Background: Individuals with neurodevelopmental disorders are unemployed or underemployed at staggering rates. Employment for this population is impacted by many factors, including contextual issues. This review was conducted to enhance understanding of contextual factors influencing employment procurement for individuals with neurodevelopmental disorders. Methodology: The Arksey and O’Malley scoping review framework was utilized to examine five databases and sources of grey literature regarding the contextual factors influencing employment procurement for individuals with neurodevelopmental disorders. Articles were analyzed using the International Classification of Functioning, Disability and Health criteria for Contextual Factors, including both Environmental and Personal Factors. Results: The findings from 41 articles indicate that Contextual Factors, Environmental Factors and Personal Factors influence employment procurement by creating both barriers and facilitators to obtaining employment for individuals with neurodevelopmental disorders. Conclusion: A focus on contextual factors that impact individuals with neurodevelopmental disorders may provide further insight into the facilitators and barriers influencing employment outcomes. Further research should aim to understand the strength of relationships and to expand the use and application of the International Classification of Functioning, Disability and Health’s biopsychosocial framework. This research can aid in promoting the employment outcomes for individuals with neurodevelopmental disorders. / Thesis / Master of Science (MSc)

As politicas de apoio a criancas com Transtornos do Neurodesenvolvimento precisam que seus cuidadores sejam responsaveis por prover o ensino especial necessario para o manejo dos problemas de comportamento e evitar que sejam objeto de rejeicao social em funcao de seus deficits comportamentais. Essa carga de trabalho pode acarretar impacto a saude mental e qualidade de vida dos cuidadores e justifica a importancia de estudos voltados para o mapeamento de tais dificuldades, afim de sustentar propostas de prevencao e intervencao destinadas a este publico. Este estudo, de corte transversal, teve como objetivo identificar associacoes entre os problemas de comportamento de criancas com Transtornos do Neurodesenvolvimento e a saude mental e qualidade de seus cuidadores, alem de descrever as praticas parentais educativas utilizadas. A amostra foi composta por 91 diades cuidadorescriancas. Todas as criancas (idade entre 3 e 18 anos) estavam matriculadas em escolas da rede publica do municipio de Barueri-SP como aluno com necessidade educacional especial e apresentavam laudo diagnostico de Deficiencia Intelectual (DI) idiopatica, Transtorno do Espectro Autista ou Sindrome de Down comorbido com DI. Para a avaliacao comportamental infantil foi empregada a Escala de Comportamentos Aberrantes, o Inventario de Problemas de Comportamento e o Inventario dos Comportamentos de Criancas e Adolescentes. Para a avaliacao dos cuidadores, aplicou-se o Inventario de Autoavaliacao para Adultos de 18 a 59 anos, o Instrumento abreviado de avaliacao de qualidade de vida (WHOQOL-Bref) e o World-Safe CORE para as praticas parentais. As analises demonstram nao haver diferenca na saude mental do cuidador em funcao do diagnostico de seu filho. A avaliacao comportamental dos cuidadores evidenciou que suas dificuldades internalizantes foram as areas mais impactadas pelos problemas de comportamento infantis. Entre 3,4% e 20% da variancia dos indicadores de saude mental dos cuidadores foi significativamente explicada pelas queixas externalizantes da crianca, especialmente hiperatividade e agressividade, e as dificuldades internalizantes infantis, principalmente o retraimento. As dificuldades comportamentais infantis nao foram preditores da qualidade de vida total dos cuidadores. Ja a frequencia de comportamento agressivo da crianca foi preditor do Dominio Psicologico do WHOQOLBref. Quanto as praticas parentais, muitos reportaram utilizar metodos coercitivos para tentar controlar o comportamento de seus filhos. As queixas internalizantes dos cuidadores, especialmente Ansiedade/ Depressao e Queixas Somaticas, devem ser alvo de atencao das iniciativas em saude. Assim propostas de intervencao para melhoria da saude mental poderiam ser destinadas a todos os cuidadores independente do diagnostico clinico de seus filhos, dado que muitos reportaram o uso de estrategias coercitivas e que seus problemas de comportamento sao similares / Policies to support children with Neurodevelopmental Disorders need their