1. Aydin Ü, Gyurkovics M, Ginestet C, Capp S, Greven CU, Palmer J, McLoughlin G. Genetic Overlap Between Midfrontal Theta Signals and Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in a Longitudinal Twin Cohort. Biological psychiatry. 2023; 94(10): 823-32.

BACKGROUND: Cognitive control has been strongly linked to midfrontal theta (4-8 Hz) brain activity. Such control processes are known to be impaired in individuals with psychiatric conditions and neurodevelopmental diagnoses, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Temporal variability in theta, in particular, has been associated with ADHD, with shared genetic variance underlying the relationship. Here, we investigated the phenotypic and genetic relationships between theta phase variability, theta-related signals (the N2, error-related negativity, and error positivity), reaction time, and ADHD and ASD longitudinally in a large twin study of young adults to investigate the stability of the genetic relationships between these measures over time. METHODS: Genetic multivariate liability threshold models were run on a longitudinal sample of 566 participants (283 twin pairs). Characteristics of ADHD and ASD were measured in childhood and young adulthood, while an electroencephalogram was recorded in young adulthood during an arrow flanker task. RESULTS: Cross-trial theta phase variability in adulthood showed large positive phenotypic and genetic relationships with reaction time variability and both childhood and adult ADHD characteristics. Error positivity amplitude was negatively related phenotypically and genetically to ADHD and ASD at both time points. CONCLUSIONS: We showed significant genetic associations between variability in theta signaling and ADHD. A novel finding from the current study is that these relationships were stable across time, indicating a core dysregulation of the temporal coordination of control processes in ADHD that persists in individuals with childhood symptoms. Error processing, indexed by the error positivity, was altered in both ADHD and ASD, with a strong genetic contribution.

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2. Biosca-Brull J, Basaure P, Guardia-Escote L, Cabré M, Blanco J, Morales-Navas M, Sánchez-Santed F, Colomina MT. Environmental exposure to chlorpyrifos during gestation, APOE polymorphism and the risk on autistic-like behaviors. Environmental research. 2023; 237(Pt 2): 116969.

Autism spectrum disorder (ASD) encompasses several neurodevelopmental conditions characterized by communication and social impairment, as well as repetitive patterns of behavior. However, it can co-occur with other mental conditions such as anxiety. The massive use of chlorpyrifos (CPF) has been linked to the increased prevalence of developmental disorders. Likewise, ASD has also been closely linked to a wide variety of genetic factors. The aims of the present investigation are to study how gestational CPF exposure and APOE polymorphism affects communication skills, early development and mid-term anxiety-like behaviors, as well as, changes in gene expression related to the cholinergic system. C57BL/6J and humanized apoE3 and apoE4 homozygous mice were exposed to 0 or 1 mg/kg/day of CPF through the diet, from gestational day (GD) 12-18. In addition, a group of C57BL/6J females were injected subcutaneously with 300 mg/kg/day of valproic acid (VPA) on GD 12 and 13. This group was used as a positive control for studying some core and associated autism-like behaviors. Communication skills by means of ultrasonic vocalizations and physical/motor development were assessed during the preweaning period, whereas locomotor activity, anxiety-like behaviors and the gene expression of cholinergic elements were evaluated during adolescence. Our results showed that C57BL/6J mice prenatally exposed to CPF or VPA showed a decrease in body weight and a delay in eye opening. Communication and anxiety behavior were affected differently depending on treatment, while gene expression was altered by sex and treatment. In addition, none of the parameters evaluated in apoE transgenic mice exposed to CPF were affected, but there were differences between genotypes. Therefore, we suggest that prenatal CPF exposure and VPA produce divergent effects on communication and anxiety.

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3. Chua SY, Abd Rahman FN, Ratnasingam S. Problem behaviours and caregiver burden among children with Autism Spectrum Disorder in Kuching, Sarawak. Frontiers in psychiatry. 2023; 14: 1244164.

OBJECTIVE: Caregivers of children with Autism Spectrum Disorder (ASD) often experience emotional and psychological distress, as well as disruptions to family life and employment due to the challenges of caring for children with ASD. This study examines the relationship between problem behaviours and caregiver burden among children with ASD. METHOD: A cross-sectional study using convenience sampling recruited 230 caregivers of children with ASD aged 4 to 18 years from selected autism centres in Kuching, Sarawak. The caregivers completed the Aberrant Behaviour Checklist-2 and the Zarit Burden Interview. RESULTS: Univariate analysis revealed a significant difference in caregiver burden for children with ASD receiving medications (p = 0.013), registered with the Social Welfare Department (p = 0.036), and having siblings with ASD (p = 0.046). About 40% of the children exhibited at least one domain of problem behaviour. More than half of the caregivers (53.9%) experienced burden, with the majority experiencing mild burden. Positive associations were seen between irritability (r = 0.458, p < 0.01), social withdrawal (r = 0.439, p < 0.01), stereotypic behaviour (r = 0.392, p < 0.01), hyperactivity/non-compliance (r = 0.467, p < 0.01), and caregiver burden. Child factors, including the duration of problem behaviour (r = 0.182, p = 0.007), medication use (eta = 0.187, p = 0.005), Social Welfare Department registration (eta = 0.138, p = 0.036), and the presence of siblings with ASD (eta = 0.130, p = 0.046) were associated with caregiver burden. Multiple linear regression showed that hyperactivity/noncompliance significantly predicted caregiver burden. CONCLUSION: Specific problem behaviours in children with ASD were associated with caregiver burden. These results highlight the need for interventions for the child with ASD and their caregivers.

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4. Demartini B, Nisticò V, Limonta S, Tarantino V, Stefanelli G, Calistro F, Giambanco L, Faggioli R, Gambini O, Turriziani P. Long-term Memory of Sensory Experiences from the First Pregnancy, its Peri-partum and Post-partum in Women with Autism Spectrum Disorders without Intellectual Disabilities: A Retrospective Study. Journal of autism and developmental disorders. 2023.

