1. Charpentier J, Latinus M, Andersson F, Saby A, Cottier JP, Bonnet-Brilhault F, Houy-Durand E, Gomot M. Brain correlates of emotional prosodic change detection in autism spectrum disorder. Neuroimage Clin ;2020 ;28:102512.

Autism Spectrum Disorder (ASD) is currently diagnosed by the joint presence of social impairments and restrictive, repetitive patterns of behaviors. While the co-occurrence of these two categories of symptoms is at the core of the pathology, most studies investigated only one dimension to understand underlying physiopathology. In this study, we analyzed brain hemodynamic responses in neurotypical adults (CTRL) and adults with autism spectrum disorder during an oddball paradigm allowing to explore brain responses to vocal changes with different levels of saliency (deviancy or novelty) and different emotional content (neutral, angry). Change detection relies on activation of the supratemporal gyrus and insula and on deactivation of the lingual area. The activity of these brain areas involved in the processing of deviancy with vocal stimuli was modulated by saliency and emotion. No group difference between CTRL and ASD was reported for vocal stimuli processing or for deviancy/novelty processing, regardless of emotional content. Findings highlight that brain processing of voices and of neutral/ emotional vocal changes is typical in adults with ASD. Yet, at the behavioral level, persons with ASD still experience difficulties with those cues. This might indicate impairments at latter processing stages or simply show that alterations present in childhood might have repercussions at adult age.

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2. Chen L, Shi XJ, Liu H, Mao X, Gui LN, Wang H, Cheng Y. Oxidative stress marker aberrations in children with autism spectrum disorder : a systematic review and meta-analysis of 87 studies (N = 9109). Transl Psychiatry ;2021 (Jan 5) ;11(1):15.

There is increasing awareness that oxidative stress may be implicated in the pathophysiology of autism spectrum disorder (ASD). Here we aimed to investigate blood oxidative stress marker profile in ASD children by a meta-analysis. Two independent investigators systematically searched Web of Science, PubMed, and Cochrane Library and extracted data from 87 studies with 4928 ASD children and 4181 healthy control (HC) children. The meta-analysis showed that blood concentrations of oxidative glutathione (GSSG), malondialdehyde, homocysteine, S-adenosylhomocysteine, nitric oxide, and copper were higher in children with ASD than that of HC children. In contrast, blood reduced glutathione (GSH), total glutathione (tGSH), GSH/GSSG, tGSH/GSSG, methionine, cysteine, vitamin B9, vitamin D, vitamin B12, vitamin E, S-adenosylmethionine/S-adenosylhomocysteine, and calcium concentrations were significantly reduced in children with ASD relative to HC children. However, there were no significance differences between ASD children and HC children for the other 17 potential markers. Heterogeneities among studies were found for most markers, and meta-regressions indicated that age and publication year may influence the meta-analysis results. These results therefore clarified blood oxidative stress profile in children with ASD, strengthening clinical evidence of increased oxidative stress implicating in pathogenesis of ASD. Additionally, given the consistent and large effective size, glutathione metabolism biomarkers have the potential to inform early diagnosis of ASD.

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3. Crane L, Lui LM, Davies J, Pellicano E. Short report : Autistic parents’ views and experiences of talking about autism with their autistic children. Autism ;2021 (Jan 4):1362361320981317.

Previous research examining how parents talk about autism with their children has tended to focus on parents who are not autistic themselves. We collected information on this topic from 34 autistic parents of autistic children (most of whom had told their children about their diagnosis). We found similarities, but also differences, between the views and experiences of autistic parents in this research and those reported in previous research (in studies of largely non-autistic parents). Similarities include the following : it is important to be open and honest about the diagnosis ; the diagnosis should be introduced/discussed as early as possible ; discussions should be tailored to each individual child’s needs ; and we should not overlook the challenges associated with autism, but it is important to focus on positive aspects too. Differences include the following : autistic parents used personal experiences in conversations about autism, which was felt to result in increased understanding and empathy with their children ; autistic parents overwhelmingly focused on more positive aspects of an autism diagnosis ; our sample did not express concerns that discussions could have negative consequences too (e.g. making children more anxious) ; and autistic parents did not want or need professional support to talk about autism with their children (instead, they felt confident in using their own knowledge/experiences to guide discussions).

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4. Day DB, Collett BR, Barrett ES, Bush NR, Swan SH, Nguyen RHN, Szpiro AA, Sathyanarayana S. Phthalate mixtures in pregnancy, autistic traits, and adverse childhood behavioral outcomes. Environ Int ;2021 (Feb) ;147:106330.

