Pubmed du 17/05/19

vendredi 17 mai 2019

1. Aron WC, Rauch LG, Benavides GF, Repetto LM. [Rett Syndrome : MECP2 gene molecular analysis in Chilean patients]. Revista chilena de pediatria. 2019 ; 90(2) : 152-6.

INTRODUCTION : Rett syndrome (RTT) is a progressive neurological disorder characterized by regres sion of psychomotor development in previously healthy girls. Most cases are due to pathogenic va riants in the MECP2 gene which encodes for the methyl CpG-binding protein 2. OBJECTIVE : To des cribe the frequency and type of pathogenic variants in the MECP2 gene in Chilean female patients with clinical diagnosis of RTT. PATIENTS AND METHOD : Chilean women with clinical suspicion of RTT were invited to participate in the study. Clinical data were collected through a questionnaire. MECP2 pathogenic variants were analyzed by Sanger sequencing method and Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect duplications or deletions. RESULTS : The study in cluded 14 patients with suspected RTT, of which eight (57%) patients had pathogenic variants. The other patients remain without molecular diagnosis. CONCLUSIONS : Pathogenic variants in MECP2 are present in Chilean patients with RTT. It is likely that there are other genes or diagnoses involved in patients without MECP2 findings. As of this study, molecular diagnosis is available in Chile.

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2. Atherton G, Cross L. Animal Faux Pas : Two Legs Good Four Legs Bad for Theory of Mind, but Not in the Broad Autism Spectrum. The Journal of genetic psychology. 2019 : 1-15.

Research shows that the general population varies with regard to both autistic traits and theory of mind (ToM) ability. Other work has shown that autistic individuals may not underperform on ToM tests when the agent of evaluation is anthropomorphic rather than typically human. Two studies examined the relation between ToM and autistic trait profiles in over 650 adults using either the standard Faux Pas Recognition Test (FPT) or an anthropomorphized version of the FPT (FPTa). Results showed that autistic trait profiles were related to faux pas detection ability in the FPT but not the FPTa. Furthermore, while those with the broad autism phenotype scored significantly worse than those who were typically developed on the FPT, scores did not significantly differ on the FPTa. These findings add to a growing body of work suggesting that ToM ability is not at a global deficit in those on the autistic spectrum, but may relate to the mindreading of specifically human agents.

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3. Avraham Y, Berry EM, Donskoy M, Ahmad WA, Vorobiev L, Albeck A, Mankuta D. Beta-carotene as a novel therapy for the treatment of "Autistic like behavior" in animal models of Autism. Behav Brain Res. 2019 ; 364 : 469-79.

Autism-affected individuals are characterized by lower plasma oxytocin and its ectoenzyme regulator CD38. Oxytocin, a hypothalamic hormone secreted upon the release of CD38, plays a role in social behavior and bonding. All-trans retinoic acid is a potent inducer of CD38 and can be used as a novel therapeutic strategy in autism. We investigated the role of beta-carotene in rescuing autistic-like behavior in BALB/c and BTBR mice. Beta-carotene derivatives are preferred as they are neither toxic nor teratogenic. Beta-carotene at 0.1-5.0mg/kg was administered orally to BALB/c and BTBR newborn mice on days 1-7. They were tested at age 2-3 months for five behavioral tests for "autism" ; in addition, brain CD38, oxytocin, oxytocin receptor, Brain Derived Neurotrophic Factor (BDNF) and retinoic acid receptor gene expression, serum oxytocin levels, and neurological score were evaluated. Beta-carotene administered at birth significantly increased T-maze alternations and led to longer time spent with an unfamiliar mouse in the "three-chamber test" and less time spent in the empty chamber. Furthermore, enhanced activity in the open field test ; increased time spent in the reciprocal social interaction test ; decreased grooming and bedding behaviors ; and enhanced brain CD38, oxytocin, oxytocin receptor, BDNF, retinoic acid gene expression, and serum oxytocin levels. No changes in neurological score were observed. Beta-carotene oral supplementation to BALB/c and BTBR mice at birth significantly reduced restricted and stereotyped behaviors and interests, increased social interactions and communication, CD38, and oxytocin, probably by enhancing brain neuroplasticity without toxicity. Thus, beta-carotene administered after birth to newborns of families predisposed to "autism" has the potential to prevent/ameliorate" autistic like behavior". These results support further clinical studies.

