1. Alshehri S, Nadeem A, Ahmad SF, Alqarni SS, Al-Harbi NO, Al-Ayadhi LY, Attia SM, Alqarni SA, Bakheet SA. Disequilibrium in the Thioredoxin Reductase-1/Thioredoxin-1 Redox Couple Is Associated with Increased T-Cell Apoptosis in Children with Autism. Metabolites;2023 (Feb 16);13(2)

Autism spectrum disorder (ASD) is a neuropsychiatric childhood disorder that affects social skill and language development, and is characterized by persistent stereotypic behaviors, restricted social interests, and impaired language/social skills. ASD subjects have dysregulated immune responses due to impairment in inflammatory and antioxidant signaling in immune cells, such as T cells. Thioredoxin reductase-1 (TrxR1) and thioredoxin-1 (Trx1) play a crucial role in the maintenance of redox equilibrium in several immune cells, including T cells. T-cell apoptosis plays a crucial role in the pathogenesis of several inflammatory diseases. However, it remains to be explored how the TrxR1/Trx1 redox couple affects T-cells apoptosis in ASD and typically developing control (TDC) groups. Therefore, this single-center cross-sectional study explored the expression/activity of TrxR1/Trx1, and Bcl2, 7-AAD/annexin V immunostaining in T cells of ASD (n = 25) and TDC (n = 22) groups. Further, effects of the LPS were determined on apoptosis in TDC and ASD T cells. Our data show that T cells have increased TrxR1 expression, while having decreased Trx1 expression in the ASD group. Further, TrxR enzymatic activity was also elevated in T cells of the ASD group. Furthermore, T cells of the ASD group had a decreased Bcl2 expression and an increased % of annexin V immunostaining. Treatment of T cells with LPS caused greater apoptosis in the ASD group than the TDC group, with same treatment. These data reveal that the redox couple TrxR1/Trx1 is dysregulated in T cells of ASD subjects, which is associated with decreased Bcl2 expression and increased apoptosis. This may lead to decreased survival of T cells in ASD subjects during chronic inflammation. Future studies should investigate environmental factors, such as gut dysbiosis and pollutants, that may cause abnormal immune responses in the T cells of ASD subjects due to chronic inflammation.

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2. Ashwood P. Preliminary Findings of Elevated Inflammatory Plasma Cytokines in Children with Autism Who Have Co-Morbid Gastrointestinal Symptoms. Biomedicines;2023 (Feb 2);11(2)

Autism spectrum disorder (AU) is present in approximately 2% of the population and is often associated with co-morbidities that can impact quality of life. One of the most common co-morbidities in autism is the presence of gastrointestinal (GI) symptoms consisting of irregular bowel habits such as constipation, diarrhea, or alternating bowel habit. Evidence of immune infiltration and immune activation has been shown in the ileum and colon of children with AU with GI symptoms. Moreover, immune dysfunction is a contributing factor in many GI diseases, and we hypothesize that it would be more apparent in children with AU that exhibit GI symptoms than those who do not present with GI symptoms. The aim of this preliminary study was to determine whether there are altered cytokine levels in plasma in children with AU with GI symptoms compared with children with AU without GI symptoms, typically developing (TD) children with GI symptoms and TD children without GI symptoms, from the same population-based cohort. Plasma cytokine levels were assessed by multiplex assays. No differences in plasma cytokines were observed in TD controls with or without GI symptoms; however, many innate (IL-1α, TNFα, GM-CSF, IFNα) and adaptive cytokines (IL-4, IL-13, IL-12p70) were increased in AU children with GI symptoms compared with children with AU with no GI symptoms. The mucosal relevant cytokine IL-15 was increased in AU with GI symptoms compared with all groups. In contrast, the regulatory cytokine IL-10, was reduced in AU with GI symptoms and may suggest an imbalance in pro-inflammatory/regulatory signals. These data suggest that children with AU and GI symptoms have an imbalance in their immune response that is evident in their circulating plasma cytokine levels. A finding that could point to potential therapeutic and/or monitoring strategies for GI issues in AU.

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3. Azzarà A, Rumore R, Brugnoletti F, Tabolacci E, Bottillo I, Sangiorgi E, Gurrieri F. RADX Gene Variant May Predispose to Familial Asperger Syndrome. Genes (Basel);2023 (Jan 23);14(2)

Asperger syndrome (AS) is a pervasive developmental disorder characterized by general impairment in socialization, stereotypical behavior, defective adaptation to the social context usually without intellectual disability, and some high functioning areas related to memory and mathematics. Clinical criteria are not well defined and the etiology is heterogeneous and mostly unknown. Like in typical autism spectrum disorders (ASD), the genetic background plays a crucial role in AS, and often an almost mendelian segregation can be observed in some families. We performed a whole exome sequencing (WES) in three relatives of a family with vertical transmission of AS-ASD to identify variants in candidate genes segregating with the phenotype. Variant p.(Cys834Ser) in the RADX gene was the only one segregating among all the affected family members. This gene encodes a single-strand DNA binding factor, which mediates the recruitment of genome maintenance proteins to sites of replication stress. Replication stress and genome instability have been reported recently in neural progenitor cells derived from ASD patients, leading to a disruption of long neural genes involved in cell-cell adhesion and migration. We propose RADX as a new gene that when mutated could represent a predisposing factor to AS-ASD.

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4. Bakombo S, Ewalefo P, Konkle ATM. The Influence of Social Media on the Perception of Autism Spectrum Disorders: Content Analysis of Public Discourse on YouTube Videos. Int J Environ Res Public Health;2023 (Feb 13);20(4)

BACKGROUND: Little is known about how social media shapes the public’s perception of autism spectrum disorder (ASD). We used a media content analysis approach to analyze the public’s perception of ASD. METHODS: We conducted a YouTube search in 2019 using keywords related to ASD. The first 10 videos displayed after each search that met the eligibility criteria were selected for analysis. The final sample size of videos analyzed was 50. The top 10 comments from each respective video were selected for commentary analysis. A total of 500 comments were used for this study. Videos and comments were categorized based on sentiment, evident themes, and subthemes. In 2022, using the same key words, we conducted a subsequent YouTube search using the same criteria, except that the videos had to be 10 min or less, whereby nine videos were selected out of 70 for commentary analysis, and a total of 180 comments were used. RESULTS: The dominant themes were « providing educational information on ASD characteristics » with the main subtheme being « no specific age or sex focus ». The most common category of comments was « anecdote ». The overwhelming sentiments of both the videos and comments were « mixed ». Individuals with ASD were stigmatized as not being able to understand emotion. Furthermore, ASD was also stigmatized as being a monolithic condition only manifesting itself in the most severe form when autism varies in severity. INTERPRETATION: YouTube is a powerful tool that allows people and organizations to raise awareness about ASD by providing a more dynamic view on autism and fostering an environment for public empathy and support.

