1. Abbasalipour H, Hajizadeh Moghaddam A, Ranjbar M. Sumac and gallic acid-loaded nanophytosomes ameliorate hippocampal oxidative stress via regulation of Nrf2/Keap1 pathway in autistic rats. Journal of biochemical and molecular toxicology. 2022: e23035.

Autism spectrum disorders cover a range of neurodevelopmental disorders characterized by impairments in social interaction and cognitive deficits. Phenolic compound applications have been restricted due to their poor solubility, bioavailability, and low stability. This paper aimed to explore the neuroprotective effects of sumac and gallic acid-loaded nanophytosomes (GNP) on oxidative stress-induced cognitive impairment and Nrf2/Keap1 gene expression in the autism model. Valproic acid (VPA) was administered intraperitoneally at doses of 500 mg/kg to female rats during gestational 12.5 days (E12.5). The prenatal VPA-exposed rats were divided into five groups, including VPA, VPA treated with sumac, gallic acid (GA), sumac-loaded nanophytosome (SNP), and GNP at doses of 20 mg/kg for 4 weeks (n = 6). A novel object test was conducted and antioxidant parameters and Nrf2/Keap1gene expression were evaluated in the hippocampus. According to the obtained results, the rat model of autism exhibited recognition memory impairment. We observed an increase in glutathione peroxidase (GPx), glutathione reductase (GRx), superoxide dismutase (SOD), catalase (CAT) enzyme activity, total antioxidant capacity (TAC), and glutathione (GSH) levels. Furthermore, sumac and GNP improved recognition memory deficits and increased GPx, GRx, SOD, and CAT activities, GSH and TAC levels, and Nrf2/Keap1gene expression in the hippocampal area. Our results also suggested that SNP and GNP ameliorate VPA-induced learning and memory deficits more efficiently than sumac extract and pure GA by reducing oxidative stress, enhancing antioxidant enzyme activity, and Keap1/Nrf2 gene expression. The present study demonstrated that the utilization of SNP and GNP significantly improved recognition memory deficits.

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2. Alexander J, Keles G, Killingsworth J, Bronson R, Perez C, Sawmiller D, Shytle RD. Autism, heparan sulfate and potential interventions. Experimental neurology. 2022; 353: 114050.

Developmental disabilities are defined as disorders that result in the limitation of function due to impaired development of the nervous system; these disabilities can be present in the form of impairments in learning, language, behavior, or physical abilities. Examples of developmental disorders include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss, blindness, intellectual disability, and learning disability. Of these disorders, ASD prevalence was 18.5 per 1000 children (1 in 54) aged 8 in 2016. Current literature suggests that deficient levels of heparan sulfate (HS), an acidic and linear glycosaminoglycan (GAG), is likely causative of ASD. The cascading effect of deficient HS levels can offer compelling evidence for the association of HS with ASD. Deficient levels of HS lead to defective Slit/Robo signaling, which affects axonal guidance and dendritic spine formation. Defective Slit/Robo signaling leads to increased Arp2/3 activity and dendritic spine density, which has been observed in the brains of persons with ASD. Therefore, interventions that target HS and its associated pathways may be viable treatment options for ASD.

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3. Attar N, Al-Hroub A, El Zein F. Effects of Three Music Therapy Interventions on the Verbal Expressions of Children With Autism Spectrum Disorder: A Combined Single-Subject Design. Frontiers in psychology. 2022; 13: 819473.

The specific aims of this research study were to (a) examine the differential effect of three different music interventions, namely the interactive music playing therapy (« music and singing »), interaction music singing therapy (« singing »), and receptive music therapy (« listening ») studying the varying latency periods in the response time it took 3-year-old children diagnosed with autism spectrum disorder (ASD) to elicit the target word vocally; and (b) assess the index of happiness of children with ASD after the implementation of the three music interventions, which can, in turn, be used to influence their overall quality of life through this specific intervention. This study used a combined single-subject research design consisting of delayed multiple baseline across the participants and a multielement design to compare the effects of each music intervention technique targeting the child’s verbal response during playback of a practiced song. Findings demonstrated « singing » to be associated with the lowest latency compared to the other two interventions (« listening » and « singing and music ») across participants. Additionally, happiness levels varied from neutral to happy, signifying an overall positive experience during participation in the music applied behavior analysis (ABA) intervention.

