1. Bazrafshan Z, Mohammadi P, Hasanzadeh A, Sanjari Moghaddam M, Kabiri M, Sanjari Moghaddam H, Abdolghaffari AH, Mohammadi MR, Akhondzadeh S. Metformin efficacy and safety as an adjunctive treatment for irritability in children with autism spectrum disorder: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2024: 2698811241303593.

BACKGROUND: Antidiabetic medications have shown efficacy in alleviating autism symptoms. However, there is a lack of clinical research on the impact of metformin on irritability associated with autism. This study aimed to assess the efficacy and safety of metformin as an adjuvant therapy with risperidone for managing irritability in children diagnosed with Autism Spectrum Disorder (ASD). METHODS: This is a randomized, 10-week, double-blind, placebo-controlled trial conducted at the children’s autism clinic of Roozbeh Hospital (Tehran, Iran) from March 2024 to May 2024. Participants were divided into two groups of risperidone plus metformin (500 mg per day) and risperidone plus placebo and were assessed at baseline, weeks 5 and 10 with the aberrant behavior checklist-community scale (ABC-C). RESULTS: A total of 55 patients were included in the final analysis. Irritability (primary outcome measure) sharply decreased in the metformin compared to the placebo group (p = 0.008). Among the other four subscales of ABC-C, the hyperactivity/noncompliance score showed a significant drop during the baseline-to-week-5 period (p = 0.021). In addition, inappropriate speech subscales decreased significantly from baseline-to-week 5 in the metformin compared to the placebo group (p = 0.045). No other significant finding was observed among ABC-C scores for lethargy/social withdrawal or stereotypic behavior subscales. CONCLUSION: Metformin demonstrated promising results in reducing irritability in ASD patients, which is in concordance with previous studies. However, further studies are required before any broad clinical recommendation.

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2. Choi JW, Oh J, Bennett DH, Kannan K, Tancredi DJ, Miller M, Schmidt RJ, Shin HM. Gestational exposure to organophosphate esters and autism spectrum disorder and other non-typical development in a cohort with elevated familial likelihood. Environ Res. 2024; 263(Pt 2): 120141.

BACKGROUND: Gestational exposure to organophosphate esters (OPEs) is known to affect offspring neurodevelopment in animal studies. However, epidemiological evidence is inconsistent. METHODS: Participants were 277 mother-child pairs from MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a cohort with elevated familial likelihood of autism spectrum disorder (ASD). Nine OPE biomarker concentrations were quantified in maternal urine collected during the 2nd or 3rd trimesters of pregnancy. At age 3 years, children underwent clinical assessment for ASD and were classified into ASD, other non-typical development (non-TD), or typical development (TD). Multinomial logistic regression was used to estimate associations between each OPE biomarker and relative risk ratios for ASD and non-TD compared to TD. We examined effect modification by child sex and socioeconomic status. We also conducted a secondary analysis by using a continuous measure of ASD symptom severity as an outcome. Quantile-based g-computation was performed to examine the associations for an OPE mixture. RESULTS: Overall, no significant association was observed between the concentrations of each OPE biomarker or their mixture and relative risk for either ASD or non-TD. Effect modifications by child sex and maternal education were not observed. When the analysis was stratified by homeownership, among non-homeowners, ASD likelihood was increased with increased levels of bis(1-chloro-2-propyl) phosphate, bis(butoxyethyl) phosphate, and sum of di-n-butyl phosphate and di-iso-butyl phosphate (DBUP/DIBP) (p(int) < 0.10). Higher DBUP/DIBP were associated with increased ASD symptom severity scores. CONCLUSION: There was no clear evidence of gestational OPE exposure in association with relative risk for ASD; however, potential effect modification by homeownership was observed. Although our cohort includes children with elevated familial likelihood of ASD, this is the first study investigating the association between gestational OPE exposure and clinically-diagnosed ASD. Further research is needed to confirm our findings in the general population.

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3. Costescu C, Tufar I, Chezan L, Șogor M, Confederat A. Assessing technology usage in relation to the quality of life of autistic children. Digit Health. 2024; 10: 20552076241304885.

