1. Alallawi B, Hastings R, Aabe N. Support Needs and Parent Outcomes in Arab Families of Children with Autism Living in the United Kingdom. Brain Sci;2022 (Aug 22);12(8)

Research on the experiences of Arab families of children with autism living in non-Arab countries is scarce. A survey investigated the support needs, psychological distress, and parental relationships of Arab parents (n = 100) of children with autism living in the United Kingdom (UK). The survey consisted of five main questionnaires: a demographic questionnaire, the GO4KIDDS Brief Adaptive Scale, the Family Needs Survey, the Strengths and Difficulties Questionnaire, and the Hospital Anxiety and Depression Scale. Descriptive analysis indicated that the most frequently identified support needs were information, community services, and explaining to others. Parents reported high levels of psychological distress, a high level of parental relationship satisfaction with their spouse, and few parental disagreements about their child with autism. Regression analyses showed that increased child behavior problems predicted more total family needs. Higher levels of child prosocial behavior, the better health status of parents, and a larger number of children in the family were associated with lower levels of parental psychological distress. A longer time living in the UK was associated with more parental disagreement over issues related to the child with ASD. Reducing child behavior problems and increasing child prosocial behavior may be important targets for support and intervention to improve outcomes for Arab parents of autistic children.

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2. Amadi CJ, Brock ME, Barczak MA, Anderson EJ. Improving Social and Play Outcomes for Students With Significant Disabilities During Recess. Am J Intellect Dev Disabil;2022 (Sep 1);127(5):400-416.

For students with autism, recess is often a missed opportunity to develop social competence and relationships. Although interventions have been developed to promote interactions and social skills for students with average or above-average intellectual functioning, there has been less focus on students with autism who have below-average intellectual functioning or who meet the criteria for intellectual disability. In this single-case design study, we tested the efficacy of a combined peer-mediated and social skills instruction intervention on the interactions, play, and social skills of three students with autism who met their state’s criteria for alternate assessment for students with significant cognitive disabilities. Social skills instruction featured video models that portrayed same-aged peers demonstrating individualized social skills on the playground. For all three students, there were substantial increases in interactions, play and social skills, and students and their peers provided positive feedback about the intervention.

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3. Andreou M, Skrimpa V. Re-Examining Labels in Neurocognitive Research: Evidence from Bilingualism and Autism as Spectrum-Trait Cases. Brain Sci;2022 (Aug 22);12(8)

Despite the fact that the urge to investigate bilingualism and neurodevelopmental disorders as continuous indices rather than categorical ones has been well-voiced among researchers with respect to research methodological approaches, in the recent literature, when it comes to examining language, cognitive skills and neurodivergent characteristics, it is still the case that the most prevalent view is the categorisation of adults or children into groups. In other words, there is a categorisation of individuals, e.g., monolingual vs. bilingual children or children with typical and atypical/non-typical/non-neurotypical development. We believe that this labelling is responsible for the conflicting results that we often come across in studies. The aim of this review is to bring to the surface the importance of individual differences through the study of relevant articles conducted in bilingual children and children with autism, who are ideal for this study. We concur with researchers who already do so, and we further suggest moving away from labels and instead shift towards the view that not everything is either white or black. We provide suggestions as to how this shift could be implemented in research, while mostly aiming at starting a discourse rather than offering a definite path.

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4. Bortoletto R, Colizzi M. Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis. Healthcare (Basel);2022 (Aug 16);10(8)

Being particularly vulnerable to the pro-psychotic effects of cannabinoid exposure, autism spectrum individuals present with an increased risk of psychosis, which may be passed on to their own children. More specifically, cannabis exposure among autism spectrum individuals seems to exert disruptive epigenetic effects that can be intergenerationally inherited in brain areas which play a critical role in schizophrenia pathophysiology. Additionally, because of such cannabinoid-induced epigenetic effects, autism candidate genes present with bivalent chromatin markings which make them more vulnerable to subsequent disruption, possibly leading to psychosis onset later in life. Thus, findings support a developmental trajectory between autism and psychosis, as per endocannabinoid system modulation. However, such evidence has not received the attention it deserves.

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5. Butler MG, Hossain WA, Steinle J, Gao H, Cox E, Niu Y, Quach M, Veatch OJ. Connective Tissue Disorders and Fragile X Molecular Status in Females: A Case Series and Review. Int J Mol Sci;2022 (Aug 13);23(16)

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers-Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders.

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6. Calub CA, Benyakorn S, Sun S, Iosif AM, Boyle LH, Solomon M, Hessl D, Schweitzer JB. Working Memory Training in Youth With Autism, Fragile X, and Intellectual Disability: A Pilot Study. Am J Intellect Dev Disabil;2022 (Sep 1);127(5):369-389.

This pilot study sought to identify potential markers of improvement from pre-post treatment in response to computerized working memory (WM) training for youth (ages 8-18) with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) in a single arm, pre-post design. Participants included 26 children with ASD and 18 with comorbid ASD and fragile X syndrome (ASD+FXS). Analyses were adjusted for age and IQ. The ASD group demonstrated greater improvement on WM training relative to the ASD+FXS group. Participants improved on WM and far transfer outcomes, however, there were no significant group differences in improvement except for repetitive behavior. Higher hyperactivity/impulsivity ratings predicted lower performance on visuospatial WM. Findings suggest cognitive training may be beneficial for youth with ASD and ID, warranting further exploration.

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7. Chen SK, Hsu LM, Chiu NC, Saleh W, Pai CW, Chen PL. Injury in Children with Developmental Disorders: A 1:1 Nested Case-Control Study Using Multiple Datasets in Taiwan. Int J Environ Res Public Health;2022 (Aug 9);19(16)

Although past studies have identified predictors related to child injuries with developmental disorders, national-level research in Asia is limited. The objective of this study was to explore the risk factors for child injuries with developmental disorders in Taiwan using a national-level integrated database for the period between 2004-2015 (The Maternal and Child Health Database, National Health Insurance Research Database, Census Registry, and Indigenous Household Registration). Children younger than 12 years old who had records of visiting the ER or being hospitalized due to injury or without injury were included in this study. A 1:1 nested case-control study (injury vs. noninjury) to examine the risk factors for child injury with developmental disorder was performed. A total of 2,167,930 children were enrolled. The risk factors were associated with repeated ER visits or hospitalization: being indigenous (adjusted odds ratio [AOR]: 1.51; CI: 1.45-1.57); having a developmental disorder (AOR: 1.74; CI: 1.70-1.78); and having parents with illicit drug use (AOR: 1.48; CI: 1.32-1.66), alcohol abuse (AOR: 1.21; CI: 1.07-1.37), or a history of mental illness (AOR: 1.43; CI: 1.41-1.46). Being indigenous, having developmental disorders, and having parents with history of illicit drug use, alcohol abuse, or mental illness were predictors related to injuries in children.

