Pubmed du 05/11/19

mardi 5 novembre 2019

1. Alvarez-Jimenez C, Munera-Garzon N, Zuluaga MA, Velasco NF, Romero E. Autism Spectrum Disorder characterization in children by capturing local-regional brain changes in MRI. Med Phys ;2019 (Nov 4)

PURPOSE : To design a multiscale descriptor capable of capturing complex local-regional unfolding patterns to support quantification and diagnosis of Autism Spectrum Disorders (ASD) using T1-weighted structural magnetic resonance images (MRI) with voxel size of 1x1x1 mm. METHODS : The proposed image descriptor uses an adapted multiscale representation, the Curvelet transform, interpretable in terms of texture (local) and shape (regional) to characterize brain regions, and a Generalized Gaussian Distribution (GGD) to reduce feature dimensionality. In this approach, each MRI is first parcelled into 3D anatomical regions. Each resultant region is represented by a single 2D image where slices are placed next to each other. Each 2D image is characterized by mapping it to the Curvelet space and each of the different Curvelet sub-bands is described by the set of GGD parameters. To assess the discriminant power of the proposed descriptor, a classification model per brain region was built to differentiate ASD patients from control subjects. Models were constructed with support vector machines and evaluated using two samples from heterogeneous databases, namely Autism Brain Imaging Data Exchange - ABIDE I (34 ASD and 34 controls, mean age 11:46+/-2:03 and 11:53+/-1:79 years respectively, male population) and ABIDE II (42 ASD and 41 controls, mean age 10:09+/-1:37 and 10:52+/-1:27 years respectively, male population), for a total of 151 individuals. RESULTS : When the model was trained with ABIDE II sample and tested with ABIDE I on a hold-out validation, an area under receiver operator curve (AUC) of 0:69 was computed. When each sample was independently used under a cross-validation scheme, the estimated AUC was 0:75+/-0:02 for ABIDE I and 0:77+/-0:01 for ABIDE II. This analysis determined a set of discriminant regions widely reported in the literature as characteristic of ASD. CONCLUSIONS : The presented image descriptor demonstrated differences at local and regional level when high differences were observed in the Curvelet sub-bands. The method is simple in conceptual terms, robust to several sources of noise and has a very low computational cost.

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2. Anderson G, Betancort Medina SR. Autism Spectrum Disorders : Role of Pre- and Post-natal GammaDelta (gammadelta) T Cells and Immune Regulation. Curr Pharm Des ;2019 (Nov 2)

BACKGROUND : It is widely accepted that alterations in immune functioning are an important aspect of the pathoetiology and pathophysiology of the autism spectrum disorders (ASD). A relatively under-explored aspect of this is the role of gammaDelta (gammadelta) T cells, including prenatally and in the postnatal gut, which seem important hubs in driving the course of ASD. METHODS : The present article looks at the role of gammadelta T cells in ASD, including via their interactions with other immune cells shown to be altered in this spectrum of conditions, including natural killer cells and mast cells. RESULTS : Other risk factors in ASD, such as decreased vitamins A & D, as well as toxin-associated activation of the aryl hydrocarbon receptor may also be intimately linked to gammadelta T cells, and alterations in the regulation of these cells. A growing body of data has highlighted an important role for alterations in mitochondria functioning in the regulation of immune cells, including natural killer cells and mast cells. This is an area that requires investigation in gammadelta T cells and their putative subtypes. CONCLUSIONS : It is also proposed that maternal stress may be acting via alterations in the maternal microbiome, leading to changes in how the balance of short chain fatty acids, such as butyrate, may act to regulate the placenta and developing foetus. Following an overview of previous research on immune, especially gammadelta T cells, effects in ASD, the future research implications are then detailed.

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3. Bilinovich SM, Lewis K, Grepo N, Campbell DB. The Long Noncoding RNA RPS10P2-AS1 Is Implicated in Autism Spectrum Disorder Risk and Modulates Gene Expression in Human Neuronal Progenitor Cells. Front Genet ;2019 ;10:970.

