1. Al-Shaban FA, Ghazal I, Thompson IR, Klingemier EW, Aldosari M, Al-Shammari H, Al-Faraj F, El-Hag S, Tolefat M, Ali M, Nasir B, Frazier TW. Development and validation of an Arabic language eye-tracking paradigm for the early screening and diagnosis of autism spectrum disorders in Qatar. Autism research : official journal of the International Society for Autism Research. 2023.

Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD). The primary aim of the present research was to develop an Arabic version of an objective measure of ASD, the « autism index » (AI), based on eye gaze tracking to social and nonsocial stimuli validated initially in the United States. The initial phase of this study included the translation of English language eye-tracking stimuli into stimuli appropriate for an Arabic-speaking culture. During the second phase, we tested it on a total of 144 children with ASD, and 96 controls. The AI had excellent internal consistency and test-retest reliability. Moreover, the AI showed good differentiation of ASD from control cases (AUC = 0.730, SE = 0.035). The AI was significantly positively correlated with SCQ total raw scores (r = 0.46, p < 0.001). ADOS-2 scores were only available in the ASD group and did not show a significant relationship with AI scores (r = 0.10, p = 0.348), likely due to the restricted range. The AI, when implemented using Arabic-translated stimuli in a Qatari sample, showed good diagnostic differentiation and a strong correlation with parent-reported ASD symptoms. Thus, the AI appears to have cross-cultural validity and may be useful as a diagnostic aide to inform clinical judgment and track ASD symptom levels as part of the evaluation process.

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2. Asgarihafshejani A, Andisseryparambi Raveendran V, Pressey JC, Woodin MA. LTP is Absent in the CA1 Region of the Hippocampus of Male and Female Rett Syndrome Mouse Models. Neuroscience. 2023.

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, resulting in severe deficits in learning and memory. Alterations in synaptic plasticity have been reported in RTT, however most electrophysiological studies have been performed in male mice only, despite the fact that RTT is primarily found in females. In addition, most studies have focused on excitation, despite the emerging evidence for the important role of inhibition in learning and memory. Here, we performed an electrophysiological characterization in the CA1 region of the hippocampus in both males and females of RTT mouse models with a focus on neurogliaform (NGF) interneurons, given that they are the most abundant dendrite-targeting interneuron subtype in the hippocampus. We found that theta-burst stimulation (TBS) failed to induce long-term potentiation (LTP) in either pyramidal neurons or NGF interneurons in male or female RTT mice, with no apparent changes in short-term plasticity (STP). This failure to induce LTP was accompanied by excitation/inhibition (E/I) imbalances and altered excitability, in a sex- and cell-type specific manner. Specifically, NGF interneurons of male RTT mice displayed increased intrinsic excitability, a depolarized resting membrane potential, and decreased E/I balance, while in female RTT mice, the resting membrane potential was depolarized. Understanding the role of NGF interneurons in RTT animal models is crucial for developing targeted treatments to improve cognition in individuals with this disorder.

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3. Ashworth M, Heasman B, Crane L, Remington A. Evaluating a new supported employment internship programme for autistic young adults without intellectual disability. Autism : the international journal of research and practice. 2023: 13623613231214834.

Internships designed for autistic people can help them to find employment, but there is little research about the experiences of those involved with internship schemes. To learn more about a new paid internship scheme in the United Kingdom, the Employ Autism network, we interviewed 19 interns, who were autistic young adults without intellectual disability taking part in one of eight different internships. We also interviewed 22 employers (who worked with the interns), and 10 parents (who supported their children in the internship). The interns, employers and parents told us that the Employ Autism network was a valuable experience that helped the interns become more confident. Also, the parents said it helped the interns become more independent. All the groups said the Employ Autism network removed common barriers to employment, and interns and parents said it would help interns get a job in future. Employers and interns said they understood each other better during the internship, and employers said the internship made them think about how their organisations might have accidentally had barriers in place that could stop autistic people getting employed (barriers that they wanted to address in future). However, all groups said some expectations of the internship were not met. These findings suggest the Employ Autism network is helpful for autistic young adults without intellectual disability and employers, but that there are ways that the internships could be improved in future. We discuss the lessons we can learn from the Employ Autism network that might help others who are thinking about setting up, or getting involved in, similar internship schemes.