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8. Choi B, Yi E. The Impact of Income and Social Capital on the Health of People with Developmental Disabilities. Healthcare (Basel);2022 (Aug 15);10(8)

This study examines the impact of income and social capital on the health of people with developmental disabilities, focusing on the moderating effects of income and social capital on health. Hierarchical regression analysis was conducted using data from 235 people with developmental disabilities who participated in the second wave of the Disability and Life Dynamics Panel. The findings show that people with developmental disabilities who were female, employed, and did not have multiple disabilities and chronic diseases were more likely to display higher levels of self-rated health. Furthermore, self-rated health was higher in those earning a higher income. The social network had a significantly positive effect on health, but its moderating effect on the impact of income did not carry statistical significance. Trust was found to have a moderating effect on the impact of income on health, where the group with greater trust and lower income was healthier than the group with lower trust. The findings suggest the need to provide income support and establish social capital for people with developmental disabilities to improve their health, and this study offers related policy implications.

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9. Christi RA, Roy D, Heung R, Flake E. Impact of Respite Care Services Availability on Stress, Anxiety and Depression in Military Parents who have a Child on the Autism Spectrum. J Autism Dev Disord;2022 (Aug 27):1-15.

OBJECTIVE: Parenting an autistic child can affect a family’s well-being. Finding resources is critical. This pilot study looked at respite’s impact on parental stress, anxiety, and depression in military families and demographic factors associated with presence of respite care. METHOD: Participants completed three surveys on anonymous basis, including two standardized surveys measuring parental stress and anxiety/depression. Data analysis used Chi-square test and regression analysis. RESULTS: Parents receiving respite reported less stress and anxiety/depression. Respite utilization was associated with absence of comorbid conditions in child and other variables. Predictor variables for parental stress and anxiety/depression included presence of comorbid conditions in child. CONCLUSION: Respite care may be linked to lower parental stress, anxiety, and depression, but more study is needed.

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10. Coulter H, Donnelly M, Mallett J, Kernohan WG. Heart Rate Variability Biofeedback to Treat Anxiety in Young People With Autism Spectrum Disorder: Findings From a Home-Based Pilot Study. JMIR Form Res;2022 (Aug 26);6(8):e37994.

BACKGROUND: People with autism spectrum disorder (ASD) frequently experience high levels of anxiety. Despite this, many clinical settings do not provide specialist ASD mental health services, and demand for professional support frequently outstrips supply. Across many sectors of health, investigators have explored digital health solutions to mitigate demand and extend the reach of professional practice beyond traditional clinical settings. OBJECTIVE: This critical appraisal and pilot feasibility study examines heart rate variability (HRV) biofeedback as an approach to help young people with ASD to manage anxiety symptoms outside of formal settings. The aim is to explore the use of portable biofeedback devices to manage anxiety, while also highlighting the risks and benefits of this approach with this population. METHODS: We assessed the feasibility of using home-based HRV biofeedback for self-management of anxiety in young people with ASD. We adopted coproduction, involving people with ASD, to facilitate development of the study design. Next, a separate pilot with 20 participants with ASD (n=16, 80% male participants and n=4, 20% female participants, aged 13-24 years; IQ>70) assessed adoption and acceptability of HRV biofeedback devices for home use over a 12-week period. Data were collected from both carers and participants through questionnaires and interviews; participants also provided single-lead electrocardiogram recordings as well as daily reports through smartphone on adoption and use of their device. RESULTS: Pre-post participant questionnaires indicated a significant reduction in anxiety in children (t(6)=2.55; P=.04; Cohen d=0.99) as well as adults (t(7)=3.95; P=.006; Cohen d=0.54). Participant age was significantly negatively correlated with all HRV variables at baseline, namely high-frequency heart rate variability (HF-HRV: P=.02), the root mean square of successive differences in normal heartbeat contractions (RMSSD: P=.02) and the variability of normal-to-normal interbeat intervals (SDNN: P=.04). At follow-up, only SDNN was significantly negatively correlated with age (P=.05). Levels of ASD symptoms were positively correlated with heart rate both before (P=.04) and after the intervention (P=.01). The majority (311/474, 65.6%) of reports from participants indicated that the devices helped when used. Difficulties with the use of some devices and problems with home testing of HRV were noted. These initial findings are discussed within the context of the strengths and challenges of remotely delivering a biofeedback intervention for people with ASD. CONCLUSIONS: HRV biofeedback devices have shown promise in this pilot study. There is now a need for larger evaluation of biofeedback to determine which delivery methods achieve the greatest effect for people with ASD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04955093; https://clinicaltrials.gov/ct2/show/NCT04955093.

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11. Defrin R, Benromano T, Pick CG. Unique Pain Responses in Different Etiological Subgroups of Intellectual and Developmental Disabilities. Am J Intellect Dev Disabil;2022 (Sep 1);127(5):417-430.

We studied whether there exist variations in pain responses between different intellectual and developmental disability (IDD) etiologies. Self-reports and facial expressions (Facial Action Coding System = FACS) were recorded during experimental pressure stimuli and compared among 31 individuals with IDD-13 with cerebral palsy (CP), nine with Down syndrome (DS), nine with unspecified origin (UIDD)-and among 15 typically developing controls (TDCs). The CP and DS groups had higher pain ratings and FACS scores compared to the UIDD and TDC groups, and steeper stimulus-response functions. The DS group exhibited the most diverse facial expressions. There were variations in the foci of facial expressions between groups. It appears that different IDD etiologies display distinct pain responses.

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12. Diek D, Smidt MP, Mesman S. Molecular Organization and Patterning of the Medulla Oblongata in Health and Disease. Int J Mol Sci;2022 (Aug 17);23(16)

The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7-r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold-Hirschhorn syndrome, Rett syndrome, and Pitt-Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.

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13. Dunn CL, Wessler JM, Pragani JK, Stewart SE. Fever and Abdominal Pain in a 10-year-old with Autism. Pediatr Rev;2021 (Dec 1);42(12):706-711.

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14. Dwyer P, Takarae Y, Zadeh I, Rivera SM, Saron CD. Multisensory integration and interactions across vision, hearing, and somatosensation in autism spectrum development and typical development. Neuropsychologia;2022 (Aug 24);175:108340.

Most prior studies of multisensory integration (MSI) in autism have measured MSI in only a single combination of modalities – typically audiovisual integration. The present study used onset reaction times (RTs) and 125-channel electroencephalography (EEG) to examine different forms of bimodal and trimodal MSI based on combinations of auditory (noise burst), somatosensory (finger tap), and visual (flash) stimuli presented in a spatially-aligned manner using a custom desktop apparatus. A total of 36 autistic and 19 non-autistic adolescents between the ages of 11-14 participated. Significant RT multisensory facilitation relative to summed unisensory RT was observed in both groups, as were significant differences between summed unisensory and multisensory ERPs. Although the present study’s statistical approach was not intended to test effect latencies, these interactions may have begun as early as ∼45 ms, constituting « early » (<100 ms) MSI. RT and ERP measurements of MSI appeared independent of one another. Groups did not significantly differ in multisensory RT facilitation, but we found exploratory evidence of group differences in the magnitude of audiovisual interactions in ERPs. Future research should make greater efforts to explore MSI in under-represented populations, especially autistic people with intellectual disabilities and nonspeaking/minimally-verbal autistic people.