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5. Bhat A, Tulsky DS, Boulton AJ. Cross-replicating findings on unique motor impairments of children with ASD using confirmatory factor analysis and a novel SPARK study sample. Autism Res;2023 (Feb 25)

A series of recent reports have shed light on the pervasive nature of motor impairments in children with ASD (Bhat, 2020, 2021, Bhat et al., 2022), underscoring the importance of providing ASD clinicians efficient and accurate tools for motor screening. The Developmental Coordination Disorder-Questionnaire (DCD-Q) is a widely used motor screening tool, yet scant evidence exists regarding its psychometric properties in children with ASD. In a recent Exploratory Factor Analysis (EFA) of the 15-item DCD-Q in a large sample of children with ASD (SPARK study), we found a 5-factor latent structure that identified unique motor impairments in a large sample of children with ASD (Bhat et al., 2022). In the current study, we extend this work by cross-replicating the EFA findings of unique ASD-related motor issues using Confirmatory Factor Analysis (CFA) in a new, more recent wave of children with ASD from the SPARK study (N = 9721). The fits and interpretability of 11 hypothesis-driven CFA models, including 8 correlated-factors, 1 second-order, and 2 bifactor models were compared. Our findings supported the previous 5-factor model with 2 gross motor subdomains, 1 fine motor domain (similar to the original DCD-Q) and 2 general coordination subdomains. This model demonstrated acceptable fit in the new sample as well as superior fit compared to several other parsimonious correlated-factors models. However, the second-order and bifactor models fit slightly better and supported the presence of a general motor skills factor, although 38% of the common variance in the DCD-Q items remained attributable to the 5 subdomains. Using one of the bifactor models, measurement invariance was also supported for DCD-Q across sex, race, and co-occurring conditions of language disorder and intellectual disability. Only partial invariance was supported when testing DCD-Q scores across different age groups. These findings reveal a more complex dimensional picture of the DCD-Q in children with ASD. Results suggest that the DCD-Q can be used in two ways, total scores adequately assess general motor skills for brief screening and subdomain scores offer unique information on the multidimensional motor problems of children with ASD. If subdomain data are of interest, our findings call into question the practice of relying on 3 original subscales of the DCD-Q when screening for ASD-related motor difficulties, whereas 4 out of 5 subscale scores may better highlight domain-specific motor problems. Future studies should continue to further validate DCD-Q’s ability to screen for multidimensional motor problems.

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6. Bhat RS, Alonazi M, Al-Daihan S, El-Ansary A. Prenatal SSRI Exposure Increases the Risk of Autism in Rodents via Aggravated Oxidative Stress and Neurochemical Changes in the Brain. Metabolites;2023 (Feb 20);13(2)

The mechanisms underlying selective serotonin reuptake inhibitor (SSRI) use during pregnancy as a major autism risk factor are unclear. Here, brain neurochemical changes following fluoxetine exposure and in an autism model were compared to determine the effects on autism risk. The study was performed on neonatal male western albino rats which were divided into Groups one (control), two (propionic acid [PPA]-induced autism model), and three (prenatal SSRI-exposed newborn rats whose mothers were exposed to 5 mg/kg of fluoxetine over gestation days 10-20). SSRI (fluoxetine) induced significant neurochemical abnormalities in the rat brain by increasing lipid peroxide (MDA), Interferon-gamma (IFN-γ), and caspase-3 levels and by depleting Glutathione (GSH), Glutathione S-transferases (GST), Catalase, potassium (K+), and Creatine kinase (CK) levels, similarly to what has been discovered in the PPA model of autism when compared with control. Prenatal fluoxetine exposure plays a significant role in asset brain damage in newborns; further investigation of fluoxetine as an autism risk factor is thus warranted.

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7. Bresciani G, Da Lozzo P, Lega S, Bramuzzo M, Di Leo G, Dissegna A, Colonna V, Barbi E, Carrozzi M, Devescovi R. Gastrointestinal Disorders and Food Selectivity: Relationship with Sleep and Challenging Behavior in Children with Autism Spectrum Disorder. Children (Basel);2023 (Jan 30);10(2)

The aim of this study was to evaluate the interaction between gastrointestinal (GI) disorders, sleep problems, and challenging behaviors in children with a diagnosis of Autism Spectrum Disorder (ASD) and their effect on parental stress. The secondary objective was to assess the frequency and type of GI and feeding disorders in a sample of children with ASD through a multidisciplinary assessment and, finally, to investigate families’ perceptions and satisfaction with the proposed multidisciplinary approach. All children underwent a comprehensive gastroenterological and neuropsychiatric evaluation supported by standardized questionnaires. Pediatric gastroenterologists, specifically trained in Applied Behavior Analysis (ABA), provided advice for parent-delivered behavioral intervention for food selectivity. Thirty-six children with an autism diagnosis (29 males, age 4.5 +/-2.2 years, mean +/- SD) were enrolled. A positive correlation between sleep problems and aggressive behavior was found, and this association was stronger in children experiencing more problematic mealtime behaviors (b = 0.788, p = 0.014). Sleep difficulties were associated with stereotyped behaviors and parent-perceived stress. Parents interviewed about the gastroenterology visit perceived this multidisciplinary approach as helpful in addressing food selectivity. This study shows that sleep and mealtime issues can have a synergistic negative impact on ASD symptoms. A multidisciplinary approach and an integrated assessment of GI, feeding problems, and sleep disorders could be helpful in diagnosing comorbidities and to provide targeted advice to parents.

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8. Carbone E, Buzzelli V, Manduca A, Leone S, Rava A, Trezza V. Maternal Immune Activation Induced by Prenatal Lipopolysaccharide Exposure Leads to Long-Lasting Autistic-like Social, Cognitive and Immune Alterations in Male Wistar Rats. Int J Mol Sci;2023 (Feb 15);24(4)

Several studies have supported the association between maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation and an increased susceptibility to the development of various psychiatric and neurological disorders, including autism and other neurodevelopmental disorders (NDDs), in the offspring. In the present work, we aimed to provide extensive characterization of the short- and long-term consequences of MIA in the offspring, both at the behavioral and immunological level. To this end, we exposed Wistar rat dams to Lipopolysaccharide and tested the infant, adolescent and adult offspring across several behavioral domains relevant to human psychopathological traits. Furthermore, we also measured plasmatic inflammatory markers both at adolescence and adulthood. Our results support the hypothesis of a deleterious impact of MIA on the neurobehavioral development of the offspring: we found deficits in the communicative, social and cognitive domains, together with stereotypic-like behaviors and an altered inflammatory profile at the systemic level. Although the precise mechanisms underlying the role of neuroinflammatory states in neurodevelopment need to be clarified, this study contributes to a better understanding of the impact of MIA on the risk of developing behavioral deficits and psychiatric illness in the offspring.

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9. Chadman KK, Adayev T, Udayan A, Ahmed R, Dai CL, Goodman JH, Meeker H, Dolzhanskaya N, Velinov M. Efficient Delivery of FMR1 across the Blood Brain Barrier Using AAVphp Construct in Adult FMR1 KO Mice Suggests the Feasibility of Gene Therapy for Fragile X Syndrome. Genes (Basel);2023 (Feb 16);14(2)

Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. Gene therapy may offer an efficient method to ameliorate the symptoms of this disorder. Methods An AAVphp.eb-hSyn-mFMR1IOS7 vector and an empty control were injected into the tail vein of adult Fmr1 knockout (KO) mice and wildtype (WT) controls. The KO mice were injected with 2 × 10(13) vg/kg of the construct. The control KO and WT mice were injected with an empty vector. Four weeks following treatment, the animals underwent a battery of tests: open field, marble burying, rotarod, and fear conditioning. The mouse brains were studied for levels of the Fmr1 product FMRP. Results: No significant levels of FMRP were found outside the CNS in the treated animals. The gene delivery was highly efficient, and it exceeded the control FMRP levels in all tested brain regions. There was also improved performance in the rotarod test and partial improvements in the other tests in the treated KO animals. Conclusion: These experiments demonstrate efficient, brain-specific delivery of Fmr1 via peripheral administration in adult mice. The gene delivery led to partial alleviation of the Fmr1 KO phenotypical behaviors. FMRP oversupply may explain why not all behaviors were significantly affected. Since AAV.php vectors are less efficient in humans than in the mice used in the current experiment, studies to determine the optimal dose using human-suitable vectors will be necessary to further demonstrate feasibility.

