1. Alcover C, Mairena MA, Mezzatesta M, Elias N, Diez-Juan M, Balana G, Gonzalez-Rodriguez M, Rodriguez-Medina J, Anguera MT, Arias-Pujol E. {{Mixed Methods Approach to Describe Social Interaction During a Group Intervention for Adolescents With Autism Spectrum Disorders}}. {Front Psychol};2019;10:1158.
Over the last 20 years, researchers have been mixing qualitative and quantitative approaches, but mixed methods research represents a new movement that arose in response to the currents of qualitative and quantitative research, considered separately. Little has been published on the use of polar coordinate analysis in psychotherapy. This type of analysis can provide detailed information and integrate the qualitative-quantitative analysis. Even less has been published on the analysis of ASD children’s behavior. The main aim of this study was to implement this mixed methods methodology to analyze patterns of social behaviors in a group of adolescents with ASD during a group social competence intervention program. Moreover, we wanted to see whether an observational scale could be combined fruitfully with polar coordinate analysis and to investigate whether typical ASD behaviors show similar interrelations (prospective and retrospective sequentialities) as behaviors observed in psychotherapy. We used an adaptation from the Social Skills Training Program (UC Davis, California). We observed that each participant took a unique course, increasing or decreasing the number and quality of their social behaviors. In accordance with previous literature, results suggest some increment in the amount of appropriate social conduct. We did not detect a generalized progress pattern but agreed that there were changes between the beginning and end of the intervention. Therefore, we consider that observational methodology is useful in the field of psychotherapy and ASD, offering detailed information about changes and development that cannot be obtained with other traditional measures, such as questionnaires.
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2. Alessandria C, Caviglia GP, Campion D, Nalbone F, Sanna C, Musso A, Abate ML, Rizzetto M, Saracco GM, Balzola F. {{HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms}}. {J Pediatr Gastroenterol Nutr};2019 (Jul);69(1):39-44.
OBJECTIVES: A correlation between autism spectrum disorders (ASDs) and gastrointestinal (GI) problems, and a possible link between gluten consumption and ASD have been increasingly reported. Gluten/casein-free diet (GCFD) is often undertaken, with conflicting results. This study aimed at evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD with GI symptoms, together with its correlation with duodenal histology and response to GCFD. METHODS: Between 2002 and 2015 all patients with ASD with GI symptoms referred to our outpatient clinic, displaying clinical, laboratory, or ultrasound findings suggestive of organic disease, underwent endoscopy, celiac disease (CD) serum antibodies testing and HLA-DQ2/DQ8 genotyping. Patients were prescribed a 6-month GCFD, and then clinically reassessed. RESULTS: Among 151 enrolled patients, 134 (89%) were negative for CD-specific antibodies; 72 (48%) were positive for HLA-DQ2/DQ8; and 56 (37%) showed duodenal microscopic inflammation. Clinical improvement was observed in non-CD patients irrespective of the rigorous or partial adherence to the diet, being the difference nonstatistically significant. Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern), but not to HLA-DQ2/DQ8 positivity (odds ratio 1.120, 95% confidence interval 0.462-2.716). CONCLUSIONS: Our data suggest that children with ASD with GI symptoms have a high prevalence of duodenal intraepithelial lymphocytic infiltration, which seems to be linked to a mechanism other than autoimmune response to gluten consumption. Alteration of duodenal histology, but not the HLA-DQ2/DQ8 status, was associated with clinical response to the diet.
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3. Gamez Corral AS, Manning R, Wang C, Cisneros A, Meeuwsen HJ, Boyle JB. {{A Novel Approach to Enhancing Upper Extremity Coordination in Children with Autism Spectrum Disorder}}. {J Mot Behav};2019 (Jun 23):1-7.