caregivers to be responsible for providing the special education in order to manage behavioral problems and avoid social rejection due to their child behavioral difficulties. This caregiver\'s workload can impact one\'s mental health and quality of life therefore supporting the importance of studies aimed to investigate this impact in order to support prevention and intervention programs for this specific public. This crosssectional study aimed to identify associations between the behavioral problems of children with Neurodevelopmental Disorders and the mental health and quality of life of their caregivers, as well as to describe their parental practices. The sample consisted of 91 caregiver and child. All children (Aged between 3 and 18 years) were enrolled in public schools in the city of Barueri-SP as students with special educational needs and diagnostic reports of Idiopathic Intellectual Disability (ID), Autism Spectrum Disorder and Down Syndrome comorbid with ID. For the child\'s behavioral assessment, the following questionnaires were used: Aberrant Behavior Checklist, Behavior Problems Inventory and Child Behavior Checklist. For the caregiver\'s evaluation were used the Adult Self-Report, the World Health Organization Quality of Life Instruments (WHOQOL-Bref) and the World-Safe CORE for parental practices. The analysis shows that there is no difference in the caregiver\'s mental health due to their child\'s diagnosis. The caregiver\'s behavioral evaluation demonstrated that their internalizing difficulties are the most impacted area due to their children\'s behavioral problems. Between 3.4% and 20% of the variance on the caregiver\'s assessment were significantly predicted by child\'s externalizing complaints, mainly hyperactivity and aggressiveness, and the child\'s internalizing difficulties, especially social withdrawal. Caregiver\'s overall quality of life were not predicted by child\'s behavioral difficulties, whereas the frequency of child\'s aggressive behavior predicts 4% of variance on the Psychological Domain of WHOQOL-Bref. Regarding parental practices, many caregivers reported the use of coercive methods to try to control their children\'s behavior. Caregiver\'s internalizing problems, especially Anxiety/ Depression and Somatic Complaints, should be addressed by health initiatives. Thus, interventions for improving mental health could be targeted to all caregivers regardless their child\'s clinical diagnosis, given that many of them have reported using coercive measures and the similarity of their behavioral problems

SYNGAP1 haploinsufficiency is one of the most common monogenic causes of nonsyndromic moderate to severe intellectual disability (NSID) and autism (Hamdan et al., 2009; Pinto et al., 2010). De novo truncating or frameshift mutations in the SYNGAP1 gene lead to the loss of the encoded protein Synaptic GTPase activating protein (SynGAP), one of the most abundant of postsynaptic proteins (Hamdan et al., 2011). SynGAP, present at excitatory and inhibitory synapses (Kim et al., 1998), acts as a key regulator of highly conserved signaling pathways linked to AMPA- and NMDA-receptor dependent plasticity at the post synaptic density (Krapivisky et al., 2004; Vazquez et al., 2004). The Syngap mouse model has been extensively used to understand the pathophysiology underlying abnormal SynGAP-mediated signaling. Syngap heterozygous (het) mice demonstrate a range of physiological and behavioural abnormalities from development to adulthood (Komiyama et al., 2002; Muhia et al., 2010). However, recent advances in techniques for genome manipulation have allowed for the generation of rat models of neurodevelopmental disorders, including Syngap; enabling phenotypes to be validated across species and to address cognitive and social dysfunction, using paradigms that are more difficult to assess in mice. In this study, we examined the pathophysiology associated with a heterozygous deletion of the C2 and catalytic GAP domain of the protein, in Long-Evans rats (het). In contrast with het mice, het rats do not present with hyperactivity and can be habituated to an open field environment. To examine associative recognition memory, we tested the rats in five spontaneous exploration tasks for short-term and long-term memory, object-recognition (OR), object-location (OL), object-place (OP), object-context (OC) and object-place-context (OPC). Both groups were able to perform short-term memory tasks, but only wild type rats performed above chance in OL with a 24hour delay, suggesting deficits in long- term spatial memory. We also tested if partial loss