1. Amada N, Kakumoto Y, Futamura T, Maeda K. Prenatal methotrexate injection increases behaviors possibly associated with depression and/or autism in rat offspring; A new animal model for mental disorder, based on folate metabolism deficit during pregnancy. Neuropsychopharmacology reports. 2022.

BACKGROUND: Deficiency of folate, an essential vitamin for DNA synthesis and methylation, is reported as a risk factor for mental disorders. Considering a possibility that folate metabolism deficit during pregnancy may disturb CNS development and increase mental disorders in offspring, we treated pregnant rats with methotrexate (MTX), an inhibitor of folate metabolic enzyme, and evaluated offspring behaviors. METHODS: Saline or MTX was intraperitoneally administered to female SD rats on gestational day 17. Offspring behaviors were evaluated during approximately 6-9 weeks old; prepulse inhibition (PPI), social interaction (SI), locomotor activity (LA), and forced swimming test (FST) for evaluation of schizophrenia, depression, and autism related behaviors; the elevated plus maze (EPM) and the light-dark box (LD) test for evaluation of anxiety. RESULTS: Compared to saline-treated group, MTX-treated group showed decrease of SI and increase of immobility time in FST. In addition, increases of time spent in the light box and shuttling between the light-dark boxes were observed in LD test. On the other hand, no changes were confirmed in EPM, LA, and PPI. CONCLUSION: Decrease of SI and increase of immobility time in FST may suggest association of this animal model with depression and/or autism. Increase of time spent in the light box and shuttling between the light-dark boxes may indicate changes in anxiety or cognitive level to environment, or repetitive behaviors in autism. Although further studies are warranted to characterize this animal model, at least we can say that prenatal MTX exposure, possibly causing folate metabolism deficit, affects offspring behaviors.

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2. Astorkia M, Lachman HM, Zheng D. Characterization of cell-cell communication in autistic brains with single-cell transcriptomes. Journal of neurodevelopmental disorders. 2022; 14(1): 29.

BACKGROUND: Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. METHODS: Recent application of single-cell technologies, especially single-cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single-cell data provides opportunities for multilevel computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single-cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. RESULTS: Our results indicate that at a global level, there are cell-cell communication differences in autism in comparison with controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of changes is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibits increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways show differential expression, but genes in the affected pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. CONCLUSIONS: Overall, our proof-of-principle computational study using single-cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type effects can be valuable for understanding autism pathogenesis.

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3. Bosch E, Fritsche M, Utzerath C, Buitelaar JK, de Lange FP. Adaptation and serial choice bias for low-level visual features are unaltered in autistic adolescents. Journal of vision. 2022; 22(6): 1.

Autism spectrum disorder (ASD), or autism, is characterized by social and non-social symptoms, including sensory hyper- and hyposensitivities. A suggestion has been put forward that some of these symptoms could be explained by differences in how sensory information is integrated with its context, including a lower tendency to leverage the past in the processing of new perceptual input. At least two history-dependent effects of opposite directions have been described in the visual perception literature: a repulsive adaptation effect, where perception of a stimulus is biased away from an adaptor stimulus, and an attractive serial choice bias, where perceptual choices are biased toward the previous choice. In this study, we investigated whether autistic participants differed in either bias from typically developing controls (TDs). Sixty-four adolescent participants (31 with ASD, 33 TDs) were asked to categorize oriented line stimuli in two tasks that were designed so that we would induce either adaptation or serial choice bias. Although our tasks successfully induced both biases, in comparing the two groups we found no differences in the magnitude of adaptation nor in the modulation of perceptual choices by the previous choice. In conclusion, we find no evidence of a decreased integration of the past in visual perception of low-level stimulus features in autistic adolescents.

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4. Davis PE, Slater J, Marshall D, Robins DL. Autistic children who create imaginary companions: Evidence of social benefits. Autism : the international journal of research and practice. 2022: 13623613221092195.

Research on neurotypical children with imaginary friends has found that those with imaginary friends have better social skills and are more able to think about how other people’s minds work compared to children without imaginary friends. Research shows that some autistic children also create imaginary friends. This article is the first to look at whether or not autistic children with imaginary friends have stronger social skills and an improved ability to think about others’ minds than those without imaginary friends. We asked parents to report about their children aged 5 to 12. Finding almost half reported their child had an imaginary friend, a much larger number than previous research with younger children. Our findings also suggested that autistic children with imaginary friends were better able to understand others’ minds and had stronger social skills than their peers without imaginary friends. The children’s language ability did not influence this. The findings of this study add to the evidence that with respect to the creation imaginary friends and their potential benefits, the play profiles of autistic children are similar to the general population. It also provides more evidence that the understanding of others’ minds is not all or nothing in autism and gives reason for researchers to investigate whether the causes of these differences are the same or different for autistic children.

