1. Chan MMY, Choi CXT, Tsoi TCW, Zhong J, Han YMY. Clinical and neuropsychological correlates of theta-band functional excitation-inhibition ratio in autism: An EEG study. Clin Neurophysiol. 2024; 163: 56-67.

OBJECTIVE: How abnormal brain signaling impacts cognition in autism spectrum disorder (ASD) remained elusive. This study aimed to investigate the local and global brain signaling in ASD indicated by theta-band functional excitation-inhibition (fE/I) ratio and explored psychophysiological relationships between fE/I, cognitive deficits, and ASD symptomatology. METHODS: A total of 83 ASD and typically developing (TD) individuals participated in this study. Participants’ interference control and set-shifting abilities were assessed. Resting-state electroencephalography (EEG) was used for estimating theta-band fE/I ratio. RESULTS: ASD individuals (n = 31 without visual EEG abnormality; n = 22 with visual EEG abnormality) generally performed slower in a cognitive task tapping interference control and set-maintenance abilities, but only ASD individuals with visually abnormal EEG performed significantly slower than their TD counterparts (Bonferroni-corrected ps < .001). Heightened theta-band fE/I ratios at the whole-head level, left and right hemispheres were observed in the ASD subgroup without visual EEG abnormality only (Bonferroni-corrected ps < .001), which remained highly significant when only data from medication-naïve participants were analyzed. In addition, higher left hemispheric fE/I ratios in ASD individuals without visual EEG abnormality were significantly correlated with faster interference control task performance, in turn faster reaction time was significantly associated with less severe restricted, repetitive behavior (Bonferroni-corrected ps ≤ .0017). CONCLUSIONS: Differential theta-band fE/I within the ASD population. Heightened theta-band fE/I in ASD without visual EEG abnormality may be associated with more efficient filtering of distractors and a less severe ASD symptom manifestation. SIGNIFICANCE: Brain signaling, indicated by theta-band fE/I, was different in ASD subgroups. Only ASD with visually-normal EEG showed heightened theta-band fE/I, which was associated with faster processing of visual distractors during a cognitive task. More efficient distractor filtering was associated with less restricted, repetitive behaviors.

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2. Cohenour T, Dickinson A, Jeste S, Gulsrud A, Kasari C. Patterns of spontaneous neural activity associated with social communication abilities among infants and toddlers showing signs of autism. Eur J Neurosci. 2024.

Early disruptions to social communication development, including delays in joint attention and language, are among the earliest markers of autism spectrum disorder (autism, henceforth). Although social communication differences are a core feature of autism, there is marked heterogeneity in social communication-related development among infants and toddlers exhibiting autism symptoms. Neural markers of individual differences in joint attention and language abilities may provide important insight into heterogeneity in autism symptom expression during infancy and toddlerhood. This study examined patterns of spontaneous electroencephalography (EEG) activity associated with joint attention and language skills in 70 community-referred 12- to 23-month-olds with autism symptoms and elevated scores on an autism diagnostic instrument. Data-driven cluster-based permutation analyses revealed significant positive associations between relative alpha power (6-9 Hz) and concurrent response to joint attention skills, receptive language, and expressive language abilities. Exploratory analyses also revealed significant negative associations between relative alpha power and measures of core autism features (i.e., social communication difficulties and restricted/repetitive behaviors). These findings shed light on the neural mechanisms underlying typical and atypical social communication development in emerging autism and provide a foundation for future work examining neural predictors of social communication growth and markers of intervention response.

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3. Demircan K, Chillon TS, Jensen RC, Jensen TK, Sun Q, Bonnema SJ, Glintborg D, Bilenberg N, Andersen MS, Schomburg L. Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: the Odense Child Cohort. Free Radic Biol Med. 2024.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9 +/- 0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90(th) percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6%) children had ASD traits and 59 of 719 (8.2%) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 μg/L increment in selenium was 0.76 (95% CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 μg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

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4. Frye RE, Rincon N, McCarty PJ, Brister D, Scheck AC, Rossignol DA. Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis. Neurobiol Dis. 2024: 106520.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.

