1. Belica I, Janšáková K, Celušáková H, Kopčíková M, Polónyiová K, Rašková B, Vidošovičová M, Ostatníková D, Babinská K. Plasma cytokine concentrations of children with autism spectrum disorder and neurotypical siblings. Cytokine;2023 (Aug 18);170:156333.

Several studies of autism spectrum disorder (ASD) have shown cytokine dysregulation in children with ASD, leading to a consideration of the immune theory of the ASD etiopathogenesis and a debate about cytokines as potential biomarkers of ASD. However, the results of these studies are still inconsistent. Overall, studies comparing the cytokine levels of children with ASD and neurotypical siblings achieved relatively different results than studies with control groups of non-siblings. The studies suggest that the immune profile of siblings of individuals with ASD serving as control is more similar to children with ASD than the profile of non-siblings. However, there are still only a few studies with control groups including neurotypical siblings of children with ASD. The aim of our study was to determine whether the concentration of plasma cytokine levels may differentiate children with ASD from their neurotypical siblings. The sample consisted of 40 children with ASD (mean age 7.11 years, SD 2.9) and 21 neurotypical siblings (mean age 7.38, SD 3.3). Levels of 20 cytokines were included into the statistical analysis. A multiple logistic regression model using multiple corrections showed that an increase in log-transformed plasma G-CSF (granulocyte colony stimulating factor) concentration is associated with an increased risk of the child being diagnosed as an ASD case (OR = 4.35, 95% CI 1.77, 10.73). Although the significantly increased concentration of G-CSF suggests a slightly different activity of the immune system of children with ASD, the overall cytokine profile of their siblings appeared to be very similar.

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2. Binder MS, Bordey A. The novel somatosensory nose-poke adapted paradigm (SNAP) is an effective tool to assess differences in tactile sensory preferences in autistic-like mice. eNeuro;2023 (Aug 18)

One of the most prevalent deficits in autism spectrum disorder (ASD) are sensitivities to sensory stimuli. Despite the prevalence of sensory deficits in autism, there are few paradigms capable of easily assessing sensory behaviors in ASD-like mouse models. We addressed this need by creating the Somatosensory Nose-poke Adapted Paradigm (SNAP), which consists of an elevated platform with 6 holes in the center, half of which are lined with sandpaper and half are smooth, requiring mice to use their whiskers to sense the texture. The SNAP paradigm assesses tactile sensory preferences as well as stereotypy, anxiety, and locomotion. We used two wildtype (neurotypical) mouse strains, C57BL/6J (C57) inbred and CD-1 outbred mice, and two ASD mouse models, BTBR (a model of idiopathic ASD) and Cntnap2(-/-) mice (a model of syndromic ASD). We found that both ASD models produced more nose pokes into the rough condition than the smooth condition, suggesting an increased preference for complex tactile stimulation when compared to the neurotypical groups, wherein no differences were observed. Furthermore, we found increased stereotypy and time spent in the center, suggestive of decreased anxiety, only for BTBR mice compared to the other mouse strains. Overall, SNAP is an easy to implement task to assess the degree of preference for complex tactile stimulation in ASD mouse models that can be further modified to exclude possible confounding effects of novelty or anxiety on the sensory preferences.Significance StatementDespite sensory deficits occurring in 90% of individuals with ASD, there are few behavioral sensory tasks available. To address this need, we developed a tactile sensory task, called the Somatosensory Nose-poke Adapted Paradigm (SNAP) that harnesses innate behavior, is easy to implement, and is not memory dependent. We assessed two neurotypical mouse strains: C57 and CD-1 mice, and two ASD mouse models: BTBR and Cntnap2(-/-) mice. Both ASD models displayed preferences for rough textures and inter-strain differences in stereotypy, anxiety, and locomotion. SNAP is thus an easy to implement test to assess differences in tactile sensory preferences in ASD mouse models.

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3. Coley-O’Rourke EJ, Hsiao EY. Microbiome alterations in autism spectrum disorder. Nat Microbiol;2023 (Aug 17)

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4. Dos Santos TR, Carlucci NSS, de Avó L, Barbato IT, Pinto LLC, Pilotto RF, Germano CMR, Melo DG. Quality of life of Brazilian families who have children with Fragile X syndrome: a descriptive study. J Community Genet;2023 (Aug);14(4):407-418.

