1. Auger E, Berry-Kravis EM, Ethridge LE. Independent evaluation of the harvard automated processing pipeline for Electroencephalography 1.0 using multi-site EEG data from children with Fragile X Syndrome. Journal of neuroscience methods. 2022; 371: 109501.

BACKGROUND: The Harvard Automatic Processing Pipeline for Electroencephalography (HAPPE) is a computerized EEG data processing pipeline designed for multiple site analysis of populations with neurodevelopmental disorders. This pipeline has been validated in-house by the developers but external testing using real-world datasets remains to be done. NEW METHOD: Resting and auditory event-related EEG data from 29 children ages 3-6 years with Fragile X Syndrome as well as simulated EEG data was used to evaluate HAPPE’s noise reduction techniques, data standardization features, and data integration compared to traditional manualized processing. RESULTS: For the real EEG data, HAPPE pipeline showed greater trials retained, greater variance retained through independent component analysis (ICA) component removal, and smaller kurtosis than the manual pipeline; the manual pipeline had a significantly larger signal-to-noise ratio (SNR). For simulated EEG data, correlation between the pure signal and processed data was significantly higher for manually-processed data compared to HAPPE-processed data. Hierarchical linear modeling showed greater signal recovery in the manual pipeline with the exception of the gamma band signal which showed mixed results. COMPARISON WITH EXISTING METHODS: SNR and simulated signal retention was significantly greater in the manually-processed data than the HAPPE-processed data. Signal reduction may negatively affect outcome measures. CONCLUSIONS: The HAPPE pipeline benefits from less active processing time and artifact reduction without removing segments. However, HAPPE may bias toward elimination of noise at the cost of signal. Recommended implementation of the HAPPE pipeline for neurodevelopmental populations depends on the goals and priorities of the research.

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2. Cheng Y, Tang B, Zhang G, An P, Sun Y, Gao M, Zhang Y, Shan Y, Zhang J, Liu Q, Lai CSW, de Villers-Sidani É, Wang Y, Zhou X. Degraded cortical temporal processing in the valproic acid-induced rat model of autism. Neuropharmacology. 2022; 209: 109000.

Hearing disorders, such as abnormal speech perception, are frequently reported in individuals with autism. However, the mechanisms underlying these auditory-associated signature deficits in autism remain largely unknown. In this study, we documented significant behavioral impairments in the sound temporal rate discrimination task for rats prenatally exposed to valproic acid (VPA), a well-validated animal model for studying the pathology of autism. In parallel, there was a large-scale degradation in temporal information-processing in their primary auditory cortices (A1) at both levels of spiking outputs and synaptic inputs. Substantially increased spine density of excitatory neurons and decreased numbers of parvalbumin- and somatostatin-labeled inhibitory inter-neurons were also recorded in the A1 after VPA exposure. Given the fact that cortical temporal processing of sound is associated with speech perception in humans, these results in the animal model of VPA exposure provide insight into a possible neurological mechanism underlying auditory and language-related deficits in individuals with autism.

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3. Han YMY, Chan MMY, Shea CKS, Lai OL, Krishnamurthy K, Cheung MC, Chan AS. Neurophysiological and behavioral effects of multisession prefrontal tDCS and concurrent cognitive remediation training in patients with autism spectrum disorder (ASD): A double-blind, randomized controlled fNIRS study. Brain stimulation. 2022; 15(2): 414-25.

