1. Ahlqvist VH, Sjöqvist H, Dalman C, Karlsson H, Stephansson O, Johansson S, Magnusson C, Gardner RM, Lee BK. Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability. Jama. 2024; 331(14): 1205-14.

IMPORTANCE: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. OBJECTIVE: To examine the associations of acetaminophen use during pregnancy with children’s risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. DESIGN, SETTING, AND PARTICIPANTS: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. EXPOSURE: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. MAIN OUTCOMES AND MEASURES: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. RESULTS: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. CONCLUSIONS AND RELEVANCE: Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

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2. Alabdulaziz HM, Alghamdi SA, Aladwani AM, Alharthi RA, Almadani LK, Niyazi KA, Alharbi YM. Assessment of Knowledge and Attitudes Toward Children With Autism Spectrum Disorder Among Undergraduate Nursing Students. Cureus. 2024; 16(3): e55829.

Background There has been a dramatic increase in the incidence and prevalence rate of autism globally. This increase could be correlated to the increase in the awareness level and understanding of the disorder among healthcare providers and autistic children’s families. Aim This study aimed to assess undergraduate nursing students’ knowledge about and attitudes toward children with autism spectrum disorder (ASD). Methods A cross-sectional quantitative study design was used. A convenience sample of 235 undergraduate nursing students from all levels was obtained. Data were collected using a questionnaire. Descriptive analysis (including mean, median, and standard deviation) was conducted. Inferential analysis was conducted to identify the relation between participants’ demographic data and the subscales. Results The majority of the studied sample was aged 20 years or over (n=194, 82.55%) and was from the second year of undergraduate nursing school (n=120, 51.1%). The total mean score of the overall knowledge levels among nursing students at King Abdulaziz University (KAU) was mild (M=0.91, SD=±1.04), whereas the overall mean percentage score of undergraduate nursing students’ attitudes toward care, education, and advocacy for autistic children was 74.38%, indicating a positive high level of attitude. Conclusions This study highlighted the level of nursing students’ knowledge about childhood autism. Additionally, it disclosed their attitudes toward autistic children. The study filled a gap in the literature by revealing the perspectives of nursing students toward ASD.

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3. Cakar ME, Okada NJ, Cummings KK, Jung J, Bookheimer SY, Dapretto M, Green SA. Functional connectivity of the sensorimotor cerebellum in autism: associations with sensory over-responsivity. Front Psychiatry. 2024; 15: 1337921.

The cerebellum has been consistently shown to be atypical in autism spectrum disorder (ASD). However, despite its known role in sensorimotor function, there is limited research on its association with sensory over-responsivity (SOR), a common and impairing feature of ASD. Thus, this study sought to examine functional connectivity of the sensorimotor cerebellum in ASD compared to typically developing (TD) youth and investigate whether cerebellar connectivity is associated with SOR. Resting-state functional connectivity of the sensorimotor cerebellum was examined in 54 ASD and 43 TD youth aged 8-18 years. Using a seed-based approach, connectivity of each sensorimotor cerebellar region (defined as lobules I-IV, V-VI and VIIIA&B) with the whole brain was examined in ASD compared to TD youth, and correlated with parent-reported SOR severity. Across all participants, the sensorimotor cerebellum was functionally connected with sensorimotor and visual regions, though the three seed regions showed distinct connectivity with limbic and higher-order sensory regions. ASD youth showed differences in connectivity including atypical connectivity within the cerebellum and increased connectivity with hippocampus and thalamus compared to TD youth. More severe SOR was associated with stronger connectivity with cortical regions involved in sensory and motor processes and weaker connectivity with cognitive and socio-emotional regions, particularly prefrontal cortex. These results suggest that atypical cerebellum function in ASD may play a role in sensory challenges in autism.

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4. Chen Q, Chen M, Bao W, Strathearn L, Zang X, Meng L, Xu G. Association of cerebral palsy with autism spectrum disorder and attention-deficit/hyperactivity disorder in children: a large-scale nationwide population-based study. BMJ Paediatr Open. 2024; 8(1).