OBJECTIVE: The aim of this study was to investigate the frequency and duration of technology use by autistic children, their primary activities when engaging with technology, and the association between technology use and quality of life. We assumed that technology serves as a means of communication with peers, and it is associated with an improved quality of life. METHODS: The study sample consisted of 61 parents of autistic children aged 5-10 years old. The Quality of Life for Children with Autism Spectrum Disorder Scale was used to measure children’s quality of life based on parent report, and the Technology Use Scale was used to measure the amount of time spent using technology and its purpose. Data collected were analyzed to identify correlations between technology use and quality of life. RESULTS: Findings indicate that autistic children primarily use technology for relaxation purposes and a smaller proportion of children in the sample used technology for socialization. A positive correlation was found between technology use for social interactions and higher parental perceptions of quality of life. These findings suggest that while social use of technology is less frequent, it is associated with improved well-being. CONCLUSIONS: We concluded that technology use among autistic children is predominantly for leisure activities; however, when used for socialization, it is linked to a better perceived quality of life. Future research should further explore the specific benefits and potential risks of technology use for communication and socialization in autistic children. Additionally, the efficacy of technology-based interventions in improving social skills and overall well-being should be evaluated.

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4. Grant A, Williams GL, Axbey H, Wilkins A, Firth E, Lim H, Cave H, Williams K, Ribbons K, Sinfield M, Craine M, Caemawr S, Holloway W, Brown A, Nicolaidis C, Kara H, Ellis R. Participatory longitudinal qualitative interview study to understand Autistic gynaecological and obstetric health: the Autism from menstruation to menopause study protocol. BMJ Open. 2024; 14(12): e088343.

INTRODUCTION: Autism is a lifelong minority neurotype present from birth. There is a dearth of credible evidence to suggest gender variation in Autism prevalence, despite historical under-diagnosis of women. Autistic people Assigned Female At Birth (AFAB) have worse physical and mental health compared with non-Autistic peers. To date, the reproductive health experiences of Autistic AFAB people have been under-investigated. METHODS AND ANALYSIS: This study aims to co-develop a quality improvement intervention to improve the reproductive health of Autistic people. The study uses Community Partnered Participatory Research (an approach similar to Community-Based Participatory Research), largely through a Community Council that co-governs the study. To understand reproductive health needs, a longitudinal qualitative investigation using creative methods will be undertaken with 100 Autistic AFAB people with 10 waves of data collection over 5 years (interview n=500-1000). Participants will be purposively selected to include harder-to-reach members of the Autistic community, including those who are non-speaking or semi-speaking, have a learning disability and those from marginalised ethnicities. Data will be analysed thematically with Community Council involvement. Intervention development will be undertaken from 2029 onwards. ETHICS AND DISSEMINATION: We are an Autistic-led team that adopts a social model of disability. However, this study raises ethical issues relating to sensitive topics and marginalised populations. Accordingly, we have robust procedures in place to assess capacity to ensure informed consent and to allow participants to take part without opting into data sharing. Ethical approval has been awarded by the Swansea University School of Health and Social Care Research Ethics Committee. We will publish our findings as open access articles in peer-reviewed journals.

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5. Loo KK, Yang SJ, Cheng JC. Autism Screening Using the Parent’s Observation of Social Interactions in a Large Integrated Healthcare System. J Pediatr. 2024; 278: 114434.

OBJECTIVE: To determine the accuracy of the Parent’s Observation of Social Interactions (POSI) when deployed for universal autism screening within a large healthcare network. STUDY DESIGN: Retrospective analysis of electronic health record data from children screened for autism spectrum disorder (ASD) using POSI at the 18- and 24- month pediatric well-child care (WCC) visits across Southern California Permanente Medical Group facilities throughout the 2022 calendar year. Data on ASD diagnoses placed in the electronic health record problem list were analyzed 1 year later (until the end of 2023) to calculate sensitivity, specificity, and positive/negative likelihood ratio (LR+ and LR-) values. RESULTS: At the 18-month WCC, 8014 of 30 375 children (26.4%) had elevated POSI scores of ≥3 (positive screen), and the sensitivity and specificity were 77.9% and 76.1%, respectively. At the 24-month WCC, 5988 children of 27 975 (21.4%) had positive POSI screens, and the sensitivity and specificity were 76.5% and 81.4%, respectively. The LR+ was 3.3 at 18 months and 4.2 at 24 months. The LR- was 0.29 at both the 18- and 24-month time points. CONCLUSIONS: The POSI screen for ASD had adequate sensitivity and specificity (both >76%) when systematically deployed in a primary care setting at 18- and 24-month WCC visits. Children diagnosed with ASD were 3.3 and 4.2 times more likely to have screened positive at 18 and 24 months, compared with children who were not diagnosed with ASD. Conversely, children not diagnosed with ASD were 3.4 times more likely to have screened negative than children with ASD at 18 and 24 months.