BACKGROUND: The clinical effects and neurophysiological mechanisms of prefrontal tDCS and concurrent cognitive remediation training in individuals with autism spectrum disorder (ASD) remain unclear. OBJECTIVE: This two-armed, double-blind, randomized, sham-controlled trial aimed to investigate the beneficial effects of tDCS combined with concurrent cognitive remediation training on adolescents and young adults with ASD. METHODS: Participants were randomly assigned to either active or sham tDCS groups and received 1.5 mA prefrontal tDCS with left dorsolateral prefrontal cortex (dlPFC) cathode placement and right supraorbital region anode placement for 20 minutes over two consecutive weeks. tDCS was delivered concurrently with a computerized cognitive remediation training program. Social functioning and its underlying cognitive processes, as well as prefrontal resting-state functional connectivity (rsFC), were measured. RESULTS: The results from 41 participants indicated that multisession prefrontal tDCS, compared to sham tDCS, significantly enhanced the social functioning of ASD individuals [F(1,39) = 4.75, p = .035, η(p)(2) = 0.11]. This improvement was associated with enhanced emotion recognition [F(1,39) = 8.34, p = .006, η(p)(2) = 0.18] and cognitive flexibility [F(1,39) = 4.91, p = .033, η(p)(2) = 0.11]. Specifically, this tDCS protocol optimized information processing efficiency [F(1,39) = 4.43, p = .042, η(p)(2) = 0.10], and the optimization showed a trend to be associated with enhanced rsFC in the right medial prefrontal cortex (ρ = 0.339, pFDR = .083). CONCLUSION: Multisession tDCS with left dlPFC cathode placement and right supraorbital region anode placement paired with concurrent cognitive remediation training promoted social functioning in individuals with ASD. This appeared to be associated with the enhancement of the functional connectivity of the right medial PFC, a major hub for flexible social information processing, allowing these individuals to process information more efficiently in response to different social situations. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03814083).

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4. Henry AR, Conner C, Zajic MC, Solari EJ. Feasibility and Initial Efficacy of an Adapted Telepractice Listening Comprehension Intervention for School-Aged Children with Autism. Journal of autism and developmental disorders. 2022: 1-11.

This study evaluates the feasibility and initial efficacy of an 11-week listening comprehension intervention, Building Vocabulary and Early Reading Strategies (BVERS) that was delivered remotely to 14 elementary-aged children with autism spectrum disorder. Children were randomly assigned to one of two groups: BVERS only, or BVERS with a parent instructional component (BVERS + PC). Results indicate that the intervention was feasible to implement. All parents were satisfied with intervention implementation, and 8 of 10 stated that they were satisfied with their child’s outcomes following the intervention. Results of a Wilcoxon signed-rank test showed growth in listening comprehension following the intervention, but no growth in narrative retell or vocabulary. There were no group differences in change scores from pre- to post-test.

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5. Lee JH, Jo HG, Min SY. East Asian Herbal Medicine Combined with Conventional Therapy for Children with Autism Spectrum Disorder: A Systematic Review and Meta-analysis. Explore (New York, NY). 2022.

BACKGROUND: There is an increasing demand to improve personal health and reduce the social burden in children with autism spectrum disorder (ASD). A comprehensive review of ASD interventions from the point of view of efficacy, safety, and compliance is needed. The purpose of this study was to evaluate the efficacy and safety of East Asian Herbal Medicine (EAHM) in the treatment of ASD. MATERIALS AND METHODS: Eleven databases (PubMed, Cochrane Library, CINAHL, EMBASE, KISS, RISS, OASIS, KCI, CNKI, Wanfang data, and CiNii) were searched from their respective inception to July 2021. A search was conducted by combining the keywords Autism Spectrum Disorder and Herbal medicine. We included a randomized controlled trial in which oral administration of EAHM was combined with conventional treatment for pediatric ASD patients. The primary outcomes were the clinical efficacy rate and the improvement in Childhood Autism Rating Scale (CARS) score. RESULTS: A total of 7 studies involving 462 children with ASD were included. The results suggest that EAHM as part of a combined therapy enhances the CARS score (MD[95% confidential interval]=4.47[5.89,3.05], p<0.01) and the clinical efficacy rate (RR=1.31[1.14,1.51], p<0.01) in comparison to the control group using only conventional therapy. Safety information was reported in 4 of the 7 included studies, and there were no adverse events or the difference in the incidence of side effects between the two groups was not significant. CONCLUSION: This meta-analysis shows that EAHM may improves the clinical efficacy rate and CARS score in children with ASD. However, in that the quality of the included studies is not generally high and the numbers are difficult to be considered sufficient, larger scale and rigorously designed randomized controlled trials need to be conducted to strengthen the evidence.

