1. Arnett MT, Herman DH, McGee AW. {{Deficits in tactile learning in a mouse model of fragile x syndrome}}. {PLoS One};2014;9(10):e109116.
The fragile X mental retardation 1 mutant mouse (Fmr1 KO) recapitulates several of the neurologic deficits associated with Fragile X syndrome (FXS). As tactile hypersensitivity is a hallmark of FXS, we examined the sensory representation of individual whiskers in somatosensory barrel cortex of Fmr1 KO and wild-type (WT) mice and compared their performance in a whisker-dependent learning paradigm, the gap cross assay. Fmr1 KO mice exhibited elevated responses to stimulation of individual whiskers as measured by optical imaging of intrinsic signals. In the gap cross task, initial performance of Fmr1 KO mice was indistinguishable from WT controls. However, while WT mice improved significantly with experience at all gap distances, Fmr1 KO mice displayed significant and specific deficits in improvement at longer distances which rely solely on tactile information from whiskers. Thus, Fmr1 KO mice possess altered cortical responses to sensory input that correlates with a deficit in tactile learning.
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2. Bone D, Goodwin MS, Black MP, Lee CC, Audhkhasi K, Narayanan S. {{Applying Machine Learning to Facilitate Autism Diagnostics: Pitfalls and Promises}}. {J Autism Dev Disord};2014 (Oct 8)
Machine learning has immense potential to enhance diagnostic and intervention research in the behavioral sciences, and may be especially useful in investigations involving the highly prevalent and heterogeneous syndrome of autism spectrum disorder. However, use of machine learning in the absence of clinical domain expertise can be tenuous and lead to misinformed conclusions. To illustrate this concern, the current paper critically evaluates and attempts to reproduce results from two studies (Wall et al. in Transl Psychiatry 2(4):e100, 2012a; PloS One 7(8), 2012b) that claim to drastically reduce time to diagnose autism using machine learning. Our failure to generate comparable findings to those reported by Wall and colleagues using larger and more balanced data underscores several conceptual and methodological problems associated with these studies. We conclude with proposed best-practices when using machine learning in autism research, and highlight some especially promising areas for collaborative work at the intersection of computational and behavioral science.
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3. Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, Siniscalco D. {{Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study}}. {Cell Transplant};2014 (Oct 9)
Autism spectrum disorders (ASDs) are heterogeneous complex neurodevelopmental pathologies defined by behavioral symptoms, but which have well characterized genetic, immunological and physiological comorbidities. Despite extensive research efforts, there are presently no agreed upon therapeutic approaches for either the core behaviors or the associated comorbidities. In particularly, the known autoimmune disorders associated with autism, are appealing targets for potential stem cell therapeutics. And of the various stem cell populations, fetal stem cells (FSCs) offer the potent immunoregulatory functions found in primordial mesenchymal stem cells, while exhibiting rapid expansion capacity and recognized plasticity. These properties enhance their potential for clinical use. Furthermore, FSCs are potent and implantable ?biopharmacies? capable of delivering trophic signals to the host which could influence brain development. This study investigated the safety and efficacy of FSC transplantations in treating children diagnosed with ASDs. Subjects were monitored at pre, and then 6 and 12 months following the transplantations which consisted of two doses of intravenously and subcutaneously administered FSCs. Autism Treatment Evaluation Checklist (ATEC) test and Aberrant Behavior Checklist (ABC) scores were performed. Laboratory examinations and clinical assessment of adverse effects were performed in order to evaluate treatment safety. No adverse events of significance were observed in ASD children treated with FSCs, including no transmitted infections or immunological complications. Statistically significant differences (p<0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory and overall health, as well as reductions in the total scores when compared to pre-treatment values. We recognize the use of FSCs remains controversial for the present. The results of this study, however, warrant addition investigations into the mechanisms of cell therapies for ASDs, while prompting the exploration of FSCs as ?biopharmacies? capable of manufacturing the full array of cell-signaling chemistry. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
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4. Busch de Ahumada LC, Ahumada JL. {{Contacting a 19 month-old mute autistic girl: A clinical narrative}}. {Int J Psychoanal};2014 (Oct 8)
Conveying that psychoanalysis offers rich opportunities for the very early treatment of autistic spectrum disorders, this clinical communication unfolds the clinical process of a 19 month-old ‘shell-type’ encapsulated mute autistic girl. It details how, in a four-weekly-sessions schedule, infant Lila evolved within two years from being emotionally out-of-contact to the affective aliveness of oedipal involvement. Following Frances Tustin’s emphasis on the analyst’s ‘quality of attention’ and Justin Call’s advice that in baby-mother interaction the infant is the initiator and the mother is the follower, it is described how the analyst must, amid excruciating non-response, even-mindedly sustain her attention in order to meet the child half-way at those infrequent points where flickers of initiative on her side are adumbrated. This helps attain evanescent ‘moments of contact’ which coalesce later into ‘moments of sharing’, eventually leading to acknowledgment of the analyst’s humanness and a receptiveness for to-and-fro communication. Thus the ‘primal dialogue’ (Spitz) is reawakened and, by experiencing herself in the mirror of the analyst, the child’s sense of I-ness is reinstated. As evinced by the literature, the mainstream stance rests on systematic early interpretation of the transference, which has in our view strongly deterred progress in the psychoanalytic treatment of autistic spectrum disorders.
