Pubmed du 23/04/20

jeudi 23 avril 2020

1. Alcaniz Raya M, Chicchi Giglioli IA, Marin-Morales J, Higuera-Trujillo JL, Olmos E, Minissi ME, Teruel Garcia G, Sirera M, Abad L. Application of Supervised Machine Learning for Behavioral Biomarkers of Autism Spectrum Disorder Based on Electrodermal Activity and Virtual Reality. Front Hum Neurosci. 2020 ; 14 : 90.

Objective : Sensory processing is the ability to capture, elaborate, and integrate information through the five senses and is impaired in over 90% of children with autism spectrum disorder (ASD). The ASD population shows hyper-hypo sensitiveness to sensory stimuli that can generate alteration in information processing, affecting cognitive and social responses to daily life situations. Structured and semi-structured interviews are generally used for ASD assessment, and the evaluation relies on the examiner’s subjectivity and expertise, which can lead to misleading outcomes. Recently, there has been a growing need for more objective, reliable, and valid diagnostic measures, such as biomarkers, to distinguish typical from atypical functioning and to reliably track the progression of the illness, helping to diagnose ASD. Implicit measures and ecological valid settings have been showing high accuracy on predicting outcomes and correctly classifying populations in categories. Methods : Two experiments investigated whether sensory processing can discriminate between ASD and typical development (TD) populations using electrodermal activity (EDA) in two multimodal virtual environments (VE) : forest VE and city VE. In the first experiment, 24 children with ASD diagnosis and 30 TDs participated in both virtual experiences, and changes in EDA have been recorded before and during the presentation of visual, auditive, and olfactive stimuli. In the second experiment, 40 children have been added to test the model of experiment 1. Results : The first exploratory results on EDA comparison models showed that the integration of visual, auditive, and olfactive stimuli in the forest environment provided higher accuracy (90.3%) on sensory dysfunction discrimination than specific stimuli. In the second experiment, 92 subjects experienced the forest VE, and results on 72 subjects showed that stimuli integration achieved an accuracy of 83.33%. The final confirmatory test set (n = 20) achieved 85% accuracy, simulating a real application of the models. Further relevant result concerns the visual stimuli condition in the first experiment, which achieved 84.6% of accuracy in recognizing ASD sensory dysfunction. Conclusion : According to our studies’ results, implicit measures, such as EDA, and ecological valid settings can represent valid quantitative methods, along with traditional assessment measures, to classify ASD population, enhancing knowledge on the development of relevant specific treatments.

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2. Begum Ali J, Charman T, Johnson MH, Jones EJH. Early Motor Differences in Infants at Elevated Likelihood of Autism Spectrum Disorder and/or Attention Deficit Hyperactivity Disorder. J Autism Dev Disord. 2020.

We investigated infant’s manual motor behaviour ; specifically behaviours crossing the body midline. Infants at elevated likelihood of Autism Spectrum Disorder (ASD) and/or Attention Deficit Hyperactivity Disorder (ADHD) produced fewer manual behaviours that cross the midline compared to infants with a typical likelihood of developing these disorders ; however this effect was limited to 10-month-olds and not apparent at age 5 and 14 months. Although, midline crossing did not predict ASD traits, it was related to ADHD traits at 2 years of age. We rule out motor ability and hand dominance as possible explanations for this pattern of behaviour, positing that these results may be a consequence of multisensory integration abilities, and the neurobehavioural shift period, in the first year of life.

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3. Buckley J, Luiselli JK, Harper JM, Shlesinger A. Teaching students with autism spectrum disorder to tolerate haircutting. Journal of applied behavior analysis. 2020.

We describe intervention with 2 adolescent male students who had autism spectrum disorder (ASD) and resisted haircutting performed by care providers at a residential school. The students were exposed to a graduated hierarchy of steps including the presence of hair clippers, and increased duration of hair clippers against their scalp and hair. Edible reinforcement was presented contingent on completion of a step without interfering behavior. Both students learned to tolerate all of the steps in the graduated hierarchy and a full haircut with maintenance at 2-, 4-, and 6-month follow-up. The study supports previous tolerance-training research with children and youth who have intellectual and developmental disabilities and resist personal care and hygiene routines.

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4. Dufour MM, Lanovaz MJ. Increasing compliance with wearing a medical device in children with autism. Journal of applied behavior analysis. 2020 ; 53(2) : 1089-96.

Health professionals often recommend the use of medical devices to assess the health, monitor the well-being, or improve the quality of life of their patients. Children with autism may present challenges in these situations as their sensory peculiarities may increase refusals to wear such devices. To address this issue, we systematically replicated prior research by examining the effects of differential reinforcement of other behavior (DRO) to increase compliance with wearing a heart rate monitor in 2 children with autism. The intervention increased compliance to 100% for both participants when an edible reinforcer was delivered every 90 s. The results indicate that DRO does not require the implementation of extinction to increase compliance with wearing a medical device. More research is needed to examine whether the reinforcement schedule can be further thinned.