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4. Bradshaw J, O’Reilly C, Everhart KC, Dixon E, Vinyard A, Tavakoli A, Iskersky V, Dail RB. Neonatal Autonomic Regulation as a Predictor of Autism Spectrum Disorder in Very Preterm Infants. medRxiv : the preprint server for health sciences. 2023.

Infants born preterm are at a significantly higher likelihood of having autism spectrum disorder (ASD). Preterm birth and ASD are both associated with neurological differences, notably autonomic nervous system (ANS) dysfunction, pointing to preterm ANS dysfunction as a potential pathway to ASD, particularly in VPT infants. In this study, a subset of very preterm (VPT) infants enrolled in a large, multisite clinical trial were enrolled in this study at birth (N=20). Continuous measures of minute-by-minute thermal gradients, defined by the difference between central and peripheral temperatures, and hour-by-hour abnormal heart rate characteristics (HRCs) were collected from birth-28 days (>40,000 samples/infant). Following NICU discharge, standardized measures of cognition, language, and motor skills were collected at adjusted ages 6, 9, and 12 months. At 12 months, assessments of social communication and early ASD symptoms were administered. Results suggest significant ASD concerns for half of the sample by 12 months of age. Neonatal abnormal HRCs were strongly associated with 12-month ASD symptoms (r=0.81, p<.01), as was birth gestational age (GA), birth weight (BW), and abnormal negative thermal gradients. ANS measures collected in the first month of neonatal life, more than a year prior to the ASD evaluation, were surprisingly strong predictors of ASD. This study highlights complementary ANS measures that describe how ANS dysfunction, likely resulting from an imbalance between the parasympathetic and sympathetic systems, may impact very early regulatory processes for neonates who later develop ASD. This finding offers a promising avenue for researching ANS-related etiological mechanisms and biomarkers of ASD.

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5. Cairney BE, West SH, Haebig E, Cox CR, Lucas HD. Interpretations of meaningful and ambiguous hand gestures in autistic and non-autistic adults: A norming study. Behavior research methods. 2023.

Gestures are ubiquitous in human communication, and a growing but inconsistent body of research suggests that people with autism spectrum disorder (ASD) may process co-speech gestures differently from neurotypical individuals. To facilitate research on this topic, we created a database of 162 gesture videos that have been normed for comprehensibility by both autistic and non-autistic raters. These videos portray an actor performing silent gestures that range from highly meaningful (e.g., iconic gestures) to ambiguous or meaningless. Each video was rated for meaningfulness and given a one-word descriptor by 40 autistic and 40 non-autistic adults, and analyses were conducted to assess the level of within- and across-group agreement. Across gestures, the meaningfulness ratings provided by raters with and without ASD correlated at r > 0.90, indicating a very high level of agreement. Overall, autistic raters produced a more diverse set of verbal labels for each gesture than did non-autistic raters. However, measures of within-gesture semantic similarity among the responses provided by each group did not differ, suggesting that increased variability within the ASD group may have occurred at the lexical rather than semantic level. This study is the first to compare gesture naming between autistic and non-autistic individuals, and the resulting dataset is the first gesture stimulus set for which both groups were equally represented in the norming process. This database also has broad applicability to other areas of research related to gesture processing and comprehension. The video database and accompanying norming data are available on the Open Science Framework.

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6. Glaser N, Thull C, Schmidt M, Tennant A, Moon J, Ousley C. Learning Experience Design and Unpacking Sociocultural, Technological, and Pedagogical Design Considerations of Spherical Video-Based Virtual Reality Systems for Autistic Learners: A Systematic Literature Review. Journal of autism and developmental disorders. 2023.

This systematic literature review discusses the use of spherical video-based virtual reality (SVVR) as a training and therapy intervention for autistic individuals. The authors emphasize the need for an evidence-based framework with guidelines and design considerations to help developers and educators tailor SVVR to the diverse needs of autistic learners. The paper highlights the unique benefits of SVVR, such as being relatively easier to develop compared to other VR technologies and high compatibility with various devices, making it more affordable for educational settings. The authors also discuss the importance of the STP (Sociotechnical-Pedagogical) framework for evaluating and designing social aspects of SVVR interventions for autistic individuals.

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7. Glass D, Yuill N. Social motor synchrony in autism spectrum conditions: A systematic review. Autism : the international journal of research and practice. 2023: 13623613231213295.

