1. Correction to « Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice ». J Pharmacol Exp Ther;2023 (Apr);385(1):76-77.

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2. Almasoud H, Ain G. Parental perspectives on autism services in Saudi Arabia: Decade comparison (2011-2021). Res Dev Disabil;2023 (Mar 28);137:104485.

In 2004, Saudi Arabia began providing services to individuals with Autism Spectrum Disorder (ASD) and their families. There are no studies-based on the researchers’ knowledge-that have aimed to measure the improvement of services provided since 2004. Therefore, this study sought to determine the extent to which services for individuals with ASD have improved from the perspective of parents. The level of improvement was determined by comparing the two time periods (2011 and 2021). This is the first study in the country to assess parental perspectives on this topic at two time points. A questionnaire was administered to 118 parents/caregivers of children with ASD. The questions were designed to determine parents’ perceptions of the quality of support received from public services, level of community awareness concerning ASD, and factors influencing the support required to care for their children. The results established that some of the problems faced in 2011 were still present in 2021, and highlighted improvements in 2021.

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3. Behl S, Mehta S, Pandey MK. The role of selenoproteins in neurodevelopment and neurological function: Implications in autism spectrum disorder. Front Mol Neurosci;2023;16:1130922.

Selenium and selenoproteins play a role in many biological functions, particularly in brain development and function. This review outlines the role of each class of selenoprotein in human brain function. Most selenoproteins play a large antioxidant role within the brain. Autism spectrum disorder (ASD) has been shown to correlate with increased oxidative stress, and the presumption of selenoproteins as key players in ASD etiology are discussed. Further, current literature surrounding selenium in ASD and selenium supplementation studies are reviewed. Finally, perspectives are given for future directions of selenoprotein research in ASD.

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4. Bruce MR, Couch ACM, Grant S, McLellan J, Ku K, Chang C, Bachman A, Matson M, Berman RF, Maddock RJ, Rowland D, Kim E, Ponzini MD, Harvey D, Taylor SL, Vernon AC, Bauman MD, Van de Water J. Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure. Mol Psychiatry;2023 (Mar 27)

Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo (1)H magnetic resonance spectroscopy ((1)H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.

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5. Chhabra S, Nardi L, Leukel P, Sommer CJ, Schmeisser MJ. Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder. Front Psychiatry;2023;14:1110525.

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopmental phenotypes united by impaired social interaction and repetitive behavior. Environmental and genetic factors are associated with the pathogenesis of ASD, while other cases are classified as idiopathic. The dopaminergic system has a profound impact in the modulation of motor and reward-motivated behaviors, and defects in dopaminergic circuits are implicated in ASD. In our study, we compare three well-established mouse models of ASD, one idiopathic, the BTBR strain, and two syndromic, Fmr1 and Shank3 mutants. In these models, and in humans with ASD, alterations in dopaminergic metabolism and neurotransmission were highlighted. Still, accurate knowledge about the distribution of dopamine receptor densities in the basal ganglia is lacking. Using receptor autoradiography, we describe the neuroanatomical distribution of D1 and D2 receptors in dorsal and ventral striatum at late infancy and adulthood in the above-mentioned models. We show that D1 receptor binding density is different among the models irrespective of the region. A significant convergence in increased D2 receptor binding density in the ventral striatum at adulthood becomes apparent in BTBR and Shank3 lines, and a similar trend was observed in the Fmr1 line. Altogether, our results confirm the involvement of the dopaminergic system, showing defined alterations in dopamine receptor binding density in three well-established ASD lines, which may provide a plausible explanation to some of the prevalent traits of ASD. Moreover, our study provides a neuroanatomical framework to explain the utilization of D2-acting drugs such as Risperidone and Aripiprazole in ASD.

