1. Bilgen Ulgar Ş, Ayaydın H, Çelik H, Koyuncu İ, Kirmit A. Evaluation of antineuronal antibodies and 8-OHdG in mothers of children with autism spectrum disorder: a case-control study. International journal of psychiatry in clinical practice. 2021: 1-7.

OBJECTIVE: The purpose of our study was to investigated the anti-Yo, anti-Hu, anti-Ri, anti-amphiphysin antibody levels and 8-OHdG in mothers of children with autism. METHODS: This study included 60 participants, 33 of whom were healthy mothers of 3-12-year-old children diagnosed with autism spectrum disorder (ASD) and the 27 others who constituted the control group, were healthy mothers with age-matched healthy children. Two groups were examined for plasma anti-Yo, anti-Hu, anti-amphiphysin and anti-Ri antibodies and, 8-OHdG levels. The participants were asked to accomplish a sociodemographic data form. The severity of ASD symptoms was evaluated according to the Childhood Autism Rating Scale (CARS). RESULTS: Anti-amphiphysin antibody levels and anti-Ri antibody positivity were significantly higher in the case group (p = 0.001; p = 0.027, respectively). The two groups did not significantly differ in terms of anti-Yo and anti-Hu antibody levels and in terms of 8-OHdG levels (p = 0.065; p = 0.099; p = 0.490, respectively). The two groups did not significantly differ in terms of sociodemographic data (p > 0.05). CONCLUSIONS: According to the our study, maternal antineuronal antibodies, such as anti-amphiphysin and anti-Ri, may contribute to the risk of childhood autism. Studies with larger samples are needed.KEY POINTSMaternal factors associated with autism should be investigated in order to create early diagnosis and treatment opportunities for autism.Based on the importance of immunological and cerebellar pathologies in autism aetiology, we aimed to investigate antineuronal antibodies in mothers of children with autism.Maternal antineuronal antibodies, such as anti-amphiphysin and anti-Ri, may contribute to the risk of childhood autism.High anti-amphiphysin antibody levels in mothers of children with autism may also occur against the amphiphysin in the structure of the SrGAP3 gene, which is associated with autism.

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2. Buckley N, Stahlhut M, Elefant C, Leonard H, Lotan M, Downs J. Parent and therapist perspectives on « uptime » activities and participation in Rett syndrome. Disability and rehabilitation. 2021: 1-8.

PURPOSE: People with a disability may spend more time sitting and lying (« downtime ») and less time standing and walking (« uptime »). Caregivers and therapists supporting individuals with Rett syndrome were surveyed, aiming to gather insights on how to support participation in « uptime » activities. METHOD: An anonymous online survey including open ended questions about the enablers and barriers to « uptime » was administered to parent/caregivers and therapists/health professionals in an international sample. Responses were coded to the International Classification of Functioning, Health and Disability (ICF) framework identifying barriers, enablers, and strategies for increasing uptime activities. RESULTS: Parents (N = 115) and therapists (N = 49) completed the survey. Barriers and enablers to « uptime » were identified for all ICF domains and additional data coded to enabling access to the physical environment. Strategies to promote « uptime » activities and participation particularly related to the individual’s physical capacity and personal factors as well as social and physical environmental factors. CONCLUSIONS: Findings can inform the design of interventions aiming to increase « uptime » in individuals with Rett syndrome. Strategies should create individualised support by considering how to build fitness using activities that are motivating, at the same time creating opportunities for social interactions within a range of environments.IMPLICATIONS FOR REHABILITATION »Uptime » participation comprised a dynamic interaction of « doing » the standing or walking activity, with a sense of self-engagement with the activities and interaction with others.Strategies to promote « uptime » participation should consider how to create support for person-related attributes, including building physical capacity for a greater volume of « uptime » in activities that are enjoyable and motivating.Strategies to promote « uptime participation should also include creating a supportive environment, comprising opportunities for social interaction within a range of environments ».

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3. Budimirovic DB, Dominick KC, Gabis LV, Adams M, Adera M, Huang L, Ventola P, Tartaglia NR, Berry-Kravis E. Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study. Frontiers in pharmacology. 2021; 12: 757825.

Background: Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABA(A)) receptor δ subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a δ-subunit-selective, extrasynaptic GABA(A) receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS. Methods: This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors. Results: A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (n = 8), 5 mg BID (n = 8), or 5 mg TID (n = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (n = 4), headache (n = 3), diarrhea (n = 2), and irritability (n = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement. Conclusions: Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03697161.

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4. Cilia F, Carette R, Elbattah M, Dequen G, Guérin JL, Bosche J, Vandromme L, Le Driant B. Computer-Aided Screening of Autism Spectrum Disorder: Eye-Tracking Study Using Data Visualization and Deep Learning. JMIR human factors. 2021; 8(4): e27706.