Recent studies examining children diagnosed with Autism Spectrum Disorder (ASD) have revealed kinematic markers highlighting deficits in the preparatory and online phases of upper extremity movements. In the following study, 12 children with high functioning ASD were first assessed (pre-test) on 15 trials of a reciprocal upper extremity Fitts Law target task by flexing and extending their right arm in the horizontal plane between two targets as fast and accurately as possible. Following the initial assessment, the children either continued with 30 additional trials of the target task (control) or were asked to track a sine wave template (experimental). All participants were then assessed on 15 trials of the target test (post-test). Results reveal that tracking the sine wave template during training not only produced faster movements compared to the control but also produced these movements in a more harmonic way.
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4. Green SA, Hernandez L, Lawrence KE, Liu J, Tsang T, Yeargin J, Cummings K, Laugeson E, Dapretto M, Bookheimer SY. {{Distinct Patterns of Neural Habituation and Generalization in Children and Adolescents With Autism With Low and High Sensory Overresponsivity}}. {Am J Psychiatry};2019 (Jun 24):appiajp201918121333.
OBJECTIVE: Sensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches. METHODS: Functional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined. RESULTS: Across repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure. CONCLUSIONS: The results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.
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5. Kim JY, Son MJ, Son CY, Radua J, Eisenhut M, Gressier F, Koyanagi A, Carvalho AF, Stubbs B, Solmi M, Rais TB, Lee KH, Kronbichler A, Dragioti E, Shin JI, Fusar-Poli P. {{Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence}}. {Lancet Psychiatry};2019 (Jul);6(7):590-600.
BACKGROUND: Numerous studies have identified potential risk factors and biomarkers for autism spectrum disorder. We aimed to study the strength and validity of the suggested environmental risk factors or biomarkers of autism spectrum disorder. METHODS: We did an umbrella review and systematically appraised the relevant meta-analyses of observational studies. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for papers published between database inception and Oct 17, 2018, and screened the reference list of relevant articles. We obtained the summary effect, 95% CI, heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We did analyses under credibility ceilings. This review is registered with PROSPERO, number CRD42018091704. FINDINGS: 46 eligible articles yielded data on 67 environmental risk factors (544 212 cases, 81 708 787 individuals) and 52 biomarkers (15 614 cases, 15 433 controls). Evidence of association was convincing for maternal age of 35 years or over (relative risk [RR] 1.31, 95% CI 1.18-1.45), maternal chronic hypertension (odds ratio [OR] 1.48, 1.29-1.70), maternal gestational hypertension (OR 1.37, 1.21-1.54), maternal overweight before or during pregnancy (RR 1.28, 1.19-1.36), pre-eclampsia (RR 1.32, 1.20-1.45), prepregnancy maternal antidepressant use (RR 1.48, 1.29-1.71), and maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy (OR 1.84, 1.60-2.11). Only two associations, maternal overweight before or during pregnancy and SSRI use during pregnancy, retained their high level of evidence under subset sensitivity analyses. Evidence from biomarkers was scarce, being supported by p values close to the significance threshold and too few cases. INTERPRETATION: Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders. FUNDING: None.
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6. Komeda H, Kosaka H, Fujioka T, Jung M, Okazawa H. {{Do Individuals With Autism Spectrum Disorders Help Other People With Autism Spectrum Disorders? An Investigation of Empathy and Helping Motivation in Adults With Autism Spectrum Disorder}}. {Front Psychiatry};2019;10:376.
Individuals with autism spectrum disorder (ASD) often lack cognitive empathy, so they experience difficulty in empathizing with others. Although deficits in social abilities, such as empathy, have been demonstrated in previous studies, most stimuli used in previous studies were developed for typically developing (TD) individuals. Previous studies have demonstrated that adults with and without ASD display empathetic responses toward similar others. Adults with ASD (n = 22, 7 women and 15 men, mean age = 26.8 years) and intelligence- and age-matched TD adults (n = 20, 8 women and 12 men, mean age = 24.0 years) participated in the study. They were instructed to read 24 stories (12 stories featured protagonists with characteristics of ASD, and the other 12 featured TD protagonists) and respond to the following questions: « How did the protagonist feel? » and « Would you help if the protagonist were in trouble? » After controlling for alexithymia and AQ based on multiple regression analyses, individuals with ASD empathize with other people who have ASD and are motivated to help other people with ASD. Additionally, social skills and attention to detail were associated with decreased helping motivation for story characters with ASD. Social skills among AQ subscales (social skills, attention switching, attention to detail, communication, and imagination) were the most potent predictor of decreased helping motivation. These findings suggest that the reason why individuals with ASD are considered to have limited cognitive empathy and helping motivation could be related to alexithymia and the lack of social skills and attention to detail, which are related to atypical perception.