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6. Galetta MS, Lorentz NA, Lan R, Chan C, Zabat MA, Raman T, Protopsaltis TS, Fischer CR. Reoperation Rates Due to ASD following Primary 1-2 level MIS vs. Open TLIF. Spine (Phila Pa 1976);2023 (Mar 23)

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To investigate the effect of the approach of the TLIF (open vs. MIS) on reoperation rates due to ASD at 2 – 4 year follow up. SUMMARY OF BACKGROUND DATA: Adjacent segment degeneration (ASDeg) is a complication of lumbar fusion surgery which may progress to adjacent segment disease (ASD) and cause debilitating postoperative pain potentially requiring additional operative management for relief. Minimally invasive (MIS) transforaminal lumbar interbody fusion surgery (TLIF) has been introduced to minimize this complication but the impact on ASD incidence is unclear. METHODS: For a cohort of patients undergoing 1- or 2-level primary TLIF between 2013 and 2019, patient demographics and follow-up outcomes were collected and compared between patients who underwent open versus MIS TLIF using Mann Whitney U test, Fischer’s exact test, and binary logistic regression. RESULTS: 238 patients met inclusion criteria. There was a significant difference in revision rates due to ASD between MIS and open TLIFs at 2 (5.8% vs. 15.4%, P=0.021) and 3 (8% vs. 23.2%, P=0.03) year follow up, with open TLIFs demonstrating significantly higher revision rates. Surgical approach was the only independent predictor of reoperation rates at both 2 and 3 year follow ups (2-year P=0.009; 3-year P=0.011). CONCLUSION: Open TLIF was found to have a significantly higher rate of reoperation due to ASD compared to the MIS approach. Additionally, surgical approach (MIS vs. Open) appears to be an independent predictor of reoperation rates.

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7. Hardiansyah I, Nyström P, Taylor MJ, Bölte S, Ronald A, Falck-Ytter T. Global motion processing in infants’ visual cortex and the emergence of autism. Commun Biol;2023 (Mar 28);6(1):339.

Autism is a heritable and common neurodevelopmental condition, with behavioural symptoms typically emerging around age 2 to 3 years. Differences in basic perceptual processes have been documented in autistic children and adults. Specifically, data from many experiments suggest links between autism and alterations in global visual motion processing (i.e., when individual motion information is integrated to perceive an overall coherent pattern). Yet, no study has investigated whether a distinctive organization of global motion processing precede the emergence of autistic symptoms in early childhood. Here, using a validated infant electroencephalography (EEG) experimental paradigm, we first establish the normative activation profiles for global form, global motion, local form, and local motion in the visual cortex based on data from two samples of 5-month-old infants (total n = 473). Further, in a sample of 5-month-olds at elevated likelihood of autism (n = 52), we show that a different topographical organization of global motion processing is associated with autistic symptoms in toddlerhood. These findings advance the understanding of neural organization of infants’ basic visual processing, and its role in the development of autism.

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8. Jatkar A, Garrido D, Zheng S, Silverman G, Elsayed H, Davis PH, Lee H, Crais ER, Sideris J, Turner-Brown L, Baranek GT, Watson LR, Grzadzinski R. Toddlers at Elevated Likelihood for Autism: Exploring Sensory and Language Treatment Predictors. J Early Interv;2023 (Mar);45(1):39-62.

Baseline child characteristics may predict treatment outcomes in children with or at elevated likelihood of developing autism (EL-ASD). Little is known about the role of child sensory and language features on treatment outcome. Participants were randomly assigned to a parent-mediated intervention or control condition. Analyses explored the relationship between baseline child sensory and language characteristics and changes in ASD symptoms over approximately 9 months. Higher baseline sensory hyporeactivity was significantly related to less improvement in social communication (SC) for the treatment group only. More baseline atypical vocalizations were significantly related to less improvement on SC across treatment and control groups. This work provides an initial framework to encourage the tailoring of interventions for EL-ASD children, suggesting sensory reactivity and atypical vocalizations may be useful behaviors to consider in treatment planning.