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5. Enikanolaiye A, Ruston J, Zeng R, Taylor C, Schrock M, Buchovecky CM, Shendure J, Acar E, Justice MJ. Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology. Genome research. 2020 ; 30(4) : 540-52.

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.

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6. Fang Z, Barlow J, Zhang C. Parenting Programs That Address Physical Abuse in Childhood for Families of Children With Developmental Disabilities in Mainland China : Systematic Review and Meta-Regression. Trauma, violence & abuse. 2020 : 1524838020915599.

Millions of children in China are diagnosed with developmental disabilities (DD), many of whom are subject to physical abuse. While a significant body of research suggests that parenting interventions can reduce the incidence and risk of such abuse, there is currently limited evidence of their effectiveness for this population or from non-English-speaking countries. This review involved searches in both English and Chinese databases to identify randomized controlled trials and quasi-experimental studies of parenting interventions for families of children with DD in mainland China. Multilevel meta-analyses were undertaken to examine the effectiveness of parenting programs. Subgroup analyses and meta-regression were conducted to investigate heterogeneity and identify potential moderators with a focus on intervention and delivery components. Risk of bias was assessed for each study. Thirty-one studies were included. The results showed that parenting interventions could reduce child emotional and behavioral problems (CEBP) and improve the parent-child relationship, although only one study directly measured the actual incidence of abuse. Programs for autism and epilepsy had stronger treatment effects. Teaching knowledge about CEBP, skills to improve parental mental health, and techniques to cultivate empathy were associated with program success ; however, positive reinforcement was associated with more problems. The results also supported the delivery of programs with longer duration, a combination of group and individual sessions, efforts to build rapport, ongoing communication outside the programs, and delivery in hospitals or service agencies. Further research is needed, however, in addition to improvements in the quality of research and reporting.

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7. Girolamo TM, Rice ML, Warren SF. Assessment of Language Abilities in Minority Adolescents and Young Adults With Autism Spectrum Disorder and Extensive Special Education Needs : A Pilot Study. American journal of speech-language pathology. 2020 : 1-15.

Purpose Little is known about the language abilities of adolescents and young adults with autism spectrum disorder (ASD) despite the importance of language in their other life outcomes. Even less is known about the language abilities of racial/ethnic minorities with ASD and extensive special education needs. These gaps limit our understanding of adolescents and young adults with ASD. Method A pilot study evaluated the efficacy of individualized age-referenced language assessment for minority adolescents and young adults with ASD in self-contained special education settings. Participants (n = 10) completed the Clinical Evaluation of Language Fundamentals-Third Edition, Test for Early Grammatical Impairment (TEGI), Columbia Mental Maturity Scale, and Wechsler Intelligence Scale for Children-Third Edition Digit Span. Results Clinical Evaluation of Language Fundamentals-Third Edition scores showed little variation, with most participants showing a floor effect. TEGI, Columbia Mental Maturity Scale, and Digit Span scores showed greater variation. Some participants had ceiling TEGI scores, and some had variable assessment profiles. Conclusion Assessment was sensitive to variability across some measures. The pilot study outcomes support the feasibility and potential informativeness of additional investigation of conventional language assessments and change over time.

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8. Haddad F, Patel S, Schmid S. Maternal Immune Activation by Poly I:C as a preclinical Model for Neurodevelopmental Disorders : A focus on Autism and Schizophrenia. Neurosci Biobehav Rev. 2020.

Maternal immune activation (MIA) in response to a viral infection during early and mid-gestation has been epidemically linked to a higher risk for the child to develop autism or schizophrenia-related symptoms. This has led to the establishment of the pathogen-free poly I:C induced MIA animal model for neurodevelopmental disorders with relatively high construct and face validity. Depending on the experimental variables, particularly the timing of poly I:C administration, different behavioural and molecular phenotypes have been described that relate to specific symptoms of neurodevelopmental disorders such as autism spectrum disorder and/or schizophrenia. We here review and summarize epidemiological evidence for the effects of maternal infection and immune activation, as well as major findings in different poly I:C MIA models with a focus on poly I:C exposure timing, behavioural and molecular changes in the offspring, and characteristics of the model that relate it to autism spectrum disorder and schizophrenia.

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9. Haglund N, Dahlgren S, Rastam M, Gustafsson P, Kallen K. Improvement of Autism Symptoms After Comprehensive Intensive Early Interventions in Community Settings. Journal of the American Psychiatric Nurses Association. 2020 : 1078390320915257.