BACKGROUND : Prenatal exposure to multiple phthalates is ubiquitous, and yet few studies have evaluated these exposures as a mixture in relation to child autistic traits and behavioral problems. OBJECTIVES : To assess cumulative associations between prenatal phthalate mixtures and child behaviors, including effect modification by exposure timing and child sex. METHODS : Analyses included 501 mother/child pairs from the multicenter pregnancy cohort The Infant Development and Environment Study (TIDES). Nine maternal urinary phthalate metabolites were measured in early and late pregnancy, and behavior was assessed at ages 4-5 years using composite T scores for the Behavioral Assessment System for Children (BASC-2), which measures several dimensions of child behavior, and the Social Responsiveness Scale (SRS-2), which measures social impairment consistent with autistic traits. We utilized weighted quantile sum (WQS) regressions to examine pregnancy period-specific associations between phthalate mixtures and behavioral outcomes. Full-sample 95% WQS confidence intervals are known to be anti-conservative, so we calculated a confirmatory p-value using a permutation test. Effect modification by sex was examined with stratified analyses. RESULTS : A one-quintile increase in the early pregnancy phthalate mixture was associated with increased SRS-2 total score (coefficient = 1.0, confirmatory p = 0.01) and worse adaptive skills (coefficient = -1.0, confirmatory p = 0.06) in both sexes. In sex-stratified analyses, the early pregnancy phthalate mixture was associated with increased SRS-2 total score in boys (coefficient = 1.2, confirmatory p = 0.04) and girls (coefficient = 1.0, confirmatory p = 0.10) and worse BASC-2 adaptive skills score in girls (coefficient = -1.5, confirmatory p = 0.06), while the late pregnancy phthalate mixture was associated with increased BASC-2 externalizing score in boys (coefficient = 1.3, confirmatory p = 0.03). CONCLUSION : Our results suggest cumulative adverse associations between prenatal phthalate mixtures and multiple facets of childhood behavior.

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5. Filice F, Janickova L, Henzi T, Bilella A, Schwaller B. The Parvalbumin Hypothesis of Autism Spectrum Disorder. Front Cell Neurosci ;2020 ;14:577525.

The prevalence of autism spectrum disorder (ASD)-a type of neurodevelopmental disorder-is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca(2+) signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca(2+)-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

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6. Haendel AD, Barrington A, Magnus B, Arias AA, McVey A, Pleiss S, Carson A, Vogt EM, Van Hecke AV. Changes in Electroencephalogram Coherence in Adolescents With Autism Spectrum Disorder After a Social Skills Intervention. Autism Res ;2021 (Jan 4)

Autism spectrum disorder (ASD) is a developmental condition that affects social communication and behavior. There is consensus that neurological differences are present in ASD. Further, theories emphasize the mixture of hypo- and hyper-connectivity as a neuropathologies in ASD [O’Reilly, Lewis, & Elsabbagh, 2017] ; however, there is a paucity of studies specifically testing neurological underpinnings as predictors of success on social skills interventions. This study examined functional neural connectivity (electroencephalogram [EEG], coherence) of adolescents with ASD before and after the Program for the Education and Enrichment of Relational Skills (PEERS®) intervention, using a randomized controlled trial of two groups : an Experimental ASD (EXP) Group and a Waitlist Control ASD (WL) Group. The study had two purposes. First, the study aimed to determine whether changes in EEG coherence differed for adolescents that received PEERS® versus those that did not receive PEERS®. Results revealed a significant increase in connectivity in the occipital left to temporal left pair for the EXP group after intervention. Second, the study aimed to determine if changes in EEG coherence related to changes in behavior, friendships, and social skills measured by questionnaires. At post-intervention, results indicated : (a) positive change in frontal right to parietal right coherence was linked to an increase in social skills scores ; and (b) positive changes in occipital right to temporal right coherence and occipital left to parietal left coherence were linked to an increase in the total number of get-togethers. Results of this study support utilizing neurobehavioral domains as indicators of treatment outcome. Lay Summary : This study examined how well various areas of the brain communicate in adolescents with ASD before and after a social skills intervention. Results revealed increased connectivity in the adolescents that received the intervention. Secondly, the study aimed to determine if changes in connectivity of brain areas related to changes in behavior, friendships, and social skills. Results indicated that changes in connectivity were also linked to increased social skills.

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7. Hine JF, Wagner L, Goode R, Rodrigues V, Taylor JL, Weitlauf A, Warren ZE. Enhancing developmental-behavioral pediatric rotations by teaching residents how to evaluate autism in primary care. Autism ;2021 (Jan 5):1362361320984313.

Most physician preparation programs do not provide enough practical experiences in autism-related care. This is especially true for how to assess for and diagnose autism. Without this training, many pediatricians are not well prepared to implement appropriate care for children with autism and their families. We designed a curriculum to improve training for medical residents that involved explicit hands-on training in diagnostic identification and care coordination for toddlers at risk for autism. We collected data to assess whether our enhanced curriculum led to increased comfort level across recommended practice behaviors. Almost all the residents were able to complete the training within their rotation and our surveys indicated significant increases in residents feeling more comfortable identifying symptoms of autism, providing feedback about diagnostic decisions, and effectively connecting families with services. A significant majority of residents considered it appropriate or very appropriate for children to receive a diagnosis solely from a primary care provider. Our results suggest feasibility of the enhanced model, and this project reflects the first step in advancing incorporation of autism training into pediatric residency programs.