When two people interact, they often fall into sync with one another by moving their bodies at the same time. Some say autistic people are not as good as non-autistic people at moving at the same time as a partner. This has led some researchers to ask whether measuring synchrony might help diagnose autism. We reviewed the research so far to look at differences in Social Motor Synchrony (SMS) (the way we move together) between autistic people and people they interact with. The research suggests that interactions involving an autistic partner (either two autistic partners, or an autistic and non-autistic partner) show lower synchrony than a non-autistic pair. However, we recognised elements in the research so far that may have affected SMS in interactions involving an autistic person. One way SMS may have been affected in research so far might be the way interactions have been set up in the research studies. Few papers studied interactions between two autistic people or looked at synchrony in comfortable environments with autistic-preferred tasks. The studies also do not explain why synchrony might be different, or weaker, in pairs involving autistic partners. We use these limitations to suggest improvements for future research.

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8. Hansford R, Ouellette-Kuntz H, Bourque MA, Decker K, Derksen S, Hallet J, Dawe DE, Cobigo V, Shooshtari S, Stirling M, Kelly C, Brownell M, Turner D, Mahar AL. Investigating inequalities in cancer staging and survival for adults with intellectual or developmental disabilities and cancer: A population-based study in Manitoba, Canada. Cancer epidemiology. 2023; 88: 102500.

BACKGROUND: Cancer is a leading cause of death among adults living with intellectual or developmental disabilities (IDD). However, few epidemiological studies exist worldwide quantifying inequalities in cancer stage at diagnosis and survival for people with IDD relative to those without IDD. METHODS: A population-based, retrospective cohort study was conducted using provincial health and social administrative data in Manitoba, Canada. Adults (≥18 years) with a cancer diagnosis between 2004 and 2017 were included. Lifetime IDD was identified before the cancer diagnosis using an established algorithm. Modified Poisson regression with robust error variance was used to estimate the association between IDD status and metastatic cancer at diagnosis. Multivariable Cox proportional hazards analyses were used to the effect of IDD on overall survival following the cancer diagnosis. RESULTS: The staging and prognosis cohorts included 62,886 (n = 473 with IDD) and 74,143 (n = 592 with IDD) cancer patients, respectively. People living with IDD were significantly more likely to be diagnosed with metastatic cancer and die following their cancer diagnosis compared to those without IDD (RR=1.20; 95 % CI 1.05-1.38; HR= 1.53; 95 % CI 1.38-1.71). Significant heterogeneity by sex was identified for cancer survival (p = 0.005). DISCUSSION: People with IDD had more advanced cancer stage at diagnosis and worse survival relative to those without IDD. Identifying and developing strategies to address the factors responsible that contribute to these disparities is required for improving patient-centred cancer care for adults with IDD.

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9. Jung W, Jeon E, Kang E, Suk HI. EAG-RS: A Novel Explainability-guided ROI-Selection Framework for ASD Diagnosis via Inter-regional Relation Learning. IEEE transactions on medical imaging. 2023; Pp.

Deep learning models based on resting-state functional magnetic resonance imaging (rs-fMRI) have been widely used to diagnose brain diseases, particularly autism spectrum disorder (ASD). Existing studies have leveraged the functional connectivity (FC) of rs-fMRI, achieving notable classification performance. However, they have significant limitations, including the lack of adequate information while using linear low-order FC as inputs to the model, not considering individual characteristics (i.e., different symptoms or varying stages of severity) among patients with ASD, and the non-explainability of the decision process. To cover these limitations, we propose a novel explainability-guided region of interest (ROI) selection (EAG-RS) framework that identifies non-linear high-order functional associations among brain regions by leveraging an explainable artificial intelligence technique and selects class-discriminative regions for brain disease identification. The proposed framework includes three steps: (i) inter-regional relation learning to estimate non-linear relations through random seed-based network masking, (ii) explainable connection-wise relevance score estimation to explore high-order relations between functional connections, and (iii) non-linear high-order FC-based diagnosis-informative ROI selection and classifier learning to identify ASD. We validated the effectiveness of our proposed method by conducting experiments using the Autism Brain Imaging Database Exchange (ABIDE) dataset, demonstrating that the proposed method outperforms other comparative methods in terms of various evaluation metrics. Furthermore, we qualitatively analyzed the selected ROIs and identified ASD subtypes linked to previous neuroscientific studies.