BACKGROUND : Preschool children with autism in southern Sweden participated in a comprehensive Naturalistic Developmental Behavioral Intervention (NDBI) program. AIMS : To evaluate the ongoing NDBI program by comparing the pre- and postintervention outcomes in terms of improved autism symptom severity. METHOD : The improvement of Autism Diagnostic Observation Schedule (ADOS-R) test results between baseline and evaluation among children participating in the NDBI program (n = 67) was compared with the results among children receiving community treatment as usual (n = 27) using analysis of covariance. RESULTS : The study showed that children in the NDBI group improved their ADOS-R total scores between baseline and evaluation (-0.8 scores per year ; 95% CI [-1.2, -0.4]), whereas no improvement was detected in the comparison group (+0.1 scores per year ; 95% CI [-0.7, +0.9]). The change in the NDBI group versus the change in the comparison group was statistically significant after adjusting for possible confounders as well. Children in the NDBI group also significantly improved their ADOS severity scores, but the scores were not significantly different from those of the comparison group. CONCLUSIONS : The results from the current naturalistic study must be interpreted cautiously, but they do support earlier studies reporting on improvement of autism symptoms after early intensive interventions. Results from observational studies are difficult to interpret, but it is nevertheless of uttermost importance to evaluate costly autism intervention programs. The results do indicate that children with autism benefit from participating in early comprehensive intensive programs.

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10. Henriksen MW, Breck H, Sejersted Y, Diseth T, von Tetzchner S, Paus B, Skjeldal OH. Genetic and clinical variations in a Norwegian sample diagnosed with Rett syndrome. Brain Dev. 2020.

BACKGROUND AND PURPOSE : Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in MECP2. The diagnostic criteria of RTT are clinical ; mutations in MECP2 are neither diagnostic nor necessary, and a mutation in another gene does not exclude RTT. We attempted to correlate genotype and phenotype to see if there are significant clinical associations. METHODS : All available females diagnosed with RTT in Norway were invited to the study. Parents were interviewed, the girl or woman with RTT examined and medical records reviewed. All diagnoses were revisited according to the current diagnostic criteria and exome-based sequencing analyses were performed in individuals without an identified causative mutation. Participants were categorized according to genotypes and RTT diagnosis. Individuals with RTT with and without mutations in MECP2 were compared. RESULTS : Ninety-one individuals were included. A presumed causative mutation was identified in 86 individuals, of these, mutations in MECP2 in 77 individuals and mutations in SMC1A, SYNGAP1, SCN1A, CDKL5, FOXG1 or chromosome 13q in nine. Seventy-two individuals fulfilled the diagnostic criteria for classic and 12 for atypical RTT. Significant differences in early development, loss of hand use and language, intense eye gaze and the presence of early onset epilepsy were revealed in individuals with RTT according to their MECP2 genotypic status. CONCLUSION : Using the current diagnostic criteria, genetic and clinical variation in RTT is considerable. Significant differences between individuals with RTT with and without MECP2 mutations indicate that MECP2 is a major determinant for the clinical phenotype in individuals with RTT.

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11. Hong T, Falcone C, Dufour B, Amina S, Perez Castro R, Regalado J, Pearson W, Noctor SC, Martinez-Cerdeno V. GABAARalpha2 is decreased in the axon initial segment of pyramidal cells in specific areas of the prefrontal cortex in autism. Neuroscience. 2020.

Some forms of Autism Spectrum Disorder, a neurodevelopmental syndrome characterized by impaired communication and social skills as well as repetitive behaviors, are purportedly associated with dysregulation of the excitation/inhibition balance in the cerebral cortex. Through human postmortem tissue analysis, we previously found a significant decrease in the number of a gamma-aminobutyric acid (GABA)ergic interneuron subtype, the chandelier (Ch) cell, in the prefrontal cortex of subjects with autism. Ch cells exclusively target the axon initial segment (AIS) of excitatory pyramidal (Pyr) neurons, and a single Ch cell forms synapses on hundreds of Pyr cells, indicating a possible role in maintaining electrical balance. Thus, we herein investigated this crucial link between Ch and Pyr cells in the anatomy of autism neuropathology by examining GABA receptor protein expression in the Pyr cell AIS in subjects with autism. We collected tissue from the prefrontal cortex (Brodmann Areas (BA) 9, 46, and 47) of 20 subjects with autism and 20 age- and sex-matched control subjects. Immunohistochemical staining with antibodies against the GABAA receptor subunit alpha2 (GABAARalpha2) - the subunit most prevalent in the Pyr cell AIS - revealed a significantly decreased percent area of GABAARalpha2 protein labeling in the Pyr cell AIS in supragranular layers of prefrontal cortex areas BA9 and BA47 in autism. Downregulated GABAARalpha2 protein in the Pyr cell AIS may result from decreased GABA synthesis in the prefrontal cortex of subjects with autism, and thereby contribute to an excitation/inhibition imbalance. Our findings support the potential forGABA receptor agonists asa therapeutic tool for autism. Glossary : Pyramidal cell:The main excitatory neuron in the mammalian prefrontal cortex Chandelier cell : A fast-spiking parvalbumin-positive GABAergic interneuron Cartridge : Chandelier cell axonal structure containing synaptic terminal boutons Axon initial segment : Proximal segment of the pyramidal cell axon and the site of chandelier cell synapses.

