1. Bonnot O, Bonneau D, Doudard A, Duverger P. {{Rationale and protocol for using a smartphone application to study autism spectrum disorders: SMARTAUTISM}}. {BMJ Open};2016 (Nov 22);6(11):e012135.
INTRODUCTION: Longitudinal studies on the evolution of autism spectrum disorder (ASD) symptoms are limited and have primarily used repeated measurements performed several months apart. However, measurements of changes in everyday life should more closely reflect the ‘real life’ of the patient and his or her family. We propose to study the child’s ASD symptoms and their effect on the quality of life, psychological status and anxiety of the child’s parents over a 6-month period using SMARTAUTISM, a smartphone application. METHOD AND ANALYSIS: This is a prospective, longitudinal, exploratory, open study with a 6-month follow-up period. Data will be recorded longitudinally over multiple weeks under natural conditions. The factors affecting the quality of life and anxiety of parents of children with ASD and the children’s functional symptoms will be examined, and the feasibility of using a smartphone application designed for parents of ASD patients will be assessed. PRIMARY OBJECTIVE: Explore the evolution of a child’s behaviour over 6 months and the (psychological and social) effects of these changes on the family. SECONDARY OBJECTIVE: Assess the feasibility of our application by examining the filling rate and application usage by parents for 6 months. 100 families containing 1 child diagnosed with ASD will be included. At baseline, sociodemographic, psychiatric and medical data will be recorded. The correlations of the general epidemiological variables (primary outcome measure) will be evaluated via multivariate analysis. The application filling rate (relative to the ideal filling rate) will be used to assess the feasibility of the application (secondary outcome measure). ETHICS AND DISSEMINATION: The SMARTAUTISM study has the approval of the local ethics committee, and data security will be ensured via the use of encryption and a secure medical server. The use of this application will be proposed at autism resource centres across France.
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2. Ding HT, Taur Y, Walkup JT. {{Gut Microbiota and Autism: Key Concepts and Findings}}. {J Autism Dev Disord};2016 (Nov 24)
There is an emerging body of evidence linking the intestinal microbiota with autism spectrum disorders (ASD). Studies have demonstrated differences in the composition of gut bacteria between children with ASD and controls. Certain intestinal bacteria have been observed in abundance and may be involved in the pathogenesis of ASD; including members of the Clostridium and Sutterella genus. Evidence from animal models suggest that certain microbial shifts in the gut may produce changes consistent with the clinical picture of autism, with proposed mechanisms including toxin production, aberrations in fermentation processes/products, and immunological and metabolic abnormalities. In this article, we review studies examining the relationship between intestinal bacteria and ASD, and discuss bacterial species that may be implicated and proposed mechanisms.
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3. Ehrhart F, Coort SL, Cirillo E, Smeets E, Evelo CT, Curfs LM. {{Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes}}. {Orphanet J Rare Dis};2016 (Nov 25);11(1):158.
Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6-18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.
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4. Harris H, Israeli D, Minshew NJ, Bonneh YS, Heeger DJ, Behrmann M, Sagi D. {{Response: Commentary: Perceptual learning in autism: over-specificity and possible remedies}}. {Front Integr Neurosci};2016;10:36.
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5. Kokoszka MA, McGoldrick PE, La Vega-Talbott M, Raynes H, Palmese CA, Wolf SM, Harden CL, Ghatan S. {{Epilepsy surgery in patients with autism}}. {J Neurosurg Pediatr};2016 (Nov 25):1-12.