BACKGROUND: The early diagnosis of autism spectrum disorder (ASD) is highly desirable but remains a challenging task, which requires a set of cognitive tests and hours of clinical examinations. In addition, variations of such symptoms exist, which can make the identification of ASD even more difficult. Although diagnosis tests are largely developed by experts, they are still subject to human bias. In this respect, computer-assisted technologies can play a key role in supporting the screening process. OBJECTIVE: This paper follows on the path of using eye tracking as an integrated part of screening assessment in ASD based on the characteristic elements of the eye gaze. This study adds to the mounting efforts in using eye tracking technology to support the process of ASD screening. METHODS: The proposed approach basically aims to integrate eye tracking with visualization and machine learning. A group of 59 school-aged participants took part in the study. The participants were invited to watch a set of age-appropriate photographs and videos related to social cognition. Initially, eye-tracking scanpaths were transformed into a visual representation as a set of images. Subsequently, a convolutional neural network was trained to perform the image classification task. RESULTS: The experimental results demonstrated that the visual representation could simplify the diagnostic task and also attained high accuracy. Specifically, the convolutional neural network model could achieve a promising classification accuracy. This largely suggests that visualizations could successfully encode the information of gaze motion and its underlying dynamics. Further, we explored possible correlations between the autism severity and the dynamics of eye movement based on the maximal information coefficient. The findings primarily show that the combination of eye tracking, visualization, and machine learning have strong potential in developing an objective tool to assist in the screening of ASD. CONCLUSIONS: Broadly speaking, the approach we propose could be transferable to screening for other disorders, particularly neurodevelopmental disorders.

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5. Elliott SJ, Marshall D, Morley K, Uphoff E, Kumar M, Meader N. Behavioural and cognitive behavioural therapy for obsessive compulsive disorder (OCD) in individuals with autism spectrum disorder (ASD). The Cochrane database of systematic reviews. 2021; 9(9): Cd013173.

BACKGROUND: Autistic spectrum disorder (ASD) is an increasingly recognised neurodevelopmental condition; that is, a neurologically-based condition which interferes with the acquisition, retention or application of specific skills. ASD is characterised by challenges with socialisation and communication, and by stereotyped and repetitive behaviours. A stereotyped behaviour is one which is repeated over and over again and which seems not to have any useful function. ASD often co-occurs with mental health disorders, including obsessive compulsive disorder (OCD). People with ASD may show certain cognitive differences (i.e. differences in ways of thinking) which influence their response to therapies. Thus, there is a need for evidence-based guidelines to treat mental health issues in this group. OCD, a common condition characterised by repeated obsessional thoughts and compulsive acts, occurs with greater frequency in persons with ASD than in the general population. Genetic, anatomic, neurobiological and psychological factors have been proposed to explain this co-occurrence. However, care should be taken to distinguish stereotyped and repetitive behaviours characteristic of ASD from obsessive compulsive acts in OCD. Cognitive behavioural therapy (CBT) is the recommended treatment for OCD, but studies have suggested that this treatment may be less effective in those with OCD co-occurring with ASD. Hence, modifications to CBT treatment may be helpful when treating OCD co-occurring with ASD to optimise outcomes. OBJECTIVES: To assess the effectiveness of behavioural and cognitive behavioural therapy for obsessive compulsive disorder (OCD) in children and adults with autism spectrum disorder (ASD). SEARCH METHODS: We searched for studies in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, five other bibliographic databases, international trial registries and other sources of grey literature (to 24 August 2020). We checked the reference lists of included studies and relevant systematic reviews to identify additional studies missed from the original electronic searches. We contacted subject experts for further information when needed. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cross-over, cluster- and quasi-randomised controlled trials involving both adults and children with diagnoses of OCD and ASD. We included studies of participants with co-occurring conditions (i.e. those experiencing other mental illnesses or neurodevelopmental conditions at the same time), but we did not include individuals who had a co-occurring global learning difficulty. Treatment could be in any setting or format and include behavioural therapy (BT) and cognitive behavioural therapy (CBT), which may have been adapted for those with ASD. Comparator interventions included no treatment, waiting list, attention placebo (where the control group receives non-specific aspects of therapy, but not the active ingredient) and treatment as usual (TAU, where the control group receives the usual treatment, according to accepted standards). DATA COLLECTION AND ANALYSIS: Three review authors independently screened studies for inclusion. The authors extracted relevant data from the one eligible study, assessed the risk of bias and certainty of evidence (GRADE). Outcomes of interest were changes in OCD symptoms and treatment completion (primary outcome), and severity of depressive symptoms, anxiety symptoms and behavioural difficulties, as well as degree of family accommodation (secondary outcomes). We did not conduct meta-analyses as only one study met the selection criteria. MAIN RESULTS: We included only one RCT of 46 participants in our analysis. This study compared CBT for OCD in persons with high-functioning ASD with a control group who received anxiety management only. There were no differences in rates of treatment completion between the CBT (87%) and anxiety management (87%) groups (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.80 to 1.25; low-certainty evidence). Behavioural difficulties were not included as an outcome measure in the study. This study showed that there may be a benefit at the end of treatment favouring CBT compared with anxiety management in OCD symptoms (mean difference (MD) -3.00, 95% CI -8.02 to 2.02), depression symptoms (MD -1.80, 95% CI -11.50 to 7.90), anxiety symptoms (MD -3.20, 95% CI -11.38 to 4.98), and quality of life (MD 5.20, 95% CI -1.41 to 11.81), but the evidence was of low certainty. AUTHORS’ CONCLUSIONS: Evidence is limited regarding the efficacy of CBT for treatment of OCD in ASD. There is much scope for future study, not only examining the efficacy of CBT for OCD in ASD, but also the particular ways that OCD manifests in and affects people with ASD and the role of the family in treatment response.