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15. Eisfeldt J, Schuy J, Stattin EL, Kvarnung M, Falk A, Feuk L, Lindstrand A. Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis. Int J Mol Sci;2022 (Aug 20);23(16)

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient’s cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient’s cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.

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16. Eissa N, Venkatachalam K, Jayaprakash P, Yuvaraju P, Falkenstein M, Stark H, Sadek B. Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism. Pharmaceuticals (Basel);2022 (Jul 27);15(8)

Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H(3)R/D(2)R/D(3)R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H(3)R/D(2)R/D(3)R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.

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17. Feldman JI, Dunham K, DiCarlo GE, Cassidy M, Liu Y, Suzman E, Williams ZJ, Pulliam G, Kaiser S, Wallace MT, Woynaroski TG. A Randomized Controlled Trial for Audiovisual Multisensory Perception in Autistic Youth. J Autism Dev Disord;2022 (Aug 26):1-18.

Differences in audiovisual integration are commonly observed in autism. Temporal binding windows (TBWs) of audiovisual speech can be trained (i.e., narrowed) in non-autistic adults; this study evaluated a computer-based perceptual training in autistic youth and assessed whether treatment outcomes varied according to individual characteristics. Thirty autistic youth aged 8-21 were randomly assigned to a brief perceptual training (n = 15) or a control condition (n = 15). At post-test, the perceptual training group did not differ, on average, on TBWs for trained and untrained stimuli and perception of the McGurk illusion compared to the control group. The training benefited youth with higher language and nonverbal IQ scores; the training caused widened TBWs in youth with co-occurring cognitive and language impairments.

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18. Gutiérrez C, Santoni JLM, Merino P, de Liaño PG. Ophthalmologic Manifestations in Autism Spectrum Disorder. Turk J Ophthalmol;2022 (Aug 25);52(4):246-251.

OBJECTIVES: The purpose of this study was to describe the ophthalmologic manifestations found in patients with autism spectrum disorder (ASD) and to assess their prevalence in the different types of ASD. MATERIALS AND METHODS: This prospective observational study included 344 patients with ASD seen over a period of 8.5 years. They were classified into four subgroups (autism, Asperger syndrome, pervasive developmental disorders not otherwise specified [PDD-NOS], and other). Data obtained from ophthalmological examinations were compared between the groups. Statistical analysis was performed with chi-square, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: Refractive defects were detected in 48.4% of the patients, with the most prevalent being hyperopia and astigmatism. There was a higher prevalence of myopia in Asperger syndrome. Evaluation of extraocular motility revealed the presence of strabismus in 15.4% of patients, with a statistically significantly higher prevalence in autism and the « other » disorders group. The most frequent type of strabismus was exotropia. Convergence was found to be normal in 43.6% of the patients. Nystagmus was observed in only 0.9% of patients. In the binocular sensory tests performed, patients with Asperger syndrome had significantly better results compared to the other groups. Optic nerve abnormalities were found in 4% of patients, with significantly higher prevalence in the « other » disorders group. CONCLUSION: Ophthalmologic manifestations occur more frequently in patients with ASD than in the general child population. Of these, the most frequent are refractive defects and ocular motility disorder. Therefore, we consider it necessary to perform an ophthalmological evaluation in patients with ASDs.

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19. Hansford R, Ouellette-Kuntz H, Péfoyo AK, Martin L. COVID-19 precautions experienced by a sample of adults with intellectual and developmental disabilities. Ann Epidemiol;2022 (Aug 27);75:10-15.

PURPOSE: This study describes factors associated with COVID-19 precautions (i.e., self-isolation and the use of personal protective equipment) among a sample of adults with intellectual and developmental disabilities (IDD) in Ontario, Canada. METHODS: The sample included 756 home care recipients with IDD who did not test positive for COVID-19 between March 2020 and July 2021. Among these, some received COVID-19 precautions. Precaution data were obtained from a large metropolitan organization serving persons with IDD in Ontario, and linked to home care assessment data. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated using logistic regression models to examine the association between COVID-19 cautions and demographic and clinical factors. Effect modification and interactions were explored. RESULTS: One hundred twenty-seven (16.8%) home care clients experienced precautions. After adjustment, congregate setting, aggression, and limited mobility were significantly associated with COVID-19 precautions. Age modified the relationship between congregate setting and precautions. CONCLUSIONS: Pandemic responses need to recognize the impact on subgroups of adults with IDD, such as those living in congregate settings (including younger individuals) or engaging in responsive behaviors. How these precautions impacted individuals-in the short and long term-warrants further investigation.

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20. Hsu JW, Tsai SJ, Bai YM, Huang KL, Su TP, Chen TJ, Chen MH. Risk of exposure to prescription opioids in children and adolescents with autism spectrum disorder: A nationwide longitudinal study. Autism Res;2022 (Aug 27)

Whether children and adolescents with autism spectrum disorder (ASD) are more likely to be exposed to prescription opioids than others remains unknown. The Taiwan National Health Insurance Research Database was employed, and 14,849 children and adolescents with ASD and 148,490 age- and sex-matched non-ASD controls were enrolled between 2001 and 2009 and followed up till the end of 2011. Those exposed to prescription opioids during the follow-up period were identified. Patients with ASD were more likely to be exposed to prescription opioids (hazard ratio [HR]: 4.95, 95% confidence interval [CI]: 4.50-5.45), including intravenous or intramuscular opioids (HR: 5.80, 95% CI: 5.23-6.43) and oral or transcutaneous opioids (HR: 2.32, 95% CI: 1.87-2.89), than were non-ASD controls. Furthermore, the ASD cohort had the increased likelihood of cumulative exposure of >14 days (HR: 6.19, 95% CI: 4.91-7.79) and >30 days (HR: 7.17, 95% CI: 5.19-9.90) to prescription opioids compared with the control cohort. ASD was a risk factor for exposure to prescription opioids. Close monitoring of prescription opioid use is necessary for at-risk children and adolescents with ASD, such as those having with or chronic pain. We found that patients with ASD were more likely to be exposed to prescription opioids, including intravenous or intramuscular opioids and oral or transcutaneous opioids, than were non-ASD controls. We suggest that close monitoring of prescription opioid use is necessary for at-risk children and adolescents with ASD, such as those having with or chronic pain.

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21. Ilijoski B, Ackovska N, Zorcec T, Popeska Z. Extending Robot Therapy for Children with Autism Using Mobile and Web Application. Sensors (Basel);2022 (Aug 9);22(16)

Robot treatments for children with autism have proven to be successful and effective. However, the resources needed for the treatments do not always meet the needs of the children. We overcame the lack of equipment and staff by extending the concept of robot therapy using a web and mobile application. This application enables greater availability and personification of the therapy itself. Its use in the majority of respondents contributes to improving their condition. This approach increases the flexibility of the therapy itself and makes it more accessible, enabling the patients to progress more rapidly. Although the robotic treatment presented in this paper is specific to children with autism, this approach can be generalized and applied to other areas where there are similar types of therapies.