OBJECTIVE The purpose of this study was to report outcomes of epilepsy surgery in 56 consecutive patients with autism spectrum disorder. METHODS Medical records of 56 consecutive patients with autism who underwent epilepsy surgery were reviewed with regard to clinical characteristics, surgical management, postoperative seizure control, and behavioral changes. RESULTS Of the 56 patients with autism, 39 were male, 45 were severely autistic, 27 had a history of clinically significant levels of aggression and other disruptive behaviors, and 30 were considered nonverbal at baseline. Etiology of the epilepsy was known in 32 cases, and included structural lesions, medical history, and developmental and genetic factors. Twenty-nine patients underwent resective treatments (in 8 cases combined with palliative procedures), 24 patients had only palliative treatments, and 3 patients had only subdural electroencephalography. Eighteen of the 56 patients had more than one operation. The mean age at surgery was 11 +/- 6.5 years (range 1.5-35 years). At a mean follow-up of 47 +/- 30 months (range 2-117 months), seizure outcomes included 20 Engel Class I, 12 Engel Class II, 18 Engel Class III, and 3 Engel Class IV cases. The age and follow-up times are stated as the mean +/- SD. Three patients were able to discontinue all antiepileptic drugs (AEDs). Aggression and other aberrant behaviors observed in the clinical setting improved in 24 patients. According to caregivers, most patients also experienced some degree of improvement in daily social and cognitive function. Three patients had no functional or behavioral changes associated with seizure reduction, and 2 patients experienced worsening of seizures and behavioral symptoms. CONCLUSIONS Epilepsy surgery in patients with autism is feasible, with no indication that the comorbidity of autism should preclude a good outcome. Resective and palliative treatments brought seizure freedom or seizure reduction to the majority of patients, although one-third of the patients in this study required more than one procedure to achieve worthwhile improvement in the long term, and few patients were able to discontinue all AEDs. The number of palliative procedures performed, the need for multiple interventions, and continued use of AEDs highlight the complex etiology of epilepsy in patients with autism spectrum disorder. These considerations underscore the need for continued analysis, review, and reporting of surgical outcomes in patients with autism, which may aid in better identification and management of surgical candidates. The reduction in aberrant behaviors observed in this series suggests that some behaviors previously attributed to autism may be associated with intractable epilepsy, and further highlights the need for systematic evaluation of the relationship between the symptoms of autism and refractory seizures.
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6. Mitelman SA, Bralet MC, Haznedar MM, Hollander E, Shihabuddin L, Hazlett EA, Buchsbaum MS. {{Diametrical relationship between gray and white matter volumes in autism spectrum disorder and schizophrenia}}. {Brain Imaging Behav};2016 (Nov 23)
Autism spectrum disorders and schizophrenia have been variously characterized as separate nosological entities with overlapping deficits in social cognition or diametrical extremes of a phenotypic continuum. This study aimed to determine how these models apply to comparative morphometric data. MRI scans of the brain were obtained in 49 subjects with schizophrenia, 20 subjects with autism and 39 healthy controls. Images were parcellated into 40 Brodmann areas and entered into repeated-measures ANOVA for between-group comparison of global and localized gray and white matter volumes. A pattern of lower gray mater volumes and greater white matter volumes was found in subjects with schizophrenia in comparison to subjects with autism. For both gray and white matter, this pattern was most pronounced in regions associated with motor-premotor and anterior frontal cortex, anterior cingulate, fusiform, superior and middle temporal gyri. Patient groups tended to diverge from healthy controls in opposite directions, with greater-than-normal gray matter volumes and lower-than-normal white matter volumes in subjects with autism and reversed patterns in subjects with schizophrenia. White matter reductions in subjects with autism were seen in posterior frontal lobe and along the cingulate arch. Normal hemispheric asymmetry in the temporal lobe was effaced in subjects with autism and schizophrenia, especially in the latter. Nearly identical distribution of changes and diametrically divergent volumetry suggest that autism and schizophrenia may occupy opposite extremes of the same cognitive continuum.
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7. Pellecchia M, Beidas RS, Marcus SC, Fishman J, Kimberly JR, Cannuscio CC, Reisinger EM, Rump K, Mandell DS. {{Study protocol: implementation of a computer-assisted intervention for autism in schools: a hybrid type II cluster randomized effectiveness-implementation trial}}. {Implement Sci};2016 (Nov 25);11(1):154.
BACKGROUND: The number of children diagnosed with autism has rapidly outpaced the capacities of many public school systems to serve them, especially under-resourced, urban school districts. The intensive nature of evidence-based autism interventions, which rely heavily on one-to-one delivery, has caused schools to turn to computer-assisted interventions (CAI). There is little evidence regarding the feasibility, effectiveness, and implementation of CAI in public schools. While CAI has the potential to increase instructional time for students with autism, it may also result in unintended consequences such as reduction in the amount of interpersonal (as opposed to computerized) instruction students receive. The purpose of this study is to test the effectiveness of one such CAI-TeachTown-its implementation, and its effects on teachers’ use of other evidence-based practices. METHODS: This study protocol describes a type II hybrid cluster randomized effectiveness-implementation trial. We will train and coach 70 teachers in autism support classrooms in one large school district in the use of evidence-based practices for students with autism. Half of the teachers then will be randomly selected to receive training and access to TeachTown: Basics, a CAI for students with autism, for the students in their classrooms. The study examines: (1) the effectiveness of TeachTown for students with autism; (2) the extent to which teachers implement TeachTown the way it was designed (i.e., fidelity); and (3) whether its uptake increases or reduces the use of other evidence-based practices. DISCUSSION: This study will examine the implementation of new technology for children with ASD in public schools and will be the first to measure the effectiveness of CAI. As importantly, the study will investigate whether adding a new technology on top of existing practices increases or decreases their use. This study presents a unique method to studying both the implementation and exnovation of evidence-based practices for children with autism in school settings. TRIAL REGISTRATION: NCT02695693 . Retrospectively registered on July 8, 2016.
