1. Boland MJ, Nazor KL, Tran HT, Szucs A, Lynch CL, Paredes R, Tassone F, Sanna PP, Hagerman RJ, Loring JF. {{Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome}}. {Brain};2017 (Jan 29)
New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models. Differentiation of human pluripotent stem cells recapitulates development of the neocortex, an area affected in both fragile X syndrome and autism spectrum disorder. We have generated induced human pluripotent stem cells from several individuals clinically diagnosed with fragile X syndrome and autism spectrum disorder. When differentiated to dorsal forebrain cell fates, our fragile X syndrome human pluripotent stem cell lines exhibited reproducible aberrant neurogenic phenotypes. Using global gene expression and DNA methylation profiling, we have analysed the early stages of neurogenesis in fragile X syndrome human pluripotent stem cells. We discovered aberrant DNA methylation patterns at specific genomic regions in fragile X syndrome cells, and identified dysregulated gene- and network-level correlates of fragile X syndrome that are associated with developmental signalling, cell migration, and neuronal maturation. Integration of our gene expression and epigenetic analysis identified altered epigenetic-mediated transcriptional regulation of a distinct set of genes in fragile X syndrome. These fragile X syndrome-aberrant networks are significantly enriched for genes associated with autism spectrum disorder, giving support to the idea that underlying similarities exist among these neurodevelopmental diseases.
Lien vers le texte intégral (Open Access ou abonnement)
2. Chouinard B, Reynolds S. {{Longitudinal Evaluation of a Parent and School Team-Mediated Workshop Intervention for Reducing Challenging Behaviours in Children with Autism Spectrum Disorder}}. {Healthc Q};2017;19(4):74-80.
Children with autism spectrum disorder often develop persistent challenging behaviours. A previous study in this journal (Reynolds et al. 2011) reported effective implementation of strategies immediately following involvement in a comprehensive positive behaviour support workshop for parents/school personnel. The current study assessed long-term efficacy more than six months after workshop completion. Parent and school behaviour scores suggested maintained improvement in child behaviour. Parent responses to a verbal questionnaire revealed important perceptions of what made workshop participation beneficial. This study provides evidence for long-term benefits from this innovative approach for caregivers working with children with challenging behaviours.
3. Cook JL, Rapp JT, Mann KR, McHugh C, Burji C, Nuta R. {{A Practitioner Model for Increasing Eye Contact in Children With Autism}}. {Behav Modif};2017 (Jan 01):145445516689323.
Although many teaching techniques for children with autism spectrum disorder (ASD) require the instructor to gain the child’s eye contact prior to delivering an instructional demand, the literature contains notably few procedures that reliably produce this outcome. To address this problem, we evaluated the effects of a sequential model for increasing eye contact in children with ASD. The model included the following phases: contingent praise only (for eye contact), contingent edibles plus praise, stimulus prompts plus contingent edibles and praise, contingent video and praise, schedule thinning, and maintenance evaluations for up to 2 years. Results indicated that the procedures increased eye contact for 20 participants (one additional participant did not require consequences). For 16 participants, praise (alone) was not sufficient to support eye contact; however, high levels of eye contact were typically maintained with these participants when therapists used combined schedules of intermittent edibles or video and continuous praise. We discuss some limitations of this model and directions for future research on increasing eye contact for children with ASD.
Lien vers le texte intégral (Open Access ou abonnement)
4. Fassbender C, Muhkerjee P, Schweitzer JB. {{Minimizing Noise in Pediatric Task-Based functional MRI; Adolescents with Developmental Disabilities and Typical Development}}. {Neuroimage};2017 (Jan 24)
Functional Magnetic Resonance Imaging (fMRI) represents a powerful tool with which to examine brain functioning and development in typically developing pediatric groups as well as children and adolescents with clinical disorders. However, fMRI data can be highly susceptible to misinterpretation due to the effects of excessive levels of noise, often related to head motion. Imaging children, especially with developmental disorders, requires extra considerations related to hyperactivity, anxiety and the ability to perform and maintain attention to the fMRI paradigm. We discuss a number of methods that can be employed to minimize noise, in particular movement-related noise. To this end we focus on strategies prior to, during and following the data acquisition phase employed primarily within our own laboratory. We discuss the impact of factors such as experimental design, screening of potential participants and pre-scan training on head motion in our adolescents with developmental disorders and typical development. We make some suggestions that may minimize noise during data acquisition itself and finally we briefly discuss some current processing techniques that may help to identify and remove noise in the data. Many advances have been made in the field of pediatric imaging, particularly with regard to research involving children with developmental disorders. Mindfulness of issues such as those discussed here will ensure continued progress and greater consistency across studies.