Most of the genetic risk for autism spectrum disorder (ASD) is inherited as common genetic variants, although some rare mutations have been identified in individuals with ASD. Common genetic variants are most parsimoniously identified by genome wide association studies. Genome wide association studies have identified several genetic loci with genome wide association with ASD. However, genome wide association studies only identify regions of the genome associated with phenotypic traits. Identification of the functional elements requires additional experimental evidence. Here, we demonstrate that a genome wide association study locus for ASD on chromosome 20p12.1, rs4141463, implicates a noncoding RNA as a functional element. Although rs4141463 lies within an intron of the protein-coding MACROD2 (MACRO domain containing 2) gene, expression of MACROD2 is neither altered in postmortem temporal cortex of individuals with ASD nor correlated with rs4141463 genotype. Our bioinformatics approaches revealed a noncoding RNA transcript near the autism susceptibility signal, RPS10P2-AS1 (ribosomal protein S10 pseudogene 2 anti-sense 1). In a panel of 15 human tissues, RPS10P2-AS1 was expressed at higher levels than the protein-coding MACROD2 in both fetal temporal cortex and adult peripheral blood. In postmortem temporal cortex, expression of RPS10P2-AS1 was increased 7-fold in individuals with ASD (P = 0.02) and increased 8-fold in individuals with the ASD-associated rs4141463 genotype (P = 0.01). Further, RPS10P2-AS1 expression was increased in human neural progenitor cells exposed to model air pollutants, indicating that both genetic and environmental factors that contribute to ASD increased RPS10P2-AS1 expression. Overexpression of RPS10P2-AS1 in human neural progenitor cells indicated substantial changes in neuronal gene expression. These data indicate that genome-wide significant associations with ASD implicate long noncoding RNAs. Because long noncoding RNAs are more abundant in human brain than protein-coding RNAs, this class of molecules is likely to contribute to ASD risk.

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4. Caldani S, Steg S, Lefebvre A, Atzori P, Peyre H, Delorme R, Bucci MP. Oculomotor behavior in children with autism spectrum disorders. Autism ;2019 (Nov 2):1362361319882861.

To identify quantitative indicators of social communication dysfunctions, we explored the oculomotor performances in subjects with autism spectrum disorders. Discordant findings in the literature have been reported for oculomotor behavior in subjects with autism spectrum disorders. This study aimed to explore reflexive and voluntary saccadic performance in a group of 32 children with autism spectrum disorders (mean age : 12.1 +/- 0.5 years) compared to 32 age-, sex-, and IQ-matched typically developing children (control group). We used different types of reflexive and voluntary saccades : gap, step, overlap, and anti-saccades. Eye movements were recorded using an eye tracker (Mobile EBT((R))) and we measured latency, percentage of anticipatory and express saccades, errors of anti-saccades and gain. Children with autism spectrum disorders reported similar latency values with respect to typically developing children for reflexive and voluntary saccades ; in contrast, they made more express and anticipatory saccades overall, as shown in paradigm testing (gap, step, overlap, and anti-saccades). Our findings support previous evidence of the atypicality of the cortical network, which is involved in saccade triggering and attentional processes in children with autism spectrum disorders.

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5. Chang MY, Gandhi N, O’Hara M. Ophthalmologic disorders and risk factors in children with autism spectrum disorder. J AAPOS ;2019 (Oct 29)

PURPOSE : To report the results of our review of all children with autism spectrum disorder (ASD) who underwent complete pediatric ophthalmologic examination at our institution over a 10-year period. METHODS : The medical records of all children (0-17 years of age) with a diagnosis of ASD seen at University of California, Davis, over a 10-year period were reviewed retrospectively. Demographic data, birth history, genetic testing results, neuropsychiatric comorbidities, and ophthalmologic findings were extracted from the record. Multiple logistic regression was used to identify risk factors for ophthalmologic disorders. RESULTS : A total of 2,555 children with ASD were seen at the university over the study period, of whom 380 (15%) were evaluated in the ophthalmology clinic. Eye examination revealed an ophthalmic diagnosis in 71% of children, of which the most common were significant refractive error (42%), strabismus (32%), and amblyopia (19%). Optic neuropathy occurred in 14 children (4%). Cerebral palsy was a significant risk factor for refractive error (OR = 3.22 ; P = 0.016), strabismus (OR = 3.59 ; P = 0.012), amblyopia (OR = 3.49 ; P = 0.0097), and optic neuropathy (OR = 14.0 ; P = 0.0009). CONCLUSIONS : Ophthalmic disorders were found in 71% of children with ASD evaluated at our university-based ophthalmology clinic. The rates of significant refractive error, strabismus, amblyopia, and optic neuropathy exceeded those of the general pediatric population. ASD and cerebral palsy may have additive risk for these disorders.

