1. Barros F, Figueiredo C, Soares SC. Autism traits dimensionality and multivariate relationship with alexithymia and anxiety in the general population. Research in developmental disabilities. 2022; 131: 104361.

BACKGROUND: Autism is characterized by social and non-social alterations observed beyond the clinical diagnosis. Research analyzing the expression of autism traits in the general population helps to unravel the relationship between autism dimensions and other associated variables, such as alexithymia and anxiety. The Autism-Spectrum Quotient (AQ) was developed to assess autism traits in the general population; however, inconsistent results regarding its dimensionality have emerged. AIMS: This study aimed to extend evidence about the AQ measurement model, and explore the multivariate relationship between autism traits, alexithymia, and trait anxiety. METHODS: 292 adults of the general population were recruited. An Exploratory Factor Analysis and Confirmatory Factor Analysis were performed to assess the factorial structure of AQ. A path analysis was carried out to explore the relationship between autism traits, alexithymia, and trait anxiety. RESULTS: The results supported a three-factor model of AQ. The path analysis model showed evidence of a significant role of alexithymia as a mediator of the relationship between autism traits and anxiety. CONCLUSIONS AND IMPLICATIONS: The present study provides empirical support for a three-factor model of AQ in the general population. The association between autism traits, alexithymia, and anxiety dimensions highlights the multidimensional nature of these variables and the need to account for their distinct impact on autism-related variables.

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2. Burrows CA, Grzadzinski RL, Donovan K, Stallworthy IC, Rutsohn J, St John T, Marrus N, Parish-Morris J, MacIntyre L, Hampton J, Pandey J, Shen MD, Botteron KN, Estes AM, Dager SR, Hazlett HC, Pruett JR, Jr., Schultz RT, Zwaigenbaum L, Truong KN, Piven J, Elison JT. A Data-Driven Approach in an Unbiased Sample Reveals Equivalent Sex Ratio of Autism Spectrum Disorder-Associated Impairment in Early Childhood. Biological psychiatry. 2022; 92(8): 654-62.

BACKGROUND: Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD. METHODS: We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total n(observations) = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; n(observations) = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership. RESULTS: We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group. CONCLUSIONS: This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.

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3. Chakravarty MM. Variation in Neuroanatomy in Autism Spectrum Disorder. Biological psychiatry. 2022; 92(8): 612-3.

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4. Dekker LP, van der Vegt EJM, Louwerse A, Visser K, van der Ende J, Maras A, Verhulst FC, Greaves-Lord K. Complementing or Congruent? Desired Characteristics in a Friend and Romantic Partner in Autistic versus Typically Developing Male Adolescents. Archives of sexual behavior. 2022.

Ideal friend and romantic partner characteristics related to self-perceived characteristics have been investigated in typically developing (TD) individuals, but not in individuals with autism spectrum disorder (ASD). Considering the autistic symptoms and challenges, investigating these concepts in autistic individuals is relevant. Given the lack of consensus, identity-first (« autistic person ») and person-first (« person with autism ») language are mixed throughout, to cover all preferences. This study explored (1) the association between self-perceived characteristics and desires in a friend/romantic partner, as well as (2) compare two groups (ASD and TD) in their desires for a friend/romantic partner. Two matched groups (ASD and TD) of 38 male adolescents (age 14-19 years) reported on the desire for nine characteristics (i.e., funny, popular, nice, cool, smart, trustworthy, good looking, similar interests, and being rich) in a friend/partner, and to what extent they felt they themselves possessed seven characteristics (i.e., funny, popular, nice, cool, smart, trustworthy, and good looking). Results showed both groups sought a friend and partner similar to themselves on intrinsic characteristics (e.g., trustworthiness), but less similar on extrinsic and social status characteristics (e.g., being less cool and popular). Particularly intrinsic characteristics, more than extrinsic and social status characteristics, were valued in both partners and friends, regardless of group. No significant differences were found between groups concerning to what extent characteristics were desired. Overall, adolescents with ASD desire similar characteristics as TD adolescents in their potential romantic partners and friends. There is some indication that the match between self-perception and desired characteristics is different.

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5. Fischer I, Shohat S, Levy G, Bar E, Trangle SS, Efrati S, Barak B. Hyperbaric Oxygen Therapy Alleviates Social Behavior Dysfunction and Neuroinflammation in a Mouse Model for Autism Spectrum Disorders. International journal of molecular sciences. 2022; 23(19).

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder (NDD) characterized by impaired social communication and repetitive behavior, among other symptoms. ASD is highly heritable, with SHANK3 being one of the high-risk genes for ASD. In recent years, knowledge has been growing regarding the neuroplasticity effect induced by hyperbaric oxygen therapy (HBOT) and its potential use for ASD. Here, we characterized the effect of HBOT on a mouse model for ASD with the human genetic condition of InsG3680 mutation in the Shank3 gene. As compared to placebo, HBOT improved social behavior and reduced neuroinflammation in the cortex of the InsG3680((+/+)) mice. Specifically, HBOT induced upregulation of Insulin-like growth factor 1 (Igf1) expression levels and reduced the number of Iba1-positive cells in the mouse model for ASD compared to placebo control. Together, our research suggests that HBOT has the potential to improve the clinical outcome of ASD by ameliorating some of the core pathophysiological processes responsible for the development of the disorder.

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6. Gagat-Matuła A. Resilience and Coping with Stress and Marital Satisfaction of the Parents of Children with ASD during the COVID-19 Pandemic. International journal of environmental research and public health. 2022; 19(19).

Raising and caring for a child with ASD is a challenge for the parents’ marriage relationship. Caring for a disabled child changes the functioning of the family and requires greater involvement in care and specialist therapy. The respondents’ answers show that such parents experience higher levels of stress related to the upbringing and future of the child. However, parenting challenges need not be a negative experience if the parents support each other. The process of bringing up children in the family are related, inter alia, to the quality of their parents ‘marriage, which is influenced by the partners’ personal resources. The resilience of the partners and coping with this situation contribute to marital satisfaction. The aim of the study is to find out about the relationship between spouses’ resilience and coping styles and their assessment of marriage satisfaction. In total, 50 married couples participated in the study-50 mothers of children with ASD and 50 fathers, the partners of these mothers (N = 100). The following tools were used: the Resilience Scale (SPP-25), the Coping Inventory for Stressful Situations (CISS) and the Well-Matched Marriage Questionnaire (KDM-2), as well as a survey questionnaire (data on respondents). The results show that the gender of the parent of a child with ASD does not differentiate the overall assessment of the quality of marriage (the overall score on the scale indicates a low level of satisfaction with the relationship). When analyzing in detail the dimensions of individual scales of satisfaction with the relationship, one statistically significant difference was noted for the sex of the respondents in the disappointment dimension, showing that the level of disappointment in the quality of the relationship is higher in wives than in husbands. In the other dimensions of satisfaction with marriage: intimacy, personal fulfillment, similarity, there were no statistically significant differences in terms of gender of the respondents. The resilience of the spouses positively correlates with their assessment of marriage satisfaction, and in particular, openness, perseverance and determination to act increase the level of Task-oriented coping (SSZ) with difficult situations. All resilience factors negatively correlate with the emotional coping style (SSE). In both the studied groups, openness is a significant predictor of intimacy, and persistence is a predictor of self-fulfilment in a relationship. A predictor of disappointment in women is managing using substitute activities (ACZ), while in men it is the Emotion-oriented coping (SSE) style. The results indicate the need to support married couples raising a child with ASD during the pandemic.

