1. Fazel Darbandi S, An JY, Lim K, Page NF, Liang L, Young DM, Ypsilanti AR, State MW, Nord AS, Sanders SJ, Rubenstein JLR. Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes. Cell Rep;2024 (Jun 7);43(6):114329.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

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2. Gholipour P, Ebrahimi Z, Mohammadkhani R, Ghahremani R, Salehi I, Sarihi A, Komaki A, Karimi SA. Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism. Sci Rep;2024 (Jun 7);14(1):13168.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

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3. Hegemann L, Corfield EC, Askelund AD, Allegrini AG, Askeland RB, Ronald A, Ask H, St Pourcain B, Andreassen OA, Hannigan LJ, Havdahl A. Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study. Mol Autism;2024 (Jun 7);15(1):25.

BACKGROUND: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. METHODS: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708-58,630) using maternal reports on 76 items assessing children’s motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. RESULTS: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items r(g) range = - 0.27-0.78), ADHD (items r(g) range = - 0.40-1), and schizophrenia (items r(g) range = - 0.24-0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. CONCLUSIONS: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs.

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4. Jeffers NK, Lu SV, Gross SM, West A. Infant Feeding Support for Pregnant and Postpartum Parents With Intellectual and Developmental Disabilities: Perspectives of WIC Staff. J Nutr Educ Behav;2024 (Jun);56(6):399-405.

OBJECTIVE: To describe the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) staff experiences, perceptions, and training needs surrounding the provision of infant feeding support for parents with intellectual and developmental disabilities (IDD). METHODS: We conducted in-depth semistructured interviews between October and November 2021 with Maryland WIC staff (N = 10) who provide infant feeding counseling and support. We analyzed interviews using conventional content analysis. RESULTS: Three themes were identified: identifying and documenting IDD, facilitating effective communication and infant feeding education, and assessing WIC staff competence and readiness. CONCLUSIONS AND IMPLICATIONS: The interviews suggested the need to explore the risks and benefits of routine and compassionate processes for identifying and documenting disability, create accessible teaching materials that facilitate understanding and engagement, and educate and train staff to provide tailored support in WIC. Engaging parents with IDD to better understand their perspectives and experiences should guide future efforts to improve inclusivity and accessibility.

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5. Kohli JS, Linke AC, Martindale IA, Wilkinson M, Kinnear MK, Lincoln AJ, Hau J, Shryock I, Omaleki V, Alemu K, Pedrahita S, Fishman I, Müller RA, Carper RA. Associations between atypical intracortical myelin content and neuropsychological functions in middle to older aged adults with ASD. Brain Behav;2024 (Jun);14(6):e3594.

INTRODUCTION: In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants. METHODS: Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio. RESULTS: Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function. CONCLUSIONS: The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.

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6. Kreutzmann JC, Kahl E, Fendt M. Sex-specific modulation of safety learning in Shank2-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry;2024 (Jun 8);132:110973.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired perceptual processing and social communication, intellectual disabilities, and repetitive behaviors. Interestingly, while not a core symptom, anxiety disorders frequently co-occur in individuals with ASD and deficits in safety learning have been described in patients with anxiety-related disorders. Because genetic factors, such as SHANK deficiency (loss-of-function mutations), have been linked to ASD, the aim of the present study was to investigate whether Shank2 deficiency interferes with associative fear and safety signal learning. To first investigate trait anxiety, male and female Shank2-deficient mice were exposed to a light-dark box test. Mice were then submitted to a combination of contextual fear conditioning and single-cue safety conditioning. The results show that Shank2 deficiency increases trait anxiety but reduces contextual fear learning. In male but not female Shank2-deficient mice, reduced single-cued safety learning was observed. This safety learning deficit was not caused by altered anxiety levels, increased locomotor activity, or reduced contextual fear since these changes were also observed in female Shank2-deficient mice. Concluding, our data indicate that the observed safety learning deficits in Shank2-deficient male mice could contribute to the emotional symptoms observed in ASD and the high comorbidity with anxiety-related disorders.

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7. Marinopoulou M, Åsberg Johnels J, Bornehag CG, Unenge Hallerbäck M, Billstedt E. Do Wechsler intelligence scales predict academic achievement in children with ADHD or autism? A systematic review and meta-analysis. Appl Neuropsychol Child;2024 (Jun 8):1-15.

