1. Beradze M, Meir N. Disfluencies as a Window into Pragmatic Skills in Russian-Hebrew Bilingual Autistic and Non-Autistic Children. J Autism Dev Disord;2024 (Sep 19)

There is little research on the production of speech disfluencies such as silent pauses, repetitions, self-corrections, and filled pauses (e.g., eh, em) in monolingual autistic children, and there is no data on this crucial part of speech production in bilingual autistic children. This study aims to address this gap by examining disfluency production in bilingual autistic and non-autistic children across two linguistically distinct languages, HL-Russian (the home language) and SL-Hebrew (the societal language). Fifty-one bilingual Russian-Hebrew-speaking autistic and non-autistic children aged 5-9 (autistic: n = 21; non-autistic: n = 30), matched for age and non-verbal intelligence, participated in picture-based story-generation tasks (LITMUS MAIN, Gagarina et al., ZAS Papers in Linguistics, 63:1-36, 2019). Audio recordings of narrative samples were transcribed, coded, and scored for eleven disfluency types using CLAN tools. The non-autistic group produced higher overall disfluency rate than the autistic group. The autistic group exhibited fewer filled and silent pauses than the non-autistic group in HL-Russian. Furthermore, non-autistic children manifested varied distribution of disfluency types across languages, while autistic children displayed more consistent patterns across languages. In summary, we replicated findings from previous research on monolinguals only partly, as no between-group difference in filled pauses was found in SL-Hebrew. Additionally, bilingual autistic children exhibited language-universal patterns of disfluency production, whereas their non-autistic peers displayed language-specific patterns.

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2. Chardon FM, McDiarmid TA, Page NF, Daza RM, Martin BK, Domcke S, Regalado SG, Lalanne JB, Calderon D, Li X, Starita LM, Sanders SJ, Ahituv N, Shendure J. Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements. Nat Commun;2024 (Sep 18);15(1):8209.

CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes. Applying this method to a library of 493 gRNAs targeting candidate cis-regulatory elements in both K562 cells and iPSC-derived excitatory neurons, we identify gRNAs capable of specifically upregulating intended target genes and no other neighboring genes within 1 Mb, including gRNAs yielding upregulation of six autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes in neurons. A consistent pattern is that the responsiveness of individual enhancers to CRISPRa is restricted by cell type, implying a dependency on either chromatin landscape and/or additional trans-acting factors for successful gene activation. The approach outlined here may facilitate large-scale screens for gRNAs that activate genes in a cell type-specific manner.

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3. Chen Y, Powers J, McDougle CJ, Zürcher NR, Thom RP. Cervical Cancer Screening and Prevention Uptake in Females with Autism Spectrum Disorder. J Autism Dev Disord;2024 (Sep 18)

This study reports on uptake rates of cervical cancer prevention and screening in a clinically-referred cohort of adolescent and adult females with autism spectrum disorder (ASD). Females with ASD (11-65 years) were invited to participate in an online survey to report on uptake of the human papillomavirus (HPV) vaccination and cervical cancer screening. Participants also provided demographic and clinical information. Chi-square statistical analysis was utilized to examine the relationship between categorical variables and receipt of cervical cancer prevention and screening. Forty-one out of 73 (56%) of adolescent (11-17 years) and 51/108 (47%) of adult (≥ 18 years) females with ASD reported having received at least one dose of the HPV vaccine. Only 30/73 (41%) and 37/108 (34%) of adolescents and adults respectively, were fully vaccinated (≥ 2 doses). Language impairment was the only clinical factor found to be associated with non-receipt of the HPV vaccine. Thirty-one out of 82 (38%) adult females (≥ 21 years) with ASD had received at least one pap smear. Language impairment, intellectual disability, non-independent living, and lower level of education were all associated with not receiving a pap smear. Females with ASD are vulnerable to invasive cervical cancer disease due to low uptake rates of the HPV vaccine and routine pap smear screening.

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4. Cosentino L, Urbinati C, Lanzillotta C, De Rasmo D, Valenti D, Pellas M, Quattrini MC, Piscitelli F, Kostrzewa M, Di Domenico F, Pietraforte D, Bisogno T, Signorile A, Vacca RA, De Filippis B. Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome. Mol Autism;2024 (Sep 19);15(1):39.