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7. Ganaiem M, Karmon G, Ivashko-Pachima Y, Gozes I. Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk. Cells. 2022; 11(19).

(1) Background: Activity-dependent neuroprotective protein (ADNP) is essential for neuronal structure and function. Multiple de novo pathological mutations in ADNP cause the autistic ADNP syndrome, and they have been further suggested to affect Alzheimer’s disease progression in a somatic form. Here, we asked if different ADNP mutations produce specific neuronal-like phenotypes toward better understanding and personalized medicine. (2) Methods: We employed CRISPR/Cas9 genome editing in N1E-115 neuroblastoma cells to form neuron-like cell lines expressing ADNP mutant proteins conjugated to GFP. These new cell lines were characterized by quantitative morphology, immunocytochemistry and live cell imaging. (3) Results: Our novel cell lines, constitutively expressing GFP-ADNP p.Pro403 (p.Ser404* human orthologue) and GFP-ADNP p.Tyr718* (p.Tyr719* human orthologue), revealed new and distinct phenotypes. Increased neurite numbers (day 1, in culture) and increased neurite lengths upon differentiation (day 7, in culture) were linked with p.Pro403*. In contrast, p.Tyr718* decreased cell numbers (day 1). These discrete phenotypes were associated with an increased expression of both mutant proteins in the cytoplasm. Reduced nuclear/cytoplasmic boundaries were observed in the p.Tyr718* ADNP-mutant line, with this malformation being corrected by the ADNP-derived fragment drug candidate NAP. (4) Conclusions: Distinct impairments characterize different ADNP mutants and reveal aberrant cytoplasmic-nuclear crosstalk.

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8. Ge D, Wei H, Wang Y, Li Y, Luo J, Liu X, Hu Y, Chen L, Cheng Q, Li T, Dai Y. Effectiveness of caregiver-mediated intervention: a pilot study for children with neurodevelopmental disorders. Primary health care research & development. 2022; 23: e63.

OBJECTIVES: Caregiver-mediated intervention (CMI), based on parent skills training, is a family-mediated intervention model for children with neurodevelopmental disorders, in particular autism spectrum disorder. This study aimed to evaluate the effectiveness of CMI. METHODS: Thirty-three children (aged 22-69 months from our department) and their caregivers participated in a two-week training course of ten 90-minute lessons. Caregivers were encouraged to try their best to apply intervention skills in both home routines and play routines to encourage the development of cognition, motion, social adaptability, and behavior of children. Demographic information, video-recorded data, and diagnostic scales were collected at two key time points: baseline and post-training (PT – within six months). RESULTS: Three aspects were assessed – primary variables, secondary variables, and correlation analyses. Results showed an improvement in PT in (1) Adult/Child Interaction Fidelity Rating (P < 0.01) and (2) adaptability of Gesell Developmental Scale and stereotyped behaviors and limited interests of Autism Diagnostic Observation Schedule (P < 0.05, P < 0.01). Moreover, a negative correlation occurred between caregiver skill improvement and parent education (P < 0.05), but without correlations with other demographics. CONCLUSIONS: As an efficacious family intervention for both children and their caregivers, CMI is worth being generalized widely.

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9. Gevezova M, Minchev D, Pacheva I, Todorova T, Yordanova R, Timova E, Ivanov I, Sarafian V. Association of NGF and Mitochondrial Respiration with Autism Spectrum Disorder. International journal of molecular sciences. 2022; 23(19).

BACKGROUND: NGF is a molecule with a pleiotropic role, affecting neuro-immune functions, energy homeostasis, and synaptic plasticity. The mechanisms of NGF-induced neuronal differentiation are well established, but its effect on mitochondria in autism spectrum disorder (ASD) is still unclear. We hypothesize that NGF-induced neuronal development requires large amounts of energy, and mitochondria in ASD are overloaded to meet the new functional requirements. METHOD: The study includes primary diagnosed ASD children. Peripheral blood mononuclear cells (PBMCs) and plasma were obtained from both patients and typically developing children (TDC). PBMCs were analyzed with Seahorse XFp, and plasma NGF protein levels were measured. RESULTS: We detected nearly 50% higher NGF levels and approximately 40% elevation in spare respiratory capacity in ASD compared to TDC. These findings are consistent with the observed difference in maximal respiration, which was also significantly higher in the patient group. Both mitochondrial respiration and NGF plasma levels exhibit a strong potential to discriminate children with ASD from TDC. CONCLUSIONS: This study is the first to link elevated NGF with mitochondrial respiration and altered energy homeostasis in ASD. High NGF correlates with basic bioenergetic signatures that may be used as a screening tool to improve early diagnosis and clinical follow-up in ASD.

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10. Góralczyk-Bińkowska A, Szmajda-Krygier D, Kozłowska E. The Microbiota-Gut-Brain Axis in Psychiatric Disorders. International journal of molecular sciences. 2022; 23(19).

Modulating the gut microbiome and its influence on human health is the subject of intense research. The gut microbiota could be associated not only with gastroenterological diseases but also with psychiatric disorders. The importance of factors such as stress, mode of delivery, the role of probiotics, circadian clock system, diet, and occupational and environmental exposure in the relationship between the gut microbiota and brain function through bidirectional communication, described as « the microbiome-gut-brain axis », is especially underlined. In this review, we discuss the link between the intestinal microbiome and the brain and host response involving different pathways between the intestinal microbiota and the nervous system (e.g., neurotransmitters, endocrine system, immunological mechanisms, or bacterial metabolites). We review the microbiota alterations and their results in the development of psychiatric disorders, including major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD).

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11. Haase F, Singh R, Gloss B, Tam P, Gold W. Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome. International journal of molecular sciences. 2022; 23(19).

