1. Arora A, Becker M, Marques C, Oksanen M, Li D, Mastropasqua F, Watts ME, Arora M, Falk A, Daub CO, Lanekoff I, Tammimies K. Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Scientific reports. 2023; 13(1): 10519.

Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.

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2. Duncan A, Risley S, Combs A, Lacey HM, Hamik E, Fershtman C, Kneeskern E, Patel M, Crosby L, Hood AM, Zoromski AK, Tamm L. School Challenges and Services Related to Executive Functioning for Fully Included Middle Schoolers with Autism. Focus Autism Other Dev Disabl. 2023; 38(2): 90-100.

The educational services available for fully included middle schoolers with autism spectrum disorder (ASD) in the general education setting are not well known. Even less is known about how the executive functioning (EF) deficits of such youth are addressed in the classroom. The current study sought to identify the challenges, including EF, that middle schoolers with ASD face and the services that they receive on their Individualized Education Program (IEP), and also explore specific strategies used to build EF skills at school. A convenience data sample was obtained from focus groups with educational personnel (n = 15), and qualitative analyses of IEPs were conducted in middle schoolers with ASD with EF deficits (n = 23). Results confirmed that social communication and EF challenges are common. Multiple services and accommodations were identified, although EF challenges were rarely targeted on IEPs. Factors that may facilitate the success of EF strategies in the classroom are discussed.

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3. Evenepoel M, Moerkerke M, Daniels N, Chubar V, Claes S, Turner J, Vanaudenaerde B, Willems L, Verhaeghe J, Prinsen J, Steyaert J, Boets B, Alaerts K. Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation. Translational psychiatry. 2023; 13(1): 235.

Alterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

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4. Fleet BG, Elliott A, Orwin M, Spencer M, Sedda L. Autism trends in a medium size coastal town of England. PloS one. 2023; 18(6): e0287808.

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental conditions which affects just under 1% of the global population. This study aims to investigate the trends in ASD diagnoses in a typical English deprived coastal community over the last two decades. ASD information for patients registered at Fleetwood GP practices were provided for the period between July 1952 to March 2022. The incidence and prevalence were calculated and Poisson regression modelling was employed to estimate the effects of age and sex on the number of ASD diagnoses over time. The study shows that there has been an upward trend in the number of ASD diagnoses over the past two decades. Model’s results showed that sex differences in ASD diagnoses are less pronounced when accounting for time trends. The study findings show that Fleetwood has experienced a similar rise in ASD cases as the rest of the UK, most likely due to increased awareness that may explain the time effects over gender differences. However, due to the small sample size of the study, confirmation of the gender results and identification of the factors determining the temporal trends are needed in order to determine the gender effects in ASD diagnosis.

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5. International BR. Retracted: Early Detection of Autism Spectrum Disorders (ASD) with the Help of Data Mining Tools. BioMed research international. 2023; 2023: 9819043.

[This retracts the article DOI: 10.1155/2022/1201129.].

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6. Irwin J, Harwood V, Kleinman D, Baron A, Avery T, Turcios J, Landi N. Neural and Behavioral Differences in Speech Perception for Children With Autism Spectrum Disorders Within an Audiovisual Context. Journal of speech, language, and hearing research : JSLHR. 2023: 1-14.

PURPOSE: Reduced use of visible articulatory information on a speaker’s face has been implicated as a possible contributor to language deficits in autism spectrum disorders (ASD). We employ an audiovisual (AV) phonemic restoration paradigm to measure behavioral performance (button press) and event-related potentials (ERPs) of visual speech perception in children with ASD and their neurotypical peers to assess potential neural substrates that contribute to group differences. METHOD: Two sets of speech stimuli, /ba/-« /a/ » (« /a/ » was created from the /ba/ token by a reducing the initial consonant) and /ba/-/pa/, were presented within an auditory oddball paradigm to children aged 6-13 years with ASD (n = 17) and typical development (TD; n = 33) within two conditions. The AV condition contained a fully visible speaking face; the pixelated (PX) condition included a face, but the mouth and jaw were PX, removing all articulatory information. When articulatory features were present for the /ba/-« /a/ » contrast, it was expected that the influence of the visual articulators would facilitate a phonemic restoration effect in which « /a/ » would be perceived as /ba/. ERPs were recorded during the experiment while children were required to press a button for the deviant sound for both sets of speech contrasts within both conditions. RESULTS: Button press data revealed that TD children were more accurate in discriminating between /ba/-« /a/ » and /ba/-/pa/ contrasts in the PX condition relative to the ASD group. ERPs in response to the /ba/-/pa/ contrast within both AV and PX conditions differed between children with ASD and TD children (earlier P300 responses for children with ASD). CONCLUSION: Children with ASD differ in the underlying neural mechanisms responsible for speech processing compared with TD peers within an AV context.

