1. Abraham A, Milham M, Martino AD, Craddock RC, Samaras D, Thirion B, Varoquaux G. {{Deriving reproducible biomarkers from multi-site resting-state data: An Autism-based example}}. {Neuroimage};2016 (Nov 16)
Resting-state functional Magnetic Resonance Imaging (R-fMRI) holds the promise to reveal functional biomarkers of neuropsychiatric disorders. However, extracting such biomarkers is challenging for complex multi-faceted neuropathologies, such as autism spectrum disorders. Large multi-site datasets increase sample sizes to compensate for this complexity, at the cost of uncontrolled heterogeneity. This heterogeneity raises new challenges, akin to those face in realistic diagnostic applications. Here, we demonstrate the feasibility of inter-site classification of neuropsychiatric status, with an application to the Autism Brain Imaging Data Exchange (ABIDE) database, a large (N=871) multi-site autism dataset. For this purpose, we investigate pipelines that extract the most predictive biomarkers from the data. These R-fMRI pipelines build participant-specific connectomes from functionally-defined brain areas. Connectomes are then compared across participants to learn patterns of connectivity that differentiate typical controls from individuals with autism. We predict this neuropsychiatric status for participants from the same acquisition sites or different, unseen, ones. Good choices of methods for the various steps of the pipeline lead to 67% prediction accuracy on the full ABIDE data, which is significantly better than previously reported results. We perform extensive validation on multiple subsets of the data defined by different inclusion criteria. These enables detailed analysis of the factors contributing to successful connectome-based prediction. First, prediction accuracy improves as we include more subjects, up to the maximum amount of subjects available. Second, the definition of functional brain areas is of paramount importance for biomarker discovery: brain areas extracted from large R-fMRI datasets outperform reference atlases in the classification tasks.
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2. Bandini LG, Curtin C, Phillips S, Anderson SE, Maslin M, Must A. {{Changes in Food Selectivity in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Nov 19)
Food selectivity is a common problem in children with autism spectrum disorder (ASD) and has an adverse impact on nutrient adequacy and family mealtimes. Despite recent research in this area, few studies have addressed whether food selectivity present in children with ASD persists into adolescence. In this study, we assessed food selectivity in 18 children with ASD at two time points (mean age = 6.8 and 13.2 years), and examined changes in food selectivity. While food refusal improved overall, we did not observe an increase in food repertoire (number of unique foods eaten). These findings support the need for interventions early in childhood to increase variety and promote healthy eating among children with ASD.
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3. D NL, Bertolin M, E LS, Keith C, Braddock B, Kaufman DA. {{Parents Perceive Improvements in Socio-emotional Functioning in Adolescents with ASD Following Social Skills Treatment}}. {J Autism Dev Disord};2016 (Nov 21)
The current study examined the effectiveness of a social skills treatment (PEERS) for improving socio-emotional competencies in a sample of high-functioning adolescents with ASD. Neuropsychological and self- and parent-report measures assessing social, emotional, and behavioral functioning were administered before and after treatment. Following social skills treatment, adolescents with ASD exhibited decreased aggression, anxiety, and withdrawal, as well as improvements in emotional responsiveness, adaptability, leadership, and participation in activities of daily living, though no change was found in affect recognition abilities. These findings suggest that PEERS social skills treatment improves particular aspects of emotional, behavioral, and social functioning that may be necessary for developing and maintaining quality peer relationships and remediating social isolation in adolescents with ASD.
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4. Finke EH, Wilkinson KM, Hickerson BD. {{Social Referencing Gaze Behavior During a Videogame Task: Eye Tracking Evidence from Children With and Without ASD}}. {J Autism Dev Disord};2016 (Nov 19)
The purpose of this study was to understand the social referencing behaviors of children with and without autism spectrum disorder (ASD) while visually attending to a videogame stimulus depicting both the face of the videogame player and the videogame play action. Videogames appear to offer a uniquely well-suited environment for the emergence of friendships, but it is not known if children with and without ASD attend to and play videogames similarly. Eyetracking technology was used to investigate visual attention of participants matched based on chronological age. Parametric and nonparametric statistical analyses were used and results indicated the groups did not differ on percentage of time spent visually attending to any of the areas of interest, with one possible exception.
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5. Hodges JL, Yu X, Gilmore A, Bennett H, Tjia M, Perna JF, Chen CC, Li X, Lu J, Zuo Y. {{Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome}}. {Biol Psychiatry};2016 (Sep 13)
BACKGROUND: Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. METHODS: Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. RESULTS: We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects. CONCLUSIONS: Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.
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6. Millar-Buchner P, Philp AR, Gutierrez N, Villanueva S, Kerr B, Flores CA. {{Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome}}. {Mol Cell Pediatr};2016 (Dec);3(1):37.
BACKGROUND: Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. METHODS: Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. RESULTS: First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. CONCLUSIONS: In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.
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7. Naaijen J, Zwiers MP, Amiri H, Williams SC, Durston S, Oranje B, Brandeis D, Boecker-Schlier R, Ruf M, Wolf I, Banaschewski T, Glennon JC, Franke B, Buitelaar JK, Lythgoe DJ. {{Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder}}. {Neuropsychopharmacology};2016 (Nov 21)
Autism spectrum disorders (ASD) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy (1H MRS) in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8 to 13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model (LCModel). Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. Additionally, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared to controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.Neuropsychopharmacology accepted article preview online, 21 November 2016. doi:10.1038/npp.2016.260.