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9. Kreis I, Zhang L, Mittner M, Syla L, Lamm C, Pfuhl G. Aberrant uncertainty processing is linked to psychotic-like experiences, autistic traits, and is reflected in pupil dilation during probabilistic learning. Cogn Affect Behav Neurosci;2023 (Mar 28)

Aberrant belief updating due to misestimation of uncertainty and an increased perception of the world as volatile (i.e., unstable) has been found in autism and psychotic disorders. Pupil dilation tracks events that warrant belief updating, likely reflecting the adjustment of neural gain. However, whether subclinical autistic or psychotic symptoms affect this adjustment and how they relate to learning in volatile environments remains to be unraveled. We investigated the relationship between behavioral and pupillometric markers of subjective volatility (i.e., experience of the world as unstable), autistic traits, and psychotic-like experiences in 52 neurotypical adults with a probabilistic reversal learning task. Computational modeling revealed that participants with higher psychotic-like experience scores overestimated volatility in low-volatile task periods. This was not the case for participants scoring high on autistic-like traits, who instead showed a diminished adaptation of choice-switching behavior in response to risk. Pupillometric data indicated that individuals with higher autistic- or psychotic-like trait and experience scores differentiated less between events that warrant belief updating and those that do not when volatility was high. These findings are in line with misestimation of uncertainty accounts of psychosis and autism spectrum disorders and indicate that aberrancies are already present at the subclinical level.

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10. Li X, Li Q, Xu L, Ma Z, Shi Y, Zhang X, Yang Y, Wang J, Fan L, Wu L. Involvement of Kir4.1 in pain insensitivity of the BTBR mouse model of autism spectrum disorder. Biochim Biophys Acta Mol Basis Dis;2023 (Mar 28);1869(5):166700.

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder. Abnormal pain sensation is a common clinical symptom of ASD that seriously affects the quality of life of patients with ASD and their families. However, the underlying mechanism is unclear. It is believed to be related to the excitability of neurons and the expression of ion channels. Herein, we confirmed that baseline pain and Complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain were impaired in the BTBR T+ Itpr3tf/J (BTBR) mouse model of ASD. RNA sequencing (RNA-seq) analyses of the dorsal root ganglia (DRG), which are closely related to pain in ASD model mice, revealed that high expression of KCNJ10 (encoding Kir4.1) might be an important factor in ASD pain sensation abnormalities. The levels of Kir4.1 were further verified by western blotting, RT-qPCR, and immunofluorescence. By inhibiting Kir4.1, the pain insensitivity of BTBR mice improved, confirming that a high expression level of Kir4.1 was highly correlated with decreased pain sensitivity in ASD. Meanwhile, we found that the anxiety behaviours and the social novelty recognition were changed after CFA induced inflammatory pain. And after inhibiting Kir4.1, the stereotyped behaviours and social novelty recognition of BTBR mice were also improved. Further, we found that the expression levels of glutamate transporters, excitatory amino acid transporter 1 (EAAT1), and excitatory amino acid transporter 2 (EAAT2) were increased in the DRG of BTBR mice but decreased after inhibiting Kir4.1. This suggests that Kir4.1 may play a key role in the improvement of pain insensitivity in ASD by regulating glutamate transporters. In conclusion, our findings revealed the possible mechanism and role of Kir4.1 in the pain insensitivity in ASD, using bioinformatics analyses and animal experiments, and provided a theoretical basis for clinically targeted intervention in ASD.

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11. Mehra A, Arora G, Sahni G, Kaur M, Singh H, Singh B, Kaur S. Gut microbiota and Autism Spectrum Disorder: From pathogenesis to potential therapeutic perspectives. J Tradit Complement Med;2023 (Mar);13(2):135-149.

