1. Absoud M. Social determinants, inequality, and autism. The Lancet Child & adolescent health. 2022; 6(12): 832-3.

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2. Belokopytova, II, Kondaurova EM, Kulikova EA, Ilchibaeva TV, Naumenko VS, Popova NK. Effects of the Cc2d1a/Freud-1 Knockdown in the Hippocampus of BTBR Mice on the Autistic-Like Behavior, Expression of Serotonin 5-HT(1A) and D2 Dopamine Receptors, and CREB and NF-kB Intracellular Signaling. Biochemistry Biokhimiia. 2022; 87(10): 1206-18.

The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 (encoded by the Cc2d1a gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT(1A) serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the Cc2d1a/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the Cc2d1a/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT(1A) serotonin and D2 dopamine receptors, and CREB and NF-κB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the Cc2d1a/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the Cc2d1a/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of Cc2d1a/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT(1A) serotonin and D2 dopamine receptors and key NF-κB signaling genes (Nfkb1 and Rela). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.

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3. Cleary M, West S, McLean L, Hunt GE, Hungerford C, Kornhaber R. A Scoping Review of Autism and the Way It Changes the Presentation of Suicidal Thoughts and Behavior Compared to the General Population. Issues in mental health nursing. 2022: 1-20.

Autism spectrum conditions are a group of neurodevelopmental conditions that carries an array of co-occurring diagnoses, including a heightened risk of suicide attempts and suicide. This scoping review examined primary research focusing on autism and suicidality, to understand what is currently known on the topic, including how autism changes the presentation of suicidal thoughts and behavior; and to assess the suicide awareness and prevention education programs currently available for autistic people, their families, and health professionals and support workers. A comprehensive search (November 2021) across Scopus, PubMed and CINAHL identified 39 articles from 38 studies. Three themes emerged, with five subthemes. 1. The prevalence of suicidality in autistic people; 2. The presentation of suicidality in autistic people, including (a) risk of suicidality; (b) gender, age, employment and education; (c) co-occurring psychiatric conditions; (d) autism traits and social communication; (e) intellectual disability; and 3. Autism-specific approaches to suicidal thoughts, behavior and prevention. Findings were mixed, including conflicting evidence on the risk of autism and suicidality, and limited evidence of resources related to autism-specific suicide awareness or information, and education or prevention programs.

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4. Hadaya L, Vanes L, Karolis V, Kanel D, Leoni M, Happé F, Edwards AD, Counsell SJ, Batalle D, Nosarti C. Distinct Neurodevelopmental Trajectories in Groups of Very Preterm Children Screening Positively for Autism Spectrum Conditions. Journal of autism and developmental disorders. 2022.

Very preterm (VPT; < 33 weeks' gestation) toddlers screening positively for autism spectrum conditions (ASC) may display heterogenous neurodevelopmental trajectories. Here we studied neonatal brain volumes and childhood ASC traits evaluated with the Social Responsiveness Scale (SRS-2) in VPT-born toddlers (N = 371; median age 20.17 months) sub-divided into three groups based on their Modified-Checklist for Autism in Toddlers scores. These were: those screening positively failing at least 2 critical items (critical-positive); failing any 3 items, but less than 2 critical items (non-critical-positive); and screening negatively. Critical-positive scorers had smaller neonatal cerebellar volumes compared to non-critical-positive and negative scorers. However, both positive screening groups exhibited higher childhood ASC traits compared to the negative screening group, suggesting distinct aetiological trajectories associated with ASC outcomes.

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5. Li C, He WQ. Trends in Autism Spectrum Disorder Among Children and Adolescents in the US From 2016 to 2020. JAMA pediatrics. 2022.

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6. Li Q, Li Y, Yang W. Trends in Autism Spectrum Disorder Among Children and Adolescents in the US From 2016 to 2020-Reply. JAMA pediatrics. 2022.

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7. Maggio MG, Calatozzo P, Cerasa A, Pioggia G, Quartarone A, Calabrò RS. Sex and Sexuality in Autism Spectrum Disorders: A Scoping Review on a Neglected but Fundamental Issue. Brain sciences. 2022; 12(11).