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10. Cheng W, Sun Z, Cai K, Wu J, Dong X, Liu Z, Shi Y, Yang S, Zhang W, Chen A. Relationship between Overweight/Obesity and Social Communication in Autism Spectrum Disorder Children: Mediating Effect of Gray Matter Volume. Brain Sci;2023 (Jan 21);13(2)

With advances in medical diagnostic technology, the healthy development of children with autism spectrum disorder (ASD) is receiving more and more attention. In this article, the mediating effect of brain gray matter volume (GMV) between overweight/obesity and social communication (SC) was investigated through the analysis of the relationship between overweight/obesity and SC in autism spectrum disorder children. In total, 101 children with ASD aged 3-12 years were recruited from three special educational centers (Yangzhou, China). Overweight/obesity in children with ASD was indicated by their body mass index (BMI); the Social Responsiveness Scale, Second Edition (SRS-2) was used to assess their social interaction ability, and structural Magnetic Resonance Imaging (sMRI) was used to measure GMV. A mediation model was constructed using the Process plug-in to analyze the mediating effect of GMV between overweight/obesity and SC in children with ASD. The results revealed that: overweight/obesity positively correlated with SRS-2 total points (p = 0.01); gray matter volume in the left dorsolateral superior frontal gyrus (Frontal_Sup_L GMV) negatively correlated with SRS-2 total points (p = 0.001); and overweight/obesity negatively correlated with Frontal_Sup_L GMV (p = 0.001). The Frontal_Sup_L GMV played a partial mediating role in the relationship between overweight/obesity and SC, accounting for 36.6% of total effect values. These findings indicate the significant positive correlation between overweight/obesity and SC; GMV in the left dorsolateral superior frontal gyrus plays a mediating role in the relationship between overweight/obesity and SC. The study may provide new evidence toward comprehensively revealing the overweight/obesity and SC relationship.

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11. Di Giovanni D, Enea R, Di Micco V, Benvenuto A, Curatolo P, Emberti Gialloreti L. Using Machine Learning to Explore Shared Genetic Pathways and Possible Endophenotypes in Autism Spectrum Disorder. Genes (Basel);2023 (Jan 25);14(2)

Autism spectrum disorder (ASD) is a heterogeneous condition, characterized by complex genetic architectures and intertwined genetic/environmental interactions. Novel analysis approaches to disentangle its pathophysiology by computing large amounts of data are needed. We present an advanced machine learning technique, based on a clustering analysis on genotypical/phenotypical embedding spaces, to identify biological processes that might act as pathophysiological substrates for ASD. This technique was applied to the VariCarta database, which contained 187,794 variant events retrieved from 15,189 individuals with ASD. Nine clusters of ASD-related genes were identified. The 3 largest clusters included 68.6% of all individuals, consisting of 1455 (38.0%), 841 (21.9%), and 336 (8.7%) persons, respectively. Enrichment analysis was applied to isolate clinically relevant ASD-associated biological processes. Two of the identified clusters were characterized by individuals with an increased presence of variants linked to biological processes and cellular components, such as axon growth and guidance, synaptic membrane components, or transmission. The study also suggested other clusters with possible genotype-phenotype associations. Innovative methodologies, including machine learning, can improve our understanding of the underlying biological processes and gene variant networks that undergo the etiology and pathogenic mechanisms of ASD. Future work to ascertain the reproducibility of the presented methodology is warranted.

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12. Esvap E, Ulgen KO. Neuroinflammation, Energy and Sphingolipid Metabolism Biomarkers Are Revealed by Metabolic Modeling of Autistic Brains. Biomedicines;2023 (Feb 16);11(2)

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders generally characterized by repetitive behaviors and difficulties in communication and social behavior. Despite its heterogeneous nature, several metabolic dysregulations are prevalent in individuals with ASD. This work aims to understand ASD brain metabolism by constructing an ASD-specific prefrontal cortex genome-scale metabolic model (GEM) using transcriptomics data to decipher novel neuroinflammatory biomarkers. The healthy and ASD-specific models are compared via uniform sampling to identify ASD-exclusive metabolic features. Noticeably, the results of our simulations and those found in the literature are comparable, supporting the accuracy of our reconstructed ASD model. We identified that several oxidative stress, mitochondrial dysfunction, and inflammatory markers are elevated in ASD. While oxidative phosphorylation fluxes were similar for healthy and ASD-specific models, and the fluxes through the pathway were nearly undisturbed, the tricarboxylic acid (TCA) fluxes indicated disruptions in the pathway. Similarly, the secretions of mitochondrial dysfunction markers such as pyruvate are found to be higher, as well as the activities of oxidative stress marker enzymes like alanine and aspartate aminotransferases (ALT and AST) and glutathione-disulfide reductase (GSR). We also detected abnormalities in the sphingolipid metabolism, which has been implicated in many inflammatory and immune processes, but its relationship with ASD has not been thoroughly explored in the existing literature. We suggest that important sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), ceramide, and glucosylceramide, may be promising biomarkers for the diagnosis of ASD and provide an opportunity for the adoption of early intervention for young children.

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13. Fu P, Luo S, Liu Z, Furuhara K, Tsuji T, Higashida H, Yokoyama S, Zhong J, Tsuji C. Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder. Brain Sci;2023 (Feb 13);13(2)

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

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14. Gao X, Lu X, Drani S. Growing in Adversity: A Narrative Study of Resilience Generation in Chinese Families of Children with ASD. Behav Sci (Basel);2023 (Feb 7);13(2)

Referring to Walsh’s theoretical framework of family resilience while taking into account China’s own cultural and institutional context, this study discussed the process of resilience generation in Chinese families of children with ASD. A qualitative approach was taken, using narrative research on 10 Chinese families of children with ASD. Category-content analysis of the data suggests that the generation of resilience in Chinese families of children with ASD is influenced by four factors: (A) cultivating positive family beliefs; (B) adjustment of the family’s organizational pattern; (C) extending external resources positively; and (D) optimizing family communication. Unlike family resilience generation mechanisms in Western countries that emphasize religious beliefs, intrinsic traits, and resources, the resilience of Chinese families of children with ASD is based on a family value system based on a sense of responsibility and the application of internal and external family resources, which is undoubtedly related to China’s long-standing emphasis on collectivist culture. This study has theoretical reference value for the implementation of related social work services.

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15. Indika NR, Frye RE, Rossignol DA, Owens SC, Senarathne UD, Grabrucker AM, Perera R, Engelen M, Deutz NEP. The Rationale for Vitamin, Mineral, and Cofactor Treatment in the Precision Medical Care of Autism Spectrum Disorder. J Pers Med;2023 (Jan 29);13(2)

Children with autism spectrum disorder may exhibit nutritional deficiencies due to reduced intake, genetic variants, autoantibodies interfering with vitamin transport, and the accumulation of toxic compounds that consume vitamins. Importantly, vitamins and metal ions are essential for several metabolic pathways and for neurotransmitter functioning. The therapeutic benefits of supplementing vitamins, minerals (Zinc, Magnesium, Molybdenum, and Selenium), and other cofactors (coenzyme Q10, alpha-lipoic acid, and tetrahydrobiopterin) are mediated through their cofactor as well as non-cofactor functions. Interestingly, some vitamins can be safely administered at levels far above the dose typically used to correct the deficiency and exert effects beyond their functional role as enzyme cofactors. Moreover, the interrelationships between these nutrients can be leveraged to obtain synergistic effects using combinations. The present review discusses the current evidence for using vitamins, minerals, and cofactors in autism spectrum disorder, the rationale behind their use, and the prospects for future use.

