Pubmed du 29/08/19

jeudi 29 août 2019

1. Borghi E, Vignoli A. Rett Syndrome and Other Neurodevelopmental Disorders Share Common Changes in Gut Microbial Community : A Descriptive Review. Int J Mol Sci ;2019 (Aug 26) ;20(17)

In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent features of the syndrome, but the pathogenic mechanisms modulating its severity are still poorly understood. Gut microbiota was recently demonstrated to be altered both in animal models and humans with different neurodevelopmental disorders and/or epilepsy. By investigating gut microbiota in RTT cohorts, a less rich microbial community was identified which was associated with alterations of fecal microbial short-chain fatty acids. These changes were positively correlated with severe clinical outcomes. Indeed, microbial metabolites can play a crucial role both locally and systemically, having dynamic effects on host metabolism and gene expression in many organs. Similar alterations were found in patients with autism and down syndrome as well, suggesting a potential common pathway of gut microbiota involvement in neurodevelopmental disorders.

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2. Doenyas C. Novel Personalized Dietary Treatment for Autism Based on the Gut-Immune-Endocrine-Brain Axis. Front Endocrinol (Lausanne) ;2019 ;10:508.

Autism spectrum disorder (ASD) is a neurodevelopmental condition manifesting with impaired social interaction and communication, and restricted and repetitive behaviors and interests. In this perspective article, a more comprehensive approach than the gut-brain axis, hereby termed the "gut-immune-endocrine-brain" axis, is taken, based on which a personalized treatment plan for ASD is presented. ASD has no known etiology or cure, making desperate parents willing to try any treatment that worked for an individual with ASD, without much regard for its effectiveness, safety or side effects. This has been the case for restrictive dietary interventions as gluten-free/casein-free and ketogenic diets and recently, probiotics have emerged as the new such fad. One of the concerns about these dietary and probiotic treatments is their non-specificity : they may not be effective for all individuals with ASD, not all probiotic strains may have the beneficial qualities advertised indiscriminately for probiotics, and strains conferring benefits in one condition may not be probiotic in another. Not all children with ASD show immune reactivity to dietary proteins in wheat and milk, and wheat and milk may not be the only dietary elements to which reactivity is exhibited, where dietary aquaporins that resemble human aquaporins may elicit antibody reactivity in genetically susceptible individuals, which may include individuals with ASD. These observations are utilized to formulate a three-step plan to create effective, targeted, personalized treatments with as few side effects as possible, enabled by a systems approach connecting the various findings for dietary, immune, and neuroautoimmune reactivity in individuals with ASD.

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3. Eckert EM, Dominick KC, Pedapati EV, Wink LK, Shaffer RC, Andrews H, Choo TH, Chen C, Kaufmann WE, Tartaglia N, Berry-Kravis EM, Erickson CA. Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome : An Initial Cross-Sectional Analysis. J Autism Dev Disord ;2019 (Aug 29)

Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.

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4. English MCW, Gignac GE, Visser TAW, Whitehouse AJO, Maybery MT. A comprehensive psychometric analysis of autism-spectrum quotient factor models using two large samples : Model recommendations and the influence of divergent traits on total-scale scores. Autism Res ;2019 (Aug 29)

The Autism-Spectrum Quotient (AQ) is a psychometric scale that is commonly used to assess autistic-like traits and behaviors expressed by neurotypical individuals. A potential strength of the AQ is that it provides subscale scores that are specific to certain dimensions associated with autism such as social difficulty and restricted interests. However, multiple psychometric evaluations of the AQ have led to substantial disagreement as to how many factors exist in the scale, and how these factors are defined. These challenges have been exacerbated by limitations in study designs, such as insufficient sample sizes as well as a reliance on Pearson, rather than polychoric, correlations. In addition, several proposed models of the AQ suggest that some factors are uncorrelated, or negatively correlated, which has ramifications for whether total-scale scores are meaningfully interpretable-an issue not raised by previous work. The aims of the current study were to provide : (a) guidance as to which models of the AQ are viable for research purposes, and (b) evidence as to whether total-scale scores are adequately interpretable for research purposes. We conducted a comprehensive series of confirmatory factor analyses on 11 competing AQ models using two large samples drawn from an undergraduate population (n = 1,702) and the general population (n = 1,280). Psychometric evidence largely supported using the three-factor model described by Russell-Smith et al. [Personality and Individual Differences 51(2), 128-132 (2011)], but did not support the use of total-scale scores. We recommend that researchers consider using AQ subscale scores instead of total-scale scores. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : We examined 11 different ways of scoring subscales in the popular Autism-Spectrum Quotient (AQ) questionnaire in two large samples of participants (i.e., general population and undergraduate students). We found that a three-subscale model that used "Social Skill," "Patterns/Details," and "Communication/Mindreading" subscales was the best way to examine specific types of autistic traits in the AQ. We also found some weak associations between the three subscales-for example, being high on the "Patterns/Details" subscale was not predictive of scores on the other subscales. This means that meaningful interpretation of overall scores on the AQ is limited.

