1. Brian J, Solish A, Dowds E, Roth I, Bernardi K, Perry K, Daoud S, Jilderda S, MacWilliam S, Smith IM, Zwaigenbaum L, Bryson S. Correction to: « Going Mobile »-increasing the reach of parent-mediated intervention for toddlers with ASD via group-based and virtual delivery. J Autism Dev Disord;2022 (Jul 25)

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2. Coorey B, Haase F, Ellaway C, Clarke A, Lisowski L, Gold WA. Gene Editing and Rett Syndrome: Does It Make the Cut?. CRISPR J;2022 (Jul 26)

Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 (MECP2) gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of MECP2 expression, where loss of expression leads to RTT and overexpression leads to MECP2 duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of MECP2 in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT.

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3. Davis CP, Eigsti IM, Healy R, Joergensen GH, Yee E. Autism-spectrum traits in neurotypicals predict the embodiment of manipulation knowledge about object concepts: Evidence from eyetracking. PLoS One;2022;17(7):e0268069.

Sensorimotor-based theories of cognition predict that even subtle developmental motor differences, such as those characterizing autism spectrum disorder (ASD), impact how we represent the meaning of manipulable objects (e.g., faucet). Here, we test 85 neurotypical participants, who varied widely on the Adult Autism Spectrum Quotient (AQ), a measure intended to capture variability in ASD characteristics in the general adult population (participant scores were all below the clinical threshold for autism). Participants completed a visual world eyetracking task designed to assess the activation of conceptual representations of manipulable objects. Participants heard words referring to manually manipulable objects (e.g., faucet) while we recorded their eye movements to arrays of four objects: the named object, a related object typically manipulated similarly (e.g., jar), and two unrelated objects. Consistent with prior work, we observed more looks to the related object than to the unrelated ones (i.e., a manipulation-relatedness effect). This effect likely reflects the overlapping conceptual representations of objects sharing manipulation characteristics (e.g., faucet and jar), due to embodied sensorimotor properties being part of their representations. Critically, we observed-among typically developed young adults-that as AQ scores increased, manipulation-relatedness effects decreased. In contrast, in a visual control condition, in which a target object was paired with related objects of a similar shape (e.g., snake and rope), relatedness effects increased with AQ scores. The results show that AQ scores can predict variation in how object-concept representations are activated for typically developed individuals. More speculatively, they are consistent with the hypothesis that in individuals with ASD, differences in object-concept representations emerge at least in part via differences in sensorimotor experience.

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4. Esnafoglu E, Subaşı B. Association of low 25-OH-vitamin D levels and peripheral inflammatory markers in patients with autism spectrum disorder: Vitamin D and inflammation in Autism. Psychiatry Res;2022 (Jul 20);316:114735.

Inflammatory mechanisms and Vitamin D are reported to play important roles in the pathophysiology of Autism Spectrum Disorders (ASD). There are ample evidences that vitamin D has an anti-inflammatory effect. In this study, we aimed, for the first time, to investigate the 25-OH-vitamin D with inflammation markers in ASD patients. The study included 154 patients with ASD and 98 healthy subjects. 25-OH-Vitamin D levels and simple peripheral inflammatory markers such as Neutrophil-Lymphocyte ratio (NLR), C-reactive protein (CRP) and, sedimentation were measured in all subjects. K-SADS-PL-DSM 5 were administered to all subjects to evaluate the psychiatric diagnosis. Childhood Autism Rating Scale was used to asses severity of autism. In the patient group, high CRP rate, leukocyte, neutrophil and NLR were significantly high compared to the healthy control group. 25-OH-Vitamin D levels were found to be statistically significantly lower in the ASD group. While a significant negative correlation was found between 25-OH-Vitamin D and CRP, NLR, neutrophil counts in ASD patients, a positive correlation was found between lymphocyte counts. Especially in male ASD patients, the relationship between 25-OH-Vitamin D and inflammation markers was more pronounced. Our findings support the association of vitamin D and inflammation in ASD.

