1. Andrade E, Portela S, Pinheiro PR, Nunes LC, Filho MS, Costa WS, Pinheiro MCD. A Protocol for the Diagnosis of Autism Spectrum Disorder Structured in Machine Learning and Verbal Decision Analysis. Computational and mathematical methods in medicine. 2021; 2021: 1628959.

Autism Spectrum Disorder is a mental disorder that afflicts millions of people worldwide. It is estimated that one in 160 children has traces of autism, with five times the higher prevalence in boys. The protocols for detecting symptoms are diverse. However, the following are among the most used: the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), of the American Psychiatric Association; the Revised Autistic Diagnostic Observation Schedule (ADOS-R); the Autistic Diagnostic Interview (ADI); and the International Classification of Diseases, 10th edition (ICD-10), published by the World Health Organization (WHO) and adopted in Brazil by the Unified Health System (SUS). The application of machine learning models helps make the diagnostic process of Autism Spectrum Disorder more precise, reducing, in many cases, the number of criteria necessary for evaluation, denoting a form of attribute engineering (feature engineering) efficiency. This work proposes a hybrid approach based on machine learning algorithms’ composition to discover knowledge and concepts associated with the multicriteria method of decision support based on Verbal Decision Analysis to refine the results. Therefore, the study has the general objective of evaluating how the mentioned hybrid methodology proposal can make the protocol derived from ICD-10 more efficient, providing agility to diagnosing Autism Spectrum Disorder by observing a minor symptom. The study database covers thousands of cases of people who, once diagnosed, obtained government assistance in Brazil.

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2. Chong PLH, Abel E, Pao R, McCormick CEB, Schwichtenberg AJ. Sleep Dysregulation and Daytime Electrodermal Patterns in Children With Autism: A Descriptive Study. The Journal of genetic psychology. 2021; 182(5): 335-47.

Sleep deficiency influences emotion and behavior regulation but the mechanisms of influence are poorly understood. Emotion, behavioral, and sleep theories highlight differences in autonomic function as a potential pathway of influence and research in typical populations draw links between sleep deficiency and autonomic dysregulation (e.g., elevated reactivity within the sympathetic nervous system). In populations at elevated risk for sleep deficiency/problems (i.e., individuals with autism), greater variability in sleep and autonomic/arousal profiles may be particularly informative. Using electrodermal activity (EDA) as an indicator of sympathetic nervous system activation, this descriptive pilot study aimed to document daytime EDA patterns in children with autism and to explore their relations with sleep dysregulation/deficiency. EDA and sleep were measured using ankle and wrist worn sensors in 13 children (Mean(age) 6.11 years). EDA indices included nonspecific skin conductance responses (NSSCR) and tonic skin conductance levels (SCL). Descriptively, children in the dysregulated sleep group had fewer NSSCRs and lower SCL in the afternoon. This blunted physiological arousal profile/pattern is consistent with previous research, but this is the first study to explore how sleep may be linked. Notably, this pattern may not reflect sleep but an overall dysregulation profile which in this sample included: dysregulated sleep, a blunted afternoon arousal profile, and elevated ASD symptom severity. Replication with larger, more diverse samples is needed to disentangle the complex relations among sleep, arousal, and ASD behavioral features. However, this study represents an important first step in documenting extended daytime arousal patterns.

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3. Cuve HC, Castiello S, Shiferaw B, Ichijo E, Catmur C, Bird G. Alexithymia explains atypical spatiotemporal dynamics of eye gaze in autism. Cognition. 2021; 212: 104710.

Recognition of emotional facial expressions is considered to be atypical in autism. This difficulty is thought to be due to the way that facial expressions are visually explored. Evidence for atypical visual exploration of emotional faces in autism is, however, equivocal. We propose that, where observed, atypical visual exploration of emotional facial expressions is due to alexithymia, a distinct but frequently co-occurring condition. In this eye-tracking study we tested the alexithymia hypothesis using a number of recent methodological advances to study eye gaze during several emotion processing tasks (emotion recognition, intensity judgements, free gaze), in 25 adults with, and 45 without, autism. A multilevel polynomial modelling strategy was used to describe the spatiotemporal dynamics of eye gaze to emotional facial expressions. Converging evidence from traditional and novel analysis methods revealed that atypical gaze to the eyes is best predicted by alexithymia in both autistic and non-autistic individuals. Information theoretic analyses also revealed differential effects of task on gaze patterns as a function of alexithymia, but not autism. These findings highlight factors underlying atypical emotion processing in autistic individuals, with wide-ranging implications for emotion research.