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5. Guo X, Simas T, Lai MC, Lombardo MV, Chakrabarti B, Ruigrok ANV, Bullmore ET, Baron-Cohen S, Chen H, Suckling J. Enhancement of indirect functional connections with shortest path length in the adult autistic brain. Hum Brain Mapp ;2019 (Aug 29)

Autism is a neurodevelopmental condition characterized by atypical brain functional organization. Here we investigated the intrinsic indirect (semi-metric) connectivity of the functional connectome associated with autism. Resting-state functional magnetic resonance imaging scans were acquired from 65 neurotypical adults (33 males/32 females) and 61 autistic adults (30 males/31 females). From functional connectivity networks, semi-metric percentages (SMPs) were calculated to assess the proportion of indirect shortest functional pathways at global, hemisphere, network, and node levels. Group comparisons were then conducted to ascertain differences between autism and neurotypical control groups. Finally, the strength and length of edges were examined to explore the patterns of semi-metric connections associated with autism. Compared with neurotypical controls, autistic adults displayed significantly higher SMP at all spatial scales, similar to prior observations in adolescents. Differences were primarily in weaker, longer-distance edges in the majority between networks. However, no significant diagnosis-by-sex interaction effects were observed on global SMP. These findings suggest increased indirect functional connectivity in the autistic brain is persistent from adolescence to adulthood and is indicative of reduced functional network integration.

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6. Hamad AF, Alessi-Severini S, Mahmud SM, Brownell M, Kuo IF. Prenatal antibiotics exposure and the risk of autism spectrum disorders : A population-based cohort study. PLoS One ;2019 ;14(8):e0221921.

BACKGROUND : Prenatal antibiotic exposure induces changes in infants’ gut microbiota composition and is suggested as a possible contributor in the development of autism spectrum disorders (ASD). In this study, we examined the association between prenatal antibiotic exposure and the risk of ASD. METHODS : This was a population-based cohort study utilizing the Manitoba Population Research Data Repository. The cohort included 214 834 children born in Manitoba, Canada between April 1, 1998 and March 31, 2016. Exposure was defined as having filled one or more antibiotic prescription during pregnancy. The outcome was autism spectrum disorder diagnosis. Multivariable Cox proportional hazards regression was used to estimate the risk of developing ASD in the overall cohort and in a sibling cohort. RESULTS : Of all subjects, 80 750 (37.6%) were exposed to antibiotics prenatally. During follow-up, 2965 children received an ASD diagnosis. Compared to children who were not exposed to antibiotics prenatally, those who were exposed had a higher risk of ASD : (adjusted HR 1.10 [95% CI 1.01, 1.19]). The association was observed in those exposed to antibiotics in the second or third trimester (HR 1.11 [95% CI 1.01, 1.23] and 1.17 [95% CI 1.06, 1.30], respectively). In the siblings’ cohort, ASD risk estimate remained unchanged (adjusted HR 1.08 [95% CI 0.90, 1.30], although it was not statistically significant. CONCLUSIONS : Prenatal antibiotic exposure is associated with a small increase in the risk of ASD. Given the potential of residual confounding beyond what it was controlled through our study design and because of possible confounding by indication, such a small risk increase in the population is not expected to be clinically significant.

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7. Joshi G, DiSalvo M, Faraone SV, Wozniak J, Fried R, Galdo M, Belser A, Hoskova B, Dallenbach NT, De Leon MF, Biederman J. Predictive utility of autistic traits in youth with ADHD : a controlled 10-year longitudinal follow-up study. Eur Child Adolesc Psychiatry ;2019 (Aug 29)

The objective of this study was to investigate the stability and predictive utility of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD). Participants were referred youth with and without ADHD, without a diagnosis of autism spectrum disorder, and their siblings, derived from identically designed longitudinal case-control family studies of boys and girls with ADHD. Subjects were assessed with structured diagnostic interviews and measures of social, cognitive, and educational functioning. The presence of ATs at baseline was operationalized using a unique profile of the Child Behavior Checklist (CBCL) consisting of an aggregate T score of >/= 195 on the Withdrawn, Social, and Thought Problems subscales (CBCL-AT profile). At the follow-up, 83% of the ADHD youth with a positive AT profile at baseline continued to have a positive CBCL-AT profile. The presence of a positive CBCL-AT profile at baseline in youth with ADHD heralded a more compromised course characterized by a greater burden of psychopathology that emerged at an earlier age, along with poorer interpersonal, educational, and neurocognitive outcomes. Findings indicate a high level of persisting ATs in ADHD youth over time, as indexed through the CBCL-AT profile, and the presence of this profile prognosticates a compromised course in adult life in multiple domains of functioning.

