1. Diverse mutations in autism-related genes and their expression in the developing brain. Nat Genet;2022 (Aug 18)

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2. Anshu K, Nair AK, Srinath S, Laxmi TR. Altered Developmental Trajectory in Male and Female Rats in a Prenatal Valproic Acid Exposure Model of Autism Spectrum Disorder. J Autism Dev Disord;2022 (Aug 17)

Early motor and sensory developmental delays precede Autism Spectrum Disorder (ASD) diagnosis and may serve as early indicators of ASD. The literature on sensorimotor development in animal models is sparse, male centered, and has mixed findings. We characterized early development in a prenatal valproic acid (VPA) model of ASD and found sex-specific developmental delays in VPA rats. We created a developmental composite score combining 15 test readouts, yielding a reliable gestalt measure spanning physical, sensory, and motor development, that effectively discriminated between VPA and control groups. Considering the heterogeneity in ASD phenotype, the developmental composite offers a robust metric that can enable comparison across different animal models of ASD and can serve as an outcome measure for early intervention studies.

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3. Bylemans T, Heleven E, Baetens K, Deroost N, Baeken C, Van Overwalle F. A narrative sequencing and mentalizing training for adults with autism: A pilot study. Front Behav Neurosci;2022;16:941272.

Adults diagnosed with autism experience difficulties with understanding the mental states of others, or themselves (mentalizing) and with adequately sequencing personal stories (narrative coherence). Given that the posterior cerebellum is implicated in both skills, as well as in the etiology of autism, we developed a narrative sequencing and mentalizing training for autistic adults. Participants with an official autism diagnosis were randomly assigned to a Training group (n = 17) or a waiting-list Control group (n = 15). The Training group took part in six weekly sessions in groups of three participants lasting each about 60 min. During training, participants had to (re)tell stories from the perspective of the original storyteller and answer questions that required mentalizing. We found significant improvements in mentalizing about others’ beliefs and in narrative coherence for the Training group compared to the Control group immediately after the training compared to before the training. Almost all participants from the Training group expressed beneficial effects of the training on their mood and half of the participants reported positive effects on their self-confidence in social situations. All participants recommended the current training to others. Results are discussed in light of cerebellar theories on sequencing of social actions during mentalizing. Further improvements to the program are suggested. Our results highlight the potential clinical utility of adopting a neuroscience-informed approach to developing novel therapeutic interventions for autistic populations.

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4. Chan AS, Lee TL, Sze SL, Yang NS, Han YMY. Eye-tracking training improves the learning and memory of children with learning difficulty. Sci Rep;2022 (Aug 17);12(1):13974.

Children who experience difficulty in learning at mainstream schools usually are provided with remediation classes after school to facilitate their learning. The present study aims to evaluate an innovative eye-tracking training as possible alternative remediation. Our previous findings showed that children who received eye-tracking training demonstrated improved attention and inhibitory control, and the present randomized controlled study aims to evaluate if eye-tracking training can also enhance the learning and memory of children. Fifty-three primary school students with learning difficulty (including autism spectrum disorder, attention-deficit/hyperactivity disorder, specific learning disorder, specific language impairment and borderline intellectual functioning) were recruited and randomly assigned to either the Eye-tracking Training group or the after-school remediation class. They were assessed on their learning and memory using the Hong Kong List Learning Test before and after 8-month training. Twenty weekly parallel sessions of training, 50 min per session, were provided to each group. Children who received the eye-tracking training, not those in the control group, showed a significant improvement in memory as measured by the delayed recall. In addition, the Eye-Tracking Training group showed significantly faster learning than the control group. Also, the two groups showed a significant improvement in their reading abilities. In sum, eye-tracking training may be effective training for enhancing the learning and memory of children with learning difficulties.

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5. Charlot LR, Hodge SM, Holland AL, Frazier JA. Psychiatric diagnostic dilemmas among people with intellectual and developmental disabilities. J Intellect Disabil Res;2022 (Aug 16)

