1. Dickerson AS. Prenatal socioenvironmental exposures and autism spectrum disorder: A web of confusion. Child Dev Perspect;2023 (Mar);17(1):32-38.

Although evidence of heritability for autism spectrum disorder (ASD) is strong, studies of twin pairs suggest that at least some portion of the etiology is attributable to environmental factors, either directly or through interaction with genes. Given the multitude of environmental and psychosocial exposures that have been reported to increase atypical neurodevelopment in offspring, in this article, we summarize what prenatal air pollutant, chemical, and occupational exposures and psychosocial stressors have been reportedly associated with ASD and co-occurring neurodevelopmental disorders. We highlight consistencies in reported associations and recommend areas for research to close gaps in our understanding of environmental risk for ASD. Because this issue is of particular importance in historically marginalized communities and low- and middle-income countries, we also discuss the importance of environmental justice issues and exposure disparities in research, and we advocate for prioritizing policies to reduce disparities and improve service provision in vulnerable populations.

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2. Divya KY, Begum F, John SE, Francis F. DIR/Floor Time in Engaging Autism: A Systematic Review. Iran J Nurs Midwifery Res;2023 (Mar-Apr);28(2):132-138.

BACKGROUND: Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, which affects various multiple areas of a child’s development. The objective of this study was to systematically review the available literature and appraise the effect of floortime in engaging autism disorder among children. MATERIALS AND METHODS: A systematic review was performed using PubMed, PsycINFO, Science Direct, Scopus, Google Scholar, and Medline. The search terms used were DIR/floor time, ASD, floortime and autism, relationship therapy and autism, floortime, and ASDs. The studies, which described floortime in engaging children with ASD, full-text available in English, the sample had no comorbid psychiatric diagnosis, and the articles published in English from 2010 to 2020 were included in the review. Twelve studies meeting the inclusion criteria were included in the review. RESULTS: The results showed substantial progress in different levels of functioning of autistic children with floortime. Home-based floortime improved emotive functioning, communication, and daily living skills, the parent-child interactions were improved as expressed by mothers, and also certain demographic factors of the parents have significantly influenced the floortime outcome. There were no adverse events to children or parents during floortime. CONCLUSIONS: In general, we concluded that floortime is a cost-effective, completely child-led approach, which could be initiated as early as possible. If started early by healthcare professionals, it can be vital in improving social and emotional development among children.

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3. Gevezova M, Sbirkov Y, Sarafian V, Plaimas K, Suratanee A, Maes M. Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment. Brain Behav Immun Health;2023 (Jul);30:100646.

BACKGROUND: Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD. PURPOSE: To delineate these underpinning signatures, we examined the two largest gene expression meta-analysis datasets obtained from the brain and peripheral blood mononuclear cells (PBMCs) of 1355 ASD patients and 1110 controls. METHODS: We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients. RESULTS: Transcription factor network analyses in up- and down-regulated genes in brain tissue and PBMCs in ASD showed eight main transcription factors, namely: BCL3, CEBPB, IRF1, IRF8, KAT2A, NELFE, RELA, and TRIM28. The upregulated gene networks in PBMCs of ASD patients are strongly associated with activated immune-inflammatory pathways, including interferon-α signaling, and cellular responses to DNA repair. Enrichment analyses of the upregulated CNS gene networks indicate involvement of immune-inflammatory pathways, cytokine production, Toll-Like Receptor signalling, with a major involvement of the PI3K-Akt pathway. Analyses of the downregulated CNS genes suggest electron transport chain dysfunctions at multiple levels. Network topological analyses revealed that the consequent aberrations in axonogenesis, neurogenesis, synaptic transmission, and regulation of transsynaptic signalling affect neurodevelopment with subsequent impairments in social behaviours and neurocognition. The results suggest a defense response against viral infection. CONCLUSIONS: Peripheral activation of immune-inflammatory pathways, most likely induced by viral infections, may result in CNS neuroinflammation and mitochondrial dysfunction, leading to abnormalities in transsynaptic transmission, and brain neurodevelopment.

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4. Hameed RA, Ahmed EK, Mahmoud AA, Atef AA. G protein-coupled estrogen receptor (GPER) selective agonist G1 attenuates the neurobehavioral, molecular and biochemical alterations induced in a valproic acid rat model of autism. Life Sci;2023 (Jun 16):121860.