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4. Cheah J, Muhammed J, Tharmathurai S, Hamzah N, Rahmat J. Optic Neuropathy in an Autistic Child With Vitamin A Deficiency: A Case Report and Literature Review. Cureus. 2022; 14(2): e22074.

An eight-year-old boy with autism developed gradual onset of vision loss and nyctalopia. Dietary history revealed a diet of only French fries and potato chips for the past four years. As a result, serum vitamin A was severely below the normal level. Ophthalmologic examination revealed a normal anterior segment with bilateral optic atrophy. Vitamin A supplementation was given to restore to normal level; however, the visual impairment was irreversible. Vitamin A deficiency is common in developing countries; however, to the best of our knowledge, there are no other reported cases of permanent visual loss secondary to vitamin A deficiency in Malaysia.

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5. Guerrero-Gonzalez J, Surgent O, Adluru N, Kirk GR, Dean Iii DC, Kecskemeti SR, Alexander AL, Travers BG. Improving Imaging of the Brainstem and Cerebellum in Autistic Children: Transformation-Based High-Resolution Diffusion MRI (TiDi-Fused) in the Human Brainstem. Frontiers in integrative neuroscience. 2022; 16: 804743.

Diffusion-weighted magnetic resonance imaging (dMRI) of the brainstem is technically challenging, especially in young autistic children as nearby tissue-air interfaces and motion (voluntary and physiological) can lead to artifacts. This limits the availability of high-resolution images, which are desirable for improving the ability to study brainstem structures. Furthermore, inherently low signal-to-noise ratios, geometric distortions, and sensitivity to motion not related to molecular diffusion have resulted in limited techniques for high-resolution data acquisition compared to other modalities such as T1-weighted imaging. Here, we implement a method for achieving increased apparent spatial resolution in pediatric dMRI that hinges on accurate geometric distortion correction and on high fidelity within subject image registration between dMRI and magnetization prepared rapid acquisition gradient echo (MPnRAGE) images. We call this post-processing pipeline T1 weighted-diffusion fused, or « TiDi-Fused ». Data used in this work consists of dMRI data (2.4 mm resolution, corrected using FSL’s Topup) and T1-weighted (T1w) MPnRAGE anatomical data (1 mm resolution) acquired from 128 autistic and non-autistic children (ages 6-10 years old). Accurate correction of geometric distortion permitted for a further increase in apparent resolution of the dMRI scan via boundary-based registration to the MPnRAGE T1w. Estimation of fiber orientation distributions and further analyses were carried out in the T1w space. Data processed with the TiDi-Fused method were qualitatively and quantitatively compared to data processed with conventional dMRI processing methods. Results show the advantages of the TiDi-Fused pipeline including sharper brainstem gray-white matter tissue contrast, improved inter-subject spatial alignment for group analyses of dMRI based measures, accurate spatial alignment with histology-based imaging of the brainstem, reduced variability in brainstem-cerebellar white matter tracts, and more robust biologically plausible relationships between age and brainstem-cerebellar white matter tracts. Overall, this work identifies a promising pipeline for achieving high-resolution imaging of brainstem structures in pediatric and clinical populations who may not be able to endure long scan times. This pipeline may serve as a gateway for feasibly elucidating brainstem contributions to autism and other conditions.

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6. Jennings AM, Mery JN, Quiroz LS, Vladescu JC. A Scoping Review of the Healthcare and Hygiene Literature for Individuals with Intellectual and Developmental Disabilities. Advances in neurodevelopmental disorders. 2022: 1-16.