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12. Lewis CR, Taguinod F, Jepsen WM, Cohen J, Agrawal K, Huentelman MJ, Smith CJ, Ringenbach SDR, Braden BB. Telomere Length and Autism Spectrum Disorder Within the Family : Relationships With Cognition and Sensory Symptoms. Autism Res. 2020.

Telomeres are repetitive noncoding deoxynucleotide sequences that cap chromosomes to protect DNA. Telomere length (TL) is affected by both genetic and environmental factors, and shortening of telomeres is associated with multiple neuropsychiatric disorders, early life stress, and age-related cognitive dysfunction. Two previous studies associated shorter TL with autism spectrum disorder (ASD). We aimed to replicate this finding, describe TL in unaffected siblings, and explore novel relationships with symptoms and cognitive function in families with ASD. Participants were 212 male children and adolescents ages 1-17 years (86 with ASD, 57 unaffected siblings, and 69 typically developing [TD]) and 64 parents. TL was measured from blood leukocytes with quantitative real-time polymerase chain reaction and results are expressed by relative ratios with a single copy gene. We replicated that children and adolescents with ASD have shorter TL, compared to TD, and show that unaffected siblings have TL in between those of TD and ASD. We present novel associations between TL and sensory symptoms in ASD. Finally, we demonstrate cognitive functions, but not autistic traits, are related to TL in parents of children with ASD. Cognitive function and TL were not related in children and adolescents. As the third replication, our results elicit confidence in the finding that ASD is associated with shorter TL. Our novel sensory investigation suggests that shortened TL may be a biological mechanism of sensory symptoms in ASD. Furthermore, results highlight the need to better understand relationships between cognition, aging, and TL in families with ASD. Autism Res 2020. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Telomeres cap chromosomes to protect DNA. They progressively shorten as people age and are related to health outcomes. We replicated previous findings that children and adolescents with autism spectrum disorder (ASD) have shorter telomeres, compared to typically developing (TD), and show that unaffected siblings have telomere length (TL) in between those of TD and ASD. We find shortened TL is related to more severe sensory symptoms. This may mean families with ASD, especially those with elevated sensory symptoms, are at risk for worse age-related health outcomes.

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13. Mackie TI, Schaefer AJ, Ramella L, Carter AS, Eisenhower A, Jimenez ME, Fettig A, Sheldrick RC. Understanding How Parents Make Meaning of Their Child’s Behaviors During Screening for Autism Spectrum Disorders : A Longitudinal Qualitative Investigation. J Autism Dev Disord. 2020.

A family’s journey in understanding their child’s behaviors in relation to Autism Spectrum Disorders (ASD) frequently begins with screening. This study aimed to characterize the interpretive processes that unfold for parents. We employed longitudinal interviews with 19 families engaged in a community-based multi-stage screening protocol. Parents participated in 1-6 interviews dependent upon children’s length of engagement in the screening protocol ; data were analyzed through modified grounded theory. Parents who moved towards understanding their child’s behaviors as ASD expressed (1) sensitization to ASD symptoms, (2) differentiation from other developmental conditions, and (3) use of the ASD diagnosis to explain the etiology of concerning behaviors. Identifying interpretive processes involved during ASD screening provides new opportunities for shared decision-making.

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14. Nag A, Haber N, Voss C, Tamura S, Daniels J, Ma J, Chiang B, Ramachandran S, Schwartz J, Winograd T, Feinstein C, Wall DP. Toward Continuous Social Phenotyping : Analyzing Gaze Patterns in an Emotion Recognition Task for Children With Autism Through Wearable Smart Glasses. Journal of medical Internet research. 2020 ; 22(4) : e13810.

BACKGROUND : Several studies have shown that facial attention differs in children with autism. Measuring eye gaze and emotion recognition in children with autism is challenging, as standard clinical assessments must be delivered in clinical settings by a trained clinician. Wearable technologies may be able to bring eye gaze and emotion recognition into natural social interactions and settings. OBJECTIVE : This study aimed to test : (1) the feasibility of tracking gaze using wearable smart glasses during a facial expression recognition task and (2) the ability of these gaze-tracking data, together with facial expression recognition responses, to distinguish children with autism from neurotypical controls (NCs). METHODS : We compared the eye gaze and emotion recognition patterns of 16 children with autism spectrum disorder (ASD) and 17 children without ASD via wearable smart glasses fitted with a custom eye tracker. Children identified static facial expressions of images presented on a computer screen along with nonsocial distractors while wearing Google Glass and the eye tracker. Faces were presented in three trials, during one of which children received feedback in the form of the correct classification. We employed hybrid human-labeling and computer vision-enabled methods for pupil tracking and world-gaze translation calibration. We analyzed the impact of gaze and emotion recognition features in a prediction task aiming to distinguish children with ASD from NC participants. RESULTS : Gaze and emotion recognition patterns enabled the training of a classifier that distinguished ASD and NC groups. However, it was unable to significantly outperform other classifiers that used only age and gender features, suggesting that further work is necessary to disentangle these effects. CONCLUSIONS : Although wearable smart glasses show promise in identifying subtle differences in gaze tracking and emotion recognition patterns in children with and without ASD, the present form factor and data do not allow for these differences to be reliably exploited by machine learning systems. Resolving these challenges will be an important step toward continuous tracking of the ASD phenotype.

