1. Angell AM, Varma DS, Deavenport-Saman A, Yin L, Solomon O, Bai C, Zou B. Effects of Sex, Race, and Ethnicity on Primary and Subspecialty Healthcare Use by Autistic Children in Florida: A Longitudinal Retrospective Cohort Study (2012-2018). Research in autism spectrum disorders. 2022; 94.

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2. Bernardino I, Dionísio A, Violante IR, Monteiro R, Castelo-Branco M. Motor Cortex Excitation/Inhibition Imbalance in Young Adults With Autism Spectrum Disorder: A MRS-TMS Approach. Frontiers in psychiatry. 2022; 13: 860448.

Excitatory/inhibitory imbalance has been suggested as a neurobiological substrate of the cognitive symptomatology in Autism Spectrum Disorder (ASD). Studies using magnetic resonance spectroscopy (MRS) attempted to characterize GABA and Glutamate brain levels in ASD. However mixed findings have been reported. Here, we characterize both neurochemical and physiological aspects of GABA system in ASD by implementing a more comprehensive approach combining MRS and transcranial magnetic stimulation (TMS). A group of 16 young ASD adults and a group of 17 controls participated in this study. We employed one MRS session to assess motor cortex GABA+ and Glutamate+Glutamine (Glx) levels using MEGAPRESS and PRESS sequences, respectively. Additionally, a TMS experiment was implemented including paired-pulse (SICI, ICF and LICI), input-output curve and cortical silent period to probe cortical excitability. Our results showed a significantly increased Glx, with unchanged GABA+ levels in the ASD group compared with controls. Single TMS measures did not differ between groups, although exploratory within-group analysis showed impaired inhibition in SICI5ms, in ASD. Importantly, we observed a correlation between GABA levels and measures of the input-output TMS recruitment curve (slope and MEP amplitude) in the control group but not in ASD, as further demonstrated by direct between group comparisons. In this exploratory study, we found evidence of increased Glx levels which may contribute to ASD excitatory/inhibitory imbalance while highlighting the relevance of conducting further larger-scale studies to investigate the GABA system from complementary perspectives, using both MRS and TMS techniques.

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3. Brandenburg C, Blatt GJ. Region-Specific Alterations of Perineuronal Net Expression in Postmortem Autism Brain Tissue. Frontiers in molecular neuroscience. 2022; 15: 838918.

Genetic variance in autism spectrum disorder (ASD) is often associated with mechanisms that broadly fall into the category of neuroplasticity. Parvalbumin positive neurons and their surrounding perineuronal nets (PNNs) are important factors in critical period plasticity and have both been implicated in ASD. PNNs are found in high density within output structures of the cerebellum and basal ganglia, two regions that are densely connected to many other brain areas and have the potential to participate in the diverse array of symptoms present in an ASD diagnosis. The dentate nucleus (DN) and globus pallidus (GP) were therefore assessed for differences in PNN expression in human postmortem ASD brain tissue. While Purkinje cell loss is a consistent neuropathological finding in ASD, in this cohort, the Purkinje cell targets within the DN did not show differences in number of cells with or without a PNN. However, the density of parvalbumin positive neurons with a PNN were significantly reduced in the GP internus and externus of ASD cases, which was not dependent on seizure status. It is unclear whether these alterations manifest during development or are a consequence of activity-dependent mechanisms that lead to altered network dynamics later in life.

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4. Castro AC, Monteiro P. Auditory Dysfunction in Animal Models of Autism Spectrum Disorder. Frontiers in molecular neuroscience. 2022; 15: 845155.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder mainly characterized by social-communication impairments, repetitive behaviors and altered sensory perception. Auditory hypersensitivity is the most common sensory-perceptual abnormality in ASD, however, its underlying neurobiological mechanisms remain elusive. Consistently with reports in ASD patients, animal models for ASD present sensory-perception alterations, including auditory processing impairments. Here we review the current knowledge regarding auditory dysfunction in rodent models of ASD, exploring both shared and distinct features among them, mechanistic and molecular underpinnings, and potential therapeutic approaches. Overall, auditory dysfunction in ASD models seems to arise from impaired central processing. Depending on the model, impairments may arise at different steps along the auditory pathway, from auditory brainstem up to the auditory cortex. Common defects found across models encompass atypical tonotopicity in different regions of the auditory pathway, temporal and spectral processing impairments and histological differences. Imbalance between excitation and inhibition (E/I imbalance) is one of the most well-supported mechanisms explaining the auditory phenotype in the ASD models studied so far and seems to be linked to alterations in GABAergic signaling. Such E/I imbalance may have a large impact on the development of the auditory pathway, influencing the establishment of connections responsible for normal sound processing.