BACKGROUND: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. METHODS: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. RESULTS: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. LIMITATIONS: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. CONCLUSIONS: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

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5. Eid L, Lokmane L, Raju PK, Tene Tadoum SB, Jiang X, Toulouse K, Lupien-Meilleur A, Charron-Ligez F, Toumi A, Backer S, Lachance M, Lavertu-Jolin M, Montseny M, Lacaille JC, Bloch-Gallego E, Rossignol E. Both GEF domains of the autism and developmental epileptic encephalopathy-associated Trio protein are required for proper tangential migration of GABAergic interneurons. Mol Psychiatry;2024 (Sep 19)

Recessive and de novo mutations in the TRIO gene are associated with intellectual deficiency (ID), autism spectrum disorder (ASD) and developmental epileptic encephalopathies (DEE). TRIO is a dual guanine nucleotide exchange factor (GEF) that activates Rac1, Cdc42 and RhoA. Trio has been extensively studied in excitatory neurons, and has recently been found to regulate the switch from tangential to radial migration in GABAergic interneurons (INs) through GEFD1-Rac1-dependent SDF1α/CXCR4 signaling. Given the central role of Rho-GTPases during neuronal migration and the implication of IN pathologies in ASD and DEE, we investigated the relative roles of both Trio’s GEF domains in regulating the dynamics of INs tangential migration. In Trio(-/-) mice, we observed reduced numbers of tangentially migrating INs, with intact progenitor proliferation. Further, we noted increased growth cone collapse in developing INs, suggesting altered cytoskeleton dynamics. To bypass the embryonic mortality of Trio(-/-) mice, we generated Dlx5/6(Cre);Trio(c/c) conditional mutant mice (Trio(cKO)), which develop spontaneous seizures and behavioral deficits reminiscent of ASD and ID. These phenotypes are associated with reduced cortical IN density and functional cortical inhibition. Mechanistically, this reduction of cortical IN numbers reflects a premature switch to radial migration, with an aberrant early entry in the cortical plate, as well as major deficits in cytoskeletal dynamics, including enhanced leading neurite branching and slower nucleokinesis reflecting reduced actin filament condensation and turnover as well as a loss of response to the motogenic effect of EphA4/ephrin A2 reverse signaling. Further, we show that both Trio GEFD1 and GEFD2 domains are required for proper IN migration, with a dominant role of the RhoA-activating GEFD2 domain. Altogether, our data show a critical role of the DEE/ASD-associated Trio gene in the establishment of cortical inhibition and the requirement of both GEF domains in regulating IN migration dynamics.

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6. Friedman C. Transportation for people with intellectual and developmental disabilities in Home- and Community-Based Services. Disabil Health J;2024 (Sep 19):101708.

BACKGROUND: Transportation can help improve the health, quality of life, and community integration of people with intellectual and developmental disabilities (IDD). Yet, transportation is one of people with IDD’s most common unmet needs. OBJECTIVE: The aim of this study was to examine if, and, how, states provide non-medical transportation to people with IDD in their Medicaid HCBS programs. METHODS: Using content analysis and descriptive statistics, this study analyzed fiscal year (FY) 2021 Medicaid HCBS 1915(c) waivers for people with IDD from across the nation to examine how they allocated transportation. RESULTS: In FY 2021, all 44 states and the District of Columbia with HCBS waivers for people with IDD provided transportation services. Transportation was included either by providing a stand-alone service that exclusively provided transportation, or by being embedded within another service. Transportation was embedded within 896 different HCBS services for people with IDD, most commonly within residential habilitation services (26.70 %), supported employment services (19.44 %), and day habilitation (18.44 %). Thirty-three states (73.33 %) also provided 145 different stand-alone transportation services in their programs for people with IDD, to increase community integration and help people gain access to waiver services. A total of $781.78 million of spending was projected for stand-alone transportation services for 261,109 people with IDD (30.32 % of waiver recipients). CONCLUSIONS: HCBS waivers are an important resource for providing transportation for people with IDD. However, significant variation in how states do so may result in disparities or unmet needs.