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22. Jadav N, Bal VH. Associations between co-occurring conditions and age of autism diagnosis: Implications for mental health training and adult autism research. Autism Res;2022 (Aug 27)

Adult autism studies are increasingly comprised of later-diagnosed adults, yet little is known about how these adults compare to those diagnosed earlier in life. The present study examines medical and psychiatric conditions endorsed by autistic adults and documents differences between those diagnosed with ASD in childhood versus adulthood, as well as across age groups and sex at birth. 4657 legally independent adults (ages 18-85, M = 33.4 years) with professional ASD diagnoses who completed a medical questionnaire were drawn from the Simons Powering Autism Research Knowledge (SPARK) study. Chi square analyses, t-tests, and logistic regressions were used to compare medical and psychiatric conditions between age groups, sex at birth and adults diagnosed in childhood (before age 21) versus adulthood (at or after 21 years). Overall number of conditions endorsed as being diagnosed by a professional was high, with an average of 1.69 (SD = 2.01) medical or developmental and 2.98 (SD = 2.29) psychiatric conditions reported across the sample. Females were more likely to endorse psychiatric conditions (OR = 1.68). Adult-diagnosed adults were more likely to endorse psychiatric conditions (OR = 2.71) and reported more lifetime psychiatric diagnoses (M = 3.15, SD = 2.23) than their childhood-diagnosed counterparts (M = 2.81, SD = 2.33). These findings underscore the need for research to better understand and treat co-occurring psychiatric conditions in autistic adults and report and consider the age of diagnosis in adult autism samples. Moreover, results suggest it is imperative that mental health professionals receive autism training to promote accurate differential diagnosis and equitable access to mental health care for autistic adults with co-occurring psychiatric conditions. LAY SUMMARY: In a large sample of independent autistic adults, those diagnosed with ASD after 21 years of age indicated having more psychiatric diagnoses than those diagnosed before 21 years of age. This highlights the importance of considering age of ASD diagnosis in research and underscores a need for autism training in the broader mental health field.

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23. Kim H, Kim D, Cho Y, Kim K, Roh JD, Kim Y, Yang E, Kim SS, Ahn S, Kang H, Bae Y, Kim E. Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming. Nat Commun;2022 (Aug 27);13(1):5051.

Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b(+/-)) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b(+/-) mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b(+/-) mice through transcriptional reprogramming.

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24. Kuznitsov-Yanovsky L, Shapira G, Gildin L, Shomron N, Ben-Yosef D. Transcriptomic Analysis of Human Fragile X Syndrome Neurons Reveals Neurite Outgrowth Modulation by the TGFβ/BMP Pathway. Int J Mol Sci;2022 (Aug 17);23(16)

Fragile X Syndrome (FXS) is the main genetic reason for intellectual disability and is caused by the silencing of fragile X mental retardation protein (FMRP), an RNA-binding protein regulating the translation of many neuronal mRNAs. Neural differentiation of FX human embryonic stem cells (hESC) mimics the neurodevelopment of FXS fetuses and thus serves as a good model to explore the mechanisms underlining the development of FXS. Isogenic hESC clones with and without the FX mutation that share the same genetic background were in vitro differentiated into neurons, and their transcriptome was analyzed by RNA sequencing. FX neurons inactivating FMR1 expression presented delayed neuronal development and maturation, concomitant with dysregulation of the TGFβ/BMP signaling pathway, and genes related to the extracellular matrix. Migration assay showed decreased neurite outgrowth in FX neurons that was rescued by inhibition of the TGFβ/BMP signaling pathway. Our results provide new insights into the molecular pathway by which loss of FMRP affects neuronal network development. In FX neurons, the lack of FMRP dysregulates members of the BMP signaling pathway associated with ECM organization which, in a yet unknown mechanism, reduces the guidance of axonal growth cones, probably leading to the aberrant neuronal network function seen in FXS.

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25. Lim S, Lee S. Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic. Molecules;2022 (Aug 10);27(16)

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by diverse behavioral symptoms such as repetitive behaviors, social deficits, anxiety, hyperactivity, and irritability. Despite their increasing incidence, the specific pathological mechanisms of ASD are still unknown, and the degree and types of symptoms that vary from patient to patient make it difficult to develop drugs that target the core symptoms of ASD. Although various atypical antipsychotics and antidepressants have been applied to regulate ASD symptoms, these drugs can only alleviate the symptoms and do not target the major causes. Therefore, development of novel drugs targeting factors directly related to the onset of ASD is required. Among the various factors related to the onset of ASD, several chemical modulators to treat ASD, focused on serotonin (5-hydroxytryptamine, 5-HT) and glutamate receptors, microbial metabolites, and inflammatory cytokines, are explored in this study. In particular, we focus on the chemical drugs that have improved various aspects of ASD symptoms in animal models and in clinical trials for various ages of patients with ASD.

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26. Mignolli E, Scialpi A, Valente D, Berardi A, Galeoto G, Tofani M. Sleep Disturbance Scale for Children: Italian Validation in Autism Spectrum Disorder Population. Int J Environ Res Public Health;2022 (Aug 16);19(16)

Sleep disorders in children with autism spectrum disorders (ASDs) are well-described. However, there is a lack of specific assessment tools to investigate sleep disturbance in this target population. The present investigation reports the Italian validation of the Sleep Disturbance Scale for Children (SDSC) in the ASD population, also investigating the correlation between sleep disorders In both children and parents. Internal consistency and test-retest reliability were investigated using Cronbach’s alpha and intraclass correlation coefficient (ICC), respectively. Concurrent validity was analyzed by comparing the score of the SDSC with the Pittsburgh Sleep Quality Index (PSQI), while the correlation between the SDCS score and the General Sleep Disturbance Scale (GSDS) was used to analyze the correlation between sleep disorders in children and sleep disorders in their parents. In total, 99 children with a diagnosis of ASD participated in the study. Cronbach’s alpha revealed satisfactory value (0.853), as well as reliability (ICC 0.972) and concurrent validity (0.745). Our results also revealed a significant linear correlation between children’s and parents’ sleep disorders (p < 0.05). In conclusion, we found the SDSC to be a useful tool for measuring sleep disorders in ASD children. Our findings offer concrete inputs to achieve adequate pathways for taking care of children with ASDs and their parents.

