1. Bölte S, Alehagen L, Black MH, Hasslinger J, Wessman E, Lundin Remnélius K, Marschik PB, D’Arcy E, Crowson S, Freeth M, Seidel A, Girdler S, Zander E. The Gestalt of functioning in autism revisited: First revision of the International Classification of Functioning, Disability and Health Core Sets. Autism;2024 (Feb 13):13623613241228896.

Autistic people experience individual strengths and challenges as well as barriers and facilitators in their environment. All of these factors contribute to how well autistic people can cope in everyday life, fulfill the roles they choose, and meet their needs. The World Health Organization has developed a system aiming to capture the many factors within people (like how someone thinks and feels) and outside of people (things around a person) that influence their daily living, called the International Classification of Functioning, Disability and Health. The International Classification of Functioning, Disability and Health can be used for different purposes in research and practice to assess people’s situations and plan support measures. Previously in 2019, the International Classification of Functioning, Disability and Health was adapted to autism by developing so-called Core Sets, which are shorter International Classification of Functioning, Disability and Health versions for use in specific conditions. Here, we present the first revisions of the International Classification of Functioning, Disability and Health Core Sets for autism, based on research, development results, and community feedback. Some factors influencing daily life for autistic people were added to the Core Sets, and other factors deemed less relevant were removed. Changes were also made in Core Sets designed for different age groups (0-5, 6-16, and ⩾17 years). Particularly, contents for sensory processing (like smell, touch, seeing, hearing) were added. We recommend these updated Core Sets for future use in autism research and practice. These changes to the Core Sets after 4 years indicate that there should be ongoing updates based on research and experience from practice and involvement of stakeholders.

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2. Brima T, Beker S, Prinsloo KD, Butler JS, Djukic A, Freedman EG, Molholm S, Foxe JJ. Probing a neural unreliability account of auditory sensory processing atypicalities in Rett Syndrome. Res Sq;2024 (Jan 30)

Background In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is « stationarity » of the underlying responses – i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary. Methods AEPs were recorded to simple 100Hz tones from 18 RTT and 27 age-matched controls (Ages: 6-22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures. Results Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a « neural unreliability » account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident. Conclusions To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.

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3. Capurro C, Telini G, Canevello C, Laffi N. A new way to approach ASD children in Dentistry. Eur J Paediatr Dent;2024 (Feb 1);25:1.

AIM: To present an innovative dental approach for children with autism spectrum disorder to the scientific community, along with the 3 questionnaires formulated to evaluate its effectiveness. METHODS: Development of the 3 questionnaires occurred in five stages: observation of the behaviours of ADS children and their caregivers attending the Dental Department in the year 2021; issues detection: anxiety in parents, crying, difficulty in waiting and hyperactivity of the children, fear of both parents and children; formulation of the questionnaires in order to obtain all the information necessary to assess the patient’s psychological well-being; validation with submission of the questionnaires to two specialists; modification and final drafting. CONCLUSION: Using the 3 questionnaires, the dentist will be able to assess the wellbeing of the patient and his/her family when attending the dental environment, monitor oral hygiene manoeuvres and verify the usefulness of the orthodontic approach to ADS child while creating a trusting relationship with the patient and his/her caregivers.

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4. Carbonell-Roig J, Aaltonen A, Cartocci V, McGuirt A, Mosharov E, Kehr J, Lieberman OJ, Sulzer D, Borgkvist A, Santini E. Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders. bioRxiv;2024 (Jan 30)

Autism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.

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5. Chaves TF, Ocampos M, Barbato IT, de Camargo Pinto LL, de Luca GR, Barbato Filho JH, Bernardi P, Costa Netto Muniz Y, Francesca Maris A. A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD. Sci Rep;2024 (Feb 14);14(1):3762.

Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3-4% of the world’s population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8-21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for « isolated » ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

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6. Chien CW, Lin CY, Lai CYY, Graham F. Parent coaching to enhance community participation in young children with developmental disabilities: A pilot randomized controlled trial. Res Dev Disabil;2024 (Feb 14);147:104696.

