1. 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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2. Ash RT, Palagina G, Fernandez-Leon JA, Park J, Seilheimer R, Lee S, Sabharwal J, Reyes F, Wang J, Lu D, Sarfraz M, Froudarakis E, Tolias AS, Wu SM, Smirnakis SM. Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism. J Neurosci;2022 (Aug 17);42(33):6469-6482.

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential « hypo-priors » theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

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3. Axelrod AE, Hooker JM. Bridging the Divide between Reductionism and the Neurodiversity Movement. ACS Chem Neurosci;2022 (Aug 17);13(16):2351-2352.

While Autism Spectrum Disorder as a label invites the idea of the heterogeneity of autism, within research we often adopt reductionist frameworks which are antithetical to heterogeneous presentations of autism. The neurodiversity movement provides insight into the vastness of the autistic experience and therefore might inform how we should restructure our research questions. Inviting sociocultural concepts of neurodiversity into the lab might better structure research to benefit the autistic community.

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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. Diek D, Smidt MP, Mesman S. Molecular Organization and Patterning of the Medulla Oblongata in Health and Disease. Int J Mol Sci;2022 (Aug 17);23(16)

The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7-r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold-Hirschhorn syndrome, Rett syndrome, and Pitt-Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.

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6. Dy ABC, Tanchanco LBS, Sy JCY, Levantino MD, Hagerman RJ. Screening for Fragile X Syndrome Among Filipino Children with Autism Spectrum Disorder. J Autism Dev Disord;2022 (Aug 16)

Individuals with autism spectrum disorder present with difficulties in social communication, restricted interests or behaviors and other co-morbidities. About 2 to 10% of cases of autism have a genetic cause, and Fragile X Syndrome (FXS) is reported in 0 to 6.5% of individuals with autism. However, the FXS and premutation prevalence among Filipino children has never been reported. The aim of the study was to establish the presence of FXS or premutation carriers among Filipino children with autism and to describe the phenotypic characteristic of cases identified. Blood was collected from 235 children aged 2-6 years old and diagnosed with autism. Samples were analyzed using PCR methods to amplify CGG repeats in the FMRI gene. The diagnosis of autism was confirmed through the Autism Diagnostic Observation Schedule-2. Additional characteristics were documented from a physical examination, Griffiths Scales of Child Development assessment and a parent-answered questionnaire using the Vineland Adaptive Behavior Scale. Fragile X testing through PCR methods in 235 children with diagnosed autism showed 220 (93.6%) were negative, no full mutations, 1 (0.436%) premutation carrier and 14 (5.95%) cases contained intermediate alleles. The FXS testing was limited to confirmed cases of autism, which is considered a high-risk group and does not provide prevalence for the general Filipino population. Subjects were self-referred or referred by clinicians, which may not represent the Filipino autism population with a bias towards those with means for clinical consultations and ability to travel to the place of testing. Samples were not measured for mosaicism, DNA methylation or AGG interspersion patterns. These may have effects on the CGG repeat expansion and overall presentation of FXS. Findings from a single premutation carrier cannot characterize features distinctly present in Filipinos with the mutation. Nevertheless, these results support the data that the prevalence of FXS in Asian populations may be lower than non-Asian populations. This can contribute to a better understanding of FXS and genetic causes of autism in the Philippines and other Asian populations.

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7. 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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8. Hegvik TA, Klungsøyr K, Kuja-Halkola R, Remes H, Haavik J, D’Onofrio BM, Metsä-Simola N, Engeland A, Fazel S, Lichtenstein P, Martikainen P, Larsson H, Sariaslan A. Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder: a cross-national cohort study of 4.5 million individuals and their siblings. Am J Obstet Gynecol;2022 (Aug 13)

BACKGROUND: A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. OBJECTIVE: This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. STUDY DESIGN: We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987-2005), Norway (1999-2015), and Sweden (1987-2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6-16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. RESULTS: A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10-1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19-1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93-1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96-1.02). CONCLUSION: In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder.