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27. Mihailescu I, Andrei LE, Frunza AA, Manea M, Rad F. Computer-Based Assessment and Self-Report Measures of Executive Functions in High-Functioning Adults with Autism. Brain Sci;2022 (Aug 12);12(8)

This study analyzes the profile of executive functions (EF) in high-functioning adults with autism (HFA), both in terms of performance on four computer-based tasks, as well as how these functions are perceived by the individuals through self-reporting measures. The study included 64 participants: 32 individuals with HFA, and 32 typically developing controls. Four CANTAB tasks were used (assessing spatial working memory, planning, visual memory, and inhibition), as well as a self-reported measure of executive functions (BDEFS) and a scale for the severity of autism symptoms (RAADS-R). The participants in the ASD group performed significantly lower than the control group on all four computer-based tasks, as measured by the total number of errors made (for the spatial working memory, visual memory, and inhibition tasks) and the number of problems solved at the first choice (for the planning task). No correlation was found in the ASD group between the severity of autism symptoms and the computer-based measures. These findings provide evidence that HFA adults may have various executive functioning impairments, and subsequent daily life problems, but these deficits do not necessarily correlate with the severity of core ASD symptoms.

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28. Munagala N, Saravanan V, Almukhtar FH, Jhamat N, Kafi N, Khan S. Supervised Approach to Identify Autism Spectrum Neurological Disorder via Label Distribution Learning. Comput Intell Neurosci;2022;2022:4464603.

Autism Spectrum Disorder (ASD) is a complicated collection of neurodevelopmental illnesses characterized by a variety of developmental defects. It is a binary classification system that cannot cope with reality. Furthermore, ASD, data label noise, high dimension, and data distribution imbalance have all hampered the existing classification algorithms. As a result, a new ASD was proposed. This strategy employs label distribution learning (LDL) to deal with label noise and uses support vector regression (SVR) to deal with sample imbalance. The experimental results show that the proposed method balances the effects of majority and minority classes on outcomes. It can effectively deal with imbalanced data in ASD diagnosis, and it can help with ASD diagnosis. This study presents a cost-sensitive approach to correct sample imbalance and uses a support vector regression (SVR)-based method to remove label noise. The label distribution learning approach overcomes high-dimensional feature classification issues by mapping samples to the feature space and then diagnosing multiclass ASD. This technique outperforms previous methods in terms of classification performance and accuracy, as well as resolving the issue of unbalanced data in ASD diagnosis.

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29. Nitschke AS, Karim JL, Vallance BA, Bickford C, Ip A, Lanphear N, Lanphear B, Weikum W, Oberlander TF, Hanley GE. Autism Risk and Perinatal Antibiotic Use. Pediatrics;2022 (Sep 1);150(3)

OBJECTIVES: Antibiotics are commonly administered during labor and delivery, and research has suggested that fetal exposure to antibiotics can increase risk for autism spectrum disorder (ASD). We assessed whether antibiotic exposure during labor and delivery increased the risk of ASD in the offspring. METHODS: This retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada, between April 1, 2000, and December 31, 2014. This cohort included 569 953 deliveries. To examine the association among pregnant individuals being treated for the same indication, we studied a subcohort of those who tested positive for group B Streptococcus. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios in both cohorts. A sensitivity analysis was conducted using length of first stage of labor as a proxy measure for dose to assess for a dose-response relationship. RESULTS: In this population-based study, antibiotic use during labor and delivery was not associated with an increased risk of ASD in offspring. The unadjusted and adjusted hazard ratios were 1.29 (95% confidence interval, 1.24-1.35) and 0.99 (0.94-1.04), respectively; and 1.07 (0.90-1.27) and 0.88 (0.74-1.05), respectively, in the group B Streptococcus-positive cohort. We observed no substantial difference in the association between antibiotic exposure and ASD depending on length of the first stage of labor. CONCLUSIONS: Our findings suggest that concern for ASD should not factor into the clinical decision on whether to administer antibiotics during labor and delivery. Future research is needed to examine longer durations of prenatal antibiotic exposure.

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30. Oster LM, Zhou G. Balance and Vestibular Deficits in Pediatric Patients with Autism Spectrum Disorder: An Underappreciated Clinical Aspect. Autism Res Treat;2022;2022:7568572.

Children with autism spectrum disorder (ASD) not only have communication and social difficulties, but also exhibit poor balance and motor control ability, which frequently affect daily activities. Effective balance and motor control rely on the integration of somatosensory, visual, and vestibular inputs. Although reports of balance dysfunction in ASD have been documented, comprehensive studies of balance and vestibular function in children with ASD are scarce. In this study, we retrospectively reviewed 36 pediatric patients diagnosed with ASD who underwent balance/vestibular laboratory testing in our speciality clinic. Results from sensory organization test (SOT) or modified clinical test for sensory integration of balance (mCTSIB) found that out of 15 patients, 80% had abnormal findings. Of the children who successfully completed each vestibular test, abnormal responses were observed in 12 (80%) sensory organization tests, 5 (24%) vestibular evoked myogenic potential (VEMP), 22 (66%) videonystagmography (VNG), and 11 (32%) sinusoidal rotary chair tests. These results indicate that balance and vestibular testing may be of diagnostic value for clinicians and providers as an aid in early detection, intervention, and the development of appropriate management and therapies for this patient population. Increased awareness of this topic is warranted to promote better clinical management of this special group of patients and improve their quality of life.

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31. Pearson G, Song C, Hohmann S, Prokhorova T, Sheldrick-Michel TM, Knöpfel T. DNA Methylation Profiles of GAD1 in Human Cerebral Organoids of Autism Indicate Disrupted Epigenetic Regulation during Early Development. Int J Mol Sci;2022 (Aug 16);23(16)

DNA methylation profiling has become a promising approach towards identifying biomarkers of neuropsychiatric disorders including autism spectrum disorder (ASD). Epigenetic markers capture genetic risk factors and diverse exogenous and endogenous factors, including environmental risk factors and complex disease pathologies. We analysed the differential methylation profile of a regulatory region of the GAD1 gene using cerebral organoids generated from induced pluripotent stem cells (iPSCs) from adults with a diagnosis of ASD and from age- and gender-matched healthy individuals. Both groups showed high levels of methylation across the majority of CpG sites within the profiled GAD1 region of interest. The ASD group exhibited a higher number of unique DNA methylation patterns compared to controls and an increased CpG-wise variance. We detected six differentially methylated CpG sites in ASD, three of which reside within a methylation-dependent transcription factor binding site. In ASD, GAD1 is subject to differential methylation patterns that may not only influence its expression, but may also indicate variable epigenetic regulation among cells.

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32. Pietrucci D, Teofani A, Milanesi M, Fosso B, Putignani L, Messina F, Pesole G, Desideri A, Chillemi G. Machine Learning Data Analysis Highlights the Role of Parasutterella and Alloprevotella in Autism Spectrum Disorders. Biomedicines;2022 (Aug 19);10(8)

In recent years, the involvement of the gut microbiota in disease and health has been investigated by sequencing the 16S gene from fecal samples. Dysbiotic gut microbiota was also observed in Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by gastrointestinal symptoms. However, despite the relevant number of studies, it is still difficult to identify a typical dysbiotic profile in ASD patients. The discrepancies among these studies are due to technical factors (i.e., experimental procedures) and external parameters (i.e., dietary habits). In this paper, we collected 959 samples from eight available projects (540 ASD and 419 Healthy Controls, HC) and reduced the observed bias among studies. Then, we applied a Machine Learning (ML) approach to create a predictor able to discriminate between ASD and HC. We tested and optimized three algorithms: Random Forest, Support Vector Machine and Gradient Boosting Machine. All three algorithms confirmed the importance of five different genera, including Parasutterella and Alloprevotella. Furthermore, our results show that ML algorithms could identify common taxonomic features by comparing datasets obtained from countries characterized by latent confounding variables.