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6. Murayama C, Iwabuchi T, Kato Y, Yokokura M, Harada T, Goto T, Tamayama T, Kameno Y, Wakuda T, Kuwabara H, Senju A, Nishizawa S, Ouchi Y, Yamasue H. Extrastriatal dopamine D2/3 receptor binding, functional connectivity, and autism socio-communicational deficits: a PET and fMRI study. Molecular psychiatry. 2022.

The social motivation hypothesis of autism proposes that social communication symptoms in autism-spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [(11)C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum-medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.

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7. Nadeem A, Ahmad SF, Al-Harbi NO, Al-Ayadhi LY, Alanazi MM, Alfardan AS, Attia SM, Algahtani M, Bakheet SA. Dysregulated Nrf2 signaling in response to di(2-ethylhexyl) phthalate in neutrophils of children with autism. International immunopharmacology. 2022; 106: 108619.

Autism spectrum disorder (ASD) is characterized by constellation of impaired behaviors that include deficits in social interaction/communication and the presence of restricted/repetitive behavioral patterns. Both genetic component and environmental factors are thought to play a key role in the initiation and progression of ASD. Several environmental factors such as heavy metals and plasticizers are known to affect the progression of ASD. One of the most common pollutants in the environment today is di-2-ethylhexyl phthalate (DEHP). DEHP is utilized as a plasticizer in several household and office materials which range from medical devices to plastic toys. Children usually get exposed to DEHP at an early age through use of plastic toys and other plastic materials. Nuclear factor erythroid 2 (NFE2)-relatedfactor-2 (Nrf2) is a master redox regulator as it controls transcription of several antioxidant genes. DEHP has been reported to cause dysregulation in Nrf2 signaling in vitro/in vivo and ASD subjects also exhibit oxidant-antioxidant imbalance.Therefore, this study attempted to delineate the effect of DEHP on Nrf2 signaling in neutrophils of ASD and typically developing healthy children (TDC) in vitro. Our data display that neutrophils of ASD subjects have dysregulated Nrf2 and hemeoxygenase-1 (HO-1) expression as compared to TDC subjects. DEHP treatment leads to elevation of oxidant stress in neutrophils of both ASD and TDC subjects, however TDC neutrophils have better antioxidant response to mitigate oxidative stress. This is depicted by enhancement of Nrf2/HO-1 signaling in TDC neutrophils in response to DEHP whereas ASD neutrophils fail to do so. These results suggest that plasticizer, DEHP may cause further dysregulation in Nrf2 signaling which may promote progression of ASD.

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8. Subhadeep D, Srikumar BN, Shankaranarayana Rao BS, Kutty BM. Ventral subicular lesion impairs pro-social empathy-like behavior in adult Wistar rats. Neuroscience letters. 2022; 776: 136535.

The subiculum, an important structure of the hippocampal formation, regulates spatial information processing, social cognition, and affective behavior. Earlier we demonstrated deficits in sociability and social novelty as a measure of social cognition in ventral subicular lesioned (VSL) rats. The present study investigated empathy-like pro-social behavior and the associated affective states in VSL rats. The ability of free rats to release trapped cagemates was assessed using a modified door-opening empathy task.The rat pairs (free rat and the trapped cagemate) used were from the same group and tested for eight days to assess the pro-social behavior displayed by the free rats. The control(free) rats learned to open the door quickly to release the trapped cagemate and both the rats displayed social responses by emitting ‘hedonic’ calls (50-kHz ultrasonic vocalizations) while playing after the release. The VSL(free) rats, however, were less exploratory, displayed apathy towards the trapped cagemate, demonstrated freezing behavior following door-opening and did not interact with the cagemate even after its release. These findings indicate deficits of social motivation and reinforcement learning associated with lesions in possibly both the rats. In addition, the VSL rat pairs elicited more 22-kHz ‘alarm’ calls and fewer 50-kHz ‘hedonic’ calls highlighting the lesion-induced alterations of contextual processing and threat perception abilities. In conclusion, VSL led to significant pro-social deficits implicating the role of ventral subiculum in social cognition and empathy. More studies are needed to substantiate whether the subiculum is implicated in social deficits associated with psychiatric conditions such as autism spectrum disorder.

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9. Taylor GL, O’Shea TM. Extreme prematurity: Risk and resiliency. Current problems in pediatric and adolescent health care. 2022; 52(2): 101132.