OBJECTIVE: To examine the association of cerebral palsy with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), providing evidence for interdisciplinary medical service for children with cerebral palsy. DESIGN: A large-scale nationwide population-based study. SETTING: The National Health Interview Survey (NHIS). PATIENTS: 177 899 children aged 3-17 years among NHIS participants from 1997 to 2003 and 2008 to 2018. RESULTS: Among the 177 899 children included in this analysis, 602 (0.33%) had cerebral palsy, 1997 (1.16%) had ASD, and 13 697 (7.91%) had ADHD. Compared with children without cerebral palsy, children with cerebral palsy had a higher prevalence of ASD (6.09% vs 1.15%; p<0.001) and ADHD (15.91% vs 7.89%; p<0.001). After adjustment for age, sex, race/ethnicity, family highest education level, family income level and geographical region, the OR among children with cerebral palsy, compared with children without cerebral palsy, was 5.07 (95% CI 3.25 to 7.91) for ASD (p<0.001) and 1.95 (95% CI 1.43 to 2.66) for ADHD (p<0.001). Furthermore, the association of cerebral palsy with ASD and ADHD remained significant in all subgroups stratified by age, sex and race. CONCLUSION: In a large, nationally representative sample of US children, this study shows that children with cerebral palsy are at an increased risk of ASD and ADHD.

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5. Cleary M, West S, McLean L, Johnston-Devin C, Kornhaber R, Hungerford C. When the Education System and Autism Collide: An Australian Qualitative Study Exploring School Exclusion and the Impact on Parent Mental Health. Issues Ment Health Nurs. 2024: 1-9.

Autistic students experience elevated rates of school exclusion, whether this be through expulsion, suspension, informal suspension, refusal of enrolment, or school refusal. This exclusion can come about from a range of factors, including sensory or cognitive overload, a lack of training in neurodiversity for teachers, an absent sense of safety by the student at school, or poor attitudes towards the inclusion of autistic students in schools. The impacts of this exclusion on parents can be logistical, financial, and psychological, with a range of mental health outcomes. This Australian qualitative study presents case studies of seven parents of autistic students, as well as four themes that capture the recommendations of parents to address school exclusion. The findings demonstrate that parents experience stress in finding a suitable school for their child, working with staff to meet the needs of the child, and attempting to maintain employment and other commitments when the child experiences exclusion. Parents recommend greater acceptance of autism by education systems, better communication and use of neuro-affirming language, the option for flexible learning, and individualised support by the school for the student.

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6. Eltokhi A, Lundstrom BN, Li J, Zweifel LS, Catterall WA, Gamal El-Din TM. Pathogenic gating pore current conducted by autism-related mutations in the Na(V)1.2 brain sodium channel. Proc Natl Acad Sci U S A. 2024; 121(15): e2317769121.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/K(V)7 potassium channel cause gating pore currents (I(gp)) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/Na(V)1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na(V)1.2 caused I(gp) in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I(gp). These potentially pathogenic I(gp) were exacerbated by the absence of the extracellular Mg(2+) and Ca(2+). In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I(gp) reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.

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7. Jording M, Hartz A, Vogel DHV, Schulte-Rüther M, Vogeley K. Impaired recognition of interactive intentions in adults with autism spectrum disorder not attributable to differences in visual attention or coordination via eye contact and joint attention. Sci Rep. 2024; 14(1): 8297.

Altered nonverbal communication patterns especially with regard to gaze interactions are commonly reported for persons with autism spectrum disorder (ASD). In this study we investigate and differentiate for the first time the interplay of attention allocation, the establishment of shared focus (eye contact and joint attention) and the recognition of intentions in gaze interactions in adults with ASD compared to control persons. Participants interacted via gaze with a virtual character (VC), who they believed was controlled by another person. Participants were instructed to ascertain whether their partner was trying to interact with them. In fact, the VC was fully algorithm-controlled and showed either interactive or non-interactive gaze behavior. Participants with ASD were specifically impaired in ascertaining whether their partner was trying to interact with them or not as compared to participants without ASD whereas neither the allocation of attention nor the ability to establish a shared focus were affected. Thus, perception and production of gaze cues seem preserved while the evaluation of gaze cues appeared to be impaired. An additional exploratory analysis suggests that especially the interpretation of contingencies between the interactants’ actions are altered in ASD and should be investigated more closely.