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5. Gupta C, Chandrashekar P, Jin T, He C, Khullar S, Chang Q, Wang D. Bringing machine learning to research on intellectual and developmental disabilities: taking inspiration from neurological diseases. Journal of neurodevelopmental disorders. 2022; 14(1): 28.

Intellectual and Developmental Disabilities (IDDs), such as Down syndrome, Fragile X syndrome, Rett syndrome, and autism spectrum disorder, usually manifest at birth or early childhood. IDDs are characterized by significant impairment in intellectual and adaptive functioning, and both genetic and environmental factors underpin IDD biology. Molecular and genetic stratification of IDDs remain challenging mainly due to overlapping factors and comorbidity. Advances in high throughput sequencing, imaging, and tools to record behavioral data at scale have greatly enhanced our understanding of the molecular, cellular, structural, and environmental basis of some IDDs. Fueled by the « big data » revolution, artificial intelligence (AI) and machine learning (ML) technologies have brought a whole new paradigm shift in computational biology. Evidently, the ML-driven approach to clinical diagnoses has the potential to augment classical methods that use symptoms and external observations, hoping to push the personalized treatment plan forward. Therefore, integrative analyses and applications of ML technology have a direct bearing on discoveries in IDDs. The application of ML to IDDs can potentially improve screening and early diagnosis, advance our understanding of the complexity of comorbidity, and accelerate the identification of biomarkers for clinical research and drug development. For more than five decades, the IDDRC network has supported a nexus of investigators at centers across the USA, all striving to understand the interplay between various factors underlying IDDs. In this review, we introduced fast-increasing multi-modal data types, highlighted example studies that employed ML technologies to illuminate factors and biological mechanisms underlying IDDs, as well as recent advances in ML technologies and their applications to IDDs and other neurological diseases. We discussed various molecular, clinical, and environmental data collection modes, including genetic, imaging, phenotypical, and behavioral data types, along with multiple repositories that store and share such data. Furthermore, we outlined some fundamental concepts of machine learning algorithms and presented our opinion on specific gaps that will need to be filled to accomplish, for example, reliable implementation of ML-based diagnosis technology in IDD clinics. We anticipate that this review will guide researchers to formulate AI and ML-based approaches to investigate IDDs and related conditions.

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6. Hoshina N, Johnson-Venkatesh EM, Rally V, Sant J, Hoshina M, Seiglie M, Umemori H. ASD/OCD-linked Protocadherin-10 regulates synapse, but not axon, development in the amygdala and contributes to fear- and anxiety-related behaviors. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2022.

The Protocadherin-10 (PCDH10) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid non-specific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find that Pcdh10 KO mice exhibit impaired development of excitatory synapses in the dorsal BLA. We further demonstrate that male Pcdh10 KO mice exhibit reduced anxiety-related behaviors, impaired fear conditioning, decreased stress-coping responses, and mildly impaired social recognition and communication. These results indicate that PCDH10 plays a critical role in excitatory synapse development, but not axon development, in the dorsal BLA and that PCDH10 regulates anxiety-, fear-, and stress-related behaviors. Our results reveal the roles of PCDH10 in the brain and its relationship to relevant psychiatric disorders such as ASD, OCD, and MD.Significance Statement Protocadherin-10 (PCDH10) encodes a cell adhesion molecule and is implicated in autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). PCDH10 is highly expressed in the basolateral nucleus of the amygdala (BLA). However, the phenotypes of previously published Pcdh10 mutant mice are debatable, and some are possibly due to the non-specific effects of the LacZ/Neo cassette inserted in the mice. We have generated a new Pcdh10 mutant mouse line without the LacZ/Neo cassette. Using our new mouse line, we reveal the roles of PCDH10 for excitatory synapse development in the BLA. The mutant mice exhibit anxiety-, fear-, and stress-related behaviors, which are relevant to ASD, OCD, and MD, suggesting a possible treatment strategy for such psychiatric disorders.

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7. Li H, Gavis ER. The Drosophila Fragile X mental retardation protein modulates the neuronal cytoskeleton to limit dendritic arborization. Development (Cambridge, England). 2022.