BACKGROUND: Parent coaching emerges as a preferred approach for enhancing performance and participation of children with developmental disabilities (DD), but limited clinical trials examine its effects on community participation. AIM: To evaluate whether parent coaching, specifically using Occupational Performance Coaching (OPC), enhances community participation among young children with DD. METHOD AND PROCEDURES: A pilot double-blind randomized controlled trial was conducted. Parents of 50 children with DD (31 male, 19 female, mean age 4 years 10 months) were randomly assigned to the OPC group (n = 25) or parent consultation group (n = 25). Each parent received a maximum of eight coaching sessions or consultations. The primary outcome was children’s community participation as assessed through parent-report measures at baseline, pre-intervention, post-intervention, and an 8-week follow-up. OUTCOMES AND RESULTS: Both groups showed significant improvements in parent-identified, goal-specific community participation after the intervention (mean difference [MD]=2.26-2.56), and these improvements were sustained during the follow-up. Despite a trend favoring parent coaching, the group difference in the improvements was not evident (MD=0.18-0.28). Both groups displayed positive improvements in children’s overall community involvement post-intervention (MD=0.32); however, the time effects were not statistically significant. CONCLUSIONS AND IMPLICATIONS: OPC, by coaching parents, could enhance goal-specific community participation in children with DD, producing effects similar to those achieved through parent consultation.

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7. Demopoulos C, Jesson X, Gerdes MR, Jurigova BG, Hinkley LB, Ranasinghe KG, Desai S, Honma S, Mizuiri D, Findlay A, Nagarajan SS, Marco EJ. Global MEG Resting State Functional Connectivity in Children with Autism and Sensory Processing Dysfunction. bioRxiv;2024 (Jan 29)

Sensory processing dysfunction not only affects most individuals with autism spectrum disorder (ASD), but at least 5% of children without ASD also experience dysfunctional sensory processing. Our understanding of the relationship between sensory dysfunction and resting state brain activity is still emerging. This study compared long-range resting state functional connectivity of neural oscillatory behavior in children aged 8-12 years with autism spectrum disorder (ASD; N=18), those with sensory processing dysfunction (SPD; N=18) who do not meet ASD criteria, and typically developing control participants (TDC; N=24) using magnetoencephalography (MEG). Functional connectivity analyses were performed in the alpha and beta frequency bands, which are known to be implicated in sensory information processing. Group differences in functional connectivity and associations between sensory abilities and functional connectivity were examined. Distinct patterns of functional connectivity differences between ASD and SPD groups were found only in the beta band, but not in the alpha band. In both alpha and beta bands, ASD and SPD cohorts differed from the TDC cohort. Somatosensory cortical beta-band functional connectivity was associated with tactile processing abilities, while higher-order auditory cortical alpha-band functional connectivity was associated with auditory processing abilities. These findings demonstrate distinct long-range neural synchrony alterations in SPD and ASD that are associated with sensory processing abilities. Neural synchrony measures could serve as potential sensitive biomarkers for ASD and SPD.

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8. Dounavi K, Koldas M. Parental Perspectives on Early Life Screening and Genetic Testing for ASD: A Systematic Review. J Autism Dev Disord;2024 (Feb 14)

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental condition for which no prenatal or early life screening tests exist. Early life recognition of ASD is key to accessing behavioral intervention when brain plasticity is at its peak. The purpose of our study was to systematically review the literature researching parental perspectives around early life screening for autism and specifically genetic testing. A total of 30 studies were included and coded against the following variables: parental characteristics, child characteristics, research design, data collection and data analysis methods, type of early screening, and parental perspectives towards early life screening and genetic testing. The outcomes of the review showed that caregivers need more knowledge about ASD genetic testing, they are in general in favor of early life screening, and they prefer to access ASD genetic testing and early behavioral intervention as early as possible. As emerging genetic tests are likely to increase diagnostic accuracy for ASD in the near future, it is of paramount importance for research and practice to embrace parental needs and preferences. Healthcare providers can be pivotal in empowering parents to make informed decisions through clear, compassionate communication and counseling. Future research should seek to fill in an essential gap in the literature, which is to capture parental views from a diverse population.

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9. Gaona VA. [Etiology of autism]. Medicina (B Aires);2024 (Mar);84 Suppl 1:31-36.

The Autism Spectrum Disorder is a neurobiological based disorder with a high percentage of heritability and a wide list of possible etiologies that presents very heterogeneous changes in neuronal architecture, connectivity and synaptogenesis with characteristic clinical manifestations whose origin points to environmental, immunological, genetic and other causes, without having been confirmed specific biomarkers. Diagnosis continues to be based on typical features including repetitive behaviors and impaired communication and social interaction. Their genetic and non-genetic risk factors are reviewed to advance knowledge about the pathological processes that may be related to their origin.

