1. Bettencourt C, Garret-Gloanec N, Pellerin H, Péré M, Squillante M, Roos-Weil F, Ferrand L, Pernel AS, Apter G, Cohen D. Migration is associated with baseline severity and progress over time in autism spectrum disorder: Evidence from a French prospective longitudinal study. PLoS One;2022;17(10):e0272693.

BACKGROUND: The prevalence of autism-spectrum disorder (ASD) has been shown to be higher in migrant families, but it is also a challenge for health care professionals to offer adequate services to families that face multiple challenges. In the context of the EPIGRAM study (a French prospective, multisite, longitudinal observational study implementing integrative care practices (ICPs) for children with ASD), we aimed to assess the impact of migration on children with ASD. METHOD AND FINDINGS: 89 children with ASD aged 3 to 6 years old (92% males) were recruited and followed up for 12 months. The children were clinically assessed using several instruments. At baseline, children had severe autism on average on the Children Autism Rating Scale (CARS, mean = 44; SD = 6.51) and moderate autism on the PsychoEducational profile-3-R (PEP-3-R) maladaptive behavior category (mean = 30; SD = 29.89). Thirty percent of the families had a low socio-economic status, and 56% were first-generation immigrants. For all clinical variables, children of immigrant parents had more severe autism and developmental delays at baseline. A linear mixed model established an improvement in all clinical characteristics over the 12 months of the study. This trend may be attributed to ICPs or any naturally occurring event during that period. Families shared this positive view over time. However, the improvements were slower for two clinical dimensions of the PEP-3-R in children from migrant families. For the inappropriate behavior category, the time effect diminished by an average of 0.83 percentile/month for children whose parents were migrants vs. children whose parents were non-migrants. Similarly, for verbal behavior characteristics, the time effect diminished by an average of 1.32 percentile/month for children whose parents were migrants vs. children whose parents were non-migrants. CONCLUSION: Despite an overall positive improvement, we found that migration is associated baseline severity and progress over time in children with ASD. There is an urgent need to target the migrant population with specific research and understand the avenues that carry such higher severity. CLINICAL TRIAL REGISTRATION: Study registration on clinicaltrials.gov under the number NCT02154828.

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2. Bradshaw J, Shi D, Federico A, Klaiman C, Saulnier C. The Pull-to-Sit Task: Examining Infant Postural Development in Autism Spectrum Disorder. J Pediatr;2022 (Oct 3)

OBJECTIVE: To evaluate the predictive relation between early trajectories of postural and head control during a pull-to-sit task and later autism diagnostic and developmental outcomes. STUDY DESIGN: Using a prospective longitudinal design, postural skills in N=100 infants at elevated and low familial likelihood of ASD were evaluated using a pull-to-sit task monthly from age 1-6 months. At 24 months, infants were seen for a developmental and diagnostic evaluation completed by examiners masked to participant group. Latent growth curve models were used to compare early trajectories of pull-to-sit performance for infants later diagnosed with ASD and typically developing infants and predict developmental outcomes. RESULTS: Pull-to-sit trajectories did not differ for elevated likelihood infants or infants with ASD when compared with low likelihood and typically developing infants, but infants with ASD were more likely to exhibit at head lag by age 4 months. In addition, pull-to-sit trajectories predicted social and speech skills two years later. CONCLUSIONS: These findings highlight the role of very early pull-to-sit skills for later social and language outcomes. Atypical postural development and persistent presence of head lag may be important early indicators of social and language vulnerabilities, including ASD.

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3. Busque AA, Jabbour E, Patel S, Couture É, Garfinkle J, Khairy M, Claveau M, Beltempo M. Incidence and risk factors for autism spectrum disorder among infants born <29 weeks' gestation. Paediatr Child Health;2022 (Oct);27(6):346-352.