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6. Enriquez KD, Gupta AR, Hoffman EJ. Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder. Frontiers in psychiatry. 2021; 12: 716673.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders associated with deficits in social communication and restrictive, repetitive patterns of behavior, that affect up to 1 in 54 children. ASDs clearly demonstrate a male bias, occurring ~4 times more frequently in males than females, though the basis for this male predominance is not well-understood. In recent years, ASD risk gene discovery has accelerated, with many whole-exome sequencing studies identifying genes that converge on common pathways, such as neuronal communication and regulation of gene expression. ASD genetics studies have suggested that there may be a « female protective effect, » such that females may have a higher threshold for ASD risk, yet its etiology is not well-understood. Here, we review common biological pathways implicated by ASD genetics studies as well as recent analyses of sex differential processes in ASD using imaging genomics, transcriptomics, and animal models. Additionally, we discuss recent investigations of ASD risk genes that have suggested a potential role for estrogens as modulators of biological pathways in ASD, and highlight relevant molecular and cellular pathways downstream of estrogen signaling as potential avenues for further investigation.

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7. Fombonne E, Croen LA, Bulkley JE, Varga AM, Daida YG, Hatch BA, Dickerson JF, Lynch FL. Emotional and Behavioral Problems in Youth with Autism: High Prevalence and Impact on Functioning. Journal of developmental and behavioral pediatrics : JDBP. 2021.

OBJECTIVE: Emotional and behavioral problems (EBPs) may co-occur with autism spectrum disorder (ASD) and impair children’s functioning beyond autism symptomatology. We compared the prevalence of EBPs in youths with or without ASD and evaluated their unique contribution to impairment in ASD. METHODS: We surveyed 1267 children (79.4% boys, mean age: 9.2 years, range: 3-17) recruited at 3 sites in Kaiser Permanente and OCHIN primary care clinical networks, with confirmed International Classification of Diseases-10th ed. diagnosis of ASD (N = 564), asthma (N = 468), or neither (N = 429). Children from the 2 comparison groups were age-matched and sex-matched to the ASD group. EBPs and impairment were measured by the Strengths and Difficulties Questionnaire and autism symptomatology by the Social Responsiveness Scale in the ASD group only. RESULTS: EBPs and impairment mean scores were significantly (p < 0.001) higher in participants with ASD compared with children from the 2 comparison groups, across sexes and age groups, with no significant difference between the asthma and control groups. Among children with ASD, both EBPs and autistic symptoms were significantly correlated with impairment (r = 0.64 and r = 0.65, respectively) and explained a significant proportion of impairment variance (R2 = 0.525; p < 0.001) in multiple linear regression. In the relative importance analysis, EBPs and autistic symptoms explained comparable proportions of impairment variance (46% and 52%, respectively) with no significant difference between their relative weights (mean difference: 0.03; 95% confidence interval: -0.049 to 0.114). CONCLUSION: Among youth with ASD, high levels of EBPs impair daily functioning as much as autistic symptoms. Systematic detection and management of EBPs may improve functioning and outcomes in youth with ASD.

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8. Hogan A, Hunt E, Smith K, Black C, Bangert K, Klusek J, Roberts J. Trajectories of Heart Activity Across Infancy to Early Childhood Differentially Predict Autism and Anxiety Symptoms in Fragile X Syndrome. Frontiers in psychiatry. 2021; 12: 727559.

Background: Fragile X syndrome (FXS) is a monogenic disorder characterized by high rates of autism spectrum disorder (ASD) and anxiety. A longstanding « hyperarousal hypothesis » in FXS has argued that ANS dysfunction underpins many symptoms of FXS. However, the developmental onset and trajectory of ANS dysfunction, as well as the consequences of ANS dysfunction on later psychiatric symptoms, remain poorly understood in FXS. Insight into the emergence, trajectory, and consequences of ANS dysfunction across early development in FXS has critical implications for prevention, intervention, and optimal outcomes in both typical and atypical development. This longitudinal study investigated whether and when males with FXS evidence atypical ANS function from infancy through early childhood, and how trajectories of ANS function across infancy and early childhood predict ASD and anxiety symptom severity later in development. Methods: Participants included 73 males with FXS and 79 age-matched typically developing (TD) males. Baseline heart activity was recorded at multiple assessments between 3 and 83 months of age, resulting in 372 observations. General arousal and parasympathetic activity were indexed via interbeat interval (IBI) and respiratory sinus arrhythmia (RSA), respectively. ASD and anxiety symptoms were assessed at 36 months of age or later in a subgroup of participants (FXS n = 28; TD n = 25). Results: Males with FXS exhibited atypical patterns of developmental change in ANS function across infancy and early childhood. As a result, ANS dysfunction became progressively more discrepant across time, with the FXS group exhibiting significantly shorter IBI and lower RSA by 29 and 24 months of age, respectively. Shorter IBI at 24 months and a flatter IBI slope across development predicted elevated anxiety symptoms, but not ASD symptoms, later in childhood in both FXS and TD males. Reduced RSA at 24 months predicted elevated ASD symptoms, but not anxiety symptoms, in both groups. Developmental change in RSA across early development did not predict later anxiety or ASD symptoms. Conclusion: This is the first longitudinal study to examine the « hyperarousal hypothesis » in infants and young children with FXS. Findings suggest that hyperarousal (i.e., shorter IBI, lower RSA) is evident in males with FXS by 24-29 months of age. Interestingly, unique aspects of early ANS function differentially relate to later ASD and anxiety symptoms. General arousal, indexed by shorter IBI that becomes progressively more discrepant from TD controls, predicts later anxiety symptoms. In contrast, parasympathetic-related factors, indexed by lower levels of RSA, predict ASD symptoms. These findings support the « hyperarousal hypothesis » in FXS, in that ANS dysfunction evident early in development predicts later-emerging symptoms of ASD and anxiety. This study also have important implications for the development of targeted treatments and interventions that could potentially mitigate the long-term effects of hyperarousal in FXS.