Rett syndrome (RTT) is a rare disorder and one of the most abundant causes of intellectual disabilities in females. Single mutations in the gene coding for methyl-CpG-binding protein 2 (MeCP2) are responsible for the disorder. MeCP2 regulates gene expression as a transcriptional regulator as well as through epigenetic imprinting and chromatin condensation. Consequently, numerous biological pathways on multiple levels are influenced. However, the exact molecular pathways from genotype to phenotype are currently not fully elucidated. Treatment of RTT is purely symptomatic as no curative options for RTT have yet to reach the clinic. The paucity of this is mainly due to an incomplete understanding of the underlying pathophysiology of the disorder with no clinically useful common disease drivers, biomarkers, or therapeutic targets being identified. With the premise of identifying universal and robust disease drivers and therapeutic targets, here, we interrogated a range of RTT transcriptomic studies spanning different species, models, and MECP2 mutations. A meta-analysis using RNA sequencing data from brains of RTT mouse models, human post-mortem brain tissue, and patient-derived induced pluripotent stem cell (iPSC) neurons was performed using weighted gene correlation network analysis (WGCNA). This study identified a module of genes common to all datasets with the following ten hub genes driving the expression: ATRX, ADCY7, ADCY9, SOD1, CACNA1A, PLCG1, CCT5, RPS9, BDNF, and MECP2. Here, we discuss the potential benefits of these genes as therapeutic targets.

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12. Hao Z, Ma J, Sun W. The Technology-Oriented Pathway for Auxiliary Diagnosis in the Digital Health Age: A Self-Adaptive Disease Prediction Model. International journal of environmental research and public health. 2022; 19(19).

The advent of the digital age has accelerated the transformation and upgrading of the traditional medical diagnosis pattern. With the rise of the concept of digital health, the emerging information technologies, such as machine learning (ML) and data mining (DM), have been extensively applied in the medical and health field, where the construction of disease prediction models is an especially effective method to realize auxiliary medical diagnosis. However, the existing related studies mostly focus on the prediction analysis for a certain disease, using models with which it might be challenging to predict other diseases effectively. To address the issues existing in the aforementioned studies, this paper constructs four novel strategies to achieve a self-adaptive disease prediction process, i.e., the hunger-state foraging strategy of producers (PHFS), the parallel strategy for exploration and exploitation (EEPS), the perturbation-exploration strategy (PES), and the parameter self-adaptive strategy (PSAS), and eventually proposes a self-adaptive disease prediction model with applied universality, strong generalization ability, and strong robustness, i.e., multi-strategies optimization-based kernel extreme learning machine (MsO-KELM). Meanwhile, this paper selects six different real-world disease datasets as the experimental samples, which include the Breast Cancer dataset (cancer), the Parkinson dataset (Parkinson’s disease), the Autistic Spectrum Disorder Screening Data for Children dataset (Autism Spectrum Disorder), the Heart Disease dataset (heart disease), the Cleveland dataset (heart disease), and the Bupa dataset (liver disease). In terms of the prediction accuracy, the proposed MsO-KELM can obtain ACC values in analyzing these six diseases of 94.124%, 84.167%, 91.079%, 72.222%, 70.184%, and 70.476%, respectively. These ACC values have all been increased by nearly 2-7% compared with those obtained by the other models mentioned in this paper. This study deepens the connection between information technology and medical health by exploring the self-adaptive disease prediction model, which is an intuitive representation of digital health and could provide a scientific and reliable diagnostic basis for medical workers.

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13. Hedley D, Batterham PJ, Bury SM, Clapperton A, Denney K, Dissanayake C, Fox P, Frazier TW, Gallagher E, Hayward SM, Robinson J, Sahin E, Trollor J, Uljarević M, Stokes MA. The Suicidal Ideation Attributes Scale-Modified (SIDAS-M): Development and preliminary validation of a new scale for the measurement of suicidal ideation in autistic adults. Autism : the international journal of research and practice. 2022: 13623613221131234.

Autistic people may be at higher risk of suicidal behavior than people in the general population. Suicidal behavior may include thinking about suicide or attempting to end one’s own life by suicide. It is important to identify autistic people who may be thinking about suicide. People who are at risk of suicidal behavior can be identified by asking questions about whether they have been thinking about suicide. A specially designed questionnaire, or screening instrument, can help someone ask the best questions to find out if someone has been thinking about suicide. This information can help to identify supports to be put in place to prevent suicidal behavior, such as a suicide attempt. However, autistic people may interpret questions differently than non-autistic people. It is important to use screening tools that have been designed with, and for autistic people. In this study, we examined the Suicidal Ideation Attributes Scale (SIDAS). The SIDAS is an existing tool that was developed to screen for suicidal thinking in the general population. We modified SIDAS for use with autistic adults. We involved autistic people in the process of modifying SIDAS. We called the modified instrument the SIDAS-M. The results of our study showed SIDAS-M may be useful for screening for suicidal thinking in autistic adults who do not have an intellectual disability.

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14. Horien C, Floris DL, Greene AS, Noble S, Rolison M, Tejavibulya L, O’Connor D, McPartland JC, Scheinost D, Chawarska K, Lake EMR, Constable RT. Functional Connectome-Based Predictive Modeling in Autism. Biological psychiatry. 2022; 92(8): 626-42.

Autism is a heterogeneous neurodevelopmental condition, and functional magnetic resonance imaging-based studies have helped advance our understanding of its effects on brain network activity. We review how predictive modeling, using measures of functional connectivity and symptoms, has helped reveal key insights into this condition. We discuss how different prediction frameworks can further our understanding of the brain-based features that underlie complex autism symptomatology and consider how predictive models may be used in clinical settings. Throughout, we highlight aspects of study interpretation, such as data decay and sampling biases, that require consideration within the context of this condition. We close by suggesting exciting future directions for predictive modeling in autism.

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15. Hwang G. Autism Spectrum Disorder: Time to Notice the Individuals More Than the Group. Biological psychiatry. 2022; 92(8): 606-8.

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16. Johnston D, Egermann H, Kearney G. The Use of Binaural Based Spatial Audio in the Reduction of Auditory Hypersensitivity in Autistic Young People. International journal of environmental research and public health. 2022; 19(19).

