Pubmed du 06/07/22

Pubmed du jour

1. Ali D, O’Brien S, Hull L, Kenny L, Mandy W. ‘The key to this is not so much the technology. It’s the individual who is using the technology’: Perspectives on telehealth delivery for autistic adults during the COVID-19 pandemic. Autism;2022 (Jul 6):13623613221108010.

The COVID-19 pandemic meant that a lot of healthcare services had to move online, such as to video-calls, or to telephone. However, not many studies have looked at how autistic adults feel about this kind of service delivery. It is important to know this, as autistic people may have poorer health than non-autistic people, and they may also struggle to access services more than non-autistic people. This study asked 11 autistic adults (aged 27-67 years), seven family members/carers (aged 44-75) reporting about autistic adults and six service providers about their experiences of accessing or providing a telehealth service. These experiences were collected through interviews, which were then analysed through thematic analysis. Two main themes were: technology aids communication and access – except when it doesn’t, and in/flexibility. The themes pointed out some positive aspects of telehealth delivery, including improved communication and decreased stress. The themes also pointed out negative aspects of telehealth, such as increased rigidity of the healthcare system, amplifying pre-existing barriers. Because autistic people have many barriers to accessing healthcare, this study encourages researchers and healthcare providers to think about how such barriers could be addressed through telehealth, and about the possible limitations of telehealth for some autistic people.

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2. Alispahic S, Pellicano E, Cutler A, Antoniou M. Auditory perceptual learning in autistic adults. Autism Res;2022 (Jul 5)

The automatic retuning of phoneme categories to better adapt to the speech of a novel talker has been extensively documented across various (neurotypical) populations, including both adults and children. However, no studies have examined auditory perceptual learning effects in populations atypical in perceptual, social, and language processing for communication, such as populations with autism. Employing a classic lexically-guided perceptual learning paradigm, the present study investigated perceptual learning effects in Australian English autistic and non-autistic adults. The findings revealed that automatic attunement to existing phoneme categories was not activated in the autistic group in the same manner as for non-autistic control subjects. Specifically, autistic adults were able to both successfully discern lexical items and to categorize speech sounds; however, they did not show effects of perceptual retuning to talkers. These findings may have implications for the application of current sensory theories (e.g., Bayesian decision theory) to speech and language processing by autistic individuals. LAY SUMMARY: Lexically guided perceptual learning assists in the disambiguation of speech from a novel talker. The present study established that while Australian English autistic adult listeners were able to successfully discern lexical items and categorize speech sounds in their native language, perceptual flexibility in updating speaker-specific phonemic knowledge when exposed to a novel talker was not available. Implications for speech and language processing by autistic individuals as well as current sensory theories are discussed.

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3. Chaudry S, Vasudevan N. mTOR-Dependent Spine Dynamics in Autism. Front Mol Neurosci;2022;15:877609.

Autism Spectrum Conditions (ASC) are a group of neurodevelopmental disorders characterized by deficits in social communication and interaction as well as repetitive behaviors and restricted range of interests. ASC are complex genetic disorders with moderate to high heritability, and associated with atypical patterns of neural connectivity. Many of the genes implicated in ASC are involved in dendritic spine pruning and spine development, both of which can be mediated by the mammalian target of rapamycin (mTOR) signaling pathway. Consistent with this idea, human postmortem studies have shown increased spine density in ASC compared to controls suggesting that the balance between autophagy and spinogenesis is altered in ASC. However, murine models of ASC have shown inconsistent results for spine morphology, which may underlie functional connectivity. This review seeks to establish the relevance of changes in dendritic spines in ASC using data gathered from rodent models. Using a literature survey, we identify 20 genes that are linked to dendritic spine pruning or development in rodents that are also strongly implicated in ASC in humans. Furthermore, we show that all 20 genes are linked to the mTOR pathway and propose that the mTOR pathway regulating spine dynamics is a potential mechanism underlying the ASC signaling pathway in ASC. We show here that the direction of change in spine density was mostly correlated to the upstream positive or negative regulation of the mTOR pathway and most rodent models of mutant mTOR regulators show increases in immature spines, based on morphological analyses. We further explore the idea that these mutations in these genes result in aberrant social behavior in rodent models that is due to these altered spine dynamics. This review should therefore pave the way for further research on the specific genes outlined, their effect on spine morphology or density with an emphasis on understanding the functional role of these changes in ASC.

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4. Chien YL, Lin HY, Tung YH, Hwang TJ, Chen CL, Wu CS, Shang CY, Hwu HG, Tseng WI, Liu CM, Gau SS. Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD. Mol Psychiatry;2022 (Jul 6)

The neurodevelopmental model of schizophrenia is supported by multi-level impairments shared among schizophrenia and neurodevelopmental disorders. Despite schizophrenia and typical neurodevelopmental disorders, i.e., autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as disorders of brain dysconnectivity, no study has ever elucidated whether whole-brain white matter (WM) tracts integrity alterations overlap or diverge between these three disorders. Moreover, whether the linked dimensions of cognition and brain metrics per the Research Domain Criteria framework cut across diagnostic boundaries remains unknown. We aimed to map deviations from normative ranges of whole-brain major WM tracts for individual patients to investigate the similarity and differences among schizophrenia (281 patients subgrouped into the first-episode, subchronic and chronic phases), ASD (175 patients), and ADHD (279 patients). Sex-specific WM tract normative development was modeled from diffusion spectrum imaging of 626 typically developing controls (5-40 years). There were three significant findings. First, the patterns of deviation and idiosyncrasy of WM tracts were similar between schizophrenia and ADHD alongside ASD, particularly at the earlier stages of schizophrenia relative to chronic stages. Second, using the WM deviation patterns as features, schizophrenia cannot be separated from neurodevelopmental disorders in the unsupervised machine learning algorithm. Lastly, the canonical correlation analysis showed schizophrenia, ADHD, and ASD shared linked cognitive dimensions driven by WM deviations. Together, our results provide new insights into the neurodevelopmental facet of schizophrenia and its brain basis. Individual’s WM deviations may contribute to diverse arrays of cognitive function along a continuum with phenotypic expressions from typical neurodevelopmental disorders to schizophrenia.

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5. Cikowski J, Holt C, Arthur B, Smith M, Gonzalez S, Lindsley CW, Niswender CM, Gogliotti RG. Optimized Administration of the M(4) PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mecp2(+/-) Mice. ACS Chem Neurosci;2022 (Jul 6);13(13):1891-1901.

Hypofunction of cholinergic circuits and diminished cholinergic tone have been associated with the neurodevelopmental disorder Rett syndrome (RTT). Specifically, deletion of Mecp2 in cholinergic neurons evokes the same social and cognitive phenotypes in mice seen with global Mecp2 knockout, and decreased choline acetyltransferase activity and vesamicol binding have been reported in RTT autopsy samples. Further, we recently identified significant decreases in muscarinic acetylcholine receptor subtype 4 (M(4)) expression in both the motor cortex and cerebellum of RTT patient autopsies and established proof of concept that an acute dose of the positive allosteric modulator (PAM) VU0467154 (VU154) rescued phenotypes in Mecp2(+/-) mice. Here, we expand the assessment of M(4) PAMs in RTT to address clinically relevant questions of tolerance, scope of benefit, dose response, chronic treatment, and mechanism. We show that VU154 has efficacy on anxiety, social preference, cognitive, and respiratory phenotypes in Mecp2(+/-) mice; however, the therapeutic range is narrow, with benefits seen at 3 mg/kg concentrations, but not 1 or 10 mg/kg. Further, sociability was diminished in VU154-treated Mecp2(+/-) mice, suggestive of a potential adverse effect. Compound efficacy on social, cognitive, and respiratory phenotypes was conserved with a 44-day treatment paradigm, with the caveat that breath rate was moderately decreased with chronic treatment in Mecp2(+/+) and Mecp2(+/-) mice. VU154 effects on respiratory function correlated with an increase in Gsk3β inhibition in the brainstem. These results identify the core symptom domains where efficacy and adverse effects may present with M(4) administration in RTT model mice and advocate for the continued evaluation as potential RTT therapeutics.

