Pubmed du 27/08/19

mardi 27 août 2019

1. Alonso-Gonzalez A, Calaza M, Rodriguez-Fontenla C, Carracedo A. Novel Gene-Based Analysis of ASD GWAS : Insight Into the Biological Role of Associated Genes. Front Genet ;2019 ;10:733.

Background : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by its significant social impact and high heritability. The latest meta-analysis of ASD GWAS (genome-wide association studies) has revealed the association of several SNPs that were replicated in additional sets of independent samples. However, summary statistics from GWAS can be used to perform a gene-based analysis (GBA). GBA allows to combine all genetic information across the gene to create a single statistic (p-value for each gene). Thus, PASCAL (Pathway scoring algorithm), a novel GBA tool, has been applied to the summary statistics from the latest meta-analysis of ASD. GBA approach (testing the gene as a unit) provides an advantage to perform an accurate insight into the biological ASD mechanisms. Therefore, a gene-network analysis and an enrichment analysis for KEGG and GO terms were carried out. GENE2FUNC was used to create gene expression heatmaps and to carry out differential expression analysis (DEA) across GTEx v7 tissues and Brainspan data. dbMDEGA was employed to perform a DEG analysis between ASD and brain control samples for the associated genes and interactors. Results : PASCAL has identified the following loci associated with ASD : XRN2, NKX2-4, PLK1S1, KCNN2, NKX2-2, CRHR1-IT1, C8orf74 and LOC644172. While some of these genes were previously reported by MAGMA (XRN2, PLK1S1, and KCNN2), PASCAL has been useful to highlight additional genes. The biological characterization of the ASD-associated genes and their interactors have demonstrated the association of several GO and KEGG terms. Moreover, DEA analysis has revealed several up- and down-regulated clusters. In addition, many of the ASD-associated genes and their interactors have shown association with ASD expression datasets. Conclusions : This study identifies several associations at a gene level in ASD. Most of them were previously reported by MAGMA. This fact proves that PASCAL is an efficient GBA tool to extract additional information from previous GWAS. In addition, this study has characterized for the first time the biological role of the ASD-associated genes across brain regions, neurodevelopmental stages, and ASD gene-expression datasets.

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2. Bhat AN, McDonald NM, Eilbott JE, Pelphrey KA. Exploring cortical activation and connectivity in infants with and without familial risk for autism during naturalistic social interactions : A preliminary study. Infant Behav Dev ;2019 (Aug 23) ;57:101337.

Behavioral signs of Autism Spectrum Disorder (ASD) are typically observable by the second year of life and a reliable diagnosis of ASD is possible by 2 to 3 years of age. Studying infants with familial risk for ASD allows for the investigation of early signs of ASD risk within the first year. Brain abnormalities such as hyper-connectivity within the first year may precede the overt signs of ASD that emerge later in life. In this preliminary study, we use functional near-infrared spectroscopy (fNIRS), an infant-friendly neuroimaging tool that is relatively robust against motion artifacts, to examine functional activation and connectivity during naturalistic social interactions in 9 high-risk (HR ; older sibling with ASD) and 6 low-risk (LR ; no family history of ASD) infants from 6 to 9 months of age. We obtained two 30-second baseline periods and a 5-minute social interaction period. HR infants showed reduced right and left-hemispheric activation compared to LR infants based on oxy (HbO2) and deoxy (HHb) signal trends. HR infants also had greater functional connectivity than LR infants during the pre- and post-social periods and showed a drop in connectivity during the social period. Our findings are consistent with previous work suggesting early differences in cortical activation associated with familial risk for ASD, and highlight the promise of fNIRS in evaluating potential markers of ASD risk during naturalistic social contexts.