Autism is a complex neurodevelopmental disorder which disrupts communication, social and interactive skills followed by appearance of repetitive behavior. The underlying etiology remains incomprehensible but genetic and environmental factors play a key role. Accumulated evidence shows that alteration in level of gut microbes and their metabolites are not only linked to gastrointestinal problems but also to autism. So far the mix of microbes that is present in the gut affects human health in numerous ways through extensive bacterial-mammalian cometabolism and has a marked influence over health via gut-brain-microbial interactions. Healthy microbiota may even ease the symptoms of autism, as microbial balance influences brain development through the neuroendocrine, neuroimmune, and autonomic nervous systems. In this article, we focused on reviewing the correlation between gut microbiota and their metabolites on symptoms of autism by utilizing prebiotics, probiotics and herbal remedies to target gut microflora hence autism.

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12. Mercaldo V, Vidimova B, Gastaldo D, Fernández E, Lo AC, Cencelli G, Pedini G, De Rubeis S, Longo F, Klann E, Smit AB, Grant SGN, Achsel T, Bagni C. Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome. Neuron;2023 (Mar 28)

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

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13. Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, Nakamura K, Hashimoto R, Hiraki Y, Son S, Kato M, Sakai Y, Osaka H, Deguchi K, Matsuishi T, Takeshita S, Fattal-Valevski A, Ekhilevitch N, Tohyama J, Yap P, Keng WT, Kobayashi H, Takubo K, Okada T, Saitoh S, Yasuda Y, Murai T, Ohga S, Matsumoto A, Inoue K, Saikusa T, Hershkovitz T, Kobayashi Y, Morikawa M, Ito A, Hara T, Uno Y, Seiwa C, Ishizuka K, Shirahata E, Fujita A, Koshimizu E, Miyatake S, Takata A, Mizuguchi T, Ozaki N, Matsumoto N. Molecular diagnosis of 405 individuals with autism spectrum disorder. Eur J Hum Genet;2023 (Mar 27)

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

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14. Nitschke AS, do Valle HA, Vallance BA, Bickford C, Ip A, Lanphear N, Lanphear B, Weikum W, Oberlander TF, Hanley GE. Association between prenatal antibiotic exposure and autism spectrum disorder among term births: A population-based cohort study. Paediatr Perinat Epidemiol;2023 (Mar 28)

BACKGROUND: Prenatal antibiotic exposure induces changes in the maternal microbiome, which could influence the development of the infant’s microbiome-gut-brain axis. OBJECTIVES: We assessed whether prenatal antibiotic exposure is associated with an increased risk of autism spectrum disorder (ASD) in offspring born at term. METHODS: This population-based retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada between April 2000 and December 2014. Exposure was defined as filling antibiotic prescriptions during pregnancy. The outcome was an ASD diagnosis from the British Columbia Autism Assessment Network, with a follow-up to December 2016. To examine the association among pregnant individuals treated for the same indication, we studied a sub-cohort diagnosed with urinary tract infections. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios (HR). The analysis was stratified by sex, trimester, cumulative duration of exposure, class of antibiotic, and mode of delivery. We ran a conditional logistic regression of discordant sibling pairs to control for unmeasured environmental and genetic confounding. RESULTS: Of the 569,953 children included in the cohort, 8729 were diagnosed with ASD (1.5%) and 169,922 were exposed to prenatal antibiotics (29.8%). Prenatal antibiotic exposure was associated with an increased risk of ASD (HR 1.10, 95% confidence interval [CI] 1.05, 1.15), particularly for exposure during the first and second trimesters (HR 1.11, 95% CI 1.04, 1.18 and HR 1.09, 95% CI 1.03, 1.16, respectively), and exposure lasting ≥15 days (HR 1.13, 95% CI 1.04, 1.23). No sex differences were observed. The association was attenuated in the sibling analysis (adjusted odds ratio 1.04, 95% CI 0.92, 1.17). CONCLUSIONS: Prenatal antibiotic exposure was associated with a small increase in the risk of ASD in offspring. Given the possibility of residual confounding, these results should not influence clinical decisions regarding antibiotic use during pregnancy.