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16. Jang HJ, Kwon KJ, Shin CY, Lee GS, Moon JH, Lee TG, Yoon S. Investigation of Phospholipid Differences in Valproic Acid-Induced Autistic Mouse Model Brain Using Mass Spectrometry Imaging. Metabolites;2023 (Jan 25);13(2)

Autism is a neurodevelopmental disorder for which the cause and treatment have yet not been determined. The polyunsaturated fatty acid (PUFA) levels change rapidly in the blood or cerebrospinal fluid of autistic children and PUFAs are closely related to autism spectrum disorder (ASD). This finding suggests that changes in lipid metabolism are associated with ASD and result in an altered distribution of phospholipids in cell membranes. To further understand ASD, it is necessary to analyze phospholipids in organs consisting of nerve cells, such as the brain. In this study, we investigated the phospholipid distribution in the brain tissue of valproic acid-induced autistic mice using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Phospholipids including phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine were identified in each brain region and exhibited differences between the ASD and control groups. These phospholipids contain docosahexaenoic acid and arachidonic acid, which are important PUFAs for cell signaling and brain growth. We expect that the differences in phospholipids identified in the brain tissue of the ASD model with MALDI-MSI, in conjunction with conventional biological fluid analysis, will help to better understand changes in lipid metabolism in ASD.

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17. Khachadourian V, Mahjani B, Sandin S, Kolevzon A, Buxbaum JD, Reichenberg A, Janecka M. Comorbidities in autism spectrum disorder and their etiologies. Transl Psychiatry;2023 (Feb 25);13(1):71.

Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.

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18. Kisaretova P, Tsybko A, Bondar N, Reshetnikov V. Molecular Abnormalities in BTBR Mice and Their Relevance to Schizophrenia and Autism Spectrum Disorders: An Overview of Transcriptomic and Proteomic Studies. Biomedicines;2023 (Jan 20);11(2)

Animal models of psychopathologies are of exceptional interest for neurobiologists because these models allow us to clarify molecular mechanisms underlying the pathologies. One such model is the inbred BTBR strain of mice, which is characterized by behavioral, neuroanatomical, and physiological hallmarks of schizophrenia (SCZ) and autism spectrum disorders (ASDs). Despite the active use of BTBR mice as a model object, the understanding of the molecular features of this strain that cause the observed behavioral phenotype remains insufficient. Here, we analyzed recently published data from independent transcriptomic and proteomic studies on hippocampal and corticostriatal samples from BTBR mice to search for the most consistent aberrations in gene or protein expression. Next, we compared reproducible molecular signatures of BTBR mice with data on postmortem samples from ASD and SCZ patients. Taken together, these data helped us to elucidate brain-region-specific molecular abnormalities in BTBR mice as well as their relevance to the anomalies seen in ASDs or SCZ in humans.

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19. Koesterich J, An JY, Inoue F, Sohota A, Ahituv N, Sanders SJ, Kreimer A. Characterization of De Novo Promoter Variants in Autism Spectrum Disorder with Massively Parallel Reporter Assays. Int J Mol Sci;2023 (Feb 9);24(4)

Autism spectrum disorder (ASD) is a common, complex, and highly heritable condition with contributions from both common and rare genetic variations. While disruptive, rare variants in protein-coding regions clearly contribute to symptoms, the role of rare non-coding remains unclear. Variants in these regions, including promoters, can alter downstream RNA and protein quantity; however, the functional impacts of specific variants observed in ASD cohorts remain largely uncharacterized. Here, we analyzed 3600 de novo mutations in promoter regions previously identified by whole-genome sequencing of autistic probands and neurotypical siblings to test the hypothesis that mutations in cases have a greater functional impact than those in controls. We leveraged massively parallel reporter assays (MPRAs) to detect transcriptional consequences of these variants in neural progenitor cells and identified 165 functionally high confidence de novo variants (HcDNVs). While these HcDNVs are enriched for markers of active transcription, disruption to transcription factor binding sites, and open chromatin, we did not identify differences in functional impact based on ASD diagnostic status.

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20. Kumazaki H, Muramatsu T, Yoshikawa Y, Matsumoto Y, Ishiguro H, Mimura M. Android robot was beneficial for communication rehabilitation in a patient with schizophrenia comorbid with autism spectrum disorders. Schizophr Res;2023 (Feb 24);254:116-117.

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21. Li YF, Byrne S, Yan W, Ewoldt KB. Self-Monitoring Intervention for Adolescents and Adults with Autism: A Research Review. Behav Sci (Basel);2023 (Feb 7);13(2)

The ability to work and function independently is one of the most important skills for the achievement of ideal post-school outcomes. The use of self-monitoring to improve independence and/or reduce undesirable behaviors is an imperative need for individuals with autism. The purpose of this literature review was to examine technology-based self-monitoring interventions for individuals with autism. We used a four-step literature search process to identify studies for review. Online databases, such as ERIC, were used to search for studies. Using four inclusion criteria and PRISMA guidelines for the selection and screening process, we identified 16 studies that met the inclusion criteria. We used coding to summarize the following information from the included studies: participants who met the inclusion criteria, primary dependent variable, primary intervention, and study design. The results of the review revealed three primary functions of technology performed in self-monitoring. The included studies targeted on-task behaviors, skill acquisition, and socially relevant behaviors as primary dependent variables. The findings of the review suggested that future research could use self-monitoring interventions to support an adult with autism in employment settings and that a self-monitoring intervention could be tailored by considering individual differences.

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22. Liu TL, Chen YL, Hsiao RC, Ni HC, Liang SH, Lin CF, Chan HL, Hsieh YH, Wang LJ, Lee MJ, Chou WJ, Yen CF. Adolescent-Caregiver Agreement Regarding the School Bullying and Cyberbullying Involvement Experiences of Adolescents with Autism Spectrum Disorder. Int J Environ Res Public Health;2023 (Feb 20);20(4)

School bullying and cyberbullying victimization and perpetration are prevalent in adolescents with autism spectrum disorder (AASD). However, the levels of adolescent-caregiver agreement regarding the bullying involvement of AASD and the factors associated with these levels remain to be evaluated. In the present study, we evaluated the levels of adolescent-caregiver agreement on the school bullying and cyberbullying involvement experiences of AASD and the factors associated with the levels of agreement. This study included 219 dyads of AASD and their caregivers. The school bullying and cyberbullying involvement experiences of the participating AASD were assessed using the School Bullying Experience Questionnaire and the Cyberbullying Experiences Questionnaire, respectively. Attention-deficit/hyperactivity disorder, oppositional defiant disorder (ODD), depressive and anxiety symptoms, and autistic social impairment were also assessed. AASD and their caregivers had poor to fair levels of agreement regarding the school bullying and cyberbullying victimization and perpetration experiences of AASD. Severe inattention, hyperactivity-impulsivity, ODD, depressive and anxiety symptoms, and autistic social impairment were associated with high levels of adolescent-caregiver agreement. When assessing the bullying involvement experiences of AASD, mental health professionals should obtain information from multiple sources. In addition, the factors influencing the levels of agreement should be considered.