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3. Carpita B, Marazziti D, Palego L, Giannaccini G, Betti L, Dell’Osso L. Microbiota, Immune System and Autism Spectrum Disorders. An Integrative Model towards Novel Treatment Options. Curr Med Chem ;2019 (Mar 28)

BACKGROUND : Autism spectrum disorder (ASD) is a condition strongly associated with genetic predisposition and familial aggregation. Among ASD patients different levels of symptoms severity are detectable, while the presence of intermediate autism phenotypes in close relatives of ASD probands is also known in literature. Recently, increasing attention has been paid to environmental factors that might play a role in modulating the relationship between genomic risk and development and severity of ASD. Within this framework, an increasing body of evidence has stressed a possible role of both gut microbiota and inflammation in the pathophysiology of neurodevelopment. The aim of this paper is to review findings about the link between microbiota dysbiosis, inflammation and ASD. METHODS : articles ranging from 1990 to 2018 were identified on PUBMED and Google Scholar databases, with keyword combinations as : microbiota, immune system, inflammation, ASD, autism, broad autism phenotype, adult. RESULTS : recent evidence suggests that microbiota alterations, immune system and neurodevelopment may be deeply intertwined, shaping each other during early life. However, results from both animal models and human samples are still heterogeneous, while few studies focused on adult patients and ASD intermediate phenotypes. CONCLUSION : A better understanding of these pathways, within an integrative framework between central and peripheral systems, might not only shed more light on neural basis of ASD symptoms, clarifying brain pathophysiology, but it may also allow to develop new therapeutic strategies for these disorders, still poorly responsive to available treatments.

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4. Cerga-Pashoja A, Gaete J, Shishkova A, Jordanova V. Improving Reading in Adolescents and Adults With High-Functioning Autism Through an Assistive Technology Tool : A Cross-Over Multinational Study. Front Psychiatry ;2019 ;10:546.

People with autism spectrum disorder (ASD) experience reading comprehension difficulties, often misinterpreting complex texts, metaphors, and idioms. We have developed and tested a new assistive technology tool for adaptive, personalized text simplification, called Open Book. This tool is an open-sourced, online platform that uses Natural Language Processing with the specific aim of assisting reading and aiding understanding of written text for people with ASD. The accessibility and effectiveness of Open Book was tested by examining the differences in text comprehension scores between the original texts and texts that were simplified by Open Book tool, randomly allocated to study participants. Two hundred forty-three participants (153 adults and 90 adolescents) with high-functioning ASD were recruited in the UK, Spain, and Bulgaria. Regarding the primary outcome, results showed that both adults and adolescents with ASD gave more correct answers for the simplified (M = 11.2, SD = 4.1) than original texts (M = 10, SD = 4.1 ; p < 0.001). This finding was consistent across age groups and countries. Regarding the secondary outcome, when participants were asked to blindly rate how easy was to understand each text, simplified texts were rated as easier (M = 7.6, SD = 2.4) to understand than the original texts (M = 8.7, SD = 2.6 ; p < 0.001). The Open Book software seems to have the potential to be a useful tool in assisting reading among people with ASD. Our findings support our primary hypothesis that texts simplified through Open Book were easier to comprehend compared to original texts.

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5. Corbett BA, Muscatello RA, Tanguturi Y, McGinn E, Ioannou S. Pubertal Development Measurement in Children With and Without Autism Spectrum Disorder : A Comparison Between Physical Exam, Parent- and Self-Report. J Autism Dev Disord ;2019 (Aug 26)

Adolescence is a time of remarkable biopsychosocial change, which may be particularly challenging for youth with autism spectrum disorder (ASD), necessitating enhanced understanding and accurate assessment of pubertal maturation. The study compared physical examination to parent- and self-report measures in 200 participants (134 males and 66 females) ages 10.0-13.5 years. Both participants with typical development (TD, n = 78) and ASD (n = 122) were included. Concordance ranged from slight-to-fair for self-assessments (kappa = .17-.32) and slight-to-moderate for parent-report (kappa = .21-.44). Concordance of physical exam with self- and parent-report of the ASD group was somewhat lower than for the TD group. Findings indicate pubertal assessments by parent or child are not reliable indices of precise pubertal staging.

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6. Giannopoulou I, Lazaratou H, Economou M, Dikeos D. Converging Psychoanalytic and Neurobiological Understanding of Autism : Promise for Integrative Therapeutic Approaches. Psychodyn Psychiatry ;2019 (Fall) ;47(3):275-290.

