La césarienne est un mode d’accouchement alternatif recommandé lorsque la vie de la mère ou du fœtus pourrait être mise en danger par l’accouchement naturel. Ces dernières années, de nombreuses études ont rapporté que la césarienne augmentait le risque de développer des troubles tels que l’autisme. Pourtant, ces études sont controversées à cause des nombreux facteurs impliqués dans la naissance par césarienne à prendre en compte. Pour résoudre ce problème, nous avons utilisé des souris nées par césarienne et évalué des paramètres liés à l’autisme. En évaluant leur sociabilité, communication verbale et comportements répétitifs, nous avons trouvé que la césarienne n’induit qu’une modification précoce et transitoire de la communication. La césarienne n’affecte pas non plus l’activité cérébrale même si de petites altérations morphologiques éphémères sont observées à la naissance. Par conséquent, la césarienne conduit à des modifications à court terme non suffisantes pour induire l’autisme. / Cesarean section (C-section) is an alternative mode of delivery which is recommended when the mother or the fetus’ life might be endangered by natural childbirth. In recent years, epidemiological studies have reported that C-section delivery might increase the probability to develop disorders such as autism. However, these reports remain controversial due to the numerous factors involved in birth by C-section. To tackle this issue, we used mice delivered by C-section and looked at parameters associated with autism. We evaluated sociability, communication and repetitive behaviors in our mice and found that C-section only induces transient and early modifications in their communication. Also, we did not find changes in brain activity, even if small temporal morphological alterations were present after C-section. Therefore, C-section delivery leads to short-term modifications that are not sufficient to induce autism.

Autism is a neurodevelopmental disorder that is characterized by deficits involving social interaction, communication, and perception. Although there is much research that has examined functional neural connectivity in individuals with autism, few have conducted these studies in very young children while awake across EEG power and coherence measures. Anomalies in EEG coherence and power have been associated with deficits in executive function and mental activity. The present study examined neural activation and functional connectivity with an EEG, in children ages 3 -5, during an eyesclosed baseline period. Discrete Fourier Transform was performed on artifact-free segments of EEG data to produce power density values. In addition, coherence measurements were examined to assess functional connectivity in the alpha bandwidth during the baseline recording. Children with autism spectrum disorder (ASD) demonstrated reduced alpha coherence in fronto-temporal regions and between right temporal sites when compared to typically developing (TD) children. In addition, the reduction in coherence was based on ASD severity, such that high-functioning children with ASD showed greater coherence than low-functioning children with ASD. Children with ASD also displayed reduced power in the alpha, beta, and theta frequency bandwidths in frontal, temporal, central, and occipital regions compared to TD children. Interestingly, delta power differentiated children based on developmental status such that high-functioning children with ASD demonstrated the greatest delta power, followed by TD children, and then low-functioning children with ASD. Finally, TD children demonstrated left anterior temporal EEG asymmetry in the alpha bandwidth, whereas children with high-functioning ASD exhibited left posterior temporal EEG asymmetry and right frontal EEG asymmetry. Thus, the results suggest that children with ASD exhibit atypical patterns of brain activity and functional connectivity compared to their typically developing counterparts. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2013.