OBJECTIVE: This study was aimed to assess the incidence of and risk factors for autism spectrum disorder (ASD) among preterm infants born <29 weeks' gestational age (GA). METHODS: A retrospective cohort study of infants born <29 weeks' GA admitted to two tertiary neonatal intensive care units (2009 to 2017) and followed ≥18 months corrected age (CA) at a neonatal follow-up clinic. The primary outcome was ASD, diagnosed using standardized testing or provisional diagnosis at ≥18 months CA. Patient data and 18-month CA developmental outcomes were obtained from the local Canadian Neonatal Follow Up Network database and chart review. Stepwise logistic regression assessed factors associated with ASD. RESULTS: Among 300 eligible infants, 26 (8.7%) were diagnosed with confirmed and 21 (7.0%) with provisional ASD for a combined incidence of 15.7% (95% confidence interval [CI] 11.7 to 20.3). The mean follow-up duration was 3.9 ± 1.4 years and the mean age of diagnosis was 3.7 ± 1.5 years. Male sex (adjusted odds ratio [aOR] 4.63, 95% CI 2.12 to 10.10), small for gestational age status (aOR 3.03, 95% CI 1.02 to 9.01), maternal age ≥35 years at delivery (aOR 2.22, 95% CI 1.08 to 4.57) and smoking during pregnancy (aOR 5.67, 95% CI 1.86 to 17.29) were significantly associated with ASD. Among ASD infants with a complete 18-month CA developmental assessment, 46% (19/41) had no neurodevelopmental impairment (Bayley-III<70, deafness, blindness, or cerebral palsy). CONCLUSIONS: ASD is common among infants born <29 weeks' GA and possibly associated with identified risk factors. Such findings emphasize the importance of ASD evaluation among infants <29 weeks' GA and for continued reporting of developmental outcomes beyond 18-months of corrected age.

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4. Cheng H, Charles I, James AF, Abdala AP, Hancox JC. QT(c) interval and ventricular action potential prolongation in the Mecp2(Null/+) murine model of Rett syndrome. Physiol Rep;2022 (Oct);10(19):e15437.

Rett Syndrome (RTT) is a congenital, X-chromosome-linked developmental disorder characterized by developmental delay, dysautonomia, and breathing irregularities. RTT is also associated with sudden death and QT intervals are prolonged in some RTT patients. Most individuals with RTT have mutations in the MECP2 gene. Whilst there is some evidence for QT prolongation in mouse models of RTT, there is comparatively little information on how loss of Mecp2 function affects ventricular action potentials (APs) and, to-date, none on ventricular APs from female RTT mice. Accordingly, the present study was conducted to determine ECG and ventricular AP characteristics of Mecp2(Null/+) female mice. ECG recordings from 12-13 month old female Mecp2(Null/+) mice showed prolonged rate corrected QT (QTc) intervals compared to wild-type (WT) controls. Although Mecp2(Null/+) animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QT(c) interval was observed. Action potentials (APs) from Mecp2(Null/+) myocytes had longer APD(90) values than those from WT myocytes and showed augmented triangulation. Application of the investigational I(Na,Late) inhibitor GS-6615 (eleclazine; 10 μM) reduced both APD(90) and AP triangulation in Mecp2(Null/+) and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2(Null/+) myocytes and provide further evidence that GS-6615 may have potential as an intervention against QT prolongation in RTT.

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5. Cleary M, West S, McLean L, Kornhaber R, Hungerford C. Two Halves of the Same Whole: A Framework to Integrate Autism and Mental Health Services. Issues Ment Health Nurs;2022 (Oct 7):1-11.

Given the higher rates of co-occurring mental health issues experienced by autistic people, there is a pressing need to implement an effective framework that integrates autism services with appropriate mental health services. This paper discusses the impact of mental illness on the person with autism and their families, and the current challenges they face when accessing mental health support. A framework for service providers is proposed to support the mental health needs and preferences of autistic people. The paper concludes by highlighting the importance of health professionals utilising mental health interventions appropriate for autistic people, including autism-specific suicide prevention and awareness programs.

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6. Haigh SM, Van Key L, Brosseau P, Eack SM, Leitman DI, Salisbury DF, Behrmann M. Assessing Trial-to-Trial Variability in Auditory ERPs in Autism and Schizophrenia. J Autism Dev Disord;2022 (Oct 7)

Sensory abnormalities are characteristic of autism and schizophrenia. In autism, greater trial-to-trial variability (TTV) in sensory neural responses suggest that the system is more unstable. However, these findings have only been identified in the amplitude and not in the timing of neural responses, and have not been fully explored in schizophrenia. TTV in event-related potential amplitudes and inter-trial coherence (ITC) were assessed in the auditory mismatch negativity (MMN) in autism, schizophrenia, and controls. MMN was largest in autism and smallest in schizophrenia, and TTV was greater in autism and schizophrenia compared to controls. There were no differences in ITC. Greater TTV appears to be characteristic of both autism and schizophrenia, implicating several neural mechanisms that could underlie sensory instability.