Autism spectrum disorders (ASDs) are a group of heterogeneous neu-rodevelopmental conditions characterized by deficits in social communication and social interaction and restricted, repetitive patterns of behaviors, interests, or activities. For many years, psychoanalysis and neurobiology have been in opposite camps regarding the understanding of autism in terms of causation and treatment. This paper aims to highlight converging points between neurobiological and psychodynamic understanding of autism, which could be useful in designing more effective early interventions. For this purpose, we give a brief overview of the psychoanalytic conceptualization of autism since its first description as well as present the most pertinent neurobiological findings underlying the disorder ; both these approaches are pointing to a dysfunction in caregiver-child interactions. In the last few decades, the convergence of the psychoanalytical with the neurobiological perspectives of the disorder enhances further our understanding of the dynamic interplay among biological and psychological processes in autism. This integrative approach, grounded in both theoretical perspectives, could inform future research focusing on interpersonal neurobiology, but also provide a base for developing multi-level and multi-component early interventions, which should start as early as possible, most appropriately during infancy.

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7. Havdahl A, Bishop S. Heterogeneity in prevalence of co-occurring psychiatric conditions in autism. Lancet Psychiatry ;2019 (Aug 22)

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8. Huisman SA, Wiedijk BM, van Eeghen AM, Hennekam RC, van Trotsenburg ASP. Thyroid function in males with fragile X syndrome. J Pediatr Endocrinol Metab ;2019 (Aug 27) ;32(8):903-905.

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9. Lai MC, Kassee C, Besney R, Bonato S, Hull L, Mandy W, Szatmari P, Ameis SH. Prevalence of co-occurring mental health diagnoses in the autism population : a systematic review and meta-analysis. Lancet Psychiatry ;2019 (Aug 22)

BACKGROUND : Co-occurring mental health or psychiatric conditions are common in autism, impairing quality of life. Reported prevalences of co-occurring mental health or psychiatric conditions in people with autism range widely. Improved prevalence estimates and identification of moderators are needed to enhance recognition and care, and to guide future research. METHODS : In this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycINFO, Scopus, Web of Science, and grey literature for publications between Jan 1, 1993, and Feb 1, 2019, in English or French, that reported original research using an observational design on the prevalence of co-occurring mental health conditions in people with autism and reported confirmed clinical diagnoses of the co-occurring conditions and autism using DSM or ICD criteria. For co-occurring mental health conditions reported with at least 15 datapoints (studies), we assessed risk of bias and we determined pooled estimates of prevalence for different co-occurring conditions in autism using random-effects models, and descriptively compared these with prevalence estimates for the general population from the literature (post hoc). We investigated heterogeneity in prevalence estimates using random-effects meta-regression models. This systematic review is registered with PROSPERO, CRD42018103176. FINDINGS : Of 9746 unique studies identified, 432 were selected for full-text review. 100 studies were eligible for inclusion in our qualitative synthesis, of which 96 were included in our meta-analyses. 11 categories of co-occurring conditions were investigated, of which eight conditions were included in the meta-analyses and three were descriptively synthesised (ie, trauma and stressor-related disorders, substance-related and addictive disorders, and gender dysphoria). From our meta-analyses, we found overall pooled prevalence estimates of 28% (95% CI 25-32) for attention-deficit hyperactivity disorder ; 20% (17-23) for anxiety disorders ; 13% (9-17) for sleep-wake disorders ; 12% (10-15) for disruptive, impulse-control, and conduct disorders ; 11% (9-13) for depressive disorders ; 9% (7-10) for obsessive-compulsive disorder ; 5% (3-6) for bipolar disorders ; and 4% (3-5) for schizophrenia spectrum disorders. Estimates in clinical sample-based studies were higher than in population-based and registry-based studies, and these estimates were mostly higher than those in the general population (post hoc). Age, gender, intellectual functioning, and country of study were associated with heterogeneity in prevalence estimates, yet remaining heterogeneity not explained was still substantial (all I(2) >95%). INTERPRETATION : Co-occurring mental health conditions are more prevalent in the autism population than in the general population. Careful assessment of mental health is an essential component of care for all people on the autism spectrum and should be integrated into clinical practice. FUNDING : Academic Scholars Awards, Department of Psychiatry, University of Toronto ; O’Brien Scholars Program, Slaight Family Child and Youth Mental Health Innovation Fund, and The Catherine and Maxwell Meighen Foundation via the Centre for Addiction and Mental Health Foundation.