of the GAP domain in SynGAP affects social behaviour in rats and we found that het rats exhibited impaired short- term social memory, with no signs of social isolation. These findings do not fully recapitulate previous abnormalities reported in the mouse model of SYNGAP1 haploinsufficiency, suggesting that some key behavioural phenotypes may be species-specific. Furthermore, based on physiological deficits that Syngap het mice exhibit, such as alterations in mEPSC/mIPSC amplitude and frequency and evoked cortical hyperexcitability in vitro (Guo et al., 2009; Ozkan et al., 2014), we also aimed to test if in vivo neuronal activity and circuit properties are altered. Using two-photon calcium imaging in awake mice, we focused on two areas of the cortex; a primary sensory area, the binocular region of the visual cortex (V1), and an association area, the medial posterior parietal cortex (PPC). Both areas have been found to maintain activity during visual discrimination tasks but to present with divergent activity trajectories (Harvey et al., 2012; Goard et al., 2016). We found preliminary evidence that neurons in layer 2-3 of the PPC of Syngap mice are hypoactive in basal conditions when animals are still in the dark, compared to wild type controls. When we assessed whether that changes when animals are running, we found that during locomotion neurons of both genotypes increase their activity, consistent with previous findings in wild type mice (McGinley et al., 2015; Pakan et al., 2016). However, this response gain is exaggerated in Syngap het neurons of the PPC. In contrast to above findings in PPC, results in V1 show that layer 2-3 neurons are hyperactive during both behavioural states, suggesting seemingly different computations of these two cortical areas. This work provides the first evidence for a dysregulated neuronal circuit in vivo in both visual and parietal cortex of Syngap mice, two areas critical for sensory processing that has been found to be affected in individuals with NSID and autism (Joosten and Bundy, 2010). We also provide first evidence of the effect of loss of SynGAP activity in behaviour of rats, complimenting existing data in the literature in a species-specific manner and providing greater insight into sensory and cognitive dysfunction associated with dysregulation in SynGAP-mediated signaling.

An important quest in genomics since the publication of the first complete human genome in 2003 has been its functional annotation. DNA holds the instructions to the production of the components necessary for the life of cells and organisms. A complete functional catalog of genomic regions will help the understanding of the cell body and its dynamics, thus creating links between genotype and phenotypic traits. The need for annotations prompted the development of several bioinformatic methods. In the context of promoter and first exon predictors, the majority of models relies principally on structural and chemical properties of the DNA sequence. Some of them integrate information from epigenomic and transcriptomic data as secondary features. Current genomic research asserts that reference genome annotations are far from being fully annotated (human organism included).Physicians rely on reference genome annotations and functional databases to understand disorders with genetic basis, and missing annotations may lead to unresolved cases. Because of their complexity, neurodevelopmental disorders are under study to figure out all genetic regions that are involved. Besides functional validation on model organisms, the search for genotype-phenotype association is supported by statistical analysis, which is typically biased towards known functional regions.This thesis addresses the use of an in-silico integrative analysis to improve reference genome annotations and discover novel functional regions associated with neurodevelopemental disorders. The contributions outlined in this document have practical applications in clinical settings. The presented bioinformatic method is based on epigenomic and transcriptomic data, thus excluding features from DNA sequence. Such integrative approach applied on brain data allowed the discovery of two novel promoters and coding first exons in the human DLG2 gene, which were also found to be statistically associated with neurodevelopmental disorders and intellectual disability in particular. The application of the same methodology to the whole genome resulted in the discovery of other novel exons expressed in brain. Concerning the in-silico method itself, the research demanded a high number of functional and clinical