Individuals diagnosed with autism spectrum disorder (ASD) are characterised as experiencing impairments in social-emotional interaction and communication, alongside frequently displaying repetitive behaviours and interests. Further to this, they are often described as experiencing difficulties in processing sensory information, with particular prevalence within the auditory modality. Provoked by common environmental sounds, auditory hypersensitivity can result in self-regulatory fear responses. Rather than a physiological pain reaction, literature suggests that these hypersensitivities are resulting through irrational fear of the sounds. This investigation evaluates the use of binaural based spatial audio as a rendering technique for delivering realistic simulations of averse stimuli within a virtual reality (VR) exposure based computer game intervention for auditory hypersensitivity in autism. Over multiple experimental sessions, 20 autistic participants experiencing auditory hypersensitivity were exposed to either spatial audio or stereo renders of target stimuli during the intervention. Measurements of self-reported emotions displayed significant reductions in associated negative emotional reactions to target stimuli for all participants. However, significant improvements were experienced by those listening to spatial audio simulations. Moreover, tracked voluntary interactions with exposure based game-mechanics increased as the study progressed. Providing further evidence of increased tolerance towards averse auditory stimuli.

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17. Krakowski A. Balanced Sex Ratios and the Autism Continuum. Biological psychiatry. 2022; 92(8): e35-e6.

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18. Kwon H, Maeng H, Chung J. Development of an ICT-Based Exergame Program for Children with Developmental Disabilities. Journal of clinical medicine. 2022; 11(19).

The purpose of this study was to develop an information and communications technology (ICT)-based exergame for children with developmental disabilities (DD) and to examine its impacts on physical fitness and fundamental motor skills (FMS). The ICT-based exergame consisted of visual and auditory demonstrations of diverse locomotor movement and object manipulation activities by the virtual characters. A total of 52 children with DD participated in the present study. The participants were divided into twenty-seven children in the experimental group and 25 children with DD in the control group. The experimental group participants engaged in the exergame program for 12 weeks. All participants’ muscle strength (i.e., standing long jump) and four fundamental motor skills, such as the horizontal jump, hop, overhand throw, and dribble, were assessed during the pre- and post-test process. There were significant impacts on physical fitness and FMS (p < 0.001) between the groups. Specifically, the results of three FMS (hop, overhand throw, and dribble) and standing long jump significantly improved in children with DD except for the horizontal jump skill. The results of this study is evidence that the ICT-based exergame program for children with DD may be utilized to improve physical fitness and FMS in children with DD.

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19. Laidi C, Floris DL, Tillmann J, Elandaloussi Y, Zabihi M, Charman T, Wolfers T, Durston S, Moessnang C, Dell’Acqua F, Ecker C, Loth E, Murphy D, Baron-Cohen S, Buitelaar JK, Marquand AF, Beckmann CF, Frouin V, Leboyer M, Duchesnay E, Coupé P, Houenou J. Cerebellar Atypicalities in Autism?. Biological psychiatry. 2022; 92(8): 674-82.

BACKGROUND: The cerebellum contains more than 50% of the brain’s neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism. METHODS: We studied cerebellar gray matter morphology in 274 individuals with autism and 219 control subjects of a multicenter European cohort, EU-AIMS LEAP (European Autism Interventions-A Multicentre Study for Developing New Medications; Longitudinal European Autism Project). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with 2 different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate (including normative modeling), and meta-analytic approaches to capture the diversity of cerebellar anatomy in individuals with autism and control subjects. Finally, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms. RESULTS: We did not find any significant difference in the cerebellum when comparing individuals with autism and control subjects using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related to age, IQ, sex, or social functioning in individuals with autism. CONCLUSIONS: Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism.

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20. Li L, Su X, Zheng Q, Xiao J, Huang XY, Chen W, Yang K, Nie L, Yang X, Chen H, Shi S, Duan X. Cofluctuation analysis reveals aberrant default mode network patterns in adolescents and youths with autism spectrum disorder. Human brain mapping. 2022; 43(15): 4722-32.

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

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21. Mansour Y, Burchell A, Kulesza R. Abnormal vestibular brainstem structure and function in an animal model of autism spectrum disorder. Brain research. 2022; 1793: 148056.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD.

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22. Moeun S, Bhoomikumar J, Pat P, Kariya T, Suzuki Y, Hamajima N, Sok D, Yamamoto E. Children with neuro-developmental disorders at Center for Child and Adolescent Mental Health in Cambodia. Nagoya journal of medical science. 2022; 84(3): 593-606.

The Center for Child and Adolescent Mental Health (CCAMH) is one of the centers that have psychiatric specialists for children in Cambodia. This study aims to understand the characteristics of children with neuro-developmental disorders, especially autism spectrum disorder (ASD), at CCAMH. This study included 440 cases that were randomly chosen from 2,147 new patients at CCAMH in 2018-2019 and were aged 0-12 years. Socio-demographic factors, parent’s information, obstetrical factors, and clinical data were collected from patients’ records. A logistic regression analysis and Pearson’s chi-square test were used to compare the characteristics between children who were finally diagnosed with ASD and the others (non-ASD). Of the 440 patients, most were male (75.2%), 0-4 years old (57.7%), and diagnosed with ASD (50.0%). Common symptoms were delay of speech, playing alone, and hyperactivity. ASD was significantly more prevalent in male patients compared to females and in the 0-4 years age group compared to the 5-12 years age group. Parents who lived in Phnom Penh and had high education were more likely to visit the CCAMH with their children who were diagnosed with ASD. Regarding treatment, approximately half of all 440 patients had family counselling and psychosocial education. ASD patients had more speech therapy, special education and structured teaching, and networking and coordination therapy compared to non-ASD patients. To provide education and therapy to children with ASD and their parents from the early stage, information about the center and ASD should be widely distributed to all parents in Cambodia.

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23. Mou TM, Lane MV, Ireland DDC, Verthelyi D, Tonelli LH, Clark SM. Association of complement component 4 with neuroimmune abnormalities in the subventricular zone in schizophrenia and autism spectrum disorders. Neurobiology of disease. 2022; 173: 105840.

An early inflammatory insult is the most recognized risk factor associated with neurodevelopmental psychiatric disorders, even more so than genetic variants. Notably, complement component 4 (C4), a molecule involved in inflammatory responses, has been strongly associated with schizophrenia (SZ) and its role in other neurodevelopmental disorders, such as autism (ASD), is an area of active investigation. However, while C4 in SZ has been implicated in the context of synaptic pruning, little is known about its neuroinflammatory role. The subventricular zone (SVZ) is a region heavily involved in neurodevelopment and neuroimmune interactions through the lifespan; thus, it is a region wherein C4 may play a vital role in disease pathology. Using in situ hybridization with radioactive riboprobes and RNAscope, we identified robust astrocytic expression of C4 in the SVZ and in the septum pellucidum. C4 was also expressed in ependyma, neurons, and Ki67(+) progenitor cells. Examination of mRNA levels showed elevated C4 in both ASD and SZ, with higher expression in SZ compared to controls. Targeted transcriptomic analysis of inflammatory pathways revealed a strong association of complement system genes with SZ, and to a lesser extent, ASD, as well as generalized immune dysregulation without a strong association with known infectious pathways. Analysis of differentially expressed genes (DEGs) showed that ASD DEGs were enriched in adaptive immune system functions such as Th cell differentiation, while SZ DEGs were enriched in innate immune system functions, including NF-κB and toll like receptor signaling. Moreover, the number of Ki67(+) cells was significantly higher in ASD compared to SZ and controls. Taken together, these results support a role for C4 into inflammatory-neuroimmune dysregulation observed in SZ and ASD pathology.

