1. AlAyadhi LY, Hashmi JA, Iqbal M, Albalawi AM, Samman MI, Elamin NE, Bashir S, Basit S. {{High-resolution SNP genotyping platform identified recurrent and novel CNVs in autism multiplex families}}. {Neuroscience};2016 (Oct 19)
Single nucleotide polymorphisms (SNPs)-based genotyping using microarray platform is now frequently used to detect copy number variants (CNVs) in the human genome. Here, we report CNVs identified using Illumina Human Omni 2.5M oligonucleotide microarrays in 11 multiplex families with autism spectrum disorder (ASD) referred to Autism Research and Treatment Center (ART) and Madinah Maternity and Children Hospital (MMCH). Of the 11 families, 22 patients with ASD (all males) and their parents, were recruited for the present study. In total, 43 individuals were genotyped with high-resolution array. Abnormal microarray results were seen in all 22 patients with ASD. A total of 17 shared CNVs were selected for further analysis. Out of these 17 CNVs, we discovered one novel CNV, previously not described, and 16 recurrent CNVs that overlap with the genomic imbalances defined in the autism database, autism chromosome rearrangement database and database of genomic variants. Recurrent CNVs include 11 common and 5 rare CNVs. All rare CNVs are duplications except a 16-kb deletion on chr2q36.3. Rare gain of copy numbers includes a 2-kb duplication on chr9q21.13, overlapping duplications of 107kb and 181kb on chrXp22.33 in 2 different families and a 10-kb duplication on chr18q21.13. A novel loss of copy number on chr3q23 was found in four ASD cases. This CNV results in deletion of intron 2 of calsyntenin 2 (CLSTN2) encoding synaptic protein calsyntenin 2. CLSTN2 is expressed exclusively in the brain, with high levels occurring in cortical gamma-aminobutyric acid (GABA)ergic interneurons and in medial temporal lobe regions. These results verify the diagnostic relevance of genome-wide small common and rare CNVs and provide further evidence of the high diagnostic yield of microarray for genetic testing in children with ASD.
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2. Andersen SL, Laurberg P. {{Authors’ reply re: Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study}}. {BJOG};2016 (Nov);123(12):2051-2052.
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3. Bottema-Beutel K. {{Associations between joint attention and language in autism spectrum disorder and typical development: A systematic review and meta-regression analysis}}. {Autism Res};2016 (Oct);9(10):1021-1035.
Using a structured literature search and meta-regression procedures, this study sought to determine whether associations between joint attention and language are moderated by group (autism spectrum disorder [ASD] vs. typical development [TD]), joint attention type (responding to joint attention [RJA] vs. other), and other study design features and participant characteristics. Studies were located using database searches, hand searches, and electronic requests for data from experts in the field. This resulted in 71 reports or datasets and 605 effect sizes, representing 1,859 participants with ASD and 1,835 TD participants. Meta-regression was used to answer research questions regarding potential moderators of the effect sizes of interest, which were Pearson’s r values quantifying the association between joint attention and language variables. In the final models, conducted separately for each language variable, effect sizes were significantly higher for the ASD group as compared to the TD group, and for RJA as compared to non-RJA joint attention types. Approximate mental age trended toward significance for the expressive language model. Joint attention may be more tightly tied to language in children with ASD as compared to TD children because TD children exhibit joint attention at sufficient thresholds so that language development becomes untethered to variations in joint attention. Conversely, children with ASD who exhibit deficits in joint attention develop language contingent upon their joint attention abilities. Because RJA was more strongly related to language than other types of joint attention, future research should involve careful consideration of the operationalization and measurement of joint attention constructs. Autism Res 2016, 9: 1021-1035. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Calabrese V, Giordano J, Ruggieri M, Berritta D, Trovato A, Ontario ML, Bianchini R, Calabrese EJ. {{Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders}}. {J Neurosci Res};2016 (Dec);94(12):1488-1498.
In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. (c) 2016 Wiley Periodicals, Inc.
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5. Caplette L, Wicker B, Gosselin F. {{Atypical Time Course of Object Recognition in Autism Spectrum Disorder}}. {Sci Rep};2016 (Oct 18);6:35494.
