1. Fass SB, Mulvey B, Chase R, Yang W, Selmanovic D, Chaturvedi SM, Tycksen E, Weiss LA, Dougherty JD. Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease. Biol Sex Differ;2024 (Jun 7);15(1):47.

BACKGROUND: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. METHODS: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks. RESULTS: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case-control gene expression studies suggests a female molecular predisposition towards Alzheimer’s disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. CONCLUSION: Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences. We sought to understand why females have higher rates of Alzheimer’s disease, and males have higher rates of autism. One idea was that the female brain at baseline may be more similar to an Alzheimer’s brain, so it is easier for them to shift into that state (likewise, males may be more similar to autism). To test this, we examined gene expression differences between brains of biological males and biological females. While all people have the same ~ 25,000 genes, each gene can be on or off (‘expressed’) to different extents. Overall, we found that there were differences in gene expression between males and females in all brain regions tested but more differences in some brain regions than others. By looking at the role of these genes we estimate that female immune system processes might be more active in the brain. We also found female brain gene expression looked slightly more like people with Alzheimer’s compared to people without Alzheimer’s, which may explain why females get Alzheimer’s disease more easily. However, the male brain gene expression did not look more like autism, suggesting that the reason males have higher rates of autism is complex and needs further investigation. eng

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2. 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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3. 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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4. 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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5. Jones CRG, Livingston LA, Fretwell C, Uljarević M, Carrington SJ, Shah P, Leekam SR. Measuring self and informant perspectives of Restricted and Repetitive Behaviours (RRBs): psychometric evaluation of the Repetitive Behaviours Questionnaire-3 (RBQ-3) in adult clinical practice and research settgs. Mol Autism;2024 (Jun 6);15(1):24.

BACKGROUND: Brief questionnaires that comprehensively capture key restricted and repetitive behaviours (RRBs) across different informants have potential to support autism diagnostic services. We tested the psychometric properties of the 20-item Repetitive Behaviours Questionnaire-3 (RBQ-3), a questionnaire that includes self-report and informant-report versions enabling use across the lifespan. METHOD: In Study 1, adults referred to a specialised adult autism diagnostic service (N = 110) completed the RBQ-3 self-report version, and a relative or long-term friend completed the RBQ-3 informant-report version. Clinicians completed the abbreviated version of the Diagnostic Interview for Social and Communication Disorders (DISCO-Abbreviated) with the same adults as part of the diagnostic process. For half of the assessments, clinicians were blind to the RBQ-3 ratings. We tested internal consistency, cross-informant reliability and convergent validity of the RBQ-3. In Study 2, a follow-up online study with autistic (N = 151) and non-autistic (N = 151) adults, we further tested internal consistency of the RBQ-3 self-report version. We also tested group differences and response patterns in this sample. RESULTS: Study 1 showed good to excellent internal consistency for both self- and informant-report versions of the RBQ-3 (total score, α = 0.90, ω = 0.90, subscales, α = 0.76-0.89, ω = 0.77-0.88). Study 1 also showed cross-informant reliability as the RBQ-3 self-report scores significantly correlated with RBQ-3 informant-report scores for the total score (r(s) = 0.71) and subscales (r(s)= 0.69-0.72). Convergent validity was found for both self and informant versions of the RBQ-3, which significantly correlated with DISCO-Abbreviated RRB domain scores (r(s) = 0.45-0.54). Moreover, the RBQ-3 scores showed significantly weaker association with DISCO -Abbreviated scores for the Social Communication domain, demonstrating divergent validity. Importantly, these patterns of validity were found even when clinicians were blind to RBQ-3 items. In Study 2, for both autistic and non-autistic groups, internal consistency was found for the total score (α = 0.82-0.89, ω = 0.81-0.81) and for subscales (α = 0.68-0.85, ω = 0.69-0.85). A group difference was found between groups. LIMITATIONS: Due to the characteristics and scope of the specialist autism diagnostic service, further testing is needed to include representative samples of age (including children) and intellectual ability, and those with a non-autistic diagnostic outcome. CONCLUSIONS: The RBQ-3 is a questionnaire of RRBs that can be used across the lifespan. The current study tested its psychometric properties with autistic adults without intellectual disability and supported its utility for both clinical diagnostic and research settings.