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9. Hongkaew Y, Gaedigk A, Wilffert B, Gaedigk R, Kittitharaphan W, Ngamsamut N, Limsila P, Puangpetch A, Sukprasong R, Sukasem C. Pharmacogenomics Factors Influencing the Effect of Risperidone on Prolactin Levels in Thai Pediatric Patients With Autism Spectrum Disorder. Frontiers in pharmacology. 2021; 12: 743494.

We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor (DRD2) gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of DRD2/ankyrin repeat and kinase domain containing 1 (ANKK1) Taq1A, DRD2 -141C indel, and DRD2 -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. DRD2 diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing DRD2 haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.

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10. Hosozawa M, Yamasaki S, Ando S, Endo K, Morimoto Y, Kanata S, Fujikawa S, Cable N, Iso H, Hiraiwa-Hasegawa M, Kasai K, Nishida A. Lower help-seeking intentions mediate subsequent depressive symptoms among adolescents with high autistic traits: a population-based cohort study. European child & adolescent psychiatry. 2021.

Adolescents with high autistic traits are at increased risk of depression. Despite the importance of seeking help for early intervention, evidence on help-seeking intentions amongst this population is scarce. Using a population-based cohort in Japan, we examined adolescents’ help-seeking intentions and preferences by the level of autistic traits and tested its mediating role on the association between high autistic traits and depressive symptoms. At age 12, we measured parent-rated autistic traits using the short version of the Autism Spectrum Quotient and classified the adolescents into two groups (≥ 6 as AQhigh, < 6 as AQlow); help-seeking intentions and preferences were assessed through a depression vignette. At age 14, depressive symptoms were self-rated using the Short Mood and Feelings Questionnaire. Hypothesised associations between autistic traits and help-seeking intentions or depressive symptoms were tested applying multivariable regression modelling, while mediation was tested with structural equation modelling. Of the 2505 adolescent participants, 200 (8%) were classified as AQhigh. In both groups, the main source of help-seeking was their family; however, 40% of the AQhigh group reported having no help-seeking intentions compared to 27% in the AQlow. The AQhigh group was at increased risk of not having help-seeking intentions (OR 1.84, 95% CI 1.35-2.50) and higher depressive symptoms (b coefficient 1.06, 0.33-1.79). Help-seeking intentions mediated 18% of the association mentioned above. Interventions to promote help-seeking intentions among adolescents with high autistic traits could reduce their subsequent depressive symptoms. Ideally, such interventions should be provided prior to adolescence and with the involvement of their parents.

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11. Janwadkar RS, Byun S, Rootes A, Prakash N. Self-Perceived Independent Living Skills and Self-Determination as a Method of Evaluating a Residential Program in Young Adults With Autism Spectrum Disorder. Cureus. 2021; 13(9): e18133.

Prior research shows that employment programs for individuals with autism spectrum disorder (ASD) fail to address ASD as a heterogeneous disorder and focus on specific ASD traits associated with difficulty in obtaining and maintaining employment. This study provides descriptive evidence that self-perceptions of self-determination improve in young adults with ASD who participate in a residential program that promotes Wehmeyer and Schalock’s essential characteristics of self-determined behavior: behavioral autonomy, self-regulated behavior, acting in a psychologically empowered manner, and self-realization. Qualitative surveys were administered to 60 participants (17-28 years old) on perceptions of self-determination, confidence in independent living skills, and program effectiveness regarding case management and sustainable employment. One-sided t-tests using pre- and post-program responses were assessed. Post- versus pre-program means were significantly higher in participants feeling confident to live alone (p = 0.0059). Findings suggest that programs adopting self-determined behavior may be more effective in increasing self-confidence for individuals with ASD. However, these findings warrant long-term analysis to assess the continuity of program success and sustained employment.

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12. Kim HJ, Bayarsaikhan D, Lee J, Bayarsaikhan G, Lee B. Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models. Frontiers in neuroscience. 2021; 15: 725398.

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene; MeCP2 regulates the expression of brain-derived neurotrophic factor (BDNF) and increasing BDNF levels ameliorates RTT symptoms. However, the clinical application of BDNF is limited, because of its short half-life and low penetrance across the blood-brain barrier. In this study, we generated BDNF-secreting mesenchymal stem cells (MSCs) from the human umbilical cord cells, using CRISPR-Cas9. We studied the effects of BDNF-MSCs in MECP2 knockout and MECP2-deficient mice. BDNF-MSCs upregulated the expression of BDNF, pAKT, and pERK1/2 and downregulated that of pp38, both in vitro and in vivo. In our in vivo experiments, BDNF-MSCs increased the body and brain weights in mice. BDNF-MSCs increased the neuronal cell numbers in the hippocampus, cortex, and striatum; in addition, they increased the number of synapses. BDNF-MSCs upregulated BDNF and the activity of BDNF downstream effectors, such as pAKT and pERK 1/2; this upregulation was persistent. In conclusion, BDNF-MSCs generated using CRISPR-Cas9 could be a therapeutic strategy for treating RTT.

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13. Klau J, Abou Jamra R, Radtke M, Oppermann H, Lemke JR, Beblo S, Popp B. Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders. European journal of human genetics : EJHG. 2022; 30(1): 117-25.