datasets to properly support and validate our discoveries.This work describes a bioinformatic method for genome annotation, in the specific area of promoter and first exons. So far the method has been applied on brain data, and the extension to the whole body data would be a logical by-product. We will leverage distributed frameworks to tackle the even higher amount of data to analyse, a task that has already begun. Another interesting research direction that came up from this work is the temporal enrichment analysis of epigenomics data across different developmental stages, in which changes of epigenomic enrichment suggest time-specific and tissue-specific functional gene and gene isoforms regulation. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

As politicas de apoio a criancas com Transtornos do Neurodesenvolvimento precisam que seus cuidadores sejam responsaveis por prover o ensino especial necessario para o manejo dos problemas de comportamento e evitar que sejam objeto de rejeicao social em funcao de seus deficits comportamentais. Essa carga de trabalho pode acarretar impacto a saude mental e qualidade de vida dos cuidadores e justifica a importancia de estudos voltados para o mapeamento de tais dificuldades, afim de sustentar propostas de prevencao e intervencao destinadas a este publico. Este estudo, de corte transversal, teve como objetivo identificar associacoes entre os problemas de comportamento de criancas com Transtornos do Neurodesenvolvimento e a saude mental e qualidade de seus cuidadores, alem de descrever as praticas parentais educativas utilizadas. A amostra foi composta por 91 diades cuidadorescriancas. Todas as criancas (idade entre 3 e 18 anos) estavam matriculadas em escolas da rede publica do municipio de Barueri-SP como aluno com necessidade educacional especial e apresentavam laudo diagnostico de Deficiencia Intelectual (DI) idiopatica, Transtorno do Espectro Autista ou Sindrome de Down comorbido com DI. Para a avaliacao comportamental infantil foi empregada a Escala de Comportamentos Aberrantes, o Inventario de Problemas de Comportamento e o Inventario dos Comportamentos de Criancas e Adolescentes. Para a avaliacao dos cuidadores, aplicou-se o Inventario de Autoavaliacao para Adultos de 18 a 59 anos, o Instrumento abreviado de avaliacao de qualidade de vida (WHOQOL-Bref) e o World-Safe CORE para as praticas parentais. As analises demonstram nao haver diferenca na saude mental do cuidador em funcao do diagnostico de seu filho. A avaliacao comportamental dos cuidadores evidenciou que suas dificuldades internalizantes foram as areas mais impactadas pelos problemas de comportamento infantis. Entre 3,4% e 20% da variancia dos indicadores de saude mental dos cuidadores foi significativamente explicada pelas queixas externalizantes da crianca, especialmente hiperatividade e agressividade, e as dificuldades internalizantes infantis, principalmente o retraimento. As dificuldades comportamentais infantis nao foram preditores da qualidade de vida total dos cuidadores. Ja a frequencia de comportamento agressivo da crianca foi preditor do Dominio Psicologico do WHOQOLBref. Quanto as praticas parentais, muitos reportaram utilizar metodos coercitivos para tentar controlar o comportamento de seus filhos. As queixas internalizantes dos cuidadores, especialmente Ansiedade/ Depressao e Queixas Somaticas, devem ser alvo de atencao das iniciativas em saude. Assim propostas de intervencao para melhoria da saude mental poderiam ser destinadas a todos os cuidadores independente do diagnostico clinico de seus filhos, dado que muitos reportaram o uso de estrategias coercitivas e que seus problemas de comportamento sao similares / Policies to support children with Neurodevelopmental Disorders need their caregivers to be responsible for providing the special education in order to manage behavioral problems and avoid social rejection due to their child behavioral difficulties. This caregiver\'s workload can impact one\'s mental health and quality of life therefore supporting the importance of studies aimed to investigate this impact in order to support prevention and intervention programs for this specific public. This crosssectional study aimed to identify associations between the behavioral problems of children with Neurodevelopmental Disorders and the mental health and quality of life of their caregivers, as well as to describe their parental practices. The sample consisted of 91 caregiver and child. All children (Aged between 3 and 18 years) were enrolled in public schools in the city of Barueri-SP as students with special educational