1. Adams D, Dargue N, Paynter J. Longitudinal studies of challenging behaviours in autistic children and adults: A systematic review and meta-analysis. Clin Psychol Rev;2023 (Aug);104:102320.

Autistic children and adults are at increased risk of showing behaviours that may be described as challenging, however, little is known about whether or how these behaviours may change over time. Given the profound impact that challenging behaviour can have on both the autistic individual and their support network, it is critical that the trajectory of challenging behaviours be better understood. This systematic review and meta-analysis identified and synthesised observational longitudinal studies of challenging behaviour in autistic individuals. Fifty-six studies were included in the systematic review, and the effect sizes of 37 independent samples arising from 34 of these reports were examined through meta-analysis. Crucially, across the 37 samples, scores on the measures of challenging behaviour reduced by a small, yet significant, extent over time. Although age of the sample at baseline assessment did not moderate the effect, the time between the baseline assessment and final follow-up and age at final follow-up both moderated the magnitude of the effect, with challenging behaviour scores reducing to a larger extent in (a) studies with longer intervals between baseline and final follow-up and (b) studies with older samples at follow-up. The results from the current systematic review and meta-analysis have both theoretical and practical implications for understanding challenging behaviour over time in autistic individuals. Avenues for future research are also highlighted that may allow better understanding, and therefore support of, challenging behaviour in autistic individuals.

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2. Croom K, Rumschlag JA, Erickson MA, Binder DK, Razak KA. Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome. J Neurodev Disord;2023 (Jul 29);15(1):23.

BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

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3. Davis R, Zaki FBM, Sargent L. Autism and bilingualism: A thematic analysis of practitioner perspectives in the United Kingdom. Int J Lang Commun Disord;2023 (Jul 30)

BACKGROUND: At least 25% of autistic children worldwide have the potential to grow up in a bilingual environment. However, many autistic children are being denied opportunities to access additional languages and the cultural, familial and community connections that come with this. There is little evidence identifying the barriers to language learning and access, and no research addressing the perspectives of speech and language therapists (SLTs), who are crucial in supporting parents to make informed choices about bilingualism with their child. AIMS: The aim of this research was to understand the experiences of SLTs working with autistic bilingual children, to understand the main considerations when working with families, and the opportunities and barriers for training, including the sources of information that current practice is based on. METHODS AND PROCEDURES: Twelve SLTs from across the United Kingdom were recruited for this study. All participants were experienced in working with autistic bilingual children and their families (M = 7 years, range 4-23 years). Semi-structured interviews were conducted and focused on the experiences of SLTs regarding familial bilingual experiences, the effect of sociocultural factors of practice, and the extent to which practice is based on current research. OUTCOMES AND RESULTS: Data were analysed using reflexive thematic analysis. Three central themes were identified from the interviews: (1) participants discussed parental uncertainties as to whether they were doing the right thing for their child, (2) while participants were in support of bilingualism, they were not always confident that they were providing the right advice and found it difficult to in keep up to date with relevant, evidence-based research, and (3) participants highlighted a need to shift towards a more inclusive and culturally diverse practice. CONCLUSIONS AND IMPLICATIONS: This is the first qualitative study to understand the perspectives of SLTs working with autistic bilingual children. We identify several key difficulties in supporting access to language learning, and these findings have immediate and longer-term implications for supporting SLTs, and in turn, the children and families they support. WHAT THIS PAPER ADDS: What is already known on the subject Research suggests that autistic children currently have fewer opportunities to maintain bilingualism compared to neurotypical peers. Despite the lack of evidence, many families remain concerned that bilingualism will have a negative impact on their child’s development. To date, little is known about the perspectives of speech and language therapists (SLTs) who play a significant role in supporting the development of autistic bilingual children. This is the first study to provide an in-depth qualitative analysis of the experiences of SLTs working with autistic bilingual children and their families in the United Kingdom. What this study adds The results highlight a number of reoccurring barriers in providing optimal support: first, frequently cited concerns about bilingualism from parents that link to a lack of understanding about autism and the role of SLTs more generally. Second, SLTs do not have confidence in the assessments and tools available and described a lack of emphasis on cultural factors in practice. Many SLTs were concerned about the limited options for resources and interventions available in other languages, which could be challenging for parents who were less proficient or confident communicating in English. Third, SLTs reported having limited opportunities to keep up to date with relevant research to support their decision-making processes. What are the clinical implications of this work? These results have several important implications for practice-they highlight the need for more inclusive practices where possible, a need for more diversity within the profession and further opportunities to be provided with evidence-based advice around good practice. The results also suggest a benefit of providing accessible, evidence-based resources for parents about autism and bilingualism, to ensure that research key findings are reaching families.

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4. Huettig F, Voeten CC, Pascual E, Liang J, Hintz F. Do autistic children differ in language-mediated prediction?. Cognition;2023 (Oct);239:105571.

Prediction appears to be an important characteristic of the human mind. It has also been suggested that prediction is a core difference of autistic(1) children. Past research exploring language-mediated anticipatory eye movements in autistic children, however, has been somewhat contradictory, with some studies finding normal anticipatory processing in autistic children with low levels of autistic traits but others observing weaker prediction effects in autistic children with less receptive language skills. Here we investigated language-mediated anticipatory eye movements in young children who differed in the severity of their level of autistic traits and were in professional institutional care in Hangzhou, China. We chose the same spoken sentences (translated into Mandarin Chinese) and visual stimuli as a previous study which observed robust prediction effects in young children (Mani & Huettig, 2012) and included a control group of typically-developing children. Typically developing but not autistic children showed robust prediction effects. Most interestingly, autistic children with lower communication, motor, and (adaptive) behavior scores exhibited both less predictive and non-predictive visual attention behavior. Our results raise the possibility that differences in language-mediated anticipatory eye movements in autistic children with higher levels of autistic traits may be differences in visual attention in disguise, a hypothesis that needs further investigation.