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8. Petrina N, Carter M, Stephenson J, Sweller N. {{Friendship Satisfaction in Children with Autism Spectrum Disorder and Nominated Friends}}. {J Autism Dev Disord};2016 (Nov 19)
The current study examined the level of friendship satisfaction of children with autism spectrum disorder (ASD) and their nominated friends (with and without diagnosis of ASD). A total of 77 target children with ASD and friends from 49 nominated friendships participated in the study. Relatively high levels of friendship satisfaction were reported by both target children and their nominated friends with no overall difference between dyads involving typically developing friends and friends with ASD. Analysis at the individual dyad level showed a high level of agreement on the reported level of satisfaction across the target participants and their friends. Limitations and directions for future research are presented.
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9. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjorklund G, Jia F, Urbina MA, Abo-Elela MG, Ahmad FA, Abd El-Baseer KA, Ahmed AE, Abdel-Salam AM. {{Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder}}. {J Child Psychol Psychiatry};2016 (Nov 21)
BACKGROUND: Autism spectrum disorder (ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children. METHODS: This study is a double-blinded, randomized clinical trial (RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10 years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4 months. The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC). TRIAL REGISTRATION NUMBER: UMIN-CTR Study Design: trial number: UMIN000020281. RESULTS: Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300 IU vitamin D3/kg/day, not to exceed 5,000 IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD. CONCLUSIONS: This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD.
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10. Sheppard E, van Loon E, Underwood G, Ropar D. {{Attentional Differences in a Driving Hazard Perception Task in Adults with Autism Spectrum Disorders}}. {J Autism Dev Disord};2016 (Nov 19)
The current study explored attentional processing of social and non-social stimuli in ASD within the context of a driving hazard perception task. Participants watched videos of road scenes and detected hazards while their eye movements were recorded. Although individuals with ASD demonstrated relatively good detection of driving hazards, they were slower to orient to hazards. Greater attentional capture in the time preceding the hazards’ onset was associated with lower verbal IQ. The findings suggest that individuals with ASD may distribute and direct their attention differently when identifying driving hazards.
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11. Torres EB, Denisova K. {{Motor noise is rich signal in autism research and pharmacological treatments}}. {Sci Rep};2016 (Nov 21);6:37422.
The human body is in constant motion, from every breath that we take, to every visibly purposeful action that we perform. Remaining completely still on command is a major achievement as involuntary fluctuations in our motions are difficult to keep under control. Here we examine the noise-to-signal ratio of micro-movements present in time-series of head motions extracted from resting-state functional magnetic resonance imaging scans in 1048 participants. These included individuals with autism spectrum disorders (ASD) and healthy-controls in shared data from the Autism Brain Imaging Data Exchange (ABIDE) and the Attention-Deficit Hyperactivity Disorder (ADHD-200) databases. We find excess noise and randomness in the ASD cases, suggesting an uncertain motor-feedback signal. A power-law emerged describing an orderly relation between the dispersion and shape of the probability distribution functions best describing the stochastic properties under consideration with respect to intelligence quotient (IQ-scores). In ASD, deleterious patterns of noise are consistently exacerbated with the presence of secondary (comorbid) neuropsychiatric diagnoses, lower verbal and performance intelligence, and autism severity. Importantly, such patterns in ASD are present whether or not the participant takes psychotropic medication. These data unambiguously establish specific noise-to-signal levels of head micro-movements as a biologically informed core feature of ASD.
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12. Warner G, Howlin P, Salomone E, Moss J, Charman T. {{Profiles of children with Down syndrome who meet screening criteria for autism spectrum disorder (ASD): a comparison with children diagnosed with ASD attending specialist schools}}. {J Intellect Disabil Res};2016 (Nov 21)
BACKGROUND: Recent research suggests that around 16% to 18% of children with Down syndrome (DS) also meet diagnostic criteria for autism spectrum disorder (ASD). However, there are indications that profiles of autism symptoms in this group may vary from those typically described in children with ASD. METHOD: Rates of autism symptoms and emotional and behavioural problems among children with DS who screened positive for ASD on the Social Communication Questionnaire (SCQ) (n = 183) were compared with a group of children with clinical diagnoses of ASD (n = 189) attending specialist schools in the UK. Groups were matched for age and approximate language level (use of phrase speech). RESULTS: Profiles of autistic symptoms in the two groups were generally similar, but children with DS meeting ASD cut-off on the SCQ tended to show fewer problems in reciprocal social interaction than those in the ASD group. They also showed slightly lower rates of emotional and peer-related problems. The results mostly confirm findings from a previous study in which the original validation sample for the SCQ was used as a comparison group. CONCLUSION: Findings suggest that children with DS who meet screening criteria for ASD show similar profiles of communication and repetitive behaviours to those typically described in autism. However, they tend to have relatively milder social difficulties. It is important that clinicians are aware of this difference if children with DS and ASD are to be correctly diagnosed and eligible for specialist intervention and education services.
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13. Westerveld MF, Paynter J, Trembath D, Webster AA, Hodge AM, Roberts J. {{The Emergent Literacy Skills of Preschool Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Nov 19)
A high percentage of school-age students with autism spectrum disorder (ASD) have reading comprehension difficulties leading to academic disadvantage. These difficulties may be related to differences in children’s emergent literacy development in the preschool years. In this study, we examined the relationship between emergent literacy skills, broader cognitive and language ability, autism severity, and home literacy environment factors in 57 preschoolers with ASD. The children showed strengths in code-related emergent literacy skills such as alphabet knowledge, but significant difficulties with meaning-related emergent literacy skills. There was a significant relationship between meaning-related skills, autism severity, general oral language skills, and nonverbal cognition. Identification of these meaning-related precursors will guide the targets for early intervention to help ensure reading success for students with ASD.