needs and diagnostic reports of Idiopathic Intellectual Disability (ID), Autism Spectrum Disorder and Down Syndrome comorbid with ID. For the child\'s behavioral assessment, the following questionnaires were used: Aberrant Behavior Checklist, Behavior Problems Inventory and Child Behavior Checklist. For the caregiver\'s evaluation were used the Adult Self-Report, the World Health Organization Quality of Life Instruments (WHOQOL-Bref) and the World-Safe CORE for parental practices. The analysis shows that there is no difference in the caregiver\'s mental health due to their child\'s diagnosis. The caregiver\'s behavioral evaluation demonstrated that their internalizing difficulties are the most impacted area due to their children\'s behavioral problems. Between 3.4% and 20% of the variance on the caregiver\'s assessment were significantly predicted by child\'s externalizing complaints, mainly hyperactivity and aggressiveness, and the child\'s internalizing difficulties, especially social withdrawal. Caregiver\'s overall quality of life were not predicted by child\'s behavioral difficulties, whereas the frequency of child\'s aggressive behavior predicts 4% of variance on the Psychological Domain of WHOQOL-Bref. Regarding parental practices, many caregivers reported the use of coercive methods to try to control their children\'s behavior. Caregiver\'s internalizing problems, especially Anxiety/ Depression and Somatic Complaints, should be addressed by health initiatives. Thus, interventions for improving mental health could be targeted to all caregivers regardless their child\'s clinical diagnosis, given that many of them have reported using coercive measures and the similarity of their behavioral problems

L’infection par le cytomégalovirus (CMV) au cours de la grossesse est fréquente et représente la première cause de pathologie neurodéveloppementale. En dépit de cette importance médicale, il n’existe à ce jour aucun traitement préventif ou curatif satisfaisant, et les mécanismes physiopathologiques mis en jeu, en particulier au niveau du cerveau foetal, restent mal connus. Des découvertes récentes sur les modèles murins d’infection cérébrale par le CMV, principalement réalisées pendant la période néonatale, ont apporté des données convergentes sur la physiopathologie de ces infections cérébrales ; notamment, le rôle joué par les cellules immunitaires périphériques dans la résolution de l’infection, et l’implication du système immunitaire cérébral (SIC) au cours du processus infectieux. Afin de compléter et préciser les résultats précédemment obtenus dans différents modèles murins, et de comprendre le rôle joué par le SIC, le premier objectif de ma thèse a consisté à mettre au point et à caractériser un nouveau modèle d’infection cérébrale par le CMV au cours du développement in utero chez le rat. Dans l'ensemble, nos résultats confirment l'altération du SIC au cours de l'infection par le CMV du cerveau en développement, et suggèrent fortement, dans ce modèle, un rôle majeur joué par le système microglie/macrophage dans l'émergence de troubles neurologiques semblables à ceux observés dans la pathologie humaine correspondante. / Cytomegalovirus (CMV) infection during pregnancy is the leading cause of neurodevelopmental disorders (polymicrogyria, microcephaly) and may lead to severe sensorineural consequences (deafness, epilepsy, cerebral palsy and hearing loss). Despite this medical importance, no preventive or curative treatment is satisfactory to date, and the pathophysiological mechanisms, notably in the fetal brain, remain poorly understood. Recent findings in murine brain CMV infection, mostly in neonatal models, have brought converging insights into the pathogenesis of these infections; the possible role played by peripheral immune cells against infection and the involvement of the brain immune system (BIS) have been proposed. The actual roles of BIS during in utero infection, and more specifically that of microglial cells and macrophages, remain unclear. In order to expand and precise the data previously obtained in the murine models, and to clarify the role of BIS, the first objective of my thesis was to design and to characterize a novel model of CMV infection during the fetal development of the rat brain. Overall, our datas confirm the altered state of BIS as a consequence of CMV infection of the developing brain, and strongly suggest, in the rat model studied here, that the microglia/macrophages system plays critical role in the pathogenesis of neurological manifestations similar to those classically seen after human congenital CMV infection.