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10. Ledbetter-Cho K, Lang R, Lee A, Murphy C, Davenport K, Kirkpatrick M, Schollian M, Moore M, Billingsley G, O’Reilly M. Teaching Children with Autism Abduction-Prevention Skills May Result in Overgeneralization of the Target Response. Behav Modif ;2019 (Aug 24):145445519865165.

We replicated previous research using behavioral skills training (BST) to teach four children with autism to engage in a safety response following lures from civilian strangers. This study extends previous research by (a) employing abduction lures incorporating highly preferred tangible items ; (b) assessing for maintenance and generalization across settings and caregivers ; and (c) probing for overgeneralization of the safety response. A multiple baseline across participants design demonstrated target behavior acquisition and generalization to novel settings and caregivers. However, children who complied with directions from police officers during baseline emitted the safety response (e.g., running away) when approached by police officers following BST. Overgeneralization of the targeted safety response was corrected with discrimination training procedures. Maintenance of appropriate responses to civilians and officers was inconsistent and booster sessions were required for two participants. Results suggest practitioners should incorporate discrimination training and program for maintenance when teaching abduction-prevention skills to children with autism.

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11. Reinhardt VP, Iosif AM, Libero L, Heath B, Rogers SJ, Ferrer E, Nordahl C, Ghetti S, Amaral D, Solomon M. Understanding Hippocampal Development in Young Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry ;2019 (Aug 23)

OBJECTIVE : We examined growth trajectories of hippocampal volume (HV) in early childhood in a longitudinal cohort of male and female participants with autism spectrum disorder (ASD) and typical development (TD), and investigated HV in those with large brains. Relations between factors potentially associated with hippocampal size and growth were investigated. METHOD : Participants received 1-3 structural magnetic resonance imaging scans between ages 25-80 months (Unique participants : ASD : n =200 ; TD : n =110 ; total longitudinal scans, N = 593). HV growth during this period was examined using mixed effects linear models. Associations between early HV and growth rates, and IQ and adaptive functioning were evaluated. RESULTS : After accounting for cerebral hemisphere volume, male participants exhibited larger left and right HV than female participants. Hippocampal growth rates did not differ by sex. In children with larger hemisphere volumes, male and female participants with ASD had relatively larger HV than TD of similar hemisphere volume. This effect was present in a broader group than just those having disproportionate megalencephaly (male participants with large cerebral volumes relative to body size). Right were larger than left hippocampi in both groups and sexes. Right versus left volume differences were greater for ASD. After adjusting for hemisphere volume, male participants with ASD showed a significant positive association between right hippocampal growth and adaptive behavior. CONCLUSION : HV was relatively greater in ASD in analyses adjusting for hemisphere volume, while only subtle differences were observed in HV and growth between ASD and TD in unadjusted analyses, suggesting ASD involves atypical coupling between HV and brain size.

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12. Sun Y, Yao X, March ME, Meng X, Li J, Wei Z, Sleiman PMA, Hakonarson H, Xia Q, Li J. Target Genes of Autism Risk Loci in Brain Frontal Cortex. Front Genet ;2019 ;10:707.

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder. A number of genetic risk loci have been identified for ASD from genome-wide association studies (GWAS) ; however, their target genes in relevant tissues and cell types remain to be investigated. The frontal cortex is a key region in the human brain for communication and cognitive function. To identify risk genes contributing to potential dysfunction in the frontal cortex of ASD patients, we took an in silico approach integrating multi-omics data. We first found genes with expression in frontal cortex tissue that correlates with ASD risk loci by leveraging expression quantitative trait loci (eQTLs) information. Among these genes, we then identified 76 genes showing significant differential expression in the frontal cortex between ASD cases and controls in microarray datasets and further replicated four genes with RNA-seq data. Among the ASD GWAS single nucleotide polymorphisms (SNPs) correlating with the 76 genes, 20 overlap with histone marks and 40 are associated with gene methylation level. Thus, through multi-omics data analyses, we identified genes that may work as target genes of ASD risk loci in the brain frontal cortex.