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15. Parvaiz R, Vindbjerg E, Crespi B, Happe F, Schalbroeck R, Al-Sayegh Z, Danielsen IM, Tonge B, Videbech P, Abu-Akel A. Protocol for the development and testing of the schiZotypy Autism Questionnaire (ZAQ) in adults: a new screening tool to discriminate autism spectrum disorder from schizotypal disorder. BMC Psychiatry;2023 (Mar 28);23(1):200.

BACKGROUND: Autism spectrum disorder (ASD) and schizotypal disorder (SD) both have a heterogenous presentation, with significant overlaps in symptoms and behaviour. Due to elevated recognition and knowledge of ASD worldwide, there is a growing rate of referrals from primary health professionals to specialised units. At all levels of assessment, the differential diagnostic considerations between ASD and SD exert major challenges for clinicians. Although several validated screening questionnaires exist for ASD and SD, none have differential diagnostic properties. Accordingly, in this study, we aim to develop a new screening questionnaire, the schiZotypy Autism Questionnaire (ZAQ), which provides a combined screening for both conditions, while also indicating the relative likelihood of each. METHODS: We aim to test 200 autistic patients and 100 schizotypy patients recruited from specialised psychiatric clinics and 200 controls from the general population (Phase 1). The results from ZAQ will be compared to the clinical diagnoses from interdisciplinary teams at specialised psychiatric clinics. After this initial testing phase, the ZAQ will be validated in an independent sample (Phase 2). CONCLUSIONS: The aim of the study is to investigate the discriminative properties (ASD vs. SD), diagnostic accuracy, and validity of the schiZotypy Autism Questionnaire (ZAQ). FUNDING: Funding was provided by Psychiatric Centre Glostrup, Copenhagen Denmark, Sofiefonden (Grant number: FID4107425), Trygfonden (Grant number:153588), Takeda Pharma. TRIAL REGISTRATION: Clinical Trials, NCT05213286, Registered 28 January 2022, clinicaltrials.gov/ct2/show/NCT05213286?cond = RAADS&draw = 2&rank = 1.

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16. Pascual F, Camilli S, Lockey RF, Kolliputi N. Mind-Body Connection: Metabolite 4-Ethylphenyl Linked to Anxiety Behavior and Oligodendrocyte Modification in Autism Spectrum Disorder. Am J Physiol Gastrointest Liver Physiol;2023 (Mar 28)

The connection between byproducts of digestion in the gastrointestinal (GI) tract and neurocognitive disorders is an expanding area of research that has implications in autism spectrum disorder (ASD). Needham et al. (Needham et al., 2022) revealed that mice with elevated levels of 4-ethylphenyl sulfate (4EPS), a GI tract-derived metabolite previously found at increased levels in the plasma of individuals with ASD, had altered brain activity, anxiety-influenced behavior, and reduced myelination of neuronal axons. This is a monumental step forward in the study of gut-derived neuroactive compounds, like 4EPS, and advances the understanding of their role in modulating behavior and brain activity in neurocognitive disorders.

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17. Pelton MK, Crawford H, Bul K, Robertson AE, Adams J, de Beurs D, Rodgers J, Baron-Cohen S, Cassidy S. The role of anxiety and depression in suicidal thoughts for autistic and non-autistic people: A theory-driven network analysis. Suicide Life Threat Behav;2023 (Mar 28)