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23. Marino F, Failla C, Bruschetta R, Vetrano N, Scarcella I, Doria G, Chilà P, Minutoli R, Vagni D, Tartarisco G, Cerasa A, Pioggia G. TeleRehabilitation of Social-Pragmatic Skills in Children with Autism Spectrum Disorder: A Principal Component Analysis. Int J Environ Res Public Health;2023 (Feb 16);20(4)

In many therapeutic settings, remote health services are becoming increasingly a viable strategy for behavior management interventions in children with autism spectrum disorder (ASD). However, there is a paucity of tools for recovering social-pragmatic skills. In this study, we sought to demonstrate the effectiveness of a new online behavioral training, comparing the performance of an ASD group carrying out an online treatment (n°8) with respect to a control group of demographically-/clinically matched ASD children (n°8) engaged in a traditional in-presence intervention (face-to-face). After a 4-month behavioral treatment, the pragmatic skills language (APL test) abilities detected in the experimental group were almost similar to the control group. However, principal component analysis (PCA) demonstrated that the overall improvement in socio-pragmatic skills was higher for ASD children who underwent in-presence training. In fact, dimensions defined by merging APL subscale scores are clearly separated in ASD children who underwent in-presence training with respect to those performing the online approach. Our findings support the effectiveness of remote healthcare systems in managing the social skills of children with ASD, but more approaches and resources are required to enhance remote services.

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24. McConkey R, O’Hagan P, Corcoran J. The Impact of a Family-Centred Intervention for Parents of Children with Developmental Disabilities: A Model Project in Rural Ireland. Children (Basel);2023 (Jan 17);10(2)

The greater risk of poor mental health and social isolation, experienced by parents of children with developmental disabilities, is compounded by family circumstances and living in rural settings. Often parents receive little personal support. Family-centred interventions have been recommended internationally for promoting children’s development, as well as boosting parental wellbeing. Yet, in many countries, current service provision is predominately child-focused and clinic-centred. An innovative, family-centred support service was designed and evaluated in a rural county of Ireland. Support staff visit the family home every month for around one year with regular check-ins by phone. The service aims included setting developmental goals for the child that were agreed with parents, alongside actions to address the personal needs of parents and siblings. In addition, community activities are identified or created to promote the social inclusion of the child and family in local communities, as well as locating opportunities for social activities for mothers. To date, 96 families with 110 children have been involved and three monthly reviews have been undertaken of each child’s progress. Baseline measures on parents’ mental health and social isolation were gathered and repeated when parents had completed their involvement with the project, along with qualitative information regarding the parents’ experiences. Most children attained their learning targets, alongside those selected as personal goals by parents; in particular, parents reported their child’s greater involvement in community activities, increased knowledge and skills, and with more confidence and resilience. Significant increases in parental well-being scores were reported, but there was a limited impact on their social participation and that of their child. This evidence-based model of provision is an example of how current social care provision for families who have a child with developmental disabilities could be cost-effectively re-envisioned even in rural areas.

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25. McCrossin R. Finding the Proportion of Females with Autistic Spectrum Disorder Who Develop Anorexia Nervosa, the True Prevalence of Female ASD and Its Clinical Significance. Children (Basel);2023 (Jan 31);10(2)

It appears that up to 80% of females with autistic spectrum disorder (ASD) have not been diagnosed by the age of 18. This translates to a prevalence of about 5-6%, and if true, has serious implications for female mental health. One way of finding the true value is to use Bayes’ Theorem with a comorbid condition as a more easily recognizable flag. An obvious choice is anorexia nervosa (AN), but it transpires that the proportion of women with ASD who develop AN is unknown. This study uses published data in novel ways to provide two methods of estimating a range for this variable, and gives a median value of 8.3% for AN in ASD and, with four other methods, a median prevalence of 6% for female ASD. The clinical implications of the diagnosis and management of ASD and its comorbidities are discussed and, as an example, a solution is provided for the rate of ASD in symptomatic generalized joint hypermobility. It is probable that one in six women with a mental health condition is autistic.

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26. Modrzejewska M, Bosy-Gąsior W. The Use of Optical Coherence Tomography and Electrophysiological Tests in the Early Diagnosis of Inflammatory Changes in the CNS in children with ASD-A Review of Contemporary Literature. Int J Environ Res Public Health;2023 (Feb 17);20(4)

This article is a review of the contemporary literature on the possibility of using modern ophthalmological diagnostics, such as optical coherence tomography and electrophysiological tests, in the assessment of changes in eyesight correlating with inflammatory changes in the central nervous system (CNS) as one of the risk factors for neurodevelopmental disorders in children with ASD. A significant role is attributed to the activation of nerve and glial cells, as well as inflammatory changes in the brain, both of which can be of great importance in regard to an autism development predisposition. This fact indicates the possibility of using certain ophthalmic markers to depict an early correlation between the CNS and its outermost layer, i.e., the retina. A comprehensive ophthalmological assessment, and above all, characteristic changes in the functional function of photoreceptors and disorders of the structures of the retina or optic nerve fibers found in the latest OCT or ERG tests may in the future become diagnostic tools, further confirming the early characteristics of autism in children and adolescents. The above information, therefore, emphasizes the importance of cooperation between specialists in improving the diagnosis and treatment of children with autism.

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27. Montanaro FAM, Alfieri P, Vicari S. « Corp-Osa-Mente », a Combined Psychosocial-Neuropsychological Intervention for Adolescents and Young Adults with Fragile X Syndrome: An Explorative Study. Brain Sci;2023 (Feb 7);13(2)

Fragile X Syndrome is the most known inherited form of intellectual disability due to an expansion in the full mutation range (>200 CGG repeats) of the promoter region of the FMR1 gene located on X chromosomes leading to gene silencing. Despite clear knowledge of the cognitive-behavioral phenotype of FXS and the necessity of tailored interventions, empirical research on the effectiveness of behavioral treatments among patients with FXS is still lacking, with studies on adolescents and young adults even more insufficient. Here we present « Corposamente », a combined psychosocial-neuropsychological intervention conducted with a group of ten adolescents/young adults with FXS, who are non-ASD and without significant behavioral problems. In total, 20 sessions were performed, alternating between online and face-to-face meetings. At the end of the intervention, participants, family members and participants’ educators anonymously completed a survey that was designed around key areas of improvement as well as treatment satisfaction. The survey results indicated that participants improved mostly in their ability to cope with negative emotions and that occupational intervention was considered the most effective technique both from families and participants. Our exploratory study suggests that group therapy for the management of the FXS cognitive-behavioral phenotype may be a promising approach to continue to pursue, mostly in adolescence when the environmental demands increase.

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28. Narzisi A. Advances in Autism Research: Series II. Brain Sci;2023 (Feb 15);13(2)

« Advances in Autism Research: Series II » is a continuation of the important Special Issue (SI) published in 2020 that collected 50 articles […].

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29. Narzisi A, Alcantud-Marin F, Alonso-Esteban Y, Battini R, Cantiani C, Conti E, Fusar-Poli L, Lecciso F, Levante A, Mazzone L, Milone A, Riva V, Siracusano M, Aguglia E. Autism and Neurodevelopmental Disorders: The SARS-CoV-2 Pandemic Implications. Brain Sci;2023 (Feb 6);13(2)

The Special Issue (SI) « Autism and Neurodevelopmental Disorders: The SARS-CoV-2 Pandemic Implications » is an interesting project that adopted a scientific point of view with important implications in clinical and practical fields […].

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30. Ornoy A, Gorobets D, Weinstein-Fudim L, Becker M. Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data. Int J Mol Sci;2023 (Feb 7);24(4)

The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3-4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood.