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4. Estes A, Yoder P, McEachin J, Hellemann G, Munson J, Greenson J, Rocha M, Gardner E, Rogers SJ. The effect of early autism intervention on parental sense of efficacy in a randomized trial depends on the initial level of parent stress. Autism : the international journal of research and practice. 2021; 25(7): 1924-34.

This is a study of the secondary effects of interventions for young children with autism on their parents. Specifically, we were interested in the impact on parent’s sense of efficacy, or how confident and competent a parent feels about themselves as a parent. We tested three ideas: (1) that the style of the intervention, whether it was more or less structured and whether the parent had a more or less formal role, would impact a parent’s sense of efficacy; (2) that the intensity of the intervention, how many hours per week the intervention was delivered, would impact parental efficacy; and (3) that the parent’s level of stress prior to intervention would impact how intensity and style effected efficacy. We randomly assigned 87 children with autism, age 13-30 months, into one of four conditions: 15 versus 25 intervention hours crossed with two different styles of intervention. We used statistical tests to examine these ideas. We found that parental efficacy was related to intervention intensity but not style. Parents with higher stress at the beginning of a 1-year, home-based, comprehensive intervention program had a higher sense of parenting efficacy if their child received lower intensity intervention; parents with lower stress at baseline had a higher sense of efficacy if their child received higher intensity intervention. If a parent can emerge from the process of diagnosis and early intervention with an increased sense that they can make a difference in their child’s life (i.e. increased sense of efficacy), it may set the stage for meeting the long-term demands of parenting a child with autism.

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5. Fang Y, Wan C, Wen Y, Wu Z, Pan J, Zhong M, Zhong N. Autism-associated synaptic vesicle transcripts are differentially expressed in maternal plasma exosomes of physiopathologic pregnancies. Journal of translational medicine. 2021; 19(1): 154.

BACKGROUND: During intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children. The current study was designed to determine the dynamic profiles of differentially-expressed SVATs in circulating exosomes (EXs) derived from autistic children and pregnant women at different gestational ages. METHODS: Blood samples were collected from autistic children and women with variant physiopathologic pregnancies. EXs were isolated with an ExoQuick Exosome Precipitation Kit and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The expression of lncRNAs and lncRNA-targeted mRNAs were quantified using real-time PCR. RESULTS: SVAT-associated lncRNAs-mRNAs were detected in autistic children and differentially expressed from the first trimester of pregnancy to the term of delivery. Pathologic pregnancies, including spontaneous preterm birth (sPTB), preeclampsia (PE), and gestational diabetes mellitus (GDM), were compared to normal physiologic pregnancies, and shown to exhibit specific correlations between SVAT-lncRNA and SVAT-mRNA of STX8, SLC18A2, and SYP with sPTB; SVAT-lncRNA and SVAT-mRNA of STX8 with PE; and SVAT-lncRNA and SVAT-mRNA of SV2C as well as SVAT-mRNA of SYP with GDM. CONCLUSION: Variant complications in pathologic pregnancies may alter the GEP of SVATs, which is likely to affect the intrauterine development of neural circuits and consequently influence fetal brain development.

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6. Fujino J, Tei S, Itahashi T, Aoki YY, Ohta H, Izuno T, Nakamura H, Shimizu M, Hashimoto RI, Takahashi H, Kato N, Nakamura M. A single session of navigation-guided repetitive transcranial magnetic stimulation over the right anterior temporoparietal junction in autism spectrum disorder. Brain stimulation. 2021; 14(3): 682-4.

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7. Gualniera L, Singh J, Fiori F, Santosh P. Emotional Behavioural and Autonomic Dysregulation (EBAD) in Rett Syndrome – EDA and HRV monitoring using wearable sensor technology. Journal of psychiatric research. 2021; 138: 186-93.