Purpose: This study aimed to investigate how neurodevelopmental disorders (NDs) are represented in the Swedish news media. The study can contribute to gaining more excellent knowledge about how Swedish news media such as Dagens Nyheter (DN) and Expressen represent disabilities such as NDs. Theory: To carry out the study, we must present theoretical starting points. The study was based on the power of journalism, representation, media representation, framing theory, and stereotypes. The power of journalism is used to explain how powerful the media is. Representation and media representation is used to describe how things make sense. Framing theory is used to describe the effect of the media on people because, according to the theory, people always try to create meaning. Finally, stereotypes are used to explain how NDs are perceived in society. Previous research: Previous research has been used to motivate studies that have previously been used on the subject and then linked to our study. The study used health communication and journalism, news media (daily- and evening newspapers), and gender as in previous research. Health communication and journalism explain how vital health-related information is to society. News media are used to create an in-depth understanding of NDs while discussing the difference between daily- and evening newspapers to understand them. Finally, studies on gender are used to explain gender differences and inequalities between the genders. Method: The study was carried out with the help of a quantitative content analysis, where the Swedish news sites DN and Expressen were analyzed by searching for news about various NDs; ADHD, ADD, ASD, Autism, Asperger's, and Tourettes. A total of 190 articles from both news sites were included—123 articles from Expressen and 67 from DN. A time frame has been set within one year, from 8 March 2021 to 8 March 2022. To obtain the survey results, the SPSS program has been used where it was prepared before the study with knowledge of statistical analysis—then prepared variables and variable values to be used in SPSS to make the study feasible. Results: The results were presented by comparing relevant variables in the SPSS software for later analysis. Variables such as "NDs diagnoses," "NDs main or secondary subject," "emotional or non-emotional," and "newspaper." Detailed analysis and discussion were performed of the results of the variables examined. The analysis was based on relevant previous research and theories related to news media, representation, and NDs. Conclusion: Journalists significantly influence how the reader perceives, interprets, and forms opinions. Therefore, the representation of NDs by both the news sites, DN and Expressen, can lead the reader to create stereotypical images about NDs. Individuals with NDs may be discriminated against because of the stereotypes that have been created about them. They can also be exposed to misunderstandings of the environment because they do not behave the same way society expects. The two news pages examined represent NDs differently in that DN is classified as a daily newspaper and Expressen is classified as an evening newspaper. The different diagnoses within NDs are represented differently in the articles. Finally, female journalists try to counter stereotypes about women with NDs. Many articles written by female journalists are about publishing their stories and encouraging others to seek help. In contrast, articles written by male journalists are often about men with NDs, whereas articles are often about crime and sports, which they are also often associated with. / Syfte: Syftet med denna studie var att undersöka hur neuropsykiatriska funktionsnedsättningar (NPF) representeras i svensk nyhetsmedia. Studien kan bidra till att få större kunskap om hur svenska nyhetsmedier som Dagens Nyheter (DN) och Expressen representerar funktionsnedsättningar som NPF. Teori: För att genomföra studien har vi behövt redovisa teoretiska utgångspunkter. Studien bygger på: journalistens makt, representation, media representation, gestaltningsteori och stereotyper. Journalistens makt används för att förklara hur mäktigt media är. Representation och mediarepresentation används för att förklara hur saker och ting får mening. Gestaltningsteorin används för att förklara mediernas effekt på människor eftersom enligt teorin människor alltid försöker skapa mening. Till sist används stereotyper för att förklara hur NPF uppfattas i samhället. Tidigare forskning: Tidigare forskning använts för att motivera studier som tidigare använts på ämnet, för att sedan koppla det till vår studie. I studien användes hälsokommunikation och journalistik, nyhetsmedia (dags- och kvällspress), och genus som tidigare forskning. Hälsokommunikation och journalistik används för att förklara hur viktig hälsorelaterad information är för samhället. Nyhetsmedia används för att skapa fördjupad förstående om neuropsykiatriska funktionsnedsättning, samtidigt diskuteras skillnaden mellan dags- och kvällspress för att förstå skillnaden mellan de. Till sist används genus för att förklara könsskillnader och ojämlikheter mellan könen. Metod: Studien genomfördes med hjälp av en kvantitativ innehållsanalys, där svenska nyhetssidorna DN och Expressen analyserades genom att söka efter nyheter om olika NPF; ADHD, ADD, ASD, Autism, Asperger's och Tourettes. Totalt inkluderades 190 artiklar från både nyhetssidorna. 