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15. Nguyen AO, Binder DK, Ethell IM, Razak KA. Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome. Journal of neurophysiology. 2020.

Sensory processing abnormalities are frequently associated with autism spectrum disorders, but the underlying mechanisms are unclear. Here we studied auditory processing in a mouse model of Fragile X Syndrome (FXS), a leading known genetic cause of autism and intellectual disability. Both humans with FXS and the Fragile X mental retardation gene (Fmr1) knock-out (KO) mouse model show auditory hypersensitivity, with the latter showing a strong propensity for audiogenic seizures (AGS) early in development. Because midbrain abnormalities cause AGS, we investigated whether the inferior colliculus (IC) of the Fmr1 KO mice shows abnormal auditory processing compared to wild-type (WT) controls at specific developmental time points. Using antibodies against neural activity marker c-Fos, we found increased density of c-Fos+ neurons in the IC, but not auditory cortex, of Fmr1 KO mice at P21 and P34 following sound presentation. In vivo single-unit recordings showed that IC neurons of Fmr1 KO mice are hyper-responsive to tone bursts and amplitude-modulated tones during development, and show broader frequency tuning curves. There were no differences in rate-level responses or phase locking to amplitude-modulated tones in IC neurons between genotypes. Taken together, these data provide evidence for the development of auditory hyper-responsiveness in the IC of Fmr1 KO mice. Although most human and mouse work in autism and sensory processing has centered on the forebrain, our new findings, along with recent work on the lower brainstem, suggest that abnormal subcortical responses may underlie auditory hypersensitivity in autism spectrum disorders.

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16. Quinde-Zlibut JM, Okitondo CD, Williams ZJ, Weitlauf A, Mash LE, Heflin BH, Woodward ND, Cascio CJ. Elevated Thresholds for Light Touch in Children With Autism Reflect More Conservative Perceptual Decision-Making Rather Than a Sensory Deficit. Front Hum Neurosci. 2020 ; 14 : 122.

Individuals with autism spectrum disorder (ASD) are often behaviorally hyper-reactive to light touch, but it is unclear to what degree this arises from a fundamental sensory difference vs. higher order systems for attention or emotion processing. Thus far, experimental findings for light touch detection are mixed, and few previous studies have independently considered sensitivity (the ability to discriminate signal from noise) and decision criterion (the overall response bias or tendency to answer "yes" or "no" in a detection task). We tested a large sample of children, adolescents, and adults with ASD (n = 88) and with neurotypical (NT) development (n = 59) using von Frey filaments to derive light touch thresholds at the palm. We calculated signal detection metrics for sensitivity (Az) and response criterion (c) from hit and false alarm rates. Both metrics exhibited significant group differences, such that the ASD group was less sensitive, but had a much more conservative response criterion. We used a best subset model selection procedure in three separate ordinal regressions for the whole group, adults, and children/adolescents. In all selected models, c was by far the most significant predictor of threshold, supplanting effects of diagnostic group that were significant in the baseline models. In contrast, Az was not a significant predictor of threshold in any of the models. Mean values of c were similar for adults with and without autism and for children/adolescents with ASD, but lower (more liberal) in neurotypical children/adolescents. This suggests that children with ASD exhibit a conservatism in their perceptual decision-making that differs from their NT peers but resembles that of adults. Across the sample, the value of c was significantly and positively correlated with age and with autism symptoms (SRS-2 total score), in addition to thresholds. The results of this study suggest that, rather than a sensory difference in detection of light touch, there is a difference in response bias such that children with ASD are more conservative/likely to report "no" if unsure, than their young NT peers. Future work should consider the implications of conservative response criterion in ASD for commonly used forced-choice psychophysical paradigms.

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17. Reisinger DL, Shaffer RC, Tartaglia N, Berry-Kravis E, Erickson CA. Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome. Brain Sci. 2020 ; 10(4).

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence ; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7-12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.

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18. Rich AJ, DiGregorio N, Strassle C. Trauma-informed care in the context of intellectual and developmental disability services : Perceptions of service providers. Journal of intellectual disabilities : JOID. 2020 : 1744629520918086.