In neurotypical observers, it is widely believed that the visual system samples the world in a coarse-to-fine fashion. Past studies on Autism Spectrum Disorder (ASD) have identified atypical responses to fine visual information but did not investigate the time course of the sampling of information at different levels of granularity (i.e. Spatial Frequencies, SF). Here, we examined this question during an object recognition task in ASD and neurotypical observers using a novel experimental paradigm. Our results confirm and characterize with unprecedented precision a coarse-to-fine sampling of SF information in neurotypical observers. In ASD observers, we discovered a different pattern of SF sampling across time: in the first 80 ms, high SFs lead ASD observers to a higher accuracy than neurotypical observers, and these SFs are sampled differently across time in the two subject groups. Our results might be related to the absence of a mandatory precedence of global information, and to top-down processing abnormalities in ASD.
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6. Chien HY, Gau SS, Isaac Tseng WY. {{Deficient visuospatial working memory functions and neural correlates of the default-mode network in adolescents with autism spectrum disorder}}. {Autism Res};2016 (Oct);9(10):1058-1072.
In addition to the essential features of autism spectrum disorder (ASD), namely social communication deficits and repetitive behaviors, individuals with ASD may suffer from working memory deficits and an altered default-mode network (DMN). We hypothesized that an altered DMN is related to working memory deficits in those with ASD. A total of 37 adolescents with ASD and 36 age- and IQ-matched typically developing (TD) controls were analyzed. Visuospatial working memory performance was assessed using pattern recognition memory (PRM), spatial recognition memory (SRM), and paired-associates learning (PAL) tasks. The intrinsic functional connectivity (iFC) of the DMN was indexed by the temporal correlations between the resting-state functional magnetic resonance imaging signals of pairs of DMN regions, including those between the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) and between the PCC and parahippocampi (PHG). The corresponding structural connectivity of the DMN was indexed by the generalized fractional anisotropy (GFA) of the dorsal and ventral cingulum bundles on the basis of diffusion spectrum imaging data. The results showed that ASD adolescents exhibited delayed correct responses in PRM and SRM tasks and committed more errors in the PAL task than the TD controls did. The delayed responses during the PRM and SRM tasks were negatively correlated with bilateral PCC-mPFC iFCs, and PAL performance was negatively correlated with right PCC-PHG iFC in ASD adolescents. Furthermore, ASD adolescents showed significant lower GFA in the right cingulum bundles than the TD group did; the GFA value was negatively correlated with SRM performance in ASD. Our results provide empirical evidence for deficient visuospatial working memory and corresponding neural correlates within the DMN in adolescents with ASD. Autism Res 2016, 9: 1058-1072. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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7. DiStefano C, Shih W, Kaiser A, Landa R, Kasari C. {{Communication growth in minimally verbal children with ASD: The importance of interaction}}. {Autism Res};2016 (Oct);9(10):1093-1102.
Little is known about language development in children with Autism Spectrum Disorders (ASD) who remain minimally verbal past age 5. While there is evidence that children can develop language after age 5, we lack detailed information. Studies of this population generally focus on discrete language skills without addressing broader social-communication abilities. As communication and social deficits are both inherent to ASD, an examination of not only what language skills are acquired, but how those skills are used in interactions is relevant. Research in typical development has examined how communication interchanges (unbroken back-and-forth exchanges around a unified purpose) develop, which can be used as a framework for studying minimally verbal children. This study examined the interchange use by 55 children with ASD over the course of a 6-month play and engagement-based communication intervention. Half of the children received intervention sessions that also incorporated a speech-generating device (SGD). Interchanges were coded by: frequency, length, function, and initiator (child or adult). Results indicated that children initiated a large proportion of interchanges and this proportion increased over time. The average length and number of interchanges increased over time, with children in the SGD group showing even greater growth. Finally, children’s total number of interchanges at baseline was positively associated with their spoken language gains over the course of intervention. This study supports the crucial relationship between social engagement and expressive language development, and highlights the need to include sustained communication interchanges as a target for intervention with this population. Autism Res 2016, 9: 1093-1102. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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8. Fluegge K. {{Re: Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study: Maternal hypothyroidism and risk of autism}}. {BJOG};2016 (Nov);123(12):2050-2051.