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10. Hervás A. [Autistic spectrum disorders, attention deficit disorders, hyperactivity and emotional dysregulation: masking and approach]. Medicina (B Aires);2024 (Mar);84 Suppl 1:43-49.

Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorders (ADHD) are Neurodevelopmental Disorders (ND) that frequently coexist together and have etiological, biological, and clinical factors in common. The comorbidity of both neurodevelopmental disorders is associated with a delay or lack of ASD diagnosis and the development of perceptual, emotional, cognitive and behavioral alterations related to Emotional Dysregulation (ED) is common. When both TN are not diagnosed in childhood, they frequently receive wrong diagnoses at later ages, the most frequent being Borderline Personality Disorder (BPD). The clinical presentation of the association of ASD and ADHD, the association with ED, differentiation of BPD, and evaluation and intervention are here analyzed. The comorbidity ASD, ADHD, ED is a more severe disorder associated to polypharmacology and hospital admissions.

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11. Idiazabal MA, Palau M, Bello X. [Treatment of sleep disorders in neurodevelopmental disorders]. Medicina (B Aires);2024 (Mar);84 Suppl 1:9-14.

Sleep disorders are common in children and affect neurological development with important cognitive, emotional and behavioral repercussions. There is a high prevalence of sleep disorders (SD) in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Sleep disorders in pediatric population have a prevalence of 6-25%, while in children with NDD this number rises to 50-80%. In NDDs, higher rates of difficulties in falling asleep, nocturnal awakenings and daytime sleepiness are observed. Disturbances in the circadian rhythm as well as respiratory sleep disorders are also observed. Consequently, there is a decrease in alertness for daytime activities with increased behavioral disorders, emotional problems and academic difficulties associated with executive and memory dysfunctions. Sleep assessment has to be a systemic part in the clinical evaluation of children with NDDs, so as to give a convenient diagnosis and treatment in each case, allowing to improve the quality of life of children and their families.

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12. Jaiswal A, Washington P. Using #ActuallyAutistic on Twitter for Precision Diagnosis of Autism Spectrum Disorder: Machine Learning Study. JMIR Form Res;2024 (Feb 14);8:e52660.

BACKGROUND: The increasing use of social media platforms has given rise to an unprecedented surge in user-generated content, with millions of individuals publicly sharing their thoughts, experiences, and health-related information. Social media can serve as a useful means to study and understand public health. Twitter (subsequently rebranded as « X ») is one such social media platform that has proven to be a valuable source of rich information for both the general public and health officials. We conducted the first study applying Twitter data mining to autism screening. OBJECTIVE: This study used Twitter as the primary source of data to study the behavioral characteristics and real-time emotional projections of individuals identifying with autism spectrum disorder (ASD). We aimed to improve the rigor of ASD analytics research by using the digital footprint of an individual to study the linguistic patterns of individuals with ASD. METHODS: We developed a machine learning model to distinguish individuals with autism from their neurotypical peers based on the textual patterns from their public communications on Twitter. We collected 6,515,470 tweets from users’ self-identification with autism using « #ActuallyAutistic » and a separate control group to identify linguistic markers associated with ASD traits. To construct the data set, we targeted English-language tweets using the search query « #ActuallyAutistic » posted from January 1, 2014, to December 31, 2022. From these tweets, we identified unique users who used keywords such as « autism » OR « autistic » OR « neurodiverse » in their profile description and collected all the tweets from their timeline. To build the control group data set, we formulated a search query excluding the hashtag, « -#ActuallyAutistic, » and collected 1000 tweets per day during the same time period. We trained a word2vec model and an attention-based, bidirectional long short-term memory model to validate the performance of per-tweet and per-profile classification models. We also illustrate the utility of the data set through common natural language processing tasks such as sentiment analysis and topic modeling. RESULTS: Our tweet classifier reached a 73% accuracy, a 0.728 area under the receiver operating characteristic curve score, and an 0.71 F(1)-score using word2vec representations fed into a logistic regression model, while the user profile classifier achieved an 0.78 area under the receiver operating characteristic curve score and an F(1)-score of 0.805 using an attention-based, bidirectional long short-term memory model. This is a promising start, demonstrating the potential for effective digital phenotyping studies and large-scale intervention using text data mined from social media. CONCLUSIONS: Textual differences in social media communications can help researchers and clinicians conduct symptomatology studies in natural settings.