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8. Kovarski K, Charpentier J, Roux S, Batty M, Houy-Durand E, Gomot M. Emotional visual mismatch negativity : a joint investigation of social and non-social dimensions in adults with autism. Transl Psychiatry ;2021 (Jan 5) ;11(1):10.

Unusual behaviors and brain activity to socio-emotional stimuli have been reported in Autism Spectrum Disorder (ASD). Atypical reactivity to change and intolerance of uncertainty are also present, but little is known on their possible impact on facial expression processing in autism. The visual mismatch negativity (vMMN) is an electrophysiological response automatically elicited by changing events such as deviant emotional faces presented among regular neutral faces. While vMMN has been found altered in ASD in response to low-level changes in simple stimuli, no study has investigated this response to visual social stimuli. Here two deviant expressions were presented, neutral and angry, embedded in a sequence of repetitive neutral stimuli. vMMN peak analyses were performed for latency and amplitude in early and late time windows. The ASD group presented smaller amplitude of the late vMMN to both neutral and emotional deviants compared to the typically developed adults (TD) group, and only the TD group presented a sustained activity related to emotional change (i.e., angry deviant). Source reconstruction of the vMMNs further revealed that any change processing elicited a reduced activity in ASD group compared to TD in the saliency network, while the specific processing emotional change elicited activity in the temporal region and in the insula. This study confirms atypical change processing in ASD and points to a specific difficulty in the processing of emotional changes, potentially playing a crucial role in social interaction deficits. Nevertheless, these results require to be further replicated with a greater sample size and generalized to other emotional expressions.

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9. Lin IF, Itahashi T, Kashino M, Kato N, Hashimoto RI. Brain activations while processing degraded speech in adults with autism spectrum disorder. Neuropsychologia ;2021 (Jan 5) ;152:107750.

Individuals with autism spectrum disorder (ASD) are found to have difficulties in understanding speech in adverse conditions. In this study, we used noise-vocoded speech (VS) to investigate neural processing of degraded speech in individuals with ASD. We ran fMRI experiments in the ASD group and a typically developed control (TDC) group while they listened to clear speech (CS), VS, and spectrally rotated VS (SRVS), and they were requested to pay attention to the heard sentence and answer whether it was intelligible or not. The VS used in this experiment was spectrally degraded but still intelligible, but the SRVS was unintelligible. We recruited 21 right-handed adult males with ASD and 24 age-matched and right-handed male TDC participants for this experiment. Compared with the TDC group, we observed reduced functional connectivity (FC) between the left dorsal premotor cortex and left temporoparietal junction in the ASD group for the effect of task difficulty in speech processing, computed as VS-(CS + SRVS)/2. Furthermore, the observed reduced FC was negatively correlated with their Autism-Spectrum Quotient scores. This observation supports our hypothesis that the disrupted dorsal stream for attentive process of degraded speech in individuals with ASD might be related to their difficulty in understanding speech in adverse conditions.

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10. Luhach K, Kulkarni GT, Singh VP, Sharma B. Attenuation of neurobehavioural abnormalities by papaverine in prenatal valproic acid rat model of ASD. Eur J Pharmacol ;2021 (Jan 5) ;890:173663.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase-10A (PDE10A) inhibition has shown to provide benefits in various brain conditions. We investigated the role of a PDE10A inhibitor, papaverine on core phenotypes in prenatal-valproic acid (Pre-VPA) model of ASD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neurogenesis-DCX, neuronal survival-BDNF, synaptic transmission-synapsin-IIa, neuronal transcription factor-pCREB, neuronal inflammation (IL-6, IL-10 and TNF-α) and neuronal oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, hippocampus and striatum. Pre-VPA induced impairments in social behaviour, presence of repetitive behaviour, hyper-locomotion, anxiety, and diminished nociception were studied in male Albino Wistar rats. Administration of papaverine to Pre-VPA animals resulted in improvements of social behaviour, corrected repetitive behaviour, anxiety, locomotor, and nociceptive changes. Also, papaverine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB, IL-10 and GSH along with significant decrease in TNF-α, IL-6 and TBARS in different brain areas of Pre-VPA group. Finally, high association between behavioural parameters and biochemical parameters was observed upon Pearson’s correlation analysis. Papaverine, administration rectified core behavioural phenotype of ASD, possibly by altering protein markers associated with neuronal survival, neurogenesis, neuronal transcription factor, neuronal transmission, neuronal inflammation, and neuronal oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ASD phenotypes.

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11. Lyons KM, Stevenson RA, Owen AM, Stojanoski B. Examining the relationship between measures of autistic traits and neural synchrony during movies in children with and without autism. Neuroimage Clin ;2020 ;28:102477.