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4. Barry CL, Kennedy-Hendricks A, Mandell D, Epstein AJ, Candon M, Eisenberg M. State Mandate Laws for Autism Coverage and High-Deductible Health Plans. Pediatrics. 2019.

OBJECTIVES : Most states have passed insurance mandates requiring health plans to cover services for children with autism spectrum disorder (ASD). Research reveals that these mandates increased treated prevalence, service use, and spending on ASD-related care. As employer-sponsored insurance shifts toward high-deductible health plans (HDHPs), it is important to understand how mandates affect children with ASD in HDHPs relative to traditional, low-deductible plans. METHODS : Insurance claims for 2008-2012 for children covered by 3 large US insurers (United Healthcare, Aetna, and Humana) available through the Health Care Cost Institute were used to compare the effects of mandates on ASD-related spending for children in HDHPs and traditional health plans. RESULTS : Relative to children in traditional plans, mandates were associated with higher average monthly spending increases for children in HDHPs. Mandate-attributable spending differences between children enrolled in HDHPs relative to traditional plans were $77 for ASD-specific services (95% confidence interval [CI] : $10 to $144), $125 for outpatient health services (95% CI : $26 to $223), and $144 for all health services (95% CI : $36 to $253). These spending differentials were driven by differences in plan spending and not out-of-pocket (OOP) spending. CONCLUSIONS : Spending on ASD-related services attributable to autism mandates was higher among children in HDHPs, but higher spending did not translate into a greater OOP burden. For families with consistently high health care expenditures on ASD-related services, high-deductible products may be worth considering in the context of mandate laws. Families in mandate states with children with ASD enrolled in HDHPs were able to increase service use without paying more OOP.

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5. Berends D, Dissanayake C, Lawson LP. Differences in Cognition and Behaviour in Multiplex and Simplex Autism : Does Prior Experience Raising a Child with Autism Matter ?. J Autism Dev Disord. 2019.

Previous research has found multiplex (MPX) children have an advantage in cognition compared to simplex (SPX) children. However, MPX parent’s previous experience with older diagnosed siblings has not been considered. We used a large database sample to investigate the MPX advantage and contribution of birth order. Children from the Autism Genetic Resource Exchange (AGRE) were stratified into first- (MPX(1), n = 152) and second-affected MPX (MPX(2), n = 143), SPX (n = 111), and only-child SPX (SPX(OC), n = 23) groups. Both MPX groups had higher cognitive scores compared to SPX groups, with no differences between MPX(1) and MPX(2) groups. No differences were found for autism symptoms or adaptive behaviour. These results suggest parent experience due to birth order is an unlikely contributor to the MPX cognitive advantage.

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6. Cohen SR, Miguel J, Wishard Guerra A. Child-rearing routines among Mexican-heritage children with autism spectrum disorder. Autism. 2019 : 1362361319849244.

This study examined the daily routines and activities of Mexican-heritage mothers and their children with autism spectrum disorder. Experienced sampling methods were used to capture families’ current daily routines and activities, how parents valued those activities, and whether the activity was part of the child’s autism spectrum disorder intervention. A total of 32 mothers were texted five times per day over five consecutive days for a total of 721 observations. Mothers frequently engaged in Self-Care (e.g. showering), General Caregiving (e.g. cooking), and House Chores (e.g. laundry). Children engaged in activities in which interventions could easily be integrated (e.g. Academics, Self-Care, and Playing with Others). Families spent less than one-third (26.1%) of their activities participating in interventions. Mothers and children jointly spent time in General Caregiving, Playing with Others, and Using Electronics. Practitioners should focus on integrating evidence-based interventions into daily joint routine activities.

