1. Alvares GA, Licari MK, Stevenson PG, Bebbington K, Cooper MN, Glasson EJ, Tan DW, Uljarević M, Varcin KJ, Wray J, Whitehouse AJO. {{Investigating associations between birth order and autism diagnostic phenotypes}}. {J Child Psychol Psychiatry}. 2020.
BACKGROUND: Birth order effects have been linked to variability in intelligence, educational attainment and sexual orientation. First- and later-born children have been linked to an increased likelihood of an Autism Spectrum Disorder (ASD) diagnosis, with a smaller body of evidence implicating decreases in cognitive functioning with increased birth order. The present study investigated the potential association between birth order and ASD diagnostic phenotypes in a large and representative population sample. METHODS: Data were obtained from an ongoing prospective diagnostic registry, collected between 1999 and 2017, including children (1-18 years of age, n = 5,404) diagnosed with ASD in the state of Western Australia. Children with ASD were ranked relative to sibling’s birth to establish birth order within families at time of ASD diagnosis. Information reported to the registry by health professionals at the time of diagnostic evaluation included demographic and family characteristics, functional abilities and intellectual capacity. RESULTS: Adaptive functioning and intelligence scores decreased with increasing birth order, with later-born children more likely to have an intellectual disability. Compared to first-born children with siblings, first-born children without siblings at the time of diagnosis also exhibited decreased cognitive functioning. CONCLUSIONS: These findings demonstrate for the first time an association between increasing birth order and variability in ASD clinical phenotypes at diagnosis, with potential evidence of reproductive curtailment in children without siblings. Taken together, these findings have significant implications for advancing understanding about the potential mechanisms that contribute to heterogeneity in ASD clinical presentations as a function of birth order and family size.
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2. Becerra LA, Higbee TS, Vieira MC, Pellegrino AJ, Hobson K. {{The effect of photographic activity schedules on moderate-to-vigorous physical activity in children with autism spectrum disorder}}. {Journal of applied behavior analysis}. 2020.
Regular moderate-to-vigorous physical activity (MVPA) has been linked to improved bone health, muscular fitness, cognitive function, sleep, and a reduced risk of depression and obesity. Many children are not engaging in the recommended amount of physical activity. Furthermore, children with autism spectrum disorder (ASD) were found to engage in less physical activity than their peers of typical development. We extended previous research by conducting a physical activity context assessment, which included a comparison of indoor to outdoor activities to evaluate which environment produced the lowest percent of MVPA as recorded by the Observational System for Recording Physical Activity in Children. Given the utility of activity schedules to increase self-management and independent engagement during unstructured and low-preferred tasks, we then taught 3 preschool children diagnosed with ASD to use photographic activity schedules to increase the number of different activities that met the definition of MVPA in the 2 lowest-responding conditions of the physical activity context assessment. MVPA remained low during baseline sessions for all participants and immediately increased with the introduction of activity schedule teaching. All participants quickly met activity schedule teaching mastery criterion and demonstrated high levels of MVPA in generalization and maintenance probes without additional teaching.
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3. Bernaerts S, Boets B, Steyaert J, Wenderoth N, Alaerts K. {{Oxytocin treatment attenuates amygdala activity in autism: a treatment-mechanism study with long-term follow-up}}. {Translational psychiatry}. 2020; 10(1): 383.
Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly considered as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD), but the effects of continual use on neural substrates are fairly unexplored and long-term effects are unknown. In this double-blind, randomized, placebo-controlled study, we investigated the effects of single-dose and multiple-dose IN-OT treatment (4 weeks of daily (24 IU) administrations) on brain activity related to processing emotional states. Thirty-eight adult men with ASD (aged between 18 and 35 years) underwent functional magnetic resonance imaging of the posterior superior temporal gyrus (pSTS) and amygdala regions while processing emotional states from point-light biological motion. In line with prior research, a single dose of IN-OT induced a reliable increase in pSTS brain activity during the processing of point-light biological motion, but no consistent long-term changes in pSTS activity were induced after the multiple-dose treatment. In terms of bilateral amygdala, the multiple-dose treatment induced a consistent attenuation in brain activity, which outlasted the period of actual administrations until four weeks and one year post-treatment. Critically, participants with stronger attenuations in amygdala-activity showed greater behavioral improvements, particularly in terms of self-reported feelings of avoidant attachment and social functioning. Together, these observations provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala functioning and provide first indications that the acute versus chronic effects of IN-OT administration may be qualitatively different. Larger studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural substrates and its behavioral consequences.