Os transtornos do espectro autista (TEA) são distúrbios neuropsiquiátricos bastante comuns, graves, e que propiciam grande impacto social e financeiro. A identificação de vias moleculares e processos celulares alterados que são compartilhados pelos pacientes, mesmo que estes apresentem causas etiológicas distintas, pode contribuir de forma significativa para o entendimento de sua patofisiologia desses transtornos. Ainda, a identificação destas vias pode propiciar o desenvolvimento de abordagens terapêuticas mais eficientes, uma vez que o uso de medicamentos nos TEA ainda é inadequado, envolvendo baixa melhora funcional e diversos efeitos colaterais, como o ganho excessivo de peso e anormalidades metabólicas associadas. Neste trabalho, selecionamos como uma primeira abordagem o estudo da via de sinalização PI3K-mTOR em pacientes com TEA não-sindrômico, via esta envolvida com diversos aspectos do desenvolvimento e funcionamento neuronal, assim como com a patofisiologia de síndromes monogênicas que apresentam alta prevalência de TEA em seu quadro clínico. Foram utilizadas como modelo experimental in vitro células-tronco mesenquimais provenientes de polpa de dente decíduo (SHEDs) de pacientes e indivíduos controles. Os resultados aqui obtidos sugerem a importância da desregulação da via PI3K/mTOR na patofisiologia de uma parcela importante dos casos de TEA não-sindrômico. Ainda, observamos que as células dos pacientes com alterações nessa via de sinalização apresentam maior capacidade proliferativa, e que a modulação deste fenótipo alterado por meio do uso concomitante de inibidores de PI3K e mTOR nas células de um destes pacientes sugere esta via como um alvo promissor para o desenvolvimento de novas abordagens terapêuticas para estes pacientes. Em seguida, na tentativa de desvendar os mecanismos subjacentes aos efeitos metabólicos adversos associados com o uso de antipsicóticos prescritos para o tratamento de pacientes com TEA, investigamos os efeitos destes psicofármacos sobre a biologia do tecido adiposo humano. Foram utilizadas como modelos in vitro células-tronco (ADSCs) e adipócitos maduros derivados de tecido adiposo humano de indivíduos controles. Os resultados obtidos sugerem que a ação direta dos antipsicóticos com alta propensão ao ganho de peso (como a olanzapina e a clozapina) sobre a proliferação, diferenciação, e o metabolismo do tecido adiposo humano parece não constituir um mecanismo importante associado ao ganho de peso apresentado pelos pacientes, e que a ação desses medicamentos sobre os sistemas centrais que regulam o peso e o metabolismo deve ser o mecanismo principal levando aos efeitos metabólicos adversos. Juntos, os resultados gerados neste trabalho podem, de certa forma, contribuir para da farmacoterapia dos TEA / Autism spectrum disorders (ASD) are common neuropsypchiatric disorders, which has serious social and economic impacts. Identification of common molecular and cellular processes altered in patients, despite the underlying genetic heterogeneity, can contribute significantly to our understanding of the disease pathophysiology and can help to develop more effective treatments, since available pharmacotherapy for ASD is inefficient and frequently associated with adverse side effects, such as weight gain and metabolic disturbances. Here, we used patient-derived Stem cells from Human Exfoliated Deciduous teeth (SHEDs) as an intro model system to investigate whether non-syndromic ASD patients show altered regulation of PI3K/mTOR signaling pathway, which is involved in multiple aspects of neuronal development and physiology, and in the pathogenesis of monogenic syndromes that share features with ASD. Our results suggest that dysregulation of PI3K/mTOR-linked networks play an important role in the pathogenesis of a subgroup of non-syndromic ASD. In addition, we found enhanced proliferative capacity in cells with altered PI3K/mTOR activity, which was rescued in one of these patients through combined pharmacological inhibition of both PI3K and mTOR kinase activity, suggesting that PI3K-mTOR signaling is a promising target for the development of new therapeutic approaches for these individuals. Next, in an attempt to better understand the mechanisms underlying the metabolic side effects of the antipsychotics prescribed for ASD treatment, we investigated the effects of some of these drugs on the biology of human adipose tissue using as in vitro model systems human adipose-derived stem cells (ADSCs) and mature adipocytes. Our results suggest that a direct and potent effect of antipsychotics with high weight gain liability (such as clozapine and olanzapine) on cell proliferation, differentiation, and metabolism of human adipose tissue is not an important mechanism by which these drugs induce metabolic disturbances. Consequently, our results suggest that these side effects may mainly reflect the action of these drugs on central pathways involved in weight control and metabolism. Together, our results can, to some extent, contribute to improving pharmacotherapy of ASD