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7. Cosentino L, Vigli D, Franchi F, Laviola G, De Filippis B. Rett syndrome before regression : a time window of overlooked opportunities for diagnosis and intervention. Neurosci Biobehav Rev. 2019.

Rett syndrome (RTT) is a rare neurological disorder primarily affecting females, causing severe cognitive, social, motor and physiological impairments for which no cure currently exists. RTT clinical diagnosis is based on the peculiar progression of the disease, since patients show an apparently normal initial development with a subsequent sudden regression at around 2 years of age. Accumulating evidences are rising doubts regarding the absence of early impairments, hence questioning the concept of regression. We reviewed the published literature addressing the pre-symptomatic stage of the disease in both patients and animal models with a particular focus on behavioral, physiological and brain abnormalities. The emerging picture delineates subtle, but reliable impairments that precede the onset of overt symptoms whose bases are likely set up already during embryogenesis. Some of the outlined alterations appear transient, suggesting compensatory mechanisms to occur in the course of development. There is urgent need for more systematic developmental analyses able to detect early pathological markers to be used as diagnostic tools and precocious targets of time-specific interventions.

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8. De Luca R, Leonardi S, Portaro S, Le Cause M, De Domenico C, Colucci PV, Pranio F, Bramanti P, Calabro RS. Innovative use of virtual reality in autism spectrum disorder : A case-study. Appl Neuropsychol Child. 2019 : 1-11.

Autism Spectrum Disorders (ASDs) are developmental disorders affecting communication and behavior. ASD incidence in the world population is about 1%, with a 4:1 ratio between males and females. In clinical practice, ASDs have been usually treated with cognitive-behavioral approaches, involving a face-to-face interaction with the therapist. Over the last years, virtual reality (VR) has played an important role in neurorehabilitation, even for ASD cognitive treatment. A 16-year-old boy with severe ASD and his caregiver were enrolled in the study. Two different cognitive trainings were administered ; first, the boy was submitted to one-month cognitive behavioral therapy (CBT) ; then, after one month of rest, a combined approach using VR (by means of the BTS-Nirvana System) and CBT was applied. Only the combined approach provided an improvement in attention processes and spatial cognition skills, with a significant reduction of ideomotor stereotypes. According to this experience, the use of VR in addition to CBT could be a useful and promising tool to improve cognitive function in individuals severely affected by ASD.

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9. DiCarlo GE, Aguilar JI, Matthies HJ, Harrison FE, Bundschuh KE, West A, Hashemi P, Herborg F, Rickhag M, Chen H, Gether U, Wallace MT, Galli A. Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. The Journal of clinical investigation. 2019 ; 130.

The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

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10. Fok M, Bal VH. Differences in profiles of emotional behavioral problems across instruments in verbal versus minimally verbal children with autism spectrum disorder. Autism Res. 2019.