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9. Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. {{Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial}}. {Mol Psychiatry};2016 (Oct 18)
We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg-1 per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-alpha autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen’s d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen’s d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.Molecular Psychiatry advance online publication, 18 October 2016; doi:10.1038/mp.2016.168.
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10. Granich J, Dass A, Busacca M, Moore D, Anderson A, Venkatesh S, Duong T, Vellanki P, Richdale A, Trembath D, Cairns D, Marshall W, Rodwell T, Rayner M, Whitehouse AJ. {{Randomised controlled trial of an iPad based early intervention for autism: TOBY playpad study protocol}}. {BMC Pediatr};2016 (Oct 19);16(1):167.
BACKGROUND: Evidence for early intensive behavioural interventions (EIBI) by therapists as an effective treatment for children with an Autism Spectrum Disorder (ASD) is growing. High-intensity and sustained delivery of quality EIBI is expensive. The TOBY (Therapy Outcomes by You) Playpad is an App-based platform delivering EIBI to facilitate learning for young children with ASD, while enabling parents to become co-therapists. Intervention targets include increasing joint attention, imitation and communication of children with ASD. The primary aim of the study presented in this protocol is to determine the effectiveness of the TOBY App in reducing ASD symptoms when used as a complement to conventional EIBI. The secondary aim is to examine parental attributes as a result of TOBY App use. METHODS AND DESIGN: Children aged less than 4;3 years diagnosed with ASD and parents will be recruited into this single-blind, randomised controlled trial using a pragmatic approach. Eligible participants will be randomised to the treatment group ‘TOBY therapy + therapy as usual’ or, the control group ‘therapy as usual’ for six months. The treatment will be provided by the TOBY App and parent where a combination of learning environments such as on-iPad child only (solo), partner (with parent) and off-iPad – Natural Environment (with parent) Tasks will be implemented. Parents in the treatment group will participate in a TOBY training workshop. Treatment fidelity will be monitored via an App-based reporting system and parent diaries. The primary outcome measure is the Autism Treatment Evaluation Checklist. The secondary outcome measures involve diagnostics, functional and developmental assessments, including parent questionnaires at baseline (T0), three months (T1) and six months (T2). DISCUSSION: This trial will determine the effectiveness of the TOBY App as a therapeutic complement to other early interventions children with ASD receive. The trial will also determine the feasibility of a parent delivered early intervention using the iPad as an educational platform, and assess the impact of the TOBY App on parents’ self-efficacy and empowerment in an effort to reduce children’s ASD symptoms. The outcomes of this trial may have EIBI services implications for newly diagnosed children with ASD and parents. TRIAL REGISTRATION: ACTRN12614000738628 retrospectively registered on 1st of July, 2014. UTN: U1111-1158-6423.
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11. Herringshaw AJ, Ammons CJ, DeRamus TP, Kana RK. {{Hemispheric differences in language processing in autism spectrum disorders: A meta-analysis of neuroimaging studies}}. {Autism Res};2016 (Oct);9(10):1046-1057.
Language impairments, a hallmark feature of autism spectrum disorders (ASD), have been related to neuroanatomical and functional abnormalities. Abnormal lateralization of the functional language network, increased reliance on visual processing areas, and increased posterior brain activation have all been reported in ASD and proposed as explanatory models of language difficulties. Nevertheless, inconsistent findings across studies have prevented a comprehensive characterization of the functional language network in ASD. The aim of this study was to quantify common and consistent patterns of brain activation during language processing in ASD and typically developing control (TD) participants using a meta-analytic approach. Activation likelihood estimation (ALE) meta-analysis was used to examine 22 previously published functional Magnetic Resonance Imaging (fMRI)/positron emission tomography studies of language processing (ASD: N = 328; TD: N = 324). Tasks included in this study addressed semantic processing, sentence comprehension, processing figurative language, and speech production. Within-group analysis showed largely overlapping patterns of language-related activation in ASD and TD groups. However, the ASD participants, relative to TD participants, showed: (1) more right hemisphere activity in core language areas (i.e., superior temporal gyrus and inferior frontal gyrus), particularly in tasks where they had poorer performance accuracy; (2) bilateral MTG hypo-activation across many different paradigms; and (3) increased activation of the left lingual gyrus in tasks where they had intact performance. These findings show that the hypotheses reviewed here address the neural and cognitive aspects of language difficulties in ASD across all tasks only in a limited way. Instead, our findings suggest the nuances of language and brain in ASD in terms of its context-dependency. Autism Res 2016, 9: 1046-1057. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Juczewski K, von Richthofen H, Bagni C, Celikel T, Fisone G, Krieger P. {{Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome}}. {Neurobiol Dis};2016 (Sep 8);96:201-215.
Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by the absence or reduction of the fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. In humans, one symptom of FXS is hypersensitivity to sensory stimuli, including touch. We used a mouse model of FXS (Fmr1 KO) to study sensory processing of tactile information conveyed via the whisker system. In vivo electrophysiological recordings in somatosensory barrel cortex showed layer-specific broadening of the receptive fields at the level of layer 2/3 but not layer 4, in response to whisker stimulation. Furthermore, the encoding of tactile stimuli at different frequencies was severely affected in layer 2/3. The behavioral effect of this broadening of the receptive fields was tested in the gap-crossing task, a whisker-dependent behavioral paradigm. In this task the Fmr1 KO mice showed differences in the number of whisker contacts with platforms, decrease in the whisker sampling duration and reduction in the whisker touch-time while performing the task. We propose that the increased excitability in the somatosensory barrel cortex upon whisker stimulation may contribute to changes in the whisking strategy as well as to other observed behavioral phenotypes related to tactile processing in Fmr1 KO mice.
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13. Kaehr E, Abele P, Little M. {{Utility of the Easy-Care Standard 2010 in the Comprehensive Geriatric Assessment of Adults Aging with Developmental Disabilities}}. {J Am Med Dir Assoc};2016 (Oct 14)
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14. Karhson DS, Golob EJ. {{Atypical sensory reactivity influences auditory attentional control in adults with autism spectrum disorders}}. {Autism Res};2016 (Oct);9(10):1079-1092.
Frequent observations of atypical sensory reactivity in people with autism spectrum disorders (ASD) suggest that the perceptual experience of those on the Spectrum is dissimilar to neurotypicals. Moreover, variable attention abilities in people with ASD, ranging from good control to periods of high distractibility, may be related to atypical sensory reactivity. This study used auditory event-related potential (ERP) measures to evaluate top-down and bottom-up attentional processes as a function of perceptual load, and examined these factors with respect to sensory reactivity. Twenty-five age and IQ-matched participants (ASD: 22.5 year, SD = 4.1 year; Controls: 22.8 year, SD = 5.1 year) completed the Adolescent/Adult Sensory Profile prior to performing a modified 3-stimulus (target, non-target, and distractor) auditory oddball target detection task EEG was recorded during task completion. ERP analysis assessed early sensory processing (P50, approximately 50 ms latency; N100, approximately 100 ms latency), cognitive control (N200, approximately 200 ms latency), and attentional processing (P3a and P3b, approximately 300 ms latency). Behavioral data demonstrates participants with ASD and neurotypical performed similarly on auditory target detection, but diverged on sensory profiles. Target ERP measures associated with top-down control (P3b latency) significantly increased under greater load in controls, but not in participants with ASD. Early ERP responses associated with bottom-up attention (P50 amplitude) were positively correlated to increased sensory sensitivity. Findings suggest specific neural mechanisms for increased perceptual capacity and enhanced bottom-up processing of sensory stimuli in people with autism. Results from participants with ASD are consistent with load theory and enhanced perceptual functioning. Autism Res 2016, 9: 1079-1092. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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15. Kissine M, Clin E, de Villiers J. {{[Pragmatics in autism spectrum disorder: recent developments]}}. {Med Sci (Paris)};2016 (Oct);32(10):874-878.