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24. Ortiz Castellanos AE, Liu CM, Shi C. Deep Mobile Linguistic Therapy for Patients with ASD. International journal of environmental research and public health. 2022; 19(19).

Autistic spectrum disorder (ASD) is one of the most complex groups of neurobehavioral and developmental conditions. The reason is the presence of three different impaired domains, such as social interaction, communication, and restricted repetitive behaviors. Some children with ASD may not be able to communicate using language or speech. Many experts propose that continued therapy in the form of software training in this area might help to bring improvement. In this work, we propose a design of software speech therapy system for ASD. We combined different devices, technologies, and features with techniques of home rehabilitation. We used TensorFlow for Image Classification, ArKit for Text-to-Speech, Cloud Database, Binary Search, Natural Language Processing, Dataset of Sentences, and Dataset of Images with two different Operating Systems designed for Smart Mobile devices in daily life. This software is a combination of different Deep Learning Technologies and makes Human-Computer Interaction Therapy very easy to conduct. In addition, we explain the way these were connected and put to work together. Additionally, we explain in detail the architecture of software and how each component works together as an integrated Therapy System. Finally, it allows the patient with ASD to perform the therapy anytime and everywhere, as well as transmitting information to a medical specialist.

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25. Pearson A, Surtees A, Crompton CJ, Goodall C, Pillai D, Sedgewick F, Au-Yeung SK. Editorial: Addressing community priorities in autism research. Frontiers in psychology. 2022; 13: 1040446.

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26. Polónyiová K, Rašková B, Ostatníková D. Changes in Mental Health during Three Waves of the COVID-19 Pandemic in Slovakia: Neurotypical Children versus Children with Autism Spectrum Disorder and Their Parents. International journal of environmental research and public health. 2022; 19(19).

The main goal of our research was to monitor changes in the mental health of Slovak families with children with autism spectrum disorder (ASD) compared to families with neurotypical children during three waves of the COVID-19 pandemic. We focused on the prevalence of depression, anxiety, stress and different stressors of parents. In children, we explored maladaptive behavior and the availability of interventions for children with ASD. The data were collected using an extensive questionnaire including the Depression, Anxiety, and Stress Scale-42 questionnaire (DASS-42) and two subscales of the Vineland Adaptive Behavior Scales (VABS-3). The research sample consisted of a total of 506 parents, 236 of whom have a child with ASD. Parents of children with ASD reported elevated anxiety during the first wave, while changes were found in parents of neurotypical children. During the second wave, the prevalence of anxiety, depression and stress experienced by parents in both groups increased, but significantly more in parents with ASD children. The internalizing maladaptive behavior of children with ASD also increased. During the third wave, no significant differences between the groups of parents were found in stress and anxiety, but parents of ASD children scored higher in depression. Externalized maladaptive behavior of neurotypical children increased, with minimal changes in children with ASD, which can be explained by the improved therapy availability for children with ASD, also observed in our study.

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27. Romano N, Di Giacomo B, Nobile V, Borreca A, Willems D, Tilesi F, Catalani E, Agrawal M, Welshhans K, Ricciardi S, Cervia D, Ceci M. Ribosomal RACK1 Regulates the Dendritic Arborization by Repressing FMRP Activity. International journal of molecular sciences. 2022; 23(19).

FMRP is an RNA-binding protein that represses the translation of specific mRNAs. In neurons, its depletion determines the exaggerated translation of mRNAs leading to dendritic and axonal aberrant development, two peculiar features of Fragile X syndrome patients. However, how FMRP binds to translational machinery to regulate the translation of its mRNA targets is not yet fully understood. Here, we show that FMRP localizes on translational machinery by interacting with the ribosomal binding protein, Receptor for Activated C Kinase 1 (RACK1). The binding of FMRP to RACK1 removes the translational repressive activity of FMRP and promotes the translation of PSD-95 mRNA, one specific target of FMRP. This binding also results in a reduction in the level of FMRP phosphorylation. We also find that the morphological abnormalities induced by Fmr1 siRNA in cortical neurons are rescued by the overexpression of a mutant form of RACK1 that cannot bind ribosomes. Thus, these results provide a new mechanism underlying FMRP activity that contributes to altered development in FXS. Moreover, these data confirm the role of ribosomal RACK1 as a ribosomal scaffold for RNA binding proteins.

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28. Song X, Hu Q, Xu X, Pan W. Protein kinase C beta relieves autism-like behavior in EN2 knockout mice via upregulation of the FTO/PGC-1α/UCP1 axis. Journal of biochemical and molecular toxicology. 2022: e23236.

Increasing evidence suggests that disruption of neuron activity contributes to the autistic phenotype. Thus, we aimed in this study to explore the role of protein kinase C beta (PKCβ) in the regulation of neuron activity in an autism model. The expression of PKCβ in the microarray data of autism animal models was obtained from the Gene Expression Omnibus database. Then, mice with autism-like behavior were prepared in EN2 knockout ((-/-) ) mice. The interaction between PKCβ on fat mass and obesity-associated protein (FTO) as well as between PGC-1α and uncoupling protein 1 (UCP1) were characterized. The effect of FTO on the N(6) -methyladenosine (m6A) modification level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assayed. Following transfection of overexpressed PKCβ and/or silenced UCP1, effects of PKCβ and UCP1 in autism-like behaviors in EN2(-/-) mice were analyzed. Results showed that PKCβ was downregulated in EN2(-/-) mouse brain tissues or neurons. PKCβ promoted the expression and stability of FTO, which downregulated the m6A modification level of PGC-1α to promote its expression. Moreover, PGC-1α positively targeted the expression of UCP1. PKCβ knockdown enhanced sociability and spatial exploration ability, and reduced neuron apoptosis in EN2(-/-) mouse models of autism, which was reversed by UCP1 overexpression. Collectively, PKCβ overexpression leads to activation of the FTO/m6A/PGC-1α/UCP1 axis, thus inhibiting neuron apoptosis and providing neuroprotection in mice with autism-like behavior.