ASD consists of a set of permanent neurodevelopmental conditions, which are studded with social and communication differences, limited interests, and repetitive behaviors. Individuals with ASD have difficulty reading eye gestures and expressions, and may also have stereotyped or repetitive language, excessive adherence to routines, fixed interests, and rigid thinking. However, sexuality in adolescents and young adults with ASD is still a poorly studied and neglected issue. This review aims to evaluate sexual function and behavior in individuals with ASD to foster a greater understanding of this important, although often overlooked, issue. This review was conducted by searching peer-reviewed articles published between 01 June 2000 and 31 May 2022 using the following databases: PubMed, Embase, Cochrane Database, and Web of Science. A comprehensive search was conducted using the terms: « Autism » OR « ASD » AND « Sexuality » OR « Romantic relation » OR « sexual behavior » AND/OR « sexual awareness ». After an accurate revision of 214 full manuscripts, 11 articles satisfied the inclusion/exclusion criteria. This review found that, although individuals with ASD may have sexual functioning, their sexuality is characterized by higher prevalence rates of gender dysphoria and inappropriate sexual behavior. Furthermore, sexual awareness is reduced in this patient population, and the prevalence of other variants of sexual orientation (i.e., homosexuality, asexuality, bisexuality, etc.) is higher in adolescents with ASD than in non-autistic peers. Sexual health and education should be included in the care path of patients with ASD in order to improve their quality of life and avoid/reduce inappropriate and risky behaviors.

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8. Mathews TL, Daly E, Kunz GM, Lugo AM, McArdle P, Menousek K, Kupzyk K. Addressing the Need for Training More School Psychologists to Serve Toddlers and Preschoolers with Autism Spectrum Disorders. Contemporary school psychology. 2022: 1-16.

The prevalence of autism spectrum disorder (ASD) has risen significantly in the past two decades. Unfortunately, there is a shortage of mental health providers who have specialized training in delivering evidenced-based services to this population. Early intensive behavioral intervention (EIBI) is an evidenced-based treatment recommended for toddlers with ASD, and school psychologists are uniquely positioned to help children with ASD receive it. However, many school psychologists do not receive adequate training in this subspecialty. This paper makes recommendations to school psychology training programs about how to add or improve training in this subspecialty based on the results of an Office of Special Education Programs grant-funded ASD training program which involved collaboration between a NASP-approved and APA-accredited school psychology training program and a community-based early intensive behavioral intervention (EIBI) clinic. The grant supported development of an interdisciplinary didactic and clinical training program to increase the ASD knowledge, skills, and competencies of school psychology graduate students, with the broader goals of developing a replicable training model and increasing the workforce of trained providers for this underserved population. Fifteen graduate students completed the training program. Outcomes related to trainee knowledge, skills, and competencies, trainee satisfaction, and lessons learned over time analyzed within a logic model that guided the project’s development and execution can be informative for other school psychology programs undertaking training in this subspecialty.

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9. Roman-Urrestarazu A, Yang JC, van Kessel R, Warrier V, Dumas G, Jongsma H, Gatica-Bahamonde G, Allison C, Matthews FE, Baron-Cohen S, Brayne C. Autism incidence and spatial analysis in more than 7 million pupils in English schools: a retrospective, longitudinal, school registry study. The Lancet Child & adolescent health. 2022; 6(12): 857-68.

