1. Bishop SL, Havdahl KA, Huerta M, Lord C. {{Subdimensions of social-communication impairment in autism spectrum disorder}}. {J Child Psychol Psychiatry}. 2016.
BACKGROUND: More refined dimensions of social-communication impairment are needed to elucidate the clinical and biological boundaries of autism spectrum disorders (ASD) and other childhood onset psychiatric disorders associated with social difficulties, as well as to facilitate investigations in treatment and long-term outcomes of these disorders. METHODS: This study was intended to identify separable dimensions of clinician-observed social-communication impairments by examining scores on a widely used autism diagnostic instrument. Participants included verbally fluent children ages 3-13 years, who were given a clinical diagnosis of ASD (n = 120) or non-ASD (i.e. ADHD, language disorder, intellectual disability, mood or anxiety disorder; n = 118) following a comprehensive diagnostic assessment. Exploratory and confirmatory factor analysis examined the factor structure of algorithm items from the Autism Diagnostic Observation Schedule (ADOS), Module 3. RESULTS: Results indicated that a three-factor model consisting of repetitive behaviors and two separate social-communication behavior factors had superior fit compared to a two-factor model that included repetitive behaviors and one social-communication behavior factor. In the three-factor model, impairments in ‘Basic Social-Communication’ behaviors (e.g. eye contact, facial expressions, gestures) were separated from impairments in ‘Interaction quality.’ Confirmatory factor analysis in an independent sample of children in the Simons Simplex Collection (SSC) further supported the division of social-communication impairments into these two factors. Scores in Interaction Quality were significantly associated with nonverbal IQ and male sex in the ASD group, and with age in the non-ASD group, while scores in basic social communication were not significantly associated with any of these child characteristics in either diagnostic group. CONCLUSIONS: Efforts to conceptualize level, or severity, of social-communication impairment in children with neurodevelopmental disorders might be facilitated by separating the most basic (or proximal) social-communication impairments from those that could arise from a range of other phenotypic variables. Identification of social-communication subdimensions also highlights potential avenues for measuring different types of social-communication impairments for different purposes (e.g. for differential diagnosis vs. response to treatment).
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2. Burrows CA, Laird AR, Uddin LQ. {{Functional connectivity of brain regions for self- and other-evaluation in children, adolescents and adults with autism}}. {Dev Sci}. 2016.
Developing strong ties between oneself and others lays the foundation for developing social competence. Neuroimaging studies have consistently identified specific cortical midline regions activated during evaluative judgments about the self and others. Individuals with autism spectrum disorder (ASD) process self-relevant information differently from their peers, both behaviorally and at the neural level. We compared resting-state functional connectivity (rsFC) of regions involved in self-referential (e.g. medial prefrontal cortex; mPFC) and other-referential (e.g. posterior cingulate cortex; PCC) processing between neurotypical individuals and individuals with ASD in three age cohorts using regions of interest (ROIs) identified through an activation likelihood estimation meta-analysis. Typically developing children demonstrated greater connectivity within the midline self- and other-referential networks compared with age-matched children with ASD. No group differences in rsFC of mPFC or PCC emerged between typically developing adolescents and adolescents with ASD. Neurotypical adults exhibited stronger rsFC of the PCC with orbitofrontal cortex compared with adults with ASD. Developmental differences in functional connectivity between areas underlying self- and other-referential thought may explain altered developmental trajectories in the understanding of self and others in individuals with ASD.
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3. de Schipper E, Mahdi S, de Vries P, Granlund M, Holtmann M, Karande S, Almodayfer O, Shulman C, Tonge B, Wong VV, Zwaigenbaum L, Bolte S. {{Functioning and disability in autism spectrum disorder: A worldwide survey of experts}}. {Autism Res}. 2016.