There has been increasing attention to the assessment of minimally verbal (MV) children with autism spectrum disorder (ASD). Previous research has begun to examine the relationship between verbal abilities and emotional and behavioral problems (EBP). The current study compared parent-reported EBP in children of differing language levels on two instruments commonly used in ASD research and clinical practice, the Child Behavior Checklist (CBCL) and Aberrant Behavior Checklist (ABC). The study consisted of 1,937 6-18 years old children with ASD from the Simons Simplex Collection. Children were divided into three language groups, by ADOS module (Module 1 = MV, 2 = phrase speech (PS), and 3 = verbally fluent (VF)) and then compared on CBCL and ABC subscales. The ABC and CBCL showed different patterns of elevations across the language groups. MV children were reported to have more impairment than VF children on the ABC irritability, lethargy, and hyperactivity scales. Children with less language (MV and PS) exhibited less impairment on the CBCL internalizing domain than VF children, but did not differ on the externalizing domain. Post hoc comparisons showed that internalizing differences were driven by fewer children with less language exhibiting clinically elevated anxious/depressed scores compared to VF children. The present study underscores the significance of considering language when assessing EBP. Results have implications for the psychiatric screening of children with ASD, particularly those with language impairments. Researchers should exercise caution when applying EBP instruments designed for use with different populations and purposes to broad samples of children. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Some emotional and behavioral problem (EBP) scales include items that may be inappropriate for children with ASD and limited language. The present study found that there was a tendency for children with language impairment to have lower internalizing scores on the Child Behavior Checklist, but higher scores lethargy and irritability scores on the Aberrant Behavior Checklist, relative to verbally fluent children. This suggests that each of these instruments may underestimate EBPs in certain subsets of children.

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11. Fontes-Dutra M, Della-Flora Nunes G, Santos-Terra J, Souza-Nunes W, Bauer-Negrini G, Hirsch MM, Green L, Riesgo R, Gottfried C, Bambini-Junior V. Abnormal empathy-like pro-social behaviour in the valproic acid model of autism spectrum disorder. Behav Brain Res. 2019 ; 364 : 11-8.

Impairments in social behaviour are a defining feature of autism spectrum disorder (ASD). Individuals with ASD also usually present some difficulty to recognize or understand another person’s feelings. Therefore, it is possible that altered empathy processing could hinder typical social interaction in ASD. Recently, robust paradigms confirmed that rodents show primordial forms of empathy-like behaviour. Therefore, in this work, we used one of these new protocols to test pro-social behaviour in the rat model of autism induced by Valproic Acid (VPA). We also evaluated possible beneficial effects of Resveratrol, since it can prevent social deficits in the VPA model. Rats were tested on their ability to open a restrainer to release a trapped conspecific. Exposure to VPA precludes the timely manifestation of this empathy-like behaviour, but does not affect its continuation after its first expression. We also found a significant correlation between average speed during the first day of test and becoming an Opener. Similarly, rats able to open the restrainer on the first day had an increased likelihood of repeating this behaviour in the later days of the testing programme. We did not find any protective effects of Resveratrol. Further investigation of empathy-like behaviour in the VPA model and in other models of autism could help to clarify the behavioural and neural processes underpinning the basic aspects of empathy alterations in autistic individuals.

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12. Howells K, Sivaratnam C, May T, Lindor E, McGillivray J, Rinehart N. Efficacy of Group-Based Organised Physical Activity Participation for Social Outcomes in Children with Autism Spectrum Disorder : A Systematic Review and Meta-analysis. J Autism Dev Disord. 2019.

The aim of this novel review and meta-analysis was to clarify the effects of group-based organised physical activity (OPA) for social and communicative outcomes in children with Autism Spectrum Disorder (ASD). Searches yielded 4347 articles. Eleven were identified for review and seven for meta-analysis. Pooled statistical results revealed a non-significant effect for communication (k = 4 ; g = 0.13, CI [- 0.12, 0.38], p = .13) and a significant small-medium improvement in overall social functioning (k = 6 ; g = 0.45, CI [0.19, 0.72], p = .001). Despite acknowledged limitations, these findings are important in the context of a growing clinical and consumer-driven demand for research that determines the role of OPA as a non-medical and inclusive treatment for children with ASD.

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13. Ireri NW, White SW, Mbwayo AW. Treating Anxiety and Social Deficits in Children with Autism Spectrum Disorder in Two Schools in Nairobi, Kenya. J Autism Dev Disord. 2019.