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33. Prany W, Patrice C, Franck D, Fabrice W, Mahdi M, Pierre D, Christian M, Jean-Marc G, Fabian G, Francis E, Jean-Marc B, Bérengère GG. EEG resting-state functional connectivity: evidence for an imbalance of external/internal information integration in autism. J Neurodev Disord;2022 (Aug 27);14(1):47.

BACKGROUND: Autism spectrum disorder (ASD) is associated with atypical neural activity in resting state. Most of the studies have focused on abnormalities in alpha frequency as a marker of ASD dysfunctions. However, few have explored alpha synchronization within a specific interest in resting-state networks, namely the default mode network (DMN), the sensorimotor network (SMN), and the dorsal attention network (DAN). These functional connectivity analyses provide relevant insight into the neurophysiological correlates of multimodal integration in ASD. METHODS: Using high temporal resolution EEG, the present study investigates the functional connectivity in the alpha band within and between the DMN, SMN, and the DAN. We examined eyes-closed EEG alpha lagged phase synchronization, using standardized low-resolution brain electromagnetic tomography (sLORETA) in 29 participants with ASD and 38 developing (TD) controls (age, sex, and IQ matched). RESULTS: We observed reduced functional connectivity in the ASD group relative to TD controls, within and between the DMN, the SMN, and the DAN. We identified three hubs of dysconnectivity in ASD: the posterior cingulate cortex, the precuneus, and the medial frontal gyrus. These three regions also presented decreased current source density in the alpha band. CONCLUSION: These results shed light on possible multimodal integration impairments affecting the communication between bottom-up and top-down information. The observed hypoconnectivity between the DMN, SMN, and DAN could also be related to difficulties in switching between externally oriented attention and internally oriented thoughts.

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34. Raditha C, Handryastuti S, Pusponegoro HD, Mangunatmadja I. Positive behavioral effect of sensory integration intervention in young children with autism spectrum disorder. Pediatr Res;2022 (Aug 27)

BACKGROUND: Sensory integration occupational therapy (SI-OT) might be useful for autism spectrum disorders (ASD) in younger age, according to Pusponegoro. Previous studies were still limited, especially in younger age. This study evaluated the effect of SI-OT in improving positive behaviors of ASD children aged 2-5 years. METHODS: Non-randomized controlled trial of SI-OT evaluation, assessed with Vineland Adaptive Behavior Scale-II. RESULTS: A total of 72 subjects were studied. Following SI-OT, communication skills (expressive, receptive), socialization (coping skills), and daily living skills (personal, community) were improved significantly. CONCLUSIONS: SI-OT with Ayres theory in 60 min, twice a week for 12 weeks improved positive behaviors. IMPACT: To address the effectivity of sensory integration occupational therapy (SI-OT) in improving positive behaviors of autism spectrum disorders (ASD) children aged 2-5 years. The first study to evaluate evidence of SI-OT in ASD younger than 3 years. Non-randomized controlled trial of SI-OT evaluation of ASD in younger children aged 2-5 years with Vineland Adaptive Behavior Scale-II. SI-OT of Ayres theory in 60 min, twice a week for 12 weeks improves communication domain (expressive, receptive, written) aged 2-4 years, and socialization domain (interpersonal relationship, play, and leisure time) aged 2 years of ASD children.

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35. Roșca AM, Rusu L, Marin MI, Ene Voiculescu V, Ene Voiculescu C. Physical Activity Design for Balance Rehabilitation in Children with Autism Spectrum Disorder. Children (Basel);2022 (Jul 30);9(8)

One of the characteristics of autism spectrum disorder (ASD) subjects is postural control deficit, which is significant when somatosensory perception is affected. This study analyzed postural stability evolution after physical therapy exercises based on balance training. The study included 28 children with ASD (average age 8 years, average weight 32.18 kg). The rehabilitation program involved performing balance exercises twice a week for three months. Subject assessment was carried out using the RSScan platform. The parameters were the surface of the confidence ellipse (A) and the length of the curve (L) described by the pressure center, which were evaluated before and after the rehabilitation program. Following data processing, we observed a significant decrease in the surface of the confidence ellipse by 92% from EV1 to EV2. Additionally, a decrease of 42% in the curve length was observed from EV1 to EV2. A t test applied to the ellipse surface showed a p = 0.021 and a Cohen’s coefficient of 0.8 (very large effect size). A t test applied to the length L showed p = 0.029 and Cohen’s coefficient of 1.27 mm. Thus, the results show a significant improvement in the two parameters. The application of the program based on physical exercise led to an improvement in the balance of children with autism under complex evaluation conditions.

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36. Roubinov D, Don B, Blades R, Epel E. Is it me or my child? The association between maternal depression and children’s behavior problems in mothers and their children with or without autism. Fam Process;2022 (Aug 25):e12810.

Bidirectional associations between maternal depression and child behavior problems have been reported in prior research, however, few studies examine these relations across varied family contexts. This study examined parenting stress and child diagnosis of autism spectrum disorder (ASD) as moderators of bidirectional associations between maternal depression and child behavior problems over time. Our sample included 86 mother-child dyads who reported maternal depressive symptoms, child behavior problems, and parenting stress at three time points over more than 1 year. Approximately half were mothers of children with ASD (n = 41) and half were mothers of neurotypical children (n = 45). We tested the bidirectional associations between maternal depressive symptoms and children’s behavior problems and the potential moderating role of parental stress or child ASD diagnosis on these bidirectional associations using aggregated, lagged, and linear mixed models. Even after controlling for lagged maternal depressive symptoms, child behavior problems were associated with greater subsequent maternal depression at the between-person level, but not at the within-person level. The converse relation of prior maternal depressive symptoms on subsequent child behavior problems was not significant. Neither parenting stress nor child ASD diagnosis moderated bidirectional associations between maternal depressive symptoms and children’s behavior problems. Child behavior predicted maternal depression, but the converse was not true, regardless of parenting stress levels or child’s ASD diagnosis. For mothers experiencing elevated parenting stress and those with children with ASD, this may help alleviate elevated feelings of guilt related to their children’s behavior problems.