This single-center study aims to determine the time, diagnostic procedure, and cost saving potential of early exome sequencing in a cohort of 111 individuals with genetically confirmed neurodevelopmental disorders. We retrospectively collected data regarding diagnostic time points and procedures from the individuals’ medical histories and developed criteria for classifying diagnostic procedures in terms of requirement, followed by a cost allocation. All genetic variants were re-evaluated according to ACMG recommendations and considering the individuals’ phenotype. Individuals who developed first symptoms of their underlying genetic disorder when Next Generation Sequencing (NGS) diagnostics were already available received a diagnosis significantly faster than individuals with first symptoms before this cutoff. The largest amount of potentially dispensable diagnostics was found in genetic, metabolic, and cranial magnetic resonance imaging examinations. Out of 407 performed genetic examinations, 296 (72.7%) were classified as potentially dispensable. The same applied to 36 (27.9%) of 129 cranial magnetic resonance imaging and 111 (31.8%) of 349 metabolic examinations. Dispensable genetic examinations accounted 302,947.07€ (90.2%) of the total 335,837.49€ in potentially savable costs in this cohort. The remaining 32,890.42€ (9.8%) are related to non-required metabolic and cranial magnetic resonance imaging diagnostics. On average, the total potentially savable costs in our study amount to €3,025.56 per individual. Cost savings by first tier exome sequencing lie primarily in genetic, metabolic, and cMRI testing in this German cohort, underscoring the utility of performing exome sequencing at the beginning of the diagnostic pathway and the potential for saving diagnostic costs and time.

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14. Kobinia GS, Zaknun JJ, Pabinger C, Laky B. Case Report: Autologous Bone Marrow Derived Intrathecal Stem Cell Transplant for Autistic Children – A Report of Four Cases and Literature Review. Frontiers in pediatrics. 2021; 9: 620188.

Despite steadily growing numbers of children diagnosed with autism spectrum disorders (ASD), causative treatment is unavailable. Recently, biological cell therapies involving pluripotent cells have raised hopes towards sustained beneficial outcome. We herein report data of four children diagnosed with ASD, who were treated with autologous, bone marrow (BM)-derived, intrathecally and simultaneously intravenously applied, point-of-care stem cell transplant (SCT). The three boys and one girl received the diagnosis at ages between 2-4 years. The decision to perform the procedure was preceded by limited beneficiary impact of conventional symptom-based, psychological and pharmacological interventions. At ages of 4-14 years the children received their SCT, no immediate or late adverse events were reported. Disappearance of symptoms were observed by the parents during the following year and consequently improved Autism Treatment Evaluation Checklist (ATEC) scores were reported. The SCT procedure, in trained hands, can be a safe and promising treatment option in children with ASD, responding in a non-satisfactory manner to conventional treatments. It is postulated that SCT may, among others, assert its positive effect by counteracting a cerebral inflammatory autoimmune process which in turn supports the responsiveness to behavioral and pharmacological interventions. Our results in this small group are encouraging, but certainly need further investigation in larger cohorts.

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15. Li B, Tsou YT, Stockmann L, Greaves-Lord K, Rieffe C. See the self through others’ eyes: The development of moral emotions in young children with autism spectrum disorder. Development and psychopathology. 2021: 1-11.

Despite the important social functions of moral emotions, they are understudied in the autism spectrum disorder (ASD) population. This three-wave longitudinal study is among the first to examine the development of moral emotions and their associations with theory of mind in 3- to 7-year-old children with ASD, using observational tasks. One hundred and forty-two children (52 with ASD) were followed over a period of 2 years. We found that while the expressions of shame and guilt remained stable in non-ASD children, they decreased with age in children with ASD. No group differences were found in the levels or the developmental trajectories of pride. Besides, better false-belief understanding was uniquely related to the expressions of pride in children with ASD. Our findings highlight the importance of enhancing understanding of moral emotion development and related factors in children with ASD.

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16. Lotufo Denucci B, Silva de Lima L, Ferreira Lima Mota I, Rocha Madureira Azevedo J, Germino Veras L, Montenegro Luzardo Bicca JV, de Miranda Santana B, Beserra Pinheiro G, Gonçalves Coelho G, Mortari MR. Current knowledge, challenges, new perspectives of the study, and treatments of Autism Spectrum Disorder. Reproductive toxicology (Elmsford, NY). 2021; 106: 82-93.

Over the past 70 years, the understanding of Autism Spectrum Disorder (ASD) improved greatly and is characterized as a heterogeneous neuropsychiatric syndrome. ASD is characterized by difficulties in social communication, restricted and repetitive behavior, interests, or activities. And it is often described as a combination of genetic predisposition and environmental factors. There are many treatments and approaches to ASD, including pharmacological therapies with antipsychotics, antidepressants, mood regulators, stimulants, and behavioral ones. However, no treatment is capable of reverting ASD. This review provides an overview of animal models of autism. We summarized genetic and environmental models and then valproic acid treatment as a useful model for ASD. As well as the main therapies and approaches used in the treatment, relating them to the neurochemical pathways altered in ASD, emphasizing the pharmacological potential of peptides and bioinspired compounds found in animal venoms as a possible future treatment for ASD.

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17. Morandini JS, Kelly A, de Graaf NM, Carmichael P, Dar-Nimrod I. Shifts in demographics and mental health co-morbidities among gender dysphoric youth referred to a specialist gender dysphoria service. Clinical child psychology and psychiatry. 2022; 27(2): 480-91.