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6. Durkut M, Blok E, Suleri A, White T. The longitudinal bidirectional relationship between autistic traits and brain morphology from childhood to adolescence: a population-based cohort study. Mol Autism;2022 (Jul 5);13(1):31.

OBJECTIVE: Autistic traits are associated with alterations in brain morphology. However, the anatomic location of these differences and their developmental trajectories are unclear. The primary objective of this longitudinal study was to explore the bidirectional relationship between autistic traits and brain morphology from childhood to adolescence. METHOD: Participants were drawn from a population-based cohort. Cross-sectional and longitudinal analyses included 1950 (mean age 13.5) and 304 participants (mean ages 6.2 and 13.5), respectively. Autistic traits were measured with the Social Responsiveness Scale. Global brain measures and surface-based measures of gyrification, cortical thickness and surface area were obtained from T(1)-weighted MRI scans. Cross-sectional associations were assessed using linear regression analyses. Cross-lagged panel models were used to determine the longitudinal bidirectional relationship between autistic traits and brain morphology. RESULTS: Cross-sectionally, higher levels of autistic traits in adolescents are associated with lower gyrification in the pars opercularis, insula and superior temporal cortex; smaller surface area in the middle temporal and postcentral cortex; larger cortical thickness in the superior frontal cortex; and smaller cerebellum cortex volume. Longitudinally, both autistic traits and brain measures were quite stable, with neither brain measures predicting changes in autistic traits, nor vice-versa. LIMITATIONS: Autistic traits were assessed at only two time points, and thus we could not distinguish within- versus between-person effects. Furthermore, two different MRI scanners were used between baseline and follow-up for imaging data acquisition. CONCLUSIONS: Our findings point to early changes in brain morphology in children with autistic symptoms that remain quite stable over time. The observed relationship did not change substantially after excluding children with high levels of autistic traits, bolstering the evidence for the extension of the neurobiology of autistic traits to the general population.

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7. Fajardo I, Joseph H. Brief report: Autistic students read between lines. J Autism Dev Disord;2022 (Jul 6)

Students with Autism Spectrum Disorder (ASD) tend to struggle with reading comprehension, often resulting in difficulties with inference generation. While most of the previous research has focused on the product of comprehension, we report a preliminary validation of an experimental reading task in English to measure, by means of eye-movements, the time course of generating consistent and inconsistent inferences during reading. The task was tested with a group of 12 students with ASD (age range: 10-15) who showed accuracy differences between inference and control conditions. Participants spent longer reading in the inconsistent than control condition regarding go past times and second pass times and made more regressions into the target and post-target regions, but these differences were not significant.

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8. Giannotti M, Bentenuto A, Venuti P, de Falco S. Explicit and implicit attachment representations in cognitively able school-age children with autism spectrum disorder: A window to their inner world. Clin Child Psychol Psychiatry;2022 (Jul 6):13591045221113390.

The few studies available on quality of attachment in school-age children with autism spectrum disorder (ASD) exclusively used questionnaires assessing explicit attachment representations. Thus, in the current study we assessed both explicit and implicit attachment representations in 23 children with ASD (without intellectual disability), 22 with learning disabilities and 27 with typical development aged from 7 to 13 years. A self-reported measure on the quality of attachment to parents and a semi-structured interview were administered to the children. In addition, a developmental assessment of the child including measures of intelligence and social-communication impairment was conducted. Despite the lack of group differences on explicit attachment representations, we found that children with ASD showed higher rates of at-risk self-protective strategies and psychological trauma compared to the TD group. Children with SLD also showed a high level of at-risk implicit attachment representations than TD, albeit to a lesser extent compared to children with ASD. These results may be related to several factors associated with ASD impairment and developmental pathways, such as the atypical learning process which occur at interpersonal level, the difficulties in social information processing and reflective functioning. Our findings suggested that children with ASD may experience difficulties in the construction of balanced implicit attachment representations. Thus, a more comprehensive assessment of attachment including both implicit and explicit representations is recommended.

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9. Gosling CJ, Cartigny A, Mellier BC, Solanes A, Radua J, Delorme R. Efficacy of psychosocial interventions for Autism spectrum disorder: an umbrella review. Mol Psychiatry;2022 (Jul 5)

INTRODUCTION: The wide range of psychosocial interventions designed to assist people with Autism Spectrum Disorder (ASD) makes it challenging to compile and hierarchize the scientific evidence that supports the efficacy of these interventions. Thus, we performed an umbrella review of published meta-analyses of controlled clinical trials that investigated the efficacy of psychosocial interventions on both core and related ASD symptoms. METHODS: Each meta-analysis that was identified was re-estimated using a random-effects model with a restricted maximum likelihood estimator. The methodological quality of included meta-analyses was critically appraised and the credibility of the evidence was assessed algorithmically according to criteria adapted for the purpose of this study. RESULTS: We identified a total of 128 meta-analyses derived from 44 reports. More than half of the non-overlapping meta-analyses were nominally statistically significant and/or displayed a moderate-to-large pooled effect size that favored the psychosocial interventions. The assessment of the credibility of evidence pointed out that the efficacy of early intensive behavioral interventions, developmental interventions, naturalistic developmental behavioral interventions, and parent-mediated interventions was supported by suggestive evidence on at least one outcome in preschool children. Possible outcomes included social communication deficits, global cognitive abilities, and adaptive behaviors. Results also revealed highly suggestive indications that parent-mediated interventions improved disruptive behaviors in early school-aged children. The efficacy of social skills groups was supported by suggestive evidence for improving social communication deficits and overall ASD symptoms in school-aged children and adolescents. Only four meta-analyses had a statistically significant pooled effect size in a sensitivity analysis restricted to randomized controlled trials at low risk of detection bias. DISCUSSION: This umbrella review confirmed that several psychosocial interventions show promise for improving symptoms related to ASD at different stages of life. However, additional well-designed randomized controlled trials are still required to produce a clearer picture of the efficacy of these interventions. To facilitate the dissemination of scientific knowledge about psychosocial interventions for individuals with ASD, we built an open-access and interactive website that shares the information collected and the results generated during this umbrella review. PRE-REGISTRATION: PROSPERO ID CRD42020212630.

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10. Guidotti M, Gateau A, Claire R, Rabaté P, Roux S, Malvy J, Bonnet-Brilhault F. Autism Spectrum Disorder during French COVID-19 lockdown: the importance of individualized support. Child Care Health Dev;2022 (Jul 4)

OBJECTIVES: This observational and repeated measures study assesses the impact of the first, most restrictive, COVID-19 lockdown in France on children with autism spectrum disorder (ASD) and their families. METHOD: During the first COVID-19 lockdown, families of ASD children enrolled in the day care center of the child and adolescent psychiatry department of the Tours University Hospital, were contacted weekly. A total of 95 parents took part in this study between the 18(th) of March and the 8(th) of May 2020. Advice and personalized support materials were provided by professionals involved in children’s care. Questions regarding clinical outcomes were addressed to parents, and their assessments reported on a 5-point Likert scale. Two time points were considered: the first 3 weeks and the 3 last weeks of the lockdown period. RESULTS: No difference was highlighted between clinical scores collected at the beginning and at the end of the lockdown. No effect of intellectual disability, accommodation type (house or apartment) or parental status was observed. The reasons for the relatively minor impact of the COVID-19 lockdown observed in this study are discussed. CONCLUSION: Individualized and regular support provided by caregivers, familiar with ASD children’s clinical specificities, in the context of a trusted relationship with parents may have contributed to the stability of this population. This « tailor-made » approach should be promoted, in order to help support families of ASD children in this challenging period.