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7. Haskins AJ, Mentch J, Botch TL, Garcia BD, Burrows AL, Robertson CE. Reduced social attention in autism is magnified by perceptual load in naturalistic environments. Autism Res;2022 (Oct 7)

Individuals with autism spectrum conditions (ASC) describe differences in both social cognition and sensory processing, but little is known about the causal relationship between these disparate functional domains. In the present study, we sought to understand how a core characteristic of autism-reduced social attention-is impacted by the complex multisensory signals present in real-world environments. We tested the hypothesis that reductions in social attention associated with autism would be magnified by increasing perceptual load (e.g., motion, multisensory cues). Adult participants (N = 40; 19 ASC) explored a diverse set of 360° real-world scenes in a naturalistic, active viewing paradigm (immersive virtual reality + eyetracking). Across three conditions, we systematically varied perceptual load while holding the social and semantic information present in each scene constant. We demonstrate that reduced social attention is not a static signature of the autistic phenotype. Rather, group differences in social attention emerged with increasing perceptual load in naturalistic environments, and the susceptibility of social attention to perceptual load predicted continuous measures of autistic traits across groups. Crucially, this pattern was specific to the social domain: we did not observe differential impacts of perceptual load on attention directed toward nonsocial semantic (i.e., object, place) information or low-level fixation behavior (i.e., overall fixation frequency or duration). This study provides a direct link between social and sensory processing in autism. Moreover, reduced social attention may be an inaccurate characterization of autism. Instead, our results suggest that social attention in autism is better explained by « social vulnerability, » particularly to the perceptual load of real-world environments. LAY SUMMARY: Real-world sensory contexts place incredible demands on selective attention. Autistic individuals report a particular challenge navigating contexts with high perceptual load, but little is known about its impact on classic, social signatures of autism. Here, we used eyetracking in immersive virtual reality to test the impact of perceptual load on social attention in naturalistic contexts. Overall, we found that group differences in social attention emerge with increasing real-world perceptual load, revealing a novel link between social and sensory processing in autism.

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8. Johnston KJ, Chin MH, Pollack HA. Health Equity for Individuals With Intellectual and Developmental Disabilities. JAMA;2022 (Oct 7)

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9. Lacroix A, Proteau-Lemieux M, Côté S, Near J, Hui SCN, Edden RAE, Lippé S, Çaku A, Corbin F, Lepage JF. Multimodal assessment of the GABA system in patients with fragile-X syndrome and neurofibromatosis of type 1. Neurobiol Dis;2022 (Oct 3);174:105881.

Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABA(B)-mediated inhibition compared to controls and NF1 patients, and that GABA(A)-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.

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10. Mannu J, Latha AM, Rajagopal S, Lalitha HDA, Muthurajan R, Loganathan A, Subbarayalu M, Ramasamy G, Jegadeesan R. Whole genome sequencing of ASD 16 and ADT 43 to identify predominant grain size and starch associated alleles in rice. Mol Biol Rep;2022 (Oct 6)

BACKGROUND: The rice cultivars ASD 16 and ADT 43 are the most popular high-yielding Indica rice cultivars in southern India. Despite their popularity very little is known about their genetic basis due to lack of studies on the complete genome. In the current study, efforts were made to identify alleles and SNP markers that differentiate the two contrasting rice genotypes, ASD 16 and ADT 43 for grain shape and starch content. METHODS AND RESULTS: The complete genome of bold grain ASD 16 and slender grain ADT 43 were sequenced via Illumina’s paired-end sequencing and the reads obtained were mapped to the Oryza sativa Indica Group cultivar 93-11 reference genome. The grain size of rice is controlled by Quantitative Trait Loci (QTL) that has a robust effect on grain yield and quality. To gain insight into genes that controlling grain size and starch content, an in-silico analysis was performed by taking into account of 72 grain elongation and starch biosynthesis genes. The identified alleles were further validated in the whole genome sequencing data of 32 bold grain and 25 slender grain varieties that were retrieved from the 3 K rice genome project. CONCLUSION: An « A to G » polymorphism leading to SER 74 PRO was identified at the CDS position 220 of the An-1 gene, encoding bHLH domain-containing protein that regulates awn formation and increase in grain length. The non-synonymous substitutions such as A545C variant leading PHE 182 CYS in ADP Glucose Pyrophosphorylase large subunit IV (AGPL4) and C3094G variant leading to VAL 1032 LEU in Starch synthase IIIb (OsSSIIIb) were also identified in the starch biosynthesis genes. These identified allelic variants may contribute to the crop improvement programs in rice.