BACKGROUND: Research regarding the accuracy of co-morbid psychiatric diagnoses in individuals with intellectual and developmental disabilities (IDD) is sparse. Yet correct diagnostic assignment is vital so that effective and appropriate treatment can be implemented, especially for the large numbers of individuals requiring expensive and restrictive behavioural health crisis services. METHOD: A retrospective review of de-identified data from multidisciplinary specialty team assessments completed for 50 individuals with ID (IntellectualDisability) with and without ASD and unresolved behavioural health challenges was conducted. The accuracy and reliability of the psychiatric diagnoses upon referral were compared with the diagnoses after the comprehensive team evaluation, and within-individual diagnostic agreement was calculated. The agreement between the Mood and Anxiety Semi-Structured interview tool (MASS) and the full team evaluation was also calculated. The influence of demographic and clinical characteristics on diagnostic agreement was explored. RESULTS: The most common chief complaints upon referral were aggression to others and self-injurious behaviour. Individuals were taking a median of six medications (interquartile range: 5 to 7); 80% were taking an antipsychotic medication. The most common medical conditions were constipation (70%) and gastroesophageal reflux disease (52%). Measures of interrater reliability of the referral diagnoses with the team assessment were below 0.5 (kappa range: -0.04 to 0.39), with the exception of ruling out dementia (kappa = 0.85). The interrater reliability estimates for the MASS evaluations for depression and anxiety were higher (kappa = 0.69 and 0.64) and reflected higher sensitivity and PPV. The odds of any referral diagnosis being confirmed by team evaluation were low: 0.25 (range: 0 to 0.67). The level of diagnostic agreement for each patient was not significantly attributable to demographic or clinical characteristics, although effect sizes indicate a possible positive relationship to age and the number of prescribed psychotropic medications at referral. CONCLUSION: Individuals in the current study had serious psychiatric and behavioural problems despite psychiatric care in their communities. The majority of psychiatric diagnoses provided upon referral were not supported by the multidisciplinary specialty team’s assessment. In addition to possible diagnostic inaccuracy, the group in the study suffered from multiple medical co-morbidities and were exposed to polypharmacy. Results emphasise the importance of multidisciplinary evaluation by clinicians with expertise in neurodevelopmental disabilities when people with ID with and without ASD have complex behavioural health needs that are unresponsive to usual care. In addition, based on agreement with the full team evaluation, the MASS shows promise as an assessment tool, especially with regards to identifying anxiety and depression.

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6. Colvin S, Lea N, Zhang Q, Wienisch M, Kaiser T, Aida T, Feng G. 341 Repeats Is Not Enough for Methylation in a New Fragile X Mouse Model. eNeuro;2022 (Sep-Oct);9(5)

Fragile X syndrome (FXS) is a leading monogenic cause of intellectual disability and autism spectrum disorders, spurring decades of intense research and a multitude of mouse models. So far, these models do not recapitulate the genetic underpinning of classical FXS-CGG repeat-induced methylation of the Fmr1 locus-and their findings have failed to translate into the clinic. We sought to answer whether this disparity was because of low repeat length and generated a novel mouse line with 341 repeats, Fmr1(hs341) , which is the largest allele in mice reported to date. This repeat length is significantly longer than the 200 repeats generally required for methylation of the repeat tract and promoter region in FXS patients, which leads to silencing of the FMR1 gene. Bisulfite sequencing fails to detect the robust methylation expected of FXS in Fmr1(hs341) mice. Quantitative real-time PCR and Western blotting results also do not resemble FXS and instead produce a biochemical profile consistent with the fragile X-associated premutation disorders. These findings suggest that repeat length is unlikely to be the core determinant preventing methylation in mice, and other organisms phylogenetically closer to humans may be required to effectively model FXS.

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7. Fu JM, Satterstrom FK, Peng M, Brand H, Collins RL, Dong S, Wamsley B, Klei L, Wang L, Hao SP, Stevens CR, Cusick C, Babadi M, Banks E, Collins B, Dodge S, Gabriel SB, Gauthier L, Lee SK, Liang L, Ljungdahl A, Mahjani B, Sloofman L, Smirnov AN, Barbosa M, Betancur C, Brusco A, Chung BHY, Cook EH, Cuccaro ML, Domenici E, Ferrero GB, Gargus JJ, Herman GE, Hertz-Picciotto I, Maciel P, Manoach DS, Passos-Bueno MR, Persico AM, Renieri A, Sutcliffe JS, Tassone F, Trabetti E, Campos G, Cardaropoli S, Carli D, Chan MCY, Fallerini C, Giorgio E, Girardi AC, Hansen-Kiss E, Lee SL, Lintas C, Ludena Y, Nguyen R, Pavinato L, Pericak-Vance M, Pessah IN, Schmidt RJ, Smith M, Costa CIS, Trajkova S, Wang JYT, Yu MHC, Cutler DJ, De Rubeis S, Buxbaum JD, Daly MJ, Devlin B, Roeder K, Sanders SJ, Talkowski ME. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet;2022 (Aug 18)

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

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8. Furar E, Wang F, Durocher JS, Ahn YA, Memis I, Cavalcante L, Klahr L, Samson AC, Van Herwegen J, Dukes D, Alessandri M, Mittal R, Eshraghi AA. The impact of COVID-19 on individuals with ASD in the US: Parent perspectives on social and support concerns. PLoS One;2022;17(8):e0270845.

The COVID-19 pandemic’s disruptions to daily routines and services have proven especially challenging for children with autism spectrum disorder (ASD) and their families. The current retrospective study aimed to determine the impact of the COVID-19 pandemic’s social environmental changes on parental ratings of personal and child concerns about family conflict, opportunities for social interaction, and loss of institutional support (school and therapy services). Analyses of responses from families with ASD in the US determined differences in concerns across three time points which were measured simultaneously: prior to COVID-19, at the start of COVID-19, and at the time of survey completion. From our sample of 246 school-aged children, parents retrospectively reported significantly increasing levels of concern for both themselves and their children over time, with parents’ personal concern levels rated consistently higher than their ratings of their child’s level of concern. Concerns about loss of institutional support were higher for parents of children reported as having co-occurring intellectual disability. Further, parents of younger children also reported more concerns about loss of services, as well as more social concerns. For parent ratings of child concerns, children who were reportedly aware of COVID-19 were determined to have higher levels of social concerns and concerns about loss of institutional support. Meanwhile, the child’s age and gender did not impact their parent ratings of child concerns. The increased level of parental and child-perceived concerns over the course of the pandemic suggests a need for improved service delivery and support for these families. The high levels of concerns observed in the current study provide support for the need to assess families’ priorities and tailor services to best meet families’ needs. This will potentially increase the quality of life of family members, and improve ASD services across the lifespan, and improve outcomes.