Autism spectrum disorder (ASD) is characterized by primary pragmatic difficulties, out of step with verbal and non-verbal developmental level. This selective survey paper addresses three recent domains of research on pragmatic functions in autism. First, we provide an up-to-date discussion of how lack of sensitivity to social cues impacts early acquisition of words. Second, we review recent findings on the comprehension of non-literal language, pointing to a more refined clinical reality. Third, we describe recent developments in the study of conversation skills in autism.
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16. Krans A, Kearse MG, Todd PK. {{RAN translation from antisense CCG repeats in Fragile X Tremor/Ataxia Syndrome}}. {Ann Neurol};2016 (Oct 19)
OBJECTIVE: Repeat associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5′ leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus. We evaluated whether this antisense CCG repeat supports RAN translation and contributes to pathology in FXTAS patients. METHODS: We generated a series of CCG RAN translation specific reporters and utilized them to measure RAN translation from CCG repeats in multiple reading frames in transfected cells. We also developed antibodies against predicted CCG RAN proteins and used immunohistochemistry and immunofluorescence on FXTAS patient tissues to measure their accumulation and distribution. RESULTS: RAN translation from CCG repeats is supported in all three potential reading frames, generating polyproline, polyarginine, and polyalanine proteins, respectively. Their production occurs whether or not the natural AUG start upstream of the repeat in the proline reading frame is present. All three frames show greater translation at larger repeat sizes. Antibodies targeted to the antisense FMR polyproline and polyalanine proteins selectively stain nuclear and cytoplasmic aggregates in FXTAS patients and colocalize with ubiquitinated neuronal inclusions. INTERPRETATION: RAN translation from antisense CCG repeats generates novel proteins that accumulate in ubiquitinated inclusions in FXTAS patients. This article is protected by copyright. All rights reserved.
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17. Kranz TM, Kopp M, Waltes R, Sachse M, Duketis E, Jarczok TA, Degenhardt F, Gorgen K, Meyer J, Freitag CM, Chiocchetti AG. {{Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder}}. {Autism Res};2016 (Oct);9(10):1036-1045.
Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview – revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 9: 1036-1045. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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18. Lamb AE, Biesecker BB, Umstead KL, Muratori M, Biesecker LG, Erby LH. {{Family functioning mediates adaptation in caregivers of individuals with Rett syndrome}}. {Patient Educ Couns};2016 (Nov);99(11):1873-1879.
OBJECTIVE: The objective of this study was to investigate factors related to family functioning and adaptation in caregivers of individuals with Rett syndrome (RS). METHODS: A cross-sectional quantitative survey explored the relationships between demographics, parental self-efficacy, coping methods, family functioning and adaptation. A forward-backward, step-wise model selection procedure was used to evaluate variables associated with both family functioning and adaptation. Analyses also explored family functioning as a mediator of the relationship between other variables and adaptation. RESULTS: Bivariate analyses (N=400) revealed that greater parental self-efficacy, a greater proportion of problem-focused coping, and a lesser proportion of emotion-focused coping were associated with more effective family functioning. In addition, these key variables were significantly associated with greater adaptation, as was family functioning, while controlling for confounders. Finally, regression analyses suggest family functioning as a mediator of the relationships between three variables (parental self-efficacy, problem-focused coping, and emotion-focused coping) with adaptation. CONCLUSION: This study demonstrates the potentially predictive roles of expectations and coping methods and the mediator role of family functioning in adaptation among caregivers of individuals with RS, a chronic developmental disorder. PRACTICE IMPLICATIONS: A potential target for intervention is strengthening of caregiver competence in the parenting role to enhance caregiver adaptation.
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19. Lombardo MV, Lai MC, Auyeung B, Holt RJ, Allison C, Smith P, Chakrabarti B, Ruigrok AN, Suckling J, Bullmore ET, Ecker C, Craig MC, Murphy DG, Happe F, Baron-Cohen S. {{Unsupervised data-driven stratification of mentalizing heterogeneity in autism}}. {Sci Rep};2016 (Oct 18);6:35333.