BACKGROUND: Understanding how certain factors affect autism incidence can help to identify inequities in diagnostic access. We aimed to investigate the incidence of autism in England as a function of geography and sociodemographics, examining spatial distribution across health service boundaries. METHODS: In this retrospective, longitudinal, school registry study, we sourced data for the years 2014-17 from the summer school census, which is a component of the National Pupil Database, a government registry of pupils under state education in England. Our main outcome was the incidence of autism in the English state-funded education system, defined by the amount of new autism-specific Education, Health and Care Plans or autism-specific special education needs and disability support recorded during each summer school census year since the 2014 baseline. After excluding prevalent cases in 2014, we calculated unadjusted incidence and age-adjusted, sex-adjusted incidence per 100 000 person-years per subsequent school year and by various sociodemographic categories and local authority districts. We report spatial effects using local indicators of spatial association. We used a three-level mixed-effects logistic regression model with two random intercepts (lower-layer super output area [a geographical area in England containing 1000-3000 residents] and pupil identifier) to calculate odds ratios (ORs) for autism incidence, adjusting for age, sex, ethnicity, claimed eligibility for free school meals, ethnic density quintile, Index of Multiple Deprivation quintile, first language spoken at home, and year, with our reference category being White girls without claimed eligibility for free school meals who speak English as their first language. FINDINGS: Between 2014 and 2017, our total sample included 31 580 512 person-years and 102 338 newly diagnosed autistic pupils, corresponding to an unadjusted annual autism incidence of 429•1 cases per 100 000 person-years (95% CI 426•4-431•7) and an age-adjusted, sex-adjusted annual incidence of 426•9 cases per 100 000 person-years (423•5-430•4). The adjusted incidence of autism was slightly higher in 2014-15 than in 2015-16 or 2016-17, and, of the age groups, pupils aged 1-3 years, 4-6 years, and 10-12 years had the highest incidence of autism. Adjusted autism incidence in boys was 3•9-times the incidence in girls (668•6 cases per 100 000 person-years [95% CI 662•5-674•6] vs 173•2 cases per 100 000 person-years [170•1-176•3]). Across ethnic groups, adjusted incidence was highest in pupils who had an unclassified ethnicity (599•4 cases per 100 000 person-years [574•5-624•3]) or were Black (466•9 cases per 100 000 person-years [450•8-483•0]). However, in our fully adjusted mixed-effects logistic regression model, we observed lower odds of autism among Asian (OR 0•65 [0•59-0•71]), Black (0•84 [0•77-0•92]), and Chinese (0•62 [0•42-0•92]) girls compared with White girls when these groups had not claimed free school meals and spoke English as a first language. Boys from all ethnicities irrespective of first language spoken and free school meals status had increased odds of autism compared with White girls with no claimed eligibility for free school meals who spoke English as their first language. We also found that claimed free school meal eligibility, first language spoken, sex, and ethnicity differentially impacted the odds of autism. Our spatial analysis showed significant spatial autocorrelation across lower-layer super output areas in England, with 2338 hotspots (high-incidence areas surrounded by other high-incidence areas). INTERPRETATION: The incidence of autism varies across sex, age, ethnicity, and geographical location. Environmental and social factors might interact with autism aetiology. Speaking a language other than English and economic hardship might increase access barriers to autism diagnostic services, autism-specific Education, Health and Care Plans, and school-level support. FUNDING: The Commonwealth Fund, the Institute for Data Valorization, the Fonds de recherche du Québec-Santé, Calcul Quebec, the Digital Research Alliance of Canada, the Wellcome Trust, the Innovative Medicines Initiative, the Autism Centre of Excellence, the Simons Foundation Autism Research Initiative, the Templeton World Charitable Fund, the Medical Research Council, the National Institute for Health and Care Research Cambridge Biomedical Research Centre, and the National Institute for Health and Care Research Applied Research Collaboration East of England-Population Evidence and Data Science.

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10. Togashi K, Minagawa Y, Hata M, Yamamoto J. Evaluation of a Telehealth Parent-Training Program in Japan: Collaboration with Parents to Teach Novel Mand Skills to Children Diagnosed with Autism Spectrum Disorder. Behavior analysis in practice. 2022: 1-12.

This study developed a telehealth parent-training program to teach parents of children with autism spectrum disorder the process of mand-training implementation in Japan, and to further the international dissemination of evidence-based training strategies. Parent-training sessions were based on a behavioral skills training (BST) model, combined with weekly graphic and video feedback. The sessions were conducted by a board-certified behavior analyst-doctoral residing in Japan. Four parents with children with autism spectrum disorder participated in this study. The results preliminarily support the effectiveness and social validity of the program. This study extends previous parent-training research conducted in Japan by comprising all of the following features: (1) online program design; (2) mand training; (3) BST model; (4) session-by-session data on children’s behavioral changes and procedural integrity; (5) within-subject experimental design; and (6) social validity evaluation.

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11. Wang L, Mirabella VR, Dai R, Su X, Xu R, Jadali A, Bernabucci M, Singh I, Chen Y, Tian J, Jiang P, Kwan KY, Pak C, Liu C, Comoletti D, Hart RP, Chen C, Südhof TC, Pang ZP. Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism. Molecular psychiatry. 2022.

Mutations in many synaptic genes are associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a key driver of ASD pathogenesis. Among these mutations, the R451C substitution in the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs. In mice, the corresponding Nlgn3 R451C-knockin mutation recapitulates social interaction deficits of ASD patients and produces synaptic abnormalities, but the impact of the NLGN3 R451C mutation on human neurons has not been investigated. Here, we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; meanwhile NLGN3 knockout neurons showed reduction in excitatory synaptic strengths. Moreover, overexpression of NLGN3 R451C recapitulated the synaptic enhancement in human neurons. Notably, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into mouse forebrain. Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders. Our findings suggest that the NLGN3 R451C mutation induces a gain-of-function enhancement in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.

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12. Weiner DJ, Ling E, Erdin S, Tai DJC, Yadav R, Grove J, Fu JM, Nadig A, Carey CE, Baya N, Bybjerg-Grauholm J, Berretta S, Macosko EZ, Sebat J, O’Connor LJ, Hougaard DM, Børglum AD, Talkowski ME, McCarroll SA, Robinson EB. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p. Nature genetics. 2022; 54(11): 1630-9.

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

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