1. Althammer F, Muscatelli F, Grinevich V, Schaaf CP. Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies. Transl Psychiatry;2022 (Aug 8);12(1):318.

The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

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2. Bertuccioli A, Cardinali M, Di Pierro F, Zonzini GB, Matera MR. Ketogenic and Low FODMAP Diet in Therapeutic Management of a Young Autistic Patient with Epilepsy and Dysmetabolism Poorly Responsive to Therapies: Clinical Response and Effects of Intestinal Microbiota. Int J Mol Sci;2022 (Aug 8);23(15)

Autism spectrum disorder (ASD) is often associated with several intestinal and/or metabolic disorders as well as neurological manifestations such as epilepsy (ASD-E). Those presenting these neuropathological conditions share common aspects in terms of gut microbiota composition. The use of microbiota intervention strategies may be an approach to consider in the management of these cases. We describe the case of a 17-year-old girl affected by ASD, reduced growth, neurological development delay, mutations in the PGM1 and EEF1A2 genes (in the absence of clinically manifested disease) and, intestinal disorders such as abdominal pain and diarrhea associated with weight loss. As she demonstrated poor responsiveness to the therapies provided, we attempted two specific dietary patterns: a ketogenic diet, followed by a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, with the aim of improving her neurological, metabolic, and intestinal symptoms through modulation of the gut microbiota’s composition. The ketogenic diet (KD) provided a reduction in Firmicutes, Bacteroidetes, and Proteobacteria. Although her intestinal symptoms improved, KD was poorly tolerated. On the other hand, the passage to a low FODMAPs diet produced a significant improvement in all neurological, intestinal, and metabolic symptoms and was well-tolerated. The following gut microbiota analysis showed reductions in Actinobacteria, Firmicutes, Lactobacilli, and Bifidobacteria. The alpha biodiversity was consistently increased and the Firmicutes/Bacteroidetes ratio decreased, reducing the extent of fermentative dysbiosis. Gut microbiota could be a therapeutic target to improve ASD-related symptoms. Further studies are needed to better understand the correlation between gut microbiota composition and ASD, and its possible involvement in the physiopathology of ASD.

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3. Bradshaw J, Wolfe K, Hock R, Scopano L. Advances in Supporting Parents in Interventions for Autism Spectrum Disorder. Pediatr Clin North Am;2022 (Aug);69(4):645-656.

The rising prevalence of autism spectrum disorder (ASD) calls for clear referral and treatment guidelines for children with ASD and their caregivers. Caregiver involvement in intervention is a standard practice of care and research suggests that teaching intervention strategies to caregivers can improve child outcomes and increase caregiver efficacy. Caregiver-mediated interventions that are naturalistic, developmental, and behavioral are effective in improving social and communication skills for children with ASD. Caregiver training models that use behavioral strategies are effective in reducing challenging behaviors. Finally, reducing caregiver barriers to treatment implementation, including stress and strain, are becoming critical components for improving the well-being and care of children with ASD and their families.

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4. Fathabadipour S, Mohammadi Z, Roshani F, Goharbakhsh N, Alizadeh H, Palizgar F, Cumming P, Michel TM, Vafaee MS. The neural effects of oxytocin administration in autism spectrum disorders studied by fMRI: A systematic review. J Psychiatr Res;2022 (Aug 4);154:80-90.

PURPOSE: Oxytocin (OXT) is a hypothalamic neuropeptide that is released from the posterior pituitary gland and at specific targets in the central nervous system (CNS). The prosocial effects of OXT acting in the CNS present it as a potential therapeutic agent for the treatment of aspects of autism spectrum disorder (ASD). In this article, we systematically review the functional MRI (fMRI) literature that reports task-state and resting-state fMRI (rsfMRI) studies of the neural effects of single or multiple dose intranasal OXT (IN-OXT) administration in individuals with ASD. METHOD: We searched four databases for relevant documents (PubMed, Web of Science, Scopus, and Google Scholar) using the keywords « autism spectrum disorder », « Asperger Syndrome », « oxytocin », and « fMRI ». Moreover, we made a manual search to assess the quality of our automatic search. The search was confined to English language articles published in the interval February 2013 until March 2021. RESULTS: The search yielded 12 fMRI studies with OXT intervention, including 288 individuals with ASD (age 8-55 years) enrolled in randomized, double-blind, placebo-controlled, parallel designs, within-subject-crossover experimental OXT trials. Studies reporting activation task and rsfMRI were summarized with region of interest (ROI) or whole-brain voxel wise analysis. The systematic review of the 12 studies supported the proposition that IN-OXT administration alters brain activation in individuals with ASD. The effects of IN-OXT interacted with the type of the task and the overall results did not indicate restoration of normal brain activation in ASD signature regions albeit the lack of statistical evidence. CONCLUSION: A large body of evidence consistently indicates that OXT alters activation to fMRI in brain networks of individuals with ASD, but with uncertain implications for alleviation of their social deficits.