BACKGROUND: Autistic adults experience more frequent suicidal thoughts and mental health difficulties than non-autistic adults, but research has yet to explain how these experiences are connected. This study explored how anxiety and depression contribute to suicidal thoughts according to the Interpersonal Theory of Suicide for autistic and non-autistic adults. METHODS: Participants (autistic adults n = 463, 61% female; non-autistic n = 342, 64% female) completed online measures of anxiety, depression, thwarted belonging, and perceived burdensomeness. Network analysis explored whether: (i) being autistic is a risk marker for suicide; and (ii) pathways to suicidal thoughts are consistent for autistic and non-autistic adults. RESULTS: Being autistic connected closely with feeling like an outsider, anxiety, and movement, which connected to suicidal thoughts through somatic experiences, low mood, and burdensomeness. Networks were largely consistent for autistic and non-autistic people, but connections from mood symptoms to somatic and thwarted belonging experiences were absent for autistic adults. CONCLUSION: Autistic people experience more life stressors than non-autistic people leading to reduced coping, low mood, and suicidal thoughts. Promoting belonging, reducing anxiety, and understanding the role of movement could inform suicide prevention for autistic people. Research should accurately capture autistic lived experience when modeling suicide to ensure suicide prevention meets autistic needs.

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18. Qi N, Yang K, Lei X, Wang F, Wu D, Gao Y, Zhang Y, Liao S. [Clinical and genetic analysis of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi;2023 (Apr 10);40(4):408-412.

OBJECTIVE: To explore the clinical features and genetic etiology of two children with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH). METHODS: Two children with MICPCH who were presented at the Henan Provincial People’s Hospital between April 2019 and December 2021 were selected as the study subjects. Clinical data of the two children were collected, along with peripheral venous blood samples of them and their parents, and amniotic fluid sample of the mother of child 1. Whole exome sequencing (WES), array-comparative genomic hybridization (aCGH) and real-time quantitative PCR (qPCR) were carried out for the children, their parents and the fetus. The pathogenicity of candidate variants were evaluated. RESULTS: Child 1 was a 6-year-old girl featuring motor and language delay, whilst child 2 was a 4.5-year-old girl mainly featuring microcephaly and mental retardation. WES revealed that child 2 has harbored a 158.7 kb duplication in Xp11.4 (chrX: 41446160_41604854), which has encompassed exons 4~14 of the CASK gene. The same duplication was not found in either of her parents. aCGH revealed that child 1 has harbored a 29 kb deletion at Xp11.4 (chrX: 41637892_41666665), which encompassed exon 3 of the CASK gene. The same deletion was not found in either of her parents and the fetus. The above results were confirmed by qPCR assay. Above deletion and duplication were not found in the ExAC, 1000 Genomes and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PS2+PM2_Supporting). CONCLUSION: The deletion of exon 3 and duplication of exons 4~14 of the CASK gene probably underlay the pathogenesis of MICPCH in these two children, respectively.

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19. Sáez-Suanes GP, García-Villamisar D, Del Pozo Armentia A. The role of intellectual disability and emotional regulation in the autism-depression relationship. Autism;2023 (Mar 26):13623613231161881.

Many people with autism and intellectual disability have significant levels of depressive symptoms. However, this relationship is not clear. For this reason, knowing the factors that are associated with having depression in autism and intellectual disability is important. Emotion regulation is associated with depression in autism spectrum disorder and intellectual disability. After evaluating a group of people with autism and intellectual disability, we found that people with mild intellectual disability have problems regulating their emotions which lead them to develop depressive symptoms. These findings suggest that interventions designed to prevent or reduce depressive symptoms in people with autism spectrum disorder and mild intellectual disability should include among their goals emotional regulation.

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20. Smith LD, Valentine A, Moore Simas TA, Parish SL, Levy A, Mitra M. Clinician-reported barriers to providing perinatal care to women with intellectual and developmental disabilities. J Intellect Dev Disabil;2023;48(1):12-22.

BACKGROUND: Research suggests that women with intellectual and developmental disabilities are at increased risk for adverse pregnancy outcomes. Further, they report unmet perinatal care needs. This qualitative study examined clinician perspectives on barriers to providing perinatal care to women with intellectual and developmental disabilities. METHOD: We conducted semi-structured interviews and one focus group with US obstetric care clinicians (n=17). We used a content analysis approach to code data and analyse them for larger themes and relationships. RESULTS: The majority of participants were white, non-Hispanic, and female. Participants reported barriers providing care to pregnant women with intellectual and developmental disabilities across individual (e.g., communication challenges), practice (e.g., identification of disability status), and system levels (e.g., lack of clinician training). CONCLUSIONS: Clinician training and evidence-based guidelines for perinatal care of women with intellectual and developmental disabilities as well as services and supports during pregnancy are needed.