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5. Eve M, Gandawijaya J, Yang L, Oguro-Ando A. Neuronal Cell Adhesion Molecules May Mediate Neuroinflammation in Autism Spectrum Disorder. Frontiers in psychiatry. 2022; 13: 842755.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by restrictive and repetitive behaviors, alongside deficits in social interaction and communication. The etiology of ASD is largely unknown but is strongly linked to genetic variants in neuronal cell adhesion molecules (CAMs), cell-surface proteins that have important roles in neurodevelopment. A combination of environmental and genetic factors are believed to contribute to ASD pathogenesis. Inflammation in ASD has been identified as one of these factors, demonstrated through the presence of proinflammatory cytokines, maternal immune activation, and activation of glial cells in ASD brains. Glial cells are the main source of cytokines within the brain and, therefore, their activity is vital in mediating inflammation in the central nervous system. However, it is unclear whether the aforementioned neuronal CAMs are involved in modulating neuroimmune signaling or glial behavior. This review aims to address the largely unexplored role that neuronal CAMs may play in mediating inflammatory cascades that underpin neuroinflammation in ASD, primarily focusing on the Notch, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades. We will also evaluate the available evidence on how neuronal CAMs may influence glial activity associated with inflammation. This is important when considering the impact of environmental factors and inflammatory responses on ASD development. In particular, neural CAM1 (NCAM1) can regulate NF-κB transcription in neurons, directly altering proinflammatory signaling. Additionally, NCAM1 and contactin-1 appear to mediate astrocyte and oligodendrocyte precursor proliferation which can alter the neuroimmune response. Importantly, although this review highlights the limited information available, there is evidence of a neuronal CAM regulatory role in inflammatory signaling. This warrants further investigation into the role other neuronal CAM family members may have in mediating inflammatory cascades and would advance our understanding of how neuroinflammation can contribute to ASD pathology.

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6. Ghasemi MR, Zargari P, Sadeghi H, Bagheri S, Sadeghgi B, Mirfakhraie R, Ekrami M, Mohammadi Sarvaleh S, Hashemi Gorji F, Razjouyan K, Omrani D, Kim HG, Miryounesi M. Analysis of Cytogenetic Abnormalities in Iranian Patients with Syndromic Autism Spectrum Disorder: A Case Series. Iranian journal of child neurology. 2022; 16(2): 117-28.

OBJECTIVE: Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric group of pervasive developmental disorders mainly diagnosed through the complex behavioral phenotype. According to strong genetic involvement, detecting the chromosome regions and the key genes linked to autism can help to elucidate its etiology. The present study aimed to investigate the value of cytogenetic analysis in syndromic autism and find an association between autism and chromosome abnormalities. MATERIALS & METHODS: Thirty-six autistic patients from 30 families were recruited, clinically diagnosed with the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). The syndromic patients with additional clinical features (including development delay, attention deficit, hyperactivity disorder, seizure, and language and intellectual impairment) were selected due to elevating the detection rate. Cytogenetics analysis was performed using GTG banding on the patients’ cultured fibroblasts. Moreover, array-comparative genomic hybridization (CGH) was also performed for patients with a de novo and novel variant. RESULTS: Karyotype analysis in 36 syndromic autistic patients detected chromosomal abnormalities in 2 (5.6%) families, including 46,XY,dup(15)(q11.1q11.2) and 46,XX,ins(7)(q11.1q21.3)dn. In the latter, array-CGH detected 3 abnormalities on chromosome 7, including deletion and insertion on both arms: 46,XX,del(7)(q21.11q21.3),dup(7)(p11.2p14.1p12.3)dn. CONCLUSION: We reported a novel and de novo cytogenetic abnormality on chromosome 7 in an Iranian patient diagnosed with syndromic autism. However, the detection rate in syndromic autism was low, implying that it cannot be utilized as the only diagnostic procedure.