OBJECTIVES: Previous reviews highlight the similarities in teaching healthcare and hygiene routines to individuals with and without intellectual and developmental disabilities. Additionally, similar interventions are used when interfering behaviors occur. Although these routines are topographically distinct, there are enough similarities to suggest effective procedures for one routine may be used to inform another. This scooping review aims to identify effective teaching and intervention procedures for healthcare and hygiene routines specifically for individuals with intellectual and developmental disabilities. We also evaluated the extent to which functional analyses were conducted; a dimension not included in previous reviews. METHODS: Eligible articles targeted compliance or tolerance within the context of a defined healthcare or hygiene routine as a dependent variable and used an experimental design with a demonstration of experimental control. Articles were identified through PsycINFO, PubMed, and Academic Search Premier databases. Additionally, a hand search of five related journals was conducted. Data were collected on dependent variables, functional analyses, baseline contingencies, teaching procedures, and additional experimental components. RESULTS: A total of 52 articles met inclusion criteria. Most experiments produced positive outcomes. The findings show all experiments involved a treatment package with multiple components. The most common teaching procedures were graduated exposure and DRA. A lack of functional analyses and social validity was noted. CONCLUSIONS: Component analyses are needed to identify the most effective and efficient procedures. Pyramidal training to teach medical professionals how to provide preventative pyramidal training should be explored. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s41252-022-00249-7.

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7. Kawano S, Baba M, Fukushima H, Miura D, Hashimoto H, Nakazawa T. Autism-associated ANK2 regulates embryonic neurodevelopment. Biochemical and biophysical research communications. 2022; 605: 45-50.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by altered social communication, restricted interests, and stereotypic behaviors. Although the molecular and cellular pathogeneses of ASD remain elusive, impaired neural stem cell differentiation and neuronal migration during cortical development are suggested to be critically involved in ASD. ANK2, which encodes for a cytoskeletal scaffolding protein involved in recruiting membrane proteins into specialized membrane domains, has been identified as a high-confidence ASD risk gene. However, the role of ANK2 in early neural development remains unclear. In this study, we analyzed the role of ANK2 in the cerebral cortex of developing mouse using in utero electroporation. We provide evidence suggesting that ANK2 regulates neural stem cell differentiation and neuronal migration in the embryonic cerebral cortex, where Ank2 is highly expressed. We also demonstrated that Ank2 knockdown alters the expression of genes involved in neural development. Taken together, these results support the view that ANK2 haploinsufficiency in patients may impair neural development, resulting in an increased risk of ASD. Our study findings provide new insights into the molecular and cellular pathogenesis of ASD, given that among high-confidence ASD genes, ANK2 is rare in that it encodes for a scaffolding protein for the membrane protein complex required for neuronal functions.

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8. Liu J, Gao Z, Liu C, Liu T, Gao J, Cai Y, Fan X. Alteration of Gut Microbiota: New Strategy for Treating Autism Spectrum Disorder. Frontiers in cell and developmental biology. 2022; 10: 792490.

Autism spectrum disorder (ASD) is defined as a complex heterogeneous disorder and characterized by stereotyped behavior and deficits in communication and social interactions. The emerging microbial knowledge has pointed to a potential link between gut microbiota dysbiosis and ASD. Evidence from animal and human studies showed that shifts in composition and activity of the gut microbiota may causally contribute to the etiopathogenesis of core symptoms in the ASD individuals with gastrointestinal tract disturbances and act on microbiota-gut-brain. In this review, we summarized the characterized gut bacterial composition of ASD and the involvement of gut microbiota and their metabolites in the onset and progression of ASD; the possible underlying mechanisms are also highlighted. Given this correlation, we also provide an overview of the microbial-based therapeutic interventions such as probiotics, antibiotics, fecal microbiota transplantation therapy, and dietary interventions and address their potential benefits on behavioral symptoms of ASD. The precise contribution of altering gut microbiome to treating core symptoms in the ASD needs to be further clarified. It seemed to open up promising avenues to develop microbial-based therapies in ASD.

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9. Özgeriş FB, Kurt N, Ibili Ucuz I, Koçak Yilmaz K, Keleş MS, Çayir A, Dursun OB. Is Serum Progranulin Level a Biomarker in Autism and Cognitive Development Disorders?. The Eurasian journal of medicine. 2022; 54(1): 50-3.