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11. Pattison E, Mantilla A, Fuller-Tyszkiewicz M, Marks D, Sciberras E, McGillivray J, Papadopoulos N, Rinehart N. Acceptability of a behavioural sleep intervention for autistic children: A qualitative evaluation of Sleeping Sound. Sleep Med;2022 (Sep 20);100:378-389.

OBJECTIVE: The aim of the current study was to evaluate parental perceptions of the acceptability of a brief behavioural sleep intervention for autistic children (aged 5-13 years) using the Theoretical Framework of Acceptability (TFA). METHODS: Qualitative data were collected during a large randomised controlled trial evaluating the efficacy of the Sleeping Sound intervention: 123 families were randomised to the intervention group, of which 115 (93%) completed at least one intervention session and 82 (67%) provided qualitative evaluation data in the 3-month follow-up survey. Consultation records from intervention sessions and parent surveys were qualitatively analysed post hoc using a hybrid approach to thematic analysis. RESULTS: Findings were categorised under the seven themes of the TFA (affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, self-efficacy) in addition to three themes that were defined following inductive and deductive coding (barriers to implementation, facilitators to implementation, suggestions for improvement). Participants spoke positively about their experience participating in the intervention and perceived the intervention to be appropriate and effective. Most parents (95.5%) reported that they would recommend the Sleeping Sound intervention to other families of autistic children. Barriers to implementation included child and parent anxiety, child health problems, parental preferences, family circumstances, and other (e.g., school holidays). Facilitators to implementation included family support and consistency with strategies. CONCLUSIONS: The Sleeping Sound intervention was considered acceptable to parents of autistic children as evidenced by largely positive feedback regarding their experience. The results highlighted areas for improvement which can be used to inform future iterations of the intervention.

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12. Perfilyeva A, Bespalova K, Perfilyeva Y, Skvortsova L, Musralina L, Zhunussova G, Khussainova E, Iskakova U, Bekmanov B, Djansugurova L. Integrative Functional Genomic Analysis in Multiplex Autism Families from Kazakhstan. Dis Markers;2022;2022:1509994.

The study of extended pedigrees containing autism spectrum disorder- (ASD-) related broader autism phenotypes (BAP) offers a promising approach to the search for ASD candidate variants. Here, a total of 650,000 genetic markers were tested in four Kazakhstani multiplex families with ASD and BAP to obtain data on de novo mutations (DNMs), common, and rare inherited variants that may contribute to the genetic risk for developing autistic traits. The variants were analyzed in the context of gene networks and pathways. Several previously well-described enriched pathways were identified, including ion channel activity, regulation of synaptic function, and membrane depolarization. Perhaps these pathways are crucial not only for the development of ASD but also for ВАР. The results also point to several additional biological pathways (circadian entrainment, NCAM and BTN family interactions, and interaction between L1 and Ankyrins) and hub genes (CFTR, NOD2, PPP2R2B, and TTR). The obtained results suggest that further exploration of PPI networks combining ASD and BAP risk genes can be used to identify novel or overlooked ASD molecular mechanisms.

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13. Tian H, Jiao Y, Guo M, Wang Y, Wang R, Wang C, Chen X, Tian W. Krüppel-like factor 7 deficiency causes autistic-like behavior in mice via regulating Clock gene. Cell Biosci;2022 (Oct 7);12(1):166.