BACKGROUND: Rett syndrome (RTT) is a severe genetic neurodevelopmental disorder. Emotional, Behavioural and Autonomic Dysregulation (EBAD), is frequent in RTT and is associated with multiple impairments. There are major challenges in the clinical assessment of emotions, behaviours, and autonomic function in RTT patients that limit the management of symptoms. METHODS: Web-based technology (HealthTracker™) to measure the phenotype, and non-invasive, wearable sensor technology to evaluate autonomic function through Electrodermal Activity (EDA) and Heart Rate Variability (HRV) in 10 RTT patients was used, and treatment response of EBAD symptoms was monitored after different pharmacological treatments. RESULTS: and discussion: 4 patients received buspirone, 2 sertraline, 1 gabapentin and 3 were not started on medications. Buspirone normalized the EDA in 3 patients with associated improvement in EBAD, whilst another patient only improved marginally. Both patients treated with sertraline (including one with normal EDA) significantly improved symptomatically. The patients on unchanged regimens showed no change in symptoms and autonomic function. Within 24 h of our assessment, one patient required intensive inpatient care due to septicaemia – this patient had been on gabapentin and showed a sharp and sustained EDA increase without obvious worsening of emotional and behavioural symptoms. Unlike the EDA, the analyses of HRV metrics did not reveal patterns that were associated with clinical outcomes. Our findings suggest a reasonable association of EDA normalization and symptomatic improvement in RTT subjects with EBAD treated with buspirone and point out its potential application as a measure of dysautonomia in RTT. Very high and sustained EDA levels may be a biomarker for concurrent serious physical illness in RTT.

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8. Jack A, Sullivan CAW, Aylward E, Bookheimer SY, Dapretto M, Gaab N, Van Horn JD, Eilbott J, Jacokes Z, Torgerson CM, Bernier RA, Geschwind DH, McPartland JC, Nelson CA, Webb SJ, Pelphrey KA, Gupta AR. A neurogenetic analysis of female autism. Brain : a journal of neurology. 2021; 144(6): 1911-26.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

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9. Kurzrok J, McBride E, Grossman RB. Autism-specific parenting self-efficacy: An examination of the role of parent-reported intervention involvement, satisfaction with intervention-related training, and caregiver burden. Autism : the international journal of research and practice. 2021; 25(5): 1395-408.

What is already known about the topic?Parents of children with autism experience enormous challenges managing the complex needs of caring for their children. This includes coordinating multiple and complex therapies and acting as partners in treatment. Parenting self-efficacy is the confidence a person has in their ability to manage the tasks that are part of raising a child. People who have more confidence, or greater parenting self-efficacy, often feel less stressed and are more able to manage the demands of family life. This is particularly important for parents with children who have autism spectrum disorder, since they experience more parenting pressures. Although a lot is known about parenting self-efficacy in parents of neurotypical children, we do not know enough about how to help parents of children with autism spectrum disorder develop greater parenting self-efficacy.What this paper adds?This study shows that parents gain a greater sense of parenting self-efficacy when they feel more involved in their child’s therapy and are more satisfied with the training they receive as part of these therapies. We also find that feeling pressure related to being a caregiver of a child with autism spectrum disorder can undermine autism-specific parenting self-efficacy. However, parents’ sense of confidence was not limited by the severity of their child’s symptoms.Implications for practice, research, or policyThe results suggest that there is an opportunity to help parents develop a greater sense of confidence in their ability to manage the complexities of raising a child with autism spectrum disorder by helping them feel more involved in treatment and by creating intervention-related training experiences that are more satisfying. Providers might also help by taking time to address the challenges and pressures that parents are experiencing, and helping them find ways to deal with these challenges. We suggest that there needs to be more research exploring how providers can best design interventions that support autism-specific parenting self-efficacy as a way of improving parental and child well-being.

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10. Liaqat S, Wu C, Duggirala PR, Cheung SS, Chuah CN, Ozonoff S, Young G. Predicting ASD Diagnosis in Children with Synthetic and Image-based Eye Gaze Data. Signal processing Image communication. 2021; 94.