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7. Kreilaus F, Chesworth R, Eapen V, Clarke R, Karl T. {{First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder}}. {Behav Brain Res};2019 (Jun 21):112057.
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, which shares some clinical features with Autism spectrum disorder (ASD). The genetic factors relevant to the development of both disorders are yet to be fully understood, however, some genetic association studies have identified inner mitochondrial membrane peptidase subunit 2 (IMMP2L) as a potential risk gene for both GTS and ASD. The impact of Immp2l deficiency on behavioural domains is currently unknown. A new genetic mouse model for Immp2l was developed. Adult heterozygous (HET) and homozygous (HOMO) Immp2l knockdown (Immp2l KD) mice of both sexes were compared to wild type-like (WT) littermates in the open field (OF), social interaction, novel object recognition, marble burying, and prepulse inhibition (PPI). The effect of acute dexamphetamine (2 mg/kg) on OF behaviour was also determined. OF locomotion was significantly higher in HET compared to HOMO male littermates. Male and female HOMO mice were much more sensitive to the locomotor-stimulating effects of dexamphetamine (DEX), whereas only HOMO males exhibited significant increased DEX-induced OF exploration compared to control groups. HOMO females failed to habituate to an acoustic startle stimulus. Furthermore, compared to HOMO females, HET females showed reduced social interaction, and a similar trend was seen in HET males. The Immp2l KD mouse model possesses moderate face validity for preclinical research into GTS and ASD, in particular as dysfunctional dopaminergic neurotransmission appears to be one mechanism leading to disease presentation. The sex-dependent differences observed in most findings reinforce the strong influence of sex in the pathophysiology of GTS and ASD.
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8. Lord C. {{Recognising the heterogeneity of autism}}. {Lancet Psychiatry};2019 (Jul);6(7):551-552.
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9. Lovato DV, Herai RR, Pignatari GC, Beltrao-Braga PCB. {{The Relevance of Variants With Unknown Significance for Autism Spectrum Disorder Considering the Genotype-Phenotype Interrelationship}}. {Front Psychiatry};2019;10:409.
Several efforts in basic and clinical research have been contributing to unveiling the genetics behind autism spectrum disorders (ASD). However, despite these advancements, many individuals diagnosed with ASD and related neuropsychiatric conditions have been genetically investigated without elucidative results. The enormous genetic complexity of ASD-related conditions makes it a significant challenge to achieve, with a growing number of genes (close to a thousand) involved, belonging to different molecular pathways and presenting distinct genetic variations. Next-generation sequencing (NGS) is the approach most used in genetic research related to ASD, identifying de novo mutation, which is closely related to more severe clinical phenotypes, especially when they affect constrained and loss-of-function intolerant genes. On the other hand, de novo mutation findings contribute to a small percentage of the ASD population, since most of the cases and genetic variants associated with neuropsychiatric conditions are inherited and phenotypes are results of additive polygenic models, which makes statistical efforts more difficult. As a result, NGS investigation can sound vainly or unsuccessful, and new mutations on genes already related with ASD are classified as variants of unknown significance (VUS), hampering their endorsement to a clinical phenotype. This review is focused on currently available strategies to clarify the impact of VUS and to describe the efforts to identify more pieces of evidence throughout clinical interpretation and genetic curation process.