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6. Cheng K, Chen YS, Yue CX, Zhang SM, Pei YP, Cheng GR, Liu D, Xu L, Dong HX, Zeng Y. Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome. Front Neurosci ;2019 ;13:1098.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability, as well as the leading monogenic cause of autism spectrum disorders (ASD), in which neurons show aberrant dendritic spine structure. The reduction/absence of the functional FMRP protein, coded by the X-linked Fmr1 gene in humans, is responsible for the syndrome. Targets of FMRP, CLSTN1, and ICAM5, play critical roles in the maturation of dendritic spines, synapse formation and synaptic plasticity. However, the implication of CLSTN1 and ICAM5 in dendritic spine abnormalities and the underlying neuropathologic processes in FXS remain uninvestigated. In this study, we demonstrated that CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. Also we showed that shRNA-mediated downregulation of CLSTN1 in cultured WT neurons increases ICAM5 on the surface of synaptic membrane, subsequently affecting the maturation of dendritic spines. Whereas, normalization of CLSTN1 level in Fmr1 KO neurons reduces ICAM5 abundance and rescues impaired dendritic spine phenotypes. Most importantly, CLSTN1 protein is reduced in the postnatal medial prefrontal cortex of Fmr1 KO mice, which is correlated with increased ICAM5 levels on the surface of synapses and excessive filopodia-like spines. In conclusion, this study demonstrates that CLSTN1 plays a critical role in dendritic spine formation and maturation in FXS by regulating ICAM5 redistribution.

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7. Corley MJ, Vargas-Maya N, Pang APS, Lum-Jones A, Li D, Khadka V, Sultana R, Blanchard DC, Maunakea AK. Epigenetic Delay in the Neurodevelopmental Trajectory of DNA Methylation States in Autism Spectrum Disorders. Front Genet ;2019 ;10:907.

Autism spectrum disorders (ASD) are hypothesized to originate in utero from perturbations in neural stem cell niche regions of the developing brain. Dynamic epigenetic processes including DNA methylation are integral to coordinating typical brain development. However, the extent and consequences of alterations to DNA methylation states in neural stem cell compartments in ASD are unknown. Here, we report significant DNA methylation defects in the subventricular zone of the lateral ventricles from postmortem brain of 17 autism diagnosed compared to 17 age- and gender-matched typically developing individuals. Both array- and sequencing-based genome-wide methylome analyses independently revealed that these alterations were preferentially targeted to intragenic and bivalently modified chromatin domains of genes predominately involved in neurodevelopment, which associated with aberrant precursor messenger RNA splicing events of ASD-relevant genes. Integrative analysis of our ASD and typically developing postmortem brain methylome datasets with that from fetal brain at different neurodevelopmental stages revealed that the methylation states of differentially methylated loci associated with ASD remarkably resemble the methylation states at earlier time points in fetal brain development. This observation was confirmed using additional methylome datasets from three other brain regions. Altogether, these findings implicate an epigenetic delay in the trajectory of normal DNA methylation states during the course of brain development that may consequently lead to deleterious transcriptomic events in ASD and support the hypothesis of an early developmental origin of ASD.

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8. Felgerolle C, Hebert B, Ardourel M, Meyer-Dilhet G, Menuet A, Pinto-Morais K, Bizot JC, Pichon J, Briault S, Perche O. Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome. Front Behav Neurosci ;2019 ;13:228.

Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability (ID) associated with autistic-like behaviors, is characterized by dys-sensitivity to sensory stimuli, especially vision. In the absence of Fragile Mental Retardation Protein (FMRP), both retinal and cerebral structures of the visual pathway are impaired, suggesting that perception and integration of visual stimuli are altered. However, behavioral consequences of these defects remain unknown. In this study, we used male Fmr1 (-/y) mice to further define visual disturbances from a behavioral perspective by focusing on three traits characterizing visual modality : perception of depth, contrasts and movements. We performed specific tests (Optomotor Drum, Visual Cliff) to evaluate these visual modalities, their evolution from youth to adulthood, and to assess their involvement in a cognitive task. We show that Fmr1 (-/y) mice exhibit alteration in their visual skills, displaying impaired perspective perception, a drop in their ability to understand a moving contrasted pattern, and a defect in contrasts discrimination. Interestingly, Fmr1 (-/y) phenotypes remain stable over time from adolescence to late adulthood. Besides, we report that color and shape are meaningful for the achievement of a cognitive test involving object recognition. Altogether, these results underline the significance of visual behavior alterations in FXS conditions and relevance of assessing visual skills in neuropsychiatric models before performing behavioral tasks, such as cognitive assessments, that involve visual discrimination.

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9. Hogeveen J, Krug MK, Geddert RM, Ragland JD, Solomon M. Compensatory Hippocampal Recruitment Supports Preserved Episodic Memory in Autism Spectrum Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging ;2019 (Sep 5)