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11. Guo M, Xie P, Liu S, Luan G, Li T. Epilepsy and Autism Spectrum Disorder (ASD): The underlying Mechanisms and Therapy Targets related with Adenosine. Curr Neuropharmacol;2022 (Jul 6)

Epilepsy and autism spectrum disorder (ASD) are highly mutually comorbid, suggesting potential overlaps in genetic etiology, pathophysiology, and neurodevelopmental abnormalities. Adenosine, an endogenous anticonvulsant and neuroprotective neuromodulator of the brain, has been proved to affect the process of epilepsy and ASD. On the one hand, adenosine plays a crucial role in preventing the progression and development of epilepsy through adenosine receptor-dependent and -independent ways. On the other hand, adenosine signaling can not only regulate core symptoms but also improve comorbid disorders in ASD. Given the important role of adenosine in epilepsy and ASD together, therapeutic strategies related to adenosine, including the ketogenic diet, neuro-modulation therapy, and adenosine augmentation therapy, have been suggested for the arrangement of epilepsy and ASD. There are several proposals in this review. Firstly, based on the comorbid symptoms and mechanisms of epilepsy and ASD, to further discuss the relationship between both diseases. Secondly, to explore the role of adenosine involved in epilepsy and ASD. Lastly, to emphasize the potential therapeutic value and clinical approaches of adenosine-related therapies in treating epilepsy and ASD.

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12. Havdahl A, Wootton RE, Leppert B, Riglin L, Ask H, Tesli M, Bugge Askeland R, Hannigan LJ, Corfield E, Øyen AS, Andreassen OA, Tilling K, Davey Smith G, Thapar A, Reichborn-Kjennerud T, Stergiakouli E. Associations Between Pregnancy-Related Predisposing Factors for Offspring Neurodevelopmental Conditions and Parental Genetic Liability to Attention-Deficit/Hyperactivity Disorder, Autism, and Schizophrenia: The Norwegian Mother, Father and Child Cohort Study (MoBa). JAMA Psychiatry;2022 (Jul 6)

IMPORTANCE: Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal genetic liability. OBJECTIVE: To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures. DESIGN, SETTING, AND PARTICIPANTS: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother’s pregnancy. Analysis took place between March 2021 and March 2022. EXPOSURES: PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies. MAIN OUTCOMES AND MEASURES: Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use. RESULTS: Data were available for up to 14 539 mothers (mean [SD] age, 30.00 [4.45] years) and 14 897 fathers (mean [SD] age, 32.46 [5.13] years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio [OR], 1.15 [95% CI, 1.06-1.25]), smoking (OR, 1.26 [95% CI, 1.19-1.33]), prepregnancy body mass index (β, 0.25 [95% CI, 0.18-0.31]), pregnancy weight gain (β, 0.20 [95% CI, 0.10-0.30]), taking folate (OR, 0.92 [95% CI, 0.88-0.96]), and not taking supplements (OR, 1.09 [95% CI, 1.04-1.14]). Schizophrenia PGS was associated with coffee consumption (OR, 1.09 [95% CI, 1.05-1.12]), smoking (OR, 1.12 [95% CI, 1.06-1.19]), prepregnancy body mass index (β, -0.18 [95% CI, -0.25 to -0.11]), and pregnancy weight gain (β, 0.17 [95% CI, 0.07-0.27]). All 3 PGSs associated with symptoms of depression/anxiety (ADHD: OR, 1.15 [95% CI, 1.09-1.22]; autism: OR, 1.13 [95% CI, 1.06-1.19]; schizophrenia: OR, 1.13 [95% CI, 1.07-1.20]). Associations were largely consistent for maternal and paternal PGS, except ADHD PGS and smoking (fathers: OR, 1.13 [95% CI, 1.09-1.17]). CONCLUSIONS AND RELEVANCE: In this study, genetic liability to neurodevelopmental conditions that is passed from mothers to children was associated with several pregnancy-related factors and may therefore confound associations between these pregnancy-related factors and offspring neurodevelopment that have previously been thought to be causal. It is crucial that future study designs account for genetic confounding to obtain valid causal inferences so that accurate advice can be given to pregnant individuals.

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13. Hollander E, Jacob S, Jou R, McNamara N, Sikich L, Tobe R, Smith J, Sanders K, Squassante L, Murtagh L, Gleissl T, Wandel C, Veenstra-VanderWeele J. Balovaptan vs Placebo for Social Communication in Childhood Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Psychiatry;2022 (Jul 6)

IMPORTANCE: There are no approved medications for the core symptoms of autism spectrum disorder (ASD), socialization and communication difficulties. OBJECTIVE: To evaluate the efficacy and safety of balovaptan, an oral selective vasopressin 1a receptor antagonist, compared with placebo in children and adolescents with ASD. DESIGN, SETTING, AND PARTICIPANTS: The aV1ation study was a randomized, double-blind, 24-week, parallel-group, placebo-controlled phase 2 trial. Between November 22, 2016, and September 3, 2019, individuals were screened and randomly assigned to treatment groups. The primary efficacy analysis population comprised participants taking age-adjusted balovaptan equivalent to a 10-mg adult dose and participants from the concurrently randomized placebo group. This multicenter trial took place across 41 sites in the US. Participants were aged 5 to 17 years with diagnosed ASD and an IQ of 70 or greater. Data were analyzed from April 8 to November 16, 2020. INTERVENTIONS: Participants were randomly assigned to daily 4-mg or 10-mg adult-equivalent balovaptan or placebo, until the 4-mg group was discontinued. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline on the Vineland-II two-domain composite (2DC; socialization and communication domains) score at week 24. RESULTS: Between November 2016 and September 2019, a total of 599 individuals were screened and 339 participants were randomly assigned to receive 4-mg balovaptan adult-equivalent dose (91 [26.8%]), 10-mg balovaptan adult-equivalent dose (126 [37.2%]), or placebo (122 [36.0%]). Primary analysis included 86 participants assigned to receive 10-mg balovaptan adult-equivalent dose and 81 assigned to receive placebo (mean [SD] age, 12.1 [3.4] years; 139 male participants [83.2%]). No statistically significant differences were observed between the balovaptan and placebo groups in change from baseline on the Vineland-II 2DC score at week 24 (difference in adjusted least-squares mean, -0.16; 90% CI, -2.56 to 2.23; P = .91). No improvements for balovaptan vs placebo were observed at week 24 for any secondary end points. Balovaptan was well tolerated with no emerging safety concerns. Similar proportions of participants reported adverse events (balovaptan, 66 of 86 [76.7%] vs placebo, 61 of 81 [75.3%]) and serious adverse events (balovaptan, 1 of 86 [1.2%] vs placebo, 4 of 81 [4.9%]). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, balovaptan did not demonstrate efficacy in improvement of socialization and communication in this population with pediatric ASD. Balovaptan was well tolerated in children 5 years or older. Further development of robust, sensitive, and objective outcome measures may help to improve future studies in the assessment of therapies targeting communication and socialization in pediatric ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02901431.

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14. Hsu TW, Bai YM, Tsai SJ, Chen TJ, Liang CS, Chen MH. Risk of parental major psychiatric disorders in patients with comorbid autism spectrum disorder and attention deficit hyperactivity disorder: A population-based family-link study. Aust N Z J Psychiatry;2022 (Jul 5):48674221108897.