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7. Kareklas K, Teles MC, Dreosti E, Oliveira RF. Autism-associated gene shank3 is necessary for social contagion in zebrafish. Molecular autism. 2023; 14(1): 23.

BACKGROUND: Animal models enable targeting autism-associated genes, such as the shank3 gene, to assess their impact on behavioural phenotypes. However, this is often limited to simple behaviours relevant for social interaction. Social contagion is a complex phenotype forming the basis of human empathic behaviour and involves attention to the behaviour of others for recognizing and sharing their emotional or affective state. Thus, it is a form of social communication, which constitutes the most common developmental impairment across autism spectrum disorders (ASD). METHODS: Here we describe the development of a zebrafish model that identifies the neurocognitive mechanisms by which shank3 mutation drives deficits in social contagion. We used a CRISPR-Cas9 technique to generate mutations to the shank3a gene, a zebrafish paralogue found to present greater orthology and functional conservation relative to the human gene. Mutants were first compared to wild types during a two-phase protocol that involves the observation of two conflicting states, distress and neutral, and the later recall and discrimination of others when no longer presenting such differences. Then, the whole-brain expression of different neuroplasticity markers was compared between genotypes and their contribution to cluster-specific phenotypic variation was assessed. RESULTS: The shank3 mutation markedly reduced social contagion via deficits in attention contributing to difficulties in recognising affective states. Also, the mutation changed the expression of neuronal plasticity genes. However, only downregulated neuroligins clustered with shank3a expression under a combined synaptogenesis component that contributed specifically to variation in attention. LIMITATIONS: While zebrafish are extremely useful in identifying the role of shank3 mutations to composite social behaviour, they are unlikely to represent the full complexity of socio-cognitive and communication deficits presented by human ASD pathology. Moreover, zebrafish cannot represent the scaling up of these deficits to higher-order empathic and prosocial phenotypes seen in humans. CONCLUSIONS: We demonstrate a causal link between the zebrafish orthologue of an ASD-associated gene and the attentional control of affect recognition and consequent social contagion. This models autistic affect-communication pathology in zebrafish and reveals a genetic attention-deficit mechanism, addressing the ongoing debate for such mechanisms accounting for emotion recognition difficulties in autistic individuals.

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8. Mayes SD, Waschbusch DA, Fernandez-Mendoza J, Calhoun SL. Cognitive Disengagement Syndrome (CDS) (Formerly Sluggish Cognitive Tempo), Autism, and Insomnia Symptoms in Childhood Predict CDS in Adolescence: A Longitudinal Population-Based Study. Child psychiatry and human development. 2023.

Our study is the first using multiple variables to compare concurrent with longitudinal predictors of cognitive disengagement syndrome (CDS). The population-based sample comprised 376 youth (mean baseline age 8.7 and follow-up 16.4 years) rated by parents on the Pediatric Behavior Scale. The baseline CDS score was the strongest predictor of follow-up CDS. Baseline autism and insomnia symptoms also predicted follow-up CDS above and beyond baseline CDS. Autism, insomnia, inattention, somatic complaints, and excessive sleep were concurrently related to CDS at baseline and follow-up. Additionally, follow-up depression was associated with follow-up CDS, and baseline hyperactivity/impulsivity was negatively associated with baseline CDS. Oppositional defiant/conduct problems and anxiety were nonsignificant. Age, sex, race, and parent occupation were unrelated to CDS, and correlations between baseline CDS and 15 IQ, achievement, and neuropsychological test scores were nonsignificant. Results indicate childhood CDS is the strongest risk factor for adolescent CDS, followed by autism and insomnia symptoms.

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9. Rakshe C, Kunneth S, Sundaram S, Agastinose Ronickom JF. Diagnostic Classification of ASD Using Fractal Functional Connectivity of fMRI and Logistic Regression. Studies in health technology and informatics. 2023; 305: 60-3.

Our study used functional magnetic resonance imaging and fractal functional connectivity (FC) methods to analyze the brain networks of Autism Spectrum Disorder (ASD) and typically developing participants using data available on ABIDE databases. Blood-Oxygen-Level-Dependent time series were extracted from 236 regions of interest of cortical, subcortical, and cerebellar regions using Gordon’s, Harvard Oxford, and Diedrichsen atlases respectively. We computed the fractal FC matrices which resulted in 27,730 features, ranked using XGBoost feature ranking. Logistic regression classifiers were used to analyze the performance of the top 0.1%, 0.3%, 0.5%, 0.7%, 1%, 2%, and 3% of FC metrics. Results showed that 0.5% percentile features performed better, with average 5-fold accuracy of 94%. The study identified significant contributions from dorsal attention (14.75%), cingulo-opercular task control (14.39%), and visual networks (12.59%). This study could be used as an essential brain FC method to diagnose ASD.