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5. Hajri M, Abbes Z, Yahia HB, Jelili S, Halayem S, Mrabet A, Bouden A. Cognitive deficits in children with autism spectrum disorders: Toward an integrative approach combining social and non-social cognition. Front Psychiatry;2022;13:917121.

Autism spectrum disorder (ASD) is associated with neurocognitive impairment, including executive dysfunctioning and social cognition (SC) deficits. Cognitive remediation (CR) is a behavioral training-based intervention aiming to improve cognitive processes. Its first use in psychiatry interested patients with schizophrenia, in whom promising results have been shown. Integrated CR programs targeting both social and non-social cognition have demonstrated to be effective in improving both cognitive domains and functional outcomes. CR studies in children and adolescents with ASD are still new, those regarding CR approaches combining social and executive functioning remediation are scares. One study examining the efficacy of cognitive enhancement therapy (CET) for improving cognitive abilities in ADS adults, showed significant differential increases in neurocognitive function and large social-cognitive improvements. Therefore, taking into account the overlap between ASD and schizophrenia, and considering the close link between executive functions (EF) and SC, we suggest that integrative approach in ASD could result in better outcomes. The present perspective aimed to highlight cognitive remediation (CR) programs contributions in ASD (especially in children and adolescents), and to discuss the value of combining social and non-social programs.

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6. Helsel BC, Foster RNS, Sherman J, Ptomey LT, Montgomery RN, Washburn RA, Donnelly JE. A Remotely Delivered Yoga Intervention for Adolescents with Autism Spectrum Disorder: Feasibility and Effectiveness for Improving Skills Related to Physical Activity. J Autism Dev Disord;2022 (Aug 8)

This study evaluated the feasibility of remotely delivered yoga for improving four physical activity-related skills: motor skills, strength, balance, and flexibility in adolescents with autism spectrum disorder (ASD). Nineteen of 20 participants enrolled (age 13.2 ± 2.2 years; 60% male) completed the 12-week intervention and attended 83% of the scheduled yoga sessions. Overall, physical activity-related skills improved pre to post intervention (Φ = 0.90, p = 0.005, 95% CI 0.72-1.0). Specifically, significant increases in leg strength (12.5%, p = 0.039), flexibility (40.3%, p = 0.008), and dynamic balance on the right (11.1%, p = 0.001) and left legs (8.1%, p = 0.003) were observed across 12 weeks. These results demonstrate the feasibility and potential effectiveness of yoga to improve physical activity-related skills in adolescents with ASD.

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7. Kadam A, Soni IG, Kadam S, Pandit A, Patole S. Video-based screening for children with suspected autism spectrum disorder – experience during the COVID-19 pandemic in India. Res Autism Spectr Disord;2022 (Oct);98:102022.

BACKGROUND: Assessments for children with autism spectrum disorder (ASD) must adapt to the current COVID-19 pandemic through innovation in screening and assessment strategies using technology. To our knowledge there are no such studies reported from India. We aimed to study the predictive ability of video-based screening tool with definitive diagnosis in children with ASD. METHOD: Thirty-nine children were screened independently by two examiners with a video-based screening tool to start intervention followed by an in-person evaluation by clinical DSM-5 diagnosis three months later. RESULT: Similar to studies from developed countries, videos assessments showed a 94.87% correlation with the final diagnosis. Interobserver video agreement had a kappa correlation of 0.803, which was classified as substantial agreement. CONCLUSION: Video-based evaluations may be used as an interim assessment to initiate early intervention in children with ASD in resource-limited setups in the current pandemic situation. Large, well-designed prospective studies are required to confirm our results.

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8. László L, Maczelka H, Takács T, Kurilla A, Tilajka Á, Buday L, Vas V, Apáti Á. A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System. Int J Mol Sci;2022 (Aug 8);23(15)

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential.

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9. Narzisi A, Stavropoulos KKM. Editorial: Enrichment of social skills in adolescent and young adults with high-functioning autism spectrum disorder. Front Psychiatry;2022;13:994914.

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10. Ren H, Ren G, Zhan Y, Jia Z. Examining the efficacy of dance movement and music mixed treatment on social communication impairment in children with autism – Based on family parent-child situation. Front Psychol;2022;13:937564.