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29. Storch EA, Schneider SC, Olsen SM, Ramirez AC, Berry LN, Goin-Kochel RP, McNeel M, Candelari AE, Guzick AG, Cepeda SL, Weinzimmer S, Voigt RG, Quast T, Goodman WK, Salloum A. Stepped-Care Cognitive Behavioral Therapy in Children on the Autism Spectrum with Co-occurring Anxiety. Journal of autism and developmental disorders. 2022: 1-16.

This trial examined stepped-care cognitive-behavioral treatment (CBT) among 96 autistic youth with co-occurring anxiety. Step 1 included an open trial of parent-led, therapist-guided bibliotherapy. Step 2 was family-based CBT for those who did not respond to Step 1 or maintenance for those who did. Eighteen participants (28%) who completed Step 1 responded. Responders reported significantly lower pre-treatment anxiety, internalizing symptoms, and functional impairment than non-responders. After Steps 1 and 2, 80% of completers (55% intent-to-treat) were responders. Anxiety, impairment, and ASD-related impairments significantly improved. Youth in maintenance experienced faster improvement through post-treatment, though there were no group differences at 3-month-follow-up. A stepped approach may help some individuals in Step 1, particularly those who are less anxious.

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30. Supekar K, Ryali S, Yuan R, Kumar D, de Los Angeles C, Menon V. Robust, Generalizable, and Interpretable Artificial Intelligence-Derived Brain Fingerprints of Autism and Social Communication Symptom Severity. Biological psychiatry. 2022; 92(8): 643-53.

BACKGROUND: Autism spectrum disorder (ASD) is among the most pervasive neurodevelopmental disorders, yet the neurobiology of ASD is still poorly understood because inconsistent findings from underpowered individual studies preclude the identification of robust and interpretable neurobiological markers and predictors of clinical symptoms. METHODS: We leverage multiple brain imaging cohorts and exciting recent advances in explainable artificial intelligence to develop a novel spatiotemporal deep neural network (stDNN) model, which identifies robust and interpretable dynamic brain markers that distinguish ASD from neurotypical control subjects and predict clinical symptom severity. RESULTS: stDNN achieved consistently high classification accuracies in cross-validation analysis of data from the multisite ABIDE (Autism Brain Imaging Data Exchange) cohort (n = 834). Crucially, stDNN also accurately classified data from independent Stanford (n = 202) and GENDAAR (Gender Exploration of Neurogenetics and Development to Advanced Autism Research) (n = 90) cohorts without additional training. stDNN could not distinguish attention-deficit/hyperactivity disorder from neurotypical control subjects, highlighting the model’s specificity. Explainable artificial intelligence revealed that brain features associated with the posterior cingulate cortex and precuneus, dorsolateral and ventrolateral prefrontal cortex, and superior temporal sulcus, which anchor the default mode network, cognitive control, and human voice processing systems, respectively, most clearly distinguished ASD from neurotypical control subjects in the three cohorts. Furthermore, features associated with the posterior cingulate cortex and precuneus nodes of the default mode network emerged as robust predictors of the severity of core social and communication deficits but not restricted/repetitive behaviors in ASD. CONCLUSIONS: Our findings, replicated across independent cohorts, reveal robust individualized functional brain fingerprints of ASD psychopathology, which could lead to more objective and precise phenotypic characterization and targeted treatments.

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31. Taboas A, Doepke K, Zimmerman C. Short report: Preferences for identity-first versus person-first language in a US sample of autism stakeholders. Autism : the international journal of research and practice. 2022: 13623613221130845.

There is currently disagreement among professionals (such as teachers, therapists, researchers, and clinicians) about the most appropriate and respectful way to refer to individuals with disabilities in general, and those with autism, in particular. Supporters of person-first language feel that it is important to emphasize the person rather than the disorder or disability, and promote the use of terms such as, « person with autism » or « a person with ASD. » The goal is to reduce stereotypes and discrimination and emphasize the person’s individuality rather than their disability. However, some people within the autism community have questioned the use of person-first terms because they are awkward and use an unconventional style of language that draws attention to the disability. Moreover, autistic individuals and their families are beginning to support the use of identity-first language that embraces all aspects of one’s identity. Surveys in the United Kingdom and Australia support the idea that both types of language are preferred by different groups of autism stakeholder groups. In our study, we surveyed autism stakeholders in the United States. Overwhelmingly, autistic adults (n = 299) preferred identity-first language terms to refer to themselves or others with autism. Professionals who work in the autism community (n = 207) were more likely to support and use person-first language. Language is dynamic and our findings support the need for open communication among autism professionals about how we communicate with and about autistic individuals and their families.

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32. Takeguchi R, Kuroda M, Tanaka R, Suzuki N, Akaba Y, Tsujimura K, Itoh M, Takahashi S. Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study. Journal of the neurological sciences. 2022; 441: 120381.

OBJECTIVE: To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI). METHODS: Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs) underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI). The measurements obtained from each modality were statistically compared between RTTs and HCs and examined for their correlation with the clinical severity of RTTs. RESULTS: Structural MRI imaging revealed volume reductions in most cortical and subcortical regions of the brain. Remarkable volume reductions were observed in the frontal and parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus, and corpus callosum. DTI analysis revealed decreased white matter integrity in broad regions of the brain. Fractional anisotropy values were greatly decreased in the superior longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI analysis showed decreased functional connectivity in the interhemispheric dorsal attention network, and between the visual and cerebellar networks. The clinical severity of RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and cerebellar peduncles. CONCLUSION: Regional volume and white matter integrity of RTT brains were reduced in broad areas, while most functional connections remained intact. Notably, two functional connectivities, between cerebral hemispheres and between the cerebrum and cerebellum, were decreased in RTT brains, which may reflect the structural changes in these brain regions.

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33. Tatzer E, Maleczek W, Waldhauser F. An assessment of what Hans Asperger knew about child euthanasia in Vienna during the Nazi occupation. Acta paediatrica (Oslo, Norway : 1992). 2022.

AIM: Hans Asperger is probably best known for Asperger syndrome. However, he has been accused of knowingly and willingly participating in the National Socialist Child Euthanasia programme by referring patients to the Am Spiegelgrund children’s home in Vienna. This later became notorious for euthanising disabled children. We investigated those allegations. METHODS: Clinicians and historians examined original documents and transcripts related to Asperger’s referrals from the Viennese Therapeutic Pedagogy Unit, and corresponding Am Spiegelgrund admissions, up to 25 March 1943, when he was drafted. RESULTS: Asperger referred 13 children to Am Spiegelgrund. Eleven survived and apparently received adequate care that allowed them to achieve positive developments, but two girls died. Asperger referred these two girls during June and October 1941, before most of the deaths at Am Spiegelgrund occurred and before its euthanasia programme became public knowledge. Our detailed investigation of the medical records, Unit referral practices and Am Spiegelgrund provided no evidence that Asperger knew about the euthanasia programme at the time of the referrals. One death was probably due to euthanasia, but the other was less clear. CONCLUSION: There was no evidence that Asperger knew about the euthanasia programme when he referred two patients who died at Am Spiegelgrund.