Children who have been diagnosed with autism spectrum disorder (ASD) often show a marked deficit in measures of social cognition. In autistic adults, measures of social cognition have been shown to relate to differences in brain synchronization (as measured by fMRI) when individuals are processing naturalistic stimuli, such as movies. However, whether children who differ in their degree of autistic traits, with or without a diagnosis of ASD, differ in their neural responses to movies has not yet been investigated. In the current study, neural synchrony, measured using fMRI, was examined in three groups of children aged 7 to 12, who differed with respect to scores on a measure of autistic traits associated with social impairment and whether or not they had been diagnosed with ASD. While watching the movie ‘Despicable Me’, those diagnosed with ASD had significantly less neural synchrony in areas that have been previously shown to be associated with social cognition (e.g. areas related to ‘theory of mind’), and plot following (e.g. the lateral prefrontal cortex), than those who did not have an ASD diagnosis. In contrast, two groups who differed in their degree of autistic traits, but did not have a diagnosis of ASD, showed no significant differences in neural synchrony across the whole brain. These results shed some light on how autistic traits may contribute to an individual’s conscious experience of the world, and how, for children with ASD, that experience may differ markedly from that of those without ASD.

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12. Marsack-Topolewski CN, Samuel PS, Tarraf W. Empirical evaluation of the association between daily living skills of adults with autism and parental caregiver burden. PLoS One ;2021 ;16(1):e0244844.

BACKGROUND : Despite the joy of parenting, the burden of daily caregiving for children with autism spectrum disorders (ASD) can be overwhelming and constant. Parents can expect to provide enduring care for their children with ASD. Given that the majority of individuals with autism spectrum disorders (ASD) remain in their family homes well into adulthood, often the need for assistance with activities of daily living (ADLs) is placed on parents. Providing ongoing support to adult children who have difficulty with completing ADLs can increase parental caregiving demands. Therefore, the purpose of this study was to examine the relationship between the ability of adults with ASD to perform ADLs with parental perceptions of caregiver burden. METHODS : Quantitative analysis of cross-sectional multi-state data gathered electronically using Qualtrics from 320 aging parents of adults with ASD was conducted. Regression models were fit to examine the association of ADL challenges with total caregiver burden and its four domains (emotional, financial, time dependence, and developmental). RESULTS : Parental perceptions of caregiver burden decreased, particularly time dependence and developmental burden, when adult children were less dependent in ADLs, even after adjusting for parental health and behavioral challenges. CONCLUSIONS : Findings support the need for family-centered interventions to improve the capacity of adults with ASD to perform ADLs independently.

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13. McPherson AC, Perez A, Buchholz A, Forhan M, Ball GDC. « It’s not a simple answer. » A qualitative study to explore how healthcare providers can best support families with a child with autism spectrum disorder and overweight or obesity. Disabil Rehabil ;2021 (Jan 5):1-7.

PURPOSE : This qualitative study aimed to explore the experiences of parents supporting their child with Autism Spectrum Disorder (ASD) and overweight or obesity (OW/OB), including their weight management support needs. METHODS : Interview transcripts were analysed using inductive thematic analysis. Nine parents (n = 9 mothers) of ten children with ASD (7 males, 3 females) participated in individual semi-structured interviews. RESULTS : The three themes developed were : (1) Our journey to obtain weight management support ; (2) I need real-world solutions ; and (3) The what, who and how of our weight management needs. Parents reported being proactive in seeking weight management support for their child but were disappointed with the services offered. Resources were not tailored to the child’s complex nutrition and behavioural issues or their abilities and functioning. A multidisciplinary approach that integrated both disability and weight management expertise was desired, but not experienced. A range of formal and informal programs were recommended. CONCLUSION : This study provides a call to action for supports that ensure children with ASD and OW/OB receive integrated, individualised support to maximise their health and wellness. Implications for rehabilitation Children with autism spectrum disorder (ASD) are at high risk of developing overweight or obesity. The weight management support needs of parents of children with ASD and overweight or obesity are not being met. Support must be tailored to the child’s needs, which are often complex. Health services that integrate expertise in both disability and weight management are needed for children with ASD and their families.

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14. Nakai N, Overton ETN, Takumi T. Optogenetic Approaches to Understand the Neural Circuit Mechanism of Social Deficits Seen in Autism Spectrum Disorders. Adv Exp Med Biol ;2021 ;1293:523-533.