Lien vers le texte intégral (Open Access ou abonnement)
5. Gates JA, Kang E, Lerner MD. {{Efficacy of group social skills interventions for youth with autism spectrum disorder: A systematic review and meta-analysis}}. {Clin Psychol Rev};2017 (Jan 18);52:164-181.
Group-based social skills interventions (GSSIs) are widely used for treating social competence among youth with autism spectrum disorder (ASD), but their efficacy is unclear. Previous meta-analysis of the literature on well-designed trials of GSSIs is limited in size and scope, collapsing across highly heterogeneous sources (parents; youths; teachers; observers; behavioral tasks). The current meta-analysis of randomized control trials (RCTs) was conducted to ascertain overall effectiveness of GSSIs and differences by reporting sources. Nineteen RCTs met inclusion criteria. Results show that overall positive aggregate effects were medium (g=0.51, p<0.001). Effects were large for self-report (g=0.92, p<0.001), medium for task-based measures (g=0.58, p<0.001), small for parent- and observer-report (g=0.47 and 0.40, respectively, p<0.001), and nonsignificant for teacher-report (p=0.11). Moderation analyses of self-report revealed the effect was wholly attributable to youth reporting that they learned about skilled social behaviors (social knowledge; g=1.15, p<0.01), but not that they enacted them (social performance; g=0.28, p=0.31). Social skills interventions presently appear modestly effective for youth with ASD, but may not generalize to school settings or self-reported social behavior. Lien vers le texte intégral (Open Access ou abonnement)
6. Muller RA, Amaral DG. {{Editorial: Time to give up on Autism Spectrum Disorder?}}. {Autism Res};2017 (Jan);10(1):10-14.
Lien vers le texte intégral (Open Access ou abonnement)
7. Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ. {{A novel human CAMK2A mutation disrupts dendritic morphology and synaptic transmission, and causes ASD-related behaviors}}. {J Neurosci};2017 (Jan 27)
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIalpha catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIalpha substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIalpha-WT autophosphorylation. The E183V mutation also reduces CaMKIIalpha binding to established ASD-linked proteins, such as Shank3 and subunits of L-type calcium channels and NMDA receptors, and increases CaMKIIalpha turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIalpha targeting to dendritic spines. Moreover, neuronal expression of CaMKIIalpha-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIalpha-E183V mutation have lower total forebrain CaMKIIalpha levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIalpha-E183V mice also display aberrant behavioral phenotypes including hyperactivity, social interaction deficits and increased repetitive behaviors. Taken together, these data suggest that CaMKIIalpha plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. SIGNIFICANCE STATEMENT: Many ASD-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIalpha linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
Lien vers le texte intégral (Open Access ou abonnement)
8. Vivanti G, Hocking DR, Fanning PA, Uljarevic M, Postorino V, Mazzone L, Dissanayake C. {{Attention to novelty versus repetition: Contrasting habituation profiles in Autism and Williams syndrome}}. {Dev Cogn Neurosci};2017 (Jan 19)
BACKGROUND: Abnormalities in habituation have been documented in Autism Spectrum Disorder (ASD) and Williams syndrome (WS). Such abnormalities have been proposed to underlie the distinctive social and non-social difficulties that define ASD, including sensory features and repetitive behaviours, and the distinctive social phenotype characterizing WS. METHODS: We measured habituation in 39 preschoolers with ASD, 20 peers with WS and 19 typically developing (TD) children using an eye-tracking protocol that measured participants’ duration of attention in response to a repeating stimulus and a novel stimulus presented side by side across multiple trials. RESULTS: Participants in the TD group and the WS group decreased their attention toward the repeating stimulus and increased their attention to the novel stimulus over time. Conversely, the ASD group showed a similar attentional response to the novel and repeating stimuli. Habituation was correlated with social functioning in the WS but not in the ASD group. Contrary to predictions, slower habituation in ASD was associated with lower severity of repetitive behaviours. CONCLUSIONS: Habituation appears to be intact in WS and impaired in ASD. More research is needed to clarify the nature of the syndrome-specific patterns of correlations between habituation and social and non-social functioning in these neurodevelopmental disorders.