Individuals affected by autism spectrum conditions (ASC) are considerably heterogeneous. Novel approaches are needed to parse this heterogeneity to enhance precision in clinical and translational research. Applying a clustering approach taken from genomics and systems biology on two large independent cognitive datasets of adults with and without ASC (n = 694; n = 249), we find replicable evidence for 5 discrete ASC subgroups that are highly differentiated in item-level performance on an explicit mentalizing task tapping ability to read complex emotion and mental states from the eye region of the face (Reading the Mind in the Eyes Test; RMET). Three subgroups comprising 45-62% of ASC adults show evidence for large impairments (Cohen’s d = -1.03 to -11.21), while other subgroups are effectively unimpaired. These findings delineate robust natural subdivisions within the ASC population that may allow for more individualized inferences and accelerate research towards precision medicine goals.
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20. Lonnqvist L, Loukusa S, Hurtig T, Makinen L, Siipo A, Vayrynen E, Palo P, Laukka S, Mammela L, Mattila ML, Ebeling H. {{How young adults with autism spectrum disorder watch and interpret pragmatically complex scenes}}. {Q J Exp Psychol (Hove)};2016 (Oct 19):1-16.
The aim of the current study was to investigate subtle characteristics of social perception and interpretation in high-functioning individuals with autism spectrum disorders (ASDs), and to study the relation between watching and interpreting. As a novelty, we used an approach that combined moment-by-moment eye tracking and verbal assessment. Sixteen young adults with ASD and 16 neurotypical control participants watched a video depicting a complex communication situation while their eye movements were tracked. The participants also completed a verbal task with questions related to the pragmatic content of the video. We compared verbal task scores and eye movements between groups, and assessed correlations between task performance and eye movements. Individuals with ASD had more difficulty than the controls in interpreting the video, and during two short moments there were significant group differences in eye movements. Additionally, we found significant correlations between verbal task scores and moment-level eye movement in the ASD group, but not among the controls. We concluded that participants with ASD had slight difficulties in understanding the pragmatic content of the video stimulus and attending to social cues, and that the connection between pragmatic understanding and eye movements was more pronounced for participants with ASD than for neurotypical participants.
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21. Moradi E, Khundrakpam B, Lewis JD, Evans AC, Tohka J. {{Predicting symptom severity in autism spectrum disorder based on cortical thickness measures in agglomerative data}}. {Neuroimage};2016 (Sep 22)
Machine learning approaches have been widely used for the identification of neuropathology from neuroimaging data. However, these approaches require large samples and suffer from the challenges associated with multi-site, multi-protocol data. We propose a novel approach to address these challenges, and demonstrate its usefulness with the Autism Brain Imaging Data Exchange (ABIDE) database. We predict symptom severity based on cortical thickness measurements from 156 individuals with autism spectrum disorder (ASD) from four different sites. The proposed approach consists of two main stages: a domain adaptation stage using partial least squares regression to maximize the consistency of imaging data across sites; and a learning stage combining support vector regression for regional prediction of severity with elastic-net penalized linear regression for integrating regional predictions into a whole-brain severity prediction. The proposed method performed markedly better than simpler alternatives, better with multi-site than single-site data, and resulted in a considerably higher cross-validated correlation score than has previously been reported in the literature for multi-site data. This demonstration of the utility of the proposed approach for detecting structural brain abnormalities in ASD from the multi-site, multi-protocol ABIDE dataset indicates the potential of designing machine learning methods to meet the challenges of agglomerative data.
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22. Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN. {{Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT)}}. {JAMA Psychiatry};2016 (Oct 19)
Importance: Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. Objective: To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. Design, Setting, and Participants: Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. Main Outcomes and Measures: Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of >/=75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of >/=65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. Results: Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9) years. QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. Conclusions and Relevance: This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.