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5. Chantiluke K, Barrett N, Giampietro V, Brammer M, Simmons A, Rubia K. {{Disorder-dissociated effects of fluoxetine on brain function of working memory in attention deficit hyperactivity disorder and autism spectrum disorder}}. {Psychol Med};2014 (Oct 8):1-11.
Background. Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often co-morbid and share performance and brain dysfunctions during working memory (WM). Serotonin agonists modulate WM and there is evidence of positive behavioural effects in both disorders. We therefore used functional magnetic resonance imaging (fMRI) to investigate shared and disorder-specific brain dysfunctions of WM in these disorders, and the effects of a single dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Method. Age-matched boys with ADHD (n = 17), ASD (n = 17) and controls (n = 22) were compared using fMRI during an N-back WM task. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomized design. Repeated-measures analyses within patients assessed drug effects on performance and brain function. To test for normalization effects of brain dysfunctions, patients under each drug condition were compared to controls. Results. Under placebo, relative to controls, both ADHD and ASD boys shared underactivation in the right dorsolateral prefrontal cortex (DLPFC). Fluoxetine significantly normalized the DLPFC underactivation in ASD relative to controls whereas it increased posterior cingulate cortex (PCC) deactivation in ADHD relative to control boys. Within-patient analyses showed inverse effects of fluoxetine on PCC deactivation, which it enhanced in ADHD and decreased in ASD. Conclusions. The findings show that fluoxetine modulates brain activation during WM in a disorder-specific manner by normalizing task-positive DLPFC dysfunction in ASD boys and enhancing task-negative default mode network (DMN) deactivation in ADHD.
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6. Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ, Ye AY, Waqar Z, Gonzalez LE, Overton JD, Frahm S, Keaney JF, 3rd, Teran NA, Dea J, Mandell JD, Hus Bal V, Sullivan CA, DiLullo NM, Khalil RO, Gockley J, Yuksel Z, Sertel SM, Ercan-Sencicek AG, Gupta AR, Mane SM, Sheldon M, Brooks AI, Roeder K, Devlin B, State MW, Wei L, Sanders SJ. {{De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder}}. {Cell Rep};2014 (Oct 9);9(1):16-23.
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 x 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
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7. Hosokawa M, Nakadoi Y, Watanabe Y, Sumitani S, Ohmori T. {{Association of autism tendency and hemodynamic changes in the prefrontal cortex during facial expression stimuli measured by multi-channel near-infrared spectroscopy}}. {Psychiatry Clin Neurosci};2014 (Oct 9)
AIM: The aim of this study is to examine the hemodynamic changes induced by cognitive process of facial expression by using multichannel near-infrared spectroscopy (NIRS) in healthy subjects with varying degree of autism tendency. METHODS: Subjects were 38 volunteers, 20 males and 18 females. Autism tendency was measured by the Autism Spectrum Quotient (AQ). The hemodynamic changes in the prefrontal cortex (PFC) were measured by 24-channel NIRS system, while they were asked to judge their own emotional response to standardized pictures of 8 kinds of facial expressions on a computer screen. RESULTS: There were significant negative correlations between AQ scores and accuracy of fearful expression recognition as well as increases in the concentration of oxygenated hemoglobin in response to four kinds of emotional faces (fear, contempt, sadness and disgust). CONCLUSION: Our findings suggest that the more tendency to autism subjects have, the more difficulty they have in recognizing fearful expression and the less hemodynamic change in the PFC they show in response to negative facial expressions.
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8. Jonch AE, Gronskov K, Carlsen Lunding JM, Nielsen JE, Brondum-Nielsen K. {{[Carriers of fragile X syndrome can present with a broad spectrum of clinical disorders.]}}. {Ugeskr Laeger};2014 (Jun 23);176(26)
Fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are three clinically distinct disorders caused by expansions of a CGG repeat sequence in the non-coding part of the FMR1. FXTAS and FXPOI are seen in carriers of smaller repeat expansions (55-200). Carriers were for many years thought to be clinically unaffected, but along with the discovery of FXPOI and FXTAS a growing number of additional clinical manifestations have been identified. We wish to make Danish physicians more aware of these conditions which we review in this paper.
9. Kodak T, Clements A, Paden AR, LeBlanc B, Mintz J, Toussaint KA. {{Examination of the relation between an assessment of skills and performance on auditory-visual conditional discriminations for children with autism spectrum disorder}}. {J Appl Behav Anal};2014 (Oct 8)
The current investigation evaluated repertoires that may be related to performance on auditory-to-visual conditional discrimination training with 9 students who had been diagnosed with autism spectrum disorder. The skills included in the assessment were matching, imitation, scanning, an auditory discrimination, and a visual discrimination. The results of the skills assessment showed that 4 participants failed to demonstrate mastery of at least 1 of the skills. We compared the outcomes of the assessment to the results of auditory-visual conditional discrimination training and found that training outcomes were related to the assessment outcomes for 7 of the 9 participants. One participant who did not demonstrate mastery of all assessment skills subsequently learned several conditional discriminations when blocked training trials were conducted. Another participant who did not demonstrate mastery of the auditory discrimination skill subsequently acquired conditional discriminations in 1 of the training conditions. We discuss the implications of the assessment for practice and suggest additional areas of research on this topic.