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9. Hodgson R, Biswas M, Palmer S, Marshall D, Rodgers M, Stewart L, Simmonds M, Rai D, Le Couteur A. Intensive behavioural interventions based on applied behaviour analysis (ABA) for young children with autism: A cost-effectiveness analysis. PLoS One;2022;17(8):e0270833.

BACKGROUND: The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK. METHODS: A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence. RESULTS: Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis. CONCLUSIONS: The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties.

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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. Iezzi D, Curti L, Ranieri G, Gerace E, Costa A, Ilari A, La Rocca A, Luceri C, D’Ambrosio M, Silvestri L, Scardigli M, Mannaioni G, Masi A. Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder. Pharmacol Res;2022 (Sep);183:106401.

We previously demonstrated that prenatal exposure to valproic acid (VPA), an environmental model of autism spectrum disorder (ASD), leads to a hyperexcitable phenotype associated with downregulation of inward-rectifying potassium currents in nucleus accumbens (NAc) medium spiny neurons (MSNs) of adolescent rats. Aberrant mTOR pathway function has been associated with autistic-like phenotypes in multiple animal models, including gestational exposure to VPA. The purpose of this work was to probe the involvement of the mTOR pathway in VPA-induced alterations of striatal excitability. Adolescent male Wistar rats prenatally exposed to VPA were treated acutely with the mTOR inhibitor rapamycin and used for behavioral tests, ex vivo brain slice electrophysiology, single-neuron morphometric analysis, synaptic protein quantification and gene expression analysis in the NAc. We report that postnatal rapamycin ameliorates the social deficit and reverts the abnormal excitability, but not the inward-rectifying potassium current defect, of accumbal MSNs. Synaptic transmission and neuronal morphology were largely unaffected by prenatal VPA exposure or postnatal rapamycin treatment. Transcriptome analysis revealed extensive deregulation of genes implied in neurodevelopmental disorders and ionic mechanisms exerted by prenatal VPA, which was partially reverted by postnatal rapamycin. The results of this work support the existence of antagonistic interaction between mTOR and VPA-induced pathways on social behavior, neurophysiological phenotype and gene expression profile, thus prompting further investigation of the mTOR pathway in the quest for specific therapeutic targets in ASD.

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12. Jenabi E, Ayubi E, Bashirian S, Seyedi M, Rezaei M. Association between previous abortion history and risk of autism spectrum disorders among offspring: A meta-analysis. Clin Exp Pediatr;2022 (Aug 17)

The present meta-analysis aimed to evaluate the association between previous abortion history and the risk of autism spectrum disorders (ASD). The PubMed, Scopus, and Web of Sciences databases were systematically searched for studies published through December 2021. The presence of statistical heterogeneity among the eligible studies was determined using the I2 value. According to heterogeneity, random- or fixed-effect models were applied to the meta-analysis of associations. Egger’s and Begg’s tests were used to assess publication bias. Thirteen studies involving 331,779 children were included in this meta-analysis. The overall odds ratio (95% confidence interval) for the association between previous abortion history and ASD through the random-effects model was 1.64 (1.28, 2.0; I2=61.7%). No publication bias was found (Begg’s: p=0.393; Egger’s: p=0.056). These results suggest a positive and significant association between a history of previous abortion and the risk of ASD in offspring.

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13. Kallitsounaki A, Williams DM. Implicit and Explicit Gender-Related Cognition, Gender Dysphoria, Autistic-Like Traits, and Mentalizing: Differences Between Autistic and Non-Autistic Cisgender and Transgender Adults. Arch Sex Behav;2022 (Aug 16)