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8. Lee KS, Choi YY, Kim YS, Kim Y, Kim MH, Lee N. Association between the COVID-19 pandemic and childhood development aged 30 to 36 months in South Korea, based on the National health screening program for infants and children database. BMC Public Health. 2024; 24(1): 989.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on the neurodevelopment of children. However, the precise effects of the virus and the social consequences of the pandemic on pediatric neurodevelopment are not yet fully understood. We aimed to compare the neurodevelopment of children between before and during the COVID-19 pandemic, as well as examine the impact of socioeconomic status (SES) and regional differences on the development. METHODS: The study used the Korean Developmental Screening Test to compare the difference in the risk of neurodevelopmental delay between before and during the COVID-19 pandemic. Multivariable logistic regression analysis was conducted to identify the relationship between experiencing the COVID-19 pandemic and the risk of neurodevelopmental delay. Stratified analyses were performed to determine whether the developmental delays caused by the pandemic’s impact varied depending on SES or regional inequality. RESULTS: This study found an association between the experience of COVID-19 and a higher risk of neurodevelopmental delay in communication (adjusted OR [aOR]: 1.21, 95% confidence interval [CI]: 1.19, 1.22; P-value: < 0.0001) and social interaction (aOR: 1.15, 95% CI: 1.13, 1.17; P-value: < 0.0001) domains among children of 30-36 months' ages. Notably, the observed association in the Medicaid group of children indicates a higher risk of neurodevelopmental delay compared to those in the non-Medicaid group. CONCLUSIONS: These findings highlight the need to be concerned about the neurodevelopment of children who experienced the COVID-19 pandemic. The study also calls for increased training and support for Medicaid children, parents, teachers, and healthcare practitioners. Additionally, policy programs focused on groups vulnerable to developmental delays are required.

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9. MacDonald R, Baker-Ericzén M, Roesch S, Yeh M, Dickson KS, Smith J. The latent structure of the Delis-Kaplan system for autism. Autism Res. 2024; 17(4): 728-38.

A core feature of autism is deficits in executive functioning (EF), including difficulty with planning, cognitive flexibility, and working memory. Despite a growing need for evidence-based assessments of EF for autism populations, statistical models of many commonly used measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), have not been investigated for a sample of autistic participants. The purpose of this study was to address a gap in the literature regarding the latent structure of the D-KEFS in a sample of autistic individuals. The D-KEFS is one of the most widely used clinical assessments of executive function, but its factor structure has not been examined in a sample of autistic participants. Reliability analyses were performed for sample subgroups based on participants’ clinical and demographic characteristics, including IQ, autism severity, age, and race/ethnicity. Verbal Fluency (VF) was found to consistently decrease or not affect the overall reliability score. Additionally, one- and two-factor structure models were tested for the D-KEFS with a sample of autistic participants. The one-factor model was not found to be a good fit for the data. However, the two-factor model, with Cognitive Flexibility and Abstraction latent factors, was found to fit the data relatively well. This two-factor model was reexamined excluding the VF observed variable, resulting in a better overall model fit. Communication deficits are a common feature of autism, which explains why the VF task, that requires participants to produce novel words, may not be an adequate measure of executive function for autism populations.

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10. Nautiyal H, Jaiswar A, Jha PK, Dwivedi S. Exploring key genes and pathways associated with sex differences in autism spectrum disorder: integrated bioinformatic analysis. Mamm Genome. 2024.

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder marked by functional abnormalities in brain that causes social and linguistic difficulties. The incidence of ASD is more prevalent in males compared to females, but the underlying mechanism, as well as molecular indications for identifying sex-specific differences in ASD symptoms remain unknown. Thus, impacting the development of personalized strategy towards pharmacotherapy of ASD. The current study employs an integrated bioinformatic approach to investigate the genes and pathways uniquely associated with sex specific differences in autistic individuals. Based on microarray dataset (GSE6575) extracted from the gene expression omnibus, the dysregulated genes between the autistic and the neurotypical individuals for both sexes were identified. Gene set enrichment analysis was performed to ascertain biological activities linked to the dysregulated genes. Protein-protein interaction network analysis was carried out to identify hub genes. The identified hub genes were examined to determine their functions and involvement in the associated pathways using Enrichr. Additionally, hub genes were validated from autism-associated databases and the potential small molecules targeting the hub genes were identified. The present study utilized whole blood transcriptomic gene expression analysis data and identified 2211 and 958 differentially expressed unique genes in males and females respectively. The functional enrichment analysis revealed that male hub genes were functionally associated with RNA polymerase II mediated transcriptional regulation whereas female hub genes were involved in intracellular signal transduction and cell migration. The top male hub genes exhibited functional enrichment in tyrosine kinase signalling pathway. The pathway enrichment analysis of male hub genes indicates the enrichment of papillomavirus infection. Female hub genes were enriched in androgen receptor signalling pathway and functionally enriched in focal adhesion specific excision repair. Identified drug like candidates targeting these genes may serve as a potential sex specific therapeutics. Wortmannin for males, 5-Fluorouracil for females had the highest scores. Targeted and sex-specific pharmacotherapies may be created for the management of ASD. The current investigation identifies sex-specific molecular signatures derived from whole blood which may serve as a potential peripheral sex-specific biomarkers for ASD. The study also uncovers the possible pharmacological interventions against the selected genes/pathway, providing support in development of therapeutic strategies to mitigate ASD. However, experimental proofs on biological systems are warranted.