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21. Stella C, Díaz-Caneja CM, Penzol MJ, García-Alcón A, Solís A, Andreu-Bernabeu Á, Gurriarán X, Arango C, Parellada M, González-Peñas J. Analysis of common genetic variation across targets of microRNAs dysregulated both in ASD and epilepsy reveals negative correlation. Front Genet;2023;14:1072563.

Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders and epilepsy. Despite their polygenic nature, genome-wide association studies have not reported a significant contribution of common genetic variation to comorbidity between both conditions. Analysis of common genetic variation affecting specific shared pathways such as miRNA dysregulation could help to elucidate the polygenic mechanisms underlying comorbidity between autism spectrum disorders and epilepsy. We evaluated here the role of common predisposing variation to autism spectrum disorders and epilepsy across target genes of 14 miRNAs selected through bibliographic research as being dysregulated in both disorders. We considered 4,581 target genes from various in silico sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected (p = 0.0228). Moreover, polygenic transmission disequilibrium test on an independent cohort of autism spectrum disorders trios (N = 233) revealed an under-transmission of autism spectrum disorders predisposing alleles within miRNAs’ target genes across autism spectrum disorders trios without comorbid epilepsy, thus reinforcing the negative relationship at the common genetic variation between both traits. Our study provides evidence of a negative relationship between autism spectrum disorders and epilepsy at the common genetic variation level that becomes more evident when focusing on the miRNA regulatory networks, which contrasts with observed clinical comorbidity and results from rare variation studies. Our findings may help to conceptualize the genetic heterogeneity and the comorbidity with epilepsy in autism spectrum disorders.

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22. Sun A, Wang J, Zhang J. Identifying autism spectrum disorder using edge-centric functional connectivity. Cereb Cortex;2023 (Mar 28)

Brain network analysis is an effective method to seek abnormalities in functional interactions for brain disorders such as autism spectrum disorder (ASD). Traditional studies of brain networks focus on the node-centric functional connectivity (nFC), ignoring interactions of edges to miss much information that facilitates diagnostic decisions. In this study, we present a protocol based on an edge-centric functional connectivity (eFC) approach, which significantly improves classification performance by utilizing the co-fluctuations information between the edges of brain regions compared with nFC to build the classification mode for ASD using the multi-site dataset Autism Brain Imaging Data Exchange I (ABIDE I). Our model results show that even using the traditional machine-learning classifier support vector machine (SVM) on the challenging ABIDE I dataset, relatively high performance is achieved: 96.41% of accuracy, 98.30% of sensitivity, and 94.25% of specificity. These promising results suggest that the eFC can be used to build a reliable machine-learning framework to diagnose mental disorders such as ASD and promote identifications of stable and effective biomarkers. This study provides an essential complementary perspective for understanding the neural mechanisms of ASD and may facilitate future investigations on early diagnosis of neuropsychiatric disorders.

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23. Svalina MN, Sullivan R, Restrepo D, Huntsman MM. From circuits to behavior: Amygdala dysfunction in fragile X syndrome. Front Integr Neurosci;2023;17:1128529.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a repeat expansion mutation in the promotor region of the FMR1 gene resulting in transcriptional silencing and loss of function of fragile X messenger ribonucleoprotein 1 protein (FMRP). FMRP has a well-defined role in the early development of the brain. Thus, loss of the FMRP has well-known consequences for normal cellular and synaptic development leading to a variety of neuropsychiatric disorders including an increased prevalence of amygdala-based disorders. Despite our detailed understanding of the pathophysiology of FXS, the precise cellular and circuit-level underpinnings of amygdala-based disorders is incompletely understood. In this review, we discuss the development of the amygdala, the role of neuromodulation in the critical period plasticity, and recent advances in our understanding of how synaptic and circuit-level changes in the basolateral amygdala contribute to the behavioral manifestations seen in FXS.