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7. I SP, I GD, L B, M S, J GR, A ME, I MA, C LM, E MP, J AA, E B, J LV, R MP, R R. The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior. Frontiers in cell and developmental biology. 2022; 10: 839715.

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.

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8. Jiang S, He M, Xiao L, Sun Y, Ding J, Li W, Guo B, Wang L, Wang Y, Gao C, Sun T, Wang F. Prenatal GABAB Receptor Agonist Administration Corrects the Inheritance of Autism-Like Core Behaviors in Offspring of Mice Prenatally Exposed to Valproic Acid. Frontiers in psychiatry. 2022; 13: 835993.

This study was performed to evaluate the effects of prenatal baclofen (a GABAB receptor agonist) treatment on the inheritance of autism-like behaviors in valproic acid (VPA)-exposed mice. VPA model mice (first generation, F1) that were prenatally exposed to VPA exhibited robust core autism-like behaviors, and we found that oral administration of baclofen to F1 mice corrected their autism-like behavioral phenotypes at an early age. Based on a previous epigenetics study, we mated the F1 male offspring with litter females to produce the second generation (F2). The F2 male mice showed obvious inheritance of autism-like phenotypes from F1 mice, implying the heritability of autism symptoms in patients with prenatal VPA exposure. Furthermore, we found prenatal baclofen administration was associated with beneficial effects on the autism-like phenotype in F2 male mice. This may have involved corrections in the density of total/mature dendritic spines in the hippocampus (HC) and medial prefrontal cortex (mPFC), normalizing synaptic plasticity. In this research, GABAB receptor agonist administration corrected the core autism-like behaviors of F1 mice and protected against the inheritance of neurodevelopmental disorders in the offspring of F1 mice, suggesting the potential of early intervention with GABAB receptor agonists in the treatment of neurodevelopmental disorders.

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9. Lan Z, Xu S, Yu X, Yu Z, Li M, Chen F, Liu Y, Wang T, Wu Y, Gan Y, Jiang G. Functional Connectivity Underlying Symptoms in Preschool Boys With Autism: A Resting-State Functional Magnetic Resonance Imaging Study. Frontiers in neuroscience. 2022; 16: 844821.

BACKGROUND: Single-sex children have been regarded as one of the best subjects to understand the abnormal development patterns of autism spectrum disorders (ASDs). However, the functional connectivity (FC) behind their symptoms is still unknown. METHODS: Based on FC analysis, the acquired resting-state functional magnetic resonance imaging (rs-fMRI) data sets, including 86 boys with ASD and 54 normal controls (NC), were used to detect the neural synchronous activity between brain regions. Pearson correlation analysis was used to evaluate the relationship between the abnormal FC value and clinical features. RESULTS: Individuals with ASD showed enhanced FC between the right calcarine and the right lingual gyrus (LG). The right medial orbital frontal cortex also showed increased FC with bilateral inferior temporal gyrus (ITG) [two-tailed, voxel-level p < 0.001, gaussian random field (GRF) correction, cluster-level p < 0.05]. We did not find a correlation between the abnormal FC value and clinical scales. CONCLUSION: Our study reveals a possible relationship between atypical visual attention and poor learning ability in subjects with ASD, and delayed social language development may be a secondary symptom to ASD.

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10. Lawley GO, Bedrick S, MacFarlane H, Dolata JK, Salem AC, Fombonne E. « Um » and « Uh » Usage Patterns in Children with Autism: Associations with Measures of Structural and Pragmatic Language Ability. Journal of autism and developmental disorders. 2022.

Pragmatic language difficulties, including unusual filler usage, are common among children with Autism Spectrum Disorder (ASD). This study investigated « um » and « uh » usage in children with ASD and typically developing (TD) controls. We analyzed transcribed Autism Diagnostic Observation Schedule (ADOS) sessions for 182 children (117 ASD, 65 TD), aged 4 to 15. Although the groups did not differ in « uh » usage, the ASD group used fewer « ums » than the TD group. This held true after controlling for age, sex, and IQ. Within ASD, social affect and pragmatic language scores did not predict filler usage; however, structural language scores predicted « um » usage. Lower « um » rates among children with ASD may reflect problems with planning or production rather than pragmatic language.