As early intervention is highly effective for young children with autism spectrum disorder (ASD), it is imperative to make accurate diagnosis as early as possible. ASD has often been associated with atypical visual attention and eye gaze data can be collected at a very early age. An automatic screening tool based on eye gaze data that could identify ASD risk offers the opportunity for intervention before the full set of symptoms is present. In this paper, we propose two machine learning methods, synthetic saccade approach and image based approach, to automatically classify ASD given children’s eye gaze data collected from free-viewing tasks of natural images. The first approach uses a generative model of synthetic saccade patterns to represent the baseline scan-path from a typical non-ASD individual and combines it with the real scan-path as well as other auxiliary data as inputs to a deep learning classifier. The second approach adopts a more holistic image-based approach by feeding the input image and a sequence of fixation maps into a convolutional or recurrent neural network. Using a publicly-accessible collection of children’s gaze data, our experiments indicate that the ASD prediction accuracy reaches 67.23% accuracy on the validation dataset and 62.13% accuracy on the test dataset.

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11. Maslowski A, Abbas H, Abrams K, Taraman S, Garberson F, Segar S. Project Rosetta: a childhood social, emotional, and behavioral developmental feature mapping. Journal of biomedical semantics. 2021; 12(1): 8.

BACKGROUND: A wide array of existing instruments are commonly used to assess childhood behavior and development for the evaluation of social, emotional and behavioral disorders such as Autism Spectrum Disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety. Many of these instruments either focus on one diagnostic category or encompass a broad set of childhood behaviors. We analyze a wide range of standardized behavioral instruments and identify a comprehensive, structured semantic hierarchical grouping of child behavioral observational features. We use the hierarchy to create Rosetta: a new set of behavioral assessment questions, designed to be minimal yet comprehensive in its coverage of clinically relevant behaviors. We maintain a full mapping from every functional feature in every covered instrument to a corresponding question in Rosetta. RESULTS: In all, 209 Rosetta questions are shown to cover all the behavioral concepts targeted in the eight existing standardized instruments. CONCLUSION: The resulting hierarchy can be used to create more concise instruments across various ages and conditions, as well as create more robust overlapping datasets for both clinical and research use.

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12. Mayor Torres JM, Clarkson T, Hauschild KM, Luhmann CC, Lerner MD, Riccardi G. Facial Emotions Are Accurately Encoded in the Neural Signal of Those With Autism Spectrum Disorder: A Deep Learning Approach. Biological psychiatry Cognitive neuroscience and neuroimaging. 2021.

BACKGROUND: Individuals with autism spectrum disorder (ASD) exhibit frequent behavioral deficits in facial emotion recognition (FER). It remains unknown whether these deficits arise because facial emotion information is not encoded in their neural signal or because it is encodes but fails to translate to FER behavior (deployment). This distinction has functional implications, including constraining when differences in social information processing occur in ASD, and guiding interventions (i.e., developing prosthetic FER vs. reinforcing existing skills). METHODS: We utilized a discriminative and contemporary machine learning approach-deep convolutional neural networks-to classify facial emotions viewed by individuals with and without ASD (N = 88) from concurrently recorded electroencephalography signals. RESULTS: The convolutional neural network classified facial emotions with high accuracy for both ASD and non-ASD groups, even though individuals with ASD performed more poorly on the concurrent FER task. In fact, convolutional neural network accuracy was greater in the ASD group and was not related to behavioral performance. This pattern of results replicated across three independent participant samples. Moreover, feature importance analyses suggested that a late temporal window of neural activity (1000-1500 ms) may be uniquely important in facial emotion classification for individuals with ASD. CONCLUSIONS: Our results reveal for the first time that facial emotion information is encoded in the neural signal of individuals with (and without) ASD. Thus, observed difficulties in behavioral FER associated with ASD likely arise from difficulties in decoding or deployment of facial emotion information within the neural signal. Interventions should focus on capitalizing on this intact encoding rather than promoting compensation or FER prostheses.

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13. McDonald NM, Jeste SS. Beyond Baby Siblings-Expanding the Definition of « High-Risk Infants » in Autism Research. Current psychiatry reports. 2021; 23(6): 34.