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4. Cicaloni V, Pecorelli A, Cordone V, Tinti L, Rossi M, Hayek J, Salvini L, Tinti C, Valacchi G. {{A proteomics approach to further highlight the altered inflammatory condition in Rett syndrome}}. {Archives of biochemistry and biophysics}. 2020; 696: 108660.
Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. RTT patients show multisystem disturbances associated with perturbed redox homeostasis and inflammation, which appear as possible key factors in RTT pathogenesis. In this study, using primary dermal fibroblasts from control and RTT subjects, we performed a proteomic analysis that, together with data mining approaches, allowed us to carry out a comprehensive characterization of RTT cellular proteome. Functional and pathway enrichment analyses showed that differentially expressed proteins in RTT were mainly enriched in biological processes related to immune/inflammatory responses. Overall, by using proteomic data mining as supportive approach, our results provide a detailed insight into the molecular pathways involved in RTT immune dysfunction that, causing tissue and organ damage, can increase the vulnerability of affected patients to unknown endogenous factors or infections.
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5. Eapen V, Hiscock H, Williams K. {{Adaptive innovations to provide services to children with developmental disabilities during the COVID-19 pandemic}}. {Journal of paediatrics and child health}. 2020.
Children with developmental disabilities are experiencing significant challenges to service access due to suspension of in-person assessments during the current COVID-19 pandemic. Telehealth is rapidly becoming the new service delivery model, which presents a unique opportunity for innovation in care that could be beneficial in the post-pandemic period. For example, using a combination of in-home video and telehealth options could form the first step in developmental assessment, allowing children to receive the necessary supports without delay. Recent telehealth funding is welcome but additional Medicare items for joint consultations including general practitioners (GPs), and paediatric, mental health and allied health professionals is critical.
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6. Greenlee JL, Winter MA, Johnson M. {{Depression symptoms in adolescents with autism spectrum disorder: A contextual approach to mental health comorbidities}}. {Journal of adolescence}. 2020; 85: 120-5.
INTRODUCTION: Although research on mental health comorbidities in autism spectrum disorder (ASD) has increased in recent years, little has been done to evaluate potential individual × environment interactions associated with these comorbidities. The current study explored whether ASD-related characteristics (social-communication impairment) and environmental factors (peer and family contexts) had additive or interactive effects on the depression symptoms of youth with ASD. METHOD: In a cross-sectional sample of adolescents with ASD (N = 176; 13-17 years old; 72.7% male), primary caregivers and adolescents responded to a series of surveys online pertaining to adolescents’ mental health (Revised Child Anxiety and Depression Scale), family functioning (Self-Report of Family Inventory), and experiences of peer victimization (Peer Experiences Questionnaire-Revised). RESULTS: There were statistically significant interactions between social-communication skills and the environment in both family (△R(2) = 0.02) and peer (△R(2) = 0.02) contexts. For youth with better social-communication skills, there was a positive association between peer victimization and depression symptoms and a negative association between family competence and depression symptoms. CONCLUSION: Findings support social-push interactive models in which better social-communication skills are associated with fewer depression symptoms in the context of less-stressful peer and family environments, highlight the utility of ecologically informed approaches to the mental health of youth with ASD, and suggest several areas for future study.
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7. Hu Y, Pereira AM, Gao X, Campos BM, Derrington E, Corgnet B, Zhou X, Cendes F, Dreher JC. {{Right temporoparietal junction underlies avoidance of moral transgression in Autism Spectrum Disorder}}. {J Neurosci}. 2020.
