1. Agarwal N, Frigerio G, Rizzato G, Ciceri T, Mani E, Lanteri F, Molteni M, Carare RO, Losa L, Peruzzo D. Parasagittal dural volume correlates with cerebrospinal fluid volume and developmental delay in children with autism spectrum disorder. Commun Med (Lond);2024 (Oct 4);4(1):191.

BACKGROUND: The parasagittal dura, a tissue that lines the walls of the superior sagittal sinus, acts as an active site for immune-surveillance, promotes the reabsorption of cerebrospinal fluid, and facilitates the removal of metabolic waste products from the brain. Cerebrospinal fluid is important for the distribution of growth factors that signal immature neurons to proliferate and migrate. Autism spectrum disorder is characterized by altered cerebrospinal fluid dynamics. METHODS: In this retrospective study, we investigated potential correlations between parasagittal dura volume, brain structure volumes, and clinical severity scales in young children with autism spectrum disorder. We employed a semi-supervised two step pipeline to extract parasagittal dura volume from 3D-T2 Fluid Attenuated Inversion Recovery sequences, based on U-Net followed by manual refinement of the extracted parasagittal dura masks. RESULTS: Here we show that the parasagittal dura volume does not change with age but is significantly correlated with cerebrospinal fluid (p-value = 0.002), extra-axial cerebrospinal fluid volume (p-value = 0.0003) and severity of developmental delay (p-value = 0.024). CONCLUSIONS: These findings suggest that autism spectrum disorder children with severe developmental delay may have a maldeveloped parasagittal dura that potentially perturbs cerebrospinal fluid dynamics. Cerebrospinal fluid (CSF) is produced in the brain. It is a medium of transport for neural growth factors and waste products. CSF is drained out of the brain through multiple pathways, one of them being the recently identified parasagittal dura (PSD) which also plays a role in the immune system within the brain. We estimated the PSD volume in children with autism spectrum disorder (ASD) and found the volume was associated with the amount of CSF in the brain. We also found that the PSD volume is smaller in children who have severe forms of developmental delay. Our findings suggest problems in the development of the PSD could have in impact on brain development and waste removal in children with ASD. More research in this area could enable a better understanding of the underlying causes of ASD. eng

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2. Altman KB, Plate SN, Britsch ER, Iverson JM. Cultivating the imagination: Caregiver input during pretend play with toddlers at elevated likelihood for autism. Autism Res;2024 (Oct 5)

Toddlers with autism spectrum disorder (ASD) may exhibit less pretend play than their neurotypical counterparts. Previous research suggests that caregivers’ input during play influences children’s play behavior, and children’s behavior may in turn prompt caregivers of differently developing children to talk about play in different ways. Caregiver input about pretend play during toy play at home was examined at 18- and 36-months in toddlers with an older sibling with ASD, who are at elevated likelihood (EL) for ASD (n = 40), and toddlers with typical likelihood (TL) for ASD (n = 12). EL toddlers were classified into three outcome groups: EL-ASD (n = 10), EL-no diagnosis (EL-ND; n = 14), or EL-language delays (EL-LD, n = 16). Caregiver utterances were categorized according to the types of pretend and non-pretend play suggested (e.g., pretending with inanimate objects vs. using objects for their intended function). Pretend utterances were further categorized as related or unrelated to the child’s own actions. All caregivers produced proportionately more utterances about complex types of pretend play over time. At 36 months, caregivers of autistic toddlers produced proportionately fewer pretend play utterances, and proportionately fewer pretend play utterances were related to EL-ASD toddlers’ actions compared to their neurotypical peers. These findings highlight bidirectional effects between caregivers and toddlers during play. While EL-ASD toddlers may provide less frequent opportunities for caregivers to talk about complex types of pretend play, the current study highlights caregivers’ high levels of attunement to their toddlers’ play skills.

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3. Dellapiazza F, Rattaz C, Michelon C, Peyre H, Picot MC, Baghdadli A. Longitudinal change in symptom severity in children with ASD: Results from the ELENA cohort. Autism Res;2024 (Oct 4)