PURPOSE: To explore the recalled experience of pregnancy and motherhood in women diagnosed with Autism Spectrum Disorders (ASD) without intellectual disabilities, focusing on sensory perceptions and mood. METHODS: We retrospectively evaluated, through an ad-hoc structured interview, the sensory sensitivity during the pre-partum, the peri-partum, and the post-partum of thirty-three mothers with ASD and thirty-two neurotypical mothers. Participants also underwent a psychometric assessment about autistic traits, general sensory sensitivity, and post-partum depressive symptomatology. RESULTS: Mothers with ASD recalled a higher sensitivity than the comparison group across the three time-points; however, during the peri-partum their recalled hypersensitivity decreases, and in the post-partum it returned as high as before childbirth. The difference in the length of recall between groups did not statistically influence our results. Higher levels of autistic traits correlated with higher depressive post-partum symptomatology. CONCLUSIONS: Mothers with ASD seem to recall their experience of pregnancy, childbirth, and post-partum period differently from neurotypical mothers, particularly in terms of hypersensitivity. The correlation with depressive symptoms and the potential role of oxytocin and of long-term memory (encoding and recollection) are discussed. Further exploring these aspects might give fundamental hints to provide tailored support to mothers with ASD during pregnancy and motherhood.

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5. Ding Z, Huang G, Wang T, Duan W, Li H, Wang Y, Jia H, Yang Z, Wang K, Chu X, Kurtz-Nelson EC, Ahlers K, Earl RK, Han Y, Feliciano P, Chung WK, Eichler EE, Jiang M, Xiong B. Genetic Ablation of GIGYF1, Associated With Autism, Causes Behavioral and Neurodevelopmental Defects in Zebrafish and Mice. Biological psychiatry. 2023; 94(10): 769-79.

BACKGROUND: Autism spectrum disorder is characterized by deficits in social communication and restricted or repetitive behaviors. Due to the extremely high genetic and phenotypic heterogeneity, it is critical to pinpoint the genetic factors for understanding the pathology of these disorders. METHODS: We analyzed the exomes generated by the SPARK (Simons Powering Autism Research) project and performed a meta-analysis with previous data. We then generated 1 zebrafish knockout model and 3 mouse knockout models to examine the function of GIGYF1 in neurodevelopment and behavior. Finally, we performed whole tissue and single-nucleus transcriptome analysis to explore the molecular and cellular function of GIGYF1. RESULTS: GIGYF1 variants are significantly associated with various neurodevelopmental disorder phenotypes, including autism, global developmental delay, intellectual disability, and sleep disturbance. Loss of GIGYF1 causes similar behavioral effects in zebrafish and mice, including elevated levels of anxiety and reduced social engagement, which is reminiscent of the behavioral deficits in human patients carrying GIGYF1 variants. Moreover, excitatory neuron-specific Gigyf1 knockout mice recapitulate the increased repetitive behaviors and impaired social memory, suggesting a crucial role of Gigyf1 in excitatory neurons, which correlates with the observations in single-nucleus RNA sequencing. We also identified a series of downstream target genes of GIGYF1 that affect many aspects of the nervous system, especially synaptic transmission. CONCLUSIONS: De novo variants of GIGYF1 are associated with neurodevelopmental disorders, including autism spectrum disorder. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission.

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6. Dorskind JM, Sudarsanam S, Hand RA, Ziak J, Amoah-Dankwah M, Guzman-Clavel L, Soto-Vargas JL, Kolodkin AL. Drebrin Regulates Collateral Axon Branching in Cortical Layer II/III Somatosensory Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2023; 43(46): 7745-65.

Proper cortical lamination is essential for cognition, learning, and memory. Within the somatosensory cortex, pyramidal excitatory neurons elaborate axon collateral branches in a laminar-specific manner that dictates synaptic partners and overall circuit organization. Here, we leverage both male and female mouse models, single-cell labeling and imaging approaches to identify intrinsic regulators of laminar-specific collateral, also termed interstitial, axon branching. We developed new approaches for the robust, sparse, labeling of Layer II/III pyramidal neurons to obtain single-cell quantitative assessment of axon branch morphologies. We combined these approaches with cell-autonomous loss-of-function (LOF) and overexpression (OE) manipulations in an in vivo candidate screen to identify regulators of cortical neuron axon branch lamination. We identify a role for the cytoskeletal binding protein drebrin (Dbn1) in regulating Layer II/III cortical projection neuron (CPN) collateral axon branching in vitro LOF experiments show that Dbn1 is necessary to suppress the elongation of Layer II/III CPN collateral axon branches within Layer IV, where axon branching by Layer II/III CPNs is normally absent. Conversely, Dbn1 OE produces excess short axonal protrusions reminiscent of nascent axon collaterals that fail to elongate. Structure-function analyses implicate Dbn1(S142) phosphorylation and Dbn1 protein domains known to mediate F-actin bundling and microtubule (MT) coupling as necessary for collateral branch initiation upon Dbn1 OE. Taken together, these results contribute to our understanding of the molecular mechanisms that regulate collateral axon branching in excitatory CPNs, a key process in the elaboration of neocortical circuit formation.SIGNIFICANCE STATEMENT Laminar-specific axon targeting is essential for cortical circuit formation. Here, we show that the cytoskeletal protein drebrin (Dbn1) regulates excitatory Layer II/III cortical projection neuron (CPN) collateral axon branching, lending insight into the molecular mechanisms that underlie neocortical laminar-specific innervation. To identify branching patterns of single cortical neurons in vivo, we have developed tools that allow us to obtain detailed images of individual CPN morphologies throughout postnatal development and to manipulate gene expression in these same neurons. Our results showing that Dbn1 regulates CPN interstitial axon branching both in vivo and in vitro may aid in our understanding of how aberrant cortical neuron morphology contributes to dysfunctions observed in autism spectrum disorder and epilepsy.

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7. Ferrara R, Ricci P, Damato FM, Iovino L, Ricci L, Cicinelli G, Simeoli R, Keller R. Pregnancy in autistic women and social medical considerations: scoping review and meta- synthesis. Frontiers in psychiatry. 2023; 14: 1222127.

INTRODUCTION: This article addresses a topic that has been largely overlooked by scientific literature, namely pregnancy in autistic women. Generally, the issue of sexuality in disability, particularly in disabled women, autistic or otherwise, has been underexplored. However, it is necessary to scientifically investigate this topic to propose adequate social and health policies. Therefore, we chose to conduct a scoping review to answer three main questions: « What does it mean for an autistic woman to be pregnant? »; « How do these two conditions coexist? »; « Are health services prepared to receive this population adequately or does autism become a stigma for pregnant women? » METHODS: We conducted a systematic review and qualitative thematic synthesis following the Preferred Reporting Guidelines for Systematic Reviews and Meta-Analyses on autistic women and pregnancy in the last 10 years. RESULTS: The studies included in our review are 7, extremely diverse in terms of methodologies and sample sizes. Despite the heterogeneity of samples and methodologies, all research tends to highlight the following results. For autistic women during pregnancy, three areas seem to be the most difficult: sensory issues, mood disorders, and relationships with specialists. DISCUSSION: Our study found that women with ASD face unique challenges during childbirth that differ from those of neurotypical women. Participants often felt belittled, ignored, and uninformed about the care they received, and being placed at the centre of attention was often seen as negative and hindering rather than positive. However, the research shows us how some « expected » results, such as difficulties in breastfeeding, have been disproven.