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5. Fan Q, Zhang X, Wang Y, Wang X. Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation. J Vis Exp;2022 (Jul 6)(185)

Fragile X mental retardation protein (FMRP) is an mRNA-binding protein that regulates local protein translation. FMRP loss or dysfunction leads to aberrant neuronal and synaptic activities in fragile X syndrome (FXS), which is characterized by intellectual disability, sensory abnormalities, and social communication problems. Studies of FMRP function and FXS pathogenesis have primarily been conducted with Fmr1 (the gene encoding FMRP) knockout in transgenic animals. Here we report an in vivo method for determining the cell-autonomous function of FMRP during the period of circuit assembly and synaptic formation using chicken embryos. This method employs stage-, site-, and direction-specific electroporation of a drug-inducible vector system containing Fmr1 small hairpin RNA (shRNA) and an EGFP reporter. With this method, we achieved selective FMRP knockdown in the auditory ganglion (AG) and in one of its brainstem targets, the nucleus magnocellularis (NM), thus providing a component-specific manipulation within the AG-NM circuit. Additionally, the mosaic pattern of the transfection allows within-animal controls and neighboring neuron/fiber comparisons for enhanced reliability and sensitivity in data analyzing. The inducible vector system provides temporal control of gene editing onset to minimize accumulating developmental effects. The combination of these strategies provides an innovative tool to dissect the cell-autonomous function of FMRP in synaptic and circuit development.

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6. Feng Y, Chen K, Zou Y, Zhou X, Liu Q, Zhong D, Deng T, Liu S, Zhang L. Posttraumatic growth and rumination among parents of children with autism spectrum disorder: The mediating role of social support. J Psychiatr Res;2022 (Jul 14);154:11-18.

Although rumination and social support are regarded as essential predictors of posttraumatic growth (PTG), few studies have explored the associations among PTG, rumination, and social support in parents of children with autism spectrum disorder (ASD). This study examined whether social support mediates the relationship between rumination and PTG. Cross-sectional questionnaire data were collected from 385 parents of children with ASD from September 2019 to November 2020 by convenience sampling. Participants completed the Posttraumatic Growth Inventory, Event Related Rumination Inventory, and Social Support Rating Scale. Path analyses showed that subjective support partially mediates the relationship between deliberate rumination and PTG (β = 0.073, P < 0.001), and indirect effects account for 15.30% of the total effects. In addition, a negative direct path was found between intrusive and PTG because of the suppression effect of subjective support (β = -0.110, P < 0.01), and indirect effects accounted for 80% of the direct effects. For future studies, it underscores the essential role of subjective support and rumination in promoting PTG in parents of children with ASD.

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7. Gómez-Marí I, Tárraga-Mínguez R, Pastor-Cerezuela G. Analysis of Spanish Parents’ Knowledge about ASD and Their Attitudes towards Inclusive Education. Eur J Investig Health Psychol Educ;2022 (Jul 21);12(7):870-881.

To make possible the inclusion of children with autism spectrum disorder (ASD) in mainstream settings, parental knowledge and attitudes towards the disorder play a key role between the home and the school setting. However, prior literature has not carried out an in-depth analysis of parents’ knowledge about ASD and their attitudes toward the inclusion of children with this diagnosis. This study examined the parental attitudes towards inclusion and knowledge about ASD. Participants were parents of children with ASD (n = 75), parents of children without ASD whose children had prior or current contact with peers with ASD (n = 44), and parents of children with no previous interactions with a peer with ASD (n = 51). The Attitudes of Regular Educators Towards Inclusion for Students with Autism Survey and the Autism Knowledge Questionnaire were filled out. Nonparametric statistical tests were used. Results showed that parents of children with ASD have better knowledge about this disorder and hold more favorable attitudes towards the inclusion of children with ASD than the other parents. These findings suggest that the benefits of inclusive schooling are limited to the school setting and do not appear to affect families of children without ASD.