Evidence indicates a link between autism spectrum disorder (ASD) and gender diversity, yet this intersection remains insufficiently understood. Here, we investigated whether (1) ASD affects gender-related cognition (i.e., mental processes of perceiving and interpreting one’s own gender self-concept), (2) autistic people have increased gender dysphoria and recall limited gender-typed behavior from childhood, and (3) transgender individuals have increased ASD-like traits and difficulties in mentalizing. A total of 106 non-autistic cisgender (51 birth-assigned female), 107 autistic cisgender (57 birth-assigned female), 78 non-autistic transgender (41 birth-assigned female), and 56 autistic transgender adults (27 birth-assigned female) participated in the study. The mean age of participants was 31.01 years (range = 18 to 70). Using an explicit as well as an implicit measure, for the first time, we found that ASD affected gender-related cognition only in autistic cisgender people. Sex differences were also observed in this group. Whereas autistic cisgender birth-assigned males showed a stronger implicit gender-group identification than non-autistic cisgender birth-assigned males, autistic cisgender birth-assigned females showed a weaker gender-group identification than non-autistic cisgender birth-assigned females. Furthermore, autistic cisgender people reported significantly more gender dysphoric feelings and recalled significantly less gender-typed behavior from childhood than non-autistic cisgender individuals. No difference was observed between non-autistic and autistic transgender people. We also found that relative to non-autistic cisgender individuals, both non-autistic transgender and autistic transgender people reported significantly more ASD-like traits. However, mentalizing difficulties were observed only in the latter group. This research enhances our understanding of the link between ASD and gender diversity.

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14. Kuznitsov-Yanovsky L, Shapira G, Gildin L, Shomron N, Ben-Yosef D. Transcriptomic Analysis of Human Fragile X Syndrome Neurons Reveals Neurite Outgrowth Modulation by the TGFβ/BMP Pathway. Int J Mol Sci;2022 (Aug 17);23(16)

Fragile X Syndrome (FXS) is the main genetic reason for intellectual disability and is caused by the silencing of fragile X mental retardation protein (FMRP), an RNA-binding protein regulating the translation of many neuronal mRNAs. Neural differentiation of FX human embryonic stem cells (hESC) mimics the neurodevelopment of FXS fetuses and thus serves as a good model to explore the mechanisms underlining the development of FXS. Isogenic hESC clones with and without the FX mutation that share the same genetic background were in vitro differentiated into neurons, and their transcriptome was analyzed by RNA sequencing. FX neurons inactivating FMR1 expression presented delayed neuronal development and maturation, concomitant with dysregulation of the TGFβ/BMP signaling pathway, and genes related to the extracellular matrix. Migration assay showed decreased neurite outgrowth in FX neurons that was rescued by inhibition of the TGFβ/BMP signaling pathway. Our results provide new insights into the molecular pathway by which loss of FMRP affects neuronal network development. In FX neurons, the lack of FMRP dysregulates members of the BMP signaling pathway associated with ECM organization which, in a yet unknown mechanism, reduces the guidance of axonal growth cones, probably leading to the aberrant neuronal network function seen in FXS.

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15. Levy T, Lerman B, Halpern D, Frank Y, Layton C, Zweifach J, Siper PM, Buxbaum JD, Kolevzon A. CHAMP1 disorder is associated with a complex neurobehavioral phenotype including autism, ADHD, repetitive behaviors and sensory symptoms. Hum Mol Genet;2022 (Aug 17);31(15):2582-2594.

CHAMP1-related neurodevelopmental disorder, or CHAMP1 disorder, is a recently described genetic syndrome associated with developmental delay, intellectual disability, behavioral symptoms, medical comorbidities, and dysmorphic features. To date, literature has focused on medical review and dysmorphology but has yet to prospectively assess neurobehavioral core domains such as autism, or behavioral, language, cognitive, and sensory features. Here, we present deep phenotyping results for 11 individuals with CHAMP1 disorder, based on approximately 12 hours of remote clinician-administered assessments and standardized caregiver questionnaires. Diagnoses of autism spectrum disorder were given to 33% of participants; repetitive behaviors and sensory-seeking symptoms were prominent in this cohort. In addition, 60% of participants met the criteria for attention-deficit/hyperactivity disorder (ADHD). High rates of ADHD and relatively low rates of treatment suggest potential areas for intervention. This study represents the first prospective phenotyping analysis of individuals with CHAMP1 disorder. The utility of specific measures as clinical endpoints, as well as benefits and limitations of remote phenotyping, are described.