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8. Greengross G, Silvia PJ, Crasson SJ. Psychotic and autistic traits among magicians and their relationship with creative beliefs. BJPsych open. 2023; 9(6): e214.

BACKGROUND: There is a common perception that creativity is associated with psychopathology. Previous studies have shown that members of creative groups such as comedians, artists and scientists scores higher than the norm on psychotic traits, and scientists in STEM (science, technology, engineering and mathematics) fields score highly on autistic traits. AIMS: To test whether magicians, a creative group that has not been studied before, also score highly on psychopathological traits and autism, and to test the associations of creative self-efficacy and creative identity with schizotypal and autistic traits among magicians. METHOD: A sample of 195 magicians and 233 people from the general population completed measures of schizotypal traits (Oxford-Liverpool Inventory of Feelings and Experiences) and autism (Abridged Version of the Autism-Spectrum Quotient), as well as the Short Scale of Creative Self. Magicians were also compared with other creative groups with respect to schizotypal traits, based on previously published data. RESULTS: Magicians scored lower than the general population sample on three of the four schizophrenia measures (cognitive disorganisation, introvertive anhedonia and impulsive nonconformity) but did not differ with respect to unusual experiences or autism scores. Magicians scored higher on creative self-efficacy and creative personal identity than the general sample. Magicians’ scores on schizotypal traits were largely lower than those of other creative groups. Originality of magic was positively correlated with unusual experiences (r = 0.208), creative self-efficacy (r = 0.251) and creative identity (r = 0.362). CONCLUSIONS: This is the first study to show a creative group with lower scores than norms on psychotic traits. The results highlight the unique characteristics of magicians and the possible myriad associations between creativity and mental disorders among creative groups.

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9. Gulati S, Israni A, Squires J, Singh A, Madaan P, Kamila G, Pandey RM. Socio-cultural Adaptation and Validation of Ages and Stages Questionnaire (ASQ 3) in Indian Children Aged 2 to 24 Months. Indian pediatrics. 2023; 60(11): 908-12.

OBJECTIVE: To socio-culturally adapt and validate a Hindi language version of ASQ-3 in Indian children aged 2-24 months. METHODS: This cross-sectional study was conducted at a tertiary-care center between March, 2017 and April, 2019. Children « at-risk » for developmental delay of either gender aged 2-24 months. Socio-cultural adaptation was done through interaction among 37 subject experts followed by validation. After piloting in 20 children, modified ASQ-3 was validated in 568 at-risk children (4 age-groups: 2-7, 7-13, 13-19 and 19-24 months). Validation was done against Development assessment scale for Indian infants (DASII). RESULTS: Results: After screening 654 children, 568 were enrolled. Among these, 420 had developmental delay on DASII while 18 failed to be identified on ASQ (4.3%). Overall sensitivity and specificity of Hindi language Indian-adaptation of ASQ-3 in detecting developmental delay were 95.9% (95%CI: 93.6%-97.5%) and 81.7% (95%CI: 74%-87.9%), respectively with a positive predictive value (PPV) of 94.6% (95%CI: 92%-96.5%) and negative predictive value (NPV) of 85.6% (95%CI: 78.2%-92.2%). The sensitivity and specificity for motor delay were 96.1% (93.8%-97.7%) and 92.4% (86.4%-96.3%) [PPV: 97.7% (95.8%-98.9%); NPV: 87.7% (81%-92.7%)]. Sensitivity and specificity for mental delay were 95.5% (93.1%-97.2%)and 95.3% (90.1%-98.3%) [PPV: 98.6% (97%-99.5%); NPV: 85.9% (79.1%-91.2%)]. CONCLUSION: The Hindi language Indian-adaptation of ASQ-3 had good psychometric properties with high sensitivity for developmental delay (95.9%), mental delay (95.5%), and motor delay (96.1%), suggesting it to be a good screening tool for neurodevelopmental delay.

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10. Hawrylycz M, Nickl-Jockschat T. Linking Neurogenetics and Functional Connectivity in Autism. Biological psychiatry. 2023; 94(10): 765-6.

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11. Jones DR, Sasson NJ. A mixed method comparison of stigma toward autism and schizophrenia and effects of person-first versus identity-first language. Frontiers in psychiatry. 2023; 14: 1263525.

INTRODUCTION: While stigma toward autistic individuals has been well documented, less is known about how autism is perceived relative to other stigmatized disabilities. As a highly stigmatized condition with similar social cognitive features to autism, schizophrenia may offer a useful comparison for stigma. Previous studies have found that autistic people may be perceived more favorably than those with schizophrenia, but little is known about the underlying volitional thoughts that contribute to differences in how these conditions are perceived. METHODS: The present study utilizes a mixed-methods approach, allowing for a detailed understanding of how young adults perceive different diagnostic labels. 533 college undergraduates completed questionnaires reflecting their perceptions of one of eight diagnostic labels: four related to autism (autism, autistic, autism spectrum disorder, or Asperger’s), two related to schizophrenia (schizophrenia or schizophrenic), and two related to an unspecified clinical condition (clinical diagnosis or clinical disorder). Participants also completed an open-ended question regarding their thoughts about, and exposure to, these labels. Responses were compared across broader diagnostic categories (autism, schizophrenia, general clinical condition), with thematic analysis used to assess the broader themes occurring within the open-ended text. RESULTS: While perceptions did not differ significantly for person-first and identity-first language within labels, several differences were apparent across labels. Specifically, quantitative results indicated greater prejudice towards autism and schizophrenia than the generic clinical condition, with schizophrenia associated with more perceived fear and danger, as well as an increased preference for social distance, compared to autism. Patterns in initial codes differed across diagnostic labels, with greater variation in responses about autism than responses about schizophrenia or the general clinical condition. While participants described a range of attitudes toward autism (patronizing, exclusionary, and accepting) and schizophrenia (fear, prejudice, and empathy), they refrained from describing their attitudes toward the general clinical label, highlighting the centrality of a cohesive group identity for the development of stigma. Finally, participants reported a number of misconceptions about autism and schizophrenia, with many believing features such as savant syndrome to be core characteristics of the conditions. CONCLUSION: These findings offer a more detailed account of how non-autistic individuals view autism and may therefore aid in the development of targeted programs to improve attitudes toward autism.