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13. Taghizadeh N, Heard G, Davidson A, Williams K, Story D. The experiences of children with autism spectrum disorder, their caregivers and health care providers during day procedure : A mixed methods study. Paediatr Anaesth ;2019 (Aug 26)

BACKGROUND : Autism Spectrum Disorder is now diagnosed in more than 1% of children in Australia and USA. Children with autism spectrum disorder may have additional health care needs, require more specialized services for their health care, or experience more difficulties during hospital attendance. Customized care for these children may assist in decreasing potentially challenging behaviours during hospitalization. The purpose of this study was to explore the experiences of children with autism spectrum disorder and their caregivers during attendance for day procedures in two hospitals in Melbourne, Australia. Further, the perceptions of their health care providers were explored. METHOD : Twenty-nine participants, including 14 health care providers and 15 caregivers of children with autism spectrum disorder, were interviewed within 72 hours of their day procedure attendance at the Royal Children’s Hospital and the Royal Dental Hospital in Melbourne, Australia. Interviews were recorded digitally, then transcribed and coded. Mixed quantitative and qualitative methods (content analysis) were used. RESULTS : Hospital attendance was often stressful. Participants identified a number of facilitating factors including good communication, clear explanations, and friendly attitudes of staff. Flexibility and individualized care of patients (such as avoiding unnecessary blood pressure measurements, and not changing into hospital gowns) were valued. Supportive aids (such as computers or special interest objects), use of social stories, and giving premedication were all considered helpful. Perceived barriers to care included prolonged waiting times for operation date as well as waiting on the day of operation, lack of private space, lack of noninvasive equipment such as cutaneous infrared thermometers, poor communication, and inadequate training of staff about autism spectrum disorder. CONCLUSION : Providing optimal care for children with autism spectrum disorder requires a multifaceted approach that may require changes to hospital work flow, staff training, better use of aids (such as tablet computers and social stories), and premedication. Good communication and flexibility are key areas of importance.

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14. Xiong X, Liu D, He W, Sheng X, Zhou W, Xie D, Liang H, Zeng T, Li T, Wang Y. Identification of gender-related metabolic disturbances in autism spectrum disorders using urinary metabolomics. Int J Biochem Cell Biol ;2019 (Aug 23):105594.

Autism spectrum disorders (ASD) are a highly heterogeneous group of neurodevelopmental disorders that are more commonly diagnosed in boys than in girls. The reasons for gender differences in ASD are unknown and no definitive current evidence can explain male predominance. Therefore, in search for laboratory biomarkers responsible for ASD, a comprehensive metabolomics study was performed by metabolic profiling of urine samples in 51 ASD subjects and 51 age- and sex-matched children with typical development. Orthogonal partial least-squares discriminant analysis (OPLS-DA) models with poor quality failed to perform the analysis based on gender in the ASD and control groups. OPLS-DA models based on single-sex samples, especially in female subjects, had better clustering between the ASD and control groups with an increase in the R(2) and Q(2) values compared with those in the whole group. Significantly increased levels of adenine, 2-Methylguanosine, creatinine, and 7alpha-hydroxytestololactone and a decrease in creatine were observed in the female ASD subjects. In particular, 7alpha-hydroxytestololactone, which has a structure similar to that of testolactone, was positively correlated with adenine (Pearson correlation coefficient, r = 0.738, p < 0.01), creatinine (r = 0.826, p < 0.01), and 2-Methylguanosine (r = 0.757, p < 0.01) and negatively correlated with creatine (r=-0.413, p < 0.05). A receiver operating characteristic curve analysis using the creatinine:creatine ratio yielded an area under the curve of 0.913 (95% CI : 0.806-1). These metabolites may be sex-related or sex-sensitive to an extent and can be valuable for identification of the molecular pathways involved in the gender bias in manifestation of ASD. The creatinine:creatine ratio has a potential to be a good predictor of ASD in the female subjects.