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5. Marinho LSR, Chiarantin GMD, Ikebara JM, Cardoso DS, de Lima-Vasconcellos TH, Higa GSV, Ferraz MSA, De Pasquale R, Takada SH, Papes F, Muotri AR, Kihara AH. The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools. Semin Cell Dev Biol;2023 (Jul 30);144:67-76.

The use of antidepressants during pregnancy benefits the mother’s well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids – self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.

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6. Melillo R, Leisman G, Machado C, Machado-Ferrer Y, Chinchilla-Acosta M, Melillo T, Carmeli E. The Relationship between Retained Primitive Reflexes and Hemispheric Connectivity in Autism Spectrum Disorders. Brain Sci;2023 (Jul 30);13(8)

BACKGROUND: Autism Spectrum Disorder (ASD) can be identified by a general tendency toward a reduction in the expression of low-band, widely dispersed integrative activities, which is made up for by an increase in localized, high-frequency, regionally dispersed activity. The study assessed ASD children and adults all possessing retained primitive reflexes (RPRs) compared with a control group that did not attempt to reduce or remove those RPRs and then examined the effects on qEEG and brain network connectivity. METHODS: Analysis of qEEG spectral and functional connectivity was performed, to identify associations with the presence or absence of retained primitive reflexes (RPRs), before and after an intervention based on TENS unilateral stimulation. RESULTS: The results point to abnormal lateralization in ASD, including long-range underconnectivity, a greater left-over-right qEEG functional connectivity ratio, and short-range overconnectivity in ASD. CONCLUSIONS: Clinical improvement and the absence of RPRs may be linked to variations in qEEG frequency bands and more optimized brain networks, resulting in more developmentally appropriate long-range connectivity links, primarily in the right hemisphere.

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7. Qiang N, Gao J, Dong Q, Li J, Zhang S, Liang H, Sun Y, Ge B, Liu Z, Wu Z, Liu T, Yue H, Zhao S. A deep learning method for autism spectrum disorder identification based on interactions of hierarchical brain networks. Behav Brain Res;2023 (Aug 24);452:114603.

BACKGROUND: It has been recently shown that deep learning models exhibited remarkable performance of representing functional Magnetic Resonance Imaging (fMRI) data for the understanding of brain functional activities. With hierarchical structure, deep learning models can infer hierarchical functional brain networks (FBN) from fMRI. However, the applications of the hierarchical FBNs have been rarely studied. METHODS: In this work, we proposed a hierarchical recurrent variational auto-encoder (HRVAE) to unsupervisedly model the fMRI data. The trained HRVAE encoder can predict hierarchical temporal features from its three hidden layers, and thus can be regarded as a hierarchical feature extractor. Then LASSO (least absolute shrinkage and selection operator) regression was applied to estimate the corresponding hierarchical FBNs. Based on the hierarchical FBNs from each subject, we constructed a novel classification framework for brain disorder identification and test it on the Autism Brain Imaging Data Exchange (ABIDE) dataset, a world-wide multi-site database of autism spectrum disorder (ASD). We analyzed the hierarchy organization of FBNs, and finally used the overlaps of hierarchical FBNs as features to differentiate ASD from typically developing controls (TDC). RESULTS: The experimental results on 871 subjects from ABIDE dataset showed that the HRVAE model can effectively derive hierarchical FBNs including many well-known resting state networks (RSN). Moreover, the classification result improved the state-of-the-art by achieving a very high accuracy of 82.1 %. CONCLUSIONS: This work presents a novel data-driven deep learning method using fMRI data for ASD identification, which could provide valuable reference for clinical diagnosis. The classification results suggest that the interactions of hierarchical FBNs have association with brain disorder, which promotes the understanding of FBN hierarchy and could be applied to other brain disorder analysis.

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8. Talvio K, Wagner VA, Minkeviciene R, Kirkwood JS, Kulinich AO, Umemori J, Bhatia A, Hur M, Käkelä R, Ethell IM, Castrén ML. An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis. Commun Biol;2023 (Jul 29);6(1):789.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.

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9. Zeitouny C, Korte M, Michaelsen-Preusse K. Prolonged and specific spatial training during adolescence reverses adult hippocampal network impairments in a mouse model of fragile X syndrome. Neurobiol Dis;2023 (Jul 27);185:106240.

The fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism. A hallmark of FXS in patients and the FXS mouse model (Fmr1 KO) is an overabundance of immature appearing dendritic spines in the cortex and hippocampus which is associated with behavioral deficits. Spine analysis in the different hippocampal subregions and at different developmental stages revealed that in adult mice, hippocampal spine pathology occurs specifically in the CA3 subregion, which plays a pivotal role in pattern completion processes important for efficient memory recall from parts of the initial memory stimulus. In line with this synaptic defect we document an impairment in memory recall during partially cued reference memory test in the Morris water maze task. This is accompanied by impaired recruitment of engram cells as well as impaired spine structural plasticity in the CA3 region. In order to promote hippocampal network development adolescent mice were either raised in an enriched environment or subjected to specific hippocampus-dependent spatial training. Intriguingly, only specific spatial training alleviated the cognitive symptoms and the spine phenotype shown in adult Fmr1 KO mice suggesting that specific stimulation of hippocampal networks during development might be used in the future as a therapeutic strategy.

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