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13. Jimenez-Gomez A, Nguyen MX, Gill JS. Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction. Front Psychiatry;2024;15:1304300.

Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the cerebro-cerebellar circuit, particularly in genetic autism related to SHANK3 or SYNGAP1 protein dysfunction function and autism associated with in utero exposure to the anti-seizure medications valproic acid and topiramate, may contribute to the disease presentation. Initially, a discussion contextualizing AMPAr signaling in the cerebro-cerebellar circuitry and microstructural circuit considerations is offered. Subsequently, a detailed review of the literature implicating mutations or deletions of SHANK3 and SYNGAP1 in disrupted AMPAr signaling reveals how bidirectional pathogenic modulation of this key circuit may contribute to autism. Finally, how pharmacological exposure may interact with this pathway, via increased risk of autism diagnosis with valproic acid and topiramate exposure and potential treatment of autism using AMPAr modulator perampanel, is discussed. Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder.

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14. Klin A. A biomarker-based solution for the limited access to early diagnosis and assessment of autism. Medicina (B Aires);2024 (Mar);84 Suppl 1:50-56.

With the upsurge of community uptake in population-based early screening for autism, the main obstacle to increasing access to early treatment and intervention services is the extremely limited access to high quality diagnosis, specifically the shortage of expert clinicians. Diagnostic evaluation models deployed by academic centers of excellence, which typically require the investment of 6-10 hours by specialized multidisciplinary teams, is not a viable solution to the vast needs of communities, resulting in parents’ « diagnostic odysseys » and delays, often of several years, for treatment, interventions and supports. Biomarker-based objective procedures for early diagnosis and assessment of autism are now available, clinically validated, and cleared for broad implementation by the US Food and Drug Administration (FDA). They are intended to increase access while maintaining high quality. Such solutions, however, will require change in entrenched models of diagnostic care, and aggressive prioritization of the needs of the community at large. If these innovations are successful, the number of children diagnosed in the first three years of life will double or triple. This will, in turn, require much greater investments in resources for treatment, including massive workforce training of providers capable of delivering community-viable caregiver-mediated interventions, and of early educators capable of serving autistic children in therapeutic inclusive preschool settings.

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15. Li N, Xiao J, Mao N, Cheng D, Chen X, Zhao F, Shi Z. Joint learning of multi-level dynamic brain networks for autism spectrum disorder diagnosis. Comput Biol Med;2024 (Feb 8);171:108054.

Graph convolutional networks (GCNs), with their powerful ability to model non-Euclidean graph data, have shown advantages in learning representations of brain networks. However, considering the complexity, multilayeredness, and spatio-temporal dynamics of brain activities, we have identified two limitations in current GCN-based research on brain networks: 1) Most studies have focused on unidirectional information transmission across brain network levels, neglecting joint learning or bidirectional information exchange among networks. 2) Most of the existing models determine node neighborhoods by thresholding or simply binarizing the brain network, which leads to the loss of edge weight information and weakens the model’s sensitivity to important information in the brain network. To address the above issues, we propose a multi-level dynamic brain network joint learning architecture based on GCN for autism spectrum disorder (ASD) diagnosis. Specifically, firstly, constructing different-level dynamic brain networks. Then, utilizing joint learning based on GCN for interactive information exchange among these multi-level brain networks. Finally, designing an edge self-attention mechanism to assign different edge weights to inter-node connections, which allows us to pick out the crucial features for ASD diagnosis. Our proposed method achieves an accuracy of 81.5 %. The results demonstrate that our method enables bidirectional transfer of high-order and low-order information, facilitating information complementarity between different levels of brain networks. Additionally, the use of edge weights enhances the representation capability of ASD-related features.

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16. Maillard AM, Romascano D, Villalón-Reina JE, Moreau CA, Almeida Osório JM, Richetin S, Junod V, Yu P, Misic B, Thompson PM, Fornari E, Gygax MJ, Jacquemont S, Chabane N, Rodríguez-Herreros B. Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion. Transl Psychiatry;2024 (Feb 14);14(1):95.