Traumatic life events have pervasive impacts on health and well-being. A growing body of literature shows that people with intellectual and developmental disabilities are disproportionately impacted by trauma. Trauma-informed care (TIC) is a philosophy of service provision that is committed to preventing traumatization and re-traumatization and promoting healing. This study explores the perceptions of 130 leaders in the field of intellectual and developmental disabilities services on the adoption and practice of TIC through the analysis of quantitative data. Results indicated a disconnect between the level of TIC integration and perceptions detailing how well organizations are currently performing in aspects of TIC. Barriers to TIC included high staff turnover, lack of accessible mental health providers, lack of affordable training, stigma, and restrictive funding structures. Implications and recommendations for service organizations and educators are provided.

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19. Rontani P, Perche O, Greetham L, Jullien N, Gepner B, Feron F, Nivet E, Erard-Garcia M. Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells. Mol Psychiatry. 2020.

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.

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20. Rumball F, Happe F, Grey N. Experience of Trauma and PTSD Symptoms in Autistic Adults : Risk of PTSD Development Following DSM-5 and Non-DSM-5 Traumatic Life Events. Autism Res. 2020.

Research to date suggests that individuals with autistic spectrum disorder (ASD) may be at increased risk of developing post-traumatic stress disorder (PTSD) following exposure to traumatic life events. It has been posited that characteristics of ASD may affect perceptions of trauma, with a wider range of life events acting as possible catalysts for PTSD development. This study set out to explore the nature of "trauma" for adults with ASD and the rates of self-reported PTSD symptomatology following DSM-5 and non-DSM-5 traumas-the latter being defined as those that would not meet the standard DSM-5 PTSD trauma Criterion A. Fifty-nine adults with ASD who reported exposure to traumatic events took part in the study, which involved completing a series of online questionnaires. Thirty-three individuals reported experiencing a "DSM-5" traumatic event (i.e., an event meeting DSM-5 PTSD Criterion A) and 35 reported a "non-DSM-5" traumautic event. Trauma-exposed ASD adults were found to be at increased risk of PTSD development, compared to previous general population statistics, with PTSD symptom scores crossing thresholds suggestive of probable PTSD diagnosis for more than 40% of ASD individuals following DSM-5 or non-DSM-5 traumas. A broader range of life events appear to be experienced as traumatic and may act as a catalyst for PTSD development in adults with ASD. Assessment of trauma and PTSD symptomatology should consider possible non-DSM-5 traumas in this population, and PTSD diagnosis and treatment should not be withheld simply due to the atypicality of the experienced traumatic event. LAY SUMMARY : This study explored the experience of trauma and rates of probable post-traumatic stress disorder (PTSD) in adults with autistic spectrum disorder (ASD). We asked 59 autistic adults to complete online questionnaires about their experiences of stressful or traumatic events and related mental health difficulties. Autistic adults experienced a wide range of life events as traumatic, with over 40% showing probable PTSD within the last month and over 60% reporting probable PTSD at some point in their lifetime. Many of the life events experienced as traumas would not be recognized in some current diagnostic systems, raising concerns that autistic people may not receive the help they need for likely PTSD.

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21. Sanders K, Staubitz J, Juarez AP, Marler S, Browning W, McDonnell E, Altstein L, Macklin EA, Warren Z. Addressing Challenging Behavior During Hospitalizations for Children with Autism : A Pilot Applied Behavior Analysis Randomized Controlled Trial. Autism Res. 2020.

This study evaluated the feasibility, acceptance, and potential clinical benefit of brief applied behavior analysis (ABA)-based interventions for children and adolescents with autism spectrum disorder (ASD) displaying challenging behaviors during hospitalizations. Participants included 36 children diagnosed with ASD, 6-17 years of age, who were medically or psychiatrically hospitalized. Children in the intervention group received a brief ABA intervention and were compared to children in the evaluation and monitoring-only group. Families and staff recommended the intervention, children receiving the intervention demonstrated significantly more improvement in unblinded ratings of clinical severity, data from physicians indicated a positive effect of the intervention on levels of staffing and restraints and attending medical providers universally reported satisfaction and benefit of the intervention. Improvements in challenging behaviors were not significantly different as reported by parents, and the length of hospitalization did not differ between the groups. Ultimately, the outcomes of this pilot study suggest incorporating specialized ABA-based assessment and intervention during hospitalization may be feasible and well accepted by clinicians and families. However, future research must address potent methodological challenges related to capturing meaningful data during hospitalizations in order to answer questions of ultimate pragmatic, clinical, and system-level benefits. Trial Registration Identifier NCT02339935, Registered 16 January 2015, First participant consented 23 February 2015. Autism Res 2020. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Inpatient hospitalizations for children with autism spectrum disorder (ASD) and severe behavior are common, challenging, and costly in terms of human experience. This study evaluated the benefit of brief applied behavior analysis-based interventions to children and adolescents with ASD displaying challenging behaviors during hospitalizations. Families and staff evaluating the procedures noted perceived potential benefits of the intervention, but this initial pilot study did not document changes in hospitalization length or blinded rating of improvement.