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10. Kewalramani S, Allen KA, Leif E, Ng A. A Scoping Review of the Use of Robotics Technologies for Supporting Social-Emotional Learning in Children with Autism. Journal of autism and developmental disorders. 2023.

This scoping review synthesises the current research into robotics technologies for promoting social-emotional learning in children with autism spectrum disorder. It examines the types of robotics technologies employed, their applications, and the gaps in the existing literature. Our scoping review adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines. The systematic search of relevant databases allowed us to identify studies that use robotics technologies for fostering social, emotional, and cognitive skills in young children with autism. Our review has revealed that various robots, such as Nao, Kaspar, and Zeno, have been used to support the development of social and emotional skills through imitation games, turn-taking, joint attention, emotional recognition, and conversation. As most of these studies were conducted in clinical settings, there is a need for further research in classroom and community-based environments. Additionally, the literature calls for more high-quality longitudinal studies to assess the long-term effectiveness and sustainability of robot-assisted therapy and to assess adaptive and personalised interventions tailored to individual needs. More emphasis is recommended on professional development for educators, parents, and health professionals to incorporate robotics technologies as evidence-based interventions as a pathway for creating inclusive learning environments for children with autism.

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11. Lefebvre A, Traut N, Pedoux A, Maruani A, Beggiato A, Elmaleh M, Germanaud D, Amestoy A, Ly-Le Moal M, Chatham C, Murtagh L, Bouvard M, Alisson M, Leboyer M, Bourgeron T, Toro R, Dumas G, Moreau C, Delorme R. Exploring the multidimensional nature of repetitive and restricted behaviors and interests (RRBI) in autism: neuroanatomical correlates and clinical implications. Molecular autism. 2023; 14(1): 45.

BACKGROUND: Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into ‘motor-driven’ and ‘cognitively driven’. RRBI symptomatology depends on the individual’s clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures-involving cortical and subcortical areas. METHOD: A sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models. RESULTS: We identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the ‘motor-driven’ RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the ‘cognitively driven’ RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001). CONCLUSION: Our results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen's integrative role in RSBI needs to be strengthened in further studies.

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12. Li Q, Li W, Hu K, Wang Y, Li Y, Xu J. A de novo variant in RERE causes autistic behavior by disrupting related genes and signaling pathway. Clinical genetics. 2023.

Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder that typically manifests childhood, characterized by a triad of symptoms: impaired social interaction, communication difficulties, and restricted interests with repetitive behaviors. De novo variants in related genes can cause ASD. We present the case of a 6-year-old Chinese boy with autistic behavior, including language communication impairments, intellectual disabilities, stunted development, and irritability in social interactions. Using Sanger sequencing, we confirmed a pathogenic in the RERE gene (NM_012102.4) (c.3732delC, p.Tyr1245Thrfs*12; EX21; Het). Subsequently, we generated an RERE point mutation cell line (ReMut) using CRISPR/Cas9 Targeted Genome Editing. Immunofluorescence was conducted to determine the location of the mutant RERE. RNA-sequencing and mass spectrometry analyses were performed to elucidate the ASD-related genes and signaling pathways disrupted by this variant in RERE. We identified 3790 differentially expressed genes and 684 differentially expressed proteins. The SHH signaling pathway was found to be downregulated, and the Hippo pathway was upregulated in ReMut. Genes implicated in autism, such as CNTNAP2, STX1A, FARP2, and GPC1, were significantly downregulated. Simultaneously, we noted alterations in HDAC1 and HDAC2, which are members of the WHHERE complex, suggesting their role in the pathogenesis of this patient. In conclusion, we report a de novo variant in RERE associated with autistic behavior. The finding that ASD is associated with RERE variants underscore the role of genetic factors in ASD and provides insights regarding the mechanisms underlying RERE variants in disease onset.

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13. Lin J, Costa MA, Rezende VL, Nascimento RR, Ambrósio PG, Madeira K, Pearson DA, Gonçalves CL. Risk factors and clinical profile of autism spectrum disorder in southern Brazil. Journal of psychiatric research. 2023; 169: 105-12.