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.2 deletion. However, the specific neuroanatomical mechanisms underlying such alterations, as well as their developmental trajectory, are still poorly understood. Here we explored differences in microstructural brain connectivity between 24 children carrying a 16p11.2 deletion and 66 typically developing (TD) children between 2 and 8 years of age. We found a large pervasive increase of intra-axonal volume widespread over a high number of white matter tracts. Such microstructural alterations in 16p11.2 deletion children were already present at an early age, and led to significant changes in the global efficiency and integration of brain networks mainly associated to language, motricity and socio-emotional behavior, although the widespread pattern made it unlikely to represent direct functional correlates. Our results shed light on the neuroanatomical basis of the previously reported increase of white matter volume, and align well with analogous evidence of altered axonal diameter and synaptic function in 16p11.2 mice models. We provide evidence of a prevalent mechanistic deviation from typical maturation of brain structural connectivity associated with a specific biological risk to develop ASD. Future work is warranted to determine how this deviation contributes to the emergence of symptoms observed in young children diagnosed with ASD and other NDDs.

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17. Minissi ME, Altozano A, Marin-Morales J, Centelles N, Sirera M, Abad L, Alcañiz M. [Virtual reality and digital biomarkers: a clinical tool for early autism diagnosis]. Medicina (B Aires);2024 (Mar);84 Suppl 1:57-64.

INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition which traditional assessment procedures encounter certain limitations. The current ASD research field is exploring and endorsing innovative methods to assess the disorder early on, based on the automatic detection of biomarkers. However, many of these procedures lack ecological validity in their measurements. In this context, virtual reality (VR) shows promise for objectively recording biosignals while users experience ecological situations. METHODS: This study outlines a novel and playful VR procedure for the early assessment of ASD, relying on multimodal biosignal recording. During a VR experience featuring 12 virtual scenes, eye gaze, motor skills, electrodermal activity and behavioural performance were measured in 39 children with ASD and 42 control peers. Machine learning models were developed to identify digital biomarkers and classify autism. RESULTS: Biosignals reported varied performance in detecting ASD, while the combined model resulting from the combination of specific-biosignal models demonstrated the ability to identify ASD with an accuracy of 83% (SD = 3%) and an AUC of 0.91 (SD = 0.04). DISCUSSION: This screening tool may support ASD diagnosis by reinforcing the outcomes of traditional assessment procedures.

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18. Nakamura T, Ueda J, Mizuno S, Honda K, Kazuno AA, Yamamoto H, Hara T, Takata A. Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk. Cell Genom;2024 (Feb 14);4(2):100488.

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.

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19. Newman BT, Jacokes Z, Venkadesh S, Webb SJ, Kleinhans NM, McPartland JC, Druzgal TJ, Pelphrey KA, Van Horn JD. Conduction Velocity, G-ratio, and Extracellular Water as Microstructural Characteristics of Autism Spectrum Disorder. bioRxiv;2024 (Feb 14)

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a novel metric termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel neuroimaging metric, aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

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20. Pan YD, Zhang Y, Zheng WY, Zhu MZ, Li HY, Ouyang WJ, Wen QQ, Zhu XH. Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice. J Neurosci;2024 (Feb 14);44(7)

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B (-/-) and Fmr1 (-/y) mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B (-/-) mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.

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21. Rexrode LE, Hartley J, Showmaker KC, Challagundla L, Vandewege MW, Martin BE, Blair E, Bollavarapu R, Antonyraj RB, Hilton K, Gardiner A, Valeri J, Gisabella B, Garrett MR, Theoharides TC, Pantazopoulos H. Molecular profiling of the hippocampus of children with autism spectrum disorder. Mol Psychiatry;2024 (Feb 14)