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12. Kretz PF, Wagner C, Mikhaleva A, Montillot C, Hugel S, Morella I, Kannan M, Fischer MC, Milhau M, Yalcin I, Brambilla R, Selloum M, Herault Y, Reymond A, Collins SC, Yalcin B. Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein. Genome biology. 2023; 24(1): 261.

BACKGROUND: Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus. RESULTS: We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp(+/-);Mapk3(+/-) mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms. CONCLUSIONS: Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice.

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13. Li C, Fleck JS, Martins-Costa C, Burkard TR, Themann J, Stuempflen M, Peer AM, Vertesy Á, Littleboy JB, Esk C, Elling U, Kasprian G, Corsini NS, Treutlein B, Knoblich JA. Author Correction: Single-cell brain organoid screening identifies developmental defects in autism. Nature. 2023.

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14. Li R, Lightbody AA, Lee CH, Bartholomay KL, Marzelli MJ, Reiss AL. Association of Intrinsic Functional Brain Network and Longitudinal Development of Cognitive Behavioral Symptoms in Young Girls With Fragile X Syndrome. Biological psychiatry. 2023; 94(10): 814-22.

BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Because males express a more severe phenotype than females, research has focused largely on identifying neural abnormalities in all-male or both-sex populations with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multidomain cognitive behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full-mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multidomain cognitive behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared with the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network, lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of the default mode network. These aberrant brain network characteristics map directly onto the cognitive behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (time 1) were predictive of the longitudinal development of participants’ multidomain cognitive behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive behavioral symptoms in girls with FXS.

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15. Li X, Peng Y, Lu Y, Zhang Y. The effect of recasting by mothers with different conversational styles on the communication behavior of autistic children: Lag sequential analysis. Autism research : official journal of the International Society for Autism Research. 2023.

Recasting is the adult rephrasing of a child’s immediately preceding utterance. It has been shown to have outstanding effects on promoting language development in autistic children. This study used lag sequential analysis to explore the impact of mothers’ conversational styles on the communicative behavior of autistic children when using recasting. This study recruited 30 Chinese autistic children (aged 3-6 years) and their mothers. The utterances of the children and their mothers during 30-min interactions were transcribed, coded, and analyzed. The mothers’ conversational styles were determined by the percentages of child-dominant, mother-dominant, and equality styles. The results indicated that mothers’ conversational styles were predominantly child-dominant, differing from the expected mother-dominant style that is typical in Eastern cultures and traditions. However, some mothers still demonstrated a significant proportion of mother-dominant style in their conversation, while some exhibited a considerable amount of equality style. Moreover, mothers with a mainly child-dominant style and minimal use of mother-dominant and equality styles used recasting after the child’s response, triggering the child to initiate new topics. Mothers with a child-dominant style combined with prominent mother-dominant features implemented untargeted self-recasting, the children did not respond significantly. Mothers with a child-dominant style combined with prominent equality features used recasting after the children responded, initiated, or expanded the conversation, which often facilitated the child’s expansion of the conversation. These findings provide suggestions for designing parent-mediated early language interventions for autistic children.

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16. Li Y, Ma L, Deng Y, Du Z, Guo B, Yue J, Liu X, Zhang Y. The Notch1/Hes1 signaling pathway affects autophagy by adjusting DNA methyltransferases expression in a valproic acid-induced autism spectrum disorder model. Neuropharmacology. 2023; 239: 109682.

As a pervasive neurodevelopmental disease, autism spectrum disorder (ASD) is caused by both hereditary and environmental elements. Research has demonstrated the functions of the Notch pathway and DNA methylation in the etiology of ASD. DNA methyltransferases DNMT3 and DNMT1 are responsible for methylation establishment and maintenance, respectively. In this study, we aimed to explore the association of DNA methyltransferases with the Notch pathway in ASD. Our results showed Notch1 and Hes1 were upregulated, while DNMT3A and DNMT3B were downregulated at the protein level in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA-induced ASD rats compared with Control (Con) group. However, the protein levels of DNMT3A and DNMT3B were augmented after treatment with 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester (DAPT), suggesting that abnormal Notch pathway activation may affect the expression of DNMT3A and DNMT3B. Besides, our previous findings revealed that the Notch pathway may participate in development of ASD by influencing autophagy. Therefore, we hypothesized the Notch pathway adjusts autophagy and contributes to ASD by affecting DNA methyltransferases. Our current results showed that after receiving the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza-2’dc), the VPA + DAPT+5-Aza-2’dc (V + D + Aza) group exhibited reduced social interaction ability and increased stereotyped behaviors, and decreased expression of DNMT3A, DNMT3B and autophagy-related proteins, but did not show changes in Notch1 and Hes1 protein levels. Our results indicated that the Notch1/Hes1 pathway may adjust DNMT3A and DNMT3B expression and subsequently affect autophagy in the occurrence of ASD, providing new insight into the pathogenesis of ASD.

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17. Lin HH, Jung CR, Lin CY, Chang YC, Hsieh CY, Hsu PC, Chuang BR, Hwang BF. Prenatal and postnatal exposure to heavy metals in PM(2.5) and autism spectrum disorder. Environmental research. 2023; 237(Pt 1): 116874.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders, and its incidence is increasing over time. Although several environmental factors have been suspected to be risk factors for ASD, studies on the effects of airborne heavy metals on newly developed ASD are still limited. We conducted a large birth cohort study of 168,062 live term births in Taichung during 2004-2011 to assess the association of heavy metals in particulate matter with an aerodynamic diameter less than 2.5 μm (PM(2.5)) with ASD, and identify sensitive time windows during prenatal and postnatal periods. Heavy metals, including arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) in PM(2.5), were estimated using the Weather Research and Forecasting/Chem (WRF/Chem), inserted from the top 75 emission sources for the module. The association between childhood ASD and 4 metals were analyzed from pregnancy to 9 months after birth. The Cox proportional hazard model with a distributed lag nonlinear model (DLNM) was used to estimate the association between heavy metals in PM(2.5) and ASD. We identified 666 incident ASD cases in 168,062 participants. A positive association between Hg and ASD was found at 9 months after birth (Hazard Ratio: 1.63; 95% CI: 1.13-2.36). According to the DLNM, there was an increased risk of exposure to Hg during 10-25 weeks after birth, and decreased risk of exposure to Hg during gestational weeks 4-6. Exposure to As and Hg on the risk of ASD were significantly stronger in low birth weight infants (<2500 g) than in those of birth weight ≥2500 g during postnatal period. Postnatal exposure to Hg in PM(2.5) may associate with increased ASD incidence. Infants with low birth weight and exposure to As and Hg in PM(2.5) are more likely to develop ASD.

