interest (ROI) using Freesurfer, FSL and AFNI. Linear regression analyses were used to analyse group differences as well as correlations between parameter values and the amount of alcohol the mother consumed during pregnancy. Results: Significant T1 differences were found in the caudate, cerebellar cortex, hippocampus, accumbens, putamen, choroid plexus, ventral diencephalon (DC), right vessel and ventricles. Significant T2 differences were found in the caudate, brain stem, corpus callosum (CC), amygdala, cerebral cortex, choroid plexus, vessels and ventricles. Significant T2* differences were found in the cerebellar cortex, optic chiasm and ventricles. Significant PD differences were found in the hippocampus and left lateral ventricle. The exploratory nature of this study resulted in none of the results surviving FDR correction for multiple comparisons. Conclusions: Overall, our findings point to regional PAE-related increases in water content and cellular and molecular changes in underlying tissue of the anatomical structure. Exceptions were the right cerebral cortex, brain stem, hippocampus, amygdala and ventral diencephalon where our findings point to less free water and increased cell density, and cerebellar cortex where simultaneous reductions in T1 and T2* suggest the possibility of increased iron content. In highly myelinated white matter structures, such as the CC and optic chiasm, our results point to PAErelated demyelination, and possibly increased iron. These findings extend previous knowledge of effects of PAE and demonstrate that tissues are affected at a microstructural level.