Past research has identified shifts in the demographics and co-occurring mental health issues of youth referred to certain gender dysphoria services. The present study examined shifts in demographics (age, sex and social transition status), social adversity (bullying experiences and abuse) and psychological functioning (mood, anxiety, suicidality and autism spectrum disorder) at time of referral (of both children and adolescents) to the Gender Identity Development Service, London between the years of 2012 and 2015. Patients were 782 children and adolescents (M = 13.94, SD = 2.94, range 4-17; 63.8% assigned female at birth). Little change in sex ratio or age was observed between these two time points. However, we observed greater rates of depression and anxiety of birth-assigned females (but not birth-assigned males) in the more recent cohort, at the same time that reported social adversity (bullying and abuse) was falling. Also, of interest, the proportion of young people who had partially or fully socially transitioned prior to contact with the service had increased overtime. We discuss potential factors driving these shifts and their implications for supporting recent cohorts of gender diverse young people.

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18. Moxon-Emre I, Daskalakis ZJ, Blumberger DM, Croarkin PE, Lyon RE, Forde NJ, Tani H, Truong P, Lai MC, Desarkar P, Sailasuta N, Szatmari P, Ameis SH. Modulation of Dorsolateral Prefrontal Cortex Glutamate/Glutamine Levels Following Repetitive Transcranial Magnetic Stimulation in Young Adults With Autism. Frontiers in neuroscience. 2021; 15: 711542.

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F ((1,) (19)) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t ((18)) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD. Clinical Trial Registration: Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

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19. Nouri N, Bahreini A, Nasiri J, Salehi M. Clinical and genetic profile of children with unexplained intellectual disability/developmental delay and epilepsy. Epilepsy research. 2021; 177: 106782.

OBJECTIVE: This study was conducted to evaluate the validity of performing whole exome sequencing in children with unexplained intellectual disability (ID), developmental delay (DD), and epilepsy. METHODS: We enrolled 61 Iranian children with unexplained DD/ID, and epilepsy with no etiologic diagnosis. 64 % of cases were male and 36 % were female, with a mean age of 6.2 years (range, 38 days to 15 years). Approximately 79 % of patients were born to consanguineous parents or had non-related parents from a highly inbred local region. Whole-exome sequencing analysis followed by Sanger sequencing was performed in all patients. RESULTS: Pathogenic/likely pathogenic variants were identified in 59% (36/61) of patients, consisting of 26 novel and 14 known alterations. Variants of unknown significance were observed in 6.5 % (4/61) of patients. Variants in 28 genes have not been previously reported in Iranian patients with ID. Several additional phenotypes, mostly microcephaly, were common in 57.4 % of cases. Additionally, epilepsy was refractory in 40 % of patients. Three groups of brain anomalies consisting of brain dysgenesis, brain atrophy, and leukodystrophy were identified in our cohort. Mutations in genes implicated in cellular metabolic pathways were the most common, followed by ion channel/ion transporter and transcription pathways. DISCUSSION: High-throughput DNA sequencing of the Iranian population with a high rate of parental consanguinity is a valuable strategy for identifying genetic etiology in children with unexplained ID/DD and epilepsy. Determining the genetic basis and most commonly involved pathways may help to identify novel genes and targeted antiepileptic treatments.

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20. Oh M, Laugeson E, Kim JH, Lee K, Kim J, Lee S, Lim B, Cha S, Bong G, Yoon NH, Bahn GH, Yoo HJ. A Randomized Controlled Trial of the Korean Version of the Program for the Education and Enrichment of Relational Skills for Young Adults (PEERS®-YA-K) With Autism Spectrum Disorder: A Pilot Study. Frontiers in psychiatry. 2021; 12: 730448.

Evidence-based social skills interventions for young adults are limited, despite social difficulties in autism spectrum disorder (ASD) persisting after transition to adulthood. The Program for the Education and Enrichment of Relational Skills for Young Adults (PEERS®-YA) is an evidence-based intervention found to be effective in improving relational skills in young adults with ASD. To translate the original American version of the PEERS®-YA treatment manual into Korean, intensive interviews were performed. Based on results from interviews, several rules of dating etiquette and social activities were modified to be culturally sensitive and linguistically appropriate. Next, young adults diagnosed with ASD (18-35 years of age; IQ > 70) and their social coaches were recruited for the randomized controlled trial (RCT). Participants were randomly assigned either to a treatment group (TG; n = 19) or a delayed treatment group (DTG; n = 18). In the analysis of group differences in the TG and DTG, social skills knowledge was improved. The within group analyses showed positive effects of improving social skills knowledge on reducing depression and anxiety symptoms. After modest cultural adaptations focusing on dating and social activities, the implementation of the PEERS®-YA-K was found feasible for the Korean community. This is one of only a few cross-cultural validation trials establishing evidence-based treatment in young adults with ASD. Clinical Trial Registration: This trial was registered at ClinicalTrials.gov, identifier: NCT03310775.

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21. Parry JA, Newton T, Linehan C, Ryan C. Dental Visits for Autistic Children: A Qualitative Focus Group Study of Parental Perceptions. JDR clinical and translational research. 2021: 23800844211049404.