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16. 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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17. Ma BX, Kong YM, Zhang XY, Zhang YT, He Q. Analysis of misdiagnosis of children with autism spectrum disorders in China. Clin Child Psychol Psychiatry;2022 (Aug 16):13591045221119936.

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18. MacLaughlin C, Booker S, Chatterji S, Hooker JM, Clark L, Müller CE. Special Issue Announcement: Insights in the Field of Autism and Neurodevelopmental Disorders. ACS Chem Neurosci;2022 (Aug 17);13(16):2349-2350.

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19. Mansour Y, Burchell A, Kulesza R. Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder. Brain Res;2022 (Oct 15);1793:148056.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD.

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20. 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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21. Menachem S, Hershkovich O, Ackshota N, Friedlander A, Givon U, Ben-Zeev B, Caspi I. Scoliosis in RETT Syndrome: A National Referral Centre Experience. Clin Spine Surg;2022 (Aug 17)

STUDY DESIGN: This was a retrospective case series. OBJECTIVE: The objective of this study was to discuss the treatment challenges in scoliosis patients with Rett syndrome (RTT) in a national referral centre for RTT. We describe structural characteristics of curves, age of onset, genetic mutation, ambulation status, and treatment through RTT progression. Based on this unique experience, we aimed to suggest guidelines for scoliosis treatment in RTT patients. SUMMARY OF BACKGROUND DATA: RTT is a neurodevelopmental disorder associated with a mutation in the methyl-CpG binding protein 2 (MECP2) gene, primarily in females with significant features of growth failure, gastrointestinal and pulmonary dysfunction, ataxia, seizures, and intellectual disability. Scoliosis is the most common orthopedic manifestation of RTT and is present in 64%-75% of patients. No clear guidelines for scoliosis treatment in RTT are available, and typically patients are treated according to guidelines of another neuromuscular scoliosis. METHODS: Clinical and radiographic data were gathered, including MECP2 mutation type, scoliosis characteristics, preoperative treatment, surgical treatment, functional status, and postoperative follow-up. RESULTS: Our cohort included 102 patients with RTT. They were 36 who presented with scoliosis; 18 were treated surgically. C-curve was found in 17 patients and S-type in 19. Scoliosis treatment onset was 8.76 years in the C-type group and 13.88 years in the S-type group. The average curve at the time of surgery was 52.42 degrees. The average time until surgery was 2.44 years. Seventeen patients underwent posterior spinal fusion, and 1 patient underwent posterior spinal fusion+anterior spinal fusion with an average correction of 40 degrees. The most common mutation was R255X nucleotide (30% of cases). The most severe curves had mutations R168X and R270X nucleotides. CONCLUSIONS: We advise early monitoring for patients with RTT and scoliosis due to early and rapid progression. Common mutations found were R255X, R168X, R270X, and T158M. We recommend surgical treatment in every curve above 45 degrees, independently of age.

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22. Murphy S, Flower RL, Jellett R. Women seeking an autism diagnosis in Australia: A qualitative exploration of factors that help and hinder. Autism;2022 (Aug 17):13623613221117911.

An autism diagnosis can have a big impact on women and make it possible to access support. This study explored women’s experiences of being diagnosed with autism as an adult in Australia, to try to understand what was helpful (facilitators) and unhelpful (barriers) for them during this process. We interviewed 10 autistic women who had been diagnosed in the last 5 years. Framework analysis was used to understand the data. We wanted to understand barriers and facilitators relating to the individual participants, the professionals they saw and the system they went through for their diagnostic assessment. Women reported that being able to recognise they were autistic, being motivated, preparing for the assessment, having social support and unmasking to be themselves were helpful during the diagnostic process. They reported that having a knowledgeable diagnostician who made accommodations for their needs assisted them during the assessment process. When providers dismissed the participants when they first raised the possibility they were autistic, it delayed them in seeking an assessment. At the system level, the women in this study found some aspects of the healthcare system difficult to navigate, particularly costs and long waitlists. Some found the assessment tools used were not well suited to them. The experiences of the women in this study highlight improvements that could be made to accessing an adulthood autism diagnosis in Australia. These include improving provider knowledge of the varied presentation of autism and the development of resources to help autistic women prepare for their diagnostic assessment.

