1. Adil KJ, Gonzales EL, Remonde CG, Boo KJ, Jeon SJ, Shin CY. Autism-Like Behavioral Phenotypes in Mice Treated with Systemic N-Methyl-D-Aspartate. Biomolecules & therapeutics. 2022; 30(3): 232-7.

Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

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2. Girard D, Courchesne V, Degré-Pelletier J, Letendre C, Soulières I. Assessing global developmental delay across instruments in minimally verbal preschool autistic children: The importance of a multi-method and multi-informant approach. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 103-16.

Intellectual assessment in preschool autistic children bears many challenges, particularly for those who have lower language and/or cognitive abilities. These challenges often result in underestimation of their potential or exclusion from research studies. Understanding how different instruments and definitions used to identify autistic preschool children with global developmental delay (GDD) affect sample composition is critical to advance research on this understudied clinical population. This study set out to examine the extent to which using different instruments to define GDD affects sample composition and whether different definitions affect resultant cognitive and adaptive profiles. Data from the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scales-Second Edition, a parent-report tool, were analyzed in a sample of 64 autistic and 73 neurotypical children (28-69 months). Our results highlight that cognitive assessment alone should not be used in clinical or research practices to infer a comorbid diagnosis of GDD, as it might lead to underestimating autistic children’s potential. Instead, using both adaptive and cognitive levels as a stratification method to create subgroups of children with and without GDD might be a promising approach to adequately differentiate them, with less risk of underestimating them.

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3. Green JM. Autism as emergent: Comments on Mottron 2021. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 11.

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4. Li T, Hoogman M, Roth Mota N, Buitelaar JK, Vasquez AA, Franke B, van Rooij D. Dissecting the heterogeneous subcortical brain volume of autism spectrum disorder using community detection. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 42-55.

Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15-22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.

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5. Masaba BB, Taiswa J, Mmusi-Phetoe RM. Challenges of Caregivers Having Children with Autism in Kenya: Systematic Review. Iranian journal of nursing and midwifery research. 2021; 26(5): 373-9.

BACKGROUND: Caring for children with Autism Spectrum Disorder (ASD) is demanding, especially where access to services and support are inadequate. The present study aimed to systematically review the challenges associated with the caregivers whose children have autism. MATERIALS AND METHODS: A systematic review design was utilized. The searches were conducted from February 2019 to January 2020. A qualitative analysis that was based on meta-aggregation approach and thematic analysis was used. Thereafter, data was presented into themes. The quality of all included studies was assessed using the Critical Appraisal Skills Program (CASP). RESULTS: The search generated 909 articles of which only 9 met the inclusion criteria. The main findings were discussed under the following three thematic domains: 1) Stigma, 2) Financial burden, and 3) Caregiving burden. CONCLUSIONS: Evidence from the data reviewed showed financial burden faced by the caregivers whose children are diagnosed with ASD. This was manifested through both direct and indirect cost of treatment. Another key finding was that majority of the caregivers faced stigma from the community. This implies the low level of awareness of the ASD within the community. The present study calls for more programs on the present research problem within the community so as to increase awareness. Furthermore, the current advocacy of Universal Health Coverage programs in the country should incorporate ASD children.

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6. Molina-López J, Leiva-García B, Planells E, Planells P. Food selectivity, nutritional inadequacies, and mealtime behavioral problems in children with autism spectrum disorder compared to neurotypical children. The International journal of eating disorders. 2021; 54(12): 2155-66.

OBJECTIVE: To evaluate body composition, nutritional status through food selectivity and degree of inadequate intake, and mealtime behavior in children with autism spectrum disorder (ASD) compared to neurotypical children. METHOD: A cross-sectional case-control study was carried out in 144 children (N = 55 with ASD; N = 91 with neurotypical children) between 6 and 18 years of age. Body composition, nutritional intake, food consumption frequency (FFQ), and mealtime behavior were evaluated. RESULTS: Results showed a greater presence of children with a low weight (18.4% ASD vs. 3.20% comparison group) and obesity (16.3% ASD vs. 8.6% comparison group) in the ASD group for body mass index (BMI) categories (p = .003; number needed to take [NNT] = 8.07). The presence of obesity in ASD children compared to the comparison group was even higher when considering the fat component (47.5% ASD vs. 19.4% comparison group, p = .002; NNT = 10.3). ASD children had greater intake inadequacy (50% ASD vs. 22% comparison group, p = .014; NNT = 3.58), high food selectivity by FFQ (60.6% ASD vs. 37.9% comparison group, p < .037; NNT = 4.41), and more eating problems (food rejection, limited variety, disruptive behavior), compared to neurotypical children (p = .001). CONCLUSION: Children with ASD showed an unbalanced body composition toward both underweight and obesity, a greater degree of inadequate intake, high food selectivity as indicated by their consumption frequency, and more disturbed eating behavior than children with neurotypical development. We suggest monitoring nutritional inadequacies and implementing nutritional strategies to expand the variety of foods children with ASD consume.