OBJECTIVE: Few studies have investigated the parental risk of major psychiatric disorders among patients with comorbid autism spectrum disorder and attention deficit hyperactivity disorder. This study examined the differences in such risk among patients with autism spectrum disorder-only, with attention deficit hyperactivity disorder-only and both conditions. METHODS: Between 2001 and 2011, we enrolled 132,624 patients with autism spectrum disorder or attention deficit hyperactivity disorder and 1:10 matched controls for age, sex and demographics from the National Health Insurance Database of Taiwan. Poisson regression models were used to examine the risk of five major psychiatric disorders in the patients’ parents compared with those of the controls, including schizophrenia, bipolar disorder, major depressive disorder, alcohol use disorder, and substance use disorder. Patients were classified into the autism spectrum disorder-only, attention deficit hyperactivity disorder-only and dual-diagnosis groups. RESULTS: The parents of attention deficit hyperactivity disorder-only and dual-diagnosis groups had a higher likelihood to be diagnosed with (odds ratios [95% confidence intervals]) schizophrenia (attention deficit hyperactivity disorder: 1.48 [1.39, 1.57]; dual: 1.79 [1.45, 1.20]), bipolar disorder (attention deficit hyperactivity disorder: 1.91 [1.82, 2.01]; dual: 1.81 [1.51, 2.17]), major depressive disorder (attention deficit hyperactivity disorder: 1.94 [1.89, 2.00]; dual: 1.99 [1.81, 2.20]), alcohol use disorder (attention deficit hyperactivity disorder: 1.39 [1.33, 1.45]; dual: 1.20 [1.01, 1.42]) and substance use disorder (attention deficit hyperactivity disorder: 1.66 [1.59, 1.73]; dual: 1.34 [1.13, 1.58]) than the controls. In contrast, the parents of autism spectrum disorder-only group had a higher likelihood to be diagnosed with schizophrenia (1.77 [1.46, 2.15]) and major depressive disorder (1.45 [1.32, 1.61]) and a lower likelihood to be diagnosed with alcohol use disorder (0.68 [0.55, 0.84]) than the controls. CONCLUSION: The autism spectrum disorder-only group had a different parental incidence of major psychiatric disorders than the attention deficit hyperactivity disorder-only and dual-diagnosis groups. Our findings have implications for clinical practice and future genetic research.

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15. Huang Y, Vangel M, Chen H, Eshel M, Cheng M, Lu T, Kong J. The Impaired Subcortical Pathway From Superior Colliculus to the Amygdala in Boys With Autism Spectrum Disorder. Front Integr Neurosci;2022;16:666439.

OBJECTIVE: Increasing evidence suggests that a subcortical pathway from the superior colliculus (SC) through the pulvinar to the amygdala plays a crucial role in mediating non-conscious processing in response to emotional visual stimuli. Given the atypical eye gaze and response patterns to visual affective stimuli in autism, we examined the functional and white matter structural difference of the pathway in boys with autism spectrum disorder (ASD) and typically developing (TD) boys. METHODS: A total of 38 boys with ASD and 38 TD boys were included. We reconstructed the SC-pulvinar-amygdala pathway in boys with ASD and TD using tractography and analyzed tract-specific measurements to compare the white matter difference between the two groups. A region of interest-based functional analysis was also applied among the key nodes of the pathway to explore the functional connectivity network. RESULTS: Diffusion tensor imaging analysis showed decreased fractional anisotropy (FA) in pathways for boys with ASD compared to TD. The FA change was significantly associated with the atypical communication pattern in boys with ASD. In addition, compared to TD, we found that the ASD group was associated with increased functional connectivity between the right pulvinar and the left SC. CONCLUSION: Our results indicated that the functional and white matter microstructure of the subcortical route to the amygdala might be altered in individuals with autism. This atypical structural change of the SC-pulvinar-amygdala pathway may be related to the abnormal communication patterns in boys with ASD.

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16. Huo Y, Lu W, Tian Y, Hou Q, Man HY. Prkn knockout mice show autistic-like behaviors and aberrant synapse formation. iScience;2022 (Jul 15);25(7):104573.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high genetic heterogeneity, affecting one in 44 children in the United States. Recent genomic sequencing studies from autistic human individuals indicate that PARK2, a gene that has long been considered in the pathogenesis of Parkinson’s disease, is involved in ASD. Here, we report that Prkn knockout (KO) mice demonstrate autistic-like behaviors including impaired social interaction, elevated repetitive behaviors, and deficits in communication. In addition, Prkn KO mice show reduced neuronal activity in the context of sociability in the prelimbic cortex. Cell morphological examination of layer 5 prelimbic cortical neurons shows a reduction in dendritic arborization and spine number. Furthermore, biochemistry and immunocytochemistry analyses reveal alterations in synapse density and the molecular composition of synapses. These findings indicate that Prkn is implicated in brain development and suggest the potential use of the Prkn KO mouse as a model for autism research.

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17. Jellinek E, Keller-Margulis M, Mire SS, Fan W. Pre-service Teachers’ Perspectives on Transition to Kindergarten Practices for Autistic Children. Early Child Educ J;2022 (Jun 25):1-10.

Autistic children present with unique challenges that may be associated with challenges during the kindergarten transition process. While teachers endorse transition to kindergarten practices as important, implementation of effective transition practices is inconsistent. One possible reason is limited training during pre-service education; however, research about this is scarce. This study examined pre-service teachers’ knowledge of autism spectrum disorder (ASD) and transitions to kindergarten. Findings indicate a lack of knowledge regarding both autism and transition, as well as significant differences in knowledge of autism, wherein those seeking special education certification reported higher levels of knowledge. These results highlight training opportunities for preparing pre-service teachers to better serve young autistic children.

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18. Kilroy E, Ring P, Hossain A, Nalbach A, Butera C, Harrison L, Jayashankar A, Vigen C, Aziz-Zadeh L, Cermak SA. Motor performance, praxis, and social skills in autism spectrum disorder and developmental coordination disorder. Autism Res;2022 (Jul 4)

Previous research has shown that individuals with autism spectrum disorder (ASD) and developmental coordination disorder (DCD) may have overlapping social and motor skill impairments. This study compares ASD, DCD, and typically developing (TD) youth on a range of social, praxis and motor skills, and investigates the relationship between these skills in each group. Data were collected on participants aged 8-17 (n = 33 ASD, n = 28 DCD, n = 35 TD). Overall, the clinical groups showed some similar patterns of social and motor impairments but diverged in praxis impairments, cognitive empathy, and Theory of Mind ability. When controlling for both social and motor performance impairments, the ASD group showed significantly lower accuracy on imitation of meaningful gestures and gesture to command, indicating a prominent deficit in these praxis skills in ASD. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) and developmental coordination disorder (DCD) have social and motor skill impairments to varying degrees. This study compares ASD, DCD, and typically developing (TD) youth on a range of social, praxis, and motor skills. ASD and DCD shared similar patterns of gross and fine motor skills, but differed in skills related to making gestures. Specifically, our results also suggest that ASD has a prominent deficit in gesture performance and meaningful imitation compared to TD and DCD groups.

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19. Kumazaki H, Muramatsu T, Yoshikawa Y, Matsumoto Y, Takata K, Ishiguro H, Mimura M. Android Robot Promotes Disclosure of Negative Narratives by Individuals With Autism Spectrum Disorders. Front Psychiatry;2022;13:899664.