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8. Hernandez-Ruiz E, Lehrer G. « Music Therapy Was Never on the Table »: Perspectives of Parents of Young Autistic Children. J Music Ther;2022 (Jul 25)

Parent coaching of music interventions is emerging as a viable model for families with young autistic children, yet recruitment difficulties have been apparent in previous studies. Understanding parent perspectives of early intervention services is critical to ensure that interventions are acceptable, feasible, and effective for all family members. In order to understand possible parental resistance to this type of parent education, we explored perspectives regarding music therapy, research, and parent coaching in parents of young autistic children. Fourteen parents attended virtual focus groups to discuss their experiences. We used a descriptive phenomenological approach to uncover the essence of their experience. Our findings indicate that, contrary to our preconceptions, participants did not show negative dispositions towards music therapy, research, or parent coaching. Instead, most participants had very little or no knowledge of music therapy services. They had limited experience with research in general, and only two participants had experienced music therapy directly. Several participants had varying amounts of experience with parent participation or parent coaching outside of music therapy and shared positive experiences with it. Parents seemed willing and eager to learn music strategies to support their children and saw value in the use of music for their child’s development. First-contact providers (i.e., early interventionists and diagnosticians) and social media seem influential in parents’ decision-making as they navigate early intervention services soon after diagnosis. Music therapy organizations are encouraged to design targeted efforts to make information on music therapy available through these sources.

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9. Kohli M, Kar AK, Bangalore A, Ap P. Machine learning-based ABA treatment recommendation and personalization for autism spectrum disorder: an exploratory study. Brain Inform;2022 (Jul 25);9(1):16.

Autism spectrum is a brain development condition that impairs an individual’s capacity to communicate socially and manifests through strict routines and obsessive-compulsive behavior. Applied behavior analysis (ABA) is the gold-standard treatment for autism spectrum disorder (ASD). However, as the number of ASD cases increases, there is a substantial shortage of licensed ABA practitioners, limiting the timely formulation, revision, and implementation of treatment plans and goals. Additionally, the subjectivity of the clinician and a lack of data-driven decision-making affect treatment quality. We address these obstacles by applying two machine learning algorithms to recommend and personalize ABA treatment goals for 29 study participants with ASD. The patient similarity and collaborative filtering methods predicted ABA treatment with an average accuracy of 81-84%, with a normalized discounted cumulative gain of 79-81% (NDCG) compared to clinician-prepared ABA treatment recommendations. Additionally, we assess the two models’ treatment efficacy (TE) by measuring the percentage of recommended treatment goals mastered by the study participants. The proposed treatment recommendation and personalization strategy are generalizable to other intervention methods in addition to ABA and for other brain disorders. This study was registered as a clinical trial on November 5, 2020 with trial registration number CTRI/2020/11/028933.

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10. Kwon H, Kim JI, Son SY, Jang YH, Kim BN, Lee HJ, Lee JM. Sparse Hierarchical Representation Learning on Functional Brain Networks for Prediction of Autism Severity Levels. Front Neurosci;2022;16:935431.

Machine learning algorithms have been widely applied in diagnostic tools for autism spectrum disorder (ASD), revealing an altered brain connectivity. However, little is known about whether an magnetic resonance imaging (MRI)-based brain network is related to the severity of ASD symptoms in a large-scale cohort. We propose a graph convolution neural network-based framework that can generate sparse hierarchical graph representations for functional brain connectivity. Instead of assigning initial features for each node, we utilized a feature extractor to derive node features and the extracted representations can be fed to a hierarchical graph self-attention framework to effectively represent the entire graph. By incorporating connectivity embeddings in the feature extractor, we propose adjacency embedding networks to characterize the heterogeneous representations of the brain connectivity. Our proposed model variants outperform the benchmarking model with different configurations of adjacency embedding networks and types of functional connectivity matrices. Using this approach with the best configuration (SHEN atlas for node definition, Tikhonov correlation for connectivity estimation, and identity-adjacency embedding), we were able to predict individual ASD severity levels with a meaningful accuracy: the mean absolute error (MAE) and correlation between predicted and observed ASD severity scores resulted in 0.96, and r = 0.61 (P < 0.0001), respectively. To obtain a better understanding on how to generate better representations, we investigate the relationships between the extracted feature embeddings and the graph theory-based nodal measurements using canonical correlation analysis. Finally, we visualized the model to identify the most contributive functional connections for predicting ASD severity scores.