OBJECTIVE: Cognitive developmental delay is a picture of the group of early-onset chronic diseases that affect 1.5-10% of children. Autism spectrum disorders are neurodevelopmental diseases with a genetic basis and abnormal brain development, characterized by disorders in areas that make up interpersonal relationships, such as communication, social cognition, and processing of emotional signals. Immune system dysfunction is thought to play a role in the pathogenesis of some neurological disorders, including autism. Progranulin is thought to be a regulator of the innate immune response. The purpose of this study was to look at plasma levels of progranulin, an anti-inflammatory neurotrophic factor, in children with autism spectrum disorder and cognitive developmental delay. MATERIALS AND METHODS: The study was conducted on 52 children who were patients and 35 healthy children. Of the 52 children of the patient group, 32 were diagnosed with CDD and 20 were diagnosed with cognitive developmental delay-autism spectrum disorder. Serum progranulin concentrations were measured using a human-specific sandwich enzyme-linked immunosorbent assay. RESULTS: Serum progranulin concentration was statistically lower in the patient group (110.746 ± 26.04) than in the healthy control group (137.346 ± 30.02). There was a statistically significant difference between the groups in levels of serum progranulin (P=.000). Receiver operating characteristic analysis was performed to evaluate the potential of progranulin as a biomarker to distinguish patients with cognitive developmental delay-autism spectrum disorder from healthy children. It detected a moderate area under the curve (0.743 ± 0.06) value and a more significant P value for progranulin (P=.000). CONCLUSION: Progranulin deficiency in patients with autism spectrum disorder-cognitive developmental delay may result in decreased neurotrophic support for many years, with cumulative damage associated with unregulated inflammation that may play a role in autism spectrum disorder-cognitive developmental delay. We believe that low progranulin levels could be a biomarker for autism spectrum disorder-cognitive developmental delay.

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10. Schwartzman JM, Williams ZJ, Richards JK, Mattheiss SR, Gotham KO. Neuroticism Drives Associations Between Repetitive Behaviors and Depression in Autistic Adults. Frontiers in psychiatry. 2022; 13: 803361.

Depression is more prevalent among autistic adults than neurotypical adults, yet risk factors are incompletely understood in this population. Some research groups have focused on relationships between negative repetitive thinking and depression in the autistic population, which may explain elevated prevalence rates in line with general population findings on rumination and internalizing disorders. Little is known about associations between depression and more prototypical repetitive cognitions and/or behaviors characteristic of autism (i.e., insistence on sameness [IS] and repetitive sensorimotor [RSM] behaviors). Therefore, the present study aimed to examine associations between IS, RSM behaviors, and depressive symptoms in 762 autistic adults, and whether observed effects are confounded by additional factors (e.g., demographic factors, trait neuroticism). To test if greater IS scores were associated with greater depressive symptoms on the BDI-II, a Bayesian linear regression was conducted with BDI-II scores (dependent variable) regressed on age, gender, educational level, RSM scores, and IS scores (independent variables). To test the effects of neuroticism on observed relationships, a second regression was conducted that included all predictors from the baseline model and neuroticism. Standardized regression coefficients were tested against an interval null hypothesis of [-0.1, 0.1] to assess for practical significance. Results indicated that IS exhibited a moderate positive relationship with depressive symptoms, while RSM behaviors provided only a slight increase in predictive ability. However in the second model, neuroticism exhibited a strong positive relationship with depressive symptoms, completely attenuating the effect of IS. Associations between RSM behaviors and depressive symptoms did not meet our criteria for practical significance, particularly when neuroticism was added to the model. Neither RSM nor IS moderated the effect of neuroticism on depression. The findings from this study add to the literature on risk factors in the pathway to depression in autism, and suggest opportunities for clinical translation to screening and intervention efforts. Screening for IS in autistic individuals is a common diagnostic practice in clinical and research settings that may be leveraged to also identify those at higher risk for depression, and increasing flexibility in daily life may promote emotional regulation and distress tolerance.

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11. Tian J, Gao X, Yang L. Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics. Frontiers in neuroscience. 2022; 16: 780407.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.

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12. Wang Z, Yuan X, Zhang Q, Wen J, Cheng T, Qin X, Ji T, Shu X, Jiang Y, Liao J, Hao H, Li L, Wu Y. Effects of Stable Vagus Nerve Stimulation Efficacy on Autistic Behaviors in Ten Pediatric Patients With Drug Resistant Epilepsy: An Observational Study. Frontiers in pediatrics. 2022; 10: 846301.