PURPOSE OF REVIEW: Much of our understanding of early development in children with autism spectrum disorder (ASD) comes from studies of children with a family history of autism. We reviewed the current literature on neurodevelopmental profiles and autism prevalence from other high-risk infant groups to expose gaps and inform next steps. We focused on infants with early medical risk (e.g., preterm birth) and genetic risk (tuberous sclerosis complex [TSC]). RECENT FINDINGS: About 7% of very preterm infants are later diagnosed with ASD. Prospective studies of early development outside of familial-risk infants are rare; however, recent work within preterm and TSC infants suggests interesting similarities and differences from infants with a family history of ASD. It is essential that we extend our knowledge of early markers of ASD beyond familial-risk infants to expand our knowledge of autism as it emerges in order to develop better, more individualized early interventions.

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14. Nakamura M, Ye K, MB ES, Yamauchi T, Hoeppner DJ, Fayyazuddin A, Kang G, Yuda EA, Nagashima M, Enomoto S, Hiramoto T, Sharp R, Kaneko I, Tajinda K, Adachi M, Mihara T, Tokuno S, Geyer MA, Broin P, Matsumoto M, Hiroi N. Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion. Molecular psychiatry. 2021; 26(11): 6578-88.

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

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15. Neitzel I, Penke M. Theory of Mind in children and adolescents with Down syndrome. Research in developmental disabilities. 2021; 113: 103945.

INTRODUCTION: To date, the evidence regarding False Belief (FB) abilities in individuals with Down syndrome (DS) has been both sparse and contradictory. Our study is the first systematic investigation targeting the relation between FB, mental age (MA), syntactic abilities (SA) and verbal short-term memory (VSTM) in individuals with DS so far. METHOD: 27 German-speaking children/adolescents with DS (aged 10;0-20;1 years) completed a location-change FB-task and four standardized measures assessing nonverbal intelligence & MA, VSTM, receptive and productive SA. RESULTS: 37.5 % (n = 9) of our participants passed the FB-task, whereas 62.5 % (n = 15) did not answer the target question correctly. While no significant differences emerged for MA and language abilities in individuals who passed and those who failed FB-testing, VSTM came out as a significantly associated factor for FB-performance in a median split analysis of raw-scores. DISCUSSION: The results suggest that a substantial proportion of individuals with DS is impaired in FB-understanding. In contrast to previous findings on children with developmental disorders such as autism, developmental language deficit or hearing impairment, general and specific SA related to sentence complementation turned out to be of limited relevance for FB-understanding in individuals with DS.

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16. O’Halloran CP, Qadir A, Ramlogan SR, Nugent AW, Tannous P. Deployed Dimensions of the GORE® CARDIOFORM ASD Occluder as Function of Defect Size. Pediatric cardiology. 2021; 42(5): 1209-15.

The GORE® CARDIOFORM ASD occluder (ASDO) is approved for closure of ASDs up to 35 mm diameter. With an adaptable central waist, each device size is suitable over a range of defect diameters. Understanding deployed dimensions across various defect sizes will assist operators. Therefore, this study investigates the deployed dimensions of the ASDO as a function of defect size. A 2-mm-thick ASD model with circular defects ranging from 5 to 35 mm was 3D printed. Diameter, width, and left-right disc diameter were measured by fluoroscopy after ASDO devices were deployed in applicable defects. Linear regression evaluated relationships between device size, defect size, and deployed dimensions. Six ASDOs of each size (27, 32, 37, 44, and 48 mm) were deployed in all applicable defects. There was significant ASDO size-defect size interaction in determining deployed ASDO diameter. Diameter was positively associated with defect size for 48-mm (B = 0.13, p < 0.001) and 44-mm (B = 0.11, p < 0.001) ASDOs, while no association was seen for 27-mm, 32-mm, or 37-mm ASDOs. No such interaction existed for deployed width or left-right disc difference. Controlling for ASDO size, width (B = - 0.12, p < 0.001) and left-right disc difference (B = - 0.06, p < 0.001) were negatively associated with defect size. In smaller defects, the 44-mm and 48-mm ASDOs display progressive diameter foreshortening, and all devices display progressive increase in width and left-right disc asymmetry. Anticipating the degree of diameter foreshortening may be critical when attempting closure of fenestrated lesions and/or in patients with limited total atrial septal length.