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11. Lin PI, Masi A, Moni MA, Kummerfeld S, Eapen V. Genetic Pathways Associated With Sleep Problems in Children With Autism Spectrum Disorder. Front Psychiatry;2022;13:904091.

AIMS: Children on the autism spectrum are more likely to have sleep problems than non-autistic children. Sleep disturbance may exacerbate emotional and behavioral problems of children on the autism spectrum. A better understanding of the biological mechanisms underlying sleep disturbance provide clues to better management for this co-morbid condition in autism. The goal of the current study is to identify genetic variants associated with sleep disturbance and melatonin levels in autistic children. METHODS: A total of 969 children on the autism spectrum were genotyped using the Global Screening Array v1 or Global Screening Array v2. Sleep problems were assessed using the Children’s Sleep Habits Questionnaire (CSHQ). Melatonin levels were measured using the urine samples of 219 probands. The relationship between the melatonin level and CSHQ score was examined using the general linear model. The genetic variants associated with the CSHQ score and melatonin level as two separate quantitative traits were determined using genomewide association studies. RESULTS: The data indicates that urine melatonin levels were positively associated with CSHQ scores, suggesting that autistic children with a poorer sleep qualiy could has higher melatonin level. Furthermore, genetic assocication studies suggest that genetic pathways involved in pro-inflammatory responses might be involved in sleep disturbance, while genetic pathways involved in catecholamine-secreting PC12 cells and Schwann cells could be associated with melatonin levels. CONCLUSIONS: Taken together, our findings indicate that sleep disturbance and melatonin metabolism could be attributable to distinct biological mechanisms in autistic children since they might not share genetic contributors.

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12. Liu G, Yu Q, Tan B, Ke X, Zhang C, Li H, Zhang T, Lu Y. Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome. Gut Microbes;2022 (Jan-Dec);14(1):2104089.

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

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13. Melillo R, Leisman G, Machado C, Machado-Ferrer Y, Chinchilla-Acosta M, Kamgang S, Melillo T, Carmeli E. Retained Primitive Reflexes and Potential for Intervention in Autistic Spectrum Disorders. Front Neurol;2022;13:922322.

We provide evidence to support the contention that many aspects of Autistic Spectrum Disorder (ASD) are related to interregional brain functional disconnectivity associated with maturational delays in the development of brain networks. We think a delay in brain maturation in some networks may result in an increase in cortical maturation and development in other networks, leading to a developmental asynchrony and an unevenness of functional skills and symptoms. The paper supports the close relationship between retained primitive reflexes and cognitive and motor function in general and in ASD in particular provided to indicate that the inhibition of RPRs can effect positive change in ASD.

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14. Noppari T, Sun L, Lukkarinen L, Putkinen V, Tani P, Lindberg N, Saure E, Lauerma H, Tiihonen J, Venetjoki N, Salomaa M, Rautio P, Hirvonen J, Salmi J, Nummenmaa L. Brain structural alterations in autism and criminal psychopathy. Neuroimage Clin;2022 (Jul 13);35:103116.

The goal of this study was to elucidate the anatomical brain basis of social cognition through two disorders with distinctively different phenotypes of social interaction. We compared structural MR images of 20 individuals with autism spectrum disorder (ASD), 19 violent offenders with high psychopathic traits, and 19 control participants using voxel-based morphometry (VBM). Our earlier study showed lower grey matter volume (GMV) values in the insula, frontal cortex, and sensorimotor cortex of the offender group compared to controls. In the present study, the images of the ASD group revealed lower GMV in the left precuneus, right cerebellum, and right precentral gyrus in comparison with controls. The comparison between the offender and ASD groups showed lower GMV values for the right temporal pole and left inferior frontal gyrus in the offender group. There was also an overlap of both disorders in the right pre-central cortex, showing lower GMV compared to controls. Our findings suggest structural differences between violent offenders with high psychopathy traits and ASD individuals in the frontotemporal social brain network areas, previously associated with empathy. We also provide evidence of similar abnormal structures in the motor cortex for both of these disorders, possibly related to uniting issues of social cognition.