This study aimed to assess the Family Quality of Life (FQoL) of Brazilian families with male children with Fragile X syndrome (FXS). Data from 53 families were collected using forms that included sociodemographic and clinical information, as well as the Beach Center Family Quality of Life Scale, a 5-point Likert scale ranging from « very dissatisfied » (1) to « very satisfied » (5). The mean overall FQoL score was 3.56 ± 0.79; the emotional well-being domain had the lowest score (2.98 ± 1.11) and showed significant differences between the other domains: family interaction (3.81 ± 0.89; p < 0.001), parenting (3.66 ± 0.89; p < 0.001), physical and material well-being (3.48 ± 0.83; p < 0.001), and disability-related support (3.75 ± 0.98; p < 0.001). Physical and material well-being was the second-lowest domain and was statistically different from the family interaction domain (p = 0.013). Lower FQoL satisfaction ratings were found in families with children who had difficulty getting along with people of the same age (t(51) = -3.193, p = 0.002; d = 1.019) and difficulty in living together on a day-to-day basis (t(51) = -3.060, p = 0.004; d = 0.888). These results highlight the importance of proper emotional support for the family, emphasizing the need to provide assistance not only for individuals with FXS but also for other family members. Besides, we advocate for the adoption of public policies that provide financial assistance to families and the implementation of the Brazilian Policy of Comprehensive Care for People with Rare Diseases.

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5. Environmental, Public Health JO. Retracted: Influence of Family Sports Games on the Development of Early Communication Skills in Autistic Children. J Environ Public Health;2023;2023:9848545.

[This retracts the article DOI: 10.1155/2022/2621476.].

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6. Fang Y, Cui Y, Yin Z, Hou M, Guo P, Wang H, Liu N, Cai C, Wang M. Comprehensive systematic review and meta-analysis of the association between common genetic variants and autism spectrum disorder. Gene;2023 (Aug 18):147723.

BACKGROUND: Autism spectrum disorder (ASD) is neurodevelopmental disorder characterized by stereotyped behavior and deficits in communication and social interactions. To date, numerous studies have investigated the associations between genetic variants and ASD risk. However, the results of these published studies lack a clear consensus. In the present study, we performed a systematic review on the association between genetic variants and ASD risk. Meanwhile, we conducted a meta-analysis on available data to identify the association between the single nucleotide polymorphisms (SNPs) of candidate genes and ASD risk. METHODS: We systematically searched public databases including English and Chinese from their inception to August 1, 2022. Two independent reviewers extracted data and assessed study quality. Odds ratio and 95% confidence interval were used as effect indexes to evaluate the association between the SNPs of candidate genes and the risk of ASD. Heterogeneity was explored through subgroup, sensitivity, and meta-regression analyses. Publication bias was assessed by using Egger’s and Begg’s tests for funnel plot asymmetry. In addition, TSA analysis were performed to confirm the study findings. RESULTS: We summarized 84 SNPs of 32 candidate genes from 81 articles included in the study. Subsequently, we analyzed 16 SNPs of eight genes by calculating pooled ORs, and identified eight significant SNPs of contactin associated protein 2 (CNTNAP2), methylentetrahydrofolate reductase (MTHFR), oxytocin receptor (OXTR), and vitamin D receptor (VDR). Results showed that seven SNPs, including the CNTNAP2 rs2710102 (homozygote, heterozygote, dominant and allelic models) and rs7794745 (heterozygote and dominant models), MTHFR C677T (homozygote, heterozygote, dominant, recessive and allelic models) and A1298C (dominant and allelic models), OXTR rs2254298 (homozygote and recessive models), VDR rs731236 (homozygote, dominant, recessive and allelic models) and rs2228570 (homozygote and recessive models), were showed to be correlated with an increased ASD risk. By contrast, the VDR rs7975232 was correlated with a decreased the risk of ASD under the homozygote and allelic models. CONCLUSION: Our study summarized research evidence on the genetic variants of ASD and provides a broad and detailed overview of ASD risk genes. The C677T and A1298C polymorphisms of MTHFR, rs2710102 and rs7794745 polymorphisms of CNTNAP2, rs2254298 polymorphism of OXTR, and rs731236 and rs2228570 polymorphisms of VDR were genetic risk factors. The rs7975232 polymorphism of VDR was a genetic protective factor for ASD. Our study provides novel clues to clinicians and healthcare decision-makers to predict ASD susceptibility.