In Brazil, as in other countries, it is expected a significant variation of epidemiological and clinical characteristics among individuals with autism spectrum disorder (ASD). This study was performed to explore maternal risk factors and clinical characteristics of children with ASD in a population located in southern Brazil. Data were collected from medical records and analyzed to explore biomarkers associated with ASD. Out of 321 children with ASD, 86.5% were males with a male-to-female ratio of 5.7:1, 50.7% were mild/moderate while 49.3% presented severe ASD. Between the risk factors investigated, gestational infection was significantly associated with severe ASD patients. There was also an association between epilepsy and severe autism. Several gastrointestinal (GI) symptoms were significantly associated with severe ASD. Obesity, followed by lower levels of cholesterol, were also significant factors associated with an ASD diagnosis when compared to age-matched controls. Finally, severe ASD was associated with significantly higher serum serotonin levels when compared to age-matched controls and mild/moderate ASD cases. Our findings demonstrate that our population shares many features associated with ASD around the world, such as GI symptoms, epilepsy, and high serotonin levels. It is worth highlighting the low cholesterol levels associated with obesity as an unusual feature that deserves more attention.

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14. Masiran R, Ilias MNA, Yubbu P. Methylphenidate-associated chest pain in a child. BMJ case reports. 2023; 16(11).

A young child was diagnosed with autism spectrum disorder with comorbid attention-deficit/hyperactivity disorder. His hyperactivity, impulsivity and absence of awareness towards danger increased his risk of harm and hence methylphenidate was indicated. Unfortunately, he developed chest pain eight months after the treatment initiation. We then stopped the stimulant and changed his treatment to atomoxetine, after which he no longer had chest pain. In the following illustrated case, we will discuss the cardiac side effect of methylphenidate.

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15. McMahon M, McCallion P, McCarron M. An invisible population: Late-stage cancer diagnosis for people with intellectual or developmental disability. Cancer. 2023.

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16. Nagai Y, Kirino E, Tanaka S, Usui C, Inami R, Inoue R, Hattori A, Uchida W, Kamagata K, Aoki S. Functional connectivity in autism spectrum disorder evaluated using rs-fMRI and DKI. Cerebral cortex (New York, NY : 1991). 2023.

We evaluated functional connectivity (FC) in patients with adult autism spectrum disorder (ASD) using resting-state functional MRI (rs-fMRI) and diffusion kurtosis imaging (DKI). We acquired rs-fMRI data from 33 individuals with ASD and 33 healthy controls (HC) and DKI data from 18 individuals with ASD and 17 HC. ASD showed attenuated FC between the right frontal pole (FP) and the bilateral temporal fusiform cortex (TFusC) and enhanced FC between the right thalamus and the bilateral inferior division of lateral occipital cortex, and between the cerebellar vermis and the right occipital fusiform gyrus (OFusG) and the right lingual gyrus, compared with HC. ASD demonstrated increased axial kurtosis (AK) and mean kurtosis (MK) in white matter (WM) tracts, including the right anterior corona radiata (ACR), forceps minor (FM), and right superior longitudinal fasciculus (SLF). In ASD, there was also a significant negative correlation between MK and FC between the cerebellar vermis and the right OFusG in the corpus callosum, FM, right SLF and right ACR. Increased DKI metrics might represent neuroinflammation, increased complexity, or disrupted WM tissue integrity that alters long-distance connectivity. Nonetheless, protective or compensating adaptations of inflammation might lead to more abundant glial cells and cytokine activation effectively alleviating the degeneration of neurons, resulting in increased complexity. FC abnormality in ASD observed in rs-fMRI may be attributed to microstructural alterations of the commissural and long-range association tracts in WM as indicated by DKI.

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17. Potabattula R, Prell A, Dittrich M, Nava C, Depienne C, Bejaoui Y, El Hajj N, Hahn T, Schorsch M, Haaf T. Effects of paternal and chronological age on BEGAIN methylation and its possible role in autism. Aging. 2023; 15(22): 12763-79.

Children from old fathers carry an increased risk for autism spectrum (ASD) and other neurodevelopmental disorders, which may at least partially be mediated by paternal age effects on the sperm epigenome. The brain enriched guanylate kinase associated (BEGAIN) protein is involved in protein-protein interactions at and transmission across synapses. Since several epigenome-wide methylation screens reported a paternal age effect on sperm BEGAIN methylation, here we confirmed a significant negative correlation between BEGAIN promoter methylation and paternal age, using more sensitive bisulfite pyrosequencing and a larger number of sperm samples. Paternal age-associated BEGAIN hypomethylation was also observed in fetal cord blood (FCB) of male but not of female offspring. There was no comparable maternal age effect on FCB methylation. In addition, we found a significant negative correlation between BEGAIN methylation and chronological age (ranging from 1 to 70 years) in peripheral blood samples of male but not of female donors. BEGAIN hypomethylation was more pronounced in male children, adolescents and adults suffering from ASD compared to controls. Both genetic variation (CC genotype of SNP rs7141087) and epigenetic factors may contribute to BEGAIN promoter hypomethylation. The age- and sex-specific BEGAIN methylation trajectories in the male germ line and somatic tissues, in particular the brain, support a role of this gene in ASD development.