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7. Qin L, Ma K, Yan Z. Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2022; 47(6): 1271-9.

Human genetic sequencing has implicated epigenetic and synaptic aberrations as the most prominent risk factors for autism. Here we show that autistic patients exhibit the significantly lower histone acetylation and elevated HDAC2 expression in prefrontal cortex (PFC). The diminished histone acetylation is also recaptured in an autism mouse model with the deficiency of the Shank3 gene encoding a synaptic scaffolding protein. Treating young (5-week-old) Shank3-deficient mice with a 4-week ketogenic diet, which can act as an endogenous inhibitor of class I HDACs via the major product β-hydroxybutyrate, elevates the level of histone acetylation in PFC neurons. Behavioral assays indicate that ketogenic diet treatment leads to the prolonged rescue of social preference deficits in Shank3-deficient mice. The HDAC downstream target genes encoding NMDA receptor subunits, GRIN2A and GRIN2B, are significantly reduced in PFC of autistic humans. Ketogenic diet treatment of Shank3-deficient mice elevates the transcription and histone acetylation of Grin2a and Grin2b, and restores the diminished NMDAR synaptic function in PFC neurons. These results suggest that the ketogenic diet provides a promising therapeutic strategy for social deficits in autism via the restoration of histone acetylation and gene expression in the brain.

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8. Royer-Bertrand B, Jequier Gygax M, Cisarova K, Rosenfeld JA, Bassetti JA, Moldovan O, O’Heir E, Burrage LC, Allen J, Emrick LT, Eastman E, Kumps C, Abbas S, Van Winckel G, Chabane N, Zackai EH, Lebon S, Keena B, Bhoj EJ, Umair M, Li D, Donald KA, Superti-Furga A. De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. Molecular autism. 2021; 12(1): 69.

BACKGROUND: De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. METHODS: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. RESULTS: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. LIMITATIONS: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. CONCLUSIONS: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

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9. Sakai Y, Okuzono S, Schaaf CP, Ohga S. Translational pediatrics: clinical perspective for Phelan-McDermid syndrome and autism research. Pediatric research. 2021.

Phelan-McDermid syndrome (PMS) is a rare genetic disorder presenting with developmental delay, epilepsy, and autism spectrum disorder (ASD). The segmental deletion of chromosome 22q13.3 affects the copy number of SHANK3, the gene encoding a scaffolding protein at the postsynaptic density. Biological studies indicate that SHANK3 plays crucial roles in the development of synaptic functions in the postnatal brain. Notably, induced pluripotent stem (iPS) cells have enabled researchers to develop brain organoids and microglia from patients and to explore the pathophysiology of neurodevelopmental disorders in human cells. Single-cell RNA sequencing of these cells revealed that human-specific genes are uniquely expressed during cortical development. Thus, patient-derived disease models are expected to identify as-yet-unidentified functions of SHANK3 in the development of human brain. These efforts may help establish a new style of translational research in pediatrics, which is expected to provide therapeutic insight for children with PMS and broader categories of disease. IMPACT: Phelan-McDermid syndrome is a prototypic model for molecular studies of autism spectrum disorder. Brain organoids are expected to provide therapeutic insight. Single-cell RNA sequencing of microglia may uncover the functional roles of human-specific genes.

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10. Tarnowska K, Gruczyńska-Sękowska E, Kowalska D, Majewska E, Kozłowska M, Winkler R. The opioid excess theory in autism spectrum disorders – is it worth investigating further?. Critical reviews in food science and nutrition. 2021: 1-14.