Individuals born extremely preterm (before 28 weeks of gestation) comprise only about 0.7% of births in the United States and an even lower proportion in other high resource countries. However, these individuals account for a disproportionate number of children with cerebral palsy, intellectual deficit, autism spectrum disorder, attention deficit hyperactivity disorder, and epilepsy. This review describes two large multiple center cohorts comprised of individuals born extremely preterm: the EPICURE cohort, recruited 1995 in the United Kingdom and the Republic of Ireland, and the Extremely Low Gestational Age Newborn (ELGAN), recruited 2002-2004 in five states in the United States. The primary focus of these studies has been neurodevelopmental disorders, but also of interest are growth, respiratory illness, and parent- and self-reported global health and well-being. Both of these studies indicate that among individuals born extremely preterm the risks of most neurodevelopmental disorders are increased. Early life factors that contribute to this risk include perinatal brain damage, some of which can be identified using neonatal head ultrasound, bronchopulmonary dysplasia, and neonatal systemic inflammation. Prenatal factors, particularly the family’s socioeconomic position, also appear to contribute to risk. For most adverse outcomes, the risk is higher in males. Young adults born extremely preterm who have neurodevelopmental impairment, as compared to those without such impairment, rate their quality of life lower. However, young adults born extremely preterm who do not have neurodevelopmental impairments rate their quality of life as being similar to that of young adults born at term. Finally, we summarize the current state of interventions designed to improve the life course of extremely premature infants, with particular focus on efforts to prevent premature birth and on postnatal efforts to prevent adverse neurodevelopmental outcomes.

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10. van den Heuvel RM, Wensing M, Geurts HM, Teunisse JP. The Social Support Network of Adults with an Autism Spectrum Condition: An Exploration Using the Network in Action-Questionnaire. Journal of autism and developmental disorders. 2022.

Actively involving the network during treatment, as recommended in Autism Spectrum Condition (ASC) guidelines, can be facilitated with the Network in Action-Questionnaire (NiA-Q), which identifies the current and potential sources of social support. The aims of this study were to (1) examine the factor structure of the NiA-Q and (2) to explore the self- and proxy-report on the social network. Before the start of treatment in a mental health institution, 193 adults with an ASC diagnosis and 84 proxies completed the NiA-Q. Factor analysis showed two factors: positive social support and interpersonal distress. Self- and proxy-report on the NiA-Q did not differ for most variables, except for social network wishes. The NiA-Q provides a basis for network involvement and strengthening.

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11. Vinen Z, Clark M, Dissanayake C. Social and Behavioural Outcomes of School Aged Autistic Children Who Received Community-Based Early Interventions. Journal of autism and developmental disorders. 2022.

The school-age outcomes of autistic children who received early interventions (EI) remains limited. Adaptive functioning, social, peer play skills, problem behaviours, and attitudes towards school of 31 autistic children who received community-based group early start Denver model (G-ESDM) were compared to 28 age matched autistic children who received other community interventions. Similar adaptive behaviours, social skills, problem behaviours and attitudes towards school were found. Play disruption was the only dimension of play to differ; children that received community interventions demonstrated higher levels of play disruption compared to the G-ESDM group. Children had pervasive challenges in adaptive behaviour, social and play behaviour at school, irrespective of EI type. Thus, ongoing provisions are needed to support development into the school years.

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12. Vivanti G. Kasari et al.: The JASPER Model for Children with Autism: Promoting Joint Attention, Symbolic Play, Engagement, and Regulation. Guilford Publications. Journal of autism and developmental disorders. 2022.