Several lines of evidence point to a key role of the hippocampus in Autism Spectrum Disorders (ASD). Altered hippocampal volume and deficits in memory for person and emotion related stimuli have been reported, along with enhanced ability for declarative memories. Mouse models have demonstrated a critical role of the hippocampus in social memory dysfunction, associated with ASD, together with decreased synaptic plasticity. Chondroitin sulfate proteoglycans (CSPGs), a family of extracellular matrix molecules, represent a potential key link between neurodevelopment, synaptic plasticity, and immune system signaling. There is a lack of information regarding the molecular pathology of the hippocampus in ASD. We conducted RNAseq profiling on postmortem human brain samples containing the hippocampus from male children with ASD (n = 7) and normal male children (3-14 yrs old), (n = 6) from the NIH NeuroBioBank. Gene expression profiling analysis implicated molecular pathways involved in extracellular matrix organization, neurodevelopment, synaptic regulation, and immune system signaling. qRT-PCR and Western blotting were used to confirm several of the top markers identified. The CSPG protein BCAN was examined with multiplex immunofluorescence to analyze cell-type specific expression of BCAN and astrocyte morphology. We observed decreased expression of synaptic proteins PSD95 (p < 0.02) and SYN1 (p < 0.02), increased expression of the extracellular matrix (ECM) protease MMP9 (p < 0.03), and decreased expression of MEF2C (p < 0.03). We also observed increased BCAN expression with astrocytes in children with ASD, together with altered astrocyte morphology. Our results point to alterations in immune system signaling, glia cell differentiation, and synaptic signaling in the hippocampus of children with ASD, together with alterations in extracellular matrix molecules. Furthermore, our results demonstrate altered expression of genes implicated in genetic studies of ASD including SYN1 and MEF2C.

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22. Ruggieri V. [Autism and camouflage]. Medicina (B Aires);2024 (Mar);84 Suppl 1:37-42.

Autism is a neurobiologically based neurodevelopmental disorder with high prevalence and a clear predominance in males. It is characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors, frequently associated with sensory dysfunction others neurodevelopmental conditions, neuropsychiatric disorders, epilepsy, and/or sleep disorders. This condition will accompany people throughout their lives, which will generate various support and treatment needs. People with autism often need to « fit in » and for this they use techniques such as camouflage, also called masking. This attitude has been observed in people with typical development and in people with autism in childhood, adolescence and adult life, although in autistic people this behavior is more intense and takes longer and with more frequency and intensity in autistic adult women. This could explain the underreporting of autism, the later diagnosis, the delay in the therapeutic approach, and the greater presence of anxiety and depression disorders related to the effort that « appearing normal » implies. Even though camouflage people appear to be « normal » and fit in perfectly, this is not an attitude that we should promote and, on the contrary, it is imperativeto work to improve the environment and the understanding of each person. In this paper we will analyze the clinical aspects, their relationship with age, sex, and ways of detecting it.

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23. Scarpitti MR, Pastore B, Tang W, Kearse MG. Characterization of ribosome stalling and no-go mRNA decay stimulated by the Fragile X protein, FMRP. bioRxiv;2024 (Feb 3)

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) and is the leading monogenic cause of autism spectrum disorders and intellectual disability. FMRP is most notably a translational repressor and is thought to inhibit translation elongation by stalling ribosomes as FMRP-bound polyribosomes from brain tissue are resistant to puromycin and nuclease treatment. Here, we present data showing that the C-terminal non-canonical RNA-binding domain of FMRP is essential and sufficient to induce puromycin-resistant mRNA•ribosome complexes. Given that stalled ribosomes can stimulate ribosome collisions and no-go mRNA decay (NGD), we tested the ability of FMRP to drive NGD of its target transcripts in neuroblastoma cells. Indeed, FMRP and ribosomal proteins, but not PABPC1, were enriched in isolated nuclease-resistant disomes compared to controls. Using siRNA knockdown and RNA-seq, we identified 16 putative FMRP-mediated NGD substrates, many of which encode proteins involved in neuronal development and function. Increased mRNA stability of the putative substrates was also observed when either FMRP was depleted or NGD was prevented via RNAi. Taken together, these data support that FMRP stalls ribosomes and can stimulate NGD of a select set of transcripts in cells, revealing an unappreciated role of FMRP that would be misregulated in FXS.

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24. Shao M, Luo S, Qian H, Li X, Wei Z, Hong M, Wang J, Li X, Meng J. The relationship between autistic traits and the stress of social isolation: Development of an explanatory model. Heliyon;2024 (Feb 29);10(4):e26082.