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6. Kowitt JS, Madaus J, Simonsen B, Freeman J, Lombardi A, Ventola P. Implementing Pivotal Response Treatment to Teach Question Asking to High School Students with Autism Spectrum Disorder. J Autism Dev Disord;2024 (Jun 7)

The purpose of this study was to test the use of Pivotal Response Treatment (PRT) in the secondary school setting. There were two main goals: (a) to evaluate secondary education providers’ ability to implement PRT with fidelity following a PRT training program; and (b) to evaluate the effects of school-implemented PRT on the social communication skills of adolescents and young adults with ASD, specifically, question-asking behavior. This concurrent multiple baseline design study across dyads investigated the use of PRT in the secondary school setting with adolescents with ASD. Specifically, it examined the impact of PRT on question-asking behavior. Education providers (n = 3) were trained to implement PRT with a secondary student with ASD. All education providers improved in their ability to use PRT strategies, though struggled with fidelity. Two students exhibited clear effects with noteworthy improvement in their use of targeted question initiations. For targeted question initiations, the weighted value for the Tau-U phase contrast between aggregated baseline and intervention phases was 0.80 and statistically significant (p < .0001). PRT is a promising approach to increasing question-asking behavior in secondary students with ASD when implemented by a trained education provider. Continued research should be a matter of priority in order to expand social skills instruction for adolescents with ASD with the hope of ultimately making a positive difference in adult outcomes.

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7. Martínez-González AE, Cervin M, Pérez-Sánchez S. Assessing gastrointestinal symptoms in people with autism: Applying a new measure based on the Rome IV criteria. Dig Liver Dis;2024 (Jun 7)

BACKGROUND: People with autism spectrum disorder (ASD) often struggle with gastrointestinal symptoms, implicating alterations of the gut-microbiota-brain axis, which has also been linked to sensory reactivity, pain, and gastro-intestinal symptoms in ASD. To better understand the prevalence and impact of gastrointestinal symptoms among individuals with ASD, a measure is needed that adhere to the Rome IV criteria of gastrointestinal symptoms and is applicable to individuals with ASD. The Gastrointestinal Symptom Severity Scale (GSSS) is a new assessment tool designed to match this need. METHODS: In a diverse sample of 265 individuals with ASD (mean age = 9.44, SD = 4.99), we examined the psychometric properties of the GSSS, the prevalence of gastrointestinal symptoms and associations with ASD traits, sensory sensitivity, repetitive behaviors, and pain. RESULTS: A unidimensional factor structure of the GSSS was confirmed and the measure showed good internal consistency, adequate test-retest reliability and strong convergent validity. Around a third of the participants evidenced clear difficulties with gastrointestinal symptoms and gastrointestinal symptoms were strongly associated with more pronounced ASD traits, sensory reactivity, and repetitive behaviors. CONCLUSIONS: The GSSS shows promise as a useful measure to analyze the prevalence, severity, and impact of gastro-intestinal symptoms in individuals with ASD.

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8. Najm R, Knoblich JA. Making sense of Timothy syndrome with 3D human neuronal models. Neuron;2024 (Jun 5);112(11):1730-1732.

In a recent issue of Nature, Chen and colleagues(1) reveal the potential for antisense oligonucleotides (ASOs) to rescue the neuropathological mechanisms underlying Timothy syndrome (TS) using three-dimensional neuronal models. Combining in vitro and in vivo approaches, the authors present a strategy to translate disease biology findings into potential therapeutics.

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9. Peterson T, Dodson J, Sherwin R, Strale F, Jr. Comparative Effects of Applied Behavior Analysis on Male and Female Individuals With Autism Spectrum Disorder. Cureus;2024 (May);16(5):e59802.