Autism spectrum disorders (ASD) are defined as neurodevelopmental disorders, which are highly variable in nature and do not form a uniform picture, either in terms of symptomatology or depth of the disturbance. Diagnosis of ASD is made for children who show signs of impairment in social interaction, communication and cognitive skills. The exact cause of autism spectrum disorders has not been determined to date. Although there is no cure for ASD, a variety interventions have been proposed. The most commonly used restrictive dietary intervention is the gluten-free casein-free diet (GFCF), which is based on the opioid excess theory. This paper summarizes and discusses research on the core elements of the opioid excess theory in ASD: increased levels of opioid peptides in body fluids in ASD patients, increased intestinal permeability, altered peptidase activity and the effectiveness of GFCF diet in alleviating symptoms of ASD. Furthermore, we discuss the difficulties and their causes in conducting research with ASD patients. The assumptions of the opioid excess theory have neither been definitively confirmed nor disproved. Research in this area should continue, taking into account the highest possible quality standards and the specific needs and abilities of patients with ASD and their families.

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11. Yan J, Chen F, Gao X, Peng G. Auditory-Motor Mapping Training Facilitates Speech and Word Learning in Tone Language-Speaking Children With Autism: An Early Efficacy Study. Journal of speech, language, and hearing research : JSLHR. 2021; 64(12): 4664-81.

PURPOSE: It has been reported that tone language-speaking children with autism demonstrate speech-specific lexical tone processing difficulty, although they have intact or even better-than-normal processing of nonspeech/melodic pitch analogues. In this early efficacy study, we evaluated the therapeutic potential of Auditory-Motor Mapping Training (AMMT) in facilitating speech and word output for Mandarin-speaking nonverbal and low-verbal children with autism, in comparison with a matched non-AMMT-based control treatment. METHOD: Fifteen Mandarin-speaking nonverbal and low-verbal children with autism spectrum disorder participated and completed all the AMMT-based treatment sessions by intoning (singing) and tapping the target words delivered via an app, whereas another 15 participants received control treatment. Generalized linear mixed-effects models were created to evaluate speech production accuracy and word production intelligibility across different groups and conditions. RESULTS: Results showed that the AMMT-based treatment provided a more effective training approach in accelerating the rate of speech (especially lexical tone) and word learning in the trained items. More importantly, the enhanced training efficacy on lexical tone acquisition remained at 2 weeks after therapy and generalized to untrained tones that were not practiced. Furthermore, the low-verbal participants showed higher improvement compared to the nonverbal participants. CONCLUSIONS: These data provide the first empirical evidence for adopting the AMMT-based training to facilitate speech and word learning in Mandarin-speaking nonverbal and low-verbal children with autism. This early efficacy study holds promise for improving lexical tone production in Mandarin-speaking children with autism but should be further replicated in larger scale randomized studies. Supplemental Material https://doi.org/10.23641/asha.16834627.

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12. Zhao F, Zhang X, Thung KH, Mao N, Lee SW, Shen D. Constructing Multi-View High-Order Functional Connectivity Networks for Diagnosis of Autism Spectrum Disorder. IEEE transactions on bio-medical engineering. 2022; 69(3): 1237-50.

Brain functional connectivity network (FCN) based on resting-state functional magnetic resonance imaging (rs-fMRI) has been widely used to identify neuropsychiatric disorders such as autism spectrum disorder (ASD). Most existing FCN-based methods only estimate the correlation between brain regions of interest (ROIs), without exploring more informative higher-level interactions among multiple ROIs which could be beneficial to disease diagnosis. To fully explore the discriminative information provided by different brain networks, a cluster-based multi-view high-order FCN (Ho-FCN) framework is proposed in this paper. Specifically, we first group the functional connectivity (FC) time series into different clusters and compute the multi-order central moment series for the FC time series in each cluster. Then we utilize the correlation of central moment series between different clusters to reveal the high-order FC relationships among multiple ROIs. In addition, to address the phase mismatch issue in conventional FCNs, we also adopt the central moments of the correlation time series as the temporal-invariance features to capture the dynamic characteristics of low-order dynamic FCN (Lo-D-FCN). Experimentalresults on the ABIDE dataset validate that: 1) the proposed multi-view Ho-FCNs is able to explore rich discriminative information for ASD diagnosis; 2) the phase mismatch issue can be well circumvented by using central moments; and 3) the combination of different types of FCNs can significantly improve the diagnostic accuracy of ASD (86.2%).

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