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9. Hadjikhani N, Galazka M, Kenet T, Joseph R, Åsberg Johnels J. Discrepancy between high non-verbal intelligence and low accuracy at reading emotional expressions in the eyes reflects the magnitude of social-emotional difficulties in autism. Eur Arch Psychiatry Clin Neurosci;2022 (Aug 18)

Many so-called « high functioning » autistic individuals struggle with daily living skills, and have poorer than expected adult outcomes in employment, relationships, and quality of life. Significant discrepancies between non-verbal intelligence and emotional processing can be observed in autism, but the role of the magnitude of this gap in achieving potential psychosocial outcome is not known. Here, we show in a large group of participants (n = 107), that only among those with an autism diagnosis (n = 33), the gap between non-verbal intelligence (as measured by Raven’s matrices) and the ability to perform the Reading the Mind in the Eyes test significantly predicts self-perceived emotional/social difficulties as assessed by the Empathy Quotient. Our results suggest that it is specifically the magnitude of the gap between (high) levels of abstract reasoning skills and poor proficiency in reading emotions expressed by the eyes that predicts self-perceived difficulties in emotional and social interactions among adults with autism. A better understanding of the underlying causes of the discrepancy between potential and actual psychosocial outcomes is the first step toward developing the most appropriate support for this vulnerable population, and our study offers some potentially important insights in this regard.

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10. Hollocks MJ, Leno VC, Chandler S, White P, Yorke I, Charman T, Pickles A, Baird G, Simonoff E. Psychiatric conditions in autistic adolescents: longitudinal stability from childhood and associated risk factors. Eur Child Adolesc Psychiatry;2022 (Aug 17)

Autistic people experience high rates of co-occurring psychiatric diagnoses. Current prevalence estimates vary considerably due to an over-reliance on clinical cohorts and the longitudinal stability of diagnoses from childhood into adolescence is poorly understood. This study aims to provide prevalence rates of co-occurring DSM-5 psychiatric diagnosis for autistic adolescence and investigate, for the first time, the stability of diagnoses from childhood. Using a longitudinal stratified sample of autistic youth (N = 77; 13-17 years; 60% male), selected from a larger community-derived sample of those with pre-existing autism diagnoses (N = 277) weighted prevalence estimates of emotional (anxiety, depression), behavioural (oppositional and conduct disorders) and ADHD diagnoses were calculated based on semi-structured psychiatric interview. Prediction of adolescent psychiatric diagnosis based on childhood diagnostic status, sex, childhood IQ (both assessed at age 4-10 years) was tested. Emotional and behavioural disorders in adolescence were particularly prevalent, and significantly predicted by childhood disorder status. Attention-deficit/hyperactivity-disorder (ADHD) was prevalent but not predicted by childhood ADHD diagnosis. Neither sex nor childhood IQ predicted diagnostic outcomes. Autistic youth have high levels of co-occurring psychiatric conditions, which are broadly persistent across childhood and adolescence. Emotional disorders are particularly prevalent and remain persistent from childhood to adolescence. Greater diagnostic variability was found for ADHD with more adolescents moving across diagnostic thresholds.

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11. Inoue M, Tatumi A, Fukuzaki T. Effectiveness of the internet based parent education program on applied behavior analysis for parents of children with autism spectrum disorder. Brain Dev;2022 (Aug 18)

BACKGROUND: Parent education (PE) in autism spectrum disorder (ASD) is recognized as an important component of support for families living with ASD. Specifically, the knowledge of how to interact with children based on applied behavior analysis (ABA) is useful for parents. In this study, a short-term, internet based on-demand PE program was conducted for parents of children with ASD to acquire knowledge of ABA and basic teaching techniques. METHODS: Parents of children with ASD were recruited as study participants. They attended on-demand lectures from their homes, performed homework tasks based on lecture content and emailed them to our team. The General Health Questionnaire 30 (GHQ) and Knowledge of Behavioral Principle as Applied to Children (KBPAC) were assessed before and after the program. RESULTS: Of the 25 participants, 21 attended all programs and completed all homework tasks and pre- and post-assessments. However, communication among participants via the bulletin board was low. KBPAC scores increased significantly from pre- to post-program scores, and GHQ subscales regarding anxiety and mood modulation decreased significantly from pre- to post-program scores. Positive results were obtained in the post-questionnaires as well. CONCLUSION: These findings suggest the practical applicability of an online PE program for parents of children with ASD based on ABA.