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31. O’Shea A, Holmes CHB, Engelhardt PE. A Parental-Report Questionnaire for Language Abilities and Pragmatics in Children and Adolescents with Autism Spectrum Disorders. Brain Sci;2023 (Jan 24);13(2)

The aim of this study was to test and validate a parental-report questionnaire, which assesses language abilities and pragmatics, in children with Autism Spectrum Disorders (ASD). We report two experiments: The first served as the initial test and the second sought to provide the first assessment of convergent validity. In total, we recruited 230 parents, where approximately two-thirds had a child with ASD. Results of factor analyses showed a consistent factor structure within each subscale, and the internal consistency was excellent for both sub-scales (Cronbach’s alpha >0.90). Convergent validity was assessed by correlating the results of the questionnaire with two sub-scales of the Autism Quotient questionnaire. The correlations were all greater than 0.60. The final version of the questionnaire (following exclusion of problematic items) contains 30 items (12 for language abilities and 18 for pragmatics). We conclude that the questionnaire is a concise and practical instrument for use in a variety of contexts for assessing language functioning and communication in children with ASD.

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32. Pai Khot AJ, Choudhury AR, Ankola AV, Sankeshwari RM, Hampiholi V, Hebbal M, Jalihal S, Kumar RS, Kabra L, Kotha SL. Evaluation of a « Picture Assisted Illustration Reinforcement » (PAIR) System for Oral Hygiene in Children with Autism: A Double-Blind Randomized Controlled Trial. Children (Basel);2023 (Feb 13);10(2)

This study evaluated the potential of a novel pre-validated « Picture Assisted Illustration Reinforcement » (PAIR) communication system and conventional verbal techniques for Oral Health Education (OHE) in terms of dentition status, gingival health, oral hygiene status, and practices in 7- to 18-year-old children with Autism Spectrum Disorder (ASD). A double-blind randomized controlled trial was undertaken in a school for children with autism from July to September 2022. A total of 60 children were randomly assigned into two groups: a PAIR group (n = 30) and a Conventional group (n = 30). Cognition and pre-evaluation of all the children were assessed by standardized scaling measures. A pre-validated closed-ended questionnaire was administered to caregivers of both groups. At a 12-week post-intervention, a clinical examination was performed using the World Health Organization (WHO) Oral Health Assessment form 2013, gingival and Oral Hygiene Index Simplified (OHI-S). The gingival scores in the PAIR group (0.35 ± 0.12) exhibited a statistically significant decline in scores as compared to Conventional group (0.83 ± 0.37), p = 0.043. Meanwhile, the oral hygiene scores in the PAIR group and Conventional group were 1.22 ± 0.14 and 1.94 ± 0.15, respectively (p < 0.05). A significant improvement in oral hygiene practices was observed in the PAIR group. Incorporating the PAIR technique resulted in significant progress in child cognitive ability and adaptive behavior, which reduced gingival scores and improved oral hygiene scores, consequently improving oral hygiene practices among children with ASD.

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33. Papuc SM, Erbescu A, Glangher A, Streata I, Riza AL, Budisteanu M, Arghir A. Autistic Behavior as Novel Clinical Finding in OFD1 Syndrome. Genes (Basel);2023 (Jan 27);14(2)

Orofaciodigital syndrome I (OFD1-MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein (OFD1), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients.

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34. Peketi S, Dhok SB. Machine Learning Enabled P300 Classifier for Autism Spectrum Disorder Using Adaptive Signal Decomposition. Brain Sci;2023 (Feb 13);13(2)

Joint attention skills deficiency in Autism spectrum disorder (ASD) hinders individuals from communicating effectively. The P300 Electroencephalogram (EEG) signal-based brain-computer interface (BCI) helps these individuals in neurorehabilitation training to overcome this deficiency. The detection of the P300 signal is more challenging in ASD as it is noisy, has less amplitude, and has a higher latency than in other individuals. This paper presents a novel application of the variational mode decomposition (VMD) technique in a BCI system involving ASD subjects for P300 signal identification. The EEG signal is decomposed into five modes using VMD. Thirty linear and non-linear time and frequency domain features are extracted for each mode. Synthetic minority oversampling technique data augmentation is performed to overcome the class imbalance problem in the chosen dataset. Then, a comparative analysis of three popular machine learning classifiers is performed for this application. VMD’s fifth mode with a support vector machine (fine Gaussian kernel) classifier gave the best performance parameters, namely accuracy, F1-score, and the area under the curve, as 91.12%, 91.18%, and 96.6%, respectively. These results are better when compared to other state-of-the-art methods.

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35. Randazzo M, Prato A, Messina M, Meli C, Casabona A, Rizzo R, Barone R. Neuroactive Amino Acid Profile in Autism Spectrum Disorder: Results from a Clinical Sample. Children (Basel);2023 (Feb 20);10(2)

Biological bases of autism spectrum disorder (ASD) include both genetic and epigenetic causes. Patients with ASD show anomalies in the profile of certain plasma amino acids, including neuroactive amino acids. Monitoring plasma amino acids may be relevant for patient care and interventions. We evaluated the plasma amino acid profile in samples extracted from dry blood spots by electrospray ionization-tandem mass spectrometry. Fourteen amino acids and eleven amino acid ratios were examined in patients with ASD and intellectual disability (ID), and neurotypical control subjects (TD). The amino acid profile in the ASD group showed reduced levels of ornithine (p = 0.008), phenylalanine (p = 0.042) and tyrosine (p = 0.013). The statistically significant amino acid ratios were Leu+Val/Phe+Tyr (p = 0.002), Tyr/Leu (p = 0.007) and Val/Phe (p = 0.028), such differences remaining significant only in the comparison between ASD and TD. Finally, a positive correlation emerged between the score of the restricted and repetitive behavior on ADOS-2 and the citrulline levels in the ASD group (p = 0.0047). To conclude, patients with ASD may show a distinguishable metabolic profile useful for studying their metabolic pathways in order to develop screening tests and targeted therapies.

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36. Samadi SA, Biçak CA, Osman N, Abdalla B, Abdullah A. Job Burnout and Job Satisfaction among Healthcare Service Providers in a Daycare Center for Individuals with Autism Spectrum Disorders in Low-Resource Settings. Brain Sci;2023 (Feb 1);13(2)

Job satisfaction and burnout are components of job morale. In general, and among healthcare provider personnel, these are psychological factors of the job and under the influence of different conditions and the organizational management of the healthcare systems. Both job burnout and job satisfaction among healthcare service providers have received scant attention in the literature, particularly in the healthcare systems of the Kurdistan Region of Iraq (KRI) as one low- or middle-income country (LMIC). The burnout rate and job satisfaction in a daycare center for children with autism spectrum disorders were reviewed and measured using a sample consisting of 34 employees from three different sections. The Maslach Burnout Inventory-Third Edition (MBI-3) and the Job Descriptive Index (JDI) were used. The relationships between the two scales and their consisting factors were examined using Pearson Correlation and Chi-square test to understand the correlation and levels of significant difference between the expected and the observed frequencies. There was a significant negative correlation between job burnout and satisfaction with the job and some significant correlations between the factors of the scales. Lower levels of emotional exhaustion and depersonalization factors of the burnout scale were statistically correlated. It was shown that the personnel were mainly satisfied with their jobs through their choices in the four parts of the job satisfaction scale. Further investigations are needed to understand different contributing factors to job satisfaction and burnout among healthcare providers in KRI. The current study might highlight the importance of understanding the healthcare providers’ perspectives on their careers.