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11. Lizé M, Monfort C, Rouget F, Limon G, Durand G, Tillaut H, Chevrier C. Prenatal exposure to organophosphate pesticides and autism spectrum disorders in 11-year-old children in the French PELAGIE cohort. Environmental research. 2022; 212(Pt C): 113348.

BACKGROUND: Organophosphate (OP) pesticides act by inhibiting acetylcholinesterase activity at synaptic junctions and have already been linked with deleterious effects on neurodevelopment, including autism spectrum disorders (ASD). OBJECTIVES: To investigate the association of prenatal exposure to OP pesticides with traits related to ASD in 11-year-old children. METHODS: The « Childhood Autism Spectrum Test » (CAST) parent questionnaire was used to screen for autistic traits in 792 children from the French PELAGIE cohort. Prenatal maternal urine samples were collected <19 weeks of gestation in which metabolites of organophosphate insecticides were assessed for 185 of them. Negative binomial regression models were performed to explore the association between the CAST score and 8 groups of urine components, adjusted for potential ASD risk factors. RESULTS: In these urine samples, dialkylphosphates (DAP) were detected most often (>80%), terbufos and its metabolites least often (<10%). No association with ASD was found for DAP, terbufos or its metabolites. Incidence rate ratios (IRRs) increased with maternal urinary diazinon concentrations, from 1.11 (95% CI: 0.87-1.42) to 1.17 (95% CI: 0.94-1.46). Higher CAST scores were statistically significantly associated with the maternal urine samples in which chlorpyrifos or two of its metabolites (chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol) were detected. The IRR for exposure to chlorpyrifos or chlorpyrifos-oxon was 1.27 (95%CI: 1.05-1.52) among all children, and 1.39 (95%CI: 1.07-1.82) among boys. CONCLUSION: These findings suggest an increase in autistic traits among 11-year-old children in association with prenatal maternal exposure to chlorpyrifos and possibly diazinon. These associations were previously suspected in the literature, in particular for chlorpyrifos. Further work establishing the causal mechanisms behind these risk association is needed.

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12. Marschik PB, Poustka L, Bölte S, Roeyers H, Nordahl-Hansen A. Editorial: Trajectories in Developmental Disabilities: Infancy-Childhood-Adolescence. Frontiers in psychiatry. 2022; 13: 893305.

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13. Massarali A, Adhya D, Srivastava DP, Baron-Cohen S, Kotter MR. Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia. Frontiers in neuroscience. 2022; 16: 834058.

Maternal immune activation (MIA) is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers altering fetal neural development. Maternal viral infection is one of the most well-known causes for immune activation in pregnant women. MIA and immune abnormalities are key players in the etiology of developmental conditions such as autism, schizophrenia, ADHD, and depression. Experimental evidence implicating MIA in with different effects in the offspring is complex. For decades, scientists have relied on either MIA models or human epidemiological data or a combination of both. MIA models are generated using infection/pathogenic agents to induce an immunological reaction in rodents and monitor the effects. Human epidemiological studies investigate a link between maternal infection and/or high levels of cytokines in pregnant mothers and the likelihood of developing conditions. In this review, we discuss the importance of understanding the relationship between virus-mediated MIA and neurodevelopmental conditions, focusing on autism and schizophrenia. We further discuss the different methods of studying MIA and their limitations and focus on the different factors contributing to MIA heterogeneity.

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14. Nakhaee S, Amirabadizadeh A, Farnia V, Ali Azadi N, Mansouri B, Radmehr F. Association Between Biological Lead Concentrations and Autism Spectrum Disorder (ASD) in Children: a Systematic Review and Meta-Analysis. Biological trace element research. 2022.

Studies have been conducted in different countries of the world to illustrate a link between autism spectrum disorder (ASD) and lead (Pb) in different specimens such as hair, blood, and urine. Therefore, we carried out a systematic review and meta-analysis to determine the association between Pb concentration in biological samples (blood, urine, and hair) and ASD in children through case-control and cross-sectional studies. In this systematic review, PubMed, Web of Sciences, Scopus, and Google Scholar were searched for relevant studies from January 2000 to February 2022. A random-effects model was used to pool the results. The effect sizes were standardized mean differences (proxied by Hedges’ g) followed by a 95% confidence interval. Pooling data under the random effect model from blood and hair studies showed a significant difference between the children in the ASD group and the control group in blood lead level (Hedges’ g: 1.21, 95% CI: 0.33-2.09, P = 0.01) and hair level (Hedges’ g: 2.20, 95% CI: 0.56-3.85, P = 0.01). For urine studies, pooling data under the random effect model from eight studies indicated no significant difference between the children in the ASD group and control group in urinary lead level (Hedges’ g: - 0.34, 95% CI: - 1.14,0.45, P = 0.40). Moreover, the funnel plot and the results of the Egger test for the blood and urine samples showed no publication bias, while, for the hair samples, the funnel plot illustrated the existence of publication bias.