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12. Lense M, Liu T, Booke L, Crawley Z, Beck S. Integrated parent-child music classes for preschoolers with and without autism: Parent expectations and experiences. Ann N Y Acad Sci;2022 (Aug 18)

Integrated recreational programs designed to support neurodiverse children and their families are important vehicles for community participation. In this mixed-methods study, we investigated the mechanisms by which parent-child music classes for autistic and neurotypical children can support community participation. Parents of autistic (n = 33) and typically developing (TD; n = 28) preschoolers were interviewed about their expectations for and experiences of participating in a 12-week psychoeducational parent-child music program. Parents completed ratings of momentary affect and social connection, and researchers coded children’s behavioral engagement during classes at multiple time points throughout the program. Primary motivations for enrolling in an integrated music class included children’s interest in music and opportunities for child socialization. Parent-focused reasons were less frequently endorsed as primary motivations for participation. Yet, momentary ratings indicated that music classes supported parents’ affect regulation and social connection with other parents at the level of individual classes and across the program. These in-class experiences were echoed by interviews following program completion, which additionally highlighted the use of new parenting strategies through the musical activities. Since parental emotional experiences of activities, supportive community relationships, and parenting confidence are all linked with increased community participation, integrated music classes may support participation and satisfaction with community experiences.

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13. Lin X, Zhuo S, Liu Z, Fan J, Peng W. Autistic traits heighten sensitivity to rejection-induced social pain. Ann N Y Acad Sci;2022 (Aug 17)

Autistic traits-subclinical forms of characteristics associated with autism spectrum disorders-are associated with poor social interactions and high risks for mental health disorders. We hypothesized that altered sensitivity to social rejection is an important contributor to psychological distress observed among individuals with high autistic traits. Experiment 1 adopted a social-judgment task and compared behavioral and neural activity in response to social rejection between participants exhibiting either high or low autistic traits (HAT and LAT, respectively). Rejection-induced hurt feelings, P3 amplitudes, and θ-oscillation magnitudes were greater in the HAT group than in the LAT group. Mediation analysis indicated that autistic traits heighten rejection-induced social pain through increasing frontal-midline θ-oscillations. Responses to nonsocial feedback in the age-judgment task were comparable, confirming that the between-group differences were specific to social negative feedback. Experiment 2 assessed the association between autistic traits, rejection sensitivity, and psychological distress among randomly recruited participants. Results showed that autistic traits affected depressive/anxious symptomatology partially through heightened rejection sensitivity. Therefore, autistic traits heighten sensitivity to rejection-induced social pain that leads to psychological distress. This finding will help facilitate the development of strategies for coping with social pain and improving mental health for individuals with high autistic traits.

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14. Mason L, Moessnang C, Chatham C, Ham L, Tillmann J, Dumas G, Ellis C, Leblond CS, Cliquet F, Bourgeron T, Beckmann C, Charman T, Oakley B, Banaschewski T, Meyer-Lindenberg A, Baron-Cohen S, Bölte S, Buitelaar JK, Durston S, Loth E, Oranje B, Persico A, Dell’Acqua F, Ecker C, Johnson MH, Murphy D, Jones EJH. Stratifying the autistic phenotype using electrophysiological indices of social perception. Sci Transl Med;2022 (Aug 17);14(658):eabf8987.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.

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15. Micsinszki SK, Ballantyne M, Cleverley K, Green P, Brennenstuhl S, Stremler R. Examining factors associated with sleep quality in parents of children 4-10 years with autism spectrum disorder. Disabil Rehabil;2022 (Aug 18):1-13.

PURPOSE: Parents of children with autism spectrum disorder often report poorer sleep compared to parents of typically developing children. When parents do not obtain enough quality sleep, functioning may be compromised placing the onus of care on already stressed parents. However, improving sleep duration may not improve sleep quality and is not always feasible. This study aimed to measure sleep quality in parents of children with autism spectrum disorder, determine if stress and children’s sleep are associated with sleep quality and whether resources, appraisals, and coping moderate these relationships. MATERIALS AND METHODS: Multivariable regression was used to determine the effects of stress and children’s sleep problems on sleep quality and test modifying effects. RESULTS: Mean (SD) Pittsburgh Sleep Quality Index scores was 8.81 (3.76), with 77.6% of parents scoring above the clinical cut-off. Mean (SD) Children’s Sleep Habits Questionnaire scores was 54.03 (8.32), with 96.3% of parents rating their child’s sleep above the clinical cut-off. Children’s sleep was the only significant predictor and none of the expected effect modifiers were significant. CONCLUSION: Children’s sleep may be an important target to improve parent sleep quality but requires systematic assessment with interventional research. Implications for rehabilitationBoth parents and their 4-10-year-old children with ASD experience high levels of sleep disturbances.Clinicians can start the conversation early with parents about their children’s sleep by providing them with information to increase awareness and recognize healthy sleep habits in their children.Clinicians are important in the assessment, management, and evaluation of pediatric sleep problems, which may have significant spillover effects on parents of children with ASD.There is a need for more resources and training to be available to clinicians to assess children and their parents for sleep problems, which could extend beyond the assessment of sleep and consider parent’s daytime functioning and mental health.