Anxiety in children with Autism Spectrum Disorder (ASD) contributes to their functional impairment. We evaluated a cognitive-behavioral program for anxiety and social deficits in children with ASD in two schools in Nairobi City, Kenya. Parents and teachers of 40 children and adolescents with ASD (5-21 years) participated, randomized by school. The two schools were randomly assigned to either intervention (n = 20) or control (n = 20). There was a significant improvement in ASD severity as well as anxiety within the treatment group, which was not seen in the control group. These findings support the expansion of treatments for ASD core deficits and secondary problems in youth with ASD in developing countries.

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14. Keller D, Reynolds A. Behavioral Pediatrics Meets Behavioral Economics : Autism, Mandates, and High Deductibles. Pediatrics. 2019.

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15. Ma W, Sai L, Tay C, Du Y, Jiang J, Ding XP. Children with Autism Spectrum Disorder’s Lying is Correlated with Their Working Memory But Not Theory of Mind. J Autism Dev Disord. 2019.

The present study examined the role of executive function in lying for children with autism spectrum disorder (ASD). The temptation resistance paradigm was used to elicit children’s self-protective lies and the Hide-and-seek task was used to elicit children’s self-benefiting lies. Results showed that children with ASD told fewer lies in the two deception tasks compared to children with intellectual disability (ID) and typically developing (TD) children. Furthermore, children with ASD’s lying were positively correlated with their working memory, but not with their theory of mind. These findings demonstrate that the mechanisms underlying deception for children with ASD are distinct from that of TD children.

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16. Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Bakheet SA, Ibrahim KE, Alqahtani F, Alqinyah M. Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice. Behav Brain Res. 2019 ; 364 : 213-24.

Autism is a neurodevelopmental disease which is characterized by its core behavioral symptoms such as impairment in social interaction and stereotyped repetitive behavior. Th17 immune responses and oxidative stress are reported to be elevated in both human autistic subjects and BTBR T + Itpr3tf/J (BTBR) mice. On the other hand, activation of nuclear factor erythroid 2 related factor (Nrf2), a master transcription factor is essential for the management of anti-inflammatory and antioxidant genes. Sulforaphane activates Nrf2 and thus is considered a potential approach to treat several neurological disorders including autism. In the current work, we used sulforaphane in asocial BTBR mice and its social counterpart C57/BL6 (C57) mice to assess its therapeutic potential and molecular mechanisms (Th17 immune responses, and oxidant-antioxidant balance) through which it acts. Our results demonstrate that BTBR treated with sulforaphane had reduced self-grooming/marble burying behavior, and increased social interaction in three chambered sociability test as compared to untreated BTBR mice. Further, sulforaphane-treated BTBR mice had reduced Th17 immune responses (STAT3, RORC, IL-17 A and IL-23R expression in CD4 + T cells), oxidative stress parameters in neutrophils/cerebellum (NFkB, iNOS, and lipid peroxides). Furthermore, sulforaphane-treated BTBR and C57 mice had upregulated enzymatic antioxidant defenses in neutrophils/cerebellum (SOD, GPx and GR expression and activity). We reason that activation of Nrf2 by sulforaphane corrected Th17 immune dysfunction and oxidant-antioxidant imbalance in periphery and brain in BTBR mice. These mechanisms lead to improvement in autism-like symptoms in BTBR mice.

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17. Nik Adib NA, Ibrahim MI, Ab Rahman A, Bakar RS, Yahaya NA, Hussin S, Wan Mansor WNA. Predictors of Caregivers’ Satisfaction with the Management of Children with Autism Spectrum Disorder : A Study at Multiple Levels of Health Care. Int J Environ Res Public Health. 2019 ; 16(10).