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18. Rehan F, Nasrumminallah M, Mukhtiar S. Trending Screen Addiction: Emerging Risk Of Increased Virtual Autism Among Toddlers. JPMA The Journal of the Pakistan Medical Association. 2023; 73(11): 2309-10.

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19. Taylor BJ, Pedersen KA, Mazefsky CA, Lamy MA, Reynolds CF, 3rd, Strathmann WR, Siegel M. From Alert Child to Sleepy Adolescent: Age Trends in Chronotype, Social Jetlag, and Sleep Problems in Youth with Autism. Journal of autism and developmental disorders. 2023.

PURPOSE: Developmental changes in sleep in youth with autism spectrum disorder (ASD) are understudied. In non-ASD youth, adolescents exhibit a « night owl chronotype » (i.e., later sleep/wake timing) and social jetlag (i.e., shifts in sleep timing across school nights and weekends), with corresponding sleep problems. The purpose of this study is to evaluate age trends in chronotype, social jetlag, and sleep problems in high-risk youth with ASD. METHODS: Youth with ASD (N = 171), ages 5-21 years old, were enrolled at the time of admission to specialized psychiatric units. Caregivers reported children’s demographic information, habitual sleep timing, and sleep problems. Multivariate analyses evaluated the effect of age on chronotype, social jetlag, and sleep problems and the effects of chronotype and social jetlag on sleep problems. Covariates and moderators included sex, race, verbal ability, autism symptom severity, supplemental melatonin, and pubertal status. RESULTS: Older age was associated with later chronotype, more social jetlag, fewer sleep anxiety/co-sleeping problems, fewer night waking and parasomnia problems, and more daytime alertness problems. The effect of age on chronotype was stronger for youth with greater social affective symptom severity. Mediation analyses showed that later chronotype statistically mediated the association between age and daytime alertness problems. CONCLUSIONS: Youth with ASD may exhibit night owl chronotype behavior and social jetlag as they enter adolescence. Shifts toward a later chronotype may be exacerbated by autism severity and may contribute to alertness problems and sleepiness during the day. Chronotype is modifiable and may be leveraged to improve daytime functioning in youth with ASD.

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20. Wu X, Liu Y, Wang X, Zheng L, Pan L, Wang H. Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome. Neuroscience bulletin. 2023.

While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome (FXS), the thalamic mechanisms underlying this remain unclear. Here, we found that the developmental elimination of synapses formed between the principal nucleus of V (PrV) and the ventral posterior medial nucleus (VPm) of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout (Fmr1 KO) mice, while the developmental strengthening of these synapses was disrupted. Immunohistochemistry showed excessive VGluT2 puncta in mutants at P12-13, but not at P7-8 or P15-16, confirming a delay in somatic pruning of PrV-VPm synapses. Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events, as well as developmental deficits in presynaptic vesicle size and density. Our results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.

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21. Yang Y, Yang R, Kang B, Qian S, He X, Zhang X. Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons. Cell reports. 2023; 42(11): 113335.

Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent of cell-type-specific splicing in human neural development remains largely uncharted. Here, single-cell long-read sequencing in induced pluripotent stem cell (iPSC)-derived cerebral organoids identifies over 31,000 uncatalogued isoforms and 4,531 cell-type-specific splicing events. Long reads uncover coordinated splicing and cell-type-specific intron retention events, which are challenging to study with short reads. Retained neuronal introns are enriched in RNA splicing regulators, showing shorter lengths, higher GC contents, and weaker 5′ splice sites. We use this dataset to explore the biological processes underlying neurological disorders, focusing on autism. In comparison with prior transcriptomic data, we find that the splicing program in autistic brains is closer to the progenitor state than differentiated neurons. Furthermore, cell-type-specific exons harbor significantly more de novo mutations in autism probands than in siblings. Overall, these results highlight the importance of cell-type-specific splicing in autism and neuronal gene regulation.

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