BACKGROUND : The degree to which individuals with autism spectrum disorder (ASD) evidence impairments in episodic memory relative to their typically developing (TD) counterparts remains unclear. According to a prominent view, ASD is associated with deficits in encoding associations between items and recollecting precise context details. Here, we evaluated behavioral and neural evidence for this impaired relational binding hypothesis using a task involving relational encoding and recollection during functional magnetic resonance imaging. METHODS : Adolescents and young adults (nASD = 47, nTD = 60) performed the Relational and Item-Specific Encoding task during functional magnetic resonance imaging, including item and associative recognition testing. We modeled functional recruitment within the medial temporal lobes (MTLs), and connectivity between MTL and the posterior medial (PM) network thought to underlie relational memory. The impaired relational binding model would predict a behavioral deficit driven by aberrant recruitment and connectivity of MTL and the PM network. RESULTS : The ASD and TD groups showed indistinguishable item and associative recognition performance. During relational encoding, the ASD group demonstrated increased hippocampal recruitment, and decreased connectivity between MTL and PM regions relative to the TD group. Within ASD, hippocampal recruitment and MTL-PM connectivity were inversely correlated. CONCLUSIONS : The lack of a behavioral deficit in ASD does not support the impaired relational binding hypothesis. Instead, the current data suggest that increased recruitment of the hippocampus compensates for decreased MTL-PM connectivity to support preserved episodic memory in ASD. These findings suggest a compensatory neurodevelopmental mechanism that may support preserved cognitive domains in ASD : local hyperrecruitment may offset connectivity aberrations in individuals with ASD relative to TD subjects.

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10. Itoi C, Kato N, Kashino M. People with autism perceive drastic illusory changes for repeated verbal stimuli. Sci Rep ;2019 (Nov 1) ;9(1):15866.

A core symptom of autism spectrum disorder (ASD) is restricted and repetitive behavior, characterized partly by insistence on sameness and excessively focused interest. This behavior has often been interpreted as a manifestation of anxiety and fear triggered by resistance to change. The implicit assumption underlying this interpretation is that perception per se (such as the judgment of sameness and changes in sensory stimuli) is not different between ASD and typically developed (TD) individuals, but that only the emotional response to the same amount of perceived change is. However, few studies have examined how individuals with ASD actually perceive a repeated presentation of the same sensory stimulus. To explore this issue, we conducted a listening test to compare perception of a repeated sound pattern, namely a spoken word, between ASD and TD groups. Prolonged listening to a repeated word without a pause may induce perceptual changes, which is known as the verbal transformation effect. We discovered that individuals with ASD tend to perceive more drastic changes or differences for the same repeated auditory pattern. This suggests that such variable perception incites individuals with ASD to persist for sameness.

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11. Krombach T, Miltenberger R. The Effects of Stability Ball Seating on the Behavior of Children with Autism During Instructional Activities. J Autism Dev Disord ;2019 (Nov 1)

Children with ASD often display behavior problems that can lead to academic and social disruptions. This has led to the introduction of stability balls as an alternative seating method for children, both on the autism spectrum and with other needs. This study used a multiple baseline design and duration data to evaluate the effects of stability ball seating on attending and in-seat behavior for children with ASD who received ABA therapy in their homes. The intervention replaced their standard seating method with a stability ball. In the final phase participants chose their own seating method before beginning table work to assess preference. Following intervention the stability ball was found to increase both attending and in-seat durations for children with ASD.

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Currently, autism spectrum disorder (ASD) is mainly diagnosed by the observation of core behavioral symptoms. Consequently, the window of opportunity for effective intervention may have passed, when the disorder is detected until 3 years of age. Thus, it is of great importance to identify imaging-based biomarkers for early diagnosis of ASD. Previous findings indicate that an abnormal pattern of the amygdala and hippocampal development in autism persists through childhood and adolescence. However, due to the low tissue contrast and small structural size of amygdala and hippocampal subfields, our knowledge on their growth in autistics in early stage still remains very limited. In this paper, for the first time, we propose a volume-based analysis of the amygdala and hippocampal subfields of the infant subjects with risk of ASD at around 24 months of age. Specifically, to address the challenge of low tissue contrast, we propose a novel deep-learning approach, i.e., dilated-dense U-Net, to automatically segment the amygdala and hippocampal subfields. Experimental results on National Database for Autism Research (NDAR) show the advantages of our proposed method in terms of segmentation accuracy. Our volume-based analysis shows the overgrowths of amygdala and CA1-3 of hippocampus, which may link to the emergence of autism spectrum disorder.

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13. Maes M, Anderson G, Betancort Medina SR, Seo M, Ojala JO. Integrating Autism Spectrum Disorder Pathophysiology : Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut. Curr Pharm Des ;2019 (Nov 2)

BACKGROUND : A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. METHODS : Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. RESULTS : Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia as well as more general prenatal stressors modulate the likelihood of offspring ASD. CONCLUSION : Such an integrated model of the pathophysiology of ASD has important preventative and treatment implications.