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16. Pavlopoulou G, Burns C, Cleghorn R, Skyrla T, Avnon J. « I often have to explain to school staff what she needs ». School experiences of non-autistic siblings growing up with an autistic brother or sister. Res Dev Disabil;2022 (Oct);129:104323.

BACKGROUND: Recent autism research has evidenced a shift from psychological outcomes to contextualised approaches to understanding the varying needs of non autistic siblings of autistic children across different systems. Yet, there is limited research exploring the lived experiences of siblings in their school context. METHODS: First, a group of school aged sibling advisors worked with the first author to codesign research aims, methods and dissemination practices around the topic of the school experiences of siblings who grow up with an autistic brother or sister in the UK. Then, 28 school-aged siblings of autistic children completed adapted photo-elicitation interviews, to discuss their school experiences. A background questionnaire was also administered to their parents and carers. RESULTS: Thematic analysis was employed. The master themes included: (i) Impact of home experiences in schoolwork, including limited personal time and sleep disruptions (ii) Siblings’ school interactions impact on overall school experience, including a wide range of both typical and difficult experiences such as school day disruptions, (iii) Varied perceived levels of support and understanding, including emotional and/or educational support by family members and a sense of connectedness with peers and teachers who are autistic themselves or connected to someone with a diagnosis of autism. IMPLICATIONS: The results underline the ways home experiences can have an impact on school life of siblings, the positive contribution of the autistic school staff and/or staff who have an autistic family member and the need for an organisational culture of inclusivity and widespread acceptance and awareness around issues of neurodiversity. Our findings suggest several implications for school psychologists in core functions of the educational psychologists’ role including training, consultation, assessment, and whole school support. DATA AVAILABILITY STATEMENT: The datasets generated for this study are not readily available because they include sensitive data (photos of siblings’ houses, family members, personal objects, and school timetables). Requests to access the datasets should be directed to corresponding author.

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17. Rozhkova IN, Okotrub SV, Brusentsev EY, Uldanova EE, Chuyko E, Lipina TV, Amstislavskaya TG, Amstislavsky SY. Neuronal density in the brain cortex and hippocampus in Clsnt2-KO mouse strain modeling autistic spectrum disorder. Vavilovskii Zhurnal Genet Selektsii;2022 (Jul);26(4):365-370.

Autistic spectrum disorders (ASD) represent conditions starting in childhood, which are characterized by diff iculties with social interaction and communication, as well as non-typical and stereotyping models of behavior. The mechanisms and the origin of these disorders are not yet understood and thus far there is a lack of prophylactic measures for these disorders. The current study aims to estimate neuronal density in the prefrontal cortex and four hippocampal subf ields, i. e. СA1, СA2, СA3, and DG in Clstn2-KO mice as a genetic model of ASD. In addition, the level of neurogenesis was measured in the DG area of the hippocampus. This mouse strain was obtained by a knockout of the calsinthenin-2 gene (Clsnt2) in C57BL/6J mice; the latter (wild type) was used as controls. To estimate neuronal density, serial sections were prepared on a cryotome for the above-mentioned brain structures with the subsequent immunohistochemical labeling and confocal microscopy; the neuronal marker (anti-NeuN) was used as the primary antibody. In addition, neurogenesis was estimated in the DG region of the hippocampus; for this purpose, a primary antibody against doublecortin (anti-DCX) was used. In all cases Goat anti-rabbit IgG was used as the secondary antibody. The density of neurons in the CA1 region of the hippocampus was lower in Clstn2-KO mice of both sexes as compared with controls. Moreover, in males of both strains, neuronal density in this region was lower as compared to females. Besides, the differences between males and females were revealed in two other hippocampal regions. In the CA2 region, a lower density of neurons was observed in males of both strains, and in the CA3 region, a lower density of neurons was also observed in males as compared to females but only in C57BL/6J mice. No difference between the studied groups was revealed in neurogenesis, nor was it in neuronal density in the prefrontal cortex or DG hippocampal region. Our new f indings indicate that calsyntenin-2 regulates neuronal hippocampal density in subf ield-specif ic manner, suggesting that the CA1 neuronal subpopulation may represent a cellular target for early-life preventive therapy of ASD.

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18. Saeliw T, Permpoon T, Iadsee N, Tencomnao T, Hu VW, Sarachana T, Green D, Sae-Lee C. LINE-1 and Alu methylation signatures in autism spectrum disorder and their associations with the expression of autism-related genes. Sci Rep;2022 (Aug 17);12(1):13970.

Long interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD). Here we interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements in ASD whole blood using publicly-available Illumina Infinium 450 K methylation datasets from heterogeneous ASD and ASD variants (Chromodomain Helicase DNA-binding 8 (CHD8) and 16p11.2del). Total DNA methylation of repetitive elements were notably hypomethylated exclusively in ASD with CHD8 variants. Methylation alteration in a family-specific manner including L1P, L1H, HAL, AluJ, and AluS families were observed in the heterogeneous ASD and ASD with CHD8 variants. Moreover, LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. The DNA methylation signatures of the LINE-1 and Alu elements in ASD whole blood, as well as their associations with the expression of ASD-related genes, have been identified. If confirmed in future larger studies, these findings may contribute to the identification of epigenomic biomarkers of ASD.