Autism spectrum disorder (ASD) is characterized by a core deficit in theory-of-mind (ToM) ability, which extends to perturbations in moral judgment and decision-making. Although the function of the right temporoparietal junction (rTPJ), a key neural marker of ToM and morality, is known to be altered in autistic individuals, the neurocomputational mechanisms underlying its specific impairment in moral decision-making remain unclear. Here, we addressed this question by employing a novel fMRI task together with computational modeling and representational similarity analysis (RSA). ASD patients and healthy controls (HC) decided in public or private whether to incur a personal cost for funding a morally-good cause (Good Context) or receive a personal gain for benefiting a morally-bad cause (Bad Context). Compared with HC, individuals with ASD were much more likely to reject the opportunity to earn ill-gotten money by supporting a bad cause than HC. Computational modeling revealed that this resulted from unduly weighing benefits for themselves and the bad cause, suggesting that ASD patients apply a rule of refusing to serve a bad cause because they over-evaluate the negative consequences of their actions. Moreover, RSA revealed a reduced rTPJ representation of the information specific to moral contexts in ASD patients. Together, these findings indicate the contribution of rTPJ in representing information concerning moral rules and provide new insights for the neurobiological basis underpinning moral behaviors illustrated by a specific dysfunction of rTPJ in ASD patients.SignificancePrevious investigations have found an altered pattern of moral behaviors in individuals with autism spectrum disorder (ASD), closely associated with a dysfunction in the right temporoparietal junction (rTPJ). However, the specific neurocomputational mechanisms at play that drive the dysfunction of the rTPJ in moral decision-making remain unclear. Here, we show that ASD individuals are more inflexible when following a moral rule even though an immoral action can benefit themselves, and suffer an undue concern about their ill-gotten gains and the moral cost. Moreover, a selectively reduced rTPJ representation of information concerning moral rules was observed in ASD patients. These findings deepen our understanding of the neurobiological roots that underlie atypical moral behaviors in ASD patients.Editor’s Note:The authors have been made aware of concerns and are working to address them in proofs, before the final version of this article is published.
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8. Ring M, Solomon M. {{Introduction to the Special Collection on « Memory in Autism Spectrum Disorder »}}. {Autism Res}. 2020.
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9. Shuai B, Jin H, Lin Y, Duan R, Zhao N, Li Z, Mao J, Luo Y, Shi M. {{Safety and efficacy of complementary and alternative medicine in the treatment of autism spectrum disorder: A protocol for systematic review and meta-analysis}}. {Medicine}. 2020; 99(45): e23128.
INTRODUCTION: The purpose of this study is to evaluate the efficacy and safety of complementary and alternative medicine in the treatment of autism spectrum disorder. METHODS AND ANALYSIS: We will electronically search Pubmed, Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trial, China National Knowledge Infrastructure, China Biomedical Literature Database, China Science Journal Database, and Wan-fang Database from their inception. Also, we will manually retrieve other resources, including reference lists of identified publications, conference articles, and gray literature. The clinical randomized controlled trials or quasi-randomized controlled trials related to complementary and alternative medicine treating autism spectrum disorder will be included in the study. The language is limited to Chinese and English. Research selection, data extraction, and research quality assessment will be independently completed by 2 researchers. Data were synthesized by using a fixed-effect model or random-effect model depend on the heterogeneity test. The Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) scores will be the primary outcomes. The scores of the Autism Treatment Evaluation Checklist and the Ritvo-Freeman Real Life Rating Scale will also be assessed as secondary outcomes. RevMan V.5.3 statistical software will be used for meta-analysis, and the level of evidence will be assessed by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Continuous data will be expressed in the form of weighted mean difference or standardized mean difference with 95% confidence intervals (CIs), whereas dichotomous data will be expressed in the form of relative risk with 95% CIs. ETHICS AND DISSEMINATION: The protocol of this systematic review does not require ethical approval because it does not involve humans. We will publish this article in peer-reviewed journals and presented at relevant conferences. SYSTEMATIC REVIEW REGISTRATION: OSF Registries, DOI: 10.17605/OSF.IO/ HA97R (https://osf.io/ha97r).
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10. Thacker S, Sefyi M, Eng C. {{Alternative splicing landscape of the neural transcriptome in a cytoplasmic-predominant Pten expression murine model of autism-like Behavior}}. {Translational psychiatry}. 2020; 10(1): 380.