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10. Pain O, Pocklington AJ, Holmans PA, Bray NJ, O’Brien HE, Hall LS, Pardinas AF, O’Donovan MC, Owen MJ, Anney R. {{Novel Insight Into the Etiology of Autism Spectrum Disorder Gained by Integrating Expression Data With Genome-wide Association Statistics}}. {Biol Psychiatry};2019 (May 11)
BACKGROUND: A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (ncases = 18,381, ncontrols = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). METHODS: Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression. RESULTS: This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (+/-500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability. CONCLUSIONS: This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.
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11. Spratt PWE, Ben-Shalom R, Keeshen CM, Burke KJ, Jr., Clarkson RL, Sanders SJ, Bender KJ. {{The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex}}. {Neuron};2019 (Jun 12)
Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.
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12. Terzi A, Marinis T, Zafeiri A, Francis K. {{Subject and Object Pronouns in High-Functioning Children With ASD of a Null-Subject Language}}. {Front Psychol};2019;10:1301.
Although the use of pronouns has been extensively investigated in children with autism spectrum disorders (ASD), most studies have focused on English, and no study to date has investigated the use of subject pronouns in null subject languages. The present study aims to fill this gap by investigating the use of subject and object pronouns in 5- to 8-year-old Greek-speaking high-functioning children with ASD compared to individually matched typically developing age and language controls. The « Frog where are you » (Mayer, 1969) narrative task was used to elicit subject and object pronouns as well as Determiner Phrases (DPs). Greek is a null subject language, and as a result, subject pronouns most often remain without phonological content. The findings showed that both groups used more null than overt subject pronouns, indicating that children with ASD know that Greek is a null subject language. TD children used more null subjects than subject DPs, whereas children with ASD used an equal proportion of null subjects and subject DPs. In terms of object pronouns, both groups produced more clitics and object DPs than strong object pronouns, but the difference between clitics and DPs did not reach significance in either of the groups. Importantly, the groups did not differ from each other in the use of ambiguous pronouns in both the subject and object position. The ASD children’s avoidance to use pronominal subjects can be taken as evidence that they use a strategy to avoid infelicitous reference. This would suggest that the ASD children’s difficulties with pronouns is not due to difficulties in core grammar.
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13. Wilson AC, King J, Bishop DVM. {{Autism and social anxiety in children with sex chromosome trisomies: an observational study}}. {Wellcome Open Res};2019;4:32.
Background: Recent studies suggest that an extra sex chromosome increases the risk of both autism and social anxiety, but it unclear whether these risks are specific to particular karyotypes. Methods: We considered diagnostic data from an online psychiatric assessment (DAWBA – The Development and Well-Being Assessment) and questionnaire responses completed by parents of children with 47,XXX (N = 29), 47,XXY (N = 28) and 47,XYY (N = 32) karyotypes. Analysis focused mainly on 54 children who were diagnosed prenatally or on the basis of other medical concerns in childhood (Low Bias subgroup), to minimise ascertainment bias. Results: Children with symptoms of autism who fell short of meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria were coded as cases of Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). The odds ratio of autism or PDDNOS in the Low Bias group was computed relative to gender-specific population norms. This gave log odds ratio (95% confidence interval) of 5.56 (4.25 – 6.88) for XXX girls; 4.00 (2.66 – 5.33) for XXY boys; and 4.60 (3.46 – 5.74) for XYY boys. Despite this elevated risk, most children had no autistic features. A diagnosis of DSM-IV Social Phobia was rare, though, in line with prediction, all three Low Bias cases with this diagnosis had 47,XXY karyotype. All three trisomy groups showed increased risk of milder symptoms of social anxiety. Conclusions: An increased risk of autism was found in girls with 47,XXX karyotype, as well as in boys with 47,XXY or 47,XYY. Symptoms of social anxiety were increased in all three karyotypes. There was wide variation in psychiatric status of children with the same karyotype, suggesting that an extra sex chromosome affects developmental stability in a non-specific way, with a diverse range of possible phenotypes.