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14. Mandic-Maravic V, Mitkovic-Voncina M, Pljesa-Ercegovac M, Savic-Radojevic A, Djordjevic M, Pekmezovic T, Grujicic R, Ercegovac M, Simic T, Lecic-Tosevski D, Pejovic-Milovancevic M. Autism Spectrum Disorders and Perinatal Complications-Is Oxidative Stress the Connection ?. Front Psychiatry ;2019 ;10:675.

Background : Autism spectrum disorders (ASD) are complex psychiatric disorders, with gene environment interaction being in the basis of their etiology. The association of perinatal complications and ASD is well established. Recent findings suggested that oxidative stress and polymorphism in genes encoding antioxidant enzymes might be involved in the development of ASD. Glutathione transferases (GSTs) have an important role in the antioxidant defense system. We aimed to establish whether the predictive effects of prenatal and perinatal complications (as possible oxidative stress inducers) on ASD risk are dependent on GST polymorphisms. Methods : The study included 113 ASD cases and 114 age- and sex group-matched healthy controls. All participants were genotyped for GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms. The questionnaire regarding prenatal and perinatal risk factors and complications was administered for all the subjects in the study. Results : The evaluated perinatal complications as a group significantly increased the risk of ASD [odds ratio (OR) = 9.415 ; p = 0.000], as well as individual perinatal complications, such as prematurity (OR = 11.42 ; p = 0.001), neonatal jaundice (OR = 8.774 ; p = 0.000), respiratory distress syndrome (OR = 4.835 ; p = 0.047), and the use of any medication during pregnancy (OR = 2.413 ; p = 0.03). In logistic regression model, adding GST genotypes did not modify the significant effects found for prematurity and neonatal jaundice as risk factors in ASD. However, there was a significant interaction of GST genotype with medication use during pregnancy and the use of tocolytics during pregnancy, which was predictive of ASD risk only in carriers of GSTM1-null, as opposed to carriers of GSTM1-active genotype. Conclusion : Specific perinatal complications may be significant risk factors for ASD. GSTM1 genotype may serve as a moderator of the effect of some prenatal factors on the risk of ASD such as using medication during pregnancy. It may be speculated that different oxidative stress-related genetic and environmental factors could lead to development of ASD. Apart from etiological mechanisms, possible therapeutic implications in ASD are also discussed.

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15. Meir N, Novogrodsky R. Prerequisites of Third-Person Pronoun Use in Monolingual and Bilingual Children With Autism and Typical Language Development. Front Psychol ;2019 ;10:2289.

The current study investigated the production of third-person subject and object pronouns in monolingual and bilingual children with High Functioning Autism (HFA) and typical language development (TLD). Furthermore, it evaluated the underlying linguistic and non-linguistic prerequisites of pronoun use, by assessing the role of morpho-syntactic skills, Theory of Mind (ToM) abilities, working memory and inhibition on pronoun use. A total of 85 children aged 4 to 9 years participated in four groups : 27 children with HFA [14 monolingual (monoHFA) and 13 bilingual (biHFA)], and 58 children with TLD [28 monolingual (monoTLD) and 30 bilingual (biTLD)]. All children spoke Hebrew and the bilingual children spoke Russian as their Heritage Language. Third-person subject and object pronouns were elicited in Hebrew. The results yielded no effect of bilingualism, and a robust effect of HFA on the use of pronouns. Bilingual Russian-Hebrew speaking children paired up with their monolingual Hebrew-speaking peers in pronominal use in Hebrew. Monolingual and bilingual children with TLD showed nearly ceiling performance on pronoun use. The facilitative effect of pronominal acquisition in Hebrew among bilingual children was attributed to similarities in the pronominal systems of the two languages of bilingual children. Age was found to be a predictive factor of pronoun use in children with TLD. Conversely, children with HFA had a lower rate of pronoun production compared to the TLD groups. Both third-person subject and object pronouns were largely predicted by morpho-syntactic abilities of children with HFA. In addition, subject pronoun use was predicted by ToM skills and working memory confirming that pronoun use is a complex phenomenon, which requires integration of multiple linguistic and non-linguistic components. To conclude, our findings suggest that morpho-syntactic development is a prerequisite for third-person subject and object pronoun use in children with HFA, and ToM and working memory are involved in third-person subject pronoun use. In addition, we show that pronoun use is not compromised by dual language exposure in children with TLD and with HFA.

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16. Mohammadi F, Rakhshan M, Molazem Z, Zareh N, Gillespie M. Parents’ Perspectives on Family Violence against Children with Autism. Arch Iran Med ;2019 (Sep 1) ;22(9):505-510.