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18. Lopez-Rodriguez AB, Murray CL, Kealy J, Towns C, Roche A, Nazmi A, Doran M, Lowry JP, Cunningham C. Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder. Molecular autism. 2023; 14(1): 43.

BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.

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19. Marion A, Bowman K, Thomas G, Harrison AJ. A mixed method examination: how stigma experienced by autistic adults relates to metrics of social identity and social functioning. Frontiers in psychiatry. 2023; 14: 1243618.

A recent meta-analysis reveals almost half of autistic individuals experience some form of victimization in their lifetime, including bullying and other forms of stigma. Research among caregivers of autistic individuals demonstrates that stigma can have a long-lasting impact on other aspects of a social identity, such as self-esteem, but less research has specifically examined this among autistic adults themselves, in spite of research suggesting these are likely constructs that contribute to the internalization of stigma and subsequent mental health consequences. The current study used a mixed method approach to assess the relation between stigma and several components of social identity and social functioning. More specifically, among 45 autistic young adults, three dimensions of self-reported stigma (discrimination, disclosure, and positive aspects) were examined in relation to self-esteem, self-efficacy, social satisfaction and adaptive social functioning. Quantitative analyses revealed higher reported discriminative and disclosure stigma were significantly associated with lower self-efficacy. Increased experience with all types of stigma were associated with lower social satisfaction. Greater reported disclosure stigma was also associated with lower self-esteem. Qualitative interviewing among eight autistic young adults helped to better understand the nature of stigma and the impact of these experiences. Thematic analysis of the qualitative data revealed that all of the participants experienced stigma in the form of exclusion or isolation and that a majority also experienced verbal bullying. Many of the negative interactions came from educators, peers, and family members. Most participants indicated that these stigmatizing interactions directly contributed to decreased social satisfaction, diminished self-efficacy, and lowered self-esteem. A greater understanding of the negative consequences of stigma can inform efforts to increase awareness and acceptance of autism.

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20. Mason D, Acland J, Stark E, Happé F, Spain D. Compassion-focused therapy with autistic adults. Frontiers in psychology. 2023; 14: 1267968.

Some autistic adults experience repeated adverse events, including rejection, victimization and stigmatization. They also describe others being critical and negatively judging them, such as for how they socially interact or for expressing passion for particular interests. The impact of these adverse events can be substantial, including increasing vulnerability for poorer mental health, and contributing to development of negative self beliefs (such as « I am different » or « I do not fit in ») and shame-based difficulties. Not all evidence-based psychological therapies are well-received by autistic people, or effective. Given high rates of self-harm and suicidality, finding acceptable and effective therapies for autistic adults is paramount. Here, writing as autistic and non-autistic clinicians and researchers, we outline the theoretical principles of compassion-focused theory and therapy (CFT). We propose that: (1) compassion-focused theory can provide a useful framework for conceptualizing shame-based difficulties some autistic adults experience; (2) CFT can be appropriate for addressing these; and (3) there is an impetus for practitioners to adopt compassion-focused approaches when supporting autistic adults.

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21. Montiel-Nava C, Vargas I, Gonzalez-Avila Z, Montenegro MC, Ramírez AC. Pilgrimage for an autism diagnosis: A study of Venezuelan parents’ experiences. Transcultural psychiatry. 2023: 13634615231211482.

It cannot be assumed that the experience of having an autistic child is the same across countries since demographic and systemic factors are as diverse as the manifestation of ASD symptomatology. This study explores the lived experiences of 20 Venezuelan parents after receiving an autism diagnosis for their child. Applied thematic analysis was used to analyze parental attitudes, challenges in identifying their child’s delay, access to diagnostic services, beliefs towards autism, professional evaluations, family support, and perceptions toward health and educational services for autistic children. Venezuelan parents reported a generalized lack of autism awareness, an unsupportive school system, and judgment from their extended family. Despite the universal health coverage in the country, Venezuelan parents commented on the scarcity of services, as well as the lengthy and costly processes to receive an ASD diagnosis. The results support previous research findings showing that socioeconomic factors influence how parents experience the process of obtaining an autism diagnosis for their children. For most Venezuelan parents, it might imply a long journey in which limited resources and knowledge about autism will determine its route and length. For parents, cultural values and spiritual and religious beliefs will serve as both coping mechanisms and barriers to accessing services.

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22. Mount RA, Athif M, O’Connor M, Saligrama A, Tseng HA, Sridhar S, Zhou C, Bortz E, San Antonio E, Kramer MA, Man HY, Han X. The autism spectrum disorder risk gene NEXMIF over-synchronizes hippocampal CA1 network and alters neuronal coding. Frontiers in neuroscience. 2023; 17: 1277501.

Mutations in autism spectrum disorder (ASD) risk genes disrupt neural network dynamics that ultimately lead to abnormal behavior. To understand how ASD-risk genes influence neural circuit computation during behavior, we analyzed the hippocampal network by performing large-scale cellular calcium imaging from hundreds of individual CA1 neurons simultaneously in transgenic mice with total knockout of the X-linked ASD-risk gene NEXMIF (neurite extension and migration factor). As NEXMIF knockout in mice led to profound learning and memory deficits, we examined the CA1 network during voluntary locomotion, a fundamental component of spatial memory. We found that NEXMIF knockout does not alter the overall excitability of individual neurons but exaggerates movement-related neuronal responses. To quantify network functional connectivity changes, we applied closeness centrality analysis from graph theory to our large-scale calcium imaging datasets, in addition to using the conventional pairwise correlation analysis. Closeness centrality analysis considers both the number of connections and the connection strength between neurons within a network. We found that in wild-type mice the CA1 network desynchronizes during locomotion, consistent with increased network information coding during active behavior. Upon NEXMIF knockout, CA1 network is over-synchronized regardless of behavioral state and fails to desynchronize during locomotion, highlighting how perturbations in ASD-implicated genes create abnormal network synchronization that could contribute to ASD-related behaviors.