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37. Scheper M, Romagnolo A, Besharat ZM, Iyer AM, Moavero R, Hertzberg C, Weschke B, Riney K, Feucht M, Scholl T, Petrak B, Maulisova A, Nabbout R, Jansen AC, Jansen FE, Lagae L, Urbanska M, Ferretti E, Tempes A, Blazejczyk M, Jaworski J, Kwiatkowski DJ, Jozwiak S, Kotulska K, Sadowski K, Borkowska J, Curatolo P, Mills JD, Aronica E, Epistop Consortium M. miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex. Biomedicines;2022 (Jul 29);10(8)

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients’ serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

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38. Schoen SA, Ferrari V, Valdez A. It’s Not Just about Bicycle Riding: Sensory-Motor, Social and Emotional Benefits for Children with and without Developmental Disabilities. Children (Basel);2022 (Aug 13);9(8)

BACKGROUND: A developing area for therapy is teaching children to ride a bicycle. Little has been written about the effectiveness of these programs. This study explored outcomes from participation in a novel bicycle riding program for children with a wide array of developmental challenges. METHOD: Two studies were conducted; a nonconcurrent, multiple baseline design with four participants and a pretest-posttest single group with 15 children. RESULTS: Study 1 participants improved on broad jump. Balance positions showed variable responses. Study 2 participants showed significant improvement on broad jump, and a trend toward significance walking forwards and backwards. Parents reported improvement in following rules, participating in daily routines, interacting with peers, and feeling good about him/herself and a change in child’s participation in community and extracurricular activities. All children improved in glide time or achieved independent riding. CONCLUSIONS: Preliminary evidence was found for the effectiveness of one approach for developing motor and social skills within the context of learning to ride a bicycle. Children over the age of 6 years were able to ride a two-wheeled bicycle at the end of the program. Participation suggested improvement in motor coordination and dynamic balance as well as changes in measures of social interaction and self-esteem.

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39. Serra D, Henriques JF, Sousa FJ, Laranjo M, Resende R, Ferreira-Marques M, de Freitas V, Silva G, Peça J, Dinis TCP, Almeida LM. Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model. Int J Mol Sci;2022 (Aug 17);23(16)

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota-gut-brain axis.

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40. Shulman Y, Kalma Y, Malcov M, Kopel R, Fouks Y, Azem F, Almog B, Cohen Y. The impact of fragile X premutation carrier status on embryo morphokinetic development. Reprod Biomed Online;2022 (Jun 26)

RESEARCH QUESTION: Does inheritance of the fragile X mental retardation 1 (FMR1) premutation allele affect embryo morphokinetic development? DESIGN: A retrospective cohort analysis of 529 embryos from 126 IVF cycles of 39 FMR1 premutation female carriers undergoing preimplantation genetic testing for monogenic/single gene defects (PGT-M). Morphological and morphokinetic parameters obtained using a time-lapse monitoring system were compared between embryos that inherited the FMR1 premutation allele (FMR1 group, n = 271) and those who received the normal allele (normal group, n = 258). The following embryo outcome measures were compared: morphokinetic parameters up to day 3, start of blastulation time (tSB) for day 5 embryos and the rate of top-quality embryos on days 3 and 5. RESULTS: No differences were found in morphokinetic parameters between the groups from the time of intracytoplasmic sperm injection (ICSI) until a biopsy on day 3. The blastulation rate in the two groups was comparable. However, the start of blastulation was delayed in FMR1 embryos compared to that in the genetically normal embryos (median tSB: 104.2 h [99.3-110.3] versus 101.6 h [94.5-106.7], P = 0.01). In addition, the rate of top-quality FMR1 embryos was lower than that of genetically normal embryos (25.6% versus 38.8%, P = 0.04). CONCLUSION: Embryos that inherit the FMR1 premutation allele are of lower quality at the blastocyst stage compared with those that do not inherit the mutated allele.

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41. Silvera-Tawil D, Bruck S, Xiao Y, Bradford D. Socially-Assistive Robots to Support Learning in Students on the Autism Spectrum: Investigating Educator Perspectives and a Pilot Trial of a Mobile Platform to Remove Barriers to Implementation. Sensors (Basel);2022 (Aug 16);22(16)

Technology offers educators tools that can tailor learning to students’ learning styles and interests. Research into the use of socially-assistive robots as a learning support for children on the autism spectrum are showing promising results. However, to date, few schools have introduced these robots to support learning in students on the autism spectrum. This paper reports on a research project that investigated the barriers to implementing socially-assistive robot supported learning, and the expectations, perceived benefits and concerns of school teachers and therapists of students on the autism spectrum and adults on the autism spectrum. First, three focus groups were conducted with six adults on the autism spectrum, and 13 teachers and therapists of students from two autism-specific schools. During the focus groups, there was cautious optimism from participants about the value of socially-assistive robots for teaching support. While the data showed that participants were in favour of trialling socially-assistive robots in the classroom, they also raised several concerns and potential barriers to implementation, including the need for teacher training. In response to their concerns, the second part of the project focussed on developing a software platform and mobile application (app) to support the introduction of robots into autism-specific classrooms. The software platform and app were then trialled in two schools (n = 7 teachers and therapists). Results from focus groups indicated that participants believe socially-assistive robots could be useful for learning support, as the mobile app provides an easy to use tool to support preparing and conducting lessons that would motivate them to trial robots in the classroom.

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42. Stefanaki A, Gkogkos G, Varlokosta S, Gena A. Applying a Parent Training Program in a Naturalistic Behavior Analytic Context to Improve Attachment in Children with ASD. J Autism Dev Disord;2022 (Aug 27)

Infants develop attachment to their caregivers very early on. The quality of attachment is considered to be crucial for the emotional development of humans and animals alike. Despite its importance, very little is known about how attachment develops between children with Autism Spectrum Disorder (ASD) and their caregivers. The purpose of the present study was to assess the attachment patterns of two young children with ASD with their parents and to identify the means for promoting parent, child, and parent-child relational characteristics that may contribute to the development of secure attachment. The results replicated prior findings pertaining to attachment quality of children with ASD and demonstrated the effectiveness of a naturalistic, behavior-analytic intervention in improving the quality of their attachment.

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43. Takeguchi R, Kuroda M, Tanaka R, Suzuki N, Akaba Y, Tsujimura K, Itoh M, Takahashi S. Structural and functional changes in the brains of patients with Rett syndrome: A multimodal MRI study. J Neurol Sci;2022 (Aug 18);441:120381.

OBJECTIVE: To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI). METHODS: Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs) underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI). The measurements obtained from each modality were statistically compared between RTTs and HCs and examined for their correlation with the clinical severity of RTTs. RESULTS: Structural MRI imaging revealed volume reductions in most cortical and subcortical regions of the brain. Remarkable volume reductions were observed in the frontal and parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus, and corpus callosum. DTI analysis revealed decreased white matter integrity in broad regions of the brain. Fractional anisotropy values were greatly decreased in the superior longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI analysis showed decreased functional connectivity in the interhemispheric dorsal attention network, and between the visual and cerebellar networks. The clinical severity of RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and cerebellar peduncles. CONCLUSION: Regional volume and white matter integrity of RTT brains were reduced in broad areas, while most functional connections remained intact. Notably, two functional connectivities, between cerebral hemispheres and between the cerebrum and cerebellum, were decreased in RTT brains, which may reflect the structural changes in these brain regions.