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7. Filandrova R, Douglas P, Zhan X, Verhey TB, Morrissy S, Turner RW, Schriemer DC. Mouse Model of Fragile X Syndrome Analyzed by Quantitative Proteomics: A Comparison of Methods. J Proteome Res;2023 (Aug 18)

Multiple methods for quantitative proteomics are available for proteome profiling. It is unclear which methods are most useful in situations involving deep proteome profiling and the detection of subtle distortions in the proteome. Here, we compared the performance of seven different strategies in the analysis of a mouse model of Fragile X Syndrome, involving the knockout of the fmr1 gene that is the leading cause of autism spectrum disorder. Focusing on the cerebellum, we show that data-independent acquisition (DIA) and the tandem mass tag (TMT)-based real-time search method (RTS) generated the most informative profiles, generating 334 and 329 significantly altered proteins, respectively, although the latter still suffered from ratio compression. Label-free methods such as BoxCar and a conventional data-dependent acquisition were too noisy to generate a reliable profile, while TMT methods that do not invoke RTS showed a suppressed dynamic range. The TMT method using the TMTpro reagents together with complementary ion quantification (ProC) overcomes ratio compression, but current limitations in ion detection reduce sensitivity. Overall, both DIA and RTS uncovered known regulators of the syndrome and detected alterations in calcium signaling pathways that are consistent with calcium deregulation recently observed in imaging studies. Data are available via ProteomeXchange with the identifier PXD039885.

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8. Hayes K, Adams HC, Robeson M, Zlomke KR. Bouncing Back: Resilience as a Protective Factor for the Impact of Child Problem Behavior on Caregiver Depressive Cognitions Among Youth with Autism Spectrum Disorder. J Autism Dev Disord;2023 (Aug 18)

Caregivers of children with autism spectrum disorder (ASD) often report higher rates of depression and the related negative thought patterns that may precede a clinical diagnosis. These negative thought patterns are referred to as depressive cognitions. Depressive cognitions are exacerbated by child problem behaviors (CPB) but may be impacted by parental resilience. The current study examines relations between CPB and depressive cognitions and the role of resilience as a moderator among caregivers of children with ASD (n = 287) and a sample of caregivers of children who are typically developing (n = 207). Significant positive associations were found between CPB and depressive cognitions for caregivers of children with ASD and who are typically developing. A moderation analysis revealed that, among the ASD sample, the model accounted for 33% of the variance in caregiver depressive cognitions (R2 = 0.33, SE = 35.52, p < 0.001). The interaction of child problem behaviors and caregiver resilience on caregiver depressive cognitions was statistically significant (B = - 0.016, SE = 0.007, p = 0.037), thus resilience was a significant moderator, for caregivers of children with ASD. Resilience serves as a protective factor in the relationship between child problem behavior and caregiver depressive cognitions for caregivers of children with ASD only. This finding highlights the importance of assessing and supporting resilience among caregivers of children with ASD. Interventions addressing child behavior would benefit from additional components to bolster caregiver resilience to enhance caregiver mental health and protect against depressive cognitions.

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9. McNair ML, Keenan EG, Houck AP, Lerner MD. Seeking contexts that promote neurodiverse social success: Patterns of behavior during minimally-structured interaction settings in autistic and non-autistic youth. Dev Psychopathol;2023 (Aug 18):1-16.

While peer interaction differences are considered a central feature of autism, little is known regarding the nature of these interactions via directly-observed measurement of naturalistic (i.e., minimally-structured) groups of autistic and non-autistic adolescent peers. 148 autistic and non-autistic adolescents (111 male, M(age) = 14.22, SD(age) = 1.90; M(IQ) = 103.22, SD(IQ) = 15.80) participated in a 50-minute, minimally-structured, naturalistic peer interaction paradigm with activities of varying social demands: an incidental social demand (eating in a room with peers), a physical social demand (playing a physically-interactive game), and a verbal social demand (playing a verbal game). While autistic youth exhibited fewer overall interaction behaviors than non-autistic youth, the two groups did not differ in amount of positive, negative, and low-level interaction behaviors. Within activities, autistic and non-autistic youth only differed in positive interaction behaviors during the context of a verbal social demand. Youth who displayed more positive interaction behaviors during this same activity had less autism spectrum disorder symptomatology, controlling for nested group effects and relevant covariates. These results point toward subtle differences in social demands across naturalistic settings that can either support or impede prosocial interaction for autistic youth, providing a guidepost for identifying settings that best promote social success for neurodiverse populations.