BACKGROUND: Social isolation can be particularly challenging for individuals with high autistic traits who struggle with social interactions. The COVID-19 pandemic led to increased isolation, exacerbating stress for those who may have difficulty in connecting with others. This study aimed to explore the relationship between autistic traits and stress associated with social isolation. METHODS: A sample of 1597 Chinese adults completed measures of autistic traits, the stress of social isolation, psychological inflexibility and core self-evaluation, during an epidemic prevention and control period of COVID-19 in Chongqing, China. Measures included the Autism-Spectrum Quotient, Coronavirus Stress Measure, Acceptance and Action Questionnaire-II, and Core Self-Evaluation Scale. RESULTS: Autistic traits were positively correlated with the stress of social isolation, which was mediated by the chain effect of core self-evaluation and psychological inflexibility. individuals with high autistic traits reported significantly higher stress than individuals with low autistic traits. LIMITATIONS: This was a cross-sectional study, which limits causal inference. In addition, data were self-reported, which may cause methodological effects. Finally, this study was conducted during China’s quarantine policy and external validation of the findings is required. CONCLUSIONS: Autistic traits are positively associated with the stress of social isolation. Autistic traits affected core self-evaluation first, and psychological inflexibility subsequently, leading to the stress of social isolation. individuals with high autistic traits tended to experience higher levels of stress during pandemic quarantines. The findings provide useful evidence for developing interventions and implementing preventive measures to reduce stress in individuals with high autistic traits and autism spectrum disorder.

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25. Wang BX, Chen S, Zhou F, Liu J, Xiao C, Chan A, Tang T. English Prosodic Focus Marking by Cantonese Trilingual Children With and Without Autism Spectrum Disorder. J Speech Lang Hear Res;2024 (Feb 14):1-20.

PURPOSE: The current study investigated English prosodic focus marking by autistic and typically developing (TD) Cantonese trilingual children, and examined the potential differences in this regard compared to native English-speaking children. METHOD: Forty-eight participants were recruited with 16 speakers for each of the three groups (Cantonese-speaking autistic [CASD], Cantonese-speaking TD [CTD], and English-speaking TD [ETD] children), and prompt questions were designed to elicit desired focus type (i.e., broad, narrow, and contrastive focus). Mean duration, mean fundamental frequency (F0), F0 range, mean intensity, and F0 curves were used as the acoustic correlates for linear mixed-effects model fitting and functional data analyses in relation to groups and focus conditions (i.e., broad, narrow, and contrastive pre-, on-, and post-focus). RESULTS: The CTD group had post-focus compression (PFC) patterns via reducing mean duration, narrowing F0 range, and lowering mean F0, F0 curve, and mean intensity for words under both narrow and contrastive post-focus conditions, while the CASD group only had shortened mean duration and lowered F0 curves. However, neither the CTD group nor CASD group showed much of on-focus expansion (OFE) patterns. The ETD group marked OFE by increasing mean duration, mean F0, mean intensity, and higher F0 curve for words under on-focus conditions. CONCLUSIONS: The CTD group utilized more acoustic cues than the CASD group when it comes to PFC. The ETD group differed from the CASD and CTD groups in the use of OFE. Furthermore, both the CASD and CTD groups showed positive first language transfer in the use of duration and intensity and, potentially, successful acquisition in the use of F0 for prosodic focus marking. Meanwhile, the differences in the use of OFE between the Cantonese-speaking and English-speaking groups, not PFC, might indicate that Cantonese-speaking children acquire PFC prior to OFE.

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26. Xing J, Wei R, Wang H, Hua Z, Tang X, Yi L, Li X, Liu J. Symptoms of ADHD and Autism Spectrum Disorder Interactively Predict Children’s Verbal Fluency. J Atten Disord;2024 (Feb 14):10870547241232081.

OBJECTIVE: Verbal fluency, the capacity to generate words from a designated category, predicts myriad cognitive and life outcomes. The study investigated verbal fluency in children with ADHD, autism spectrum disorder (ASD), and comorbid ADHD and ASD, to understand how ADHD- and ASD-related symptoms individually and jointly predict verbal fluency, and the underlying linguistic and cognitive substrates. METHOD: Thirty-three school-aged children with ADHD, 27 with ASD, 25 with comorbid ADHD and ASD, and 39 with typical development, were assessed for ADHD and ASD symptoms and completed a semantic verbal fluency task. RESULTS: Findings indicated that ADHD and ASD symptoms, especially ADHD hyperactivity-impulsivity symptoms and language-related ASD symptoms, interactively predicted verbal fluency across diagnostic groups. CONCLUSION: The study implicated the potential cognitive and linguistic mechanisms underlying verbal fluency differences in ADHD and/or ASD, and clinical practices on enhancing verbal fluency in these clinical groups.