AIMS: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a rising prevalence in boys rather than girls. G protein-coupled estrogen receptor (GPER) activation by its agonist G1 showed a neuroprotective effect, similar to estradiol. The present study aimed to examine the potential of the selective GPER agonist G1 therapy on the behavioral, histopathological, biochemical, and molecular alterations induced in a valproic acid (VPA)-rat model of autism. MAIN METHODS: VPA (500 mg/kg) was intraperitoneally administered to female Wistar rats (on gestational day 12.5) to induce the VPA-rat model of autism. The male offspring were intraperitoneally administered with G1 (10 and 20 μg/kg) for 21 days. After the treatment process, rats performed behavioral assessments. Then, sera and hippocampi were collected for biochemical and histopathological examinations and gene expression analysis. KEY FINDINGS: GPER agonist G1 attenuated behavioral deficits, including hyperactivity, declined spatial memory and social preferences, anxiety, and repetitive behavior in VPA rats. G1 improved neurotransmission and reduced oxidative stress and histological alteration in the hippocampus. G1 reduced serum free T levels and interleukin-1β and up-regulated GPER, RORα, and aromatase gene expression levels in the hippocampus. SIGNIFICANCE: The present study suggests that activation of GPER by its selective agonist G1 altered the derangements induced in a VPA-rat model of autism. G1 normalized free T levels via up-regulation of hippocampal RORα and aromatase gene expression. G1 provoked estradiol neuroprotective functions via up-regulation of hippocampal GPER expression. The G1 treatment and GPER activation provide a promising therapeutic approach to counteract the autistic-like symptoms.

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5. Harris E, Carciofo R. The association between eveningness and autistic traits: Mediating effects of depression and insomnia. Chronobiol Int;2023 (Jun 19):1-9.

There is a lack of research on the relationships between autistic traits and morningness-eveningness. The current research explored associations between autistic traits (preferences for routine, difficulties with imagination, difficulties with social skills, fixations with numbers and patterns, and difficulties with attention switching) and morningness-eveningness, including the component of Morning Affect (alertness/energy upon awakening). The potential mediation effects of depression and insomnia were also tested. 163 adults (university students and general population) completed an online survey including questionnaire measures of autistic traits, morningness-eveningness, depression, and insomnia. Positive correlations were found between most autistic trait subcomponents, depression, and insomnia. The autistic trait of difficulties in attention switching was correlated with more eveningness and with less Morning Affect, but significant correlations were not observed with any other autistic trait. Depression mediated the relationship between eveningness and difficulties in attention switching. Although insomnia alone was not a significant mediator, when combined with depression in a serial mediator model, a significant mediation effect was shown. The current results suggest that greater eveningness may be related with the autistic trait of difficulties in attention switching possibly through the mechanism of increased insomnia and elevated risk for depression. These findings may potentially inform interventions.

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6. Kamalmaz N, Ben Bacha A, Alonazi M, Albasher G, Khayyat AIA, El-Ansary A. Unveiling sex-based differences in developing propionic acid-induced features in mice as a rodent model of ASD. PeerJ;2023;11:e15488.

BACKGROUND: Males are more likely to develop autism as a neurodevelopmental disorder than females are, although the mechanisms underlying male vulnerability are not fully understood. Therefore, studying the role of autism etiologies considering sex differences in the propionic acid (PPA) rodent model of autism would build greater understanding of how females are protected from autism spectrum disorder, which may be used as a treatment strategy for males with autism. OBJECTIVES: This study aimed to investigate the sex differences in oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut microbiota impairment as etiological mechanisms for many neurological diseases, with specific reference to autism. METHOD: Forty albino mice were divided into four groups of 10 animals each with two control and two treated groups of both sexes received only phosphate-buffered saline or a neurotoxic dose of PPA (250 mg/kg body weight) for 3 days, respectively. Biochemical markers of energy metabolism, oxidative stress, neuroinflammation, and excitotoxicity were measured in mouse brain homogenates, whereas the presence of pathogenic bacteria was assessed in mouse stool samples. Furthermore, the repetitive behavior, cognitive ability, and physical-neural coordination of the animals were examined. RESULTS: Collectively, selected variables related to oxidative stress, glutamate excitotoxicity, neuroinflammation, and gut bacteria were impaired concomitantly with altered behavior in PPA-induced rodent model, with males being more susceptible than females. CONCLUSION: This study explains the role of sex in the higher vulnerability of males to develop autistic biochemical and behavioral features compared with females. Female sex hormones and the higher detoxification capacity and higher glycolytic flux in females serve as neuroprotective contributors in a rodent model of autism.

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7. Miller HL, Licari MK, Bhat A, Aziz-Zadeh LS, Van Damme T, Fears NE, Cermak SA, Tamplain PM. Motor problems in autism: Co-occurrence or feature?. Dev Med Child Neurol;2023 (Jun 18)

Motor features of autism have long been acknowledged by clinicians, researchers, and community stakeholders. Current DSM-5 and ICD-11 guidelines allow clinicians to assign a co-occurring diagnosis of developmental [motor] coordination disorder (DCD) for autistic individuals with significant motor problems. DCD is characterized by poor motor proficiency with an onset of symptoms in early development. Studies have shown considerable overlap in the behavioral motor features observed in autism and DCD. However, others indicate that motor problems in autism and DCD may stem from different underlying sensorimotor mechanisms. Regardless of whether autism has a unique motor phenotype or an overlap with DCD, changes need to be made in the clinical pipeline to address motor problems in autism at the stages of recognition, assessment, diagnosis, and intervention. Consensus is needed to address unmet needs in research on the etiology of motor problems in autism and their overlap with DCD, to optimize clinical practice guidelines. The development of screening and assessment tools for motor problems that are valid and reliable for use with autistic individuals is essential, and an evidence-based clinical pipeline for motor problems in autism is urgently needed.