Introduction Current evidence-based treatments for autism spectrum disorder (ASD) are based on applied behavior analysis (ABA). However, research on gender differences in ABA therapy response is limited. This study seeks to (1) confirm the 4:1 male-to-female ratio reported in the literature and (2) identify any possible gender differences in target behaviors over seven timepoints measured every two weeks. Materials and methods For three months, from March 19, 2023, to June 11, 2023, a team of 3-5 behavioral technicians per individual collected daily data on general target mastery for 100 individuals with ASD treated with ABA. Data was collected at seven timepoints every two weeks. Descriptive demographics were computed. Two independent sample t-tests were performed to determine significant or nonsignificant gender differences with the seven timepoint variables. Results Nonstatistically significant gender differences (p > .05) were found on all seven cumulative target behavior timepoints measured at two-week intervals. For targets mastered Time 1, baseline between males and females, there was no significant difference in the means for males (M = 1.0571, SD = 1.9196) and females (M = 2.0455, SD = 3.9457) (t(90) = -1.591, p = 0.115, confidence interval (CI) = -2.2223, 0.2456, d = -0.389). For targets mastered Time 2, two weeks between males and females, there was no significant difference in the means for males (M = 3.7132; SD = 4.5065) and females (M = 4.0682, SD = 5.1508) (t(88) = -0.310, p = 0.757, CI = -2.6305, 1.92056, d = -0.076). For targets mastered Time 3, four weeks between males and females, there was no significant difference in the means for males (M = 7.0956; SD = 8.7781) and females (M = 8.6136; SD = 11.2799) (t(88) = -0.656, p = 0.514, CI = -6.1173, 3.0811, d = -0.161). For targets mastered Time 4, six weeks between males and females, there was no significant difference in the means for males (M = 13.1728, SD = 16.2003) and females (M = 13.0682, SD = 16.9272) (t(88) = 0.026, p = 0.979, CI = -7.8779, 8.0871, d = 0.006). For targets mastered Time 5, eight weeks between males and females, there was no significant difference in the means for males (M = 17.2096; SD = 18.8546) and females (M = 17.4286, SD = 22.1683) (t(87) = -0.045, p = 0.965, CI = -9.9773, 9.5393, d = -0.011). For targets mastered Time 6, 10 weeks between males and females, there was no significant difference in the means for males (M = 21.0074, SD = 21.3329) and females (M = 20.6818, SD = 26.1231) (t(88) = 0.059, p = 0.953, CI = -10.6752, 11.3262, d = 0.014). For targets mastered Time 7, 12 weeks between males and females, there was no significant difference in the means for males (M = 26.1196, SD = 24.2235) and females (M = 29.6364, SD = 33.7406) (t(89) = -0.536, p = 0.593, CI = -16.5431, 9.5094, d = -0.131). Conclusions The study indicates that ABA treatments may be equally beneficial for both genders with ASD, showing no significant gender differences. However, the broad CIs in this study imply a level of statistical uncertainty, indicating potential gender differences, suggesting the results may not be uniform across genders. These findings challenge assumptions on gender-specific treatment responses, implying that ABA treatments shouldn’t be recommended based on gender. Instead, individual needs should guide treatment recommendations. Future research could consider other response moderators like age, ASD severity, or coexisting mental health conditions.

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10. Pope L, Light J, Laubscher E. The Effect of Naturalistic Developmental Behavioral Interventions and Aided AAC on the Language Development of Children on the Autism Spectrum with Minimal Speech: A Systematic Review and Meta-analysis. J Autism Dev Disord;2024 (Jun 7)

Both naturalistic developmental behavioral interventions (NDBIs) and augmentative and alternative communication (AAC) have been shown to support the language development of children with a diagnosis of autism spectrum disorder and minimal speech. However, little research has addressed the impact of incorporating AAC systems within NDBIs. This systematic review was conducted to assess the relative impact of NDBI procedures with and without AAC on the language development of children on the autism spectrum with minimal speech. Relevant studies were located through systematic database searching, targeted review of relevant journals, and ancestral search of references from identified and associated papers. Relevant study characteristics were coded for all included studies, as well as determining certainty of evidence and calculating effect sizes for language variables. All procedures followed the systematic review guidelines set by the Cochrane Collaboration. A total of 29 relevant studies were included within this review, covering both single-case and group design research. Three studies were identified that directly compared NDBI and AAC interventions. NDBIs had a strong impact on language across study types (i.e., with and without AAC), though both aggregate and comparative effect sizes were notably larger when AAC was included within NDBI procedures, as compared to NDBIs without AAC. Results suggest that combining AAC with NDBI procedures may lead to better language outcomes than NDBIs alone for children on the autism spectrum with minimal speech.

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11. Silva B, Santos L, Barata C, Geminiani A, Fassina G, Gonzalez AR, Ferreira S, Barahona-Correa B, Olivieri I, Pedrocchi A, Santos-Victor J. Attention Analysis in Robotic-Assistive Therapy for Children with Autism. IEEE Trans Neural Syst Rehabil Eng;2024 (Jun 7);Pp

Children with Autism Spectrum Disorder (ASD) show severe attention deficits, hindering their capacity to acquire new skills. The automatic assessment of their attention response would provide the therapists with an important biomarker to better quantify their behaviour and monitor their progress during therapy. This work aims to develop a quantitativemodel, to evaluate the attention response of children with ASD, during robotic-assistive therapeutic sessions. Previous attempts to quantify the attention response of autistic subjects during human-robot interaction tasks were limited to restrained child movements. Instead, we developed an accurate quantitative system to assess the attention of ASD children in unconstrained scenarios. Our approach combines gaze extraction (Gaze360 model) with the definition of angular Areas-of-Interest, to characterise periods of attention towards elements of interest in the therapy environment during the session. The methodology was tested with 12 ASD children, achieving a mean test accuracy of 79.5 %. Finally, the proposed attention index was consistent with the therapists’ evaluation of patients, allowing a meaningful interpretation of the automatic evaluation. This encourages the future clinical use of the proposed system.

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12. 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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