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15. Oe S, Hayashi S, Tanaka S, Koike T, Hirahara Y, Seki-Omura R, Kakizaki R, Sakamoto S, Nakano Y, Noda Y, Yamada H, Kitada M. Cytoplasmic Polyadenylation Element-Binding Protein 1 Post-transcriptionally Regulates Fragile X Mental Retardation 1 Expression Through 3′ Untranslated Region in Central Nervous System Neurons. Frontiers in cellular neuroscience. 2022; 16: 869398.

Fragile X syndrome (FXS) is an inherited intellectual disability caused by a deficiency in Fragile X mental retardation 1 (Fmr1) gene expression. Recent studies have proposed the importance of cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in FXS pathology; however, the molecular interaction between Fmr1 mRNA and CPEB1 has not been fully investigated. Here, we revealed that CPEB1 co-localized and interacted with Fmr1 mRNA in hippocampal and cerebellar neurons and culture cells. Furthermore, CPEB1 knockdown upregulated Fmr1 mRNA and protein levels and caused aberrant localization of Fragile X mental retardation protein in neurons. In an FXS cell model, CPEB1 knockdown upregulated the mRNA levels of several mitochondria-related genes and rescued the intracellular heat shock protein family A member 9 distribution. These findings suggest that CPEB1 post-transcriptionally regulated Fmr1 expression through the 3′ untranslated region, and that CPEB1 knockdown might affect mitochondrial function.

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16. Palacios-Muñoz A, de Paula Moreira D, Silva V, García IE, Aboitiz F, Zarrei M, Campos G, Rennie O, Howe JL, Anagnostou E, Ambrozewic P, Scherer SW, Passos-Bueno MR, Ewer J. Mutations in trpγ, the homologue of TRPC6 autism candidate gene, causes autism-like behavioral deficits in Drosophila. Molecular psychiatry. 2022.

Autism Spectrum Disorder (ASD) is characterized by impaired social communication, restricted interests, and repetitive and stereotyped behaviors. The TRPC6 (transient receptor potential channel 6) represents an ASD candidate gene under an oligogenic/multifactorial model based on the initial description and cellular characterization of an individual with ASD bearing a de novo heterozygous mutation disrupting TRPC6, together with the enrichment of disruptive TRPC6 variants in ASD cases as compared to controls. Here, we perform a clinical re-evaluation of the initial non-verbal patient, and also present eight newly reported individuals ascertained for ASD and bearing predicted loss-of-function mutations in TRPC6. In order to understand the consequences of mutations in TRPC6 on nervous system function, we used the fruit fly, Drosophila melanogaster, to show that null mutations in transient receptor gamma (trpγ; the fly gene most similar to TRPC6), cause a number of behavioral defects that mirror features seen in ASD patients, including deficits in social interactions (based on courtship behavior), impaired sleep homeostasis (without affecting the circadian control of sleep), hyperactivity in both young and old flies, and defects in learning and memory. Some defects, most notably in sleep, differed in severity between males and females and became normal with age. Interestingly, hyperforin, a TRPC6 agonist and the primary active component of the St. John’s wort antidepressant, attenuated many of the deficits expressed by trpγ mutant flies. In summary, our results provide further evidence that the TRPC6 gene is a risk factor for ASD. In addition, they show that the behavioral defects caused by mutations in TRPC6 can be modeled in Drosophila, thereby establishing a paradigm to examine the impact of mutations in other candidate genes.

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17. Piven E, Derakhshanrad SA. Making lighting adjustments to establish new behavioral patterns in a child with autism: A follow-up study. Iranian journal of child neurology. 2022; 16(2): 143-8.