OBJECTIVE: This study is the second of four to prepare International Classification of Functioning, Disability and Health (ICF; and Children and Youth version, ICF(-CY)) Core Sets for Autism Spectrum Disorder (ASD).The objective of this study was to survey the opinions and experiences of international experts on functioning and disability in ASD. METHODS: Using a protocol stipulated by the World Health Organization (WHO) and monitored by the ICF Research Branch, an email-based questionnaire was circulated worldwide among ASD experts, and meaningful functional ability and disability concepts were extracted from their responses. These concepts were then linked to the ICF(-CY) by two independent researchers using a standardized linking procedure. RESULTS: N = 225 experts from 10 different disciplines and all six WHO-regions completed the survey. Meaningful concepts from the responses were linked to 210 ICF(-CY) categories. Of these, 103 categories were considered most relevant to ASD (i.e., identified by at least 5% of the experts), of which 37 were related to Activities and Participation, 35 to Body functions, 22 to Environmental factors, and 9 to Body structures. A variety of personal characteristics and ASD-related functioning skills were provided by experts, including honesty, loyalty, attention to detail and creative talents. Reported gender differences in ASD comprised more externalizing behaviors among males and more internalizing behaviors in females. CONCLUSION: The ICF(-CY) categories derived from international expert opinions indicate that the impact of ASD on functioning extends far beyond core symptom domains. Autism Res 2016. (c) 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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4. Doehring P, Volkmar FR. {{Knowledge Gaps in ASD Research: Short and Long Term Implications for Policy}}. {J Autism Dev Disord}. 2016.
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5. Duyzend MH, Nuttle X, Coe BP, Baker C, Nickerson DA, Bernier R, Eichler EE. {{Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV}}. {Am J Hum Genet}. 2015.
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 x 10-11), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 x 10-2). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 x 10-3). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV.
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6. Fulceri F, Morelli M, Santocchi E, Cena H, Del Bianco T, Narzisi A, Calderoni S, Muratori F. {{Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder}}. {Dig Liver Dis}. 2015.
BACKGROUND: Gastrointestinal (GI) symptoms are frequently reported in children with Autism Spectrum Disorder (ASD), and an impact of GI comorbidity on ASD behavioral problems has been hypothesized. AIMS: To explore the type and the prevalence of GI symptoms in ASD patients and typical development (TD) controls, and to investigate their possible association with behavioral problems. METHODS: A total of 230 preschoolers were included in this study. Specifically, four groups of children were evaluated: ASD individuals suffering from GI symptoms (ASD/GI+), ASD subjects without GI symptoms (ASD/GI-), TD peers with (TD/GI+) and without (TD/GI-) GI symptoms. Parental report of behavioral problems and GI symptoms were assessed through the Child Behavior Check List 1(1/2)-5. RESULTS: A significant higher percentage of ASD (37.4%) versus TD (14.8%) with GI symptoms was observed. ‘Constipated’ and ‘Not-Eat’ were the most frequent GI symptoms both in ASD and in TD groups, but they were evaluated as more severe in ASD patients. ASD/GI+ children had more anxiety problems, somatic complaints, externalizing and total problems than ASD/GI- individuals. TD/GI+ did not show more behavioral problems than TD/GI-. CONCLUSION: Development of evidence-based guidelines for identification of GI problems in ASD preschoolers is warranted. GI symptomatology should be accurately assessed, especially in ASD children with anxiety and/or externalizing behavioral problems.
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7. Herringshaw AJ, Ammons CJ, DeRamus TP, Kana RK. {{Hemispheric differences in language processing in autism spectrum disorders: A meta-analysis of neuroimaging studies}}. {Autism Res}. 2016.
Language impairments, a hallmark feature of autism spectrum disorders (ASD), have been related to neuroanatomical and functional abnormalities. Abnormal lateralization of the functional language network, increased reliance on visual processing areas, and increased posterior brain activation have all been reported in ASD and proposed as explanatory models of language difficulties. Nevertheless, inconsistent findings across studies have prevented a comprehensive characterization of the functional language network in ASD. The aim of this study was to quantify common and consistent patterns of brain activation during language processing in ASD and typically developing control (TD) participants using a meta-analytic approach. Activation likelihood estimation (ALE) meta-analysis was used to examine 22 previously published functional Magnetic Resonance Imaging (fMRI)/positron emission tomography studies of language processing (ASD: N = 328; TD: N = 324). Tasks included in this study addressed semantic processing, sentence comprehension, processing figurative language, and speech production. Within-group analysis showed largely overlapping patterns of language-related activation in ASD and TD groups. However, the ASD participants, relative to TD participants, showed: (1) more right hemisphere activity in core language areas (i.e., superior temporal gyrus and inferior frontal gyrus), particularly in tasks where they had poorer performance accuracy; (2) bilateral MTG hypo-activation across many different paradigms; and (3) increased activation of the left lingual gyrus in tasks where they had intact performance. These findings show that the hypotheses reviewed here address the neural and cognitive aspects of language difficulties in ASD across all tasks only in a limited way. Instead, our findings suggest the nuances of language and brain in ASD in terms of its context-dependency. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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8. Mendelson JL, Gates JA, Lerner MD. {{Friendship in School-Age Boys With Autism Spectrum Disorders: A Meta-Analytic Summary and Developmental, Process-Based Model}}. {Psychol Bull}. 2016.