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15. Zamberletti E, Gabaglio M, Woolley-Roberts M, Bingham S, Rubino T, Parolaro D. Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats. Front Cell Neurosci ;2019 ;13:367.

Autism spectrum disorder (ASD) is a developmental condition whose primary features include social communication and interaction impairments with restricted or repetitive motor movements. No approved treatment for the core symptoms is available and considerable research efforts aim at identifying effective therapeutic strategies. Emerging evidence suggests that altered endocannabinoid signaling and immune dysfunction might contribute to ASD pathogenesis. In this scenario, phytocannabinoids could hold great pharmacological potential due to their combined capacities to act either directly or indirectly on components of the endocannabinoid system and to modulate immune functions. Among all plant-cannabinoids, the phytocannabinoid cannabidivarin (CBDV) was recently shown to reduce motor impairments and cognitive deficits in animal models of Rett syndrome, a condition showing some degree of overlap with autism, raising the possibility that CBDV might have therapeutic potential in ASD. Here, we investigated the ability of CBDV treatment to reverse or prevent ASD-like behaviors in male rats prenatally exposed to valproic acid (VPA ; 500 mg/kg i.p. ; gestation day 12.5). The offspring received CBDV according to two different protocols : symptomatic (0.2/2/20/100 mg/kg i.p. ; postnatal days 34-58) and preventative (2/20 mg/kg i.p. ; postnatal days 19-32). The major efficacy of CBDV was observed at the dose of 20 mg/kg for both treatment schedules. CBDV in symptomatic rats recovered social impairments, social novelty preference, short-term memory deficits, repetitive behaviors and hyperlocomotion whereas preventative treatment reduced sociability and social novelty deficits, short-term memory impairments and hyperlocomotion, without affecting stereotypies. As dysregulations in the endocannabinoid system and neuroinflammatory markers contribute to the development of some ASD phenotypes in the VPA model, neurochemical studies were performed after symptomatic treatment to investigate possible CBDV’s effects on the endocannabinoid system, inflammatory markers and microglia activation in the hippocampus and prefrontal cortex. Prenatal VPA exposure increased CB1 receptor, FAAH and MAGL levels, enhanced GFAP, CD11b, and TNFalpha levels and triggered microglia activation restricted to the hippocampus. All these alterations were restored after CBDV treatment. These data provide preclinical evidence in support of the ability of CBDV to ameliorate behavioral abnormalities resembling core and associated symptoms of ASD. At the neurochemical level, symptomatic CBDV restores hippocampal endocannabinoid signaling and neuroinflammation induced by prenatal VPA exposure.

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16. Zhang Y, Song W, Tan Z, Wang Y, Lam CM, Hoi SP, Xiong Q, Chen J, Yi L. Theory of Robot Mind : False Belief Attribution to Social Robots in Children With and Without Autism. Front Psychol ;2019 ;10:1732.

This study aims to probe how children with and without autism spectrum disorders (ASD) attribute false belief to a social robot and predict its action accordingly. Twenty 5- to 7-year-old children with ASD and 20 age- and IQ-matched typically developing (TD) children participated in two false belief tasks adapted for robot settings (change-of-location task and the unexpected-contents task). The results showed that most TD children are capable of attributing false belief to the social robot, that is, they could infer higher level mental states in robots, which extends our understanding in TD children’s perception and cognition on social robots. Conversely, children with ASD still show difficulty in interpreting robots’ mental states compared to their TD peers, which would greatly interfere with their interactions and communications with social robots and might impact on efficiency of robot-based intervention and education approaches. This group difference in attributing false belief to social robots could not be explained by the different perception and categorization of the robot. Our study implies that although children with ASD appear to be highly attracted by social robots, they still have difficulty in understanding mental states when socially interacting with robots, which should be taken into consideration when designing the robot-based intervention approach targeting to improve social behaviors of ASD.

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