Acknowledging the importance of lighting adjustment (a less-studied aspect of the environmental modification), this study showed novel effects of black light conditions, where white objects became part of the foreground of a blackened environment to train a child with autism to master a series of self-care tasks. This follow-up study provided details about how training progressed under black light conditions to teach the child a second task called self-feeding. The process of training self-feeding for this child was undergone after the child mastered the self-care task of toothbrushing. Healthcare practitioners may want to illuminate overlooked aspects of the non-human environment, which may be ignored by children with autism, to stimulate interest in objects following lighting adjustments.

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18. Rothman EF, Graham Holmes L, Brooks D, Krauss S, Caplan R. Reasons for alcohol use and non-use by underage U.S. autistic youth: A qualitative study. Autism : the international journal of research and practice. 2022: 13623613221091319.

What is already known about the topic? Hazardous alcohol use is when a person’s drinking puts them at increased risk for negative events (e.g. health problems or car crashes). Some studies show that autistic people may be at greater risk for hazardous alcohol use than non-autistic people, while other studies have found that hazardous alcohol use is less common among autistic people than non-autistic people. We need to learn why autistic underage youth choose to drink alcohol or not. The goal of this study was to learn from US autistic youth about their attitudes and behavior related to alcohol. Forty autistic youth aged 16-20 years old were interviewed.What this article adds? Youth described several reasons why they choose to drink alcohol, including feeling like non-autistic people are more accepting when drinking, that it puts them in a less irritable or bored mood, helps them cope with problems, and helps them fit in. Reasons for not drinking alcohol include worries about becoming addicted, medication interactions, not liking the taste, fear of experiencing hangover and other health problems, and concern about acting foolish when drunk.Implications for practice, research, or policy Results reveal that hazardous alcohol use in autistic adults could have its roots in underage experiences that give autistic youth temporary relief from social anxiety, feeling lonely, and challenges with sensory processing. Right now, there are no evidence-based alcohol prevention programs in the United States for autistic people. One or more such programs may be needed. The results from this study could be used to adapt existing programs for non-autistic youth to the unique needs and risk factors of autistic youth.

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19. Seng GJ, Lai MC, Goh JOS, Tseng WI, Gau SS. Gray matter volume alteration is associated with insistence on sameness and cognitive flexibility in autistic youth. Autism research : official journal of the International Society for Autism Research. 2022.

Restricted and repetitive behaviors (RRBs) are hallmark characteristics of autism spectrum disorder (ASD). Previous studies suggest that insistence on sameness (IS) characterized as higher-order RRBs may be a promising subgrouping variable for ASD. Cognitive inflexibility may underpin IS behaviors. However, the neuroanatomical correlates of IS and associated cognitive functions remain unclear. We analyzed data from 140 autistic youth and 124 typically developing (TD) youth (mean age = 15.8 years). Autistic youth were stratified by median-split based on three current IS items in the autism diagnostic interview-revised into two groups (high, HIS, n = 70, and low, LIS, n = 70). Differences in cognitive flexibility were assessed by the Cambridge neuropsychological test automated battery (CANTAB). T1-weighted brain structural images were analyzed using voxel-based morphometry (VBM) to identify differences in gray matter (GM) volume among the three groups. GM volume of regions showing group differences was then correlated with cognitive flexibility. The HIS group showed decreased GM volumes in the left supramarginal gyrus compared to the LIS group and increased GM volumes in the vermis VIII and left cerebellar lobule VIII compared to TD individuals. We did not find significant correlations between regional GM volumes and extra-dimensional shift errors. IS may be a unique RRB component and a potentially valuable stratifier of ASD. However, the neurocognitive underpinnings require further clarification. LAY SUMMARY: The present study found parietal, temporal and cerebellar gray matter volume alterations in autistic youth with greater insistence on sameness. The findings suggest that insistence on sameness may be a useful feature to parse the heterogeneity of the autism spectrum yet further research investigating the underlying neurocognitive mechanism is warranted.

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20. Somnay YR, Wang A, Griffiths KK, Levy RJ. Altered brown adipose tissue mitochondrial function in newborn fragile X syndrome mice. Mitochondrion. 2022; 65: 1-10.