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5. Janes A, McClay E, Gurm M, Boucher TQ, Yeung HH, Iarocci G, Scheerer NE. Predicting Social Competence in Autistic and Non-Autistic Children: Effects of Prosody and the Amount of Speech Input. J Autism Dev Disord. 2024.

PURPOSE: Autistic individuals often face challenges perceiving and expressing emotions, potentially stemming from differences in speech prosody. Here we explore how autism diagnoses between groups, and measures of social competence within groups may be related to, first, children’s speech characteristics (both prosodic features and amount of spontaneous speech), and second, to these two factors in mothers’ speech to their children. METHODS: Autistic (n = 21) and non-autistic (n = 18) children, aged 7-12 years, participated in a Lego-building task with their mothers, while conversational speech was recorded. Mean F0, pitch range, pitch variability, and amount of spontaneous speech were calculated for each child and their mother. RESULTS: The results indicated no differences in speech characteristics across autistic and non-autistic children, or across their mothers, suggesting that conversational context may have large effects on whether differences between autistic and non-autistic populations are found. However, variability in social competence within the group of non-autistic children (but not within autistic children) was predictive of children’s mean F0, pitch range and pitch variability. The amount of spontaneous speech produced by mothers (but not their prosody) predicted their autistic children’s social competence, which may suggest a heightened impact of scaffolding for mothers of autistic children. CONCLUSION: Together, results suggest complex interactions between context, social competence, and adaptive parenting strategies in driving prosodic differences in children’s speech.

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6. Kale G, Addepalli V, Joshi S. A snapshot on introspection of autism spectrum disorder. Mol Biol Rep. 2024; 51(1): 610.

Autism spectrum disorder is a neurodevelopmental condition marked by restricted interests and difficulty with social communication. ASD is characterized by heightened neuroinflammation and irregular neuronal connections. ASD is more frequent in male than female with male-female ratio of around 4:1. ASD affects 2.8% or 1 in 36 8-year-olds, based on the CDC’s Morbidity and Mortality Weekly Report. Various factors like Environmental, Genetic, Epigenetic and Developmental factors are linked with genesis of ASD. Repetitive behaviors, Impaired communication skills, difficulty with social interaction are some of the clinical features of ASD. Current Pharmacotherapy of ASD limits to management of symptoms only, not cure. The stem cell therapy has a promising potential to be a breakthrough in treating ASD. Various types of stem cells have been successfully tested in children with ASD. AI has a potential to emerge as a tool for early detection of ASD. Robotics can assist the children with ASD to overcome the challenges associated with ASD.

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7. Kotagal S, Malow B, Spruyt K, Wang G, Bolaños Almeida CE, Tavera Saldaña LM, Blunden S, Narang I, Ipsiroglu OS, Bruni O, Strazisar BG, Simakajornboon N, Nunes ML, Cortese S. Melatonin use in managing insomnia in children with autism and other neurogenetic disorders – An assessment by the international pediatric sleep association (IPSA). Sleep Med. 2024; 119: 222-8.

Though it is widely prescribed for improving sleep of children with autism and other neurogenetic disorders, there is a need for practical guidance to clinicians on the use of melatonin for managing insomnia in this population. Because data were either lacking or inconclusive, a task force was established by the International Pediatric Sleep Association (IPSA) to examine the literature based on clinical trials from 2012 onwards. A summary of evidence pertaining to melatonin’s utility and potential side effects, practice-related caveats, and insights for use are published herewith.