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27. Zarate-Lopez D, Garzón-Partida AP, Gonzalez-Perez O, Gálvez-Contreras AY. Sex differences in autism-like behavior and dopaminergic neurons in substantia nigra of juvenile mice prenatally exposed to valproate. Dev Psychobiol;2024 (Feb);66(2):e22469.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication and repetitive and restricted behaviors. Sex dimorphism in the brain, including midbrain dopaminergic circuits, can explain differences in social behavior impairment and stereotypic behaviors between male and female individuals with ASD. These abnormal patterns may be due to alterations in dopamine synthesis in the ventral tegmental area (VTA) and substantia nigra (SN). We used an autism-like mouse model by prenatal valproic acid (VPA) exposure. CD1 pregnant female mice were injected with 500 mg/kg VPA or 0.9% NaCl as a vehicle on gestational day 12.5. In the offspring, on postnatal day 31, we examined the social and repetitive behaviors and the number of tyrosine hydroxylase (TH)-positive cells in VTA and SN by sex. Male VPA mice showed impaired social behavior and increased repetitive behaviors when compared to male vehicles. In females, we did not find statistically significant differences in social or repetitive behaviors between the groups. Male VPA mice had fewer TH(+) cells in the SN than control-vehicle mice. Interestingly, no cellular changes were observed between females. This study supports the notion that sex dimorphism of certain brain regions is involved in the etiopathogenesis and clinical presentation of ASD.

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28. Zhan L, Gao Y, Huang L, Zhang H, Huang G, Wang Y, Sun J, Xie Z, Li M, Jia X, Cheng L, Yu Y. Brain functional connectivity alterations of Wernicke’s area in individuals with autism spectrum conditions in multi-frequency bands: A mega-analysis. Heliyon;2024 (Feb 29);10(4):e26198.

Characterized by severe deficits in communication, most individuals with autism spectrum conditions (ASC) experience significant language dysfunctions, thereby impacting their overall quality of life. Wernicke’s area, a classical and traditional brain region associated with language processing, plays a substantial role in the manifestation of language impairments. The current study carried out a mega-analysis to attain a comprehensive understanding of the neural mechanisms underpinning ASC, particularly in the context of language processing. The study employed the Autism Brain Image Data Exchange (ABIDE) dataset, which encompasses data from 443 typically developing (TD) individuals and 362 individuals with ASC. The objective was to detect abnormal functional connectivity (FC) between Wernicke’s area and other language-related functional regions, and identify frequency-specific altered FC using Wernicke’s area as the seed region in ASC. The findings revealed that increased FC in individuals with ASC has frequency-specific characteristics. Further, in the conventional frequency band (0.01-0.08 Hz), individuals with ASC exhibited increased FC between Wernicke’s area and the right thalamus compared with TD individuals. In the slow-5 frequency band (0.01-0.027 Hz), increased FC values were observed in the left cerebellum Crus II and the right lenticular nucleus, pallidum. These results provide novel insights into the potential neural mechanisms underlying communication deficits in ASC from the perspective of language impairments.

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29. Zhang X, Gao Y, Zhang Y, Li F, Li H, Lei F. Identification of Autism Spectrum Disorder Using Topological Data Analysis. J Imaging Inform Med;2024 (Feb 13)

Autism spectrum disorder (ASD) is a pervasive brain development disease. Recently, the incidence rate of ASD has increased year by year and posed a great threat to the lives and families of individuals with ASD. Therefore, the study of ASD has become very important. A suitable feature representation that preserves the data intrinsic information and also reduces data complexity is very vital to the performance of established models. Topological data analysis (TDA) is an emerging and powerful mathematical tool for characterizing shapes and describing intrinsic information in complex data. In TDA, persistence barcodes or diagrams are usually regarded as visual representations of topological features of data. In this paper, the Regional Homogeneity (ReHo) data of subjects obtained from Autism Brain Imaging Data Exchange (ABIDE) database were used to extract features by using TDA. The average accuracy of cross validation on ABIDE I database was 95.6% that was higher than any other existing methods (the highest accuracy among existing methods was 93.59%). The average accuracy for sampling with the same resolutions with the ABIDE I on the ABIDE II database was 96.5% that was also higher than any other existing methods (the highest accuracy among existing methods was 75.17%).

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