A presente pesquisa tem como objetivo investigar o percurso histórico da classificação psiquiátrica Transtorno do Espectro Autista (TEA). Os deslizamentos taxonômicos desde sua primeira forma, o Autismo Precoce, nas cinco versões de um dos principais sistemas de classificação psiquiátricas utilizados no Brasil, o Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM), trouxeram impactos socioeconômicos, éticos e políticos que merecem ser observados com cautela. Essa nova forma de diagnosticar o autismo não se mostrou nada sutil, uma vez que se trata de uma categoria nosográfica muito abrangente e que trouxe consigo uma epidemia de diagnósticos de TEA. Para alcançar esse objetivo, foram utilizadas as pesquisas bibliográfica e documental. Na discussão final, propomos, com base na investigação realizada, um olhar crítico para a comodificação da psicopatologia denominada TEA / The purpose of this research is to investigate the historical path of the Autism Spectrum Disorder (ASD) psychiatric classification. The nomenclature changes since its initial form, Autism Infantile, contained in the five versions of one of the main psychiatric classification systems used in Brazil, the Diagnostic and Statistical Manual of Mental Disorders (DSM) have generated socio-economic, ethical and political impacts that need be carefully analyzed. This new method of diagnosing autism has proven to be not subtle at all, since it pertains to a very comprehensive nosographic category and which gave rise to an epidemic of ASD diagnoses. In order to meet such purpose, we used bibliographic and documentary researches. In the final discussion we propose, from the investigation conducted, a critical analysis on the commodification of the psychopathology referred to as ASD

Thesis advisor: Marilyn Cochran-Smith / The number of autistic students receiving special education services increased 478% between the years 2000 and 2013 (National Center for Education Statistics, 2016). U.S. schools and teachers are educating more autistic students with complex educational needs resulting from differences in communication, social interaction and behavior. As a result, schools need increasing numbers of teachers who are equipped to educate them. Quality special education teacher preparation is critical for teachers of autistic students, because it can affect the quality of education and outcomes for this highly unique student population. Very little research has been conducted to determine the extent to which special education teacher preparation programs provide teachers with preparation to teach autistic students, or about the extent to which special educators feel prepared to teach this population at the point of conclusion of their preparation programs. This study used a mixed methods sequential explanatory design to examine the perceptions of special educators about their preparedness to teach autistic students based on preparation program/licensure, specialized autism coursework, and on-the-job experiences after licensure programs. A researcher-created survey was followed by interviews to explore participants’ survey responses more deeply. Survey data (n =121) were used to inform both question construction and participant selection for a purposive sample of follow-up interviews (n= 10). Regression analyses, means, summary scores, and thematic coding were employed to analyze the survey data. Results indicated that the majority (77%) of special education teachers felt unprepared to teach autistic students at the end of their licensure programs. However, specialized autism coursework was a significant predictor of teachers’ sense of preparedness. Limitations of the study and implications for special education teacher preparation and education are discussed. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Lynch School of Education. / Discipline: Teacher Education, Special Education, Curriculum and Instruction.