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7. Linke AC, Chen B, Olson L, Cordova M, Wilkinson M, Wang T, Herrera M, Salmina M, Rios A, Mahmalji J, Do T, Vu J, Budman M, Walker A, Fishman I. Altered development of the Hurst Exponent in medial prefrontal cortex in preschoolers with autism. Biol Psychiatry Cogn Neurosci Neuroimaging;2024 (Sep 16)

BACKGROUND: Atypical balance of excitation (E) and inhibition (I) in the brain is thought to contribute to the emergence and symptomatology of autism spectrum disorders (ASD). E/I ratio can be estimated from resting state functional magnetic resonance imaging (fMRI) using the Hurst Exponent (H). A recent study reported decreased ventromedial prefrontal cortex (vmPFC) H in male adults with ASD. Part of the default mode network (DMN), vmPFC plays an important role in emotion regulation, decision making, and social cognition. It frequently shows altered function and connectivity in autistic individuals. METHODS: The current study presents the first fMRI evidence of altered early development of vmPFC H and its link to DMN functional connectivity (FC) and emotional control in toddlers and preschoolers with ASD. 83 children (n=45 ASD), ages 1½ – 5 years, underwent natural sleep fMRI as part of a longitudinal study. RESULTS: In a cross-sectional analysis, vmPFC H decreased with age in children with ASD, reflecting increasing E/I ratio, but not in typically developing children. This effect remained significant when controlling for gestational age at birth, socioeconomic status, or ethnicity. The same pattern was also observed in a subset of children with longitudinal fMRI data acquired two years apart on average. Lower vmPFC H was further associated with reduced FC within the DMN as well as with higher emotional control deficits (though only significant transdiagnostically). CONCLUSIONS: These results suggest an early onset of E/I imbalances in vmPFC in ASD with likely consequences for the maturation of the DMN.

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8. Mbachu CNP, Hagerman R, Eseigbe E, Odita A, Mbachu I, Ilikanu S, Akowundu K, Ndukwu C, Echezona M, Okereke O, Echendu S, Udigwe I. Knowledge and perceptions about fragile X syndrome and fragile X-premutation-associated conditions among medical doctors in Nigeria. Clin Genet;2024 (Sep 18)

Fragile X syndrome (FXS) is a significant cause of intellectual disability and autism, while Fragile X Premutation -Associated Conditions (FXPAC) are a significant cause of morbidity and mortality globally. This study assessed the level of knowledge and perceptions about FXS and FXPAC among doctors in Nigeria. It was a web-based, cross-sectional study conducted among a cohort of doctors in Nigeria. Socio-demographic profile, knowledge of FXS, perceptions about FXS, knowledge of FXPAC, experience of doctors, and suggested ways of improving knowledge and management of FXS were obtained. Data were analyzed using STATA 16.0. Chi-square and Fisher’s exact tests of association were used to determine the association between variables, with the significance level set at p < 0.05. A total of 274 doctors participated in the study. A significant proportion of respondents had limited knowledge about the clinical features of FXS. Nine of ten (90.0%) participants with good knowledge of FXS had good perceptions of FXS management. This was statistically significant (p < 0.001). There was a high nonresponse rate to what FXPAC is (164/274, 59.9%) among the respondents because of insufficient knowledge. Suboptimal knowledge of FXS which influenced perception was noted among doctors. More strategies should be considered to improve doctors' knowledge and management of FXS and FXPAC in Nigeria.

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9. Melamu NJ, Tsabedze WF, Erasmus P, Schlebusch L. « We call it Bokoa jwa tlhaloganyo »: Setswana parents’ perspective on autism spectrum disorder. Front Psychiatry;2024;15:1381160.