Many individuals with autism spectrum disorders (ASD) demonstrate some challenges with personal narrative writing. Sentence completion tests (SCT) is a class of semi-structured projective techniques and encourage respondents to disclose their private narratives. Even in SCT, only providing beginning of sentences is inadequate to compensate atypicalities in their creativity and imagination, and self-disclosure is difficult for many individuals with ASD. It is reported that many individuals with ASD often achieve a higher degree of task engagement through interactions with robots and that robotic systems may be useful in eliciting and promoting social communication such as self-disclosure for some individuals with ASD. There is a possibility that exemplification by android robots in place of human interviewers can result in a higher degree of task engagement for individuals with ASD. The objective of this study was to investigate whether additional exemplifications by android robots in the SCT can prompt self-disclosure for individuals with ASD. We compared the difference in disclosure statements and subjective emotion in the testing paper of the SCT in additional exemplification by an android robot and a human interviewer. In addition, we assessed the disclosure statements and subjective emotions in the SCT, for which exemplifications were written on testing paper to make the comparison. Our quantitative data suggested that exemplification by android robot promoted more self-disclosure, especially about the negative topic compared to exemplification by a human interviewer and that written on test paper. In addition, the level of participant embarrassment in response to exemplification by the android robot seemed to be lower compared to that in the human interviewer condition. In the assessment and support for individuals with ASD, eliciting self-disclosure is a pressing issue. It is hoped that the appropriate use of robots will lead to a better understanding and support for their application.

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20. Kurt N, Ozgeris FB, Ucuz I, Bayraktutan Z, Yilmaz KK, Demirdogen EY, Cayir A. Could Fetuin-A Be a Biomarker for Autism Spectrum Disorder and Cognitive Developmental Delay?. Biochemistry (Mosc);2022 (Jun);87(6):559-565.

Early detection of cognitive developmental delay (CDD) and autism spectrum disorder (ASD) is challenging, despite the numerous scientific studies conducted and different therapeutic strategies. Lack of a biomarker for autism is a limiting factor for early diagnosis, which could provide better outcome with early start of therapy. Because of the high serum fetuin-A concentration during intrauterine life, it has been suggested that fetuin-A may have a role in brain development. The current study sought to determine if fetuin-A, a multifunctional glycoprotein thought to have a role in brain development, may be used as a biomarker for the diagnosis of ASD and developmental delay. The study involved 55 children with cognitive developmental delays and 40 healthy children. Two categories of children with cognitive developmental delays were identified. The participants were subjected to a psychiatric assessment as well as developmental testing. Only 54.5% of the 55 individuals had CDD, whereas 45.5% had ASD. Using an ELISA kit, the levels of serum fetuin-A were determined spectrophotometrically. The serum fetuin-A levels in the patients from the test group were found to be significantly lower than in the healthy individuals (p < 0.001). The cutoff value for the serum fetuin-A levels for cognitive developmental delay and autism spectrum disorder was 518 µg/liter, according to the results of ROC analysis (84.6% sensitivity and 91.4% specificity, AUC: 0.95, p < 0.001). The findings suggest that the serum fetuin-A level may be used to diagnose autism spectrum disorder and cognitive developmental delays.

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21. Li L, Su X, Zheng Q, Xiao J, Huang XY, Chen W, Yang K, Nie L, Yang X, Chen H, Shi S, Duan X. Cofluctuation analysis reveals aberrant default mode network patterns in adolescents and youths with autism spectrum disorder. Hum Brain Mapp;2022 (Jul 4)

Resting-state functional connectivity (rsFC) approaches provide informative estimates of the functional architecture of the brain, and recently-proposed cofluctuation analysis temporally unwraps FC at every moment in time, providing refined information for quantifying brain dynamics. As a brain network disorder, autism spectrum disorder (ASD) was characterized by substantial alteration in FC, but the contribution of moment-to-moment-activity cofluctuations to the overall dysfunctional connectivity pattern in ASD remains poorly understood. Here, we used the cofluctuation approach to explore the underlying dynamic properties of FC in ASD, using a large multisite resting-state functional magnetic resonance imaging (rs-fMRI) dataset (ASD = 354, typically developing controls [TD] = 446). Our results verified that the networks estimated using high-amplitude frames were highly correlated with the traditional rsFC. Moreover, these frames showed higher average amplitudes in participants with ASD than those in the TD group. Principal component analysis was performed on the activity patterns in these frames and aggregated over all subjects. The first principal component (PC1) corresponds to the default mode network (DMN), and the PC1 coefficients were greater in participants with ASD than those in the TD group. Additionally, increased ASD symptom severity was associated with the increased coefficients, which may result in excessive internally oriented cognition and social cognition deficits in individuals with ASD. Our finding highlights the utility of cofluctuation approaches in prevalent neurodevelopmental disorders and verifies that the aberrant contribution of DMN to rsFC may underline the symptomatology in adolescents and youths with ASD.

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22. Li Q, Li Y, Liu B, Chen Q, Xing X, Xu G, Yang W. Prevalence of Autism Spectrum Disorder Among Children and Adolescents in the United States from 2019 to 2020. JAMA Pediatr;2022 (Jul 5)

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23. Lu S, Chen Y, Wang Z. Advances in the pathogenesis of Rett syndrome using cell models. Animal Model Exp Med;2022 (Jul 4)

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders. MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity. As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models, cell models cultured in vitro play indispensable roles. Here we reviewed the research progress in the pathogenesis of RTT at the cellular level, summarized the preclinical-research-related applications, and prospected potential future development.

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24. Lui A, Feldstein E, Clare K, Dicpinigaitis AJ, Reddy M, Khan F, Semaan R, Galluzzo D, Shapiro S, Kamal H, Yaghi S, Pisapia J, Muh C, Nuoman R, Overby P, Etienne M, Chong J, Mayer S, Gandhi CD, Al-Mufti F. Acute ischemic strokes in patients with developmental disabilities: A cross-sectional analysis. Interv Neuroradiol;2022 (Jul 3):15910199221110327.

OBJECTIVE: Patients with developmental disabilities (DD) are frequently excluded from acute ischemic stroke (AIS) randomized control trials. We sought to evaluate the impact of having DD on this patient cohort. METHODS: The National Inpatient Sample was analyzed to explore the impact of AIS and treatment on discharge dispositions in patients with DD. Clinical characteristics, treatments, and outcomes were compared to fully-abled patients with AIS. RESULTS: 1,605,723 patients with AIS were identified from 2010-2019, of whom 4094 (0.30%) had a DD. AIS patients with DD were younger (60.31 vs 70.93 years, p < 0.01), less likely to be Caucasian (66.37%vs 68.09%, p = 0.01), and had higher AIS severity (0.63 vs 0.58, p < 0.01). Tissue plasminogen activator (tPA) was administered in 99,739 (6.2%) fully-abled patients and 196 (4.79%) of patients with DD (p < 0.01). Endovascular thrombectomy (EVT) was performed in 21,066 (1.31%) of fully-abled patients and 35 (0.85%) of patients with DD (p < 0.01). The presence of developmental disabilities were predictive of lower rates of tPA (OR:0.71,CI:0.56-0.87,p < 0.01) and EVT (OR:0.24,CI:0.16-0.36,p < 0.01). In a propensity score-matched cohort of all AIS patients who underwent EVT, there was no difference in functional outcome (p = 0.41), in-hospital mortality (0.10), and LOS (p = 0.79). CONCLUSION: AIS patients with DD were less likely to receive tPA and EVT compared to fully-abled patients. Individuals with DD had higher mortality and worse discharge disposition. There was no significant difference in post-EVT outcomes between fully-abled patients and patients with developmental disabilities. In the absence of prospective clinical trials, population based cross-sectional analyses such as the present study provide valuable clinical insight.