O Transtorno do Espectro Autista (TEA) é um transtorno neuropsiquiátrico grave caracterizado por comprometimento da capacidade de interação social e comunicação e pela presença de interesses, atividades e comportamentos repetitivos e restritos. O TEA apresenta alta heterogeneidade genética e pode ser enquadrado em diferentes modelos de herança, o que torna difícil apontar os fatores genéticos associados ao transtorno e compreender de que forma eles interagem e ocasionam, em última instância, sua manifestação clínica. Ainda, fenômenos como penetrância incompleta e discordância entre gêmeos monozigóticos são frequentemente observados em famílias com indivíduos afetados, tornando ainda mais complexo o entendimento do envolvimento de cada um dos fatores genéticos na etiologia do TEA. Uma forma de contornar esses problemas é a utilização de abordagens transcriptômicas no estudo desse transtorno. Nesse contexto, a busca por variantes patogênicas deixa de ser o principal foco do estudo e a atenção volta-se para a investigação de vias de sinalização e processos biológicos que estejam desregulados durante o processo de diferenciação neuronal e que sejam compartilhados pelos indivíduos afetados. Usando como principal ferramenta o sequenciamento do transcriptoma de células progenitoras neurais (NPC) e neurônios derivados de células-tronco pluripotentes induzidas (iPSC), identificamos uma série de alterações transcricionais importantes entre pacientes e controles, sugerindo que, a despeito da grande heterogeneidade genética associada ao transtorno, essas alterações se refletem em processos biológicos comuns. Nossos resultados são consistentes com os obtidos em trabalhos anteriores realizados com outros modelos de estudo e as linhagens celulares geradas a partir de nosso protocolo parecem refletir de forma fidedigna o perfil de expressão do cérebro fetal. Ainda, em um caso particular incluído neste estudo, investigamos as consequências transcricionais e funcionais de uma duplicação na região 17p13.3 - alteração previamente implicada em outros casos de autismo - nas células neuronais deste paciente, contribuindo para a compreensão do papel desta duplicação na patofisiologia do TEA. Dessa forma, nosso trabalho reforça a validade do uso de células neurais derivadas de iPSC e de abordagens transcricionais para o estudo de transtornos do neurodesenvolvimento / Autism Spectrum Disorder (ASD) is a severe neuropsychiatry disorder characterized by impaired social interaction and communication, restricted interests and repetitive behaviors. ASD is highly genetically heterogeneous and can be caused by different inheritance models, which hampers the identification of the genetic factors associated to the disorder. Incomplete penetrance and discordance between monozygotic twins are often observed in families of affected individuals, making it even more complex to understand the involvement of genetic factors in ASD. Applying transcriptomic approaches to study this disorder is an interesting way to overcome these problems. In this context, searching for pathogenic variants is no longer the study\'s main focus. Instead, one aims to investigate signaling pathways and biological process that are deregulated during neuronal differentiation and shared by affected individuals. Based on the transcriptome sequencing of neural progenitor cells (NPC) and neurons derived from induced pluripotent stem cells (iPSC), we were able to identify a series of important transcriptional alterations between patients and controls, which suggest that despite the great genetic heterogeneity associated to ASD, those alterations are reflected in common biological processes. Our results are consistent with those obtained in previous studies performed with other models and the lineages generated by our protocol seem to reliably reflect fetal brain expression profile. Moreover, in a particular case included in this study, we investigated transcriptional and functional consequences of a duplication located at 17p13.3 - an alteration previously found in other autism cases - in the neuronal cells of this patient, contributing towards a better comprehension of the role of this duplication in ASD pathophysiology. Hence, our work reinforces the validity of the use of neural cell derived from iPSC and transcriptional approaches in the studies of neurodevelopmental disorders