Despite impairments in social communication in children with autism spectrum disorder (ASD), existing studies only examine the effects of either MT or DMT interventions. In the family setting, few studies have investigated interventions for social communication impairments in children with ASD. This study designed and tested a mixed intervention program of both MT and DMT through a 3-month intervention and training for children with ASD in the family setting including parent and child. A pre-test and post-test were conducted in the experimental and control groups, and the childhood autism rating scale (CARS) and autism treatment evaluation checklist (ATEC) scales were used to assess the severity of ASD symptoms and the effects of intervention. A t-test and analysis of variance were performed based on the experimental results. The results indicated that the experimental and control groups did not differ significantly on the CARS pre-test (t = 1.218, p > 0.05) and that there was no significant difference in the ATEC pre-test (t = 0.546, p > 0.05; F = 0.074, p > 0.05, partial η(2) = 0.003). There was no significant difference between the pre- and post-test scores for the CARS in the control group (t = 0.635, p > 0.05), and there was no significant difference between the pre- and post-test scores for the ATEC in the control group (t = 0.027, p > 0.05; F = 5.251, p > 0.05, partial η(2) = 0.313). There was a significant difference between the pre- and post-test scores on the CARS in the experimental group (t = 4.327, p > 0.05) and the pre- and post-test scores on the ATEC in the experimental group (t = 5.763, p > 0.01; F = 32.615, p > 0.01, partial η(2) = 0.759), with the post-test scores being lower than the pre-test scores. This demonstrates that the mixed intervention of MT and DMT in the family parent-child setting can reduce autism and improve social communication impairment in children with ASD.

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11. Salehinejad MA, Ghanavati E, Glinski B, Hallajian AH, Azarkolah A. A systematic review of randomized controlled trials on efficacy and safety of transcranial direct current stimulation in major neurodevelopmental disorders: ADHD, autism, and dyslexia. Brain Behav;2022 (Aug 8):e2724.

OBJECTIVE: Among the target groups in child and adolescent psychiatry, transcranial direct current stimulation (tDCS) has been more applied in neurodevelopmental disorders specifically, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and dyslexia. This systematic review aims to provide the latest update on published randomized-controlled trials applying tDCS in these disorders for evaluating its efficacy and safety. METHODS: Based on a pre-registered protocol (PROSPERO: CRD42022321430) and using the PRISMA approach, a literature search identified 35 randomized controlled trials investigating the effects of tDCS on children and adolescents with ADHD (n = 17), ASD (n = 11), and dyslexia (n = 7). RESULTS: In ADHD, prefrontal anodal tDCS is reported more effective compared to stimulation of the right inferior frontal gyrus. Similarly in ASD, prefrontal anodal tDCS was found effective for improving behavioral problems. In dyslexia, stimulating temporoparietal regions was the most common and effective protocol. In ASD and dyslexia, all tDCS studies found an improvement in at least one of the outcome variables while 64.7% of studies (11 of 17) in ADHD found a similar effect. About 88% of all tDCS studies with a multi-session design in 3 disorders (16 of 18) reported a significant improvement in one or all outcome variables after the intervention. Randomized, double-blind, controlled trials consisted of around 70.5%, 36.3%, and 57.1% of tDCS studies in ADHD, ASD, and dyslexia, respectively. tDCS was found safe with no reported serious side effects in 6587 sessions conducted on 745 children and adolescents across 35 studies. CONCLUSION: tDCS was found safe and partially effective. For evaluation of clinical utility, larger randomized controlled trials with a double-blind design and follow-up measurements are required. Titration studies that systematically evaluate different stimulation intensities, duration, and electrode placement are lacking.

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12. Sherman HT, Liu K, Kwong K, Chan ST, Li AC, Kong XJ. Carbon monoxide (CO) correlates with symptom severity, autoimmunity, and responses to probiotics treatment in a cohort of children with autism spectrum disorder (ASD): a post-hoc analysis of a randomized controlled trial. BMC Psychiatry;2022 (Aug 8);22(1):536.