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10. Ortega DP, Walsh K, Bődi CB, Hawkins LB, Bright MA. School-based prevention education for children and youth with intellectual developmental disabilities. Child Abuse Negl;2023 (Aug 15);145:106397.

Children with intellectual developmental disabilities (IDD) are at a heightened risk of experiencing child maltreatment (CM) when compared to their peers without IDD. Despite expanding evidence supporting the efficacy of school-based CM prevention programs, there are limited programs that tailor their lessons to the unique needs of children with IDD. This discussion first presents information regarding the prevalence and risk factors of CM among children with IDD. We then present existing peer-reviewed CM programs that have been developed for children with IDD. Finally, based on the latest research of CM prevention and special education, we present our considerations for a comprehensive school-based CM prevention program for children with IDD. Prevention programs for children with IDD may increase risk awareness among children with IDD and their parents, equip children with IDD with the protective skills necessary to navigate unsafe situations, and decrease the overall incidence of CM against this population.

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11. Poole D, Gowen E, Poliakoff E, Lambrechts A, Jones LA. EXPRESS: When 2 become 1: autistic simultaneity judgements about asynchronous audiovisual speech. Q J Exp Psychol (Hove);2023 (Aug 18):17470218231197518.

It has been proposed that autistic people experience a temporal distortion whereby the temporal binding window of multisensory integration is extended. Research to date has focused on autistic children so whether these differences persist into adulthood remains unknown. Additionally, the possibility that the previous observations have arisen from between group differences in response bias, rather than perceptual differences, has not been addressed.Participants completed simultaneity judgements of audiovisual speech stimuli at a range of stimulus onset asynchronies. Response times and accuracy data were fitted to a drift diffusion model so that the drift rate (a measure of processing efficiency) and starting point (response bias) could be estimated. In Experiment 1, we tested a sample of non-autistic adults who completed the Autism Quotient questionnaire. Autism Quotient score was not correlated with either drift rate or response bias, nor were there between group differences when splitting based on the 1st and 3rd quantiles of scores. In Experiment 2, we compared the performance of autistic with a group of non-autistic adults. There were no between group differences in either drift rate or starting point.The results of the present study do not support the previous suggestion that autistic people have an extended temporal binding window for audiovisual speech. Additionally, exploratory analysis revealed that operationalising the temporal binding window in different ways influenced whether a group difference was observed, which is an important consideration for future work .

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12. Purcell RH, Sefik E, Werner E, King AT, Mosley TJ, Merritt-Garza ME, Chopra P, McEachin ZT, Karne S, Raj N, Vaglio BJ, Sullivan D, Firestein BL, Tilahun K, Robinette MI, Warren ST, Wen Z, Faundez V, Sloan SA, Bassell GJ, Mulle JG. Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion. Sci Adv;2023 (Aug 18);9(33):eadh0558.

The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.

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13. Saadat M, Taherian AA, Aldaghi MR, Raise-Abdullahi P, Sameni HR, Vafaei AA. Prangos ferulacea (L.) ameliorates behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid. Brain Behav;2023 (Aug 18):e3224.

BACKGROUND: Prenatal exposure to valproic acid (VPA) may enhance the risk of autism spectrum disorder (ASD) in children. This study investigated the effect of Prangos ferulacea (L.) on behavioral alterations, hippocampal oxidative stress markers, and apoptotic deficits in a rat model of autism induced by valproic acid. METHODS: Pregnant rats received VPA (600 mg/kg, intraperitoneally [i.p.]) or saline on gestational day 12.5 (E 12.5). Starting from the 30th postnatal day (PND 30), the pups were i.p. administered Prangos ferulacea (PF, 100 and 200 mg/kg), or the vehicle, daily until PND 58. On PND 30 and 58, various behavioral tasks were used to evaluate pups, including the open field, elevated plus-maze, hot-plate, and rotarod test. On PND 65, the animals were euthanized, and their brains were removed for histopathological and biochemical assay. RESULTS: Prenatal exposure to VPA caused significant behavioral changes in the offspring, reversed by administering an extract of Prangos ferulacea (L.). Additionally, prenatal VPA administration resulted in increased levels of malondialdehyde and deficits in antioxidant enzyme activities in the hippocampus, including catalase and glutathione, ameliorated by PF. Likewise, postnatal treatment with PF improved VPA-induced dysregulation of Bax and Blc2 in the hippocampus and reduced neuronal death in CA1, CA3, and dentate gyrus. CONCLUSION: The findings of this study suggest that postnatal administration of PF can prevent VPA-induced ASD-like behaviors by exhibiting antiapoptotic and antioxidant properties. Therefore, PF may have the potential as an adjunct in the management of ASD.