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17. Saitoh BY, Tanaka E, Yamamoto N, Kruining DV, Iinuma K, Nakamuta Y, Yamaguchi H, Yamasaki R, Matsumoto K, Kira JI. Early postnatal allergic airway inflammation induces dystrophic microglia leading to excitatory postsynaptic surplus and autism-like behavior. Brain, behavior, and immunity. 2021; 95: 362-80.

Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.

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18. Salimi Z, Jenabi E, Bashirian S. Are social robots ready yet to be used in care and therapy of autism spectrum disorder: A systematic review of randomized controlled trials. Neuroscience and biobehavioral reviews. 2021; 129: 1-16.

Autism is a neurodevelopmental disorder that affects the everyday life of people who have this lifelong condition. Robots hold great promise for uplifting therapy and care of the affected population. We searched Scopus, Medline, ScienceDirect, Web of Science, and PubMed databases for randomized controlled trials that had evaluated robot use in the therapy of people with autism, to see how effective social robots have been incorporated in autism care. Out of 240 papers initially identified, 19 satisfied the inclusion criteria and were fully evaluated. Overall, 10 different robots were utilized in the trials, out of which, four were non-humanoids. The number of papers with positive results for using robots on the main and secondary parameters was 11 and 5, respectively. Three papers reported that robot groups did not achieve better results than others. Robots in the papers included here were mainly added as the « entertainment agent » to elicit greater engagement from the participants, which is understandable, as robots at this stage might not be ready yet to deliver high-end care.

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19. Sase T, Kitajo K. The metastable brain associated with autistic-like traits of typically developing individuals. PLoS computational biology. 2021; 17(4): e1008929.

Metastability in the brain is thought to be a mechanism involved in the dynamic organization of cognitive and behavioral functions across multiple spatiotemporal scales. However, it is not clear how such organization is realized in underlying neural oscillations in a high-dimensional state space. It was shown that macroscopic oscillations often form phase-phase coupling (PPC) and phase-amplitude coupling (PAC), which result in synchronization and amplitude modulation, respectively, even without external stimuli. These oscillations can also make spontaneous transitions across synchronous states at rest. Using resting-state electroencephalographic signals and the autism-spectrum quotient scores acquired from healthy humans, we show experimental evidence that the PAC combined with PPC allows amplitude modulation to be transient, and that the metastable dynamics with this transient modulation is associated with autistic-like traits. In individuals with a longer attention span, such dynamics tended to show fewer transitions between states by forming delta-alpha PAC. We identified these states as two-dimensional metastable states that could share consistent patterns across individuals. Our findings suggest that the human brain dynamically organizes inter-individual differences in a hierarchy of macroscopic oscillations with multiple timescales by utilizing metastability.

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20. Shafizadeh M, Parvinpour S, Balali M, Pazhuh FS, Broom D. Effects of locomotion task constraints on running in boys with overweight/obesity: The mediating role of developmental delays. Gait & posture. 2021; 86: 354-9.

BACKGROUND: Childhood obesity adversely affects the musculoskeletal system and is accompanied with motor development delays. Movement interventions that change the body composition and movement patterns is suggested as an effective way to minimise the childhood obesity adverse effects. RESEARCH QUESTION: Whether a locomotion task constraints intervention is effective to change body composition, motor performance and running efficiency in overweight/obese boys with different levels of motor development. METHODS: Forty young boys (age: 8.21 ± 1.01 years) whose body mass index (BMI) was above the 85th normative ranked score were divided into 4 independent groups according to their development and BMI: intervention-typical, intervention-delay, control-typical and control-delay. A 6-week task constraints intervention with an emphasis on improving locomotion skills such as fast walking, running, jumping, hopping, skipping and leaping were carried out in the intervention group. RESULTS: The pre and post-intervention difference score on the sample dependent variables showed decreases in body mass and BMI and improvements in agility, joint kinematics and running economy in the intervention-typical group relative to other groups. SIGNIFICANCE: The findings highlight that the boys with overweight/obesity and typical development can benefit more from a short-term developmentally-appropriate intervention to refine the running pattern and agility skill that was accompanied by positive changes in body composition.

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21. Xi T, Wu J. A Review on the Mechanism Between Different Factors and the Occurrence of Autism and ADHD. Psychology research and behavior management. 2021; 14: 393-403.