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25. McQuaid GA, Weiss CH, Said AJ, Pelphrey KA, Lee NR, Wallace GL. Increased perceived stress is negatively associated with activities of daily living and subjective quality of life in younger, middle, and older autistic adults. Autism Res;2022 (Jul 5)

Few studies have examined self-reported perceived stress in autistic adults. Existing studies have included relatively small, predominantly male samples and have not included older autistic adults. Using a large autistic sample (N = 713), enriched for individuals designated female at birth (59.3%), and spanning younger, middle, and older adulthood, we examined perceived stress and its associations with independence in activities of daily living and subjective quality of life (QoL). Perceived stress for autistic adults designated male or female at birth was compared to their same birth-sex counterparts in a general population sample. In addition, within the autistic sample, effects of sex designated at birth, age, and their interaction were examined. Regression modeling examined associations between perceived stress and independence in activities of daily living and domains of subjective QoL in autistic adults, after controlling for age, sex designated at birth, and household income. Autistic adults reported significantly greater perceived stress than a general population comparison sample. Relative to autistic adults designated male at birth, those designated female at birth demonstrated significantly elevated perceived stress. Perceived stress contributed significantly to all regression models, with greater perceived stress associated with less independence in activities of daily living, and poorer subjective QoL across all domains-Physical, Psychological, Social, Environment, and Autism-related QoL. Findings are contextualized within the literature documenting that autistic individuals experience elevated underemployment and unemployment, heightened rates of adverse life events, and increased exposure to minority stress. LAY SUMMARY: This study looked at self-reported perceived stress in a large sample of autistic adults. Autistic adults reported more perceived stress than non-autistic adults. Autistic individuals designated female at birth reported higher stress than autistic individuals designated male at birth. In autistic adults, greater perceived stress is related to less independence in activities of daily living and poorer subjective quality of life.

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26. Pan ZY, Zhong HJ, Huang DN, Wu LH, He XX. Beneficial Effects of Repeated Washed Microbiota Transplantation in Children With Autism. Front Pediatr;2022;10:928785.

OBJECTIVE: While fecal microbiota transplantation is demonstrated to improve symptoms of autism spectrum disorder (ASD), it remains unclear whether additional treatment courses yield better results. This study sought to evaluate the efficacy of repeated washed microbiota transplantation (WMT) in children with ASD. METHODS: Retrospective data from children who were serially treated with WMT, including ASD symptoms, sleep disorders, gastrointestinal (GI) symptoms, and white blood cell (WBC) and globulin levels were obtained. The effect of WMT on children with ASD and whether additional WMT courses led to a further improvement in symptoms were assessed. RESULTS: Aberrant Behavior Checklist (ABC), Childhood Autism Rating Scale, and Sleep Disturbance Scale for Children (SDSC) scores, the proportion of children with constipation and abnormal fecal forms, and WBC and globulin levels were all significantly lower in ASD children after WMT. More WMT treatment courses led to significantly lower scores on the ABC and SDSC. CONCLUSION: WMT significantly improved ASD and GI symptoms and sleep disorders in children with ASD, and reduced systemic inflammation. Additional WMT courses led to more obvious improvements in ASD symptoms within three treatment courses.

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27. Rabeling A, Goolam M. Cerebral organoids as an in vitro model to study autism spectrum disorders. Gene Ther;2022 (Jul 5)

Autism spectrum disorders (ASDs) are a set of disorders characterised by social and communication deficits caused by numerous genetic lesions affecting brain development. Progress in ASD research has been hampered by the lack of appropriate models, as both 2D cell culture as well as animal models cannot fully recapitulate the developing human brain or the pathogenesis of ASD. Recently, cerebral organoids have been developed to provide a more accurate, 3D in vitro model of human brain development. Cerebral organoids have been shown to recapitulate the foetal brain gene expression profile, transcriptome, epigenome, as well as disease dynamics of both idiopathic and syndromic ASDs. They are thus an excellent tool to investigate development of foetal stage ASDs, as well as interventions that can reverse or rescue the altered phenotypes observed. In this review, we discuss the development of cerebral organoids, their recent applications in the study of both syndromic and idiopathic ASDs, their use as an ASD drug development platform, as well as limitations of their use in ASD research.

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28. Rodgers J, Goodwin J, Garland D, Grahame V, Isard L, Kernohan A, Labus M, Osborne MM, Parr JR, Rob P, Wright C, Freeston M. Coping with uncertainty in everyday situations (CUES©) to address intolerance of uncertainty in autistic children: an intervention feasibility trial. J Autism Dev Disord;2022 (Jul 5)

BACKGROUND: Anxiety related to uncertainty is common in autism. Coping with Uncertainty in Everyday Situations (CUES©) is a parent-mediated group intervention aiming to increase autistic children’s tolerance to uncertain situations. A pilot study was conducted to test its feasibility and acceptability. METHODS: Parents of 50 autistic children were randomised to receive CUES© or enhanced services as usual. RESULTS: All children met the clinical threshold for at least one anxiety disorder. Of the 26 participants randomised to CUES©, 72% attended 4-8 sessions. Parents and therapists reported they found CUES© useful and acceptable. CONCLUSIONS: Families were willing to be recruited and randomised, the format/content was feasible to deliver, and the outcome measures were acceptable. CUES© should be evaluated in a clinical and cost effectiveness randomised controlled trial.

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29. Roudbarani F, Tablon Modica P, Maddox BB, Bohr Y, Weiss JA. Clinician factors related to the delivery of psychotherapy for autistic youth and youth with attention-deficit hyperactivity disorder. Autism;2022 (Jul 2):13623613221106400.

Autistic children and youth often experience mental health problems, such as anxiety, depression and behavioural challenges. Although there are therapy programmes that have been found helpful in reducing these issues, such as cognitive behaviour therapy, autistic children often struggle to receive adequate mental health care. Clinicians’ knowledge, attitudes, confidence and beliefs about treating mental health problems in autistic people may be related to their choices in providing psychotherapy. Across Ontario, Canada, 611 mental health clinicians, working in publicly funded agencies, completed an online survey about their experiences and opinions on delivering therapy for autistic clients compared to those with attention-deficit hyperactivity disorder. Clinician knowledge was associated with their intention to treat autistic clients or clients with attention-deficit hyperactivity disorder, partly because of their attitudes and the social pressures or values they felt. Clinicians reported feeling less intent on providing therapy to autistic youth compared to youth with attention-deficit hyperactivity disorder because of differences in their attitudes, social pressures and knowledge. This research can inform the training and educational initiatives for mental health practitioners.

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30. Silkey M, Durán-Pacheco G, Johnson M, Liu C, Clinch S, Law K, Loss G. The Autism Impact Measure (AIM): Meaningful Change Thresholds and Core Symptom Changes Over One Year from an Online Survey in the U.S. J Autism Dev Disord;2022 (Jul 4)

Validated outcome measures with the capacity to reflect meaningful change are key to assessing potential interventions for autism spectrum disorder (ASD). We derive clinically meaningful change thresholds (MCTs) of the Autism Impact Measure (AIM) and identify factors associated with meaningful change. Baseline and 12-months follow-up survey of caregivers of 2,761 children with ASD aged 3-17 years from the U.S. Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort were analyzed. Using caregiver-reported anchors for change, the 12-month change in estimated AIM MCT (95% confidence interval) for symptom improvement was -4.5 (-7.61, -1.37) points and 9.9 (5.12, 14.59) points for symptom deterioration. These anchor-based MCTs will facilitate future assessments of caregiver-reported change in AIM scores.

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31. So WC, Song XK. Whose Gestures are More Predictive of Expressive Language Abilities among Chinese-Speaking Children with Autism? A Comparison of Caregivers’ and Children’s Gestures. J Autism Dev Disord;2022 (Jul 4)

In spite of the close relationship between gestures and expressive language, little research has examined the roles of the parents’ and children’s gestures in the development of expressive language abilities in autistic children. Previous findings are also inconclusive. In the present study, we coded the gestures produced by the parents and their autistic children in parent-child interactions and compared the influence of their gestures on the children’s expressive language abilities (N = 35; M = 4;10). Autistic children’s deictic gestures positively predicted their Mean Length Utterance (MLU), word types, and word tokens whereas parents’ deictic gesture inputs negatively predicted MLU and word types. The findings shed light on the importance of the gestures made by autistic children, which may trigger parents’ gesture-to-word translation.