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37. Santarone ME, Zambrano S, Zanotta N, Mani E, Minghetti S, Pozzi M, Villa L, Molteni M, Zucca C. EEG Features in Autism Spectrum Disorder: A Retrospective Analysis in a Cohort of Preschool Children. Brain Sci;2023 (Feb 17);13(2)

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG recordings in children with these clinical pictures are abnormal, however the precise frequency of these abnormalities and their relationship with the pathogenic mechanisms and in particular with epileptic seizures are still unknown. We retrospectively reviewed 292 routine polysomnographic EEG tracings of preschool children (age < 6 years) who had received a first multidisciplinary diagnosis of ASD according to DSM-5 clinical criteria. Children (mean age: 34.6 months) were diagnosed at IRCCS E. Medea (Bosisio Parini, Italy). We evaluated: the background activity during wakefulness and sleep, the presence and the characteristics (focal or diffuse) of the slow-waves abnormalities and the interictal epileptiform discharges. In 78.0% of cases the EEG recordings were found to be abnormal, particularly during sleep. Paroxysmal slowing and epileptiform abnormalities were found in the 28.4% of the subjects, confirming the high percentage of abnormal polysomnographic EEG recordings in children with ASD. These alterations seem to be more correlated with the characteristics of the underlying pathology than with intellectual disability and epilepsy. In particular, we underline the possible significance of the prevalence of EEG abnormalities during sleep. Moreover, we analyzed the possibility that EEG data reduces the ASD clinical heterogeneity and suggests the exams to be carried out to clarify the etiology of the disorder.

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38. Santos JLS, Araújo CA, Rocha CAG, Costa-Ferro ZSM, Souza BSF. Modeling Autism Spectrum Disorders with Induced Pluripotent Stem Cell-Derived Brain Organoids. Biomolecules;2023 (Jan 30);13(2)

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders that affect communication and social interactions and present with restricted interests and repetitive behavior patterns. The susceptibility to ASD is strongly influenced by genetic/heritable factors; however, there is still a large gap in understanding the cellular and molecular mechanisms underlying the neurobiology of ASD. Significant progress has been made in identifying ASD risk genes and the possible convergent pathways regulated by these gene networks during development. The breakthrough of cellular reprogramming technology has allowed the generation of induced pluripotent stem cells (iPSCs) from individuals with syndromic and idiopathic ASD, providing patient-specific cell models for mechanistic studies. In the past decade, protocols for developing brain organoids from these cells have been established, leading to significant advances in the in vitro reproducibility of the early steps of human brain development. Here, we reviewed the most relevant literature regarding the application of brain organoids to the study of ASD, providing the current state of the art, and discussing the impact of such models on the field, limitations, and opportunities for future development.

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39. Saxami G, Mitsou EK, Kerezoudi EN, Mavrouli I, Vlassopoulou M, Koutrotsios G, Mountzouris KC, Zervakis GI, Kyriacou A. In Vitro Fermentation of Edible Mushrooms: Effects on Faecal Microbiota Characteristics of Autistic and Neurotypical Children. Microorganisms;2023 (Feb 6);11(2)

Children with autism spectrum disorder (ASD) often suffer gastrointestinal disturbances consistent with gut microbiota (GM) alterations. Treatment with pro/prebiotics may potentially alleviate gut symptoms, but the evidence for prebiotics is scarce. This study aims to evaluate the effects of edible mushrooms (Pleurotus, Basidiomycota) and prebiotic compounds on GM composition and metabolite production in vitro, using faecal samples from autistic and non-autistic children. Specific microbial populations were enumerated after 24 h of fermentation by quantitative PCR, and the metabolic production was determined by gas chromatography. Higher levels of Prevotella spp. and Bifidobacterium spp. were measured in neurotypical children compared to ASD children. A total of 24 h fermentation of Pleurotus eryngii and P. ostreatus mushroom powder increased the levels of Bifidobacterium, while known prebiotics increased the levels of total bacteria and Bacteroides in both groups. Only P. eryngii mushrooms resulted in significantly elevated levels of total bacteria Bacteroides and Feacalibacterium prausnitzii compared to the negative control (NC) in the ASD group. Both mushrooms induced elevated levels of butyrate after 24 h of fermentation, while short-chain fructooligosaccharides induced increased levels of acetate in the ASD group, compared to NC. Overall, this study highlights the positive effect of edible mushrooms on the GM and metabolic activity of children with ASD.

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40. Teh JL, Teoh AYB. Techniques and Outcomes of Endoscopic Ultrasound Guided-Pancreatic Duct Drainage (EUS- PDD). J Clin Med;2023 (Feb 17);12(4)

Endoscopic ultrasound guided-pancreatic duct drainage (EUS- PDD) is one of the most technically challenging procedures for the interventional endoscopist. The most common indications for EUS- PDD are patients with main pancreatic duct obstruction who have failed conventional endoscopic retrograde pancreatography (ERP) drainage or those with surgically altered anatomy. EUS- PDD can be performed via two approaches: the EUS-rendezvous (EUS- RV) or the EUS-transmural drainage (TMD) techniques. The purpose of this review is to provide an updated review of the techniques and equipment available for EUS- PDD and the outcomes of EUS- PDD reported in the literature. Recent developments and future directions surrounding the procedure will also be discussed.

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41. Thomas SD, Jha NK, Ojha S, Sadek B. mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder. Molecules;2023 (Feb 16);28(4)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available for autistic patients. Numerous genetic disorders are associated with high prevalence of ASD, including tuberous sclerosis complex, phosphatase and tensin homolog, and fragile X syndrome. Preclinical investigations in animal models of these diseases have revealed irregularities in the PI3K/Akt/mTOR signaling pathway as well as ASD-related behavioral defects. Reversal of the downstream molecular irregularities, associated with mTOR hyperactivation, improved the behavioral deficits observed in the preclinical investigations. Plant bioactive molecules have shown beneficial pre-clinical evidence in ASD treatment by modulating the PI3K/Akt/mTOR pathway. In this review, we summarize the involvement of the PI3K/Akt/mTOR pathway as well as the genetic alterations of the pathway components and its critical impact on the development of the autism spectrum disorder. Mutations in negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in ASD-like phenotypes through the disruption of the mTORC1-mediated signaling. We further discuss the various naturally occurring phytoconstituents that have been identified to be bioactive and modulate the pathway to prevent its disruption and contribute to beneficial therapeutic effects in ASD.

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42. Thompson K, Wallisch A, Nowell S, Meredith J, Boyd B. Short report: The role of oral hypersensitivity in feeding behaviors of young autistic children. Autism;2023 (Feb 24):13623613221135091.

Feeding problems are common among autistic children and are linked to negative health consequences. Therefore, understanding feeding problems and factors that influence these behaviors is important for developing supports for children and families. While certain sensory processing patterns are commonly associated with feeding problems, less is known about the link between sensory processing and feeding behaviors in autism, as well as how parent behaviors and feelings during mealtime differ based on child sensory preferences. This research examined two groups of young autistic children who were reported to be picky eaters by their parents: those with and those without oral hypersensitivity. Children with oral hypersensitivity had more difficulty with food acceptance and their parents reported more negative feelings around feeding their child. However, the two groups of children (oral hypersensitive and not) did not differ in their medical/oral motor symptoms, mealtime behavior, or parent use of strategies at mealtimes. This research supports the need for personalized treatment strategies based on the child’s sensory preferences to support both the child and parent in managing mealtimes.