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19. Shaffer RC, Reisinger DL, Schmitt LM, Lamy M, Dominick KC, Smith EG, Coffman MC, Esbensen AJ. Systematic Review: Emotion Dysregulation in Syndromic Causes of Intellectual and Developmental Disabilities. J Am Acad Child Adolesc Psychiatry;2022 (Aug 18)

OBJECTIVE: To summarize the current state of the literature regarding emotion dysregulation (ED) in syndromic causes of intellectual disability (S-IDs) in six of the most common forms of S-IDs: Down syndrome (DS), Fragile X syndrome (FXS), tuberous-sclerosis complex (TSC), Williams syndrome (WS), Prader-Willi syndrome (PWS), and Angelman syndrome (AS); and to determine future research directions for identification and treatment of ED. METHOD: PubMed bibliographic database was searched from date of inception to May 2021. PRISMA 2020 guidelines were followed with the flow chart, table of included studies, list of excluded studies, and checklist provided. Filters applied included human research and English. Only original research articles were included in the final set, but review articles were utilized to identify secondary citations of primary studies. All articles were reviewed for appropriateness by two authors and summarized. A total of 145 articles met inclusion criteria (DS=29, FXS=55, TSC=11, WS=18, PWS=24, AS=8). RESULTS: Each syndrome review was summarized separately and further subdivided into articles related to underlying neurobiology, behaviors associated with ED, assessment, and targeted intervention. FXS had the most thorough research base, followed by DS and PWS with the other syndromes having more limited available research. Very limited research was available regarding intervention for all disorders except FXS. CONCLUSION: Core underlying characteristics of S-IDs appear to place youth at higher risk for ED, but further research is needed to better assess and treat ED in S-IDs. Future studies should have a standard assessment measure of ED, such as the Emotion Dysregulation Inventory and explore adapting established curricula for ED from the neurotypical and autism spectrum disorder fields.

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20. Shahmoradi L, Rezayi S. Cognitive rehabilitation in people with autism spectrum disorder: a systematic review of emerging virtual reality-based approaches. J Neuroeng Rehabil;2022 (Aug 18);19(1):91.

INTRODUCTION: Emerging virtual technologies and cognitive rehabilitation methods are two new treatment approaches that can be used to strengthen cognitive functions in Autism Spectrum Disorder (ASD). The main aim of this study was to examine the effect of using virtual reality-based approaches on cognitive disorders of children and adults with ASD. METHODS: This systematic review was conducted on scientific papers to determine the effects of virtual reality-based technologies on the cognitive functions of children and adults with ASD. We identified 688 studies related to this topic and filtered them down to 17 articles, and then extracted the effects of interventions on cognitive outcomes. RESULTS: A total of 17 studies met the inclusion criteria, in which 226 persons with ASD had taken place. The sample size in the selected studies ranged from 1 to 56 participants (Median: 8, Q1: 3.5, Q3: 15.5). Four of the studies were case-control studies, ten were pre-test/post-test studies, and three were Randomized Control Trials (RCTs). Results of 16 studies showed significant progress in various cognitive indexes, such as task learning, attention, executive functioning, and daily skills in people with ASD. In most studies, virtual technologies had beneficial effects on reducing cognitive problems, but existing limitations could reduce their effectiveness. These limitations included the cost of virtual reality devices, inappropriate size of software, the weight of devices, potential addiction, intolerance of wearing glasses or headsets by people with autism (especially in children), and the possibility of eye injury. CONCLUSION: Applying appropriate virtual-based approaches could improve cognitive indexes in people with ASD. However, further studies are needed to investigate the real effects of these technologies in the long run.

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21. Smith J, Sulek R, Van Der Wert K, Cincotta-Lee O, Green CC, Bent CA, Chetcuti L, Hudry K. Parental Imitations and Expansions of Child Language Predict Later Language Outcomes of Autistic Preschoolers. J Autism Dev Disord;2022 (Aug 17):1-14.

Both the amount and responsiveness of adult language input contribute to the language development of autistic and non-autistic children. From parent-child interaction footage, we measured the amount of adult language input, overall parent responsiveness, and six discrete parent responsive behaviours (imitations, expansions, open-ended questions, yes/no questions, comments and acknowledgements) to explore which types of responsiveness predicted autistic preschoolers’ language five months later, after controlling for adult language input. We found expansions and particularly imitations to be more important for later language than overall responsiveness. This study emphasises the need to capture what exactly about parent language input influences child language acquisition, and adds to the evidence that imitating and expanding early language might be particularly beneficial for autistic preschoolers.

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22. Sridhar A, Drahota A, Tschida JE. Implementation strategy mapping methods to improve autism intervention use in community settings: a study protocol. Implement Sci Commun;2022 (Aug 18);3(1):92.