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15. Panzenhagen AC, Cavalcanti A, Stein DJ, de Castro LL, Vasconcelos M, Abreu MB, Almeida RF, Bertoglio LJ, Herrmann AP. Behavioral manifestations in rodent models of autism spectrum disorder: protocol for a systematic review and network meta-analysis. Syst Rev;2022 (Jul 26);11(1):150.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with severe social communication, interaction, and sensory processing impairments. Efforts to understand its etiology and pathophysiology are crucial for improving treatment and prevention measures. Preclinical models of ASD are essential for investigating the biological mechanisms and should present translatability potential. We aim to evaluate the consistency of the most commonly used rodent models of ASD in displaying autistic-like behavior through a systematic review and meta-analysis. METHODS: This review will focus on the most frequently used autism models, surveying studies of six genetic (Ube3a, Pten, Nlgn3, Shank3, Mecp2, and Fmr1), three chemically induced (valproic acid (VPA), lipopolysaccharide (LPS), and polyinosinic:polycytidylic acid (poly(I:C))), and one inbred model (BTBR T+ Itpr3tf/J mouse strain). Two independent reviewers will screen the records. Data extraction of behavioral outcomes and risk of bias evaluation will be performed. We will conduct a meta-analysis whenever at least five studies investigate the same model and behavioral outcome. We will also explore the heterogeneity and publication bias. Network meta-analyses are planned to compare different models. DISCUSSION: By shortening the gap between animal behavior and human endophenotypes or specific clinical symptoms, we expect to help researchers on which rodent models are adequate for research of specific behavioral manifestations of autism, which potentially require a combination of them depending on the research interest. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021226299 .

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16. Peru A. Calendar calculating or simply memory for dates? Evidence from a young female with autistic spectrum disorder. Acta Neurol Belg;2022 (Jul 25)

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17. Raja A, Shekhar N, Singh H, Prakash A, Medhi B. In-silico discovery of dual active molecule to restore synaptic wiring against autism spectrum disorder via HDAC2 and H3R inhibition. PLoS One;2022;17(7):e0268139.

Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2’s differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico. The importance of ligand contacts with the Zn2+ ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.

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18. Rajcsanyi LS, Diebels I, Pastoors L, Kanber D, Peters T, Volckmar AL, Zheng Y, Grosse M, Dieterich C, Hebebrand J, Kaiser FJ, Horsthemke B, Hinney A. Evidence for correlations between BMI-associated SNPs and circRNAs. Sci Rep;2022 (Jul 25);12(1):12643.

Circular RNAs (circRNAs) are regulators of processes like adipogenesis. Their expression can be modulated by SNPs. We analysed links between BMI-associated SNPs and circRNAs. First, we detected an enrichment of BMI-associated SNPs on circRNA genomic loci in comparison to non-significant variants. Analysis of sex-stratified GWAS data revealed that circRNA genomic loci encompassed more genome-wide significant BMI-SNPs in females than in males. To explore whether the enrichment is restricted to BMI, we investigated nine additional GWAS studies. We showed an enrichment of trait-associated SNPs in circRNAs for four analysed phenotypes (body height, chronic kidney disease, anorexia nervosa and autism spectrum disorder). To analyse the influence of BMI-affecting SNPs on circRNA levels in vitro, we examined rs4752856 located on hsa_circ_0022025. The analysis of heterozygous individuals revealed an increased level of circRNA derived from the BMI-increasing SNP allele. We conclude that genetic variation may affect the BMI partly through circRNAs.

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19. Shirama A, Stickley A, Kamio Y, Saito A, Haraguchi H, Wada A, Sueyoshi K, Sumiyoshi T. Emotional and behavioral problems in Japanese preschool children with subthreshold autistic traits: findings from a community-based sample. BMC Psychiatry;2022 (Jul 26);22(1):499.