BACKGROUND : Children are among the most susceptible groups of family violence and this is an important and worrying issue all over the world. Children with disabilities are more vulnerable to family violence. Children with autism are exposed to various types of violence due to their wide range of disabilities, as well as high tensions that are imposed on their families. Family violence against children with autism has not been studied in Iran, therefore, this study was conducted to explain the concept of family violence against children with autism from the perspectives of parents in Iran. METHODS : This is a qualitative research study. Data were gathered using individual and semi-structured interviews. Eighteen parents of autistic children were selected using purposeful sampling. Qualitative content analysis was used to analyze and interpret the data. RESULTS : Four themes for family violence were defined with 9 sub-categories including physical violence, emotional violence, verbal violence and Sexual violence. CONCLUSION : Based on the findings of the present study from the perspective of parents, autistic children need to be cared and educated in a safe environment where they are free from any kind of violence. Their privacy and individual identities are respected, and they are provided with the required treatment and education. These conditions would maintain the dignity of such children and consequently result in appropriate behavioral outcomes. Therefore, it is suggested that a culturally sound, and stable background be provided, which when supported by professional caregivers, will ensure that the rights of autistic children are protected and emphasized.

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17. Mohammadi MR, Ahmadi N, Khaleghi A, Zarafshan H, Mostafavi SA, Kamali K, Rahgozar M, Ahmadi A, Hooshyari Z, Alavi SS, Shakiba A, Salmanian M, Molavi P, Sarraf N, Hojjat SK, Mohammadzadeh S, Amiri S, Arman S, Ghanizadeh A. Prevalence of Autism and its Comorbidities and the Relationship with Maternal Psychopathology : A National Population-Based Study. Arch Iran Med ;2019 (Oct 1) ;22(10):546-553.

BACKGROUND : There is no clear picture regarding the prevalence rates of autism and its comorbidities among Iranian children and adolescents. The present study aimed to estimate these rates as part of a large national population-based study on epidemiology of psychiatric disorders in Iranian children and adolescents. METHODS : The total sample consisted of 31000 children and adolescents between 6 to 18 years of age. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Present and Life time version (K-SADS-PL) was used as the diagnostic tool. RESULTS : The prevalence of autism in the total sample is equal to 0.1% (10 per 10000), with a 2:1 male-to-female ratio. In total, 86% of people with autism had at least one comorbid condition. Intellectual disability, epilepsy, enuresis and attention deficit and hyperactivity disorder (ADHD) with prevalence rates of 70.3%, 29.7%, 27% and 21.62%, respectively, were the most prevalent comorbid conditions in people with autism. Maternal personality disorders were also shown to be associated with increasing risk of autism. CONCLUSION : The present study shows high prevalence rates for autism and its comorbid conditions among Iranian children and adolescents. It also reveals that there is a relationship between some maternal psychiatric disorders and the risk of autism.

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18. O’Nions E, Ceulemans E, Happe F, Benson P, Evers K, Noens I. Parenting Strategies Used by Parents of Children with ASD : Differential Links with Child Problem Behaviour. J Autism Dev Disord ;2019 (Nov 1)

Here, we explored the structure of the ’Parenting Strategies Questionnaire’, a new scale designed to measure parenting strategies for problem behaviour in ASD. We then examined links between child behaviour and parenting in a sample of 222 predominantly-UK parents of ASD children exhibiting behaviour found difficult or challenging. Analysis revealed three parenting subscales : Accommodation, Reinforcement Approaches and Reducing Uncertainty. Both Accommodation and Reducing Uncertainty were linked to child problem behaviour. Child factors explained up to 29% of the variance in Accommodation, with Socially Inflexible Non-compliance the strongest predictor, and up to 24% of the variance in Reducing Uncertainty, with Intolerance of Uncertainty the strongest predictor. Child factors were not related to Reinforcement Approaches. Longitudinal studies investigating these relationships are needed.

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19. Pinato L, Galina Spilla CS, Markus RP, Cruz-Machado SDS. Dysregulation of circadian rhythms in autism spectrum disorders. Curr Pharm Des ;2019 (Nov 2)

BACKGROUND : The alterations in neurological and neuroendocrine functions observed in the autism spectrum disorder (ASD) involves environmentally dependent dysregulation of neurodevelopment, in interaction with multiple coding gene defects. Disturbed sleep-wake patterns, as well as abnormal melatonin and glucocorticoid secretion, show the relevance of an underlying impairment of the circadian timing system to the behavioral phenotype of ASD. Thus, understanding the mechanisms involved in the circadian dysregulation in ASD could help to identify early biomarkers to improve the diagnosis and therapeutics as well as providing a significant impact on the lifelong prognosis. OBJECTIVE : In this review, we discuss the organization of the circadian timing system and explore the connection between neuroanatomic, molecular and neuroendocrine responses of ASD and its clinical manifestations. Here we propose interconnections between circadian dysregulation, inflammatory baseline and behavioral changes in ASD. Taking into account the high relevancy of melatonin in orchestrating both circadian timing and the maintenance of physiological immune quiescence, we raise the hypothesis that melatonin or analogs should be considered as a pharmacological approach to supress inflammation and circadian misalignment in ASD patients. STRATEGY : This review provides a comprehensive update on the state-of-art of studies relating to inflammatory states and ASD with a special focus on the relationship with melatonin and clock genes. The hypothesis raised above was analyzed according to published data. CONCLUSION : Current evidence supports the existence of associations between ASD to circadian dysregulation, behavior problems, increased inflammatory levels of cytokines, sleep disorders, as well as reduced circadian neuroendocrine responses. Indeed, major effects may be related to a low melatonin rhythm. We propose that maintaining the proper rhythm of the circadian timing system may be helpful to improve the health and to cope with several behavioral changes observed in ASD subjects.