Alternative splicing (AS) is a posttranscriptional mechanism regulating gene expression that complex organisms utilize to expand proteome diversity from a comparatively limited set of genes. Recent research has increasingly associated AS with increased functional complexity in the central nervous systems in higher order mammals. This work has heavily implicated aberrant AS in several neurocognitive and neurodevelopmental disorders, including autism. Due to the strong genetic association between germline PTEN mutations and autism spectrum disorder (ASD), we hypothesized that germline PTEN mutations would alter AS patterns, contributing to the pathophysiology of ASD. In a murine model of constitutional mislocalization of Pten, recapitulating an autism-like phenotype, we found significant changes in AS patterns across the neural transcriptome by analyzing RNA-sequencing data with the program rMATS. A few hundred significant alternative splicing events (ASEs) that differentiate each m3m4 genotype were identified. These ASEs occur in genes enriched in PTEN signaling, inositol metabolism, and several other pathways relevant to the pathophysiology of ASD. In addition, we identified expression changes in several splicing factors known to be enriched in the nervous system. For instance, the master regulator of microexons, Srrm4, has decreased expression, and consequently, we found decreased inclusion of microexons in the Pten(m3m4/m3m4) cortex (~10% decrease). We also demonstrated that the m3m4 mutation disrupts the interaction between Pten and U2af2, a member of the spliceosome. In sum, our observations point to germline Pten disruption changing the landscape of alternative splicing in the brain, and these changes may be relevant to the pathogenesis and/or maintenance of PTEN-ASD phenotypes.
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11. Tse HM, Ho IT, Wong K. {{The Learning, Social and Emotion Adaptation Questionnaire-Short Form: A Measure of Adaptive Behavior for Primary School Students with Autism Spectrum Disorder}}. {Autism Res}. 2020.
Students with autism spectrum disorder (ASD) studying in mainstream classrooms have diverse adjustment difficulties in learning, social interaction, and emotion regulation. It is crucial to identify the areas these students find most challenging so that teachers can provide training and support accordingly. We therefore developed, examined, and provided norms for the Learning, Social and Emotion Adaptation Questionnaire-Short Form (LSEAQ-S), a teacher report instrument measuring 53 essential adaptive behaviors for mainstream primary school students in Hong Kong. Teachers completed the LSEAQ-S for three samples of 2,298, 2,690, and 3,305 students with ASD from 204 schools and a sample of 1,869 students without ASD from 112 schools. Our study showed that an 11-factor structure best describes the LSEAQ-S, which has high internal consistency and good convergent validity examined with the Social Responsiveness Scale-Second Edition (SRS-2). Normative data of the LSEAQ-S stratified by gender and grade (grades 1 to 3; grades 4 to 6) are presented. Gender and grade differences were found, with girls with ASD lagging behind their same-gender peers in related skills more than boys with ASD did, across both grade levels and especially in senior grades. The LSEAQ-S, together with its normative data, can reveal students’ difficulties and needs, inform intervention priorities, and help monitor training progress. LAY SUMMARY: This study introduces the Learning, Social and Emotion Adaptation Questionnaire-Short Form (LSEAQ-S), a teacher report instrument developed in Hong Kong measuring school adaptation of students with autism spectrum disorder (ASD) in mainstream primary schools. The measure helps education personnel identify behaviors in which a student falls behind his/her peers and facilitate training and support targeting those behaviors.
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12. Van Dyke MV, Guevara MVC, Wood KS, McLeod BD, Wood JJ. {{The Pediatric Autism Spectrum Therapy Observation System: Development, Psychometric Properties, and Sensitivity to Treatment}}. {Child Psychiatry Hum Dev}. 2020.
An observational coding system was developed to track clinical change in children with autism spectrum disorder (ASD) during psychotherapy. The Pediatric Autism Spectrum Therapy Observation System (PASTOS) consists of 23 items divided into 5 subscales and is used to rate child behaviors in individual psychotherapy sessions. Manual-based cognitive behavioral therapy session transcripts of 22 children diagnosed with ASD (IQ > 70) and a concurrent anxiety disorder (M = 9.41 years, SD = 1.56 years) enrolled in a randomized, controlled trial were coded. Results suggested that the PASTOS exhibited promising interrater reliability, internal consistency, convergent validity at post-treatment, and treatment sensitivity. The PASTOS may be a useful tool for studying process and outcome in psychotherapy research on children with ASD.