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8. Mohamed MS, Klann E. Autism- and epilepsy-associated EEF1A2 mutations lead to translational dysfunction and altered actin bundling. bioRxiv;2023 (Jun 7)

Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, e ukaryotic E longation F actor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three most common EEF1A2 patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease de novo protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the EEF1A2 mutations not only decrease de novo protein synthesis, but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin skeleton, which is essential for proper neuron development and function. SIGNIFICANCE STATEMENT: E ukaryotic E longation F actor 1A2 (eEF1A2) is a muscle- and neuron-specific translation factor responsible for bringing charge tRNAs to the elongating ribosome. Why neurons express this unique translation factor is unclear; however, it is known that mutations in EEF1A2 cause severe drug-resistant epilepsy, autism and neurodevelopmental delay. Here, we characterize the impact of three common disease-causing mutations in EEF1A2 and demonstrate that they cause decreased protein synthesis via reduced translation elongation, increased tRNA binding, decreased actin bundling activity, as well as altered neuronal morphology. We posit that eEF1A2 serves as a bridge between translation and the actin cytoskeleton, linking these two processes that are essential for neuronal function and plasticity.

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9. Peraire M, Cantos P, Sampedro-Vidal M, Bonet-Mora L, Arnau-Peiró F. Characterization of autism spectrum disorder inside prison. Rev Esp Sanid Penit;2023 (Jan-Apr);25(1):30-39.

INTRODUCTION: Autism is a neurodevelopmental disorder characterized by intolerance of change, empathy deficits, misunders- tandings, and emotional dysregulation. Core symptoms can determine criminal behaviour and subsequent interactions with the penal system. A significant presence of such symptoms is detected in forensic settings. The objective of this study is to analyze the characteristics of autism within the prison context, summarizing and updating the knowledge in this field. MATERIAL AND METHOD: Systematic review through databases on studies that analyze the socio-demographic, clinical, and judi- cial characteristics of prisoners diagnosed with autism spectrum disorder. RESULTS: Autistic traits constitute an independent risk factor for incarceration. Those inmates with autism spectrum disorder frequently present a psychiatric comorbidity, especially substance use disorder, psychotic disorders, and other neuro-develop- mental disorders. They are associated with a greater probability of self-harming thoughts and disruptive behaviours, which are not predicted by the usual evaluation tools. DISCUSSION: Prisoners with autism spectrum disorder have a differential socio-demographic, clinical, and criminal profile. A specific approach that is different from the one provided for neurotypical prisoners should be offered to these inmates. In- frastructures should be adapted to reduce fragility, make the environment more flexible and specific methods for evaluation and treatment should be developed.

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10. Reisli S, Molholm S. Pre-attentive representation of prediction certainty in autism: A mismatch negativity (MMN) study. bioRxiv;2023 (Jun 7)

According to predictive processing theories of perception, the brain generates predictions to prepare for sensory input, and calibrates certainty of predictions based on their likelihood. When an input doesn’t match the prediction, an error signal leads to updating of the predictive model. Prior research suggests altered prediction certainty in autism, but predictive processing occurs across the cortical hierarchy, and the stage(s) of processing where prediction certainty breaks down is unknown. We therefore tested the integrity of prediction certainty in autism at pre-attentive and relatively automatic processing stages using the pre-attentive Mismatch Negativity (MMN) brain response. The MMN occurs in response to a « deviant » presented in a stream of « standards » and is measured while the participant performs an orthogonal task. Most critically, MMN amplitude typically varies with the level of certainty associated with the prediction. We recorded high-density EEG while presenting adolescents and young adults with and without autism with repetitive tones every half second (the standard) interspersed with infrequent pitch and inter-stimulus-interval (ISI) deviants. Pitch and ISI deviant probabilities were manipulated at 4, 8, or 16% within a block of trials to test whether MMN amplitude varied in a typical manner with respect to probability. For both groups, Pitch-MMN amplitude increased as the probability of deviance decreased. Unexpectedly, ISI-MMN amplitude did not reliably vary by probability in either group. Our Pitch-MMN findings suggest intact neural representation of pre-attentive prediction certainty in autism, addressing a critical knowledge gap in autism research. The implications of these findings are considered. LAY SUMMARY: Our brains are always trying to predict what will happen next. For example, when you open your utensil drawer, it would be surprising to see books because your brain expected to see utensils. In our study, we looked at whether the brains of autistic individuals automatically and accurately recognize when something unexpected happens. Results showed similar brain patterns in individuals with and without autism, suggesting that responses to prediction violations are generated in a typical manner during early cortical information processing.