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20. Poon VWK, Shu DST, Chan RWS, Leung CNW, Leung PWL. Comparing the Psychometric Properties of the Self- and Parent-Report Versions of Autism-Spectrum Quotient-Adult in Hong Kong (AQ-Adult-HK). J Autism Dev Disord ;2019 (Nov 1)

The Autism-Spectrum Quotient-Adult (AQ-Adult) is a screening tool for adults with autism spectrum disorder (ASD). The present study examined the psychometric properties of the Chinese self- and parent-report versions of the AQ-Adult in Hong Kong (AQ-Adult-HK). Participants included adults with ASD (n = 27) and community controls (n = 345). Parents of a subset of adults with ASD (n = 21) and controls (n = 87) also participated as informants. The parent-report version showed significantly stronger psychometric properties, including a larger area under receiver operating characteristic curve (AUC) and higher sensitivity/specificity, than those of the self-report version. The stronger psychometric properties of the former were related to its significantly higher ratings of ASD symptoms in the ASD adults.

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21. Salloum-Asfar S, Satheesh NJ, Abdulla SA. Circulating miRNAs, Small but Promising Biomarkers for Autism Spectrum Disorder. Front Mol Neurosci ;2019 ;12:253.

Autism spectrum disorder (ASD) refers to a heterogeneous group of complex neurodevelopmental disorders characterized by social skill and communication deficits, along with stereotyped repetitive behavior. miRNAs, small non-coding RNAs that have been recognized as critical regulators of gene expression, play a key role in the neurodevelopmental transcriptional networks of the human brain. Previous investigations have proven that circulating miRNAs open up new possibilities for the emerging roles of diagnostic and prognostic biomarkers in human disorders and diseases. Biomarker development has been progressively becoming more recognized as a cornerstone in medical diagnosis, paving the way to drug discoveries and limiting the progression of various diseases. Due to the complexity of ASD, considerable endeavors have either unsuccessfully identified biomarkers for the disorder or have not yet been established. Cell-free circulating miRNAs in biofluids are extraordinarily stable and considered to represent the next-generation of clinical, non-invasive, biomarkers for many pathologies including neurological and neurodevelopmental disorders. Here, we conducted a review of all peer-reviewed articles addressing the circulating profiles of miRNAs, mostly performed in serum and saliva samples in individuals with ASD.

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22. Sato W, Kochiyama T, Uono S, Yoshimura S, Kubota Y, Sawada R, Sakihama M, Toichi M. Atypical Amygdala-Neocortex Interaction During Dynamic Facial Expression Processing in Autism Spectrum Disorder. Front Hum Neurosci ;2019 ;13:351.

Atypical reciprocal social interactions involving emotional facial expressions are a core clinical feature of autism spectrum disorder (ASD). Previous functional magnetic resonance imaging (fMRI) studies have demonstrated that some social brain regions, including subcortical (e.g., amygdala) and neocortical regions (e.g., fusiform gyrus, FG) are less activated during the processing of facial expression stimuli in individuals with ASD. However, the functional networking patterns between the subcortical and cortical regions in processing emotional facial expressions remain unclear. We investigated this issue in ASD (n = 31) and typically developing (TD ; n = 31) individuals using fMRI. Participants viewed dynamic facial expressions of anger and happiness and their corresponding mosaic images. Regional brain activity analysis revealed reduced activation of several social brain regions, including the amygdala, in the ASD group compared with the TD group in response to dynamic facial expressions vs. dynamic mosaics (p < 0.05, eta p 2 = 0.19). Dynamic causal modeling (DCM) analyses were then used to compare models with forward, backward, and bi-directional effective connectivity between the amygdala and neocortical networks. The results revealed that : (1) the model with effective connectivity from the amygdala to the neocortex best fit the data of both groups ; and (2) the same model best accounted for group differences. Coupling parameter (i.e., effective connectivity) analyses showed that the modulatory effects of dynamic facial processing were substantially weaker in the ASD group than in the TD group. These findings suggest that atypical modulation from the amygdala to the neocortex underlies impairment in social interaction involving dynamic facial expressions in individuals with ASD.