BACKGROUND: Implementation strategies are purported to facilitate adoption and use of evidence-based practices (EBPs) across settings. The use of tailored implementation strategies may be particularly effective, as they are selected with the explicit purpose of addressing setting-specific implementation determinants. However, methods to select and tailor implementation strategies, including in community settings, remain understudied. This project will identify and describe implementation strategy mapping methods (ISMMs) from extant peer-reviewed literature and pilot test a method to match implementation strategies with determinants in low-resourced community mental health (CMH) agencies that deliver services to children on the autism spectrum. METHODS: Aim 1: A scoping review, following PRISMA guidelines, will be conducted to identify implementation strategy mapping methods (ISMMs) utilized in child mental health settings. Data extraction will identify and describe each ISMM, including identifying methodological and procedural steps, analyzing the frequency of ISMM use, and identifying outcomes measured in eligible ISMM studies. Aim 2: Using scoping review findings, select and pilot test one ISMM within five community mental health agencies in Michigan that provide services to autistic children. We will recruit five directors/agency leaders, supervisors, and direct providers at each of the eligible agencies (expected N = 25). A sequential explanatory (QUAN➔ QUAL) mixed methods design will be used. Participants will complete a demographics and client survey, as well as a needs assessment to identify implementation determinants. The impact of the ISMM on organizational readiness for change (from pre- to post-ISMM), as well as implementation outcomes of the ISMM (feasibility, acceptability, appropriateness, usability), will be examined. Semi-structured interviews will elicit stakeholder perspectives on the mapping method. DISCUSSION: The current project aims to advance our knowledge of methods for selecting, tailoring, and mapping implementation strategies to address context-specific determinants to implementation. Additionally, this project will contribute to growing science found at the intersection of implementation science and autism research by utilizing the implementation determinants framework, the CFIR, to guide data collection, analysis, and interpretation of findings. Finally, these findings may support future EBP implementation efforts within low-resourced communities, with the ultimate goal of increasing equity in access to EBPs for autistic children.

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23. Stone-Heaberlin M, Hartley N, Lynch JD, Fisher AP, Justice N. Implementation of a Parent-Mediated Discrete Trial Teaching Intervention for Children with Autism Spectrum Disorder. Behav Anal Pract;2022 (Aug 18):1-5.

For young children with autism spectrum disorder (ASD), early intensive intervention is imperative. The Bridge Skill Development Program is a parent-mediated intervention designed to « bridge the gap » during the period after a diagnosis of ASD while children wait for intensive intervention. This program introduces applied behavior analysis (ABA) teaching techniques, including the use of parent-mediated discrete trial teaching (DTT), to promote skill acquisition of target behaviors. Significant improvements were observed across four target behaviors taught to all participants. The program also aims to connect participants to intensive ABA programming.

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24. Susam BT, Riek NT, Beck K, Eldeeb S, Hudac CM, Gable PA, Conner C, Akcakaya M, White S, Mazefsky C. Quantitative EEG Changes in Youth With ASD Following Brief Mindfulness Meditation Exercise. IEEE Trans Neural Syst Rehabil Eng;2022;30:2395-2405.

Mindfulness has growing empirical support for improving emotion regulation in individuals with Autism Spectrum Disorder (ASD). Mindfulness is cultivated through meditation practices. Assessing the role of mindfulness in improving emotion regulation is challenging given the reliance on self-report tools. Electroencephalography (EEG) has successfully quantified neural responses to emotional arousal and meditation in other populations, making it ideal to objectively measure neural responses before and after mindfulness (MF) practice among individuals with ASD. We performed an EEG-based analysis during a resting state paradigm in 35 youth with ASD. Specifically, we developed a machine learning classifier and a feature and channel selection approach that separates resting states preceding (Pre-MF) and following (Post-MF) a mindfulness meditation exercise within participants. Across individuals, frontal and temporal channels were most informative. Total power in the beta band (16-30 Hz), Total power (4-30 Hz), relative power in alpha band (8-12 Hz) were the most informative EEG features. A classifier using a non-linear combination of selected EEG features from selected channel locations separated Pre-MF and Post-MF resting states with an average accuracy, sensitivity, and specificity of 80.76%, 78.24%, and 82.14% respectively. Finally, we validated that separation between Pre-MF and Post-MF is due to the MF prime rather than linear-temporal drift. This work underscores machine learning as a critical tool for separating distinct resting states within youth with ASD and will enable better classification of underlying neural responses following brief MF meditation.

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25. Takamatsu R. Responses to Infantile Cuteness Explain the Link between Autistic Traits and Reduced Maternal Attachment. J Genet Psychol;2022 (Aug 17):1-8.

This study examined the link between autistic traits and mother-to-child attachment by introducing two mediators: emotional responsiveness to the infantile cuteness of children and negative parental self-concept. We screened 1,317 mothers and recruited those who have a child with high or low autistic traits based on their Autism Spectrum Quotient score. Fifty mothers in the high autistic and 71 mothers in the low autistic groups participated. Results showed that the autistic traits of children are related to weak maternal attachment. Reduced emotional responses to cuteness and negative self-concept mediated the link. These findings suggest that supporting mothers who have a child with autism spectrum disorder may benefit securing mother-to-child attachment as well as the wellbeing of both mother and child.

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26. Takeguchi R, Kuroda M, Tanaka R, Suzuki N, Akaba Y, Tsujimura K, Itoh M, Takahashi S. Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study. J Neurol Sci;2022 (Aug 18);441:120381.