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34. Thorsteinsdottir S, Njardvik U, Bjarnason R, Olafsdottir AS. Changes in Eating Behaviors Following Taste Education Intervention: Focusing on Children with and without Neurodevelopmental Disorders and Their Families: A Randomized Controlled Trial. Nutrients. 2022; 14(19).

Fussy-eating children often display problematic behaviors around mealtimes, such as irritation, opposition, or may even throw tantrums. This may lead to reduced food variety and poor nutritional profiles, which may increase parents’ worries about their children’s diet, particularly when the children also have neurodevelopmental disorders (ND) such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD). To investigate the effect of Taste Education on problematic mealtime behaviors, 81 children aged 8-12 years, with ND (n = 33) and without (n = 48), and their parents, participated in a 7-week Taste Education intervention. Children were matched on age, sex, and ND, and allocated at random into Immediate-intervention and Delayed-intervention groups. Parents completed the Meals in Our Household Questionnaire (MiOH). To examine changes in MiOH-scores, repeated-measures analysis-of-variance with time-points were used, with condition as factors (Immediate intervention and Delayed intervention). Baseline measures were adjusted for, and a robust linear mixed-model was fitted. Results showed superior outcomes for Intervention compared to waiting on all measures of MiOH, with stable effects through six-month follow-up. Differences were non-significant between children with and without ND. The Taste Education program suggests a promising, simple, and non-intrusive way to reduce children’s problematic mealtime behaviors in the long term.

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35. van den Bos N, Houwen S, Schoemaker M, Rozenblum S. Using Structural Equation Modeling to analyze handwriting of children and youth with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022.

This study tests a handwriting model for children and youth with Autism Spectrum Disorder (ASD) that displays the relationships between handwriting process and product characteristics, and the predictors of these characteristics. Structural Equation Modelling was used to test the model for children and youth with ASD (n = 50) and typically developing peers (n = 50), ages 10 to 15, for a copying and freestyle handwriting task. Findings suggest a generic handwriting model applying to both groups and both handwriting tasks. Unique effects for children and youth with ASD were identified for: (1) high interdependence of handwriting process characteristics, (2) longer pen stroke in air leading to better legibility, and (3) lower scores for executive functions leading to lower scores for legibility.

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36. van Hoogstraten WS, Lute MCC, Nusselder H, Kros L, van den Maagdenberg A, De Zeeuw CI. cATR Tracing Approach to Identify Individual Intermediary Neurons Based on Their Input and Output: A Proof-of-Concept Study Connecting Cerebellum and Central Hubs Implicated in Developmental Disorders. Cells. 2022; 11(19).

Over the past decades, it has become increasingly clear that many neurodevelopmental disorders can be characterized by aberrations in the neuro-anatomical connectome of intermediary hubs. Yet, despite the advent in unidirectional transsynaptic tracing technologies, we are still lacking an efficient approach to identify individual neurons based on both their precise input and output relations, hampering our ability to elucidate the precise connectome in both the healthy and diseased condition. Here, we bridge this gap by combining anterograde transsynaptic- and retrograde (cATR) tracing in Ai14 reporter mice, using adeno-associated virus serotype 1 expressing Cre and cholera toxin subunit B as the anterograde and retrograde tracer, respectively. We have applied this innovative approach to selectively identify individual neurons in the brainstem that do not only receive input from one or more of the cerebellar nuclei (CN), but also project to the primary motor cortex (M1), the amygdala or the ventral tegmental area (VTA). Cells directly connecting CN to M1 were found mainly in the thalamus, while a large diversity of midbrain and brainstem areas connected the CN to the amygdala or VTA. Our data highlight that cATR allows for specific, yet brain-wide, identification of individual neurons that mediate information from a cerebellar nucleus to the cerebral cortex, amygdala or VTA via a disynaptic pathway. Given that the identified neurons in healthy subjects can be readily quantified, our data also form a solid foundation to make numerical comparisons with mouse mutants suffering from aberrations in their connectome due to a neurodevelopmental disorder.

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37. Wilkinson M, Keehn RJJ, Linke AC, You Y, Gao Y, Alemu K, Correas A, Rosen BQ, Kohli JS, Wagner L, Sridhar A, Marinkovic K, Müller RA. fMRI BOLD and MEG theta power reflect complementary aspects of activity during lexicosemantic decision in adolescents with ASD. Neuroimage Reports. 2022; 2(4).

Neuroimaging studies of autism spectrum disorder (ASD) have been predominantly unimodal. While many fMRI studies have reported atypical activity patterns for diverse tasks, the MEG literature in ASD remains comparatively small. Our group recently reported atypically increased event-related theta power in individuals with ASD during lexicosemantic processing. The current multimodal study examined the relationship between fMRI BOLD signal and anatomically-constrained MEG (aMEG) theta power. Thirty-three adolescents with ASD and 23 typically developing (TD) peers took part in both fMRI and MEG scans, during which they distinguished between standard words (SW), animal words (AW), and pseudowords (PW). Regions-of-interest (ROIs) were derived based on task effects detected in BOLD signal and aMEG theta power. BOLD signal and theta power were extracted for each ROI and word condition. Compared to TD participants, increased theta power in the ASD group was found across several time windows and regions including left fusiform and inferior frontal, as well as right angular and anterior cingulate gyri, whereas BOLD signal was significantly increased in the ASD group only in right anterior cingulate gyrus. No significant correlations were observed between BOLD signal and theta power. Findings suggest that the common interpretation of increases in BOLD signal and theta power as ‘activation’ require careful differentiation, as these reflect largely distinct aspects of regional brain activity. Some group differences in dynamic neural processing detected with aMEG that are likely relevant for lexical processing may be obscured by the hemodynamic signal source and low temporal resolution of fMRI.

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38. Xie T, Ma H, Wang L, Du Y. Can Enactment and Motor Imagery Improve Working Memory for Instructions in Children with Autism Spectrum Disorder and Children with Intellectual Disability?. Journal of autism and developmental disorders. 2022.