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8. Powell JL, Pringle L, Greig M. {{Investigation of the Association Between Motor Stereotypy Behavior With Fundamental Movement Skills, Adaptive Functioning, and Autistic Spectrum Disorder Symptomology in Children With Intellectual Disabilities}}. {J Child Neurol};2016 (Nov 25)
Motor stereotypy behaviors are patterned, coordinated, repetitive behaviors that are particularly evident in those with an autistic spectrum disorder and intellectual disabilities. The extent to which motor stereotypy behavior severity is associated with motor skills and maladaptive behavior, measures of adaptive functioning, along with fundamental movement skills and degree of autistic spectrum disorder symptomology is assessed in this preliminary report. Twelve participants, aged 7 to 16 years, with a reported motor stereotypy behavior and either mild or severe intellectual disability comprising developmental or global delay took part in the study. Spearman rho correlational analysis showed that severity of motor stereotypy behavior was significantly positively correlated with autistic spectrum disorder symptomology (P = .008) and maladaptive behavior (P = .008) but not fundamental movement skills (P > .05). An increase in fundamental movement skills score was associated with a decrease in autistic spectrum disorder symptomology (P = .01) and an increase in motor skills (P = .002). This study provides evidence showing a significant relationship between motor stereotypy behavior severity with degree of autistic spectrum disorder symptomology and maladaptive behavior.
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9. Tao J, Wu H, Coronado AA, de Laittre E, Osterweil EK, Zhang Y, Bear MF. {{Negative Allosteric Modulation of mGluR5 Partially Corrects Pathophysiology in a Mouse Model of Rett Syndrome}}. {J Neurosci};2016 (Nov 23);36(47):11946-11958.
Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated « translatome. » We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that were functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5-negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In Mecp2 KO mice, we found that mGluR5 NAM treatment significantly reduced the level of overexpressed ribosome-associated transcripts, particularly those that were also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and lifespan. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions. SIGNIFICANCE STATEMENT: Altered regulation of synaptic protein synthesis has been hypothesized to contribute to the pathophysiology that underlies multiple forms of intellectual disability and autism spectrum disorder. Here, we show in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus. We found that a subset of ribosome-bound mRNAs was aberrantly upregulated in hippocampal CA1 neurons of Mecp2 KO mice, that these significantly overlapped with FMRP direct targets and/or SFARI human autism genes, and that chronic treatment of Mecp2 KO mice with an mGluR5-negative allosteric modulator tunes down upregulated ribosome-bound mRNAs and partially improves mutant mice phenotypes.
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10. Verschuur R, Huskens B, Verhoeven L, Didden R. {{Increasing Opportunities for Question-Asking in School-Aged Children with Autism Spectrum Disorder: Effectiveness of Staff Training in Pivotal Response Treatment}}. {J Autism Dev Disord};2016 (Nov 25)
Deficits in question-asking are common in children with autism spectrum disorder (ASD). Furthermore, their opportunities to self-initiate questions are often hindered by directive behavior of their conversation partners. This study assessed the effectiveness of staff training in pivotal response treatment (PRT) on staff member-created opportunities and self-initiated questions of school-aged children with ASD. Generalization and maintenance were also assessed. Participants were 14 staff members and children with ASD attending an inpatient treatment facility. Data showed that PRT resulted in significant increases in both staff member-created opportunities and child-initiated questions. Generalization to group situations and collateral changes in children’s language, pragmatic, and adaptive skills, and maladaptive behaviors did not occur. Implications for clinical practice and directions for future research are discussed.