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition and understanding the changes in autism symptoms over time is crucial for tailoring support and interventions. This study therefore aimed to investigate the changes in symptom severity in a large cohort of children with ASD over a three-year follow-up period and identify factors that influence these changes. The study included 575 children diagnosed with ASD, ranging in age from 2 to 12 years, who were assessed at baseline and again 3 years later using the Autism Diagnostic Observational Schedule-2 (ADOS-2). ASD severity changes were investigated using the ADOS calibrated severity score (CSS) scores for total, social affect (SA) and restricted and repetitive behaviors (RRB). Results highlight four distinct patterns: stable high, stable low, increased, and decreased severity. The ADOS CSS total score changed for half of the sample, reflecting an increase in ASD severity for 21.9% and a decrease for 29.1% of children. For the other half, the ADOS CSS score remained stable, either high (34.4%) or low (14.6%). While the majority of previous studies reported stability in ASD severity, our findings revealed significant variability with frequent improvements in SA symptoms whereas RRBs remained stable or worsened. Our findings also showed that an improvement in SA was associated with the youngest group and early diagnosis. However, no clinical or sociodemographic factors were linked to changes in RRB, emphasizing the necessity for RRB-specific therapies. The third six-year follow-up point of the ongoing ELENA cohort study will map the long-term trajectories of the severity of ASD symptoms and their potential risk factors.

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4. Gerges P, Bangarusamy DK, Bitar T, Alameddine A, Nemer G, Hleihel W. Turicibacter and Catenibacterium as potential biomarkers in autism spectrum disorders. Sci Rep;2024 (Oct 5);14(1):23184.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by social, behavioral, and cognitive impairments. Several comorbidities, including gastrointestinal (GI) dysregulations, are frequently reported in ASD children. Although studies in animals have shown the crucial role of the microbiota in key aspects of neurodevelopment, there is currently no consensus on how the alteration of microbial composition affects the pathogenesis of ASD. Moreover, disruption of the gut-brain axis (GBA) has been reported in ASD although with limited studies conducted on the Mediterranean population. In our study, we aimed to investigate gut microbiota composition in Lebanese ASD subjects, their unaffected siblings, and a control group from various regions in Lebanon using the 16 S-rRNA sequencing (NGS). Our study revealed a lower abundance of Turicibacter and a significant enrichment on Proteobacteria in the ASD and siblings’ groups compared to the controls, indicating that gut microbiota is probably affected by dietary habits, living conditions together with host genetic factors. The study also showed evidence of changes in the gut microbiome of ASD children compared to their siblings and the unrelated control. Bacteroidetes revealed a lower abundance in the ASD group compared to controls and siblings, conversely, Catenibacterium and Tenericutes revealed an increased abundance in the ASD group. Notably, our study identifies alterations in the abundance of Turicibacter and Catenibacterium in ASD children suggesting a possible link between these bacterial taxa and ASD and contributing to the growing body of evidence linking the microbiome to ASD.

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5. Gora C, Dudas A, Vaugrente O, Drobecq L, Pecnard E, Lefort G, Pellissier LP. Deciphering autism heterogeneity: a molecular stratification approach in four mouse models. Transl Psychiatry;2024 (Oct 4);14(1):416.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

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6. Greenfield E, Kendrick-Allwood S. Autism and cerebral palsy: evidence for converging phenotypes. Pediatr Res;2024 (Oct 5)

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7. Leachman C, Nichols ES, Al-Saoud S, Duerden EG. Anxiety in children and adolescents with autism spectrum disorder: behavioural phenotypes and environmental factors. BMC Psychol;2024 (Oct 5);12(1):534.

BACKGROUND: Anxiety is the most prevalent comorbidity among children and adolescents with autism spectrum disorder (ASD), yet little is known about the associated risk factors. METHODS: In a heterogenous cohort of children aged 5-18 years old (n = 262, 42% ASD), participants and their parents completed standardized questionnaires to assess anxiety, ASD symptom severity, inattention/hyperactivity, emotional problems, depressive symptoms, parental styles and stress, and demographic factors. RESULTS: An artificial neural network analysis using a self-organizing map, a statistical technique used to cluster large datasets, revealed 3 distinct anxiety profiles: low (n = 114, 5% ASD), moderate (n = 70, 64% ASD) and high (n = 78, 96% ASD) anxiety. A recursive feature elimination analysis revealed that depression and peer problems contributed the most to differences between the anxiety profiles. Difficulties with peers in individuals with ASD who experience anxiety may be related to challenges with social competence and this may heighten depressive symptoms. CONCLUSION: Findings highlight the importance of assessing depressive symptoms in children and adolescents with ASD who experience anxiety. Identifying anxiety profiles among children and adolescents with ASD may prove beneficial in clinical practice by facilitating the development of tailored interventions that aid in managing anxiety and depressive symptoms. Furthermore, strengthening social communication skills may improve peer relationships and could aid in managing depressive symptoms among children and adolescents with ASD who experience anxiety.

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8. Liang K, Lai Lam KK, Huang L, Lin X, Wang Z, Liu H, Chi P. Self-compassion, mental health, and parenting: Comparing parents of autistic and non-autistic children. Autism;2024 (Oct 5):13623613241286683.