Individuals with neurodevelopmental disorders, such as autism spectrum disorders (ASDs), are diagnosed based on nonquantitative objective parameters such as behavioral phenotypes. It is still unclear how any neural mechanism affects such behavioral phenotypes in these patients. In human genetics, a large number of genetic abnormalities including single nucleotide variation (SNV) and copy number variation (CNV) have been found in individuals with ASDs. It is thought that influence of such variations converges on dysfunction of neural circuit resulting in common behavioral phenotypes of ASDs such as deficits in social communication and interaction. Recent studies suggest that an excitatory/inhibitory (E/I) imbalanced state, which induces disruption of neural circuit activities, is one of the pathophysiological abnormalities in ASD brains. To assess the causal relationship between brain abnormalities and behavioral deficits, we can take advantage of optogenetics with animal models of ASDs that recapitulate human genetic mutations. Here, we review optogenetics studies being utilized to dissect neural circuit mechanisms associated with social deficits in model mice of ASD. Optogenetic manipulation of disrupted neural activities would help us understand how neural circuits affect behavioral deficits observed in ASDs.

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15. Newman RS, Kirby LA, Von Holzen K, Redcay E. Read my lips ! Perception of speech in noise by preschool children with autism and the impact of watching the speaker’s face. J Neurodev Disord ;2021 (Jan 5) ;13(1):4.

BACKGROUND : Adults and adolescents with autism spectrum disorders show greater difficulties comprehending speech in the presence of noise. Moreover, while neurotypical adults use visual cues on the mouth to help them understand speech in background noise, differences in attention to human faces in autism may affect use of these visual cues. No work has yet examined these skills in toddlers with ASD, despite the fact that they are frequently faced with noisy, multitalker environments. METHODS : Children aged 2-5 years, both with and without autism spectrum disorder (ASD), saw pairs of images in a preferential looking study and were instructed to look at one of the two objects. Sentences were presented in the presence of quiet or another background talker (noise). On half of the trials, the face of the target person speaking was presented, while half had no face present. Growth-curve modeling was used to examine the time course of children’s looking to the appropriate vs. opposite image. RESULTS : Noise impaired performance for both children with ASD and their age- and language-matched peers. When there was no face present on the screen, the effect of noise was generally similar across groups with and without ASD. But when the face was present, the noise had a more detrimental effect on children with ASD than their language-matched peers, suggesting neurotypical children were better able to use visual cues on the speaker’s face to aid performance. Moreover, those children with ASD who attended more to the speaker’s face showed better listening performance in the presence of noise. CONCLUSIONS : Young children both with and without ASD show poorer performance comprehending speech in the presence of another talker than in quiet. However, results suggest that neurotypical children may be better able to make use of face cues to partially counteract the effects of noise. Children with ASD varied in their use of face cues, but those children who spent more time attending to the face of the target speaker appeared less disadvantaged by the presence of background noise, indicating a potential path for future interventions.

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16. Reyes ST, Mohajeri S, Krasinska K, Guo SG, Gu M, Pisani L, Rosenberg J, Spielman DM, Chin FT. GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using (1)H-Magnetic Resonance Spectroscopy and Mass Spectrometry. Front Mol Neurosci ;2020 ;13:612685.

Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABA(A) subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain’s biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both (1)H magnetic resonance imaging ((1)H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether (1)H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. (1)H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our (1)H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using (1)H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.

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17. Ronconi L, Vitale A, Federici A, Pini E, Molteni M, Casartelli L. Altered neural oscillations and connectivity in the beta band underlie detail-oriented visual processing in autism. Neuroimage Clin ;2020 ;28:102484.

Sensory and perceptual anomalies may have a major impact on basic cognitive and social skills in humans. Autism Spectrum Disorder (ASD) represents a special perspective to explore this relationship, being characterized by both these features. The present study employed electroencephalography (EEG) to test whether detail-oriented visual perception, a recognized hallmark of ASD, is associated with altered neural oscillations and functional connectivity in the beta frequency band, considering its role in feedback and top-down reentrant signalling in the typical population. Using a visual crowding task, where participants had to discriminate a peripheral target letter surrounded by flankers at different distances, we found that detail-oriented processing in children with ASD, as compared to typically developing peers, could be attributed to anomalous oscillatory activity in the beta band (15-30 Hz), while no differences emerged in the alpha band (8-12 Hz). Altered beta oscillatory response reflected in turn atypical functional connectivity between occipital areas, where the initial stimulus analysis is accomplished, and infero-temporal regions, where objects identity is extracted. Such atypical beta connectivity predicted both ASD symptomatology and their detail-oriented processing. Overall, these results might be explained by an altered feedback connectivity within the visual system, with potential cascade effects in visual scene parsing and higher order functions.

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18. Sergi L, Mingione E, Ricci MC, Cavallaro A, Russo F, Corrivetti G, Operto FF, Frolli A. Autism, Therapy and COVID-19. Pediatr Rep ;2021 (Jan 5) ;13(1):35-44.