BACKGROUND: Krüppel-like factor 7 (klf7), a transcription factor in the nervous system to regulate cell proliferation and differentiation, has been recently identified as a causal gene for autism spectrum disorder (ASD), but the mechanism behind remains unknown. RESULT: To uncover this mechanism, in this study we characterized the involvement of klf7 in circadian rhythm by knocking down klf7 in N2A cells and examining the rhythmic expression of circadian genes, especially Clock gene. We constructed klf7(-/-) mice and then investigated into klf7 regulation on the expression of rhythm genes in vivo as well as the use of melatonin to rescue the autism behavior. Our results illustrated that circadian rhythm was disrupted in klf7 knockdown cells and that klf7(-/-) mice showed autism-like behavior. Also, we found that Clock gene was downregulated in the brain of these klf7(-/-) mice and that the downstream rhythm genes of Clock were disturbed. Melatonin, as a circadian regulation drug, could regulate the expression level and amplitude of rhythm genes in klf7 knockout cells and further rescue the autistic behavior of klf7(-/-) mice. CONCLUSION: Klf7 deficiency causes ASD by disrupting circadian rhythm related genes to trigger rhythm oscillations. To treat ASD, maintaining circadian homeostasis is promising with the use of melatonin.

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14. Visser TAW, English MCW, Maybery MT. No evidence for superior distractor filtering amongst individuals high in autistic-like traits. Atten Percept Psychophys;2022 (Oct 7)

Autistic individuals and individuals with high levels of autistic-like traits often show better visual search performance than their neurotypical peers. The present work investigates whether this advantage stems from increased ability to filter out distractors. Participants with high or low levels of autistic-like traits completed an attentional blink task in which trials varied in target-distractor similarity. The results showed no evidence that high levels of autistic-like traits were associated with superior distractor filtering (indexed by the difference in the size of the attentional blink across the high- and low-similarity distractors). This suggests that search advantages seen in previous studies are likely linked to other mechanisms such as enhanced pre-attentive scene processing, better decision making, or more efficient response selection.

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15. Wang Y, Chiola S, Yang G, Russell C, Armstrong CJ, Wu Y, Spampanato J, Tarboton P, Ullah HMA, Edgar NU, Chang AN, Harmin DA, Bocchi VD, Vezzoli E, Besusso D, Cui J, Cattaneo E, Kubanek J, Shcheglovitov A. Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes. Nat Commun;2022 (Oct 6);13(1):5688.

Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity.

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16. Zhang X, Shu S, Zhu Z, Gu Q, Liu Z, Qiu Y, Bao H. Proximal junctional kyphosis is a compensation for post-operative negative C2-FH in ASD patients: a cross-sectional study. J Orthop Surg Res;2022 (Oct 7);17(1):442.

BACKGROUND: Recent studies have found that C2-FH is close to 0 cm in both standing and sitting position for asymptomatic adults. We hypothesize that the thoracic spine may compensate with PJK when the immediate post-operative C2-FH was not ideally restored in adult spinal deformity (ASD). METHODS: The inclusion criteria were as follows: ASD patients over 45 years old; Cobb angle > 30°; with posterior spinal correction surgery; at least 2 years follow-up. C2-FH was defined as the distance between the femoral heads to the C2 vertical line. All participants were divided into two groups according to the occurrence of PJK at the last follow-up: PJK group and non-PJK group. RESULTS: 68 ASD patients, with a minimum follow-up of 2.5 years, were included. PJK was found in 24 patients (35.3%) while the rest 44 patients remained no sagittal malalignment. Immediately post-operative C2-FH showed significant difference between PJK group and non-PJK group (p = 0.015). However, at the last follow-up, C2-FH showed no significant difference between PJK and non-PJK group and the mean value of C2-FH in both groups was approximately - 1 cm, indicating that ASD patients could develop various compensatory mechanisms to maintain sagittal global balance. The AUC was 0.84 (95%CI 0.68-0.97), indicating the well effectiveness of ROC curve and cut-off value in predicting occurrence of PJK in ASD patients. Based on the ROC curve, the optimal cut-off value of C2-FH as indicators for occurrence of PJK was - 42.3 mm. CONCLUSION: Immediate postoperative negative global malalignment (C2-FH < - 42.3 mm) may predict proximal junctional kyphosis in ASD patients. The normal value of C2-FH, - 1 cm, may be the target of global sagittal compensation, and PJK is a compensatory mechanism. TRIAL REGISTRATION: 2021-LCYJ-DBZ-05, 2021.07, Retrospective study.

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