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23. Passias PG, Krol O, Williamson TK, Lafage V, Lafage R, Smith JS, Line B, Vira S, Lipa S, Daniels A, Diebo B, Schoenfeld A, Gum J, Kebaish K, Park P, Mundis G, Hostin R, Gupta MC, Eastlack R, Anand N, Ames C, Hart R, Burton D, Schwab FJ, Shaffrey C, Klineberg E, Bess S. The Benefit of Addressing Malalignment in Revision Surgery for Proximal Junctional Kyphosis Following ASD Surgery. Spine. 2023; 48(22): 1581-7.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Understand the benefit of addressing malalignment in revision surgery for proximal junctional kyphosis (PJK). SUMMARY OF BACKGROUND DATA: PJK is a common cause of revision surgery for adult spinal deformity patients. During a revision, surgeons may elect to perform a proximal extension of the fusion, or also correct the source of the lumbopelvic mismatch. MATERIALS AND METHODS: Recurrent PJK following revision surgery was the primary outcome. Revision surgical strategy was the primary predictor (proximal extension of fusion alone compared with combined sagittal correction and proximal extension). Multivariable logistic regression determined rates of recurrent PJK between the two surgical groups with lumbopelvic surgical correction assessed through improving ideal alignment in one or more alignment criteria [Global Alignment and Proportionality (GAP), Roussouly-type, and Sagittal Age-Adjusted Score (SAAS)]. RESULTS: A total of 151 patients underwent revision surgery for PJK. PJK occurred at a rate of 43.0%, and PJF at 12.6%. Patients proportioned in GAP postrevision had lower rates of recurrent PJK [23% vs. 42%; odds ratio (OR): 0.3, 95% confidence interval (CI): 0.1-0.8, P =0.024]. Following adjusted analysis, patients who were ideally aligned in one of three criteria (Matching in SAAS and/or Roussouly matched and/or achieved GAP proportionality) had lower rates of recurrent PJK (36% vs. 53%; OR: 0.4, 95% CI: 0.1-0.9, P =0.035) and recurrent PJF (OR: 0.1, 95% CI: 0.02-0.7, P =0.015). Patients ideally aligned in two of three criteria avoid any development of PJF (0% vs. 16%, P <0.001). CONCLUSIONS: Following revision surgery for PJK, patients with persistent poor sagittal alignment showed increased rates of recurrent PJK compared with patients who had abnormal lumbopelvic alignment corrected during the revision. These findings suggest addressing the root cause of surgical failure in addition to proximal extension of the fusion may be beneficial.

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24. Rasero J, Jimenez-Marin A, Diez I, Toro R, Hasan MT, Cortes JM. The Neurogenetics of Functional Connectivity Alterations in Autism: Insights From Subtyping in 657 Individuals. Biological psychiatry. 2023; 94(10): 804-13.

BACKGROUND: There is little consensus and controversial evidence on anatomical alterations in the brains of people with autism spectrum disorder (ASD), due in part to the large heterogeneity present in ASD, which in turn is a major drawback for developing therapies. One strategy to characterize this heterogeneity in ASD is to cluster large-scale functional brain connectivity profiles. METHODS: A subtyping approach based on consensus clustering of functional brain connectivity patterns was applied to a population of 657 autistic individuals with quality-assured neuroimaging data. We then used high-resolution gene transcriptomic data to characterize the molecular mechanism behind each subtype by performing enrichment analysis of the set of genes showing a high spatial similarity with the profiles of functional connectivity alterations between each subtype and a group of typically developing control participants. RESULTS: Two major stable subtypes were found: subtype 1 exhibited hypoconnectivity (less average connectivity than typically developing control participants) and subtype 2, hyperconnectivity. The 2 subtypes did not differ in structural imaging metrics in any of the analyzed regions (68 cortical and 14 subcortical) or in any of the behavioral scores (including IQ, Autism Diagnostic Interview, and Autism Diagnostic Observation Schedule). Finally, only subtype 2, comprising about 43% of ASD participants, led to significant enrichments after multiple testing corrections. Notably, the dominant enrichment corresponded to excitation/inhibition imbalance, a leading well-known primary mechanism in the pathophysiology of ASD. CONCLUSIONS: Our results support a link between excitation/inhibition imbalance and functional connectivity alterations, but only in one ASD subtype, overall characterized by brain hyperconnectivity and major alterations in somatomotor and default mode networks.

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25. Samadi SA, Rashid HM. Impacts of Caregiving for Individuals with Autism in Low-Resource Settings, a Report from the Kurdistan Region of Iraq. Journal of autism and developmental disorders. 2023.

Caring for children with different developmental trajectories brings various challenges, which are often exacerbated in low-resource settings. International research has shown that raising a child with autism strongly impacts family caregivers, particularly mothers. There is a dearth of information regarding caregiving for individuals with autism in the Kurdistan Region of Iraq (KRI) and for fathers as well as mothers. This study examined the similarities and differences in caregiving for mothers and fathers of a child with autism in KRI using validated rating scales to measure various aspects of their general well-being. Over two years, a sample of 118 parents of individuals with autism (81 mothers and 37 fathers) self-completed the rating scales, which were further discussed through individual interviews with service personnel mainly known to them. The findings indicated that mothers and fathers were similarly impacted. Although there were no statistically significant differences in the ratings of their general health, sources of stress, family functioning, and satisfaction with caregiving, the majority of parents had elevated ratings on all the measures. In addition, parents who rated their children higher on the Aberrant Behavior Checklist had significantly higher scores on their general health issues and were less satisfied with their caregiving role. Parents of female individuals with autism were also significantly more stressed compared to the male individuals with autism and parents of children who received a diagnosis before three years of age, reported fewer behavioral problems with their child compared to the parents who received a diagnosis when the child was older. In this sample, mothers and fathers seem to be similarly impacted by caring for a child with autism, which is contrary to findings from other countries. However, in this region, family bonds between couples and the wider family may have had an influence which further cross-cultural research in low-resource settings could help elucidate, notwithstanding the challenges this poses. The findings have policy implications for health authorities in the KRI to improve the support provided to both mothers and fathers who care for children with autism, which presently is rarely available to them.