While numerous treatments for ASD are available, intervention based on the principles and procedures of Applied Behavior Analysis (ABA) has garnered substantial scientific support. In this study we evaluated the effects of the lockdown during the COVID-19 pandemic outbreak, followed by quarantine provisions and during the three months after the resumption of activities. The study was conducted on a group of children taking part on a ABA-based intervention funded by the Local Health Authority (ASL) of the province of Caserta. In this study we considered a sample of 88 children who had been diagnosed with Autism Spectrum Disorder, aged between 18 and 30 months. The following inclusion criteria were observed : age at the time of diagnosis less than 30 months, absence of other neurological, genetic, or sensorineural pathologies, and severity level 1 measured by symptoms evaluation based on the ADOS 2 module T (used for diagnosis). During the lockdown children experienced improvements in communication, socialization, and personal autonomy. During the three months after the ABA treatment, the acquired skills were maintained but no significant improvement was demonstrated. In this study, we describe how parent training was significant in avoiding delays in the generalization of socially significant behaviors, following the drastic interruption of the treatment in this group of children.

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19. Settanni CR, Bibbò S, Ianiro G, Rinninella E, Cintoni M, Mele MC, Cammarota G, Gasbarrini A. Gastrointestinal involvement of autism spectrum disorder : focus on gut microbiota. Expert Rev Gastroenterol Hepatol ;2021 (Jan 5):1-24.

INTRODUCTION : Autism spectrum disorder (ASD) is a neurodevelopmental disorder typical of early age, characterized by impaired communication, social interaction, and repetitive behaviors. ASD patients frequently suffer from gastrointestinal (GI) symptoms. Neuro-psychological functions, intestinal homeostasis, and functional GI disturbances are modulated by the gut microbiota through the so-called ‘microbiota-gut-brain axis’. AREAS COVERED : Literature regarding GI symptoms among the ASD community as well as the involvement and modulation of the gut microbiota in GI disturbances of ASD patients was searched. Constipation, diarrhea, reflux, abdominal bloating, pain, and discomfort are reported with variable prevalence. ASD is characterized by a reduction of Bacteroidetes/Firmicutes, of the abundance of Bacteroidetes and other imbalances. ASD patients with GI symptoms present microbial changes with plausible relation with deficiency of digestive enzymes, carbohydrate malabsorption, selective eating, bacterial toxins, serotonin metabolism, and inflammation. The strategies to mitigate the GI distress through the gut microbiota modulation comprise antimicrobials, probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. EXPERT OPINION : The modulation of the gut microbiota in ASD individuals with GI disturbances seems a promising target for the future medicine. A standardization of the research strategies for large-scale studies together with a focus on poorly explored fields is necessary to strengthen this hypothesis.

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20. Shabani S. A mechanistic view on the neurotoxic effects of air pollution on central nervous system : risk for autism and neurodegenerative diseases. Environ Sci Pollut Res Int ;2021 (Jan 4)

Many reports have shown a strong association between exposure to neurotoxic air pollutants like heavy metal and particulate matter (PM) as an active participant and neurological disorders. While the effects of these toxic pollutants on cardiopulmonary morbidity have principally been studied, growing evidence has shown that exposure to polluted air is associated with memory impairment, communication deficits, and anxiety/depression among all ages. So, these toxic pollutants in the environment increase the risk of neurodegenerative disease, ischemia, and autism spectrum disorders (ASD). The precise mechanisms in which air pollutants lead to communicative inability, social inability, and declined cognition have remained unknown. Various animal model studies show that amyloid precursor protein (APP), processing, oxidant/antioxidant balance, and inflammation pathways change following the exposure to constituents of polluted air. In the present review study, we collect the probable molecular mechanisms of deleterious CNS effects in response to various air pollutants.

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21. Sun JM, Kurtzberg J. Stem cell therapies in cerebral palsy and autism spectrum disorder. Dev Med Child Neurol ;2021 (Jan 4)

Across disciplines, there is great anticipation that evolving cell therapies may finally provide a therapeutic option for conditions in dire need. These conditions are typically complex and their pathophysiology incompletely understood, hindering the development of robust preclinical models and the precise assessment of therapeutic effects in human studies. This article provides an overview of the status of cell therapy investigations in two common neurodevelopmental disorders, cerebral palsy and autism spectrum disorder. Challenges facing this line of study, including inherent heterogeneity, knowledge gaps, and unrealistic expectations, are discussed. Much progress has been made in the past decade, but to definitively determine if cell therapies have a role in the treatment of neurodevelopmental disorders, both fields will need to evolve together.

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22. Tárraga-Mínguez R, Gómez-Marí I, Sanz-Cervera P. Interventions for Improving Reading Comprehension in Children with ASD : A Systematic Review. Behav Sci (Basel) ;2020 (Dec 30) ;11(1)

Children with autism spectrum disorder (ASD) often have comorbid learning difficulties in reading comprehension, an essential skill in accessing any area of the curriculum. The aim of this systematic review is to analyze the effectiveness of reading comprehension interventions in students with ASD. We conducted a search for scientific articles published from 2000 to 2019 using the keyword « autis* » in combination with the terms « reading comprehension » and « intervention » or « instruction » in Psyc Info and Scopus databases. After applying inclusion and exclusion criteria, a total of 25 studies were selected. The content analysis of these studies shows that when specific interventions are carried out, students with ASD are able to take advantage of the instruction they receive and compensate for difficulties. Understanding inferences and the main idea of the text are the most common reading comprehension topics, and direct instruction is the most widely-used intervention method in the reviewed studies. Nonetheless, it must be kept in mind that some of the reviews do not specify which sub-processes are addressed in the intervention. Future work should include this aspect, consider the importance of the interventions being implemented by teachers, and take specific aspects of ICT into account that can contribute to improving reading comprehension.