INTRODUCTION: There is a dearth of knowledge in South Africa about the incidence, prevalence, and effect of autism spectrum disorder (ASD). Consequently, national autism data is outdated, and World Health Organization (WHO) prevalence rates are being used. METHODS: This study focused on Ngaka Modiri Molema District to explore the cultural perspective of ASD in the Setswana culture from a parental or caregiver perspective, specifically those who attended the World Health Organization Caregiver Skills Training (WHO-CST) on ASD. This qualitative study used a phenomenological design and purposively sampled 6 out of 12 participants who wererecipients of WHO-CST. Semi-structured interviews, audio recordings, and field notes were used to collect data. RESULTS: The study found five main themes: understanding autism, indigenous perceptions of ASD, ways of interacting with children living with autism spectrum disorder, creating a friendly environment and symptoms of ASD. DISCUSSION: It was concluded that there is a lack of knowledge in Setswana culture about what ASD entails, and there are still some superstitious beliefs regarding ASD, resulting in late diagnoses. ASD studies with larger sample sizes, including medical professionals and policymakers, are recommended.

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10. Naicker VV, Hedley D, Bury SM. Does hope mediate the relationship between parent’s resolution of their child’s autism diagnosis and parental stress. Front Psychol;2024;15:1443707.

INTRODUCTION: Resolution of a child’s diagnosis, the process of accepting and adjusting to the reality of a child’s significant diagnosis, has been often associated with decreased parental stress. Hope, a potential buffer against psychological distress, has been suggested as a potential explanation for this relationship. However, the mediating role of hope in the relationship between resolution of diagnosis and parental stress has not been explored. METHODS: This study aimed to examine whether four types of hope (child, parental, societal, denial of diagnosis) mediated the relationship between resolution to an autism diagnosis and reduced parental stress. Participants included 73 parents (M(age) = 43.22, SD = 7.69, female 97.3%) of autistic children (M(age)  = 11.15, SD = 4.56, male = 67.1%). RESULTS: Resolution to diagnosis was negatively and significantly correlated with resolution to diagnosis, as well as child, parental and societal hope. These three hopes were also significantly and negatively correlated with parental stress. Importantly, when controlling for level of support and autism awareness, parental hope mediated the relationship between resolution to diagnosis and parental stress. Denial of diagnosis was not correlated with resolution or parental stress but did have significant but weak associate with the other hopes. DISCUSSION: These findings suggest that hope based on parent’s abilities to support their child and be supported themselves play an important role in parental stress once parents are more resolved to their child’s diagnosis. Supporting parents to manage factors associated with supporting their child’s needs, may benefit parents of autistic children.

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11. Neff RC, Stangis KA, Beniwal U, Hergenreder T, Ye B, Murphy GG. Cognitive behavioral phenotyping of DSCAM heterozygosity as a model for autism spectrum disorder. Genes Brain Behav;2024 (Oct);23(5):e70002.

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM, as in the DSCAM(2J)+/-, that is, DSCAM heterozygous mice, displayed hyperactivity, increased anxiety-like behavior, and motor coordination deficits. Additionally, hippocampal-dependent learning and memory was affected, including impairments in working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM(2J)+/- as a suitable model for ASD research.

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12. Pittas E, Warreyn P. Introduction to the Special Issue: The post-COVID-19 psychological and educational effects on the home and school lives of students with developmental disabilities. Res Dev Disabil;2024 (Sep 19);154:104847.

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13. Saeliw T, Kanlayaprasit S, Thongkorn S, Songsritaya K, Sanannam B, Jindatip D, Hu VW, Sarachana T. Investigation of chimeric transcripts derived from LINE-1 and Alu retrotransposons in cerebellar tissues of individuals with autism spectrum disorder (ASD). Sci Rep;2024 (Sep 19);14(1):21889.