Brown adipose tissue (BAT) mitochondria generate heat via uncoupled respiration due to excessive proton leak through uncoupling proteins (UCPs). We previously found hyperthermia in a newborn mouse model of fragile X syndrome and excessive leak in Fmr1 KO forebrain mitochondria caused by CoQ deficiency. The inefficient thermogenic nature of Fmr1 mutant forebrain mitochondria was reminiscent of BAT metabolic features. Thus, we aimed to characterize BAT mitochondrial function in these hyperthermic mice using a top-down approach. Although there was no change in steady-state levels of UCP1 expression between strains, BAT weighed significantly less in Fmr1 mutants compared with controls. Fmr1 KO BAT mitochondria demonstrated impaired substrate oxidation, lower mitochondrial membrane potentials and rates of respiration, and CoQ deficiency. The CoQ analog decylubiquinone normalized CoQ-dependent electron flux and unmasked excessive proton leak. Unlike mutant forebrain, where such deficiency resulted in pathological proton leak, CoQ deficiency within BAT mitochondria resulted largely in abnormal substrate oxidation. This suggests that CoQ is important in BAT for uncoupled respiration to produce heat during development. Although our data provide further evidence of a link between fragile X mental retardation protein (FMRP) and CoQ biosynthesis, the results highlight the importance of CoQ in developing tissues and suggest tissue-specific differences from CoQ deficiency. Because BAT mitochondria are primarily responsible for regulating core body temperature, the defects we describe in Fmr1 KOs could manifest as an adaptive downregulated response to hyperthermia or could result from FMRP deficiency directly.

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21. Tan Z, Wei H, Song X, Mai W, Yan J, Ye W, Ling X, Hou L, Zhang S, Yan S, Xu H, Wang L. Positron Emission Tomography in the Neuroimaging of Autism Spectrum Disorder: A Review. Frontiers in neuroscience. 2022; 16: 806876.

Autism spectrum disorder (ASD) is a basket term for neurodevelopmental disorders characterized by marked impairments in social interactions, repetitive and stereotypical behaviors, and restricted interests and activities. Subtypes include (A) disorders with known genetic abnormalities including fragile X syndrome, Rett syndrome, and tuberous sclerosis and (B) idiopathic ASD, conditions with unknown etiologies. Positron emission tomography (PET) is a molecular imaging technology that can be utilized in vivo for dynamic and quantitative research, and is a valuable tool for exploring pathophysiological mechanisms, evaluating therapeutic efficacy, and accelerating drug development in ASD. Recently, several imaging studies on ASD have been published and physiological changes during ASD progression was disclosed by PET. This paper reviews the specific radioligands for PET imaging of critical biomarkers in ASD, and summarizes and discusses the similar and different discoveries in outcomes of previous studies. It is of great importance to identify general physiological changes in cerebral glucose metabolism, cerebral blood flow perfusion, abnormalities in neurotransmitter systems, and inflammation in the central nervous system in ASD, which may provide excellent points for further ASD research.

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22. Wong NM, Dipasquale O, Turkheimer F, Findon JL, Wichers RH, Dimitrov M, Murphy CM, Stoencheva V, Robertson DM, Murphy DG, Daly E, McAlonan GM. Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter: A randomised placebo-controlled single-dose crossover trial. Journal of psychopharmacology (Oxford, England). 2022: 2698811221092509.

BACKGROUND: Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. METHODS: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. RESULTS: Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram ‘shifted’ the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. CONCLUSIONS: Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.

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23. Wu H, Zhao G, Liu S, Zhang Q, Wang P, Cao Y, Wu L. Supplementation with Selenium Attenuates Autism-Like Behaviors and Improves Oxidative Stress, Inflammation and Related Gene Expression in an Autism Disease Model. The Journal of nutritional biochemistry. 2022: 109034.