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10. Kumar M, Duda JT, Hwang WT, Kenworthy C, Ittyerah R, Pickup S, Brodkin ES, Gee JC, Abel T, Poptani H. {{High Resolution Magnetic Resonance Imaging for Characterization of the Neuroligin-3 Knock-in Mouse Model Associated with Autism Spectrum Disorder}}. {PLoS One};2014;9(10):e109872.
Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.
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11. Libertus K, Landa RJ. {{Scaffolded reaching experiences encourage grasping activity in infants at high risk for autism}}. {Front Psychol};2014;5:1071.
Recent findings suggest impaired motor skill development during infancy in children later diagnosed with autism spectrum disorders (ASD). However, it remains unclear whether infants at high familial risk for ASD would benefit from early interventions targeting the motor domain. The current study investigated this issue by providing 3-month-old infants at high familial risk for ASD with training experiences aimed at facilitating independent reaching. A group of 17 high-risk (HR) infants received 2 weeks of scaffolded reaching experiences using « sticky mittens, » and was compared to 72 low-risk (LR) infants experiencing the same or alternative training procedures. Results indicate that HR infants – just like LR infants – show an increase in grasping activity following « sticky mittens » training. In contrast to LR infants, evidence that motor training encouraged a preference for faces in HR infants was inconclusive.
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12. Lin LY. {{Quality of life of taiwanese adults with autism spectrum disorder}}. {PLoS One};2014;9(10):e109567.
BACKGROUND: To date, few recent studies have investigated the quality of life of adults with autism spectrum disorder (ASD). It remains unclear how individuals with ASD view their own quality of life. OBJECTIVE: The primary purpose of this study was to compare the quality of life scores among adults with ASD with those of a non-ASD control group and the Taiwanese health population reference group. METHODS: The study comprised 41 adults with ASD (M age = 26.9, SD = 5.0), and without intellectual disabilities (IQ>70). A comparison sample of 41 adults without ASD was selected by matching the age and sex of the participants with ASD. A validated measure, the Taiwanese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF), was used. Independent t-tests were performed to examine the differences in the quality of life between groups. RESULTS: The highest quality of life was scored in the environment domain, followed by the physical health and psychological health domains. The lowest quality of life score was found in the social relationship domain. Adults with ASD scored significantly lower in all domains than did the non-ASD control group. Additionally, adults with ASD scored significantly lower in the physical health, psychological health, and social relationship domains than did the Taiwanese health population reference group. Comorbid psychiatric disorders, self-rated health status, and perceived happiness were correlated with quality of life among adults with ASD. CONCLUSION: The preliminary findings suggest that adults with ASD need more supportive social contexts and interventions to promote their quality of life. Based on our findings, social relationship must be considered in designing and applying treatment programs for adults with ASD.
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13. Rodriguez NM, Thompson RH. {{Behavioral variability and autism spectrum disorders}}. {J Appl Behav Anal};2014 (Oct 8)
Restricted and repetitive behavior is a diagnostic characteristic of autism spectrum disorder (ASD). To the extent that the behavior of individuals with ASD can be conceptualized as problems of invariance, our understanding of environmental variables that influence restricted and repetitive behavior may be informed by the basic and applied literature on response variability. The purposes of this paper are (a) to describe how restricted and repetitive behavior can be conceptualized as problems of invariance, (b) to consider the implications of a lack of varied responding for individuals with ASD, (c) to review relevant basic and applied research on response variability, (d) to present methods to address invariant responding for individuals with ASD, and (e) to suggest areas for future research.
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14. Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME. {{CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors}}. {Proc Natl Acad Sci U S A};2014 (Oct 7)
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10-8) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10-10). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.
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15. Wilkes-Gillan S, Falkmer M. {{A peer-mediated school intervention significantly improved the social skills and playground interactions of children with autism spectrum disorder}}. {Aust Occup Ther J};2014 (Oct);61(5):371-372.
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16. Xin JF, Leonard DA. {{Using iPads to Teach Communication Skills of Students with Autism}}. {J Autism Dev Disord};2014 (Oct 8)
The purpose of this study was to examine the effects of using an iPad to assist students with autism in learning communication skills. Three, 10 years old learners diagnosed with autism who present little or no functional speech, participated in the study. A multiple baseline design with AB phases across academic and social settings was used. During the baseline, students were given access to an iPad with the SonoFlex speech-generating device application, while no communicative attempts were observed. During the intervention, the students were taught to use the iPad to communicate with their teacher and peers for 6 weeks. With a least-to-most prompting hierarchy, all students increased initiating requests, responding to questions and making social comments in both class and recess settings.