Dendritic arbor development is a complex, highly regulated process. Post-transcriptional regulation mediated by RNA-binding proteins plays an important role in neuronal dendrite morphogenesis by delivering on-site, on-demand protein synthesis. Here, we show how the Drosophila Fragile X mental retardation protein (dFMRP), a conserved RNA-binding protein, limits dendrite branching to ensure proper neuronal function during larval sensory neuron development. dFMRP knockdown causes increased dendritic terminal branch growth and a resulting overelaboration defect due in part to altered microtubule stability and dynamics. dFMRP also controls dendrite outgrowth by regulating the Drosophila profilin homolog chickadee. dFMRP colocalizes with chickadee mRNA in dendritic granules and regulates its dendritic localization and protein expression. Whereas RNA-binding domains KH1 and KH2 are both crucial for dFMRP-mediated dendritic regulation, KH2 specifically is required for dFMRP granule formation and chickadee mRNA association, suggesting a link between dendritic dFMRP granules and dFMRP function in dendrite elaboration. Our studies implicate dFMRP-mediated modulation of both the neuronal microtubule and actin cytoskeletons in multidendritic neuronal architecture and provide molecular insight into dFMRP granule formation and its relevance to its role in dendritic patterning.

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8. Sadeghi S, Pouretemad HR. Executive functions predict restricted and repetitive behaviors in toddlers under 36 months old with autism spectrum disorder. Infant behavior & development. 2022; 67: 101721.

BACKGROUND: Executive functions (EFs) and restricted and repetitive behaviors (RRBs) have been studied mainly in older individuals with autism spectrum disorder (ASD), while little is known about the relationship between EFs and RRBs in toddlers. AIMS: The purpose of this study was to investigate the relationship between EFs and RRBs of toddlers with ASD symptoms. In addition, we tested whether EFs were predictive of RRBs in toddlers. METHODS: Cross-sectional data were collected from parents of forty-five toddlers under 36 months old. The modified checklist for autism in toddlers (M-CHAT), the Gilliam autism rating scale (GARS-2), the behavior rating inventory of executive functioning-preschool version (BRIEF-P), and the repetitive behavior scale- revised (RBS-R) administered to parents. RESULTS: We found significant associations between EFs and (1) stereotyped behaviors, (2) self-injurious behaviors, (3) ritualistic behaviors, (4) sameness behaviors, (5) restricted behaviors, (6) compulsive behaviors, and (7) repetitive behaviors total score. Increases in EFs differences predicted an increase in RRBs. CONCLUSIONS: Our results indicate a link between EFs and RRBs. Future research on RRBs in ASD may benefit from focusing on specific EFs rather than general categories.

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9. Seiffe A, Ramírez MF, Sempé L, Depino AM. Juvenile handling rescues autism-related effects of prenatal exposure to valproic acid. Scientific reports. 2022; 12(1): 7174.

Environmental factors acting on young animals affect neurodevelopmental trajectories and impact adult brain function and behavior. Psychiatric disorders may be caused or worsen by environmental factors, but early interventions can improve performance. Understanding the possible mechanisms acting upon the developing brain could help identify etiological factors of psychiatric disorders and enable advancement of effective therapies. Research has focused on the long-lasting effects of environmental factors acting during the perinatal period, therefore little is known about the impact of these factors at later ages when neurodevelopmental pathologies such as autism spectrum disorder (ASD) are usually diagnosed. Here we show that handling mice during the juvenile period can rescue a range of behavioral and cellular effects of prenatal valproic acid (VPA) exposure. VPA-exposed animals show reduced sociability and increased repetitive behaviors, along with other autism-related endophenotypes such as increased immobility in the forced swim test and increased neuronal activity in the piriform cortex (Pir). Our results demonstrate that briefly handling mice every other day between postnatal days 22 and 34 can largely rescue these phenotypes. This effect can also be observed when animals are analyzed across tests using an « autism » factor, which also discriminates between animals with high and low Pir neuron activity. Thus, we identified a juvenile developmental window when environmental factors can determine adult autism-related behavior. In addition, our results have broader implications on behavioral neuroscience, as they highlight the importance of adequate experimental design and control of behavioral experiments involving treating or testing young animals.

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10. Shao J, Zhang F, Chen C, Wang Y, Wang Q, Zhou J. Brain Network for Exploring the Change of Brain Neurotransmitter 5-Hydroxytryptamine of Autism Children by Resting-State EEG. Computational and mathematical methods in medicine. 2022; 2022: 5451277.