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8. Lai W, Zhao Y, Chen Y, Dai Z, Chen R, Niu Y, Chen X, Chen S, Huang G, Shan Z, Zheng J, Hu Y, Chen Q, Gong S, Kang S, Guo H, Ma X, Song Y, Xia K, Wang J, Zhou L, So KF, Wang K, Qiu S, Zhang L, Chen J, Shi L. Autism patient-derived SHANK2B(Y29X) mutation affects the development of ALDH1A1 negative dopamine neuron. Mol Psychiatry. 2024.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2B(Y29X). This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2B(Y29X) mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

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9. Mori M, Yoshii S, Noguchi M, Takagi D, Shimizu T, Ito H, Matsuo-Takasaki M, Nakamura Y, Takahashi S, Hamada H, Ohnuma K, Shiohama T, Hayashi Y. Generation of human induced pluripotent stem cell lines derived from four Rett syndrome patients with MECP2 mutations. Stem Cell Res. 2024; 77: 103432.

Rett syndrome is characterized by severe global developmental impairments with autistic features and loss of purposeful hand skills. Here we show that human induced pluripotent stem cell (hiPSC) lines derived from four Japanese female patients with Rett syndrome are generated from peripheral blood mononuclear cells using Sendai virus vectors. The generated hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift, missense, or nonsense mutations in the MECP2 gene. Since the molecular pathogenesis caused by MECP2 dysfunction remains unclear, these cell resources are useful tools to establish disease models and develop new therapies for Rett syndrome.

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10. Taylor JL, Sullivan V, Bishop SL, Zheng S, Adams RE. Associations between Social Experiences and Psychological Health for Autistic Youth with Low IQ. J Autism Dev Disord. 2024.

PURPOSE: Social experiences are consistently associated with psychological health among autistic individuals. However, most extant studies on this topic exclude individuals with autism who have lower IQ or are otherwise unable to self-report. The current study addresses this gap by examining associations of negative peer experiences and social participation with psychological health among autistic youth with low IQ. METHODS: An online survey was collected from 268 parents of autistic adolescents and adults ages 15-25. Negative peer experiences included measures of peer victimization and being ignored. Social participation was assessed by the amount of participation and parents’ perceptions of whether their youth felt the amount of participation was meeting their needs. Psychological health was assessed by parents’ report of their youth’s psychological quality of life, as well as whether they felt their son/daughter was currently depressed. RESULTS: Results suggested low rates of social participation in this sample, with relatively high rates of being ignored. Regression analysis found that lower rates of peer victimization and more activities in which parents perceived that the amount of time was meeting their youth’s needs was associated with higher psychological quality of life and lower likelihood that parents felt their son/daughter was depressed. CONCLUSION: Though youth with autism and low IQ are often excluded from interventions aimed at improving social experiences, these findings suggest that promoting positive social experiences and ameliorating negative ones might be an avenue to improving psychological health in this group.

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11. Zhu Y, Yang Q, Gu J, Chen Z, Jing N, Jin T, Lin J, Wang X, Hu J, Ji G, An Y. ‘Environmental standard limit concentration’ arsenic exposure is associated with anxiety, depression, and autism-like changes in early-life stage zebrafish. J Hazard Mater. 2024; 469: 133953.

Arsenic is a worldwide environmental pollutant that can impair human health. Previous studies have identified mental disorders induced by arsenic, but the environmental exposure concentrations in the early life stages associated with these disorders are poorly understood. In the present study, early-life stage zebrafish were used to explore the effects on mental disorders under ‘environmental standard limit concentrations’ arsenic exposures of 5, 10, 50, 150, and 500 μg/L. The results showed that arsenic exposure at these concentrations changed the locomotor behavior in larval zebrafish and was further associated with anxiety, depression, and autism-like behavior in both larval and juvenile zebrafish. Changes were noted at benchmark dose limit (BMDL) concentrations as low as 0.81 μg/L. Transcriptomics showed that immediate early genes (IEGs) fosab, egr1, egr2a, ier2b, egr3, and jund were decreased after arsenic exposure in larval and juvenile zebrafish. Nervous system impairment and anxiety, depression, and autism-like behaviors in early-life stage zebrafish at ‘environmental standard limit concentrations’ may be attributed to the downregulation of IEGs. These findings in zebrafish provided new experimental support for an arsenic toxicity threshold for mental disorders, and they suggest that low levels of environmental chemicals may be causative developmental factors for mental disorders.

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