123 artiklar från Expressen och 67 artiklar från DN. En tidsram har ställts in inom ett år, från datumen, 8 mars 2021 till 8 mars 2022. För att få fram undersökningens resultat har programmet SPSS använts där det förbereddes innan studien med kunskap om statistisk analys. Därefter förberett variabler och variabelvärden för att användas i SPSS för att göra studien genomförbar. Resultat: Resultaten presenterades genom att relevanta variabler har ställts mot varandra i programvaran SPSS för att senare analysera de. Variabler såsom “NPF diagnoser”, “NPF huvud- eller biämne”, “känslomässig eller icke känslomässig” samt “tidning”. En utförlig analys och diskussion genomfördes av resultaten av de undersökta variablerna. Analysen byggdes på relevanta tidigare forskning och teorier som är relaterade till nyhetsmedier, representation och NPF. Slutsats: Journalister har stor påverkan på hur läsaren uppfattar, tolkar och bildar åsikter. Därför representationen av NPF av både nyhetssidorna, DN och Expressen, kan leda till att läsaren skapar stereotypa bilder om NPF. Individer med NPF kan utsättas för diskriminering på grund av de stereotyperna som har skapats om de. De kan också utsättas för missuppfattning av omgivningen på grund av att de inte beter sig på samma sätt som samhället förväntar sig. De två undersökta nyhetssidorna representerar NPF annorlunda i och med att DN klassas som dagstidning och Expressen klassas som kvällstidning. De olika diagnoserna inom NPF representeras på olika sätt i artiklarna. Slutligen kvinnliga journalister försöker att motverka stereotyper om kvinnor med NPF. Många artiklar skrivna av kvinnliga journalister handlar om att ge ut deras berättelser och uppmana andra till att söka hjälp. Medan artiklar skrivna av manliga journalister handlar ofta om män med NPF, där artiklar ofta handlar om brott och sport, vilket de också ofta är associerade med.

The 15q13.3 microdeletion is a common genetic disorder associated with multiple neurodevelopmental disorders including autism spectrum disorder, epilepsy, and schizophrenia. Patients have diverse clinical presentations, often prompting genetic assays that identify the CNV in the clinic. This late-stage screening leaves a considerable gap in our understanding of the prenatal and prediagnostic developmental impairments in these individuals, providing a barrier to understanding the disease pathobiology. We provide the first investigation into embryonic brain development of individuals with the 15q13.3 microdeletion by generating multiple 3D neural organoid models from the largest clinical cohort in reported literature. We incorporated unguided and guided forebrain organoid models into our multi-transcriptomic phenotyping pipeline to uncover changes in cell type emergence and disruptions to circuit development, all of which had underlying changes to cell adhesion pathways. Specifically, we identified accelerated growth trajectories in 15q13.3del unguided neural organoids and used single cell RNA sequencing to identify changes in radial glia dynamics that affect neurogenesis. We measured changes in the pseudotemporal trajectory of matured unguided neural organoids, and later identified disruptions in synaptic signaling modules amongst the primary constituents to neural circuitry, excitatory and inhibitory neurons. We leveraged dorsal and ventral forebrain organoid models to better assess circuit dynamics, as they faithfully produce the excitatory and inhibitory neurons in the pallium and subpallium, respectively. We then used the entire 15q13.3del cohort and performed bulk RNA sequencing on each tissue type at two timepoints and discovered convergence on transcriptional dysregulation and disruptions to human-specific zinc finger proteins localized to chromosome 19. We also identified cell type-specific vulnerabilities to DNA damage and cell migration amongst the dorsal and ventral organoids, respectively, which was consistent with the excitatory and inhibitory neural subpopulations amongst the unguided neural organoids scRNA Seq, respectively. We then examined neuron migration in a 3D assembloid model by sparsely labeling dorsal-ventral forebrain organoids from multiple genotype-lineage combinations. Light sheet microscopy identified deficits in inhibitory neuron migration and morphology, but not migration distance, suggesting a complex disruption to cortical circuitry. This novel combination of cell type characterization, pathway identification, and circuitry phenotyping provides a novel perspective of how the 15q13.3 deletions impair prenatal development and can be applied to other NDD models to leverage understanding of early disease pathogenesis. / Dissertation / Doctor of Science (PhD) / The development of the human brain is a highly complex and tightly regulated process that requires the participation of multiple cell types throughout development. Disturbances to the emergence, differentiation, or placement of these cell types can cause disruptions and local miswiring of neural circuits, which is often associated with neurodevelopmental disorders (NDDs). The 15q13.3 microdeletion syndrome is a highly complex condition associated with multiple NDDs and has seldom been studied in a human context. To address this, we used stem cells derived from a 15q13.3 microdeletion syndrome cohort and their typically developing familial controls to generate unguided (“whole brain”) and region-specific organoids to investigate early fetal development across time. We used the largest 15q13.3 microdeletion cohort in reported literature to identify shared disruptions in early developmental milestones such as neurogenesis, neural migration, and neural patterning. We identified expansion of specific cell populations, including progenitors that later give rise to mature neurons. Abnormalities persisted in more mature cell populations, including the inhibitory neurons responsible for establishing critical microcircuitry in the human cortex. By generating guided organoids that enrich for excitatory and inhibitory neural populations, we were able to merge the models to form assembloids, where we captured early migratory and morphological deficits in inhibitory neuron populations, which is supported by the multi-transcriptomics experiments performed in both organoid models. This study provides a framework for examining fetal development in a neurodevelopmental disorder context. By using the 15q13.3 microdeletion background, we found novel disruptions in cell type emergence and circuit formation previously unreported in mouse or 2D neuron models, highlighting the utility of the phenotyping platform for disease modeling.