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6. Mamun MA, Al-Mamun F, Roy N, Raquib A, Kaggwa MM, MM AL, Gozal D, Hossain MS. Preconception and gestational versus postnatal exposure to air pollutants and risk of autism spectrum disorder: a systematic review and meta-analysis. Int Arch Occup Environ Health. 2024.

PURPOSE: The rising prevalence of ASD has prompted extensive research into potential environmental risk factors, with air pollution particularly emerging as a major concern. A systematic review and meta-analysis on the effect of air pollutants and time of exposure (particularly, PM(2.5), PM(10), NO(2), and O(3)) and the risk of ASD was therefore performed. METHODS: Following PRISMA guidelines and PROSPERO registration (Ref: CRD42023464592), a thorough literature search was conducted across multiple databases, including Scopus, PubMed/MEDLINE, Embase, PsycINFO, Web of Science, and Cochrane Library. The analysis included 27 studies encompassing 369,460 participants, 47,973 of whom were diagnosed with ASD. RESULTS: Preconception exposure to air pollutants showed a protective trend for PM(2.5), PM(10), and O(3) with a 10%, 5%, and 19% reduced risk of ASD, whereas NO(2) had a 28% higher likelihood of ASD. During gestation, PM(2.5) exposure increased ASD risk by 15%, with 13% and 9%, 25% and 7%, and 25% and 10% increases in ASD risk with PM(2.5) and NO(2) for the first, second, and third trimesters, respectively. In the first year of life, 20%, 8%, 33%, and 14% increases in risk were found for PM(2.5), PM(10), NO(2), and O(3), respectively, while such risk estimates increased to 179%, 60%, 12%, and 179% for the second year of life. CONCLUSIONS: In this meta-analysis, the relationships between air pollutants and ASD risk revealed significant associations, particularly for PM(2.5) and NO(2). Exposure during preconception exhibited a protective trend, while postnatal exposure, particularly during the second year of life uncovered substantially higher ASD risk.

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7. Namgung JY, Mun J, Park Y, Kim J, Park BY. Sex differences in autism spectrum disorder using class imbalance adjusted functional connectivity. Neuroimage. 2024; 304: 120956.

Autism spectrum disorder (ASD) is an atypical neurodevelopmental condition with a diagnostic ratio largely differing between male and female participants. Due to the sex imbalance in participants with ASD, we lack an understanding of the differences in connectome organization of the brain between male and female participants with ASD. In this study, we matched the sex ratio using a Gaussian mixture model-based oversampling technique and investigated the differences in functional connectivity between male and female participants with ASD using low-dimensional principal gradients. Between-group comparisons of the gradient values revealed significant interaction effects of sex in the sensorimotor, attention, and default mode networks. The sex-related differences in the gradients were highly associated with higher-order cognitive control processes. Transcriptomic association analysis provided potential biological underpinnings, specifying gene enrichment in the cortex, thalamus, and striatum during development. Finally, the principal gradients were differentially associated with symptom severity of ASD between sexes, highlighting significant effects in female participants with ASD. Our work proposed an oversampling method to mitigate sex imbalance in ASD and observed significant sex-related differences in functional connectome organization. The findings may advance our knowledge about the sex heterogeneity in large-scale brain networks in ASD.

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8. Raul P, Rowe E, van Boxtel JJA. High neural noise in autism: A hypothesis currently at the nexus of explanatory power. Heliyon. 2024; 10(23): e40842.

Autism is a neurodevelopmental difference associated with specific autistic experiences and characteristics. Early models such as Weak Central Coherence and Enhanced Perceptual Functioning have tried to capture complex autistic behaviours in a single framework, however, these models lacked a neurobiological explanation. Conversely, current neurobiological theories of autism at the cellular and network levels suggest excitation/inhibition imbalances lead to high neural noise (or, a ‘noisy brain’) but lack a thorough explanation of how autistic behaviours occur. Critically, around 15 years ago, it was proposed that high neural noise in autism produced a stochastic resonance (SR) effect, a phenomenon where optimal amounts of noise improve signal quality. High neural noise can thus capture both the enhanced (through SR) and reduced performance observed in autistic individuals during certain tasks. Here, we provide a review and perspective that positions the « high neural noise » hypothesis in autism as best placed to provide research direction and impetus. Emphasis is placed on evidence for SR in autism, as this promising prediction has not yet been reviewed in the literature. Using this updated approach towards autism, we can explain a spectrum of autistic experiences all through a neurobiological lens. This approach can further aid in developing specific support or services for autism.