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13. Wang X, Guo Z, Mei D, Zhang Y, Zhao S, Hu S, Luo S, Wang Q, Gao C. The GluN2B-Trp373 NMDA Receptor Variant is Associated with Autism-, Epilepsy-Related Phenotypes and Reduces NMDA Receptor Currents in Rats. Neurochemical research. 2022.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with core clinical features of abnormal communication, social interactions, atypical intelligence, and a higher risk of epilepsy. Prior work has suggested that de novo heterozygous mutations in the GRIN2B gene that encodes the GluN2B subunit of N-methyl-D-aspartic acid receptors are likely linked to ASD. However, whether GLuN2B-Trp373 mutation derived from autistic individuals causes ASD-like behavioral aberrations in rats remains to be determined. Here, through in utero electroporation and in vivo studies, we conducted a battery of tests to examine ASD-associated behaviors, cognitive impairments, and susceptibility to pentylenetetrazol-induced seizures. Whole-cell patch recording was utilized to determine whether the GluN2B-Trp373 mutation influences GluN2B-containing NMDA receptor currents in rats. Results show that, behaviorally, GLuN2B-Trp373 mutant rats exhibited core behavioral manifestations of ASD, such as social interaction deficits, increases in stereotyped behaviors and anxiety stereotyped/repetitive, impaired spatial memory, and enhanced risk of pentylenetetrazol-induced seizures, consistent with many of the hallmarks of low-functioning ASD in humans. Functionally, the GluN2B-Trp373 mutation results in reduced GluN2B surface protein expression together with decreased hippocampal NMDA receptor currents. Collectively, our findings highlight that GluN2B-Trp373 mutations can drive the manifestation of ASD-associated symptoms via the suppression of NMDA receptor currents.

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14. Wojcik DZ, Moulin CJA, Souchay C. Memory and metamemory for actions in children with autism: Exploring global metacognitive judgements. Research in developmental disabilities. 2022; 124: 104195.

BACKGROUND: Standards in education emphasize the role of metacognition in successful academic outcomes for those with and without learning challenges. Research into metamemory in Autism Spectrum Disorder (ASD) has produced mixed outcomes, with some studies finding children with ASD to have spared metacognitive accuracy and others finding it impaired. While most research has used item-by-item metamemory judgements, the novelty of the current study was to use global judgments-of-learning (global JOLs). METHOD: Twenty-three children with and twenty without ASD were presented with two lists of action words during a learning phase and were asked to either act out the words in a self-performed task or just listen to them being read aloud in a verbal task (control condition). Typically, self-performance produces memory benefits called the enactment effect. For both tasks, children also made pre-learning and post-learning global JOLs, stating how many words they thought they would recall. RESULTS: Both groups demonstrated the enactment effect, but neither predicted its beneficial effect. Compared to controls, participants with ASD were found to be less accurate in predicting their future memory performance, specifically in the self-performed task. Both groups were comparable in terms of metacognitive monitoring. CONCLUSIONS: Overall, the findings suggest that success or failure in metacognitive tasks in ASD might depend on task difficulty, and the type of metacognitive judgement used.

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15. Xu L, Zheng X, Yao S, Li J, Fu M, Li K, Zhao W, Li H, Becker B, Kendrick KM. The mirror neuron system compensates for amygdala dysfunction – associated social deficits in individuals with higher autistic traits. NeuroImage. 2022; 251: 119010.

The amygdala is a core node in the social brain which exhibits structural and functional abnormalities in Autism spectrum disorder and there is evidence that the mirror neuron system (MNS) can functionally compensate for impaired emotion processing following amygdala lesions. In the current study, we employed an fMRI paradigm in 241 subjects investigating MNS and amygdala responses to observation, imagination and imitation of dynamic facial expressions and whether these differed in individuals with higher (n = 77) as opposed to lower (n = 79) autistic traits. Results indicated that individuals with higher compared to lower autistic traits showed worse recognition memory for fearful faces, smaller real-life social networks, and decreased left basolateral amygdala (BLA) responses to imitation. Additionally, functional connectivity between the left BLA and the left inferior frontal gyrus (IFG) as well as some other MNS regions was increased in individuals with higher autistic traits, especially during imitation of fearful expressions. The left BLA-IFG connectivity significantly moderated the autistic group differences on recognition memory for fearful faces, indicating that increased amygdala-MNS connectivity could diminish the social behavioral differences between higher and lower autistic trait groups. Overall, findings demonstrate decreased imitation-related amygdala activity in individuals with higher autistic traits in the context of increased amygdala-MNS connectivity which may functionally compensate for amygdala dysfunction and social deficits. Training targeting the MNS may capitalize on this compensatory mechanism for therapeutic benefits in Autism spectrum disorder.

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