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23. Nicholas DB, Hodgetts S, Zwaigenbaum L, Smith LE, Shattuck P, Parr JR, Conlon O, Germani T, Mitchell W, Sacrey L, Stothers ME. {{Research needs and priorities for transition and employment in autism: Considerations reflected in a « Special Interest Group » at the International Meeting for Autism Research}}. {Autism Res};2016 (Oct 17)
Research related to supports for adults with autism spectrum disorder (ASD) is under-developed. As an example, system and service development to support successful transition to adulthood and meaningful vocation for adults has received relatively little research scrutiny until recently, with practitioners and program developers lacking evidence-informed approaches guiding service delivery. A Special Interest Group (SIG) was convened at the International Meeting for Autism Research in May 2014 and May 2015, with a focus on transitional and vocational issues in ASD. The SIG consisted of 120 international delegates, including self-advocates, family members, researchers, program and policy developers, practitioners, and interdisciplinary ASD trainees. Following a summary of the literature, subgroups of attendees were convened in smaller groups to identify research needs and priorities. International researchers facilitated these discussions with notes taken in each subgroup. Using a qualitative analytic approach, key themes across groups were identified. These key themes, outlined in this paper, address the identified need to (a) advance research capacity; (b) build employer capacity relative to employing persons with ASD; and (c) enhance support resources for adults with ASD and their families. Heightened research activity guiding practice and policy, community/employer engagement, and person and family-centered services were recommended. Implications for advancement and implementation are offered. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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24. Panahi Y, Salasar Moghaddam F, Ghasemi Z, Hadi Jafari M, Shervin Badv R, Eskandari MR, Pedram M. {{Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children}}. {Int J Mol Sci};2016 (Oct 12);17(10)
Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s) is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naive non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs) was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children.
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25. Rogers C, Lepherd L, Ganguly R, Jacob-Rogers S. {{Perinatal issues for women with high functioning autism spectrum disorder}}. {Women Birth};2016 (Oct 14)
PROBLEM: Autistic Spectrum Disorder (ASD) is an increasingly commonly diagnosed disability. People with ASD commonly report challenges in social interaction and a heightened sensory perception. These challenges may be particularly difficult for women during pregnancy, birthing and beyond. BACKGROUND: Very little is known about the experiences and needs of birthing women who have ASD. There is a large body of literature about women who have autistic children, but almost nothing about women who may have this disability themselves. Internet blogs provide some insights and suggest that birthing women with ASD may have particular challenges related to communication, decision making and sensory overload. QUESTION: This study explores the particular issues and experiences of birthing women who have ASD, through pregnancy, birth and early mothering. METHOD: This qualitative research used a case study approach, with in-depth interviewing and email exchange providing the data for the study. This data was verified, transcribed and analysed thematically. FINDINGS: The findings of this case study identified three key issues: communication and service difficulties; sensory stress and parenting challenges. DISCUSSION AND CONCLUSION: Findings suggest that women with ASD may face particular challenges during pregnancy, birthing and early mothering. These challenges evolve from perceptions of the woman about her midwives and other caregivers. If a woman perceives that her midwife is judgemental about her, then she may withdraw from the care and support she and her baby need.
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26. Ruzich E, Allison C, Smith P, Ring H, Auyeung B, Baron-Cohen S. {{The Autism-Spectrum Quotient in siblings of people with Autism}}. {Autism Res};2016 (Oct);9(10):1114.
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27. Stavropoulos KK, Viktorinova M, Naples A, Foss-Feig J, McPartland JC. {{Autistic traits modulate conscious and nonconscious face perception}}. {Soc Neurosci};2016 (Oct 18)
BACKGROUND: Difficulty with emotion perception is a core feature of autism spectrum disorder (ASD) that is also associated with the broader autism phenotype. OBJECTIVES: The current study explored the neural underpinnings of conscious and non-conscious perceptions of affect in typically developing individuals with varying levels of autistic-like traits, as measured by the Autism Quotient (AQ). We investigated the relationship between autistic traits and face processing efficiency using event-related potentials (ERPs). METHODS: In 20 typically developing adults, we utilized ERPs (the P100, N170, and P300) to measure differences in face processing for emotional faces that were presented either (a) too quickly to reach conscious awareness (16 ms) or (b) slowly enough to be consciously observed (200 ms). RESULTS: All individuals evidenced increased P100 and P300 amplitude and and shorter N170 latencies for nonconscious versus consciously presented faces. Individuals with high AQ scores evidenced delayed ERP components. CONCLUSIONS: Nonconsciously perceived emotional faces elicited enhanced neural responses regardless of AQ score. Higher levels of autistic traits were associated with inefficient face perception (i.e., longer latency of ERP components). This delay parallels processing delays observed in ASD. These data suggest that inefficient social perception is present in individuals with subclinical levels of social impairment.