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9. Sun YY, Liu H, Liu M, Mei SY, Ma YL. [Autosomal dominant intellectual developmental disorder 60 with seizures: a case report]. Zhongguo Dang Dai Er Ke Za Zhi. 2024; 26(12): 1362-6.

The patient is a 10-month and 21-day-old girl who began to show developmental delays at 3 months of age, with severe language developmental disorders, stereotyped movements, and easily provoked laughter. Physical examination revealed fair skin and a flattened occiput. At 10 months of age, a video electroencephalogram suggested atypical absence seizures, with migrating slow-wave activity observed during the interictal period. Whole exome sequencing of three family members indicated a novel mutation in the AP2M1 gene, c.508C>T (p.R170W), in the patient. A total of six cases of autosomal dominant intellectual developmental disorder 60 with seizures associated with mutations in the AP2M1 gene have been reported both domestically and internationally (including this study). The main clinical features included developmental delays (6 cases), language developmental disorders (5 cases), stereotyped movements (3 cases), a tendency to smile (1 case), and atypical absence seizures (4 cases). Interictal electroencephalograms showed widespread spike waves and spike-slow wave discharges (5 cases), and migrating slow-wave activity (1 case). The c.508C>T (p.R170W) mutation may be a hotspot for mutations in the AP2M1 gene, and its clinical features are similar to those of Angelman syndrome.

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10. Uldbjerg CS, Leader J, Minguez-Alarcon L, Chagnon O, Dadd R, Ford J, Fleury E, Williams P, Juul A, Bellinger DC, Calafat AM, Hauser R, Braun JM. Associations of maternal and paternal preconception and maternal pregnancy urinary phthalate biomarker and bisphenol A concentrations with offspring autistic behaviors: The PEACE study. Environ Res. 2024; 263(Pt 3): 120253.

BACKGROUND: Environmental chemical exposures in utero may play a role in autism development. While preconception risk factors for autism are increasingly being investigated, little is known about the influence of chemical exposures during the preconception period, particularly for paternal exposures. METHODS: In 195 children from the Preconception Environmental exposures And Childhood health Effects (PEACE) cohort born to parents recruited from a fertility clinic in Boston, Massachusetts between 2004 and 2017, we quantified concentrations of 11 phthalate metabolites and bisphenol A (BPA) in urine samples collected from mothers and fathers before conception and mothers throughout pregnancy. When children were 6-15 years old, parents completed the Social Responsiveness Scale (SRS) questionnaire assessing autistic behaviors. We used linear mixed effect models to estimate covariate-adjusted associations of phthalate biomarker and BPA concentrations, separately for maternal preconception (n = 179), paternal preconception (n = 121), and maternal pregnancy (n = 177), with SRS T-scores, based on age and gender, in offspring. We used quantile g-computation models for mixture analyses and evaluated modification by selected dietary factors. RESULTS: The mean SRS T-score was 47.7 (±7.4), lower than the normative mean of 50. In adjusted models for individual biomarkers or mixtures, few associations were observed and estimates were generally negative (e.g., lower SRS T-scores) and imprecise. We observed associations of higher mono-isobutyl phthalate (MiBP) concentrations measured in maternal preconception and paternal preconception periods with lower SRS T-scores (β(maternal_precon) = -1.6, 95% CI -2.7; -0.4; β(paternal_precon) = -2.9, 95% CI -4.6; -1.2) for each log(e) increase. In a subset of participants with maternal preconception nutrition information, we generally observed stronger inverse associations with higher folate and iron intake, particularly for folate intake and MiBP concentrations. CONCLUSIONS: Urinary phthalate biomarker and BPA concentrations during preconception (maternal and paternal) and pregnancy (maternal) were not associated with adverse autistic behaviors in these children. Larger studies are needed to elucidate the observed associations, while considering interactions between maternal nutrition and chemical exposures.

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