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44. Taniguchi E, Conant K, Keller K, Kim SJ. A Retrospective Chart Review of Factors Impacting Psychotropic Prescribing Patterns and Polypharmacy Rates in Youth with Autism Spectrum Disorder during the COVID-19 Pandemic. J Clin Med;2022 (Aug 18);11(16)

High but variable rates of psychotropic polypharmacy (PP) in youth with autism spectrum disorder (ASD) have been reported in previous studies. The effect of the COVID-19 pandemic on prescribing patterns has not been well described. This study aims to examine the factors associated with psychotropic prescribing patterns, including rates of PP and multiclass polypharmacy (MPP) in youth with ASD during the COVID-19 pandemic. We examined the prescription records and clinical characteristics of youth aged between 3-21 years with a clinical diagnosis of ASD who were followed at an urban tertiary autism center psychiatry clinic between 1 January 2019, and 31 December 2020. For study purposes, we treated 2019 as the pre-pandemic year and 2020 as the pandemic year and compared the clinical characteristics of the « total clinic cohort (n = 898) » across two years. We examined the clinical characteristics of patients seen in both years (« paired-sample, » n = 473) and those seen only in 219 (« not-paired sample, » n = 378) to identify factors associated with the likelihood of patients’ return to clinic in 2020. As the total clinic cohort was a naturalistic sample containing duplicate patients, we created a separate data set by randomly assigning duplicate patients to one of the years (« random unique sample, » n = 898) and examined the clinical characteristics across two years. We defined PP and MPP broadly as the use of ≥2 unique medications (PP) and ≥2 unique medication classes (MPP) within a calendar year in this study. In the total clinic cohort, increased rates of PP (71.6% to 75.6%), MPP (61.9% to 67.8%, p = 0.027), and antidepressant prescriptions (56.9% to 62.9%, p = 0.028) were noted, although only the latter two were nominally significant. The paired-sample had a higher proportion of teens (31.0% vs. 39.7%, p < 0.001 and persons who self-identified as non-Hispanic (77.8% vs. 85.4%, p = 0.016)), higher rates of anxiety (78.9% vs. 48.7%, p < 0.001), ADHD (71.0% vs. 44.4%, p < 0.001), depression (23.9% vs. 13.0%, p < 0.001) and disruptive behavior (63.3% vs. 33.3%, p < 0.001) diagnoses, higher rates of antidepressants (63.4% vs. 48.7%, p < 0.001), ADHD medications (72.5% vs. 59.8%, p < 0.001), and antipsychotics (36.8% vs. 26.2%, p < 0.001) prescribed, and higher rates of PP (81.6% vs. 59.0%, p < 0.001) and MPP (71.0% vs. 50.5%, p < 0.001) than the not-paired sample. In the random unique sample, the patient group assigned to 2020 had higher rates of anxiety (75.0% vs. 60.2%, p < 0.001), ADHD (69.9% vs. 54.6%, p < 0.001), and disruptive behavior (57.9% vs. 45.4%, p < 0.001) diagnoses but the PP and MPP rates did not differ across years. Overall, we found high rates of PP and MPP, likely due to the broader definition of PP and MPP used in this study than those in other studies as well as the study site being a tertiary clinic. While our study suggests a possible impact of the COVID-19 pandemic on comorbidity rates and prescribing patterns, a replication study is needed to confirm how pandemic-related factors impact prescribing patterns and polypharmacy rates in youth with ASD.

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45. Tartaglione AM, Serafini MM, Ferraris F, Raggi A, Mirabello A, Di Benedetto R, Ricceri L, Midali M, Cubadda F, Minghetti L, Viviani B, Calamandrei G. Short- and Long-Term Effects of Suboptimal Selenium Intake and Developmental Lead Exposure on Behavior and Hippocampal Glutamate Receptors in a Rat Model. Nutrients;2022 (Aug 10);14(16)

Selenium (Se) is an essential trace element required for normal development as well as to counteract the adverse effects of environmental stressors. Conditions of low Se intake are present in some European countries. Our aim was to investigate the short- and long-term effects of early-life low Se supply on behavior and synaptic plasticity with a focus on the hippocampus, considering both suboptimal Se intake per se and its interaction with developmental exposure to lead (Pb). We established an animal model of Se restriction and low Pb exposure; female rats fed with an optimal (0.15 mg/kg) or suboptimal (0.04 mg/kg) Se diet were exposed from one month pre-mating until the end of lactation to 12.5 µg/mL Pb via drinking water. In rat offspring, the assessment of motor, emotional, and cognitive endpoints at different life stages were complemented by the evaluation of the expression and synaptic distribution of NMDA and AMPA receptor subunits at post-natal day (PND) 23 and 70 in the hippocampus. Suboptimal Se intake delayed the achievement of developmental milestones and induced early and long-term alterations in motor and emotional abilities. Behavioral alterations were mirrored by a drop in the expression of the majority of NMDA and AMPA receptor subunits analyzed at PND 23. The suboptimal Se status co-occurring with Pb exposure induced a transient body weight increase and persistent anxiety-like behavior. From the molecular point of view, we observed hippocampal alterations in NMDA (Glun2B and GluN1) and AMPA receptor subunit trafficking to the post-synapse in male rats only. Our study provides evidence of potential Se interactions with Pb in the developing brain.

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46. 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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47. Vorstman JAS, Freitag CM, Persico AM. From Genes to Therapy in Autism Spectrum Disorder. Genes (Basel);2022 (Aug 1);13(8)

In recent years, findings from genetic and other biological studies are starting to reveal the role of various molecular mechanisms that contribute to the etiology of ASD […].

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48. Zamani Esfahlani F, Byrge L, Tanner J, Sporns O, Kennedy DP, Betzel RF. Edge-centric analysis of time-varying functional brain networks with applications in autism spectrum disorder. Neuroimage;2022 (Aug 27);263:119591.

The interaction between brain regions changes over time, which can be characterized using time-varying functional connectivity (tvFC). The common approach to estimate tvFC uses sliding windows and offers limited temporal resolution. An alternative method is to use the recently proposed edge-centric approach, which enables the tracking of moment-to-moment changes in co-fluctuation patterns between pairs of brain regions. Here, we first examined the dynamic features of edge time series and compared them to those in the sliding window tvFC (sw-tvFC). Then, we used edge time series to compare subjects with autism spectrum disorder (ASD) and healthy controls (CN). Our results indicate that relative to sw-tvFC, edge time series captured rapid and bursty network-level fluctuations that synchronize across subjects during movie-watching. The results from the second part of the study suggested that the magnitude of peak amplitude in the collective co-fluctuations of brain regions (estimated as root sum square (RSS) of edge time series) is similar in CN and ASD. However, the trough-to-trough duration in RSS signal is greater in ASD, compared to CN. Furthermore, an edge-wise comparison of high-amplitude co-fluctuations showed that the within-network edges exhibited greater magnitude fluctuations in CN. Our findings suggest that high-amplitude co-fluctuations captured by edge time series provide details about the disruption of functional brain dynamics that could potentially be used in developing new biomarkers of mental disorders.

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