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8. Kalkbrenner AE, Meier SM, Madley-Dowd P, Ladd-Acosta C, Fallin MD, Parner E, Schendel D. Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring. Autism Res ;2019 (Aug 29)

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991-2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism - no ADHD, 2,205 autism + ID, and 11,342 autism - no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13-1.22]) but attenuated in the maternal cluster (0.98 [0.88-1.09]) and sibling (0.86 [0.64-1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Smoking during pregnancy has many harmful impacts, which may include harming the baby’s developing brain. However, in a study of thousands of families in Denmark, it does not appear that smoking in pregnancy leads to autism or autism in combination with intellectual problems or attention deficits, once you account for the way smoking patterns and developmental disabilities run in families.

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9. Kinnaird E, Norton C, Pimblett C, Stewart C, Tchanturia K. Eating as an autistic adult : An exploratory qualitative study. PLoS One ;2019 ;14(8):e0221937.

BACKGROUND : Although eating difficulties are known to be common in children on the autism spectrum, there is a lack of research on whether these behaviours persist or change into adulthood. Emerging evidence suggests that autistic adults may experience higher levels of disordered eating than the general population, indicating the impact of autism on eating in this adult population warrants further exploration. METHOD : This study interviewed 12 autistic adults about their eating habits, with a focus on the continuing or changing presence of behaviours often seen in autistic children such as sensory sensitivity or a preference for routines. Interviews were transcribed and analysed using thematic analysis. RESULTS : Overall, participants suggested that autism did continue to impact their eating into adulthood, particularly in the areas of sensory sensitivity, medical difficulties, executive functioning difficulties, and rigidity, but that they had learned to adapt so that these issues no longer represented a problem. However, a minority of participants did feel that their autism had a negative effect on their eating, particularly those diagnosed with eating disorders. Additionally, eating behaviours associated with autism were identified as potentially contributing to having an unhealthy body weight. CONCLUSIONS : Certain traits associated with autism, such as cognitive rigidity and sensory sensitivity, could potentially continue to influence the eating behaviours of autistic adults. These traits are typically experienced as differences which can be adapted around and managed, rather than specific problems. However, these traits can potentially contribute to difficulties such as disordered eating and weight gain, and the implications of these should be explored by future research.

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10. Koren G, Moser-Sharman S. Corrigendum to : "Does high-dose gestational folic acid increase the risk for autism ? The birth order hypothesis" [Medical Hypotheses 132 (2019) 109350]. Med Hypotheses ;2019 (Aug 29) ;133:109378.

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11. Lee C, Kang EY, Gandal MJ, Eskin E, Geschwind DH. Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage. Nat Neurosci ;2019 (Sep) ;22(9):1521-1532.

One fundamental but understudied mechanism of gene regulation in disease is allele-specific expression (ASE), the preferential expression of one allele. We leveraged RNA-sequencing data from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box small nucleolar RNAs (snoRNAs), are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA-targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis.

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12. McKechanie AG, Barnicoat A, Trender-Gerhard I, Allison M, Stanfield AC. Fragile X-associated conditions : implications for the whole family. Br J Gen Pract ;2019 (Sep) ;69(686):460-461.

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13. Muharib R, Alrasheed F, Ninci J, Walker VL, Voggt AP. Thinning Schedules of Reinforcement Following Functional Communication Training for Children with Intellectual and Developmental Disabilities : A Meta-analytic Review. J Autism Dev Disord ;2019 (Aug 27)

Functional communication training (FCT) is an evidence-based practice used to mitigate challenging behavior by increasing functional communication skills. To increase the practicality and feasibility of FCT in natural settings, thinning schedules of reinforcement are typically programmed following FCT. In this review, we meta-analyzed 28 studies that incorporated a thinning schedule procedure following FCT for 51 children with intellectual and developmental disabilities ages 8 and younger. Using Tau-U, the results demonstrated overall moderate effect sizes for both challenging behavior and functional communication responses. Additionally, moderator analyses pertaining to participant characteristics, interventions, and study quality were conducted. Thinning procedures were most effective for children who had stronger communication repertoire. Implications for future research and practice are discussed.

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14. Rapanelli M, Tan T, Wang W, Wang X, Wang ZJ, Zhong P, Frick L, Qin L, Ma K, Qu J, Yan Z. Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Mol Psychiatry ;2019 (Aug 27)

Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency. Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum. Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits. Large-scale profiling has identified sets of misregulated proteins resulting from Cul3 deficiency in different regions, including Smyd3, a histone methyltransferase involved in gene transcription. Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC. These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits.

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15. Saaybi S, AlArab N, Hannoun S, Saade M, Tutunji R, Zeeni C, Shbarou R, Hourani R, Boustany RM. Pre- and Post-therapy Assessment of Clinical Outcomes and White Matter Integrity in Autism Spectrum Disorder : Pilot Study. Front Neurol ;2019 ;10:877.