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23. Nudel R, Thompson WK, Børglum AD, Hougaard DM, Mortensen PB, Werge T, Nordentoft M, Benros ME. Maternal pregnancy-related infections and autism spectrum disorder-the genetic perspective. Transl Psychiatry;2022 (Aug 16);12(1):334.

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders which include deficits in behavior, social interaction and communication. ASD has a complex genetic architecture, and it is also influenced by certain environmental exposures. Both types of predisposing factors may be related to immunological mechanisms, involving, for example, immune system genes and infections. Past studies have shown an association between infections occurring during the pregnancy in the mother and increased risk of ASD in the child, an observation which has received recent support from experimental animal studies of ASD-like behavior. The aim of this study was to study the genetic contribution to this effect. We employed genetic correlation analyses across potential ASD subtypes stratified on the basis of maternal pregnancy-related infections within the iPSYCH ASD case-cohort sample, as well as a case-case GWAS. We validated the trends of the genetic correlation analyses observed in our sample using GWAS summary statistics from the PGC ASD study (excluding iPSYCH). The genetic correlation between ASD with a history of maternal pregnancy-related infections and ASD without a history of maternal infections in iPSYCH was r(g) = 0.3811. We obtained a similar estimate between the former and the PGC ASD phenotype (r(g) = 0.3997). Both estimates are lower compared to the genetic correlation between ASD without a history of maternal infections and the PGC ASD phenotype (r(g) = 0.6735), and between ASD with a history of maternal infections occurring only more than 2 months following childbirth and the PGC ASD phenotype (r(g) = 0.6293). Additionally, we observed genetic variance between the two main ASD phenotypes using summary statistics from the case-case GWAS in iPSYCH (h(2)(cc) = 0.1059), indicating genome-wide differences between the phenotypes. Our results suggest potentially different etiologies of ASD based on a history of maternal pregnancy-related infections, which may, in part, be genetic. This highlights the relevance of maternal pregnancy-related infections to genetic studies of ASD and provides new insights into the molecular underpinnings of ASD.

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24. Ochi R, Saito S, Hiromitsu K, Shigemune Y, Shinoura N, Yamada R, Midorikawa A. Sensory hypo- and hypersensitivity in patients with brain tumors. Brain Inj;2022 (Jul 3);36(8):1053-1058.

OBJECTIVES: Hyper- and hyposensitivity in multiple modalities have been well-documented in subjects with autistic spectrum disorder (ASD) but not in subjects with acquired brain injury (ABI). The purpose of this study was to determine whether subjects with ABI experience altered sensory processing in multiple sensory modalities, and to examine the relationships between impaired sensory processing and the emotional state. METHODS AND PROCEDURES: Sixty-eight patients with brain or spinal cord tumors participated in the study. Cognitive ability and emotional function were tested, and subjective changes were evaluated in two directions (hyper- and hyposensitivity) and five modalities (visual, auditory, tactile, olfactory, and gustatory) at two time points (after disease onset and after surgery). RESULTS: One-fifth of the participants complained of hypersensitivity in the visual domain, and a similar proportion complained of hyposensitivity in the auditory and tactile domains. Additionally, one-third of participants complained of two or more sensory abnormalities after disease onset. A hierarchical regression analysis indicated that auditory and tactile sensory changes predicted a depressive state. CONCLUSION: In conclusion, multimodal sensory changes occurred in patients with brain tumors, manifesting as hyper- or hyposensitivity. Sensory changes might be related to depressive state, but the results were inconclusive.