Parenting can be challenging for any parent, particularly for those parenting autistic children. Research has shown that being kind, accepting, and mindful toward oneself during suffering, a concept known as self-compassion, can help enhance mental health. However, it is not fully understood how self-compassion benefits parenting experiences for parents of autistic children. Therefore, we conducted a study involving 178 parents of autistic children and 178 of autistic children to explore the associations between self-compassion, mental health, and parenting experiences. We found that parents of autistic children reported less self-compassion compared to parents of non-autistic children. For both groups of parents, self-compassion was linked to lower levels of ill-being and parenting stress, as well as higher levels of well-being and parenting competence. In parents of non-autistic children, both ill-being and well-being played a mediating role in the relationship between self-compassion and parenting experiences. However, in parents of autistic children, only well-being was found to mediate this relationship. These findings emphasize the importance of self-compassion and well-being in improving parenting experiences for parents of autistic children.

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9. Matuskey D, Yang Y, Naganawa M, Koohsari S, Toyonaga T, Gravel P, Pittman B, Torres K, Pisani L, Finn C, Cramer-Benjamin S, Herman N, Rosenthal LH, Franke CJ, Walicki BM, Esterlis I, Skosnik P, Radhakrishnan R, Wolf JM, Nabulsi N, Ropchan J, Huang Y, Carson RE, Naples AJ, McPartland JC. (11)C-UCB-J PET imaging is consistent with lower synaptic density in autistic adults. Mol Psychiatry;2024 (Oct 4)

The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using (11)C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a (11)C-UCB-J PET scan. Binding potential, BP(ND), was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower (11)C-UCB-J BP(ND) compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes.

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10. Mazzini S, Seijdel N, Drijvers L. Autistic individuals benefit from gestures during degraded speech comprehension. Autism;2024 (Oct 5):13623613241286570.

Our study explored how meaningful hand gestures, alongside spoken words, can help autistic individuals to understand speech, especially when the speech quality is poor, such as when there is a lot of noise around. Previous research has suggested that meaningful hand gestures might be processed differently in autistic individuals, and we therefore expected that these hand gestures might aid them less in understanding speech in adverse listening conditions than for non-autistic people. To this end, we asked participants to watch and listen to videos of a woman uttering a Dutch action verb. In these videos, she either made a meaningful gesture while speaking, or not, and speech was clear, or noisy. The task for participants was to identify the verb in the videos. Contrary to what we expected, we found that both autistic and non-autistic individuals use meaningful information from hand gestures when understanding unclear speech. This means that gestural information can aid in communication, especially when communicative settings are suboptimal.

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11. Qing P, Zhang X, Liu Q, Huang L, Xu D, Le J, Kendrick KM, Lai H, Zhao W. Structure-function coupling in white matter uncovers the hypoconnectivity in autism spectrum disorder. Mol Autism;2024 (Oct 4);15(1):43.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder associated with alterations in structural and functional coupling in gray matter. However, despite the detectability and modulation of brain signals in white matter, the structure-function coupling in white matter in autism remains less explored. METHODS: In this study, we investigated structural-functional coupling in white matter (WM) regions, by integrating diffusion tensor data that contain fiber orientation information from WM tracts, with functional connectivity tensor data that reflect local functional anisotropy information. Using functional and diffusion magnetic resonance images, we analyzed a cohort of 89 ASD and 63 typically developing (TD) individuals from the Autism Brain Imaging Data Exchange II (ABIDE-II). Subsequently, the associations between structural-functional coupling in WM regions and ASD severity symptoms assessed by Autism Diagnostic Observation Schedule-2 were examined via supervised machine learning in an independent test cohort of 29 ASD individuals. Furthermore, we also compared the performance of multi-model features (i.e. structural-functional coupling) with single-model features (i.e. functional or structural models alone). RESULTS: In the discovery cohort (ABIDE-II), individuals with ASD exhibited widespread reductions in structural-functional coupling in WM regions compared to TD individuals, particularly in commissural tracts (e.g. corpus callosum), association tracts (sagittal stratum), and projection tracts (e.g. internal capsule). Notably, supervised machine learning analysis in the independent test cohort revealed a significant correlation between these alterations in structural-functional coupling and ASD severity scores. Furthermore, compared to single-model features, the integration of multi-model features (i.e., structural-functional coupling) performed best in predicting ASD severity scores. CONCLUSION: This work provides novel evidence for atypical structural-functional coupling in ASD in white matter regions, further refining our understanding of the critical role of WM networks in the pathophysiology of ASD.

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12. Schmitt LM, Nelson M, Shaffer RC, Erickson CA. A near normal distribution of IQ in Fragile X Syndrome. Sci Rep;2024 (Oct 4);14(1):23058.