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10. Ratnaik R, Rakshe C, Kumar M, Agastinose Ronickom JF. Diagnostic Classification of ASD Improves with Structural Connectivity of DTI and Logistic Regression. Studies in health technology and informatics. 2023; 305: 64-7.

In this study, we examined the structural connectivity (SC) of autism spectrum disorder (ASD) and typical development using the distance correlation and machine learning algorithm. We preprocessed diffusion tensor images using a standard pipeline and parcellated the brain into 48 regions using atlas. We derived diffusion measures in white matter tracts, such as fractional anisotropy, radial diffusivity, axial diffusivity, mean diffusivity, and mode of anisotropy. Additionally, SC is determined by the Euclidean distance between these features. The SC were ranked using XGBoost and significant features were fed as the input to the logistic regression classifier. We obtained an average 10-fold cross-validation classification accuracy of 81% for the top 20 features. The SC computed from the anterior limb of internal capsule L to superior corona radiata R regions significantly contributed to the classification models. Our study shows the potential utility of adopting SC changes as the biomarker for the diagnosis of ASD.

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11. Villar de Araujo T, Rüesch A, Bankwitz A, Rufer M, Kleim B, Olbrich S. Autism spectrum disorders in adults and the autonomic nervous system: Heart rate variability markers in the diagnostic procedure. Journal of psychiatric research. 2023; 164: 235-42.

The diagnostic assessment of autism spectrum disorders (ASD) in adults is a challenging and time-consuming procedure. In order to address the lack of specialised health-care professionals and improve the waiting time, we aimed to identify specific electrocardiogram (ECG) derived Heart Rate Variability (HRV) parameters that could be used for diagnostic purposes. 152 patients were diagnosed based on a standardised clinical procedure and assigned to one of three groups: ASD (n = 56), any other psychiatric disorder (OD) (n = 72), and patients with no diagnosis (ND) (n = 24). Groups were compared using ANOVA. Discriminative power of biological parameters and the clinical assessment were compared using receiver operating characteristic curves (ROCs). Patients with ASD showed reduced parasympathetic and increased sympathetic activity compared to ND. The accuracy determined by the area under the curve (AUC) of the biological parameters for discrimination between ASD vs. pooled OD/ND was 0.736 (95% CI = 0.652-0.820), compared to .856 (95% CI = 0.795-0.917) for the extensive clinical assessment. Our results confirmed the dysregulation of the autonomic nervous system in ASD with reduced parasympathetic and increased sympathetic activity as compared to ND. The discriminative power of biological markers including HRV was considerable and could supplement less sophisticated clinical assessments.

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12. Wroten M, Yoon S, Andrews P, Yamrom B, Ronemus M, Buja A, Krieger AM, Levy D, Ye K, Wigler M, Iossifov I. Sharing parental genomes by siblings concordant or discordant for autism. Cell genomics. 2023; 3(6): 100319.

Studying thousands of families, we find siblings concordant for autism share more of their parental genomes than expected by chance, and discordant siblings share less, consistent with a role of transmission in autism incidence. The excess sharing of the father is highly significant (p value of 0.0014), with less significance for the mother (p value of 0.31). To compare parental sharing, we adjust for differences in meiotic recombination to obtain a p value of 0.15 that they are shared equally. These observations are contrary to certain models in which the mother carries a greater load than the father. Nevertheless, we present models in which greater sharing of the father is observed even though the mother carries a greater load. More generally, our observations of sharing establish quantitative constraints that any complete genetic model of autism must satisfy, and our methods may be applicable to other complex disorders.

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13. Xing L, Simon JM, Ptacek TS, Yi JJ, Loo L, Mao H, Wolter JM, McCoy ES, Paranjape SR, Taylor-Blake B, Zylka MJ. Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice. Cell reports. 2023; 42(7): 112706.

The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent of origin. Here, we engineered a mouse line that harbors an autism-linked UBE3A(T485A) (T503A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We find that paternally and maternally expressed UBE3A(T503A) results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3A(T503A) from the maternal allele, but not the paternal one, leads to a persistent elevation of UBE3A activity in neurons. Mutant mice display behavioral phenotypes that differ by parent of origin. Expression of UBE3A(T503A), irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3a(T503A) mice are distinct from Angelman syndrome model mice. Our study has clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.

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