Friendship-making is considered a well-established domain of deficit for children with autism spectrum disorders (ASD; American Psychiatric Association, 2013), with this population sometimes described as incapable of making friends. However, the majority of children with ASD indicate a desire for friends, and many report having friends. To what degree, then, do youth with ASD succeed in achieving friendships with peers? If and when they do succeed, by what means do these friendships emerge relative to models of typically developing (TD) youths’ friendships? To address these questions, we first meta-analyzed the descriptive friendship literature (peer-reported sociometrics, self-report, parent-report) among school-age boys with ASD. Using random effects models, we found that youth with ASD do make friends according to peers and parents (Hedges’s g > 2.84). However, self-reported friendship quality (Hedges’s g = -1.09) and parent- and peer-reported quantity (Hedges’s g < -0.63) were poorer than TD peers. We consider these findings in light of 2 conceptual frameworks for understanding social deficits in ASD (social cognition and social motivation theory) and in view of a leading model of friendship in TD youth (Hartup & Stevens, 1997). We then present a model that synthesizes these domains through the construct of social information processing speed, and thereby present the first developmental, process-based model of friendship development among youth with ASD. (PsycINFO Database Record Lien vers le texte intégral (Open Access ou abonnement)
9. Robertson CE, Ratai EM, Kanwisher N. {{Reduced GABAergic Action in the Autistic Brain}}. {Curr Biol}. 2016; 26(1): 80-5.
An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1], inspired in part by the striking prevalence of seizures among individuals with the disorder [2]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [3-7], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8, 9], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [11], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12-15]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.
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10. Schendel DE, Overgaard M, Christensen J, Hjort L, Jorgensen M, Vestergaard M, Parner ET. {{Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population}}. {JAMA Pediatr}. 2016: 1-8.
Importance: Increased mortality has been reported among persons with autism spectrum disorder (ASD), especially among those who also have the comorbid condition of epilepsy or intellectual disability. The effects of psychiatric and neurologic comorbidity on mortality among persons with ASD have not been rigorously examined in large, population-based studies. Objective: To investigate the mortality patterns among persons with ASD overall and to assess the associations of comorbid mental, behavioral, and neurologic disorders with mortality among persons with ASD. Design, Setting, and Participants: Longitudinal cohort study of children born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013. This population-based sample of children (N = 1912904) was identified via linkage between the Danish Civil Registration Service and the Danish Medical Birth Register using a unique 10-digit identifier assigned to all live births and new residents in Denmark. Children were followed up for diagnoses of ASD (International Classification of Diseases, Eighth Revision [ICD-8] codes 299.00, 299.01, 299.02, and 299.03 and ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9) and other mental/behavioral disorders (ICD-8 codes 290-315 and ICD-10 codes F00-F99) in the Danish Psychiatric Central Research Register and for diagnoses of neurologic disorders (ICD-8 codes 320-359 and ICD-10 codes G00-G99) in the Danish National Patient Register. Data analysis was performed in December 2014. Main Outcomes and Measures: Deaths and causes of death among cohort members were identified via the Danish Civil Registration Service and the Danish Cause of Death Register, respectively. Regressions analyses were performed using Cox regression. Results: Of the 1912904 persons included in our study, 20492 (1.1%) had ASD (15901 [77.6%] were male). Of the 20492 persons with ASD, 68 died (0.3%) (57 of 68 [83.8%] had comorbid mental/behavioral or neurologic disorders). The adjusted hazard ratio (aHR) for overall mortality was 2.0 (95% CI, 1.5-2.8) for ASD. The aHRs for ASD-associated mortality among cohort members who did not have neurologic (2.0 [95% CI, 1.4-3.0]) or other mental/behavioral disorders (1.7 [95% CI, 1.0-3.1]) were similar. The co-occurrence of ASD added no additional mortality risk for persons with neurologic (aHR, 0.7 [95% CI, 0.4-1.3]) or mental/behavioral disorders (aHR, 0.8 [95% CI, 0.5-1.2]) compared with persons with these disorders and no ASD. Conclusions and Relevance: The mortality risk was 2-fold higher through young adulthood for persons with ASD than for persons without ASD, although mortality affected only 0.3% of persons with ASD. The mechanisms underlying ASD-associated mortality may be mediated through or shared with neurologic or mental/behavioral disorders, thereby providing insights into their potential neurobiological links. Health care professionals and family members should recognize the importance of these disorders with regard to the mortality risk for persons with ASD.