Fragile X Syndrome (FXS) is an X-linked disorder leading to the loss of expression of FMR1-protein product, FMRP. The absence or deficiency of FMRP is thought to result in the characteristic FXS phenotypes, including intellectual disability. Identifying the relationship between FMRP levels and IQ may be critical to better understand underlying mechanisms and advance treatment development and planning. A sample of 143 individuals with FXS (69% male), aged 8-50 years, completed IQ testing and blood draw via venipuncture to determine the relationship between Deviation IQ scores and FMRP levels as well as the distribution of Deviation IQ scores. In both males and females with FXS, higher FMRP levels were associated with higher Deviation IQ. However, this relationship was no longer significant when only examining full mutation, fully-methylated males. Yet, both the full and restricted male samples showed a downward shifted but otherwise normal distribution of Deviation IQ scores. Our findings support and extend previous studies establishing molecular markers of disease severity in FXS as well as provide novel evidence of a « FXS IQ standard curve ». This latter finding suggests inter-individual variation in Deviation IQ in FXS, especially among males, may be driven by similar factors known to impact cognitive outcomes in typically-developing individuals. Thus, future work aimed at understanding the mechanisms by which FMRP loss leads to intellectual disability should revisit the biological/genetic, socio-environmental, and epigenetic factors contributing to inter-individual variation in IQ in FXS.

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13. Stroud J, Rice C, Orsini A, Schlosser M, Lee J, Mandy W, Kamboj SK. Perceived changes in mental health and social engagement attributed to a single psychedelic experience in autistic adults: results from an online survey. Psychopharmacology (Berl);2024 (Oct 5)

RATIONALE: Anecdotal reports suggest that psychedelic drugs can improve psychological wellbeing and social engagement in autistic people. However, there are few contemporary studies on this topic. OBJECTIVES: To examine autistic participants’ experiences with psychedelic drugs and the extent to which they attributed changes in mental health and social engagement to their most ‘impactful’ psychedelic experience. We also explored associations between these changes and mechanistically important variables (e.g., aspects of the acute psychedelic experience and changes in ‘psychological flexibility’). METHODS: Self-selecting autistic participants (n = 233) with high autism quotient scores completed an online survey relating to their most impactful psychedelic experience. Questionnaires assessed the acute psychedelic experience and perceived psychedelic-induced changes in distress, social engagement and psychological flexibility, among other relevant variables. RESULTS: The majority of participants attributed reductions in psychological distress (82%) and social anxiety (78%) and increases in social engagement (70%) to their most ‘impactful’ psychedelic experience. A substantial minority (20%) also reported undesirable effects such as increases in anxiety with some describing their psychedelic experience as among the most negatively impactful experiences of their lives. The only substantial predictor of reductions in psychological distress was increased psychological flexibility. CONCLUSION: Autistic people attributed changes in mental health and social engagement to a single highly impactful psychedelic experience. The results and their implications are discussed with caution considering the use of a non-experimental design and biased sampling.

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14. Zhang B, Wu H, Zhang C, Wan L, Yang G. Prevalence Trends and Treatment Patterns of Autism Spectrum Disorder Among Children and Adolescents in the United States from 2017 to 2020. Neurol Ther;2024 (Oct 5)

BACKGROUND: Autism spectrum disorder (ASD) poses a significant challenge due to its diverse impact on individuals, emphasizing the need for personalized treatment plans. The financial burden of ASD-related healthcare is substantial, necessitating a comprehensive understanding of its prevalence and evolving trends. METHODS: This study aims to analyze the prevalence and trends of ASD, treatment patterns, gender differences, and racial-ethnic disparities in the United States from 2017 to 2020, utilizing nationally representative data from the National Survey of Children’s Health (NSCH). The NSCH, a leading annual national survey, provided rich data on child health. A total of 108,142 participants aged 3-17 years were included, with ASD prevalence assessed based on self-reported diagnoses. RESULTS: Between 2017 and 2020, ASD prevalence in children aged 3-17 was 2.94% (95% confidence interval: 2.68-3.18). Significant disparities were observed: older age and male gender correlated with higher prevalence, while family income-to-poverty ratio and insurance coverage influenced prevalence. Racial/ethnic disparities existed, with Hispanics showing the highest prevalence. Treatment trends showed stability overall, but age influenced behavioral and medication interventions. The prevalence remained stable from 2017 to 2020, with variations in age groups and a significant increase among non-Hispanic Whites. CONCLUSIONS: This study highlights a higher but stable overall ASD prevalence, with nuanced disparities among different demographic groups. Gender differences persist, emphasizing the need for tailored interventions. Racial-ethnic disparities call for targeted healthcare strategies. The stability in treatment trends underscores the persistent challenge of addressing core ASD symptoms.

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