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11. Prince N, Peralta Marzal LN, Markidi A, Ahmed S, Adolfs Y, Pasterkamp RJ, Kumar H, Roeselers G, Garssen J, Kraneveld AD, Perez-Pardo P. Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder. Acta Pharmacol Sin. 2024.

Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by deficits in communication and behavior. Increasing evidence suggests that the microbiota-gut-brain axis and the likely related immune imbalance may play a role in the development of this disorder. Gastrointestinal deficits and gut microbiota dysfunction have been linked to the development or severity of autistic behavior. Therefore, treatments that focus on specific diets may improve gastrointestinal function and aberrant behavior in individuals with ASD. In this study, we investigated whether a diet containing specific prebiotic fibers, namely, 3% galacto-oligosaccharide/fructo-oligosaccharide (GOS/FOS; 9:1), can mitigate the adverse effects of in utero exposure to valproic acid (VPA) in mice. Pregnant BALB/cByJ dams were injected with VPA (600 mg/kg, sc.) or phosphate-buffered saline (PBS) on gestational day 11 (G11). Male offspring were divided into four groups: (1) in utero PBS-exposed with a control diet, (2) in utero PBS-exposed with GOS/FOS diet, (3) in utero VPA-exposed with a control diet, and (4) in utero VPA-exposed with GOS/FOS diet. Dietary intervention started from birth and continued throughout the duration of the experiment. We showed that the prebiotic diet normalized VPA-induced alterations in male offspring, including restoration of key microbial taxa, intestinal permeability, peripheral immune homeostasis, reduction of neuroinflammation in the cerebellum, and impairments in social behavior and cognition in mice. Overall, our research provides valuable insights into the gut-brain axis involvement in ASD development. In addition, dietary interventions might correct the disbalance in gut microbiota and immune responses and, ultimately, might improve detrimental behavioral outcomes in ASD.

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12. Thorsson M, Galazka MA, Åsberg Johnels J, Hadjikhani N. Influence of autistic traits and communication role on eye contact behavior during face-to-face interaction. Sci Rep. 2024; 14(1): 8162.

Eye contact is a central component in face-to-face interactions. It is important in structuring communicative exchanges and offers critical insights into others’ interests and intentions. To better understand eye contact in face-to-face interactions, we applied a novel, non-intrusive deep-learning-based dual-camera system and investigated associations between eye contact and autistic traits as well as self-reported eye contact discomfort during a referential communication task, where participants and the experimenter had to guess, in turn, a word known by the other individual. Corroborating previous research, we found that participants’ eye gaze and mutual eye contact were inversely related to autistic traits. In addition, our findings revealed different behaviors depending on the role in the dyad: listening and guessing were associated with increased eye contact compared with describing words. In the listening and guessing condition, only a subgroup who reported eye contact discomfort had a lower amount of eye gaze and eye contact. When describing words, higher autistic traits were associated with reduced eye gaze and eye contact. Our data indicate that eye contact is inversely associated with autistic traits when describing words, and that eye gaze is modulated by the communicative role in a conversation.

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13. Van Hirtum L, Van Damme T, Van Hove JLK, Steyaert JG. The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype. Orphanet J Rare Dis. 2024; 19(1): 150.

AIM: We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore associations between the behavioral phenotype and age, sex, plasma glycine levels and drug treatment. METHOD: Parents of children with attenuated NKH completed questionnaires assessing maladaptive behavior, adaptive behavior, social communication, speech/language development and motor development in addition to demographic and medical questions. RESULTS AND INTERPRETATION: Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. Their speech/language development was in line with their developmental quotient. Relative to their intellectual functioning, their motor development and communication were weaker in comparison to their general development. Their adaptive behavior, however, appeared a relative strength. There was no evidence for autism spectrum disorder occurring more frequently than expected, rather social skills, except for communication, were rated as a relative strength. Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children. Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. Future studies will need to evaluate causality in the observed relation between dextromethorphan use and maladaptive behaviors. Clinicians should reconsider the benefit of dextromethorphan when presented with disruptive behaviors in children with attenuated NKH.

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