BACKGROUND: Recently, there has been a growing recognition that autistic traits exist along a continuum beyond diagnostic categories and that even subclinical symptoms may be associated with an increased risk for the psychosocial well-being and mental health of children. However, as yet, there has been little research on whether preschool children with autism spectrum disorder (ASD) symptoms, who do not meet the diagnostic criteria for ASD, are more likely to experience difficulties. To address this deficit this study examined whether young children with subthreshold autistic traits have an increased risk for emotional/behavioral difficulties. METHODS: Data were analyzed from 1057 Japanese preschool children aged 5-years old collected during the first wave of the Tama Children’s Survey (TCS) cohort study. Parent-reported autistic traits were assessed with the Social Responsiveness Scale (SRS), while they provided information on their child’s emotional/behavioral problems using the Strengths and Difficulties Questionnaire (SDQ). Logistic regression analysis was used to examine associations. RESULTS: Preschool children with mild-to-moderate autistic traits, corresponding to subclinical autism were significantly more likely to score above the clinical thresholds for emotional/behavioral problems compared to children with fewer autistic traits. Follow-up diagnostic assessments and analyses of 72 children from the cohort confirmed these findings and showed that these children with subthreshold autistic traits also had a significantly lower intelligence quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). CONCLUSIONS: Although subthreshold autistic traits are difficult to define due to the sometimes vague border between typical and atypical development, there may be a large number of preschool children with subthreshold autistic traits, who may have an increased risk for a variety of different emotional/behavioral difficulties as well as lower cognitive functioning.

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20. Starry R, Stokes TF, Longerbeam M, Richardson E. Incorporating merged treatment procedures for children with autism: A case report. J Interprof Care;2022 (Jul 26):1-9.

We examined interprofessional collaboration in a pre-service training model which incorporated the merging of three treatments: Occupational Therapy, Speech-Language Pathology, and Applied Behavior Analysis. We examined the effects of changes in the clinician interprofessional skill repertoire on therapeutic outcomes for children with Autism Spectrum Disorder. Three licensed professionals modeled core techniques from their respective professions to establish benchmark standards for skill demonstration in the treatment of children with autism. Treatment phases were implemented sequentially targeting multiple therapist and child behaviors within a multiple-baseline across participants’ single case experimental design. Therapist skills improved to show a diverse repertoire of intervention techniques to match supervisor proficiencies. These interprofessional skills were delivered simultaneously in a timely and efficient manner. Assessed outcomes for children with autism included increased frequency of verbalizations, engagement during adult-directed interactions, visual-motor task productivity, and improved postural alignment. The study suggests that integrated training across interprofessional techniques enhanced a diverse repertoire of clinician skills, while systematically demonstrating child improvement on many interprofessional treatment goals.

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21. Stephenson KG, Fenning RM, Macklin EA, Lu F, Norris M, Steinberg-Epstein R, Butter EM. Child Behavior Problems and Parenting Stress in Underserved Families of Children with ASD: Investigation of Family Resources and Parenting Self-efficacy. J Autism Dev Disord;2022 (Jul 25)

Behavior problems in children with autism spectrum disorder (ASD) may exacerbate parenting stress. Parenting self-efficacy and family resources may influence this association. We examined cross-sectional statistical mediation effects of parenting self-efficacy on the relationship between child behavior problems and parenting stress and hypothesized that family-level resources moderated this indirect effect. Participants included 132 underserved (Medicaid-eligible) children with ASD (ages 3-13) with racial/ethnic diversity; many (63%) had intellectual disability. Greater externalizing problems were linked with lower parenting self-efficacy, which in turn was associated with increased parenting stress. A larger mediation effect was observed for families with fewer resources. A plausible alternative model (parenting stress mediating parenting self-efficacy) exhibited poorer fit. Implications for family supports and benefits of longitudinal follow-up are discussed.