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26. Sandbank M, Bottema-Beutel K, Crowley LaPoint S, Feldman JI, Barrett DJ, Caldwell N, Dunham K, Crank J, Albarran S, Woynaroski T. Autism intervention meta-analysis of early childhood studies (Project AIM): updated systematic review and secondary analysis. BMJ (Clinical research ed). 2023; 383: e076733.

OBJECTIVE: To summarize the breadth and quality of evidence supporting commonly recommended early childhood autism interventions and their estimated effects on developmental outcomes. DESIGN: Updated systematic review and meta-analysis (autism intervention meta-analysis; Project AIM). DATA SOURCES: A search was conducted in November 2021 (updating a search done in November 2017) of the following databases and registers: Academic Search Complete, CINAHL Plus with full text, Education Source, Educational Administration Abstracts, ERIC, Medline, ProQuest Dissertations and Theses, PsycINFO, Psychology and Behavioral Sciences Collection, and SocINDEX with full text, Trials, and ClinicalTrials.gov. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any controlled group study testing the effects of any non-pharmacological intervention on any outcome in young autistic children younger than 8 years. REVIEW METHODS: Newly identified studies were integrated into the previous dataset and were coded for participant, intervention, and outcome characteristics. Interventions were categorized by type of approach (such as behavioral, developmental, naturalistic developmental behavioral intervention, and technology based), and outcomes were categorized by domain (such as social communication, adaptive behavior, play, and language). Risks of bias were evaluated following guidance from Cochrane. Effects were estimated for all intervention and outcome types with sufficient contributing data, stratified by risk of bias, using robust variance estimation to account for intercorrelation of effects within studies and subgroups. RESULTS: The search yielded 289 reports of 252 studies, representing 13 304 participants and effects for 3291 outcomes. When contributing effects were restricted to those from randomized controlled trials, significant summary effects were estimated for behavioral interventions on social emotional or challenging behavior outcomes (Hedges’ g=0.58, 95% confidence interval 0.11 to 1.06; P=0.02), developmental interventions on social communication (0.28, 0.12 to 0.44; P=0.003); naturalistic developmental behavioral interventions on adaptive behavior (0.23, 0.02 to 0.43; P=0.03), language (0.16, 0.01 to 0.31; P=0.04), play (0.19, 0.02 to 0.36; P=0.03), social communication (0.35, 0.23 to 0.47; P<0.001), and measures of diagnostic characteristics of autism (0.38, 0.17 to 0.59; P=0.002); and technology based interventions on social communication (0.33, 0.02 to 0.64; P=0.04) and social emotional or challenging behavior outcomes (0.57, 0.04 to 1.09; P=0.04). When effects were further restricted to exclude caregiver or teacher report outcomes, significant effects were estimated only for developmental interventions on social communication (0.31, 0.13 to 0.49; P=0.003) and naturalistic developmental behavioral interventions on social communication (0.36, 0.23 to 0.49; P<0.001) and measures of diagnostic characteristics of autism (0.44, 0.20 to 0.68; P=0.002). When effects were then restricted to exclude those at high risk of detection bias, only one significant summary effect was estimated-naturalistic developmental behavioral interventions on measures of diagnostic characteristics of autism (0.30, 0.03 to 0.57; P=0.03). Adverse events were poorly monitored, but possibly common. CONCLUSION: The available evidence on interventions to support young autistic children has approximately doubled in four years. Some evidence from randomized controlled trials shows that behavioral interventions improve caregiver perception of challenging behavior and child social emotional functioning, and that technology based interventions support proximal improvements in specific social communication and social emotional skills. Evidence also shows that developmental interventions improve social communication in interactions with caregivers, and naturalistic developmental behavioral interventions improve core challenges associated with autism, particularly difficulties with social communication. However, potential benefits of these interventions cannot be weighed against the potential for adverse effects owing to inadequate monitoring and reporting.

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27. St George-Hyslop F, Haneklaus M, Kivisild T, Livesey FJ. Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development. Biological psychiatry. 2023; 94(10): 780-91.

BACKGROUND: Loss-of-function mutations in the contactin-associated protein-like 2 (CNTNAP2) gene are causal for neurodevelopmental disorders, including autism, schizophrenia, epilepsy, and intellectual disability. CNTNAP2 encodes CASPR2, a single-pass transmembrane protein that belongs to the neurexin family of cell adhesion molecules. These proteins have a variety of functions in developing neurons, including connecting presynaptic and postsynaptic neurons, and mediating signaling across the synapse. METHODS: To study the effect of loss of CNTNAP2 function on human cerebral cortex development, and how this contributes to the pathogenesis of neurodevelopmental disorders, we generated human induced pluripotent stem cells from one neurotypical control donor null for full-length CNTNAP2, modeling cortical development from neurogenesis through to neural network formation in vitro. RESULTS: CNTNAP2 is particularly highly expressed in the first two populations of early-born excitatory cortical neurons, and loss of CNTNAP2 shifted the relative proportions of these two neuronal types. Live imaging of excitatory neuronal growth showed that loss of CNTNAP2 reduced neurite branching and overall neuronal complexity. At the network level, developing cortical excitatory networks null for CNTNAP2 had complex changes in activity compared with isogenic controls: an initial period of relatively reduced activity compared with isogenic controls, followed by a lengthy period of hyperexcitability, and then a further switch to reduced activity. CONCLUSIONS: Complete loss of CNTNAP2 contributes to the pathogenesis of neurodevelopmental disorders through complex changes in several aspects of human cerebral cortex excitatory neuron development that culminate in aberrant neural network formation and function.

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28. Tamada K, Takumi T. The East Asian-Specific Risk Genes in Autism Spectrum Disorder. Biological psychiatry. 2023; 94(10): 762-4.

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29. Twala B, Molloy E. On effectively predicting autism spectrum disorder therapy using an ensemble of classifiers. Scientific reports. 2023; 13(1): 19957.