O transtorno do espectro autista (TEA) é um transtorno de desenvolvimento que prejudica persistentemente a comunicação e a interação social e causa padrões restritos e repetitivos de comportamento, interesses e atividades. Esses sintomas estão presentes desde o início da infância e limitam ou prejudicam o cotidiano do indivíduo. Contudo, vários fatores impedem que seja possível diagnosticar antes dos três anos de idade, entre eles o fato de que o diagnóstico é essencialmente clínico e realizado com base nos critérios descritos no Manual diagnóstico e estatístico de transtornos mentais da sociedade americana de psiquiatria (DSM), entrevistas com os pais, observação do comportamento e aplicação de questionários e escalas padronizadas. Estas ferramentas e questionários para a realização do diagnóstico ainda carecem de validação e adaptação ao contexto brasileiro. O estudo das características antropométricas em indivíduos com TEA e indivíduos em desenvolvimento típico mostrou que podem existir diferenças como distâncias entre as pupilas, formato das orelhas, estrabismo e circunferência da cabeça. A hipótese é que seria possível classificar indivíduos com TEA e indivíduos em desenvolvimento típico com base nas medidas antropométricas faciais. Desta forma, este trabalho teve como objetivo a construção de um classificador que, dada uma imagem facial de uma criança, consiga discriminar entre os dois grupos, auxiliando assim o diagnóstico. A fim de testar a hipótese, foram coletadas imagens bidimensionais de crianças e adolescentes com TEA e em desenvolvimento tipico para a construção de uma base de dados. As imagens foram processadas por meio de um pipeline definido neste trabalho e foram testados e comparados diferentes métodos de redução de dimensionalidade e classificação e como resultado obteve-se acurácia de 80% na classificação com Random Forests / Autism Spectrum Disorder (ASD) is a developmental disorder that persistently impairs communication and social interaction and causes restricted and repetitive patterns of behavior, interests, and activities. These symptoms are present from the beginning of childhood and limit or impair the daily life of the individual. However, several factors prevent it from being possible to diagnose before the age of three, including the fact that the diagnosis is essentially clinical and performed based on the criteria described in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatry Association (DSM) , interviews with parents, observation of behavior and application of questionnaires and standardized scales. These tools and questionnaires to carry out the diagnosis still lack validation and adaptation to the brazilian context. The study of anthropometric features in individuals with ASD and individuals in typical development showed that there may be differences such as distances between the pupils, ear format, strabismus and head circumference. The hypothesis is that it would be possible to classify individuals with ASD and individuals in typical development based on anthropometric facial measures. Therefore, this work aimed to construct a classifier that, given a childs facial image, can discriminate between the two groups, thus helping the diagnosis. In order to test the hypothesis, two-dimensional images of children and adolescents with ASD and in typical development were collected for the database construction. The images were processed in a pipeline defined in this work and different methods of dimensionality reduction and classification were tested and compared and as a result 80% accuracy was obtained in the classification with Random Forests algorithm

Os transtornos do espectro autista (TEA) são caracterizados por dificuldades na interação social e na comunicação, interesses restritos e comportamentos estereotipados. Trata-se de doença complexa, podendo estar relacionada a fatores ambientais, genéticos ou a ambos. A heterogeneidade genética dos TEA pode ser explicada pela presença de variantes raras patogênicas únicas (modelo monogênico) bem como pela combinação de alelos raros (modelo oligogênico) ou ainda pela combinação de alelos comuns de baixo risco (poligênicos). Há um esforço mundial na tentativa de se identificar variantes que conferem risco e, nos últimos anos, a identificação de variantes raras tem sido mais bem sucedida. As estimativas indicam que 10% dos indivíduos dentro do espectro do autismo possuem uma síndrome de padrão de herança mendeliana dentre elas a síndrome do cromossomo X frágil cujo mecanismo molecular se explica pela mutação completa no gene FMR1. A partir dos anos 2000 aproximadamente, alguns trabalhos na literatura sugeriram que a pré-mutação do gene FMR1, associada à síndrome do tremor e ataxia e a insuficiência ovariana primária associada ao X frágil (FXTAS e FXPOI), pudesse estar relacionada ao TEA. Essa ligação, no entanto é incerta, sendo por isso, o foco deste trabalho. Para tanto, foi realizada uma revisão bibliográfica buscando dados na literatura que comparassem pacientes portadores da pré-mutação com controles quanto à manifestação dos TEA. Foi levantada a frequência de portadores da pré- mutação no gene FMR1 entre 1056 probandos do grupo de pesquisas em transtornos do espectro autista do Centro de Pesquisas sobre o Genoma Humano e Células Tronco. Nesses pacientes foram também realizados exames complementares. Efetuou-se também um levantamento de eventuais casos de TEA entre os portadores da pré-mutação em outra casuística, composta de famílias de afetados pela síndrome do X frágil, no laboratório de genética humana do Departamento de Biologia Evolutiva - Instituto de Biociências - USP O primeiro levantamento revelou uma frequência de 0.19% de pré-mutados na casuística