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32. Soleymani Z, Koegel LK, Mohammadzaheri F, Peyghambari M, Bajalan M, Naderi Malek A, Bakhshi E. Development and validation of the Autism Communicative Skills Questionnaire (ACSQ); An autism screening measure in Farsi. Appl Neuropsychol Child;2022 (Jul 4):1-12.

There has been a steady increase in the number of children diagnosed with autism spectrum disorder (ASD) worldwide. However, screening tools that focus primarily on communicative development that are culturally sensitive and linguistically appropriate are needed, particularly in languages, such as Farsi, which is spoken in countries that may benefit from additional resources. Therefore, the purpose of this study was to develop and validate a screening tool, written in Farsi by Iranians, that focuses on communication and factors affecting the development of communication for children with autism. A variety of statistical analyses were conducted and implemented to assess the relevance of various questions related to communication, along with other behaviors that interfere with the development of communication, that may distinguish between children with and without ASD. Exploratory factor analysis was performed to examine the underlying structure of the Autism Communicative Skills Questionnaire (ACSQ). This study represents the first stage in the development of a comprehensive questionnaire to assist with the screening of areas that impact the development of social communication and are unique to ASD.

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33. Sticinski EV, Eidelman S, Karpyn A, Chai SC, Earnshaw VA. Short report: Social support access among single caregivers with children on the autism spectrum. Res Dev Disabil;2022 (Jul 1);128:104291.

BACKGROUND: Caregivers of children with autism are more likely to experience parenting stress than parents of neurotypical children. Research on parenting stress focuses on partnered caregivers and little is known about the comparative social support experienced by single caregivers. AIM: To explore differences in perceived social support between single versus partnered caregivers of adolescent and adult children on the autism spectrum. METHODS AND PROCEDURES: A cross-sectional, quantitative study using the ENRICHD Social Support Instrument (ESSI) as a measure of perceived social support. Univariate and multivariable analyses were conducted to examine the association between caregiver relationship status and perceived social support. OUTCOMES AND RESULTS: There were statistically significant associations between relationship status and perceived social support, with single caregivers perceiving less social support than partnered caregivers (p < .001). CONCLUSIONS AND IMPLICATIONS: Single caregivers of adolescent and adult children on the autism spectrum perceive less social support than partnered caregivers. Service providers should routinely evaluate the support access of this single caregivers and target support services to address the distinct needs of this population.

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34. Tse ACY, Lee PH, Lau EYY, Cheng JCH, Ho AWY, Lai EWH. Study protocol for a randomized controlled trial comparing the effectiveness of physical exercise and melatonin supplement on treating sleep disturbance in children with autism spectrum disorders. PLoS One;2022;17(7):e0270428.

BACKGROUND: Previous study showed that both melatonin supplement and physical exercise intervention could improve sleep quality in children with autism spectrum disorders (ASD) with the increase in endogenous melatonin level. However, none of the studies have directly compared the effectiveness between the two interventions on treating sleep disturbance in children with ASD. Without direct comparison, we do not know which intervention is better. Thus, we designed a study to compare which intervention is more effective to treat sleep disturbance in children with ASD and to examine whether the combination of the two could be the most efficacious. We present a protocol for conducting a randomized controlled trial to compare the effectiveness of physical exercise and melatonin supplement on treating sleep disturbance in children with ASD. STUDY DESIGN: The proposed study will be a four-group randomised control trial (RCT) design, with equal allocation of participants to the three intervention groups and one control group. METHODS: All eligible participants will be randomly allocated to a morning jogging group, a melatonin supplement group, a combination group and a control group. Changes in sleep quality will be monitored through actigraphic assessment and parental sleep logs. Melatonin levels represented by 6-sulfoxymelatonin will be measured from the participants’ 24-h and the first morning void urinary samples. All the assessments will be carried out before the intervention (T1), in the mid of the study (5 weeks after the commencement of the study) (T2) and after the 10-week intervention (T3). Level of statistical significance will be set at 5% (i.e. p < .05). The results of this trial will be submitted for publication in peer-reviewed journal. FINDINGS: The findings will provide evidence to determine whether physical exercise or melatonin supplement or the combination of interventions is the most effective to treat sleep disturbance in children with ASD.

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35. Ueda Y, Sugimoto N, Ozawa T. Increased spine PIP3 is sequestered from dendritic shafts. Mol Brain;2022 (Jul 4);15(1):59.

Phosphatidylinositol 3,4,5-trisphosphate (PIP3) is a lipid second messenger that is crucial for the synaptic plasticity underlying learning and memory in pyramidal neurons in the brain. Our previous study uncovered PIP3 enrichment in the dendritic spines of hippocampal pyramidal neurons in the static state using a fluorescence lifetime-based PIP3 probe. However, the extent to which PIP3 enrichment is preserved in different states has not been fully investigated. Here, we revealed that PIP3 accumulation in dendritic spines is strictly controlled even in an active state in which PIP3 is increased by glutamate stimulation and high potassium-induced membrane depolarization. Time-course PIP3 analysis clarified the gradual PIP3 accumulation in dendritic spines over days during neuronal development. Collectively, these results deepen our understanding of PIP3 dynamics in dendritic spines, and the dysregulation of the PIP3 gradient between dendritic spines and shafts could cause neuronal diseases and mental disorders, such as autism spectrum disorder.

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36. Villamor E, Susser ES, Cnattingius S. Defective placentation syndromes and autism spectrum disorder in the offspring: population-based cohort and sibling-controlled studies. Eur J Epidemiol;2022 (Jul 5)

Defective placentation underlies diverse syndromic manifestations that could affect brain development including: (1) placental abruption, (2) term preeclampsia with a small-for-gestational age (SGA) infant, (3) preterm preeclampsia, and (4) spontaneous preterm birth. We investigated the relations between these defective placentation syndromes and the incidence of Autism Spectrum Disorder (ASD) in offspring. We conducted a population-based cohort study of 1,645,455 non-malformed singleton infants born in Sweden 2000-2016 who were followed for up to 17 years using national registers. We compared ASD rates for children prenatally exposed and unexposed to defective placentation syndromes with use of adjusted hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression. We also conducted sibling-controlled analyses among 1,092,132 full siblings. The association of the syndromes with ASD independent of preterm birth was estimated in mediation analyses. There were 23,810 cases of ASD. In both general cohort and sibling analyses, adjusted HRs (95% CI) of ASD were increased in children of mothers with term preeclampsia combined with SGA [1.5 (1.3, 1.9) and 1.9 (1.1, 3.3), respectively], preterm preeclampsia < 34 weeks [1.8 (1.4, 2.2) and 4.2 (2.1, 8.5), respectively], and spontaneous very or extremely preterm birth (≤ 31 weeks) [2.6 (2.2, 3.0) and 2.4 (1.5, 3.8), respectively]. Placental abruption was associated with increased HR of ASD in general cohort analysis only. The association between preeclampsia and ASD was not fully explained by preterm birth. In conclusion, syndromes linked to defective placentation are associated with increased incidence of ASD in the offspring.

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37. Xiong T, McGrath PJ, Stewart SH, Bagnell A, Kaltenbach E. Risk and protective factors for posttraumatic stress and posttraumatic growth in parents of children with intellectual and developmental disorders. Eur J Psychotraumatol;2022;13(1):2087979.