OBJECTIVE: To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI). METHODS: Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs) underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI). The measurements obtained from each modality were statistically compared between RTTs and HCs and examined for their correlation with the clinical severity of RTTs. RESULTS: Structural MRI imaging revealed volume reductions in most cortical and subcortical regions of the brain. Remarkable volume reductions were observed in the frontal and parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus, and corpus callosum. DTI analysis revealed decreased white matter integrity in broad regions of the brain. Fractional anisotropy values were greatly decreased in the superior longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI analysis showed decreased functional connectivity in the interhemispheric dorsal attention network, and between the visual and cerebellar networks. The clinical severity of RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and cerebellar peduncles. CONCLUSION: Regional volume and white matter integrity of RTT brains were reduced in broad areas, while most functional connections remained intact. Notably, two functional connectivities, between cerebral hemispheres and between the cerebrum and cerebellum, were decreased in RTT brains, which may reflect the structural changes in these brain regions.

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27. Taniguchi E, Conant K, Keller K, Kim SJ. A Retrospective Chart Review of Factors Impacting Psychotropic Prescribing Patterns and Polypharmacy Rates in Youth with Autism Spectrum Disorder during the COVID-19 Pandemic. J Clin Med;2022 (Aug 18);11(16)

High but variable rates of psychotropic polypharmacy (PP) in youth with autism spectrum disorder (ASD) have been reported in previous studies. The effect of the COVID-19 pandemic on prescribing patterns has not been well described. This study aims to examine the factors associated with psychotropic prescribing patterns, including rates of PP and multiclass polypharmacy (MPP) in youth with ASD during the COVID-19 pandemic. We examined the prescription records and clinical characteristics of youth aged between 3-21 years with a clinical diagnosis of ASD who were followed at an urban tertiary autism center psychiatry clinic between 1 January 2019, and 31 December 2020. For study purposes, we treated 2019 as the pre-pandemic year and 2020 as the pandemic year and compared the clinical characteristics of the « total clinic cohort (n = 898) » across two years. We examined the clinical characteristics of patients seen in both years (« paired-sample, » n = 473) and those seen only in 219 (« not-paired sample, » n = 378) to identify factors associated with the likelihood of patients’ return to clinic in 2020. As the total clinic cohort was a naturalistic sample containing duplicate patients, we created a separate data set by randomly assigning duplicate patients to one of the years (« random unique sample, » n = 898) and examined the clinical characteristics across two years. We defined PP and MPP broadly as the use of ≥2 unique medications (PP) and ≥2 unique medication classes (MPP) within a calendar year in this study. In the total clinic cohort, increased rates of PP (71.6% to 75.6%), MPP (61.9% to 67.8%, p = 0.027), and antidepressant prescriptions (56.9% to 62.9%, p = 0.028) were noted, although only the latter two were nominally significant. The paired-sample had a higher proportion of teens (31.0% vs. 39.7%, p < 0.001 and persons who self-identified as non-Hispanic (77.8% vs. 85.4%, p = 0.016)), higher rates of anxiety (78.9% vs. 48.7%, p < 0.001), ADHD (71.0% vs. 44.4%, p < 0.001), depression (23.9% vs. 13.0%, p < 0.001) and disruptive behavior (63.3% vs. 33.3%, p < 0.001) diagnoses, higher rates of antidepressants (63.4% vs. 48.7%, p < 0.001), ADHD medications (72.5% vs. 59.8%, p < 0.001), and antipsychotics (36.8% vs. 26.2%, p < 0.001) prescribed, and higher rates of PP (81.6% vs. 59.0%, p < 0.001) and MPP (71.0% vs. 50.5%, p < 0.001) than the not-paired sample. In the random unique sample, the patient group assigned to 2020 had higher rates of anxiety (75.0% vs. 60.2%, p < 0.001), ADHD (69.9% vs. 54.6%, p < 0.001), and disruptive behavior (57.9% vs. 45.4%, p < 0.001) diagnoses but the PP and MPP rates did not differ across years. Overall, we found high rates of PP and MPP, likely due to the broader definition of PP and MPP used in this study than those in other studies as well as the study site being a tertiary clinic. While our study suggests a possible impact of the COVID-19 pandemic on comorbidity rates and prescribing patterns, a replication study is needed to confirm how pandemic-related factors impact prescribing patterns and polypharmacy rates in youth with ASD.

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28. Vilela J, Martiniano H, Marques AR, Santos JX, Rasga C, Oliveira G, Vicente AM. Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disorders. Front Mol Neurosci;2022;15:932305.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.

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29. Zhou X, Feliciano P, Shu C, Wang T, Astrovskaya I, Hall JB, Obiajulu JU, Wright JR, Murali SC, Xu SX, Brueggeman L, Thomas TR, Marchenko O, Fleisch C, Barns SD, Snyder LG, Han B, Chang TS, Turner TN, Harvey WT, Nishida A, O’Roak BJ, Geschwind DH, Michaelson JJ, Volfovsky N, Eichler EE, Shen Y, Chung WK. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat Genet;2022 (Aug 18)

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10(-6)), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10(-6)). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

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