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13. Yamada S, Nakagawa I, Nishimura F, Motoyama Y, Park YS, Nakase H. {{The Possibility of Intracranial Hypertension in Patients with Autism Spectrum Disorder Using Computed Tomography}}. {J Clin Med}. 2020; 9(11).
Although intracranial pressure is considered to be normal in children with autism spectrum disorder (ASD), we aimed to assess whether such children may have increased intracranial pressure using noninvasive computed tomography (CT). Head CT scans of children with ASD (109 cases, male 91 and female 18, average age 4.3 years) and of children with typical development (60 cases, male 35 and female 25, average age 4.5 years) were acquired. The images were processed to map the shape of the inner skull surface. We predicted that a complex skull shape, based on a marked digital impression, would be indicative of chronically increased intracranial pressure. The data of the scans were extracted and processed to automatically establish inner and outer cranial circumferences. The circularity (reflecting inner skull shape and area) and C-ratio (ratio of inner/outer circumference) were determined and statistically analyzed. The circularity and C-ratio were significantly lower in children with ASD than in children with typical development. A lower circularity was associated with a more complex shape of the inner skull surface, which indicated the presence of intracranial hypertension. Our study suggests that children with ASD may be at a risk for chronic intracranial hypertension. Our technique incorporating the circularity and C-ratio is a useful noninvasive method for screening such patients and could impact future investigations of ASD.
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14. Zabihi M, Floris DL, Kia SM, Wolfers T, Tillmann J, Arenas AL, Moessnang C, Banaschewski T, Holt R, Baron-Cohen S, Loth E, Charman T, Bourgeron T, Murphy D, Ecker C, Buitelaar JK, Beckmann CF, Marquand A. {{Fractionating autism based on neuroanatomical normative modeling}}. {Translational psychiatry}. 2020; 10(1): 384.
Autism is a complex neurodevelopmental condition with substantial phenotypic, biological, and etiologic heterogeneity. It remains a challenge to identify biomarkers to stratify autism into replicable cognitive or biological subtypes. Here, we aim to introduce a novel methodological framework for parsing neuroanatomical subtypes within a large cohort of individuals with autism. We used cortical thickness (CT) in a large and well-characterized sample of 316 participants with autism (88 female, age mean: 17.2 ± 5.7) and 206 with neurotypical development (79 female, age mean: 17.5 ± 6.1) aged 6-31 years across six sites from the EU-AIMS multi-center Longitudinal European Autism Project. Five biologically based putative subtypes were derived using normative modeling of CT and spectral clustering. Three of these clusters showed relatively widespread decreased CT and two showed relatively increased CT. These subtypes showed morphometric differences from one another, providing a potential explanation for inconsistent case-control findings in autism, and loaded differentially and more strongly onto symptoms and polygenic risk, indicating a dilution of clinical effects across heterogeneous cohorts. Our results provide an important step towards parsing the heterogeneous neurobiology of autism.
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15. Zhu Y, Mordaunt CE, Durbin-Johnson BP, Caudill MA, Malysheva OV, Miller JW, Green R, James SJ, Melnyk SB, Fallin MD, Hertz-Picciotto I, Schmidt RJ, LaSalle JM. {{Expression Changes in Epigenetic Gene Pathways Associated With One-Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non-Typical Neurodevelopment}}. {Autism Res}. 2020.
The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non-typical development (Non-TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. Genome-wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies-Learning Early Signs. Sixteen different one-carbon metabolites, including folic acid, betaine, 5′-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to one-carbon metabolites. Using differential gene expression analysis, six transcripts (TGR-AS1, SQSTM1, HLA-C, and RFESD) were associated with child outcomes (ASD, Non-TD, and TD) with genome-wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5-MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one-carbon metabolite status and changes relevant to children’s later neurodevelopmental outcomes. LAY SUMMARY: Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non-typical neurodevelopment and were associated with maternal nutrients.