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22. Schaaf CP, Betancur C, Yuen RKC, Parr JR, Skuse DH, Gallagher L, Bernier RA, Buchanan JA, Buxbaum JD, Chen CA, Dies KA, Elsabbagh M, Firth HV, Frazier T, Hoang N, Howe J, Marshall CR, Michaud JL, Rennie O, Szatmari P, Chung WK, Bolton PF, Cook EH, Scherer SW, Vorstman JAS. A framework for an evidence-based gene list relevant to autism spectrum disorder. Nature reviews Genetics. 2020.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

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23. Thurman AJ, Potter LA, Kim K, Tassone F, Banasik A, Potter SN, Bullard L, Nguyen V, McDuffie A, Hagerman R, Abbeduto L. Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome. J Neurodev Disord. 2020 ; 12(1) : 12.

BACKGROUND : The purpose of this study was to conduct a 20-week controlled trial of lovastatin (10 to 40 mg/day) in youth with fragile X syndrome (FXS) ages 10 to 17 years, combined with an open-label treatment of a parent-implemented language intervention (PILI), delivered via distance video teleconferencing to both treatment groups, lovastatin and placebo. METHOD : A randomized, double-blind trial was conducted at one site in the Sacramento, California, metropolitan area. Fourteen participants were assigned to the lovastatin group ; two participants terminated early from the study. Sixteen participants were assigned to the placebo group. Lovastatin or placebo was administered orally in a capsule form, starting at 10 mg and increasing weekly or as tolerated by 10 mg increments, up to a maximum dose of 40 mg daily. A PILI was delivered to both groups for 12 weeks, with 4 activities per week, through video teleconferencing by an American Speech-Language Association-certified Speech-Language Pathologist, in collaboration with a Board-Certified Behavior Analyst. Parents were taught to use a set of language facilitation strategies while interacting with their children during a shared storytelling activity. The main outcome measures included absolute change from baseline to final visit in the means for youth total number of story-related utterances, youth number of different word roots, and parent total number of story-related utterances. RESULTS : Significant increases in all primary outcome measures were observed in both treatment groups. Significant improvements were also observed in parent reports of the severity of spoken language and social impairments in both treatment groups. In all cases, the amount of change observed did not differ across the two treatment groups. Although gains in parental use of the PILI-targeted intervention strategies were observed in both treatment groups, parental use of the PILI strategies was correlated with youth gains in the placebo group and not in the lovastatin group. CONCLUSION : Participants in both groups demonstrated significant changes in the primary outcome measures. The magnitude of change observed across the two groups was comparable, providing additional support for the efficacy of the use of PILI in youth with FXS. TRIAL REGISTRATION : US National Institutes of Health (, NCT02642653. Registered 12/30/2015.

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24. Tomova A, Soltys K, Kemenyova P, Karhanek M, Babinska K. The Influence of Food Intake Specificity in Children with Autism on Gut Microbiota. International journal of molecular sciences. 2020 ; 21(8).

Autism spectrum disorder (ASD) is a complex of neurodevelopmental conditions with increasing incidence. The microbiota of children with ASD is distinct from neurotypical children, their food habits are also different, and it is known that nutrient intake influences microbiota in a specific way. Thus, this study investigates the food habits of children with ASD and their association with the gut microbiota. Children with ASD had their dietary energy intakes similar to controls, but they more often demonstrated food selectivity, which seemed to result in deficiency of micronutrients such as vitamins K, B6, C, iron, cooper, docosahexaenoic and docosapentanoic acid. Using high-throughput sequencing, a DNA library of intestinal microbiota was performed. Core microbiota was similar in children with and without ASD, but Dichelobacter, Nitriliruptor and Constrictibacter were found to be putative markers of ASD. The changes in gut microbiota that we observed in connection to food selectivity, intake of fats and omega-3 in particular, fermented milk products and animal/plant protein consumption had similar character, independent of diagnosis. However, high fibre intake was connected with a decreased alpha-diversity only in children with ASD. High carbohydrate and fibre intake influenced beta-diversity, changing the abundance of Bacteroides and other genera, many of them members of the Clostidiaceae. Modulating food habits of ASD children can influence their gut microbiota composition.

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25. Verma AK, Khan E, Mishra SK, Mishra A, Charlet-Berguerand N, Kumar A. Curcumin Regulates the r(CGG)(exp) RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome. Front Neurosci. 2020 ; 14 : 295.