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11. Storch EA, Nadeau JM, Johnco C, Timpano K, McBride N, Jane Mutch P, Lewin AB, Murphy TK. {{Hoarding in Youth with Autism Spectrum Disorders and Anxiety: Incidence, Clinical Correlates, and Behavioral Treatment Response}}. {J Autism Dev Disord}. 2016.
This study examined the nature and correlates of hoarding among youth with autism spectrum disorders (ASD). Forty children with ASD and a comorbid anxiety disorder were administered a battery of clinician-administered measures assessing presence of psychiatric disorders and anxiety severity. Parents completed questionnaires related to child hoarding behaviors, social responsiveness, internalizing and externalizing behaviors, and functional impairment. We examined the impact of hoarding behaviors on treatment response in a subsample of twenty-six youth who completed a course of personalized cognitive-behavioral therapy targeting anxiety symptoms. Hoarding symptoms were common and occurred in a clinically significant manner in approximately 25 % of cases. Overall hoarding severity was associated with increased internalizing and anxiety/depressive symptoms, externalizing behavior, and attention problems. Discarding items was associated with internalizing and anxious/depressive symptoms, but acquisition was not. Hoarding decreased following cognitive-behavioral therapy but did not differ between treatment responders and non-responders. These data are among the first to examine hoarding among youth with ASD; implications of study findings and future directions are highlighted.
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12. Turner TN, Hormozdiari F, Duyzend MH, McClymont SA, Hook PW, Iossifov I, Raja A, Baker C, Hoekzema K, Stessman HA, Zody MC, Nelson BJ, Huddleston J, Sandstrom R, Smith JD, Hanna D, Swanson JM, Faustman EM, Bamshad MJ, Stamatoyannopoulos J, Nickerson DA, McCallion AS, Darnell R, Eichler EE. {{Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA}}. {Am J Hum Genet}. 2015.
We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.
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13. Yang L, Faraone SV, Zhang-James Y. {{Autism spectrum disorder traits in Slc9a9 knock-out mice}}. {Am J Med Genet B Neuropsychiatr Genet}. 2016.
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which begin in childhood and persist into adulthood. They cause lifelong impairments and are associated with substantial burdens to patients, families, and society. Genetic studies have implicated the sodium/proton exchanger (NHE) nine gene, Slc9a9, to ASDs and attention-deficit/hyperactivity disorder(ADHD). Slc9a9 encodes, NHE9, a membrane protein of the late recycling endosomes. The recycling endosome plays an important role in synapse development and plasticity by regulating the trafficking of membrane neurotransmitter receptors and transporters. Here we tested the hypothesis that Slc9a9 knock-out (KO) mice would show ADHD-like and ASD-like traits. Ultrasonic vocalization (USV) recording showed that Slc9a9 KO mice emitted fewer calls and had shorter call durations, which suggest communication impairment. Slc9a9 KO mice lacked a preference for social novelty, but did not show deficits in social approach; Slc9a9 KO mice spent more time self-grooming, an indicator for restricted and repetitive behavior. We did not observe hyperactivity or other behavior impairments which are commonly comorbid with ASDs in human, such as anxiety-like behavior. Our study is the first animal behavior study that links Slc9a9 to ASDs. By eliminatingNHE9 activity, it provides strong evidence that lack of Slc9a9leads to ASD-like behaviors in mice and provides the field with a new mouse model of ASDs. (c) 2016 Wiley Periodicals, Inc.