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43. Tseng A, DuBois M, Biagianti B, Brumley C, Jacob S. Auditory Domain Sensitivity and Neuroplasticity-Based Targeted Cognitive Training in Autism Spectrum Disorder. J Clin Med;2023 (Feb 18);12(4)

Sensory processing, along with the integration of external inputs into stable representations of the environment, is integral to social cognitive functioning; challenges in these processes have been reported in Autism Spectrum Disorder (ASD) since the earliest descriptions of autism. Recently, neuroplasticity-based targeted cognitive training (TCT) has shown promise as an approach to improve functional impairments in clinical patients. However, few computerized and adaptive brain-based programs have been trialed in ASD. For individuals with sensory processing sensitivities (SPS), the inclusion of some auditory components in TCT protocols may be aversive. Thus, with the goal of developing a web-based, remotely accessible intervention that incorporates SPS concerns in the auditory domain, we assessed auditory SPS in autistic adolescents and young adults (N = 25) who started a novel, computerized auditory-based TCT program designed to improve working memory and information processing speed and accuracy. We found within-subject gains across the training program and between pre/post-intervention assessments. We also identified auditory, clinical, and cognitive characteristics that are associated with TCT outcomes and program engagement. These initial findings may be used to inform therapeutic decisions about which individuals would more likely engage in and benefit from an auditory-based, computerized TCT program.

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44. Wang W, Fu P. Gut Microbiota Analysis and In Silico Biomarker Detection of Children with Autism Spectrum Disorder across Cohorts. Microorganisms;2023 (Jan 22);11(2)

The study of human gut microbiota has attracted increasing interest in the fields of life science and healthcare. However, the complicated and interconnected associations between gut microbiota and human diseases are still difficult to determine in a predictive fashion. Artificial intelligence such as machine learning (ML) and deep learning can assist in processing and interpreting biological datasets. In this study, we aggregated data from different studies based on the species composition and relative abundance of gut microbiota in children with autism spectrum disorder (ASD) and typically developed (TD) individuals and analyzed the commonalities and differences of ASD-associated microbiota across cohorts. We established a predictive model using an ML algorithm to explore the diagnostic value of the gut microbiome for the children with ASD and identify potential biomarkers for ASD diagnosis. The results indicated that the Shenzhen cohort achieved a higher area under the receiver operating characteristic curve (AUROC) value of 0.984 with 97% accuracy, while the Moscow cohort achieved an AUROC value of 0.81 with 67% accuracy. For the combination of the two cohorts, the average prediction results had an AUROC of 0.86 and 80% accuracy. The results of our cross-cohort analysis suggested that a variety of influencing factors, such as population characteristics, geographical region, and dietary habits, should be taken into consideration in microbial transplantation or dietary therapy. Collectively, our prediction strategy based on gut microbiota can serve as an enhanced strategy for the clinical diagnosis of ASD and assist in providing a more complete method to assess the risk of the disorder.

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45. Wang Y, Xu L, Fang H, Wang F, Gao T, Zhu Q, Jiao G, Ke X. Social Brain Network of Children with Autism Spectrum Disorder: Characterization of Functional Connectivity and Potential Association with Stereotyped Behavior. Brain Sci;2023 (Feb 7);13(2)

Objective: To identify patterns of social dysfunction in adolescents with autism spectrum disorder (ASD), study the potential linkage between social brain networks and stereotyped behavior, and further explore potential targets of non-invasive nerve stimulation to improve social disorders. Methods: Voxel-wise and ROI-wise analysis methods were adopted to explore abnormalities in the functional activity of social-related regions of the brain. Then, we analyzed the relationships between clinical variables and the statistical indicators of social-related brain regions. Results: Compared with the typically developing group, the functional connectivity strength of social-related brain regions with the precentral gyrus, postcentral gyrus, supplementary motor area, paracentral lobule, median cingulum, and paracingulum gyri was significantly weakened in the ASD group (all p < 0. 01). The functional connectivity was negatively correlated with communication, social interaction, communication + social interaction, and the total score of the ADOS scale (r = -0.38, -0.39, -0.40, and -0.3, respectively; all p < 0.01), with social awareness, social cognition, social communication, social motivation, autistic mannerisms, and the total score of the SRS scale (r = -0.32, -0.32, -0.40, -0.30, -0.28, and -0.27, respectively; all p < 0.01), and with the total score of SCQ (r = -0.27, p < 0.01). In addition, significant intergroup differences in clustering coefficients and betweenness centrality were seen across multiple brain regions in the ASD group. Conclusions: The functional connectivity between social-related brain regions and many other brain regions was significantly weakened compared to the typically developing group, and it was negatively correlated with social disorders. Social network dysfunction seems to be related to stereotyped behavior. Therefore, these social-related brain regions may be taken as potential stimulation targets of non-invasive nerve stimulation to improve social dysfunction in children with ASD in the future.

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46. Yang Y, Jiang L, He R, Song P, Xu P, Wang Y, Li F. Repetitive transcranial magnetic stimulation modulates long-range functional connectivity in autism spectrum disorder. J Psychiatr Res;2023 (Feb 21);160:187-194.

Repetitive transcranial magnetic stimulation (rTMS) is growingly applied in autism spectrum disorder (ASD) due to its potential therapeutic value, however, its effects on functional network configuration and the mechanism underlying clinical improvement are still unclear. In this study, we examined the alternations of functional connectivity induced by rTMS using resting-state electroencephalogram (EEG) in children with ASD. Resting-state EEG was obtained from 24 children with ASD before and after rTMS intervention and from 24 age- and gender-matched typically developing (TD) children. The rTMS intervention course consisted of five 5-s trains at 15 Hz, with 10-min inter-train intervals, on the left parietal lobe each consecutive weekday for 3 weeks (15 sessions in total). Children with ASD showed significantly hypo-connected networks and sub-optimal network properties at both global and local levels, compared with TD peers. After rTMS intervention, long-range intra- and inter-hemispheric connections were significantly promoted, especially those within the alpha band. Meanwhile, network properties at both local and global levels were greatly promoted in the delta, theta, and alpha bands. Consistent with the changes in the network connectivities and properties, the core symptoms in ASD were also relieved measured by clinical scales after treatment. The findings of this study demonstrate that high-frequency rTMS over the parietal lobe is potentially an effective strategy to improve core symptoms by enhancing long-range connectivity reorganization in ASD.

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47. Zhang B, Hu Y, Kong Q, Feng P, Liu J, Ma J. Comparison of Oblique Lumbar Interbody Fusion Combined with Posterior Decompression (OLIF-PD) and Posterior Lumbar Interbody Fusion (PLIF) in the Treatment of Adjacent Segmental Disease(ASD). J Pers Med;2023 (Feb 19);13(2)

BACKGROUND: An unintended consequence following lumbar fusion is the development of adjacent segment disease (ASD). Oblique lumbar interbody fusion combined with posterior decompression (OLIF-PD) is another feasible option for ASD, and there is no literature report on this combined surgical strategy. METHODS: A retrospective analysis was performed on 18 ASD patients requiring direct decompression in our hospital between September 2017 and January 2022. Among them, eight patients underwent OLIF-PD revision and ten underwent PLIF revision. There were no significant differences in the baseline data between the two groups. The clinical outcomes and complications were compared between the two groups. RESULTS: The operation time, operative blood loss and postoperative hospital stay in the OLIF-PD group were significantly lower than those in the PLIF group. The VAS of low back pain in the OLIF-PD group was significantly better than that in the PLIF group during the postoperative follow-up. The ODI at the last follow-up in the OLIF-PD group and the PLIF group were significantly relieved compared with those before operation. The excellent and good rate of the modified MacNab standard at the last follow-up was 87.5% in the OLIF-PD group and 70% in the PLIF group. There was a statistically significant difference in the incidence of complications between the two groups. CONCLUSION: For ASD requiring direct decompression after posterior lumbar fusion, compared with traditional PLIF revision surgery, OLIF-PD has a similar clinical effect, but has a reduced operation time, blood loss, hospital stay and complications. OLIF-PD may be an alternative revision strategy for ASD.

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