BACKGROUND : Caregivers are the initial gatekeepers in the health care management of children with autism spectrum disorder (ASD). METHODS : This cross-sectional study aimed to determine the factors associated with caregivers’ satisfaction with different levels of health care services in managing children with ASD in Kelantan. The satisfaction scores of 227 main caregivers of confirmed ASD children were assessed with a modified Parent Satisfaction Scale (PSS) questionnaire. RESULTS : The analysis showed that caregivers who waited longer for a doctor’s consultation in primary care had a reduced PSS score, whereas caregivers who were satisfied with the waiting time in primary care had higher PSS scores. At the secondary care level, caregivers who possessed at least a diploma had reduced PSS scores, whereas caregivers who were satisfied with both doctors’ consultation times and occupational therapy appointments had higher PSS scores. At the tertiary care level, caregivers with an underlying medical problem and who had children undergoing occupational therapy for two months or more had reduced PSS scores. Nevertheless, the analysis showed that caregivers who were concerned with their children’s sleeping problems, who had been informed about parental support, who were satisfied with speech and occupational therapy appointments, who were satisfied with waiting times at tertiary care clinics, and who were satisfied with their doctor’s knowledge and experience had higher PSS scores. CONCLUSIONS : This study elucidated the importance of understanding caregivers’ satisfaction in attaining care for their ASD children and highlighted the need to promote factors that would increase caregivers’ satisfaction with current ASD services.

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18. Ouellette-Kuntz H, Smith G, Fulford C, Cobigo V. Are we making a difference in primary care for adults with intellectual and developmental disabilities ?. Revista panamericana de salud publica = Pan American journal of public health. 2018 ; 42 : e154.

Objectives : To examine the impact of the dissemination of guidelines to physicians and of a population-level health communication intervention on the percentage of adults with intellectual and developmental disabilities (IDD) receiving preventive care through primary care. Methods : Noninstitutionalized adults with IDD in the province of Ontario, Canada, aged 40 to 64 years were matched to Ontarians without such disabilities each fiscal year (FY) from 2003 to 2016. Health administrative data were used to create a composite measure of receipt of recommended preventive primary care. Age-adjusted rates were used to assess trends, and average two-year rate ratios (RRs) and confidence intervals (CIs) were used to evaluate the effectiveness of the interventions. Results : The number of adults with IDD identified ranged from 20 030 in FY 2003 to 28 080 in FY 2016. The percentage of adults with IDD receiving recommended preventive primary care ranged from 43.4% in 2003 to 55.7% in 2015. Men with IDD had a 53.7% increase across the 13 years, while women with IDD only had a 30.9% increase. When evaluating the impact of the interventions, men with IDD were 4% more likely (RR : 1.04 ; 95% CI : 1.02-1.05) to receive recommended primary care in FY 2015 and FY 2016 as compared to FY 2009 and FY 2010 ; in contrast, women with IDD were 5% less likely (RR : 0.95 ; 95% CI : 0.93-0.98). A comparable drop was observed among women without IDD. Conclusions : Nearly 45% of adults with IDD in Ontario still do not receive recommended preventive care through primary care. Long-term impacts of the interventions introduced in the province may still occur over time, so ongoing monitoring is warranted. Special attention should be given to the preventive care needs of women with IDD.

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19. Owada K, Okada T, Munesue T, Kuroda M, Fujioka T, Uno Y, Matsumoto K, Kuwabara H, Mori D, Okamoto Y, Yoshimura Y, Kawakubo Y, Arioka Y, Kojima M, Yuhi T, Yassin W, Kushima I, Benner S, Ogawa N, Kawano N, Eriguchi Y, Uemura Y, Yamamoto M, Kano Y, Kasai K, Higashida H, Ozaki N, Kosaka H, Yamasue H. Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism. Brain. 2019.

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule : the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57 ; 95% CI, -1.27 to 0.13 ; P = 0.023) and confirmatory trials (-0.41 ; -0.62 to -0.20 ; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = -0.78 ; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = -0.46 ; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen’s d = -0.35 ; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = -1.24 ; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

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20. Pugliese CE, Ratto AB, Granader Y, Dudley KM, Bowen A, Baker C, Anthony LG. Feasibility and preliminary efficacy of a parent-mediated sexual education curriculum for youth with autism spectrum disorders. Autism. 2019 : 1362361319842978.