composta por pacientes com TEA (2:1055), semelhante à da população em geral. O segundo levantamento não revelou nenhum paciente com TEA entre os pré- mutados. Além disso, os dois pacientes pré-mutados na primeira casuística são portadores de uma CNV patogênica. Este estudo não apóia, portanto, uma relação causal entre TEA e a pré-mutação do gene FMR1 / Autism spectrum disorders (ASDs) are characterized by impairments in social interaction and comunication as well as restricted interests and stereotyped behaviors. ASD is a complex disease that may be related to environmental factors, genetic factors or both. Genetic heterogeneity in ASD may be explained by rare pathogenic variants (monogenic model), by a combination of rare alleles (oligogenic model) or by other combinations of low-impact common alleles (polygenic model). Researchers are working to identify risk variants and have been more successful in finding rare variants in recent years. Monogenic disorders (Mendelian disorders), such as fragile X syndrome, are found in 10% of ASD patients. Fragile X syndrome is caused by full mutation in the FMR1 gene and account for a fraction of ASD cases. FMR1 premutation is related to two different conditions: fragile X-associated tremor/ataxia syndrome (FRAXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). In the last two decades some researchers have associated premutation with behavior problems. However the association between premutation and ASD remains unclear and thus it was the focus of this investigation. This study includes an extensive review of articles that compare ASD manifestations in premutation carriers and controls. The study also estimated the premutation frequency in 1056 male patients from the ASD cohort at the Human Genome and Stem Cell Research Center. Complementary tests were performed on these patients to rule out any other genetic alterations that could explain clinical presentations of ASD. Moreover, a survey was performed of possible ASD cases among premutation males from fragile X families in the database of the Human Genetics Laboratory at the Biology Department of the Biosciences Institute. A frequency of 0.19% of premutation carriers was detected in the sample of ASD patients(2:1055), which is similar to the general population. No ASD patients were detected among the premutated males. Furthermore the two pre-mutated patients in the first sample harbored a pathogenic CNV. Therefore this study do not support an association between the FMR1 premutation and ASD

Young people with Autism Spectrum Disorders (ASD) are more prone to experience anxiety disorders at a greater level compared to their neurotypical developing counterparts, causing lifelong impairments in family, social, academic and adaptive functioning. Early interventions in childhood have been designed to minimize these stressful events and to optimize children’s developmental outcomes. Cognitive behavioural therapy (CBT) is considered a first-line intervention of anxiety. The review aimed to synthesize empirical literature on modified CBT interventions from 2009 until 2019 focusing on reducing anxiety in children and adolescents with ASD. A systematic review of the literature was conducted in five databases. As a result, 10 articles were included to review. Modifications found were: a) audiovisual support and written materials, b) parental partic-ipation, c) sessions length, d) language, e) sensory and motor accommodations, f) emphasis into the behav-ioural component, g) enhancement of individual’s attention and participation, h) facilitating materials to access the content of CBT, and i) participants’ specific interests and worries. The interventions showed significant reductions in youth anxiety levels. Future research should focus on addressing which specific modifications contribute to anxiety reduction since to date, there is no evidence comparing standard CBT to modified CBT interventions. Moreover, there is a lack of anxiety-assessment instruments specially designed for individuals with ASD. In addition, considering the longstanding prevalence of male autistic rates, ASD diagnostic instru-ments should be revised to reduce bias that can mislead to an inattentive ascertainment of females with ASD.

This study examined the use of an iPhone and List Recorder application to teach three adolescents with autism spectrum disorder to enhance their interpersonal daily living skills in a community setting. Participants were taught to use interpersonal skills to perform an ordering and purchasing task. A multiple probe design across participants was used to demonstrate the effects of the intervention on the participants’ performance. Results indicated an increase in interpersonal skills used in a community setting. Participants were able to generalize these skills to another community setting. Finally, participants were able to demonstrate these skills once the intervention was removed during follow-up. Implications for future research are discussed. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection