1. Borrie SC, Plasschaert E, Callaerts-Vegh Z, Yoshimura A, D’Hooge R, Elgersma Y, Kushner SA, Legius E, Brems H. MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders. Molecular autism. 2021; 12(1): 53.

BACKGROUND: RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. METHODS: We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. RESULTS: Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. LIMITATIONS: This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. CONCLUSIONS: These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.

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2. Davidson D, Stagnitti K. The process of Learn to Play Therapy with parent-child dyads with children who have autism spectrum disorder. Australian occupational therapy journal. 2021; 68(5): 419-33.

INTRODUCTION: Learn to Play Therapy aims to build children’s ability to spontaneously initiate pretend play. The purpose of this study was to explore evidence for this therapy for children with autism spectrum disorder by investigating the changes in a child’s pretend play and key techniques used in the process of therapy. METHODS: Six children with a diagnosis of autism spectrum disorder (mean age = 3.8 years; SD = 1.2 years) were engaged in therapy sessions with a parent. Four therapy session videos for each child were selected across four time points from 15 videos of each child, representing 6 months of therapy. Retrospective video analysis was used to investigate the changes in the child’s ability by coding six play skills and enjoyment of play. Key techniques in the process of Learn to Play Therapy were analysed by frequency of occurrence during sessions. RESULTS: There was a significant increase in the child’s pretend play ability for play scripts (p = .042), sequences of play actions (p = .043), object substitution (p = .043), doll/teddy play (p = .028), social interaction (p = .043) and enjoyment (p = .026). There was a mirroring of the therapist, parent and child for all key techniques, with parents showing increased frequency rates after Time 1. Repetition with variation decreased by Time 4. Challenging the child showed higher rates in Times 2 and 4. Focussed attention remained stable, and the child’s talk during play had the highest total frequency. CONCLUSION: Learn to Play Therapy is an effective therapy in building pretend play ability in children with autism, with parents increasing their involvement in using the key techniques after Time 1. The results inform therapists on how the key techniques were used within the therapy sessions to increase the child’s pretend play ability.

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3. Dionne O, Corbin F. A new strategy to uncover fragile X proteomic biomarkers using the nascent proteome of peripheral blood mononuclear cells (PBMCs). Scientific reports. 2021; 11(1): 15148.

Fragile X syndrome (FXS) is the most prevalent inherited cause of intellectual disabilities and autism spectrum disorders. FXS result from the loss of expression of the FMRP protein, an RNA-binding protein that regulates the expression of key synaptic effectors. FXS is also characterized by a wide array of behavioural, cognitive and metabolic impairments. The severity and penetrance of those comorbidities are extremely variable, meaning that a considerable phenotypic heterogeneity is found among fragile X individuals. Unfortunately, clinicians currently have no tools at their disposal to assay a patient prognosis upon diagnosis. Since the absence of FMRP was repeatedly associated with an aberrant protein synthesis, we decided to study the nascent proteome in order to screen for potential proteomic biomarkers of FXS. We used a BONCAT (Biorthogonal Non-canonical Amino Acids Tagging) method coupled to label-free mass spectrometry to purify and quantify nascent proteins of peripheral blood mononuclear cells (PBMCs) from 7 fragile X male patients and 7 age-matched controls. The proteomic analysis identified several proteins which were either up or downregulated in PBMCs from FXS individuals. Eleven of those proteins were considered as potential biomarkers, of which 5 were further validated by Western blot. The gene ontology enrichment analysis highlighted molecular pathways that may contribute to FXS physiopathology. Our results suggest that the nascent proteome of PBMCs is well suited for the discovery of FXS biomarkers.

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4. Eyring KW, Geschwind DH. Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment. Human molecular genetics. 2021; 30(20): R236-r44.

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.

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5. Foster TR, Young RL. Brief Report: Sentencing Outcomes for Offenders on the Autism Spectrum. Journal of autism and developmental disorders. 2021.

Although people diagnosed with autism spectrum disorder (ASD) are not more likely to commit crimes, they are overrepresented in the criminal justice system as reported by Howlin (Autism and Asperger syndrome: Preparing for adulthood, Routledge, 2004). This may, in part, be due to unfavourable interactions with the criminal judiciary. Evidence suggests the autistic population are perceived unfavourably in adjudicative proceedings resulting in harsher penalties. The present study explores whether ASD offenders (ASD-O) receive longer sentences compared to national sentencing data. Sentencing data from the Australian Bureau of Statistics (ABS) were used to compare ASD-O with similar offences. ASD-O attracted longer sentences across all offence classifications. Inferential analyses indicated sexual assault sentences were significantly higher in the ASD-O sample. No significant differences were found for murder, manslaughter, and assault.

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6. Golden CEM, Wang VX, Harony-Nicolas H, Hof PR, Buxbaum JD. Reduced brain volume and white matter alterations in Shank3-deficient rats. Autism research : official journal of the International Society for Autism Research. 2021; 14(9): 1837-42.

Mutations and deletions in the SHANK3 gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS), which is characterized by intellectual disability, autism spectrum disorder, and sensory hyporeactivity. SHANK3 encodes a key structural component of excitatory synapses important for synaptogenesis. Clinical assessments and limited brain imaging studies of patients with PMS have uncovered regional volume reductions and white matter thinning. While these impairments have been replicated ex vivo in pups of a rat model, brain structure has not been assessed in rats in vivo or in adults. We assessed the brain structure of heterozygous and homozygous adult Shank3-deficient male rats in comparison to wild-type littermates with magnetic resonance imaging using both anatomical assessments and diffusion tensor imaging (DTI). Shank3-deficient rats showed a reduction in overall brain size and the absolute volume of the neocortex, piriform cortex, thalamus, forebrain, inferior and superior colliculi, internal capsule, and anterior commissure. The superior colliculus was decreased in relative volume. DTI revealed that axial diffusion and fractional anisotropy were reduced in the external capsule and mean diffusion was increased in the fornix, suggesting that restriction of diffusion perpendicular to the axis of the axonal fibers was impaired in these white matter tracts. Therefore, Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in PMS. Our results indicate that the loss of a glutamatergic synaptic protein, Shank3, has structural consequences at the level of the whole brain. The brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.

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7. Goodman LD, Cope H, Nil Z, Ravenscroft TA, Charng WL, Lu S, Tien AC, Pfundt R, Koolen DA, Haaxma CA, Veenstra-Knol HE, Wassink-Ruiter JSK, Wevers MR, Jones M, Walsh LE, Klee VH, Theunis M, Legius E, Steel D, Barwick KES, Kurian MA, Mohammad SS, Dale RC, Terhal PA, van Binsbergen E, Kirmse B, Robinette B, Cogné B, Isidor B, Grebe TA, Kulch P, Hainline BE, Sapp K, Morava E, Klee EW, Macke EL, Trapane P, Spencer C, Si Y, Begtrup A, Moulton MJ, Dutta D, Kanca O, Wangler MF, Yamamoto S, Bellen HJ, Tan QK. TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila. American journal of human genetics. 2021; 108(9): 1669-91.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

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8. Gopal M. Ano-scrotal distance (ASD): Is it a marker for the severity of chordee?. Journal of pediatric urology. 2021; 17(5): 672-3.

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9. Hocking MC, Albee M, Brodsky C, Shabason E, Wang L, Schultz RT, Herrington J. Face Processing and Social Functioning in Pediatric Brain Tumor Survivors. Journal of pediatric psychology. 2021; 46(10): 1267-75.

OBJECTIVE: Pediatric brain tumor survivors (PBTS) experience deficits in social functioning. Facial expression and identity recognition are key components of social information processing and are widely studied as an index of social difficulties in youth with autism spectrum disorder (ASD) and other neurodevelopmental conditions. This study evaluated facial expression and identity recognition among PBTS, youth with ASD, and typically developing (TD) youth, and the associations between these face processing skills and social impairments. METHODS: PBTS (N = 54; ages 7-16) who completed treatment at least 2 years prior were matched with TD (N = 43) youth and youth with ASD (N = 55) based on sex and IQ. Parents completed a measure of social impairments and youth completed a measure of facial expression and identity recognition. RESULTS: Groups significantly differed on social impairments (p < .001), with youth with ASD scoring highest followed by PBTS and lastly TD youth. Youth with ASD performed significantly worse on the two measures of facial processing, while TD youth and PBTS were not statistically different. The association of facial expression recognition and social impairments was moderated by group, such that PBTS with higher levels of social impairment performed worse on the expression task compared to TD and ASD groups (p < .01, η2 = 0.07). CONCLUSIONS: Variability in face processing may be uniquely important to the social challenges of PBTS compared to other neurodevelopmental populations. Future directions include prospectively examining associations between facial expression recognition and social difficulties in PBTS and face processing training as an intervention for PBTS.

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10. Iles A. Autism Spectrum Disorders. Primary care. 2021; 48(3): 461-73.

This article describes the current understanding of the identification, classification, and diagnosis of autism spectrum disorder (ASD) as it relates to the practice of primary care providers. In addition, the most updated information regarding risk factors, as well as effective treatment strategies are provided. Although primary care providers are not typically the experts in ASD treatment, they constitute a critical component of the care team responsible for early identification and intervention initiation for patients with ASD.

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11. Isvoranu AM, Ziermans T, Schirmbeck F, Borsboom D, Geurts HM, de Haan L. Autistic Symptoms and Social Functioning in Psychosis: A Network Approach. Schizophrenia bulletin. 2022; 48(1): 273-82.

Psychotic and autistic symptoms are related to social functioning in individuals with psychotic disorders (PD). The present study used a network approach to (1) evaluate the interactions between autistic symptoms, psychotic symptoms, and social functioning, and (2) investigate whether relations are similar in individuals with and without PD. We estimated an undirected network model in a sample of 504 PD, 572 familial risk for psychosis (FR), and 337 typical comparisons (TC), with a mean age of 34.9 years. Symptoms were assessed with the Autism Spectrum Quotient (AQ; 5 nodes) and the Community Assessment of Psychic Experiences (CAPE; 9 nodes). Social functioning was measured with the Social Functioning Scale (SFS; 7 nodes). We identified statistically significant differences between the FR and PD samples in global strength (P < .001) and network structure (P < .001). Our results show autistic symptoms (social interaction nodes) are negatively and more closely related to social functioning (withdrawal, interpersonal behavior) than psychotic symptoms. More and stronger connections between nodes were observed for the PD network than for FR and TC networks, while the latter 2 were similar in density (P = .11) and network structure (P = .19). The most central items in strength for PD were bizarre experiences, social skills, and paranoia. In conclusion, specific autistic symptoms are negatively associated with social functioning across the psychosis spectrum, but in the PD network symptoms may reinforce each other more easily. These findings emphasize the need for increased clinical awareness of comorbid autistic symptoms in psychotic individuals.

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12. Kim JI, Lee J, Lee KS, Lee YA, Shin CH, Hong YC, Kim BN, Lim YH. Association of phthalate exposure with autistic traits in children. Environment international. 2021; 157: 106775.

BACKGROUND: Phthalates are synthetic chemicals with endocrine-disrupting properties. They are reportedly associated with various neurotoxic outcomes. Studies on exposure to phthalates and children’s autistic traits have shown inconsistent results with respect to sex and susceptible time periods. We investigated the association of phthalate exposure during the prenatal period and childhood with autistic traits over time using a birth cohort in South Korea. METHODS: Five phthalate metabolites were measured during mid-term pregnancy and children’s follow-up at ages of 4, 6, and 8 years among a total of 547 mother-child pairs. The social communication questionnaire (SCQ) was used to assess autistic traits of children at each time point. The relationship between phthalate metabolites and SCQ scores were analyzed by exposure windows and sex. RESULTS: A 2.7 fold increase in di-(2-ethylhexyl) phthalate metabolite levels, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) during pregnancy was associated with increased SCQ scores at 4 years by 8.5% (95% confidence intervals [CI]: 1.9%, 15.5%) and 7.4% (95% CI: 0.3%, 15.0%), respectively, but not at the age of 6 or 8 years. Moreover, MEHHP levels at ages of 4 and 8 years were associated with increased SCQ scores at 8 years by 9.9% (95% CI: 1.8%, 18.6%) and 9.6% (95% CI: 1.3%, 18.6%), respectively. Boys showed stronger associations between phthalate exposure and SCQ scores than girls. CONCLUSION: The study suggested different susceptible time windows of phthalate exposure: exposure during pregnancy is associated with autistic traits in young children, whereas exposure during early childhood years leads to autistic traits in school-aged children, particularly boys.

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13. Mehta D, Davis M, Epstein AJ, Wensel B, Grinnell T, Thach A, Williams GR. Comparative economic outcomes in patients with focal seizures initiating eslicarbazepine acetate versus brivaracetam as their first adjunctive ASD. Journal of medical economics. 2021; 24(1): 939-48.

AIMS: To study the association between initiation of first adjunctive therapy with eslicarbazepine acetate (ESL) vs. brivaracetam (BRV) on healthcare resource utilization (HCRU) and charges among patients with treated focal seizures (FS). MATERIALS AND METHODS: Symphony Health’s Integrated Dataverse (IDV) claims data (1 April 2015 to 30 June 2018) were used to identify two cohorts as first adjunctive therapy with ESL or BRV following a generic anti-seizure drug (ASD). The index date was the earliest claim for a new ESL or BRV prescription. Key inclusion criteria were only 1 generic ASD in the 12 months before the index date; ≥1 medical claim with an FS diagnosis. Unit of analysis was the 90-day person-time-block. Changes in HCRU and charges were assessed using a difference-in-differences framework. Both unadjusted and adjusted analyses were performed. The adjusted model utilized person-specific fixed effects and propensity score-based weighting to control for differences in baseline covariates. Bias-corrected bootstrap confidence intervals (CIs) were calculated for charge outcomes. RESULTS: 208 and 137 patients initiated first adjunctive therapy with ESL (43.7 years, 51.9% female) or BRV (39.3 years, 51.8% female). Patients in the ESL cohort had numerically larger reductions in all-cause and FS-related inpatient hospitalizations and outpatient visits and FS-related emergency department visits. Compared to patients initiating BRV, patients treated with ESL had significantly larger reductions in total charges (-$3,446, CI: -$13,716, -$425), all-cause (-$3,166, CI: -$13,991, -$323) and FS-related (-$2,969, CI: -$21,547, -$842) medical charges, all-cause (-$3,397, CI: -$15,676, -$818) and FS-related (-$2,863, CI: -$19,707, -$787) outpatient charges, and non-ASD-related prescription charges (-$420, CI: -$1,058, -$78). LIMITATIONS: Claims may be missing, or miscoded; outcomes may be influenced by variables not accounted for in the analysis; only information on submitted charges was included. CONCLUSIONS: Among patients with FS, initiation of first adjunctive therapy with ESL was associated with significantly larger reductions in medical and non-ASD-related prescriptions charges compared to BRV.

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14. Schroder CM, Banaschewski T, Fuentes J, Hill CM, Hvolby A, Posserud MB, Bruni O. Pediatric prolonged-release melatonin for insomnia in children and adolescents with autism spectrum disorders. Expert opinion on pharmacotherapy. 2021; 22(18): 2445-54.

Introduction: Insomnia is common among children and adolescents with Autism spectrum disorder (ASD). The first drug licensed for insomnia in this population, a pediatric-appropriate prolonged-release melatonin (PedPRM) formulation is described.Areas covered: Literature search on PedPRM efficacy and safety profile in clinical trials, and a proposed decision-making algorithm to optimize outcome in the treatment of insomnia in children and adolescents with ASD.Expert opinion: PedPRM treatment effectively improves sleep onset, duration and consolidation, and daytime externalizing behaviors in children and adolescents with ASD and subsequently caregivers’ quality of life and satisfaction with their children’s sleep. The coated, odorless and taste-free mini-tablets are well-accepted in this population who often have sensory hypersensitivity and problems swallowing standard tablet preparations. The most frequent long-term treatment-related adverse events were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%) with no evidence of delay in height, BMI, or pubertal development, or withdrawal effects. The starting dose is 2 mg once daily independent of age or weight, escalated to 5-10 mg/day if predefined treatment success criteria are unmet. Slow melatonin metabolizers (~10% of children), may require lower doses. Given its long-term efficacy, safety and acceptance, PedPRM may ameliorate long-term consequences of insomnia in this population.

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15. Sherby MR, Walsh T, Lai AM, Neidich JA, Balls-Berry JE, Morris SM, Head R, Prener C, Newland JG, Gurnett CA. SARS-CoV-2 Screening Testing in Schools for Children with Intellectual and Developmental Disabilities. Research square. 2021.

BACKGROUNDTransmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD.METHODSFrom 11/23/20 to 5/28/21, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies.RESULTSA total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7,289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening.CONCLUSIONSDuring 24 weeks that included the peak of the COVID-19 pandemic, we found no evidence for elevated SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure.Clinical Trial RegistryPrior to enrollment, this study was registered at ClinicalTrials.gov on 9/25/2020, identifier NCT04565509, titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic (https://clinicaltrials.gov/ct2/show/NCT04565509?term=NCT04565509).

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16. Takahashi Y, Murata S, Idei H, Tomita H, Yamashita Y. Neural network modeling of altered facial expression recognition in autism spectrum disorders based on predictive processing framework. Scientific reports. 2021; 11(1): 14684.

The mechanism underlying the emergence of emotional categories from visual facial expression information during the developmental process is largely unknown. Therefore, this study proposes a system-level explanation for understanding the facial emotion recognition process and its alteration in autism spectrum disorder (ASD) from the perspective of predictive processing theory. Predictive processing for facial emotion recognition was implemented as a hierarchical recurrent neural network (RNN). The RNNs were trained to predict the dynamic changes of facial expression movies for six basic emotions without explicit emotion labels as a developmental learning process, and were evaluated by the performance of recognizing unseen facial expressions for the test phase. In addition, the causal relationship between the network characteristics assumed in ASD and ASD-like cognition was investigated. After the developmental learning process, emotional clusters emerged in the natural course of self-organization in higher-level neurons, even though emotional labels were not explicitly instructed. In addition, the network successfully recognized unseen test facial sequences by adjusting higher-level activity through the process of minimizing precision-weighted prediction error. In contrast, the network simulating altered intrinsic neural excitability demonstrated reduced generalization capability and impaired emotional clustering in higher-level neurons. Consistent with previous findings from human behavioral studies, an excessive precision estimation of noisy details underlies this ASD-like cognition. These results support the idea that impaired facial emotion recognition in ASD can be explained by altered predictive processing, and provide possible insight for investigating the neurophysiological basis of affective contact.

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17. Wan Y, Zuo T, Xu Z, Zhang F, Zhan H, Chan D, Leung TF, Yeoh YK, Chan FKL, Chan R, Ng SC. Underdevelopment of the gut microbiota and bacteria species as non-invasive markers of prediction in children with autism spectrum disorder. Gut. 2022; 71(5): 910-8.

OBJECTIVE: The gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD. DESIGN: We performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model. RESULTS: ASD and chronological age had the most significant and largest impacts on children’s faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum. CONCLUSIONS: Gut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers.

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18. Wierzchowski A, Sablich-Duley S, Bordes Edgar V. Variability in Neuropsychological Phenotypes in Patients with 22Q11.2 Deletion Syndrome: Case Series. Developmental neuropsychology. 2021; 46(5): 381-92.

Children with 22q11.2 deletion syndrome (22q11.2DS) have diverse neurodevelopmental and mental health profiles involving cognitive impairments and behavioral symptomatology that evolve over the lifespan. 22q11.2DS is the second-most common cause of developmental delay in children. Frequent physical manifestations include impact to skeletal, cardiac, immunological, respiratory, renal, auditory, and gastrointestinal systems. Neuropsychological impact ranges from early developmental delay to learning disabilities to more global intellectual disability. This population is also at higher risk for psychiatric conditions including Attention Deficit Hyperactivity Disorder, Anxiety Disorder, Bipolar Disorder and early Schizophrenia. The present case series relays cross-sectional findings from a 3-year -old Black/Non-Hispanic male, a 5-year -old White/Hispanic/Latina female, and an 8-year -old White/Hispanic/Latina female, diagnosed with 22q11.2DS via whole exome sequencing. Based on the referral question, various components of intellectual, attention/executive, memory, language, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning were examined across cases. Results revealed cognitive scores that ranged from exceptionally low to below average, consistent with the variability in cognitive functioning documented in the literature. Their neurodevelopmental and mental health symptoms appear to be consistent with time points reported in the literature including Autism Spectrum Disorder in the youngest patient and elevated levels of anxiety and internalizing behaviors in the oldest patient, placing that patient at a greater risk for further psychiatric difficulties. Therefore, longitudinal documentation of linkages between clinical neuropsychological presentations and specific genetic characteristics in 22q11.2DS is warranted to identify consistent developmental differences across the lifespan.

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19. Wigham S, McKinnon I, Reid K, Milton D, Lingam R, Rodgers J. Questionnaires used in complex trauma intervention evaluations and consideration of their utility for autistic adults with mild intellectual disability: A systematic review. Research in developmental disabilities. 2021; 117: 104039.

INTRODUCTION: Research suggests some trauma symptoms e.g. avoidance are difficult to recognise in autistic people with intellectual disability while arousal/emotional and interpersonal difficulties may be useful signals. This review aims to (i) identify questionnaires used in general population complex trauma interventions to measure emotional and interpersonal difficulty and (ii) evaluate their psychometric properties to inform selection of a potential measure/s for use and/or adaptation for autistic people with mild intellectual disability and trauma related mental health conditions. METHODS: Stage 1: we searched Medline, Cinahl, Embase and PsycInfo for general population and clinical complex trauma intervention studies. Stage 2: we used a search filter in Embase to identify psychometric evaluations of relevant questionnaires used in Stage 1 studies and assessed these with the COnsensus based Standards for the selection of health based Measurement Instruments (COSMIN) checklist. RESULTS: five studies were identified in Stage 1 utilising three measures of emotion dysregulation and interpersonal difficulties. Thirty-three articles on their psychometric properties were identified in Stage 2. Strongest psychometric evidence was found for the Emotion Regulation Questionnaire (ERQ) and Difficulties in Emotion Regulation Scale (DERS). CONCLUSIONS: Evaluating content validity/acceptability of the ERQ and DERS for autistic people with mild intellectual disability and trauma-related mental health conditions are useful next steps.

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20. Wilfert AB, Turner TN, Murali SC, Hsieh P, Sulovari A, Wang T, Coe BP, Guo H, Hoekzema K, Bakken TE, Winterkorn LH, Evani US, Byrska-Bishop M, Earl RK, Bernier RA, Zody MC, Eichler EE. Recent ultra-rare inherited variants implicate new autism candidate risk genes. Nature genetics. 2021; 53(8): 1125-34.

Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.

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21. Zhang T, Huang W, Wu X, Sun W, Lin F, Sun H, Li J. Altered complexity in resting-state fNIRS signal in autism: a multiscale entropy approach. Physiological measurement. 2021; 42(8).

Objective.Feature extraction and recognition in brain signal processing is of great significance for understanding the neurological mechanism of autism spectrum disorder (ASD). Resting-state (RS) functional near-infrared spectroscopy measurement provides a way to investigate the possible alteration in ASD-related complexity of resting-state (RS) functional near-infrared spectroscopy (fNIRS) signals and to explore the relationship between brain functional connectivity and complexity.Approach.Using the multiscale entropy (MSE) of fNIRS signals recorded from the bilateral temporal lobes (TLs) on 25 children with ASD and 22 typical development (TD) children, the pattern of brain complexity was assessed for both the ASD and TD groups.Main results.The quantitative analysis of MSE revealed the increased complexity in RS-fNIRS in children with ASD, particularly in the left temporal lobe. The complexity in the RS signal and resting state functional connectivity (RSFC) were also observed to exhibit negative correlation in the medium magnitude.Significance.These results indicated that the MSE might serve as a novel measure for RS-fNIRS signals in characterizing and understanding ASD.

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22. Zieger HL, Choquet D. Nanoscale synapse organization and dysfunction in neurodevelopmental disorders. Neurobiology of disease. 2021; 158: 105453.

Neurodevelopmental disorders such as those linked to intellectual disabilities or autism spectrum disorder are thought to originate in part from genetic defects in synaptic proteins. Single gene mutations linked to synapse dysfunction can broadly be separated in three categories: disorders of transcriptional regulation, disorders of synaptic signaling and disorders of synaptic scaffolding and structures. The recent developments in super-resolution imaging technologies and their application to synapses have unraveled a complex nanoscale organization of synaptic components. On the one hand, part of receptors, adhesion proteins, ion channels, scaffold elements and the pre-synaptic release machinery are partitioned in subsynaptic nanodomains, and the respective organization of these nanodomains has tremendous impact on synaptic function. For example, pre-synaptic neurotransmitter release sites are partly aligned with nanometer precision to postsynaptic receptor clusters. On the other hand, a large fraction of synaptic components is extremely dynamic and constantly exchanges between synaptic domains and extrasynaptic or intracellular compartments. It is largely the combination of the exquisitely precise nanoscale synaptic organization of synaptic components and their high dynamic that allows the rapid and profound regulation of synaptic function during synaptic plasticity processes that underlie adaptability of brain function, learning and memory. It is very tempting to speculate that genetic defects that lead to neurodevelopmental disorders and target synaptic scaffolds and structures mediate their deleterious impact on brain function through perturbing synapse nanoscale dynamic organization. We discuss here how applying super-resolution imaging methods in models of neurodevelopmental disorders could help in addressing this question.

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