Youth with autism spectrum disorder can face social-communication challenges related to sexuality, dating, and friendships. The purpose of this study was to assess the feasibility, acceptability, and preliminary efficacy of the Supporting Teens with Autism on Relationships program. In total, 84 youth with autism spectrum disorder aged 9 to 18 and their parents participated in this study ; two groups received the Supporting Teens with Autism on Relationships program (interventionist-led parent group vs parent self-guided), while an attentional control group received a substance abuse prevention program that included instruction in problem-solving and social skills. Feasibility and acceptability of the Supporting Teens with Autism on Relationships program was high overall. The Supporting Teens with Autism on Relationships program was effective in increasing parent and youth knowledge of sexuality, while the attentional control was not. There was preliminary support for improvement in parenting efficacy related to discussing sexuality with their children. Gains were seen among completers regardless of whether the parent received support from a facilitator. Implications and future directions are discussed.

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21. Schmidt RJ, Niu Q, Eyles DW, Hansen RL, Iosif AM. Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case-control study. Autism Res. 2019.

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child’s later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health’s Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97 ; CI : 0.87-1.08) or DD (OR = 0.91 ; 95% CI : 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74 ; 95% CI : 0.55-0.99, Pinteraction = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79 ; 95% CI : 0.63-0.98, Pinteraction = 0.11 for Hispanic, Pinteraction = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Vitamin D appears essential for brain development and function. We examined neonatal total 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

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22. Skorupski W, Trojnarska O, Bartczak-Rutkowska A, Sikora W, Lesiak M, Grygier M. The curious case of acute myocardial infarction due to paradoxical embolism in young man with ASD II. Kardiologia polska. 2019.

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23. Talebi N, Nasrabadi AM, Mohammad-Rezazadeh I, Coben R. nCREANN : Nonlinear Causal Relationship Estimation by Artificial Neural Network ; applied for autism connectivity study. IEEE transactions on medical imaging. 2019.

Quantifying causal (effective) interactions between different brain regions is very important in neuroscience research. Many of conventional methods estimate effective connectivity based on linear models. However, using linear connectivity models may oversimplify functions and dynamics of the brain. In the present study, we propose a causal relationship estimator called "nCREANN" (nonlinear Causal Relationship Estimation by Artificial Neural Network) that identifies both linear and nonlinear components of effective connectivity in the brain. Furthermore, it can distinguish between these two types of connectivity components by calculating the linear and nonlinear parts of the network input-output mapping. The nCREANN performance has been verified using synthesized data and then it has been applied on EEG data collected during rest in children with autism spectrum disorder (ASD) and Typically Developing (TD) children. Results show that overall linear connectivity in TD subjects is higher, while the nonlinear connectivity component is more dominant in ASDs. We suggest that our findings may represent different underlying neural activation dynamics in ASD and TD subjects. The results of nCREANN may provide new insight into the connectivity between the interactive brain regions.

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24. Tei S, Fujino J, Itahashi T, Aoki Y, Ohta H, Kubota M, Hashimoto RI, Nakamura M, Kato N, Takahashi H. Egocentric biases and atypical generosity in autistic individuals. Autism Res. 2019.