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23. Wang J, Zhang P, Li W, Wen Q, Liu F, Xu J, Xu Q, Zhu D, Ye Z, Yu C. Right Posterior Insula and Putamen Volume Mediate the Effect of Oxytocin Receptor Polygenic Risk for Autism Spectrum Disorders on Reward Dependence in Healthy Adults. Cereb Cortex ;2021 (Jan 5) ;31(2):746-756.

Much evidence indicates the influence of the oxytocin receptor (OXTR) gene on autism spectrum disorders (ASDs), a set of disorders characterized by a range of deficits in prosocial behaviors, which are closely related to the personality trait of reward dependence (RD). However, we do not know the effect of the OXTR polygenic risk score for ASDs (OXTR-PRSASDs) on RD and its underlying neuroanatomical substrate. Here, we aimed to investigate associations among the OXTR-PRSASDs, gray matter volume (GMV), and RD in two independent datasets of healthy young adults (n = 450 and 540). We found that the individuals with higher OXTR-PRSASDs had lower RD and significantly smaller GMV in the right posterior insula and putamen. The GMV of this region showed a positive correlation with RD and a mediation effect on the association between OXTR-PRSASDs and RD. Moreover, the correlation map between OXTR-PRSASDs and GMV showed spatial correlation with OXTR gene expression. All results were highly consistent between the two datasets. These findings highlight a possible neural pathway by which the common variants in the OXTR gene associated with ASDs may jointly impact the GMV of the right posterior insula and putamen and further affect the personality trait of RD.

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24. Wang K, Duan W, Duan Y, Yu Y, Chen X, Xu Y, Chen H, Huang H, Xiong B. A Bibliometric Insight of Genetic Factors in ASD : Emerging Trends and New Developments. Brain Sci ;2020 (Dec 31) ;11(1)

Autism spectrum disorder (ASD) cases have increased rapidly in recent decades, which is associated with various genetic abnormalities. To provide a better understanding of the genetic factors in ASD, we assessed the global scientific output of the related studies. A total of 2944 studies published between 1997 and 2018 were included by systematic retrieval from the Web of Science (WoS) database, whose scientific landscapes were drawn and the tendencies and research frontiers were explored through bibliometric methods. The United States has been acting as a leading explorer of the field worldwide in recent years. The rapid development of high-throughput technologies and bioinformatics transferred the research method from the traditional classic method to a big data-based pipeline. As a consequence, the focused research area and tendency were also changed, as the contribution of de novo mutations in ASD has been a research hotspot in the past several years and probably will remain one into the near future, which is consistent with the current opinions of the major etiology of ASD. Therefore, more attention and financial support should be paid to the deciphering of the de novo mutations in ASD. Meanwhile, the effective cooperation of multi-research centers and scientists in different fields should be advocated in the next step of scientific research undertaken.

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25. Weiss MW, Sharda M, Lense M, Hyde KL, Trehub SE. Enhanced Memory for Vocal Melodies in Autism Spectrum Disorder and Williams Syndrome. Autism Res ;2021 (Jan 4)

Adults and children with typical development (TD) remember vocal melodies (without lyrics) better than instrumental melodies, which is attributed to the biological and social significance of human vocalizations. Here we asked whether children with autism spectrum disorder (ASD), who have persistent difficulties with communication and social interaction, and adolescents and adults with Williams syndrome (WS), who are highly sociable, even indiscriminately friendly, exhibit a memory advantage for vocal melodies like that observed in individuals with TD. We tested 26 children with ASD, 26 adolescents and adults with WS of similar mental age, and 26 children with TD on their memory for vocal and instrumental (piano, marimba) melodies. After exposing them to 12 unfamiliar folk melodies with different timbres, we required them to indicate whether each of 24 melodies (half heard previously) was old (heard before) or new (not heard before) during an unexpected recognition test. Although the groups successfully distinguished the old from the new melodies, they differed in overall memory. Nevertheless, they exhibited a comparable advantage for vocal melodies. In short, individuals with ASD and WS show enhanced processing of socially significant auditory signals in the context of music. LAY SUMMARY : Typically developing children and adults remember vocal melodies better than instrumental melodies. In this study, we found that children with Autistic Spectrum Disorder, who have severe social processing deficits, and children and adults with Williams syndrome, who are highly sociable, exhibit comparable memory advantages for vocal melodies. The results have implications for musical interventions with these populations.