This study explored the impacts of enactment and motor imagery on working memory for instructions in children with autism spectrum disorder (ASD), children with intellectual disability (ID) and typically developing (TD) children. The participants were asked to hear (hearing condition), imagine enacting (motor imagery condition) and actually enact (enactment condition) instruction sequences and then recall them orally. Compared with the hearing condition, all groups performed better in the enactment condition, with the greatest advantage exhibited by the TD group; however, only the TD children performed better in the motor imagery condition. In summary, enactment has a weaker facilitating effect on ASD children and ID children than on TD children, and motor imagery is ineffective in the former two groups.

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39. Xu M, Qi S, Calhoun V, Dai J, Yu B, Zhang K, Pei M, Li C, Wei Y, Jiang R, Zhi D, Huang Z, Qiu Z, Liang Z, Sui J. Aberrant brain functional and structural developments in MECP2 duplication rats. Neurobiology of disease. 2022; 173: 105838.

Transgenic animal models with homologous etiology provide a promising way to pursue the neurobiological substrates of the behavioral deficits in autism spectrum disorder (ASD). Gain-of-function mutations of MECP2 cause MECP2 duplication syndrome, a severe neurological disorder with core symptoms of ASD. However, abnormal brain developments underlying the autistic-like behavioral deficits of MECP2 duplication syndrome are rarely investigated. To this end, a human MECP2 duplication (MECP2-DP) rat model was created by the bacterial artificial chromosome transgenic method. Functional and structural magnetic resonance imaging (MRI) with high-field were performed on 16 male MECP2-DP rats and 15 male wildtype rats at postnatal 28 days, 42 days, and 56 days old. Multimodal fusion analyses guided by locomotor-relevant metrics and social novelty time separately were applied to identify abnormal brain networks associated with diverse behavioral deficits induced by MECP2 duplication. Aberrant functional developments of a core network primarily composed of the dorsal medial prefrontal cortex (dmPFC) and retrosplenial cortex (RSP) were detected to associate with diverse behavioral phenotypes in MECP2-DP rats. Altered developments of gray matter volume were detected in the hippocampus and thalamus. We conclude that gain-of-function mutations of MECP2 induce aberrant functional activities in the default-mode-like network and aberrant volumetric changes in the brain, resulting in autistic-like behavioral deficits. Our results gain critical insights into the biomarker of MECP2 duplication syndrome and the neurobiological underpinnings of the behavioral deficits in ASD.

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40. Yokota S, Tanaka M. Less Negative Implicit Attitudes Toward Autism Spectrum Disorder in University Students: A Comparison with Physical Disabilities. Journal of autism and developmental disorders. 2022.

People with autism spectrum disorder (ASD) experience stigmatization rooted in negative attitudes or prejudice toward them due to social awkwardness. However, little is known about implicit attitudes toward ASD, especially differences in attitudes compared to those of more visible conditions; physical disabilities. In this study, we implemented implicit association tests (IATs) to assess implicit attitudes. Sixty-three university students participated in IATs and answered questionnaires that measured explicit attitudes, social desirability, knowledge about-and familiarity with-disorders. The results demonstrated that implicit attitude toward ASD was significantly less negative than toward physical disabilities. Regarding the discrepancy, not socially awkward behavior but appearance of people with ASD can be evaluated as ‘in-group’ members and lead to less negative attitude compared with physical disabilities.

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41. Zerman N, Zotti F, Chirumbolo S, Zangani A, Mauro G, Zoccante L. Insights on dental care management and prevention in children with autism spectrum disorder (ASD). What is new?. Frontiers in oral health. 2022; 3: 998831.

Autistic subjects represent a severe concern to dentistry due to the considerable difficulty in managing their oral health, maintaining routine toothbrushing, and preventing dental and periodontal problems. The social and economic burden of managing dental care in autism spectrum disorder (ASD) children is particularly cumbersome for families and public and private health expenditure, especially when children reach the dentist following a late diagnosis with evident oral health problems. An early diagnosis of ASD helps dentists better address these children’s oral health. Unfortunately, insufficient attention is paid to the training and education of general pediatricians, dentists, and dental hygienists, allowing them to get to approach the different clinical aspects of ASD. Usually, children diagnosed with ASD are scheduled for dental appointments like their neurotypical peers, whereas their needs are typically complex and personalized. Scant attention is also devoted to these patients by commercial manufacturers of dental products and devices for oral hygiene and prevention of caries and periodontal diseases, leaving parents without the support and often failing when they address the oral health of autistic children. The difficulties of oral care do not derive simply from the behavior of ASD patients, as is commonly assumed, and therefore cannot be overcome solely by the patience and attention of parents and dentists. Genetics, dietary habits, sensory impairments, and cognition disorders are other causes contributing in various degrees to the impact on the mood and psychological reactions of autistic children towards dentists. How can we prevent teeth caries, periodontal disorders, and other oral health impairments by properly managing ASD children? This manuscript gives an up-to-date overview of these problems and helps to provide good remarks.

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42. Zheng Y, Prince NZ, Peralta Marzal LN, Ahmed S, Garssen J, Perez Pardo P, Kraneveld AD. The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10. International journal of molecular sciences. 2022; 23(19).

The bacterial metabolite 4-methylphenol (para-cresol or p-cresol) and its derivative p-cresyl sulfate (pCS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that p-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of p-cresol, specifically its metabolite pCS that can reach the brain, in ASD remain to be investigated. The pCS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of pCS in ASD pathogenesis. In microglial cells pCS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, pCS treatment attenuates TNF-α and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-α, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of p-cresol-associated metabolites pCS and p-cresyl glucuronide (pCG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-α and TGF-β1 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with pCS-induced ASD pathogenesis.

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43. Zhou B, Yan X, Yang L, Zheng X, Chen Y, Liu Y, Ren Y, Peng J, Zhang Y, Huang J, Tang L, Wen M. Effects of arginine vasopressin on the transcriptome of prefrontal cortex in autistic rat model. Journal of cellular and molecular medicine. 2022; 26(21): 5493-505.

Our previous studies have also demonstrated that AVP can significantly improve social interaction disorders and stereotypical behaviours in rats with VPA-induced autism model. To further explore the mechanisms of action of AVP, we compared the PFC transcriptome changes before and after AVP treatment in VPA-induced autism rat model. The autism model was induced by intraperitoneally injected with VPA at embryonic day 12.5 and randomly assigned to two groups: the VPA-induced autism model group and the AVP treatment group. The AVP treatment group were treated with intranasal AVP at postnatal day 21 and for 3 weeks. The gene expression levels and function changes on the prefrontal cortex were measured by RNA-seq and bioinformatics analysis at PND42 and the mRNA expression levels of synaptic and myelin development related genes were validated by qPCR. Our results confirmed that AVP could significantly improve synaptic and axon dysplasia and promote oligodendrocyte development in the prefrontal cortex in VPA-induced autism models by regulating multiple signalling pathways.

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