LINE-1 and Alu retrotransposons are components of the human genome and have been implicated in many human diseases. These elements can influence human transcriptome plasticity in various mechanisms. Chimeric transcripts derived from LINE-1 and Alu can also impact the human transcriptome, such as exonization and post-transcriptional modification. However, its specific role in ASD neuropathology remains unclear, particularly in the cerebellum tissues. We performed RNA-sequencing of post-mortem cerebellum tissues from ASD and unaffected individuals for transposable elements profiling and chimeric transcript identification. The majority of free transcripts of transposable elements were not changed in the cerebellum tissues of ASD compared with unaffected individuals. Nevertheless, we observed that chimeric transcripts derived from LINE-1 and Alu were embedded in the transcripts of differentially expressed genes in the cerebellum of ASD, and these genes were related to developments and abnormalities of the cerebellum. In addition, the expression levels of these genes were correlated with the significantly decreased thickness of the molecular layer in the cerebellum of ASD. We also found that global methylation and expression of LINE-1 and Alu elements were not changed in ASD, but observed in the ASD sub-phenotypes. Our findings showed associations between transposable elements and cerebellar abnormalities in ASD, particularly in distinct phenotypic subgroups. Further investigations using appropriate models are warranted to elucidate the structural and functional implications of LINE-1 and Alu elements in ASD neuropathology.

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14. Shi Q, Wu L, Ren B, Guo K, Jiang YH, Zhang YQ, Hu L. Impaired tactile processing in autism-associated Shank3 mutant dogs: neural mechanism and intervention. Sci Bull (Beijing);2024 (Sep 10)

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15. Van Damme S, Mumford L, Johnson A, Chau T. Case report: Novel use of clinical brain-computer interfaces in recreation programming for an autistic adolescent with co-occurring attention deficit hyperactivity disorder. Front Hum Neurosci;2024;18:1434792.

BACKGROUND: In recent years, several autistic children and youth have shown interest in Holland Bloorview Kids Rehabilitation Hospital’s clinical brain computer interface (BCI) program. Existing literature about BCI use among autistic individuals has focused solely on cognitive skill development and remediation of challenging behaviors. To date, the benefits of recreational BCI programming with autistic children and youth have not been documented. PURPOSE: This case report summarizes the experiences of an autistic male adolescent with co-occurring attention deficit hyperactivity disorder using a BCI for recreation and considers possible benefits with this novel user population. METHODS: A single retrospective chart review was completed with parental guardian’s consent. FINDINGS: The participant demonstrated enjoyment in BCI sessions and requested continued opportunities to engage in BCI programming. This enjoyment correlated with improved Canadian Occupational Performance Measure (COPM) scores in BCI programming, outperforming scores from other recreational programs. Additionally, clinicians observed changes in social communication efforts and self-advocacy in this first autistic participant. CONCLUSION: The use of brain computer interfaces in recreational programming provides a novel opportunity for engagement for autistic children and youth that may also support skill development.

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16. Wang J, Yao J, He Y. A comparison of the physical activity levels of 3-to-6-year-old children with autism spectrum disorder and children with typical development. Front Psychol;2024;15:1432389.

BACKGROUND: Physical activity during early development is closely related to health. Differences in physical activity between young children with autism spectrum disorder and those with typical development are unclear. The purpose of this study was to compare the physical activity levels in children with autism spectrum disorder and typically developing children from the same area, including their sedentary physical activity, light physical activity, moderate-to-vigorous physical activity, and number of days in which the moderate-to-vigorous physical activity guideline recommendation of 60 min per day was met. METHODS: A total of 77 participants aged 3-6 years were included: 41 children with autism spectrum disorder (mean age = 61.41 ± 10.69 months) and 36 children with typical development (mean age = 60.36 ± 10.16 months). The physical activity of the children was measured using an ActiGraph GT3x accelerometer. RESULTS: There were no significant differences in daily sedentary physical activity (439.70 ± 54.98 vs. 450.42 ± 53.67) or moderate-to-vigorous physical activity (46.62 ± 18.93 vs. 47.47 ± 18.26) between the two groups. The average daily moderate-to-vigorous physical activity of the two groups did not reach 60 min, and they had similar proportions of participants who reached 60 min a given number of times (24.4% vs. 25%). Daily light physical activity was significantly higher in the autism spectrum disorder group (263.96 ± 43.17 vs. 242.32 ± 37.91, p < 0.05). The moderate-to-vigorous physical activity of both groups was similar and lower than the recommended minimum physical activity. CONCLUSION: Targeted interventions should be considered in early intervention programs for children with autism spectrum disorder to increase their moderate-to-vigorous physical activity.

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