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22. Tassanakijpanich N, Wright R, Tassone F, Shankar SP, Hagerman R. Fragile X syndrome in a girl with variant Turner syndrome and an isodicentric X chromosome. BMJ Case Rep;2022 (Jul 26);15(7)

Fragile X (FXS) and Turner (TS) syndromes are X-chromosome-associated disorders. Herein, we report the case of a girl in middle childhood with bicuspid aortic valve in infancy, growth failure, global developmental delay (GDD), visual problems, and coexisting attention-deficit/hyperactivity and anxiety disorders. A high-resolution karyotype in 20 cells revealed 46,X,Idic(X)(p11.21)[19]/45,X[1], suggestive of variant TS. Given her atypical phenotype, subsequent DNA testing was performed. Four FMR1 cytosine-guanine-guanine repeats (30, 410, 580 and 800) were identified, confirming the additional FXS diagnosis. This case study highlights the importance of additional genetic testing in individuals with atypical variant TS, such as unexplained GDD and distinct facial characteristics. The additional FXS diagnosis prompted new therapeutic development for the patient to advance precision healthcare.

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23. Triyasakorn K, Ubah UDB, Roan B, Conlin M, Aho K, Awale PS. The Antiepileptic Drug and Toxic Teratogen Valproic Acid Alters Microglia in an Environmental Mouse Model of Autism. Toxics;2022 (Jul 9);10(7)

Autism spectrum disorder (ASD), a neurodevelopmental condition affecting approximately 1 in 44 children in North America, is thought to be a connectivity disorder. Valproic acid (VPA) is a multi-target drug widely used to treat epilepsy. It is also a toxic teratogen as well as a histone deacetylase inhibitor, and fetal exposure to VPA increases the risk of ASD. While the VPA model has been well-characterized for behavioral and neuronal deficits including hyperconnectivity, microglia, the principal immune cells of CNS that regulate dendrite and synapse formation during early brain development, have not been well-characterized and may provide potential hints regarding the etiology of this disorder. Therefore, in this study, we determined the effect of prenatal exposure to VPA on microglial numbers during early postnatal brain development. We found that prenatal exposure to VPA causes a significant reduction in the number of microglia in the primary motor cortex (PMC) during early postnatal brain development, particularly at postnatal day 6 (P6) and postnatal day 10 (P10) in male mice. The early microglial reduction in the VPA model coincides with active cortical synaptogenesis and is significant because it may potentially play a role in mediating impaired connectivity in ASD.

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24. Wong A, Zhou A, Cao X, Mahaganapathy V, Azaro M, Gwin C, Wilson S, Buyske S, Bartlett CW, Flax JF, Brzustowicz LM, Xing J. MicroRNA and MicroRNA-Target Variants Associated with Autism Spectrum Disorder and Related Disorders. Genes (Basel);2022 (Jul 26);13(8)

Autism spectrum disorder (ASD) is a childhood neurodevelopmental disorder with a complex and heterogeneous genetic etiology. MicroRNA (miRNA), a class of small non-coding RNAs, could regulate ASD risk genes post-transcriptionally and affect broad molecular pathways related to ASD and associated disorders. Using whole-genome sequencing, we analyzed 272 samples in 73 families in the New Jersey Language and Autism Genetics Study (NJLAGS) cohort. Families with at least one ASD patient were recruited and were further assessed for language impairment, reading impairment, and other associated phenotypes. A total of 5104 miRNA variants and 1,181,148 3′ untranslated region (3′ UTR) variants were identified in the dataset. After applying several filtering criteria, including population allele frequency, brain expression, miRNA functional regions, and inheritance patterns, we identified high-confidence variants in five brain-expressed miRNAs (targeting 326 genes) and 3′ UTR miRNA target regions of 152 genes. Some genes, such as SCP2 and UCGC, were identified in multiple families. Using Gene Ontology overrepresentation analysis and protein-protein interaction network analysis, we identified clusters of genes and pathways that are important for neurodevelopment. The miRNAs and miRNA target genes identified in this study are potentially involved in neurodevelopmental disorders and should be considered for further functional studies.

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25. Yamazaki M, Arai T, Yarimizu J, Matsumoto M. The 5-HT5A receptor antagonist ASP5736 ameliorates several abnormal behaviors in an Fmr1-targeted transgenic male rat model of fragile X syndrome. Int J Neuropsychopharmacol;2022 (Jul 26)

BACKGROUND: Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-HT5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS. METHODS: We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (PPI; 0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (NORT; 0.1 mg/kg) in Frmr1-knockout (KO) rats. RESULTS: Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment. CONCLUSIONS: ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

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