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11. Wang C, Derderian KD, Hamada E, Zhou X, Nelson AD, Kyoung H, Ahituv N, Bouvier G, Bender KJ. Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A -associated ASD. bioRxiv;2023 (Jun 7)

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity, or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify the mechanisms that underlie hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss-of-function in the ASD risk-factor gene SCN2A . The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one’s gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A -encoded Na (V) 1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in adolescent mice via a CRISPR-activator approach that increases Scn2a expression, highlighting how evaluation of simple reflexes can be used as quantitative readout of therapeutic interventions.

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12. Xie H, Moraczewski D, McNaughton KA, Warnell KR, Alkire D, Merchant JS, Kirby LA, Yarger HA, Redcay E. Social reward network connectivity differs between autistic and neurotypical youth during social interaction. bioRxiv;2023 (Jun 7)

A core feature of autism is difficulties with social interaction. Atypical social motivation is proposed to underlie these difficulties. However, prior work testing this hypothesis has shown mixed support and has been limited in its ability to understand real-world social-interactive processes in autism. We attempted to address these limitations by scanning neurotypical and autistic youth (n = 86) during a text-based reciprocal social interaction that mimics a « live » chat and elicits social reward processes. We focused on task-evoked functional connectivity (FC) of regions responsible for motivational-reward and mentalizing processes within the broader social reward circuitry. We found that task-evoked FC between these regions was significantly modulated by social interaction and receipt of social-interactive reward. Compared to neurotypical peers, autistic youth showed significantly greater task-evoked connectivity of core regions in the mentalizing network (e.g., posterior superior temporal sulcus) and the amygdala, a key node in the reward network. Furthermore, across groups, the connectivity strength between these mentalizing and reward regions was negatively correlated with self-reported social motivation and social reward during the scanner task. Our results highlight an important role of FC within the broader social reward circuitry for social-interactive reward. Specifically, greater context-dependent FC (i.e., differences between social engagement and non-social engagement) may indicate an increased « neural effort » during social reward and relate to differences in social motivation within autistic and neurotypical populations.

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13. Zhang T, Sun Y, Wei J, Zhao G, Hao W, Lv Z, Chen X, Liu Y, Wei F. Shorter telomere length in children with autism spectrum disorder is associated with oxidative stress. Front Psychiatry;2023;14:1209638.

OBJECTIVE: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. The balance between antioxidant capacity and oxidative stress (OS) induced free radicals may be crucial during the pathophysiological development of ASD. METHODS: In this study, 96 children with ASD who met the diagnostic and statistical manual of mental disorders were collected, and the number of children in the typical development (TD) group was matched by 1:1. Digital PCR (dPCR) for telomere length (TL) expression in ASD in peripheral blood leukocytes. Urine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) content were measured by tandem triple quadrupole mass spectrometry and corrected by urinary creatinine levels. The levels of superoxide dismutase (SOD), catalase (CAT), and capacity (AOC) were detected by kits. RESULTS: The TL of the ASD group was shorter than the TD group (p < 0.01) and had some accurate predictive significance for the identification of ASD (AUC = 0.632, 95% CI: 0.533-0.710, p = 0.002). Both 8-OHdG content and SOD activity in the ASD group were significantly higher than those in the TD group (p < 0.05). Shortened TL (Monofactor: 2.20 (1.22, 3.96), p = 0.009; Multifactor: 2.22 (1.22, 4.00), p = 0.008) and reduced CAT activity (Monofactor: 2.31 (1.28, 4.17), p = 0.006; Multifactor: 2.31 (1.28, 4.18), p = 0.006) are risk factors for the development of ASD, while reduced 8-OHdG content (Monofactor: 0.29 (0.14, 0.60), p = 0.001; Multifactor: 0.27 (0.13, 0.57), p = 0.001) and reduced SOD activity (Monofactor: 0.55 (0.31, 0.98), p = 0.042; Multifactor: 0.54 (0.30, 0.98), p = 0.042) are protective factors for the development of ASD. CONCLUSION: In this study, TL and OS were significantly different between the ASD group and the TD group. As guanine-rich telomere sequences were likely damaged by oxygen free radicals, creating OS, which is a factor in the incidence and progression of ASDs. In conclusion, oxidative damage occurs in the bodies of children with ASD, which may lead to sustained disease progression and severe clinical manifestations. We assume that timely supplementation of antioxidants is very likely to be a potential treatment for early intervention in children with ASD. Identification and detection of OS-related biomarkers may contribute to early diagnosis and timely interventions in young patients with ASD.

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