Intelligence tests predict academic achievement in typically developed children, however if this is the case also in children with attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) is not clear. This systematic review and meta-analysis examined if Wechsler intelligence scales predict academic achievement and/or grades in children, ages 6-16 years, with ADHD and/or ASD. We searched the databases PubMed, PsycINFO and Education Research Complete for studies published between 2000 and 2023. We used the Newcastle-Ottawa Scale to assess risk of bias. Narrative synthesis and meta-analysis were performed. Twelve studies (ADHD n = 1,834, ASD n = 176) were included in the review, and six samples (ADHD n = 1,112) of those were included in the meta-analyses. The results of the meta-analyses showed moderate overall weighted correlations between IQ and word reading, written language, and mathematics respectively. Similarly, the overall weighted correlations between processing speed and the aforementioned domains of academic achievement were moderate. Meta-analysis with additional Wechsler scales composite scores could not be conducted. In the narrative synthesis, Full Scale IQ was associated with academic achievement in both ADHD and ASD, and grades in ADHD. The limited number of ASD participants and the heterogeneity of the samples need to be considered when interpreting results. Generally, the results indicate that Wechsler scales are valuable in predicting academic achievement in children with ADHD or ASD. Motivation and other factors related with academic achievement need to be further explored in these groups.

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8. Miao Y, Zheng M, Li Q, Xiong L, Feng J, Liu X, Fan G, Chaturvedi R, Zhang F, Yin N. Comparison of propofol-esketamine versus propofol-sufentanil for deep sedation and analgesia in children with autism: A randomized double-blind clinical trial. Autism Res;2024 (Jun 8)

Propofol sedation, routinely used for endoscopic procedures, is safe and acceptable for children. Adjuvants, such as esketamine or sufentanil, are commonly added to improve the efficacy and safety of propofol sedation. This study aimed to compare the clinical efficacy and safety of propofol-esketamine (PE) versus propofol-sufentanil (PS) for deep sedation and analgesia in children with autism undergoing colonoscopy procedure. One hundred and twenty-four children with autism undergoing colonoscopy procedure were included in the study. Patients were randomly assigned to receive one of the two adjuvants: esketamine (0.3 mg/kg) or sufentanil (0.2 μg/kg), subsequently administered propofol 2.0 mg/kg to induce anesthesia. Additional doses of propofol (0.5-1.0 mg/kg) were administered as needed to ensure patient tolerance for the remaining duration of the procedure. Movement during the procedure, hemodynamic variables, the total dose of propofol, recovery time, and adverse events were recorded. The PE group exhibited a significantly lower incidence of severe movement during the procedure compared with the PS group (14.52% vs. 32.26%, p = 0.020). The PE group showed significantly lower incidence of respiratory depression, hypotension, and severe injection pain of propofol than the PS group during the procedure (all p < 0.05). The mean arterial pressure (MAP) decreased significantly after anesthesia induction in the PS group and remained lower than baseline (all p < 0.05). Compared with the combination of low-dose sufentanil (0.2 μg/mg) with propofol, the low-dose esketamine (0.3 mg/kg) combined with propofol provided more stable hemodynamics, higher quality of sedation, and fewer adverse events in children with autism undergoing colonoscopy procedure.

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9. Solomon S, Elbedour L, Meiri G, Michaelovski A, Sadaka Y, Ilan M, Faroy M, Dinstein I, Menashe I. Sleep disturbances are associated with greater healthcare utilization in children with autism spectrum disorder. J Neurodev Disord;2024 (Jun 7);16(1):29.

BACKGROUND: Sleep disturbances are frequently reported in children with autism spectrum disorder (ASD) and are associated with the severity of co-occurring symptoms. This study’s aim was to examine the extent of healthcare utilization and clinical outcomes associated with sleep disturbances in children with ASD. STUDY DESIGN: A retrospective, cross-sectional study of 541 children with ASD from the Azrieli National Center for Autism and Neurodevelopment Research (ANCAN) whose parents completed the Children’s Sleep Habits Questionnaire (CSHQ). Children with a total CSHQ score ≥ 48 were defined as having sleep disturbances. Sociodemographic characteristics, ASD diagnostic measures, chronic co-occurring conditions, medication usage, hospitalizations, visits to the emergency room (ER), and visits to specialists were compared in ASD children with and without sleep disturbances. Multivariate logistic regression models were then used to assess the independent association of sleep disturbances with clinical characteristics and healthcare utilization. RESULTS: Of the 541 children with ASD, 257 (47.5%) had sleep disturbances. Children with sleep disturbances exhibited higher rates of multiple (≥ 3) co-occurring conditions (19.1% vs. 12.7%; p = 0.0414) and prescribed medications (45.5% vs. 32.7%; p = 0.0031) than other children. Finally, ASD children with sleep disturbances were 1.72 and 2.71 times more likely to visit the ER and be hospitalized than their counterparts (aOR = 1.72; 99%CI = 1.01-2.95; and aOR = 2.71; 99%CI = 1.10-6.67, respectively). CONCLUSIONS: Our findings suggest that sleep disturbances are associated with greater healthcare utilization among children with ASD. Further studies could examine whether treating sleep disturbances in children with ASD yields additional clinical benefits beyond improvements in sleep.

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