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders. The etiology and pathological mechanisms of ASD are still unknown, and its prognosis is poor. This study investigated the effects of selenium (Se) supplementation on abnormal behavior and cognitive function in ASD model mice, as well as the potential action pathways. BTBR mice were randomly assigned to either a model group (BTBR group), a model selenium supplement group (BTBR+Se group), a normal control group (B6 group) or a normal selenium supplement group (B6+Se group). Sodium selenite, at a dosage of 1 mg/kg/day, was administered to the selenium supplementation groups by gavage. The mice in the BTBR group and the B6 group received the same amount of 0.9% saline by gavage. After 4 weeks of continuous intervention, the social functions and cognitive behaviors of the mice and the selenium concentration in hippocampal tissue were assessed. Hippocampal tissue structures were observed. Changes in neurotransmitter levels, oxidative stress and neuroinflammatory indicators were detected. SelP protein expression was significantly lower in hippocampal tissue from BTBR mice than in hippocampal tissue from B6 mice. The administration of sodium selenite in BTBR mice: (1) increased the expression of SelP; (2) attenuated spatial learning, memory impairment and improved social behaviors; (3) changed the serum levels of 5-HT, DA and Glu; (4) decreased the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in serum and hippocampal tissue; (5) reduced the ROS and MDA contents and significantly increased SOD activity, CAT activity, GSH-px activity, and antioxidant GSH levels; and (6) protected against neuronal loss in the hippocampus. Se supplementation significantly improved the social functioning, repetitive stereotyped behavior and cognitive function in BTBR mice. Se may play a protective role in the hippocampus of BTBR mice by regulating neurotransmitter levels, reducing oxidative stress, alleviating neuroinflammation and rescuing neural cell damage.

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24. Yang T, Chen L, Dai Y, Jia F, Hao Y, Li L, Zhang J, Wu L, Ke X, Yi M, Hong Q, Chen J, Fang S, Wang Y, Wang Q, Jin C, Chen J, Li T. Vitamin A Status Is More Commonly Associated With Symptoms and Neurodevelopment in Boys With Autism Spectrum Disorders-A Multicenter Study in China. Frontiers in nutrition. 2022; 9: 851980.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, and show a striking male bias in prevalence. Vitamin A (VA) is essential for brain development, and abnormalities in its metabolite retinoic acid are associated with the pathophysiology of ASD. This national multicenter study was conducted to investigate the relationship between serum VA level and core symptoms in ASD children and whether there are still sex differences. METHOD: A total of 1,300 children with ASD and 1,252 typically-developing (TD) controls aged 2-7 years old from 13 cities in China were enrolled in this study. The symptoms of children with ASD were evaluated by the Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Childhood autism rating scale (CARS). The neurodevelopmental level of the children was evaluated with the revised Children Neuropsychological and Behavior Scale (CNBS-R2016). The serum level of VA was measured by high-performance liquid chromatography (HPLC). RESULTS: The serum VA level in children with ASD was significantly lower than that in TD children, especially in boys with ASD. Furthermore, VA levels in male children with ASD were lower than those in female children with ASD. In addition, we found that serum VA level was negatively correlated the SRS, CARS and communication warming behavior of CBNS-R2016 scores in boys with ASD. In terms of developmental quotients, serum VA level was positively associated with the general quotient, language quotient, gross motor quotient and personal-social quotient of boys with ASD, but no difference was found in girls with ASD. CONCLUSIONS: ASD children, especially boys, have lower serum VA levels than TD children. Moreover, serum VA status is more commonly associated with clinical symptoms and neurodevelopment in boys with ASD.

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25. Zhang H, Sun Y, Zhu Y, Hong J, Zheng M. Corrigendum: Case Report: Prenatal Diagnosis for a Rett Syndrome Family Caused by a Novel MECP2 Deletion With Heteroduplexes of PCR Product. Frontiers in pediatrics. 2022; 10: 823860.

[This corrects the article DOI: 10.3389/fped.2021.748641.].

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26. Zielinski BA, Andrews DS, Lee JK, Solomon M, Rogers SJ, Heath B, Nordahl CW, Amaral DG. Sex-Dependent Structure of Socioemotional Salience, Executive Control, and Default Mode Networks in Preschool-Aged Children with Autism. NeuroImage. 2022: 119252.

The structure of large-scale intrinsic connectivity networks is atypical in adolescents diagnosed with autism spectrum disorder (ASD or autism). However, the degree to which alterations occur in younger children, and whether these differences vary by sex, is unknown. We utilized structural magnetic resonance imaging (MRI) data from a sex- and age- matched sample of 122 autistic and 122 typically developing (TD) children (2-4 years old) to investigate differences in underlying network structure in preschool-aged autistic children within three large scale intrinsic connectivity networks implicated in ASD: the Socioemotional Salience, Executive Control, and Default Mode Networks. Utilizing structural covariance MRI (scMRI), we report network-level differences in autistic versus TD children, and further report preliminary findings of sex-dependent differences within network topology.

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