The incidence of neurodevelopmental disorders especially in children has been on the rise in recent decades, which is possibly caused by many different factors. In order to further explain this situation and arouse enough attention, this review will specifically elaborate genetic aspects and pathogenic hypothesis of these two kinds of neurodevelopmental diseases in children, autism and attention deficit hyperactivity disorder (ADHD) while analyzing the relationship between different environmental toxins and these two disorders. The effects of these pathogenic factors such as heavy metal lead, mercury, polyvinyl chloride (PVC) and polychlorinated biphenyls (PCBs) and their strong pathogenicity will be explained in detail through literature data retrieval and analysis. In addition, other neurotransmitter such as norepinephrine (NE) and serotonin (5-HT) signaling factors coming down to these two neurodevelopmental disorders and how their abnormal concentration present in the blood as well as the completely opposite results among experimental groups and control group will be elaborated. Furthermore, other high-risk and high-exposure factors may contribute to both diseases, such as alcohol and smoking abuse among parents, air pollutants PM2.5 and PM10 in the environment will also be discussed in the review. Since these environmental toxins and other harmful substances discussed in the paper have been linked to an increasing number of children with autism and ADHD in recent decades, from the medical perspective, this review will put forward certain succinct points to the aspects of minimizing relevant exposure or risks in clinical and daily life, as well as feasible suggestions in public health area for children, parents and prospective parents, to curb the growth of these two diseases in part by raising awareness in the population and reducing unnecessary exposure.

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22. Yeo-Teh NSL, Tang BL. Moral obligations in conducting stem cell-based therapy trials for autism spectrum disorder. Journal of medical ethics. 2022; 48(5): 343-8.

Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder (ASD). While the former direct-to-consumer practice is usually considered rogue and should be legally constrained, regulated clinical trials could also be ethically questionable. Here, we outline principal objections against these trials as they are currently conducted. Notably, these often lack a clear rationale for how transplanted cells may confer a therapeutic benefit in ASD, and thus, have ill-defined therapeutic outcomes. We posit that ambiguous and unsubstantiated descriptions of outcome from such clinical trials may nonetheless appeal to the lay public as being based on authentic scientific findings. These may further fuel caregivers of patients with ASD to pursue unregulated direct-to-consumer treatments, thus exposing them to unnecessary risks. There is, therefore, a moral obligation on the part of those regulating and conducting clinical trials of stem cell-based therapeutic for ASD minors to incorporate clear therapeutic targets, scientific rigour and reporting accuracy in their work. Any further stem cell-based trials for ASD unsupported by significant preclinical advances and particularly sound scientific hypothesis and aims would be ethically indefensible.

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23. Zinna S, Luxton R, Papachristou E, Dima D, Kyriakopoulos M. Comorbid chronic tic disorder and tourette syndrome in children requiring inpatient mental health treatment. Clinical child psychology and psychiatry. 2021; 26(3): 894-905.

OBJECTIVE: Children needing admission to an inpatient mental health unit often present with severe neuropsychiatric disorders characterised by complex psychopathology. We aimed to examine all admitted children with comorbid chronic tic disorder (CTD) and Tourette syndrome (TS) over a 10-year period and determine the clinical significance of these diagnoses. METHOD: A retrospective, naturalistic study was conducted, comparing children with and without CTD/TS in terms of co-morbid diagnoses, medication use, access to education, aggression contributing to the admission, duration of admission, functional outcomes and satisfaction with treatment. Data were analysed using Chi-square/Fisher’s exact test and t-test for categorical and continuous variables, respectively, and subsequently with unadjusted and adjusted linear and logistic regression analyses. RESULTS: A relatively high proportion of children had co-morbid CTD/TS (19.7%). There was a significant association with co-morbid obsessive-compulsive disorder, intellectual disability and autism spectrum disorder but not attention deficit hyperactivity disorder. CTD/TS were associated with longer admissions even after adjustments for confounding but did not seem to be independently associated with other examined clinical characteristics. CONCLUSIONS: The prevalence of CTD/TS in children needing inpatient treatment is significant. In our sample, comorbid CTD/TS seem to represent a marker of overall symptom severity as evidenced by longer admissions.

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