Objective : This pilot study aims to identify white matter (WM) tract abnormalities in Autism Spectrum Disorders (ASD) toddlers and pre-schoolers by Diffusion Tensor Imaging (DTI), and to correlate imaging findings with clinical improvement after early interventional and Applied Behavior Analysis (ABA) therapies by Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP). Methods : DTI scans were performed on 17 ASD toddlers/pre-schoolers and seven age-matched controls. Nine ASD patients had follow-up MRI 12 months following early intervention and ABA therapy. VB-MAPP was assessed and compared at diagnosis, 6 and 12 months after therapies. Tract-Based Spatial Statistics (TBSS) was used to measure fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial (RD) diffusivity. Results : VB-MAPP scores improved at 6 and 12 months after early intervention and ABA therapy compared to scores at baseline. TBSS analysis showed significant FA decrease and/or RD increase in ASD patients before therapy vs. controls in inferior fronto-occipital fasciculi, uncinate fasciculi, left superior fronto-occipital fasciculus, forceps minor, left superior fronto-occipital fasciculus, right superior longitudinal fasciculus, corona radiate bilaterally, and left external capsule. A significantly FA increase in 21 tracts and ROIs is reported in post- vs. pre-therapy DTI analysis. Conclusion : DTI findings highlighted ASD patient WM abnormalities at diagnosis and confirmed the benefits of 12 months of early intervention and ABA therapy on clinical and neuro imaging outcomes.

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16. Topuz C, Ulke-Kurkcuoglu B. Increasing Verbal Interaction in Children with Autism Spectrum Disorders Using Audio Script Procedure. J Autism Dev Disord ;2019 (Aug 29)

This study aimed at investigating the effectiveness of audio script and script-fading procedure in teaching initiation to children with ASD. Three children with ASD and a parent of each child participated in the study. A nonconcurrent multiple baseline design across children was used. The findings showed that the initiation emitted by the children increased during audio script and script-fading procedure. Children also generalized initiation across different conditions and maintained the acquired skills. Finally, the social validity findings showed that the opinions of the parents regarding the procedure were overall positive. Results were discussed in terms of recommendations for practitioners and future research.

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17. Van der Donck S, Dzhelyova M, Vettori S, Thielen H, Steyaert J, Rossion B, Boets B. Fast Periodic Visual Stimulation EEG Reveals Reduced Neural Sensitivity to Fearful Faces in Children with Autism. J Autism Dev Disord ;2019 (Aug 29)

We objectively quantified the neural sensitivity of school-aged boys with and without autism spectrum disorder (ASD) to detect briefly presented fearful expressions by combining fast periodic visual stimulation with frequency-tagging electroencephalography. Images of neutral faces were presented at 6 Hz, periodically interleaved with fearful expressions at 1.2 Hz oddball rate. While both groups equally display the face inversion effect and mainly rely on information from the mouth to detect fearful expressions, boys with ASD generally show reduced neural responses to rapid changes in expression. At an individual level, fear discrimination responses predict clinical status with an 83% accuracy. This implicit and straightforward approach identifies subtle deficits that remain concealed in behavioral tasks, thereby opening new perspectives for clinical diagnosis.

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18. Williams ZJ, Failla MD, Davis SL, Heflin BH, Okitondo CD, Moore DJ, Cascio CJ. Thermal Perceptual Thresholds are typical in Autism Spectrum Disorder but Strongly Related to Intra-individual Response Variability. Sci Rep ;2019 (Aug 29) ;9(1):12595.

Individuals with autism spectrum disorder (ASD) are often reported to exhibit an apparent indifference to pain or temperature. Leading models suggest that this behavior is the result of elevated perceptual thresholds for thermal stimuli, but data to support these assertions are inconclusive. An alternative proposal suggests that the sensory features of ASD arise from increased intra-individual perceptual variability. In this study, we measured method-of-limits warm and cool detection thresholds in 142 individuals (83 with ASD, 59 with typical development [TD], aged 7-54 years), testing relationships with diagnostic group, demographics, and clinical measures. We also investigated the relationship between detection thresholds and a novel measure of intra-individual (trial-to-trial) threshold variability, a putative index of "perceptual noise." This investigation found no differences in thermal detection thresholds between individuals with ASD and typical controls, despite large differences between groups in sensory reactivity questionnaires and modest group differences in intra-individual variability. Lower performance IQ, male sex, and higher intra-individual variability in threshold estimates were the most significant predictors of elevated detection thresholds. Although no psychophysical measure was significantly correlated with questionnaire measures of sensory hyporeactivity, large intra-individual variability may partially explain the elevated psychophysical thresholds seen in a subset of the ASD population.

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