BACKGROUND: Parents of children with intellectual and developmental disorders often experience potentially traumatic events while caring for their children. Heightened posttraumatic stress (PTS) and posttraumatic growth (PTG) have been found in this population. OBJECTIVE: We aimed to explore risk and protective factors for their PTS and PTG. METHOD: A cross-sectional study was conducted with 385 parents (average age M = 43.14 years, SD = 7.40; 95.3% mothers). RESULTS: Parenting trauma showed an adverse effect on developing PTS (beta = 0.25, p < .01) and a positive role in promoting PTG (beta = 0.16, p < .01). Social support was protective in its correlation with lower levels of PTS (beta = -0.12, p < .01) and higher levels of PTG (beta = 0.22, p < .01). Barriers to care were associated with increased PTS (beta = 0.23, p < .01), but unrelated to PTG (beta = .01, p = .855). Negative parenting showed a significant, but small, correlation with more severe PTS (beta = 0.11, p < .05), and was unrelated to PTG (beta = -0.09, p = .065). CONCLUSIONS: Our study increases the understanding of posttraumatic reactions in parents, predominantly mothers, of children with IDD and identified parenting-related trauma, social support, and barriers to mental health care as predictive factors of the reactions. More research is needed to confirm and validate the effects of the discussed factors. Although causation can not be inferred, prompt and adequate screening and therapeutic resources should be provided to those mothers who were exposed to multiple stressful caregiving events and had limited healthcare access and less support from their spouses, peers, and caregiving partners. HIGHLIGHTS: Parents of a child with Intellectual and Developmental Disorders with parenting trauma had higher posttraumatic stress (PTS) and posttraumatic growth (PTG).Social support was related to lower PTS and higher PTG.Barriers to care were related to higher PTS but unrelated to PTG.

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38. Xu P, Yue Y, Su J, Sun X, Du H, Liu Z, Simha R, Zhou J, Zeng C, Lu H. Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2. Nat Commun;2022 (Jul 6);13(1):3899.

Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit’s ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.

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39. Yarar EZ, Roestorf A, Spain D, Howlin P, Bowler D, Charlton R, Happé F. Aging and autism: Do measures of autism symptoms, co-occurring mental health conditions, or quality of life differ between younger and older autistic adults?. Autism Res;2022 (Jul 5)

Previous research has indicated that autistic adults experience higher rates of co-occurring mental health difficulties and poorer quality of life (QoL) than their non-autistic peers. Little is known, however, about these aspects in older age or whether younger and older autistic adults experience similar patterns This cross-sectional study investigated potential age-related effects on autism symptoms, self-reported mental health, and QoL in younger and older autistic adults (n = 79, aged 19-71 years) compared to a non-autistic control group (n = 57) matched for gender, age and IQ. Results showed that autistic adults had higher levels of self-reported autism symptoms and poorer QoL than controls. There were no significant age effects on autism symptoms or on most self-rated mental health symptoms. However, significantly more autistic adults in the younger versus older group scored above the clinical threshold for anxiety, somatoform disorders and eating disorders. Older autistic adults rated social QoL as significantly better than younger autistic adults; there was no significant age difference in the control group. Self-reported QoL was best predicted by self-ratings of severity of depressive symptoms in both groups. Further research is needed to track autism and co-occurring mental health symptomatology across the lifespan, so that service provision can be tailored accordingly. LAY SUMMARY: Young autistic adults have reported more psychological difficulties and poorer quality of life (QoL) than the general population. We investigated whether these difficulties continue into older age. Autism symptoms and mental health problems were common in autistic adults, with no difference between age groups, except for anxiety, physical and eating problems. Although QoL was poorer in both younger and older autistic compared to non-autistic adults, older autistic adults reported better social QoL than those who were younger.

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40. Zarokanellou V, Papanikolaou K, Tafiadis D, Kolaitis G. Qualitative analysis of verbal fluency in school-age children with high-functioning autism spectrum disorders. Associations with age and IQ. Appl Neuropsychol Child;2022 (Jul 4):1-10.

This study analyzes performance on both a Semantic and a Letter verbal fluency (VF) task in school-age children with high-functioning autism spectrum disorder (HF-ASD) (n = 20) and without ASD (n = 20) and investigates the relationship between VF indicators and age, verbal and non-verbal IQ, ASD severity, and attention deficit hyperactivity disorder (ADHD) symptomatology. Furthermore, the Poor Lexical-Semantic Structure Model and the Slow-Retrieval Model are tested if they could account for semantic retrieval difficulties in children with HF-ASD. The HF-ASD group generated significantly fewer correct responses in both VF tasks in comparison to the control group. The type of task significantly affected performance and both groups showed higher word generativity on the Semantic task. The groups did not differ in clustering, switching, and errors. Age significantly correlated with the VF indicators in the ASD group, but in the control group, there was a significant negative correlation with the number of errors. Non-verbal and verbal IQ did not correlate with any VF indicators in both groups, while ASD severity and ADHD symptomatology correlated positively and significantly with error responses in the ASD group. The Slow-Retrieval Model explains VF difficulties in the HF-ASD group indicating that poorer word generativity can be attributed to slower retrieval of words from the semantic network.

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41. Zhang Y, Zhang S, Chen B, Jiang L, Li Y, Dong L, Feng R, Yao D, Li F, Xu P. Predicting the symptom severity in autism spectrum disorder based on EEG metrics. IEEE Trans Neural Syst Rehabil Eng;2022 (Jul 5);PP

Autism spectrum disorder (ASD) is associated with the impaired integrating and segregating of related information that is expanded within the large-scale brain network. The varying ASD symptom severities have been explored, relying on their behaviors and related brain activity, but how to effectively predict ASD symptom severity needs further exploration. In this study, we aim to investigate whether the ASD symptom severity could be predicted with electroencephalography (EEG) metrics. Based on a publicly available dataset, the EEG brain networks were constructed, and four types of EEG metrics were calculated. Then, we statistically compared the brain network differences among ASD children with varying severities, i.e., high/low autism diagnostic observation schedule (ADOS) scores, as well as with the typically developing (TD) children. Thereafter, the EEG metrics were utilized to validate whether they could facilitate the prediction of the ASD symptom severity. The results demonstrated that both high-and low-scoring ASD children showed the decreased long-range frontal-occipital connectivity, increased anterior frontal connectivity and altered network properties. Furthermore, we found that the four types of EEG metrics are significantly correlated with the ADOS scores, and their combination can serve as the features to effectively predict the ASD symptom severity. The current findings will expand our knowledge of network dysfunction in ASD children and provide new EEG metrics for predicting the symptom severity.

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42. Zhao S, Liu Y, Wei K. Pupil-Linked Arousal Response Reveals Aberrant Attention Regulation among Children with Autism Spectrum Disorder. J Neurosci;2022 (Jul 6);42(27):5427-5437.

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus-norepinephrine (LC-NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC-NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurrent stimuli as well as a diminished phasic response to deviants, particularly those containing social information. Their tonic habituation impairment predicts their phasic orienting impairment, and both impairments correlated with the severity of ASD symptom. Because of the fact that these pupil-linked responses are observed when individuals passively listen without any task engagement, our findings imply that the intricate and dynamic attention allocation mechanism, mediated by the subcortical LC-NE system, is impaired in ASD.SIGNIFICANCE STATEMENT Autistic individuals show attentional abnormalities to even simple sensory inputs, which emerge even before formal diagnosis. One possible mechanism behind these abnormalities is a malfunctioning pacemaker of their attention system, the locus ceruleus-norepinephrine pathway. Here we found, according to the pupillary response (a noradrenergic activity proxy), autistic children are hypersensitive to repeated sounds but hyposensitive to surprising deviant sounds when compared with age-matched controls. Importantly, hypersensitivity to repetitions predicts hyposensitivity to deviant sounds, and both abnormalities positively correlate to the severity of autistic symptoms. This provides strong evidence that autistic children have faulty noradrenergic regulation, which might underly the attentional atypicalities previously evidenced in various cortical responses in autistic individuals.

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