BACKGROUND: Inflammation, autoimmunity, and gut-brain axis have been implicated in the pathogenesis of autism spectrum disorder (ASD). Carboxyhemoglobin (SpCO) as a non-invasive measurement of inflammation has not been studied in individuals with ASD. We conducted this post-hoc study based on our published clinical trial to explore SpCO and its association with ASD severity, autoimmunity, and response to daily Lactobacillus plantarum probiotic supplementation. METHODS: In this study, we included 35 individuals with ASD aged 3-20 years from a previously published clinical trial of the probiotic Lactobacillus plantarum. Subjects were randomly assigned to receive daily Lactobacillus plantarum probiotic (6 × 10(10) CFUs) or a placebo for 16 weeks. The outcomes in this analysis include Social Responsiveness Scale (SRS), Aberrant Behavior Checklist second edition (ABC-2), Clinical Global Impression (CGI) scale, SpCO measured by CO-oximetry, fecal microbiome by 16 s rRNA sequencing, blood serum inflammatory markers, autoantibodies, and oxytocin (OT) by ELISA. We performed Kendall’s correlation to examine their interrelationships and used Wilcoxon rank-sum test to compare the means of all outcomes between the two groups at baseline and 16 weeks. RESULTS: Elevated levels of serum anti-tubulin, CaM kinase II, anti-dopamine receptor D1 (anti-D1), and SpCO were found in the majority of ASD subjects. ASD severity is correlated with SpCO (baseline, R = 0.38, p = 0.029), anti-lysoganglioside GM1 (R = 0.83, p = 0.022), anti-tubulin (R = 0.69, p = 0.042), and anti-D1 (R = 0.71, p = 0.045) in treatment group. CONCLUSIONS: The findings of the present study suggests that the easily administered and non-invasive SpCO test offers a potentially promising autoimmunity and inflammatory biomarker to screen/subgroup ASD and monitor the treatment response to probiotics. Furthermore, we propose that the associations between autoantibodies, gut microbiome profile, serum OT level, GI symptom severity, and ASD core symptom severity scores are specific to the usage of probiotic treatment in our subject cohort. Taken together, these results warrant further studies to improve ASD early diagnosis and treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03337035 , registered November 8, 2017.

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13. Sinnamon JR, Jacobson ME, Yung JF, Fisk JR, Jeng S, McWeeney SK, Parmelee LK, Chan CN, Yee SP, Mandel G. Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A;2022 (Aug 16);119(33):e2206053119.

Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editase(wt)) and either Mecp2-targeting or nontargeting gfp RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the Mecp2-targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the Mecp2-targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control gfp guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editase(wt). Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.

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14. Thurman AJ, Dimachkie Nunnally A. Joint attention performance in preschool-aged boys with autism or fragile X syndrome. Front Psychol;2022;13:918181.

Early development marks a period of rapid learning facilitated by children’s natural curiosity about the people around them. In children with typical development, these early social attentional preferences set the foundation for learning about and from the surrounding world of people. Much of this learning happens using joint attention, the ability to coordinate attention between people and objects of mutual interest. It is well documented that decreased gaze use is commonly observed in individuals with autism and individuals with fragile X syndrome (FXS). Despite the growing body of research comparing phenotypic similarities between individuals with autism and individuals with FXS, no studies have directly compared joint attention performance between these groups. In the present study, we considered the similarities and differences in joint attention between preschool-aged boys with autism or FXS, and the relation between joint attention, language, and other phenotypic characteristics known to differ between boys with autism and boys with FXS. Although joint attention appeared similar, between-group differences emerged when controlling for the influence of age, non-verbal IQ, and autism symptom severity. Differences were also observed when considering how joint attention performance related to other aspects of the phenotype. For example, strong positive associations were observed between joint attention and language performance in boys with autism but not boys with FXS, even after controlling for non-verbal IQ. In contrast, the negative association between joint attention and anxiety symptom severity was significant and stronger in boys with FXS than in autism. These data offer preliminary insights into the similarities and differences between the autism and FXS phenotypes.

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15. Varian BJ, Weber KT, Kim LJ, Chavarria TE, Carrasco SE, Muthupalani S, Poutahidis T, Zafarullah M, Al Olaby RR, Barboza M, Solakyildirim K, Lebrilla C, Tassone F, Wu F, Alm EJ, Erdman SE. Maternal Microbiota Modulate a Fragile X-like Syndrome in Offspring Mice. Genes (Basel);2022 (Aug 8);13(8)

Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation.

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16. Waldron DA, Stokes J, Coyle CE, Kramer J, Dugan E. Aging on the Autism Spectrum: Physical Activity in Individuals Receiving State Services in the United States. J Autism Dev Disord;2022 (Aug 7)

This study explores factors associated with participation in moderate physical activity and muscle strengthening activity in adults with autism receiving state services (age: 18-78 years). Researchers analyzed the National Core Indicators-In Person Survey (2017-2018) data using multilevel mixed effects logistic regression. Older adults on the autism spectrum engaged in both moderate physical activity and muscle strengthening activity less often than younger adults on the autism spectrum (OR 0.99; p < 0.05; OR 0.98; p < 0.001). Individuals reportedly in fair/poor health had 50% lower odds of engaging in moderate physical activity and 30% lower odds of engaging in muscle strengthening compared to those in good/ excellent health (OR 0.50; p < 0.001; OR 0.70; p < 0.001). Moderate physical activity/muscle strengthening initiatives may help foster this group's healthy aging.

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