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24. Vidriales-Fernández R, Plaza-Sanz M, Hernández-Layna C, Verde-Cagiao M, Benito-Ruiz G, Carvajal-Molina F. Characterizing the physical and mental health profile of children, adolescents and adults with autism spectrum disorder in Spain. Front Psychiatry;2023;14:1088727.

INTRODUCTION: Autistic men and women are more likely to experience health issues than the general population, although the available epidemiological studies addressing co-occurrence conditions are limited. This is the first Spanish epidemiologic study addressing the health profile and poor-health exacerbating factors in individuals of all ages with autism spectrum disorder (ASD). METHODS: We analyzed 2,629 registries extracted from Autism Spain’s sociodemographic registry (November 2017-May 2020). A descriptive health data analysis was conducted to assess the prevalence of other conditions associated to ASD in the Spanish population. Nervous system disorders (12.9%), mental health diagnoses (17.8%), and other comorbidities (25.4%) were reported. Men-to-women ratio was 4:1. RESULTS: Women, elder individuals and those with intellectual disability (ID) were at an increased risk of health comorbidities and psychopharmacological exposure. Women were also more prone to severe intellectual and functional impairment. Nearly all individuals had difficulties in their adaptative functioning, especially those with ID (50% of the population). Almost half of the sample received psychopharmacological treatments starting from infancy and early childhood, mostly antipsychotics and anticonvulsants. DISCUSSION: This study represents an important first approach to the health status of autistic people in Spain and can contribute to the development of public policies and innovative health strategies.

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25. Weinschutz Mendes H, Neelakantan U, Liu Y, Fitzpatrick SE, Chen T, Wu W, Pruitt A, Jin DS, Jamadagni P, Carlson M, Lacadie CM, Enriquez KD, Li N, Zhao D, Ijaz S, Sakai C, Szi C, Rooney B, Ghosh M, Nwabudike I, Gorodezky A, Chowdhury S, Zaheer M, McLaughlin S, Fernandez JM, Wu J, Eilbott JA, Vander Wyk B, Rihel J, Papademetris X, Wang Z, Hoffman EJ. High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways. Cell Rep;2023 (Mar 28);42(3):112243.

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.

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26. Zhang H, Xu L, Yu J, Li J, Wang J. Identification of autism spectrum disorder based on functional near-infrared spectroscopy using adaptive spatiotemporal graph convolution network. Front Neurosci;2023;17:1132231.

The accurate diagnosis of autism spectrum disorder (ASD) is of great practical significance in clinical practice. The spontaneous hemodynamic fluctuations were collected by functional near-infrared spectroscopy (fNIRS) from the bilateral frontal and temporal cortices of typically developing (TD) children and children with ASD. Since traditional machine learning and deep learning methods cannot make full use of the potential spatial dependence between variable pairs, and require a long time series to diagnose ASD. Therefore, we use adaptive spatiotemporal graph convolution network (ASGCN) and short time series to classify ASD and TD. To capture spatial and temporal features of fNIRS multivariable time series without the pre-defined graph, we combined the improved adaptive graph convolution network (GCN) and gated recurrent units (GRU). We conducted a series of experiments on the fNIRS dataset, and found that only using 2.1 s short time series could achieve high precision classification, with an accuracy of 95.4%. This suggests that our approach may have the potential to detect pathological signals in autism patients within 2.1 s. In different brain regions, the left frontal lobe has the best classification effect, and the abnormalities occur more frequently in left hemisphere and frontal lobe region. Moreover, we also found that there were correlations between multiple channels, which had different degrees of influence on the classification of ASD. From this, we can also generalize to a wider range, there may be potential correlations between different brain regions. This may help to better understand the cortical mechanism of ASD.

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