Individuals with autism spectrum conditions (ASCs) often experience difficulty and confusion in acknowledging others’ perspectives and arguably exhibit egocentricity. However, whether this egocentricity necessarily results in selfish behavior during social situations remains a matter of debate. To study this relationship, we used computerized visuospatial perspective-taking task (VPT) and social-discounting task (SDT), derived from cognitive psychology and behavioral economics, and examined egocentric and other-oriented judgments in participants with ASCs (mean age 29.0 +/- 4.2 years) and a group of matched typically developing (TD) controls (30.8 +/- 8.5). The response time in VPT showed altered perspective-taking in the ASCs group compared with the TD group that involved in enhanced self-other intrusion and condition-insensitive response. Regardless of self/other perspective judgments, responses were relatively slower and consistent in duration in the ASCs group compared with the TD group. Social discounting was attenuated rather than steep discounting in the ASCs group. Their discounting was comparatively more consistent, irrespective of the task condition (i.e., self-other closeness-level). In effect, ASCs group exhibited more generous decisions than the TD group in this task. Finally, those with more egocentric perspective intrusion in VPT paradoxically showed more generous behaviors in SDT in the ASCs group. Our findings suggest that having ASCs does not always exhibit selfish behavior during interpersonal communication. Reduced flexibility in distinguishing self/other perspective and shifting decision-rules might account for this unique relationship between egocentricity and apparently generous behaviors. These results extend the recent suggestion that more careful attention should be paid to the idea of egocentricity in individuals with ASCs. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : We aimed to examine whether seeing the world from another person’s point of view and being generous toward other people are related in autistic and nonautistic people. We used a visual perspective-taking task and a social task in which individuals made decisions about how to divide a sum of money with others. Our results suggest that being autistic does not always make someone bad at seeing the world from another’s viewpoint, and that autistic people may make fairer social decisions toward unfamiliar people because of lower bias.

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25. Tekola B, Girma F, Kinfe M, Abdurahman R, Tesfaye M, Yenus Z, Salomone E, Pacione L, Fekadu A, Servili C, Hanlon C, Hoekstra RA. Adapting and pre-testing the World Health Organization’s Caregiver Skills Training programme for autism and other developmental disorders in a very low-resource setting : Findings from Ethiopia. Autism. 2019 : 1362361319848532.

The World Health Organization’s Caregiver Skills Training programme for children with developmental disorders or delays teaches caregivers strategies to help them support their child’s development. Ethiopia has a severe lack of services for children with developmental disorders or delays. This study explored the perspectives of Ethiopian caregivers, professionals and other stakeholders to inform adaptation and implementation of the World Health Organization’s Caregiver Skills Training in Ethiopia. Data collection included (1) a consultation and review, comprising stakeholder meetings, review of draft Caregiver Skills Training materials and feedback from Ethiopian Master Trainees and (2) a pre-pilot including quantitative feasibility and acceptability measures and qualitative interviews with caregivers (n = 9) and programme facilitators/observers (n = 5). The consultation participants indicated that the Caregiver Skills Training addresses an urgent need and is relevant to the Ethiopian context. Several adaptations were proposed, including more emphasis on psycho-education, stigma, parental feelings of guilt and expectations of a cure. The adapted Caregiver Skills Training was pre-piloted with excellent participation (100%) and retention (90%) rates. Four themes were developed from the qualitative data : (1) Programme acceptability and relevance, (2) Perceived programme benefits, (3) Challenges and barriers and (4) Suggestions for improvement. The World Health Organization’s Caregiver Skills Training addresses a local need and, with careful adaptations, is feasible and acceptable to be implemented in Ethiopia. These findings may have relevance to low-resource settings worldwide.

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26. Torrico B, Shaw AD, Mosca R, Vivo-Luque N, Hervas A, Fernandez-Castillo N, Aloy P, Bayes M, Fullerton JM, Cormand B, Toma C. Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes. Journal of psychiatry & neuroscience : JPN. 2019 ; 44(4) : 1-10.

Background : Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism. Methods : We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100). Results : We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the beta-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders : de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects ; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 x E-07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 x E-03) ; and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 x E-05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls. Limitations : We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders. Conclusion : Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

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27. Velmeshev D, Schirmer L, Jung D, Haeussler M, Perez Y, Mayer S, Bhaduri A, Goyal N, Rowitch DH, Kriegstein AR. Single-cell genomics identifies cell type-specific molecular changes in autism. Science (New York, NY). 2019 ; 364(6441) : 685-9.

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

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Annonces

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