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25. 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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26. Serra D, Henriques JF, Sousa FJ, Laranjo M, Resende R, Ferreira-Marques M, de Freitas V, Silva G, Peça J, Dinis TCP, Almeida LM. Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model. Int J Mol Sci;2022 (Aug 17);23(16)

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota-gut-brain axis.

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27. 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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28. Takagi S, Hori H, Yamaguchi T, Ochi S, Nishida M, Maruo T, Takahashi H. Motor Functional Characteristics in Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorders: A Systematic Review. Neuropsychiatr Dis Treat;2022;18:1679-1695.

BACKGROUND: The development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) has various influences on physical abilities. Identification of specific physical abilities of people with ADHD/ASDs as biomarkers for diagnosing these conditions is necessary. Therefore, in the present review, we aimed firstly to extract the difference in physical abilities of people with ADHD or ASDs compared to those of normal individuals. Secondly, we aimed to extract the specific physical ability characteristics for identifying potential diagnostic biomarkers in people with ADHD/ASDs. METHODS: A systematic literature review was performed. The databases were searched for relevant articles on motor function deficits and characteristics of ADHD or ASD. RESULTS: Forty-one cross-sectional studies and three randomized controlled trials were identified, comprising 33 studies of ADHD, 10 studies of ASDs, and 1 study of both ADHD and ASDs. The quality of studies varied. Three types of physical activities/exercises were identified, including coordinated movement, resistance-type sports, and aerobic-type sports. People with ADHD/ASDs generally exhibited poorer physical abilities for all types of activities, possibly because of low levels of physical activity. Specifically, we found temporal discoordination of movement in ADHD and integration or synchronization of separate movements in ASDs. CONCLUSION: Specific deficits in physical ability may be attributed to ADHD/ASDs. However, there is not enough research on the physical abilities of people with ADHD and ASDs to clarify the specific deficits. Investigation of specific motor functions that characterize ADHD/ASDs should be facilitated.

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29. 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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30. Thapar A, Livingston LA, Eyre O, Riglin L. Practitioner Review: Attention-deficit hyperactivity disorder and autism spectrum disorder – the importance of depression. J Child Psychol Psychiatry;2022 (Aug 16)

Young people with neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), show high rates of mental health problems, of which depression is one of the most common. Given that depression in ASD and ADHD is linked with a range of poor outcomes, knowledge of how clinicians should assess, identify and treat depression in the context of these neurodevelopmental disorders is much needed. Here, we give an overview of the latest research on depression in young people with ADHD and ASD, including possible mechanisms underlying the link between ADHD/ASD and depression, as well as the presentation, assessment and treatment of depression in these neurodevelopmental disorders. We discuss the implications for clinicians and make recommendations for critical future research in this area.

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31. Zakai-Mashiach M. « I Was Like a Bird Without Wings »: Autistic Women’s Retrospective Experiences in General Schools. J Autism Dev Disord;2022 (Aug 16)

Autistic individuals’ experience of the inclusion process is poorly understood, especially that of female pupils. This study retrospectively explored the views of autistic women who were included in general schools throughout childhood and adolescence, from elementary to high school, to understand their unique experiences and learn more about their needs in general schools. Semi-structured interviews were conducted, data were thematically analyzed, and key issues emerged pertaining to each educational level. The women described a complex journey within the general education system. Their responses highlight the need for greater attention to autistic females’ patterns of behavior in research and practice. Implications and recommendations for educators and schools are provided, and directions for future research are outlined.

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32. Zlatic SA, Duong D, Gadalla KKE, Murage B, Ping L, Shah R, Fink JJ, Khwaja O, Swanson LC, Sahin M, Rayaprolu S, Kumar P, Rangaraju S, Bird A, Tarquinio D, Carpenter R, Cobb S, Faundez V. Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome. iScience;2022 (Sep 16);25(9):104966.

MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in Mecp2 (-/y) and Mecp2 (-/+) . Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction.

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