INTRODUCTION: Patient groups who pose behavioral challenges during dental attendance may be offered more restricted dental treatment options. Unsuccessful participation with dental visit tasks and demands has been commonly reported for autistic children. OBJECTIVES: This study aimed to examine parental perceptions of difficulties associated with dental attendance and oral care for autistic children and young adults, to highlight reported challenges and potential adaptations, and to identify interventions that will encourage positive experiences of dental attendance. METHODS: Qualitative data were gathered through 2 focus groups with parents of primary school and secondary school pupils with autism, interviewed in separate groups. Questions about parents’ perceptions of dental attendance and oral care were asked. The groups were audio-recorded and transcribed verbatim. The transcripts were analyzed and initial codes generated. Development of subthemes and themes followed a process of thematic analysis. RESULTS: Parental perceptions, which confirmed data from other studies, included the need for understanding and training, awareness of sensory issues, recognition of the individuality of autistic traits, time and clarity for communication, and factors affecting the confidence of parents to advocate in the clinical environment. Focus group participants identified the critical value of empathizing with an autistic perspective and highlighted the importance of positive oral health messages. They also noted the lack of understanding regarding the complexity of altering self-imposed, ritualistic dietary regimes and attempting to enact good dental preventive habits for their children. CONCLUSIONS: Analysis of data from parent focus groups provided a greater understanding of the needs and responsivity required for successful dental visits for autistic children and young adults. A range of potential interventions was identified and incorporated within a model of needs. Interventions based on Partnership Working, System Change, and Training of Dental Staff could be effective in reducing challenges posed by dental attendance for many children with autism. KNOWLEDGE TRANSFER STATEMENT: Sensory sensitivities, communication difficulties, comorbid intellectual disability, and dental anxiety are barriers to successful participation during dental attendance for autistic children. This research proposes that interventions supporting Partnership Working, System Change, and Training of Dental Staff can reduce challenges posed by dental attendance. The model of interventions developed as part of this project can be used by oral care teams to help reduce barriers and improve the success of dental visits for autistic children.

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22. Razak KA, Binder DK, Ethell IM. Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome. Frontiers in psychiatry. 2021; 12: 720752.

The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

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23. Reynolds KE, Krasovska V, Scott AL. Converging purinergic and immune signaling pathways drive IL-6 secretion by Fragile X cortical astrocytes via STAT3. Journal of neuroimmunology. 2021; 361: 577745.

The symptoms of Fragile X syndrome (FXS) are driven in part by abnormal glial-mediated function. FXS astrocytes release elevated levels of immune-related factors interleukin-6 (IL-6) and tenascin C (TNC), and also demonstrate increased purinergic signaling, a pathway linked to signaling factor release. Here, in cortical astrocytes from the Fmr1 knockout (KO) FXS mouse model, purinergic agonism enhanced TNC secretion and STAT3 phosphorylation, two processes linked to elevated IL-6 secretion in FXS, while STAT3 knockdown and TLR4 antagonism normalized Fmr1 KO IL-6 release. We therefore suggest that purinergic signaling and immune regulatory pathways converge to drive FXS cortical pro-inflammatory responses.

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24. Smith AR, Hunt RA, Grunewald W, Jeon ME, Stanley IH, Levinson CA, Joiner TE. Identifying Central Symptoms and Bridge Pathways Between Autism Spectrum Disorder Traits and Suicidality Within an Active Duty Sample. Archives of suicide research : official journal of the International Academy for Suicide Research. 2021: 1-16.

OBJECTIVE: This study employed network analysis to characterize central autism spectrum disorder (ASD) traits and suicide symptoms within an active duty military sample as well as to identify symptoms that may bridge between ASD traits and suicidality (i.e., suicidal ideation and behaviors). METHOD: Participants were active duty U.S. military service members (N = 287). Autism spectrum traits, suicidality, depression, and suicide related constructs were assessed online via self-report. RESULTS: Within the combined ASD trait-suicidality network, suicide rumination, suicide behaviors, and depression had the highest strength centrality. The most central bridge symptoms between ASD and suicidality were thwarted belongingness, social skills deficits, and depressive symptoms. CONCLUSIONS: Social skills deficits and thwarted belongingness may function as a meaningful bridge between ASD symptoms and suicidality within active duty members. Individuals with ASD symptoms who additionally present with high levels of thwarted belongingness and/or considerable social skills deficits may be at increased risk for suicidality.HIGHLIGHTSWithin an ASD-suicidality network, social skills deficits, low belonging, and depression had the greatest bridge strength.Although low belonging emerged as a bridge symptom, perceived burdensomeness did not.Suicide rumination, suicide behaviors, and depression were the most central symptom in an ASD-suicidality network.Symptoms related to social skills deficits may connect ASD traits and suicidality.

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25. Tasew S, Mekonnen H, Goshu AT. Knowledge of childhood autism among nurses working in governmental hospitals of Addis Ababa, Ethiopia. SAGE open medicine. 2021; 9: 20503121211049121.

INTRODUCTION: Autism is a neurodevelopmental disorder that occurs in the early childhood period and is characterized by altered social interaction, communication problems, repetitive, and stereotyped behavior. Genetic, environmental, or physical risk factors are associated with prenatal, natal, or postnatal complications, leading to the development of autism spectrum disorders. Prompt diagnosis and management should be an integral component of the care provision in countries like Ethiopia. OBJECTIVE: This study aimed to assess knowledge of childhood autism among nurses working in governmental hospitals in Addis Ababa, Ethiopia. METHODS: Institutional based cross-sectional study design was used. The sample size was calculated using the single population proportion formula, and the final sample size was 360. Final study subjects were selected by using the simple random sampling method. Data were collected using structured self-administered questionnaires and were then coded and entered into Epi-data version 3.1 and exported to SPSS version 21 for analysis. Descriptive statistics were utilized to show frequencies and percentages, and analysis of variance was carried out to compute the association between the dependent and independent variables. Independent t-test was also done to see the association between dependent variables and independent variables with two means. A p-value of less than 0.05 was considered statistically significant. RESULTS: The mean score for knowledge-related items was 8.79 ± 0.4. In this study, out of 331 nurses, 180 (54.35%) had good knowledge. Significant mean score difference was observed among age distribution (F-Ratio = 2.8, p-value = 0.04), level of education (F-ratio = 13.97, p < 0.001) and work experience (F-Ratio = 3.07 p-value = 0.017). CONCLUSION: A significant gap was observed in the overall knowledge of childhood autism among nurses employed in the governmental hospitals of Addis Ababa. The respondents' knowledge level was significantly different among age group distributions, education levels, and work experience.