Fragile X-associated tremor ataxia syndrome is an untreatable neurological and neuromuscular disorder caused by unstable expansion of 55-200 CGG nucleotide repeats in 5’ UTR of Fragile X intellectual disability 1 (FMR1) gene. The expansion of CGG repeats in the FMR1 mRNA elicits neuronal cell toxicity through two main pathogenic mechanisms. First, mRNA with CGG expanded repeats sequester specific RNA regulatory proteins resulting in splicing alterations and formation of ribonuclear inclusions. Second, repeat-associated non-canonical translation (RANT) of the CGG expansion produces a toxic homopolymeric protein, FMRpolyG. Very few small molecules are known to modulate these pathogenic events, limiting the therapeutic possibilities for FXTAS. Here, we found that a naturally available biologically active small molecule, Curcumin, selectively binds to CGG RNA repeats. Interestingly, Curcumin improves FXTAS associated alternative splicing defects and decreases the production and accumulation of FMRpolyG protein inclusion. Furthermore, Curcumin decreases cell cytotoxicity promptly by expression of CGG RNA in FXTAS cell models. In conclusion, our data suggest that small molecules like Curcumin and its derivatives may be explored as a potential therapeutic strategy against the debilitating repeats associated neurodegenerative disorders.

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26. Xiao R, Zhong H, Li X, Ma Y, Zhang R, Wang L, Zang Z, Fan X. Abnormal Cerebellar Development Is Involved in Dystonia-Like Behaviors and Motor Dysfunction of Autistic BTBR Mice. Frontiers in cell and developmental biology. 2020 ; 8 : 231.

Motor control and learning impairments are common complications in individuals with autism spectrum disorder (ASD). Abnormal cerebellar development during critical phases may disrupt these motor functions and lead to autistic motor dysfunction. However, the underlying mechanisms behind these impairments are not clear. Here, we utilized BTBR T(+) Itpr(tf) /J (BTBR) mice, an animal model of autism, to investigate the involvement of abnormal cerebellar development in motor performance. We found BTBR mice exhibited severe dystonia-like behavior and motor coordination or motor learning impairments. The onset of these abnormal movements coincided with the increased proliferation of granule neurons and enhanced foliation, and Purkinje cells displayed morphological hypotrophy with increased dendritic spine formation but suppressed maturation. The migration of granule neurons seemed unaffected. Transcriptional analyses confirmed the differential expression of genes involved in abnormal neurogenesis and revealed TRPC as a critical regulator in proliferation and synaptic formation. Taken together, these findings indicate that abnormal cerebellar development is closely related to dystonia-like behavior and motor dysfunction of BTBR mice and that TRPC may be a novel risk gene for ASD that may participate in the pathological process of autistic movement disorders.

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27. Zaenglein A, Martin A, Carlson L, Williams KE. Pellagra secondary to selective eating in a child with autism. Pediatric dermatology. 2020.

Once a significant cause of morbidity and mortality, health care providers rarely see primary pellagra in developed countries where fortification of foods with niacin is commonplace and niacin-rich foods are generally widely available. We report a ten-year-old boy with autism spectrum disorder who presented with photosensitive dermatitis which resolved after vitamin supplementation and dietary changes. In this child, the pellagra developed as the result of a long-term pattern of selective eating. Restricted diets, even to the point of nutrient deficiencies, are well-documented among children with autism spectrum disorders (ASD).

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28. Zaidman-Zait A, Mirenda P, Szatmari P, Duku E, Smith IM, Zwaigenbaum L, Vaillancourt T, Kerns C, Volden J, Waddell C, Bennett T, Georgiades S, Ungar WJ, Elsabbagh M. Profiles and Predictors of Academic and Social School Functioning among Children with Autism Spectrum Disorder. J Clin Child Adolesc Psychol. 2020 : 1-13.

Objective : The purpose of the study was to identify profiles and predictors of academic and social functioning in a sample of school-age children with autism spectrum disorder.Method : The study included 178 children (88% boys, 75% Caucasian, ages 10-11) who completed a standardized measure of academic skills and whose teachers completed a related measure. Measures of both academic and social performance were used to construct profiles of school functioning. Measures of language, nonverbal IQ, autism symptom severity, behavior difficulties, and early social-communication skills between ages 3 and 4 were used to examine predictors of profile membership. Latent Profile Analysis was used to identify and describe profiles of children’s academic and social school functioning. Profile membership was then regressed on each of the predictors using a series of multinomial logistic regression models. Finally, a multivariate model that included all significant predictors was built to examine the best fitting constellation of profile predictors.Results : Four profiles - reflecting variation in academic achievement, school engagement, socialization skills, pragmatic language use, and social relationships - captured the diverse school functioning outcomes of the sample. Profile membership was predicted by variation in imitation, responding to joint attention, language ability, nonverbal IQ and behavior difficulties between ages 3 and 4 years. However, in a multivariate model, only language and behavior difficulties emerged as significant predictors.Conclusions : A person-centered approach to targeted early intervention that reduces behavior difficulties and enhances social-communication and language abilities may prove especially important for the promotion of later academic and social functioning at school.

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