An ensemble of classifiers combines several single classifiers to deliver a final prediction or classification decision. An increasingly provoking question is whether such an ensemble can outperform the single best classifier. If so, what form of ensemble learning system (also known as multiple classifier learning systems) yields the most significant benefits in the size or diversity of the ensemble? In this paper, the ability of ensemble learning to predict and identify factors that influence or contribute to autism spectrum disorder therapy (ASDT) for intervention purposes is investigated. Given that most interventions are typically short-term in nature, henceforth, developing a robotic system that will provide the best outcome and measurement of ASDT therapy has never been so critical. In this paper, the performance of five single classifiers against several multiple classifier learning systems in exploring and predicting ASDT is investigated using a dataset of behavioural data and robot-enhanced therapy against standard human treatment based on 3000 sessions and 300 h, recorded from 61 autistic children. Experimental results show statistically significant differences in performance among the single classifiers for ASDT prediction with decision trees as the more accurate classifier. The results further show multiple classifier learning systems (MCLS) achieving better performance for ASDT prediction (especially those ensembles with three core classifiers). Additionally, the results show bagging and boosting ensemble learning as robust when predicting ASDT with multi-stage design as the most dominant architecture. It also appears that eye contact and social interaction are the most critical contributing factors to the ASDT problem among children.

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30. Ulu Aydin H, Cifci Tekinarslan I, Gulec Aslan Y. The Power Card Strategy: Strength-Based Intervention Against Bullying for Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2023.

The pattern of behaviors and abilities that reflect the core characteristics of students with autism spectrum disorder (ASD) and an environment that lacks the ability to understand individuals with ASD can make these students targets of bullying. Bullying is a serious problem for students with ASD, and practices against it are important in terms of improving students’ coping strategies and overall well-being. In this study, we used a multiple probe model with an interprobe phase across participants to evaluate the effectiveness of the power card strategy to teach three students with ASD to respond to bullying. At baseline, the students gave few appropriate responses based on coping strategies for bullying after listening to stories about bullying. During the application of the power cards, the students read scenarios and power cards created for their favorite heroes or special interests, which included coping strategies for three different bullying situations (exclusion, being pushed, and being tickled). Then, they watched animations prepared for these bullying situations and were asked to answer questions about strategies to deal with bullying. The findings showed that all three students learned targeted strategies for coping with bullying in the context of the sessions using power cards. The students were able to generalize to different bullying situations (teasing, damaging one’s belongings, being ignored) while retaining their strategies for coping with bullying in the context of the sessions held after the teaching was completed. The social validity findings of the power card strategy showed that one out of three students exhibited coping strategies for bullying in the school environment. The findings of the present study are discussed in the context of bullying and ASD, limitations, and recommendations.

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31. Wang J, Yu J, Wang M, Zhang L, Yang K, Du X, Wu J, Wang X, Li F, Qiu Z. Discovery and Validation of Novel Genes in a Large Chinese Autism Spectrum Disorder Cohort. Biological psychiatry. 2023; 94(10): 792-803.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes impairments in social communication and stereotypical behaviors, often accompanied by developmental delay or intellectual disability. A growing body of evidence suggests that ASD is highly heritable, and genetic studies have defined numerous risk genes. However, most studies have been conducted with individuals of European and Hispanic ancestry, and there is a lack of genetic analyses of ASD in the East Asian population. METHODS: We performed whole-exome sequencing on 772 Chinese ASD trios and combined the data with a previous study of 369 Chinese ASD trios, identifying de novo variants in 1141 ASD trios. We used single-cell RNA sequencing analysis to identify the cell types in which ASD-related genes were enriched. In addition, we validated the function of a candidate high-functioning autism gene in mouse models using genetic approaches. RESULTS: Our findings showed that ASD without developmental delay or intellectual disability carried fewer disruptive de novo variants than ASD with developmental delay or intellectual disability. Moreover, we identified 9 novel ASD candidate genes that were not present in the current ASD gene database. We further validated one such novel ASD candidate gene, SLC35G1, by showing that mice harboring a heterozygous deletion of Slc35g1 exhibited defects in interactive social behaviors. CONCLUSIONS: Our work nominates novel ASD candidate genes and emphasizes the importance of genome-wide genetic studies with ASD cohorts of different ancestries to reveal the comprehensive genetic architecture of ASD.

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32. Whitaker-Fornek JR, Jenkins PM, Levitt ES. Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome mice. Journal of neurophysiology. 2023.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects females due to silencing mutations in the X-linked MECP2 gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations in Mecp2 exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kölliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole-cell voltage-clamp recordings from KF neurons in acute brain slices to examine spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice, but surprisingly not female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male, but not female, RTT mice, which was positively correlated with paired pulse facilitation, indicating decreased probability of release. KF neurons from male RTT mice were also more excitable and exhibited shorter duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male, but not female RTT mice, and suggest that sex-dependent mechanisms contribute to breathing problems in RTT.

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33. Winocur-Arias O, Amitai BC, Winocur E, Shmuly T, Grinstein Koren O, Reiter S. The prevalence of bruxism and oral parafunction activities among Israeli juveniles with autism spectrum disorder: A preliminary study during the COVID-19 pandemic. Cranio : the journal of craniomandibular practice. 2023: 1-9.

OBJECTIVE: To evaluate the prevalence of oral habits, bruxism, and Temporomandibular Disorders (TMD) injuvenileswithautisticspectrumdisorder(ASD). METHODS: Data included 165 juveniles diagnosed with ASD, allocated to younger group aged 6 21 (n=86) and older group aged 13-21 (n=79). RESULTS: Sleep bruxism was reported by 26.7% in the younger group and by 5% in the older group. Awake bruxism was reported by 22% and 17.7%, respectively. Oral habits were reported by 43% of all participants, with similar rate in both groups. TMD related p ain was low in both groups (6.3% and 7% respectively). The influence of the COVID 19 pandemic on oral parafunction was moderate in the younger group (17.4%) and mild in the older group (8.6%), influence on bruxism was mild in both groups (5.8% and 2.5%, respectively). CONCLUSION: The prevalence of bruxism and oral parafunctions was similar to the reported in the literature for the general population.

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34. Yu X, Rahman MM, Carter SA, Lin JC, Chow T, Lurmann FW, Chen JC, Martinez MP, Schwartz J, Eckel SP, Chen Z, McConnell R, Xiang AH, Hackman DA. Neighborhood Disadvantage and Autism Spectrum Disorder in a Population With Health Insurance. JAMA psychiatry. 2023.

IMPORTANCE: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance. OBJECTIVE: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics. DESIGN, SETTING, AND PARTICIPANTS: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023. EXPOSURE: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis. MAIN OUTCOMES AND MEASURES: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed. RESULTS: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association. CONCLUSIONS AND RELEVANCE: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

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