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23. Shiri E, Pouretemad H, Fathabadi J, Narimani M. A pilot study of family-based management of behavioral excesses in young Iranian children with autism spectrum disorder. Asian J Psychiatr ;2019 (Oct 16) ;47:101845.

OBJECTIVE : Parent-mediated early behavioral interventions are considered as effective approaches in the treatment of children with Autism Spectrum Disorder (ASD). The majority of these interventions focus on social-communication deficits rather than behavioral excesses which severely irrupt child and family social life as well as the child’s appearance behavior and learning processes. The study examines the effectiveness and feasibility of Family-based Management of Behavioral Excesses of Autism Program (FMBEAP) on Iranian families. METHOD : This pre-post and follow-up intervention study involved 17 parents of children with DSM-5 diagnosis of ASD recruited from Tehran Autism Center. All parents conducted FMBEAP on their children while receiving 10-weekly group supervision on top of everyday on-line individual coaching. The study’s measures were Repetitive Behavior Scale-R, video-monitoring of child-parent Interaction, Clinical Global Impression-Improvement Scale, Parental Self-Efficacy and Parenting Stress Index-short form. The measures were applied to the sample three times : pre and post-intervention and at one-month follow-up. RESULTS : The Results showed high and low order behavioral excesses significantly decreased at post-intervention and the follow-up. 15 out of 17 children reached to recovered or highly recovered at post-test. Parents showed significant improvements in self-efficacy and parenting stress scales. The intervention was highly accepted by them. CONCLUSION : FMBEAP is shown to be a feasible, acceptable and effective intervention to improve autistic behavioral. The parents should also benefit from the program in terms of self-efficacy and parenting stress. FMBEAP is highly recommended for overcoming behavioral excesses along with those interventions focus on behavioral deficits in ASD.

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24. Telias M. Pharmacological treatments for fragile X syndrome based on synaptic dysfunction. Curr Pharm Des ;2019 (Nov 2)

BACKGROUND : Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment, including intellectual disability, autism, hyperactivity and epilepsy. METHODS : This article reviews the literature pertaining to the role of synaptic dysfunction in FXS. RESULTS : In FXS, synaptic dysfunction alters the excitation-inhibition ratio, dysregulating molecular and cellular processes underlying cognition, learning, memory and social behavior. Decades of research have yielded important hypotheses that could explain, at least in part, the development of these neurological disorders in FXS patients. However, the main goal of translating lab research in animal models to pharmacological treatments in the clinic, has been so far largely unsuccessful, leaving FXS a still uncurable disease. CONCLUSION : In this concise review, we summarize and analyze the main hypotheses proposed to explain synaptic dysregulation in FXS, by reviewing the scientific evidence that led to pharmaceutical clinical trials and their outcome.

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25. Vivanti G. Ask the Editor : What is the Most Appropriate Way to Talk About Individuals with a Diagnosis of Autism ?. J Autism Dev Disord ;2019 (Nov 1)

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26. Yook C, Kim K, Kim D, Kang H, Kim SG, Kim E, Kim SY. A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice. Front Mol Neurosci ;2019 ;12:241.

Mutations in Tbr1, a high-confidence ASD (autism spectrum disorder)-risk gene encoding the transcriptional regulator TBR1, have been shown to induce diverse ASD-related molecular, synaptic, neuronal, and behavioral dysfunctions in mice. However, whether Tbr1 mutations derived from autistic individuals cause similar dysfunctions in mice remains unclear. Here we generated and characterized mice carrying the TBR1-K228E de novo mutation identified in human ASD and identified various ASD-related phenotypes. In heterozygous mice carrying this mutation (Tbr1 (+/K228E) mice), levels of the TBR1-K228E protein, which is unable to bind target DNA, were strongly increased. RNA-Seq analysis of the Tbr1 (+/K228E) embryonic brain indicated significant changes in the expression of genes associated with neurons, astrocytes, ribosomes, neuronal synapses, and ASD risk. The Tbr1 (+/K228E) neocortex also displayed an abnormal distribution of parvalbumin-positive interneurons, with a lower density in superficial layers but a higher density in deep layers. These changes were associated with an increase in inhibitory synaptic transmission in layer 6 pyramidal neurons that was resistant to compensation by network activity. Behaviorally, Tbr1 (+/K228E) mice showed decreased social interaction, increased self-grooming, and modestly increased anxiety-like behaviors. These results suggest that the human heterozygous TBR1-K228E mutation induces ASD-related transcriptomic, protein, neuronal, synaptic, and behavioral dysfunctions in mice.

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