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14. Sergio M, Gabriella L, Mario T, Francesco R, Marialaura O, Maria S, Angela TS, Antonio A, Daniela AC, Maria L, Fatima-Zahra A, Agostino P, Sestina S, Francesca B, Gaetano C, Tilman F, Alena S, Edward C, Uwe W, Vittorio C. Antioxidants, Hormetic Nutrition, and Autism. Curr Neuropharmacol;2023 (Aug 17)

Autism spectrum disorder (ASD) includes a heterogeneous group of complex neurodevel opmental disorders characterized by atypical behaviors with two core pathological manifestations: deficits in social interaction/communication and repetitive behaviors, which are associated with disturbed redox homeostasis. Modulation of cellular resilience mechanisms induced by low levels of stressors represents a novel approach for the development of therapeutic strategies, and in this context, neuroprotective effects of a wide range of polyphenol compounds have been demonstrated in several in vitro and in vivo studies and thoroughly reviewed by [2, 3]. Mushrooms have been used in traditional medicine for many years and have been associated with a long list of therapeutic properties, including antitumor, immunomodulatory, antioxidant, antiviral, antibacterial, and hepatoprotective effects [4]. Our recent studies on neuroprotection have strikingly indicated the presence of polyphenols in nutritional mushrooms and demonstrated their protective effects in different models of neurodegenerative disorders in humans and rats [5, 6]. Although their therapeutic effects are exerted through multiple mechanisms, increasing attention is focusing on their capacity to induce endogenous defense systems by modulating cellular signaling processes, such as nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) pathways. Here we discuss the protective role of hormesis and its modulation by hormetic nutrients in ASD.

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15. Wang J, Gao Y, Xiao L, Lin Y, Huang L, Chen J, Liang G, Li W, Yi W, Lao J, Zhang B, Gao TM, Zhong M, Yang X. Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1(-/-) mice. iScience;2023 (Aug 18);26(8):107476.

Mutations of the GABA-A receptor subunit β1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1(-/-) mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABA(A)R-currents in the CA1 neurons were detected in Gabrb1(-/-) mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1(-/-) mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

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16. Wang X, Delgado J, Marchesotti S, Kojovic N, Sperdin HF, Rihs TA, Schaer M, Giraud AL. Speech reception in young children with autism is selectively indexed by a neural oscillation coupling anomaly. J Neurosci;2023 (Aug 18)

Communication difficulties are one of the core criteria in diagnosing ASD, and are often characterized by speech reception difficulties, whose biological underpinnings are not yet identified. This deficit could denote atypical neuronal ensemble activity, as reflected by neural oscillations. Atypical cross-frequency oscillation coupling, in particular, could disrupt the joint tracking and prediction of dynamic acoustic stimuli, a dual process that is essential for speech comprehension. Whether such oscillatory anomalies already exist in very young children with ASD, and with what specificity they relate to individual language reception capacity is unknown. We collected neural activity data using electroencephalography (EEG) in 64 very young children with and without ASD (mean age 3; 17 females, 47 males) while they were exposed to naturalistic-continuous speech. EEG power of frequency bands typically associated with phrase-level chunking (delta, 1-3 Hz), phonemic encoding (low-gamma, 25-35 Hz), and top-down control (beta, 12-20 Hz) were markedly reduced in ASD relative to typically developing (TD) children. Speech neural tracking by delta and theta (4-8 Hz) oscillations was also weaker in ASD compared to TD children. After controlling gaze-pattern differences, we found that the classical theta/gamma coupling was replaced by an atypical beta/gamma coupling in children with ASD. This anomaly was the single most specific predictor of individual speech reception difficulties in ASD children. These findings suggest that early interventions (e.g., neurostimulation) targeting the disruption of beta/gamma coupling and the upregulation of theta/gamma coupling could improve speech processing coordination in young children with ASD and help them engage in oral interactions.Significance StatementVery young children already present marked alterations of neural oscillatory activity in response to natural speech at the time of ASD diagnosis.Hierarchical processing of phonemic- and syllabic-range information (theta/gamma coupling) is disrupted in ASD children.Abnormal bottom-up (low-gamma) and top-down (low-beta) coordination specifically predicts speech reception deficits in very young ASD children, and no other cognitive deficit.

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