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28. Thomas S, Hovinga ME, Rai D, Lee BK. {{Brief Report: Prevalence of Co-occurring Epilepsy and Autism Spectrum Disorder: The U.S. National Survey of Children’s Health 2011-2012}}. {J Autism Dev Disord};2016 (Oct 17)
Epilepsy is reported to co-occur in individuals with autism spectrum disorder (ASD). Previous studies across the world have found prevalence estimates ranging from 4 to 38 %. We examined parent-reported prevalence of co-occurring epilepsy and ASD in the most recent U.S. National Survey of Children’s Health, 2011-2012. All analyses accounted for survey weights to account for the complex sampling design. In the overall analytic sample of 85,248 children ages 2-17, there were 1604 children with ASD (prevalence of 1.8 %) and 1083 children with epilepsy (prevalence of 1.2 %). Epilepsy was reported to co-occur in 8.6 % of ASD cases. In children with ASD, the co-occurrence of epilepsy was associated with increasing child age, female gender, intellectual disability, speech problems and lower socioeconomic status.
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29. Uljarevic M, Lane A, Kelly A, Leekam S. {{Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder}}. {Autism Res};2016 (Oct);9(10):1073-1078.
This study aimed to identify sensory subtypes in older children and adolescents with Autism Spectrum Disorders (ASD) and examine the relationship of sensory subtypes with anxiety levels in this group. Mothers of 57 children and adolescents with ASD aged 11-17 years (Mean age = 14 years. 2.4 months, SD = 1.81) completed the short sensory profile and Spence anxiety scales. Model-based cluster analysis was applied to sensory profile scores to identify sensory subtypes. Three sensory subtypes, sensory adaptive (N = 19), sensory moderate (N = 29) and sensory severe (N = 9) were identified. The results indicated that the differences between the subtypes were well characterised by the severity of sensory symptoms and were not attributable to sensory modality or varying types of sensory-related behaviors. Children and adolescents from the adaptive subtype had significantly lower anxiety scores when compared with other two subtypes. There were no differences between subtypes based on chronological age, expressive language, or severity of autism diagnostic features as measured by the social communication questionnaire (SCQ total score). This is the first study to identify the existence of sensory subtypes among older children and adolescents with ASD and explore their association with anxiety levels. Autism Res 2016, 9: 1073-1078. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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30. van Boxtel JJ, Dapretto M, Lu H. {{Intact recognition, but attenuated adaptation, for biological motion in youth with autism spectrum disorder}}. {Autism Res};2016 (Oct);9(10):1103-1113.
Given the ecological importance of biological motion and its relevance to social cognition, considerable effort has been devoted over the past decade to studying biological motion perception in autism. However, previous studies have asked observers to detect or recognize briefly presented human actions placed in isolation, without spatial or temporal context. Research on typical populations has shown the influence of temporal context in biological motion perception: prolonged exposure to one action gives rise to an aftereffect that biases perception of a subsequently displayed action. Whether people with autism spectrum disorders (ASD) show such adaptation effects for biological motion stimuli remains unknown. To address this question, this study examined how well youth with ASD recognize ambiguous actions and adapt to recently-observed actions. Compared to typically-developing (TD) controls, youth with ASD showed no differences in perceptual boundaries between actions categories, indicating intact ability in recognizing actions. However, children with ASD showed weakened adaptation to biological motion. It is unlikely that the reduced action adaptability in autism was due to delayed developmental trajectory, as older children with ASD showed weaker adaptation to actions than younger children with ASD. Our results further suggest that high-level (i.e., action) processing weakens with age for children with ASD, but this change may be accompanied by a potentially compensatory mechanism based on more involvement of low-level (i.e., motion) processing. Autism Res 2016, 9: 1103-1113. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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31. Zhong W, Johnson CM, Wu Y, Cui N, Xing H, Zhang S, Jiang C. {{Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome}}. {J Neurodev Disord};2016;8:37.
BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABAARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABAARs, there is a group of GABAARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT. METHODS: Wild-type and MECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology. RESULTS: With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of MECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression. CONCLUSIONS: THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in MECP2-null mice and perhaps in people with RTT as well.