The study was aimed at understanding the brain network and the change rule of brain neurotransmitter 5-hydroxytryptamine (5-HT) in autism children through resting-state electroencephalogram (EEG). 20 autistic children in hospital were selected and defined as the observation group. Meanwhile, 20 healthy children were defined as the control group. EEG signals were collected for the two groups. Fuzzy C-means (FCM) algorithm was used to extract features of EEG signals, and DTF was applied for the causal association between multichannel EEG signals. The two groups were compared for the average function value and regional efficiency of the brain neurotransmitter 5-HT. The results showed that the classification accuracy of frontal F7 channel, left frontal FP1 channel, and temporal T6 channel was 95.2%, 95.3%, and 91.2%, respectively. The average of high beta frequency band, low beta frequency band, theta frequency band, and alpha frequency band in the control group was significantly higher than that in the observation group under the optimal threshold (P < 0.05). Compared with normal subjects (34.27), the average function of 5-HT in the brain was 20.13 in patients with low function and 45.74 in patients with hyperfunction. In conclusion, FCM algorithm can feature extraction of EEG signals, especially in the frontal F7 channel, the left frontal FP1 channel, and the TEMPORAL T6 channel, which has high classification accuracy and can well express the EEG signals of autistic children. The level of 5-HT in autistic children is lower than that in healthy people, and it is closely related to loneliness and depression.

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11. Simonoff E, Mowlem F, Pearson O, Anagnostou E, Donnelly C, Hollander E, King BH, McCracken JT, Scahill L, Sikich L, Pickles A. Citalopram Did Not Significantly Improve Anxiety in Children with Autism Spectrum Disorder Undergoing Treatment for Core Symptoms: Secondary Analysis of a Trial to Reduce Repetitive Behaviors. Journal of child and adolescent psychopharmacology. 2022.

Objective: Anxiety disorders are among the most common co-occurring conditions in autism spectrum disorder (ASD). Despite their prevalence and impact, there are no randomized controlled trials (RCTs) aimed at evaluating the efficacy of selective serotonin reuptake inhibitors (SSRIs) for anxiolysis in this population, who may have a different biological basis for anxiety. Methods: Secondary analyses of the STAART double-blind, placebo-controlled RCT of citalopram in children with ASD examined whether citalopram reduced anxiety measured on the parent-reported Child and Adolescent Symptom Inventory-4 (CASI-4) as the primary outcome. An intention-to-treat analysis involving all 149 participants used multiple imputations for missing data and included baseline stratification factors of age group and site, among others. We prespecified as clinically significant a 33% reduction in anxiety in citalopram versus placebo, coinciding with 80% power. We tested whether communicative ability on the Vineland Communication score moderated treatment effect and explored whether initial anxiety was associated with greater adverse events, which could impact on dose titration and achieving optimal dose. Results: Both groups showed substantial reduction in anxiety. Citalopram was associated with a nonsignificant 16.5% greater reduction (observed coefficient = -0.181, bootstrap standard error = 0.126, p = 0.151, confidence interval = -0.428 to 0.066). Anxiety reports were significantly lower in children with reduced communicative ability, but communicative ability did not moderate the treatment effect (interaction p = 0.294). Initial anxiety levels were not associated with increased adverse effects (interaction ps 0.162-0.954). Conclusion: Citalopram did not statistically significantly improve anxiety in children with ASD. Clinicians should be cautious in their use of SSRIs for this indication. There remains a need for well-powered clinical trials testing the efficacy of SSRIs among autistic children with anxiety disorders.

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12. Zarokanellou V, Kotsopoulos A, Tafiadis D, Prentza A, Kolaitis G, Papanikolaou K. Specificity of phonological representations in school-age high-functioning ASD children. International journal of speech-language pathology. 2022: 1-11.

Purpose: Well-specified phonological representations are important for the development of spoken and written language. This study investigates the types of speech errors and the quality of phonological representations in Greek-speaking school-age children with high-functioning autism spectrum disorder (HF-ASD), as well as the relationship between stored phonological representations and speech output in this sample, according to Stackhouse and Wells’ (1997) model.Method: All participants completed a phonological and a naming test, and a non-word repetition task. A receptive phonological task was administered to a subgroup of HF-ASD and typically developing (TD) participants. According to performance in the phonological test, the HF-ASD children were categorised as ASD with Speech Sound Disorder (SSD) or ASD without SSD.Result: The HF-ASD children made significantly more speech errors and showed significant difficulties in the repetition of non-words and the stored phonological representations compared to the TD group but had the same naming abilities with their TD peers. The ASD children with SSD and without SSD performed alike in the receptive task, indicating that both groups had unspecified phonological representations.Conclusion: These results support the hypothesis of distinct phonological representations for speech input and output and highlight the need of using receptive tasks to evaluate underlying phonological knowledge, a process which could allow clinicians to identify the level of speech breakdown.

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