Vagus nerve stimulation (VNS) is a safe and effective therapy for pediatric patients with drug-resistant epilepsy (DRE). However, in children with DRE, the effects of VNS on autistic behaviors remain controversial. We retrospectively collected data from 10 children with DRE who underwent VNS implantation and regular parameter regulation in three pediatric epilepsy centers, and completed the behavioral assessments, including the autistic behavior checklist and the child behavior checklist, at follow-ups 1 (mean 2.16 years) and 2 (mean 2.98 years). The 10 children maintained stable seizure control between the two follow-ups. Their autistic behaviors, especially in language, social and self-help, were reduced at follow-up 2 compared to follow-up 1 (p = 0.01, p = 0.01, respectively). Moreover, these improvements were not associated with their seizure control, whether it was positive or negative. These results suggested that the VNS had a positive effect on autistic behaviors, which provided a preliminary clinical basis that VNS may benefit to younger children with DRE comorbidity autism spectrum disorder (ASD).

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13. Wolff N, Eberlein M, Stroth S, Poustka L, Roepke S, Kamp-Becker I, Roessner V. Abilities and Disabilities-Applying Machine Learning to Disentangle the Role of Intelligence in Diagnosing Autism Spectrum Disorders. Frontiers in psychiatry. 2022; 13: 826043.

OBJECTIVE: Although autism spectrum disorder (ASD) is a relatively common, well-known but heterogeneous neuropsychiatric disorder, specific knowledge about characteristics of this heterogeneity is scarce. There is consensus that IQ contributes to this heterogeneity as well as complicates diagnostics and treatment planning. In this study, we assessed the accuracy of the Autism Diagnostic Observation Schedule (ADOS/2) in the whole and IQ-defined subsamples, and analyzed if the ADOS/2 accuracy may be increased by the application of machine learning (ML) algorithms that processed additional information including the IQ level. METHODS: The study included 1,084 individuals: 440 individuals with ASD (with a mean IQ level of 3.3 ± 1.5) and 644 individuals without ASD (with a mean IQ level of 3.2 ± 1.2). We applied and analyzed Random Forest (RF) and Decision Tree (DT) to the ADOS/2 data, compared their accuracy to ADOS/2 cutoff algorithms, and examined most relevant items to distinguish between ASD and Non-ASD. In sum, we included 49 individual features, independently of the applied ADOS module. RESULTS: In DT analyses, we observed that for the decision ASD/Non-ASD, solely one to four items are sufficient to differentiate between groups with high accuracy. In addition, in sub-cohorts of individuals with (a) below (IQ level ≥4)/ID and (b) above average intelligence (IQ level ≤ 2), the ADOS/2 cutoff showed reduced accuracy. This reduced accuracy results in (a) a three times higher risk of false-positive diagnoses or (b) a 1.7 higher risk for false-negative diagnoses; both errors could be significantly decreased by the application of the alternative ML algorithms. CONCLUSIONS: Using ML algorithms showed that a small set of ADOS/2 items could help clinicians to more accurately detect ASD in clinical practice across all IQ levels and to increase diagnostic accuracy especially in individuals with below and above average IQ level.

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14. Yang D, Tao H, Ge H, Li Z, Hu Y, Meng J. Altered Processing of Social Emotions in Individuals With Autistic Traits. Frontiers in psychology. 2022; 13: 746192.

Social impairment is a defining phenotypic feature of autism. The present study investigated whether individuals with autistic traits exhibit altered perceptions of social emotions. Two groups of participants (High-AQ and Low-AQ) were recruited based on their scores on the autism-spectrum quotient (AQ). Their behavioral responses and event-related potentials (ERPs) elicited by social and non-social stimuli with positive, negative, and neutral emotional valence were compared in two experiments. In Experiment 1, participants were instructed to view social-emotional and non-social emotional pictures. In Experiment 2, participants were instructed to listen to social-emotional and non-social emotional audio recordings. More negative emotional reactions and smaller amplitudes of late ERP components (the late positive potential in Experiment 1 and the late negative component in Experiment 2) were found in the High-AQ group than in the Low-AQ group in response to the social-negative stimuli. In addition, amplitudes of these late ERP components in both experiments elicited in response to social-negative stimuli were correlated with the AQ scores of the High-AQ group. These results suggest that individuals with autistic traits have altered emotional processing of social-negative emotions.

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