The aim of this study was to explore temperament, psychopathology and quality of life (QOL) in adolescents born at extremely low birth weight (ELBW), i.e., < 1000g. ELBW adolescents (N = 15) completed the Revised Cheek and Buss Scale and Mini International Neuropsychiatric Interview 5.0.0 (M.I.N.I.), while their legal guardians completed a biographical questionnaire and the Short Form 12 version 2. The median age of the sample was 13 SD = 2.526 years (60% male) and all participants spoke English. ELBW adolescents with social phobia (n = 6) were more shy (p = .041) and had poorer mental health-related QOL (p = .041) than those without such symptoms. The results suggest that ELBW could be a predisposing factor for increased shyness and psychological disorders including social phobia. Planning of interventions for ELBW individuals should therefore include strategies to prevent or mitigate the effects of these factors in adolescence / Psychology / M.A. (Clinical Psychology)

Schizophrenia is a complex disorder affecting 1% of the population and is highly heritable, but the majority of contributing genetic factors has remained elusive. Current risk estimates for clinical practice are primarily determined by family history and associated empirical risk. Copy number variants (CNVs) may hold the key to explaining the missing heritability in schizophrenia research; schizophrenia risk estimates as high as 30% have been found for the most-studied CNV associated with schizophrenia, 22q11. Currently, there are methods to identify CNVs though previously collected data from SNP microarrays that would facilitate these types of studies. To determine if algorithms that call CNVs from microarray data are robust four genomic regions with putative CNVs called by the Wellcome Trust Consortium using Birdseye in Birdsuite with Affymetrix 6.0 array raw SNP intensities, primarily affecting genes CHD1L, COX5B, PAK7, ZFYVE20, were validated using Taqman real-time qPCR assays in 29 samples by research groups at VCU and Dublin. CNVs called from the algorithm were 100% validated at VCU though there were false negatives from the algorithm that were validated. Two samples at loci with putative duplications were not called by the Dublin group, which may be because of differing sensitivities of the Taqman assays to be able to detect a 50% difference in copy number between duplications and diploid controls, or because of another technical or analytical difference between the two sites. Deletion frequency of one common CNV found in the gene ERBB4, was assessed by qPCR in both Irish singleton (ICCSS) and Irish family (IHDSF) samples and compared with Irish control (Trinity Biobank) and North American control populations. The ERBB4 deletion frequency was not significantly different when comparing the Irish controls to the Irish singleton or the Irish family samples though the family samples were different when compared against the North American control population, which suggests population stratification, rather than a true association between ERBB4 and increased schizophrenia risk. Current clinical practice has been improved by knowledge and evaluation of CNV-related disorders that include risk for psychosis and additional phenotypes. Genotyping of individuals with known psychosis has led to improved patient care for non-psychosis-related phenotypes associated with CNVs. Individuals with suspected genomic disorders that are found to have CNVs can be counseled on potential psychosis risk and potential risk to their offspring. Recurrent CNVs may hold promise in future clinical practice in order to individualize risk estimates in the general patient population, and increase the number of individuals able to receive anticipatory treatment to minimize disease severity.