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26. Todorova GK, Pollick FE, Muckli L. Special treatment of prediction errors in autism spectrum disorder. Neuropsychologia. 2021; 163: 108070.

For autistic individuals, sensory stimulation can be experienced as overwhelming. Models of predictive coding postulate that cortical mechanisms disamplify predictable information and amplify prediction errors that surpass a defined precision level. In autism, the neuronal processing is putting an inflexibly high precision on prediction errors according to the HIPPEA theory (High, Inflexible Precision of Prediction Errors in Autism). We used an apparent motion paradigm to test this prediction. In apparent motion paradigms, the illusory motion of an object creates a prediction about where and when an internally generated token would be moving along the apparent motion trace. This illusion facilitates the perception of a flashing stimulus (target) appearing in-time with the apparent motion token and is perceived as a predictable event (predictable target). In contrast, a flashing stimulus appearing out-of-time with the apparent motion illusion is an unpredictable target that is less often detected even though it produces a prediction error signal. If a prediction error does not surpass a given precision threshold the stimulation event is discounted and therefore less often detected than predictable tokens. In autism, the precision threshold is lower and the same prediction errors (unpredictable target) triggers a detection similar to that of a predictable flash stimulus. To test this hypothesis, we recruited 11 autistic males and 9 neurotypical matched controls. The participants were tasked to detect flashing stimuli placed on an apparent motion trace either in-time or out-of-time with the apparent motion illusion. Descriptively, 66% (6/9) of neurotypical and 64% (7/11) of autistic participants were better at detecting predictable targets. The prediction established by illusory motion appears to assist autistic and neurotypical individuals equally in the detection of predictable over unpredictable targets. Importantly, 55% (6/11) of autistic participants had faster responses for unpredictable targets, whereas only 22% (2/9) of neurotypicals had faster responses to unpredictable compared to predictable targets. Hence, these tentative results suggest that for autistic participants, unpredictable targets produce an above threshold prediction error, which leads to faster response. This difference in unpredictable target detection can be encapsulated under the HIPPEA theory, suggesting that precision setting could be aberrant in autistic individuals with respect to prediction errors. These tentative results should be considered in light of the small sample. For this reason, we provide the full set of materials necessary to replicate and extend the results.

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27. Uchigashima M, Cheung A, Futai K. Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction. Frontiers in molecular neuroscience. 2021; 14: 749164.

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.

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28. Unwin KL, Powell G, Jones CR. The use of Multi-Sensory Environments with autistic children: Exploring the effect of having control of sensory changes. Autism : the international journal of research and practice. 2021: 13623613211050176.

Multi-Sensory Environments (also called sensory or Snoezelen(®) rooms) are rooms that contain equipment which can create light, sound and touch experiences. Multi-Sensory Environments are often used with autistic children, particularly in schools, but there is no evidence for how best to use them. We investigated whether having control over the sensory equipment in the Multi-Sensory Environment affected how a group of 41 (8 female) autistic children aged 4-12 years behaved. We found that when autistic children could control the sensory equipment, they paid more attention and performed fewer repetitive and sensory behaviours. They also used less stereotyped speech, produced fewer vocalisations and showed lower levels of activity. Other behaviours were not affected. Our findings demonstrate that how a Multi-Sensory Environment is used can impact behaviour and that providing control of sensory changes to autistic children may help create better conditions for learning.

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29. Wu C, Liaqat S, Helvaci H, Cheung SS, Chuah CN, Ozonoff S, Young G. Machine Learning Based Autism Spectrum Disorder Detection from Videos. Healthcom International Conference on e-Health Networking, Applications and Services. 2021; 2020.

Early diagnosis of Autism Spectrum Disorder (ASD) is crucial for best outcomes to interventions. In this paper, we present a machine learning (ML) approach to ASD diagnosis based on identifying specific behaviors from videos of infants of ages 6 through 36 months. The behaviors of interest include directed gaze towards faces or objects of interest, positive affect, and vocalization. The dataset consists of 2000 videos of 3-minute duration with these behaviors manually coded by expert raters. Moreover, the dataset has statistical features including duration and frequency of the above mentioned behaviors in the video collection as well as independent ASD diagnosis by clinicians. We tackle the ML problem in a two-stage approach. Firstly, we develop deep learning models for automatic identification of clinically relevant behaviors exhibited by infants in a one-on-one interaction setting with parents or expert clinicians. We report baseline results of behavior classification using two methods: (1) image based model (2) facial behavior features based model. We achieve 70% accuracy for smile, 68% accuracy for look face, 67% for look object and 53% accuracy for vocalization. Secondly, we focus on ASD diagnosis prediction by applying a feature selection process to identify the most significant statistical behavioral features and a over and under sampling process to mitigate the class imbalance, followed by developing a baseline ML classifier to achieve an accuracy of 82% for ASD diagnosis.

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