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26. You Y, Correas A, Jao Keehn RJ, Wagner LC, Rosen BQ, Beaton LE, Gao Y, Brocklehurst WT, Fishman I, Müller RA, Marinkovic K. MEG Theta during Lexico-Semantic and Executive Processing Is Altered in High-Functioning Adolescents with Autism. Cereb Cortex ;2021 (Jan 5) ;31(2):1116-1130.

Neuroimaging studies have revealed atypical activation during language and executive tasks in individuals with autism spectrum disorders (ASD). However, the spatiotemporal stages of processing associated with these dysfunctions remain poorly understood. Using an anatomically constrained magnetoencephalography approach, we examined event-related theta oscillations during a double-duty lexical decision task that combined demands on lexico-semantic processing and executive functions. Relative to typically developing peers, high-functioning adolescents with ASD had lower performance accuracy on trials engaging selective semantic retrieval and cognitive control. They showed an early overall theta increase in the left fusiform cortex followed by greater activity in the left-lateralized temporal (starting at 250 ms) and frontal cortical areas (after 450 ms) known to contribute to language processing. During response preparation and execution, the ASD group exhibited elevated theta in the anterior cingulate cortex, indicative of greater engagement of cognitive control. Simultaneously increased activity in the ipsilateral motor cortex may reflect a less lateralized and suboptimally organized motor circuitry. Spanning early sensory-specific and late response selection stages, the higher event-related theta responsivity in ASD may indicate compensatory recruitment to offset inefficient lexico-semantic retrieval under cognitively demanding conditions. Together, these findings provide further support for atypical language and executive functions in high-functioning ASD.

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27. Zhang W, Noland R, Chin S, Petkovic M, Zuniga R, Santarra B, Conklin B, Hou HH, Nagapudi K, Gruenhagen JA, Yehl P, Chen T. Impact of polymer type, ASD loading and polymer-drug ratio on ASD tablet disintegration and drug release. Int J Pharm ;2021 (Jan 5) ;592:120087.

Amorphous solid dispersion (ASD) has become an attractive strategy to enhance solubility and bioavailability of poorly water-soluble drugs. To facilitate oral administration, ASDs are commonly incorporated into tablets. Disintegration and drug release from ASD tablets are thus critical for achieving the inherent solubility advantage of amorphous drugs. In this work, the impact of polymer type, ASD loading in tablet and polymer-drug ratio in ASD on disintegration and drug release of ASD tablets was systematically studied. Two hydrophilic polymers PVPVA and HPMC and one relatively hydrophobic polymer HPMCAS were evaluated. Dissolution testing was performed, and disintegration time was recorded during dissolution testing. As ASD loading increased, tablet disintegration time increased for all three polymer-based ASD tablets, and this effect was more pronounced for hydrophilic polymer-based ASD tablets. As polymer-drug ratio increased, tablet disintegration time increased for hydrophilic polymer-based ASD tablets, however, it remained short and largely unchanged for HPMCAS-based ASD tablets. Consequently, at high ASD loadings or high polymer-drug ratios, HPMCAS-based ASD tablets showed faster drug release than PVPVA- or HPMC-based ASD tablets. These results were attributed to the differences between polymer hydrophilicities and viscosities of polymer aqueous solutions. This work is valuable for understanding the disintegration and drug release of ASD tablets and provides insight to ASD composition selection from downstream tablet formulation perspective.

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28. Zhou T, Kang J, Li Z, Chen H, Li X. Transcranial direct current stimulation modulates brain functional connectivity in autism. Neuroimage Clin ;2020 ;28:102500.

Autism spectrum disorder (ASD) is characterized by deficits in social interactions, impairments in language and communication, and highly restricted behavioral interests. Transcranial direct current stimulation (tDCS) is a widely used form of noninvasive stimulation and may have therapeutic potential for ASD. So far, despite the widespread use of this technique in the neuroscience field, its effects on network-level neural activity and the underlying mechanisms of any effects are still unclear. In the present study, we used electroencephalography (EEG) to investigate tDCS induced brain network changes in children with ASD before and after active and sham stimulation. We recorded 5 min of resting state EEG before and after a single session of tDCS (of approximately 20 min) over dorsolateral prefrontal cortex (DLPFC). Two network-based methods were applied to investigate tDCS modulation on brain networks : 1) temporal network dynamics were analyzed by comparing « flexibility » changes before vs after stimulation, and 2) frequency specific network changes were identified using non-negative matrix factorization (NMF). We found 1) an increase in network flexibility following tDCS (rapid network configuration of dynamic network communities), 2) specific increase in interhemispheric connectivity within the alpha frequency band following tDCS. Together, these results demonstrate that tDCS could help modify both local and global brain network dynamics, and highlight stimulation-induced differences in the manifestation of network reconfiguration. Meanwhile, frequency-specific subnetworks, as a way to index local and global information processing, highlight the core modulatory effects of tDCS on the modular architecture of the functional connectivity patterns within higher frequency bands.

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