1. Bedford R, Jones EJ, Johnson MH, Pickles A, Charman T, Gliga T. {{Erratum to: Sex differences in the association between infant markers and later autistic traits}}. {Mol Autism};2016;7:33.
[This corrects the article DOI: 10.1186/s13229-016-0081-0.].
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2. Cassidy SA, Stenger B, Van Dongen L, Yanagisawa K, Anderson R, Wan V, Baron-Cohen S, Cipolla R. {{Expressive visual text-to-speech as an assistive technology for individuals with autism spectrum conditions}}. {Comput Vis Image Underst};2016 (Jul);148:193-200.
Adults with Autism Spectrum Conditions (ASC) experience marked difficulties in recognising the emotions of others and responding appropriately. The clinical characteristics of ASC mean that face to face or group interventions may not be appropriate for this clinical group. This article explores the potential of a new interactive technology, converting text to emotionally expressive speech, to improve emotion processing ability and attention to faces in adults with ASC. We demonstrate a method for generating a near-videorealistic avatar (XpressiveTalk), which can produce a video of a face uttering inputted text, in a large variety of emotional tones. We then demonstrate that general population adults can correctly recognize the emotions portrayed by XpressiveTalk. Adults with ASC are significantly less accurate than controls, but still above chance levels for inferring emotions from XpressiveTalk. Both groups are significantly more accurate when inferring sad emotions from XpressiveTalk compared to the original actress, and rate these expressions as significantly more preferred and realistic. The potential applications for XpressiveTalk as an assistive technology for adults with ASC is discussed.
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3. Chin EW, Marcy G, Yoon SI, Ma D, Rosales FJ, Augustine GJ, Goh EL. {{Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome}}. {Neuromolecular Med};2016 (Jul 5)
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 R306C and MECP2 1155Delta32) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.
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4. Datko M, Gougelet R, Huang MX, Pineda JA. {{Resting State Functional Connectivity MRI among Spectral MEG Current Sources in Children on the Autism Spectrum}}. {Front Neurosci};2016;10:258.
Social and communicative impairments are among the core symptoms of autism spectrum disorders (ASD), and a great deal of evidence supports the notion that these impairments are associated with aberrant functioning and connectivity of various cortical networks. The present study explored the links between sources of MEG amplitude in various frequency bands and functional connectivity MRI in the resting state. The goal of combining these modalities was to use sources of neural oscillatory activity, measured with MEG, as functionally relevant seed regions for a more traditional pairwise fMRI connectivity analysis. We performed a seed-based connectivity analysis on resting state fMRI data, using seed regions derived from frequency-specific amplitude sources in resting state MEG data in the same nine subjects with ASD (10-17 years of age). We then compared fMRI connectivity among these MEG-source-derived regions between participants with autism and typically developing, age-matched controls. We used a source modeling technique designed for MEG data to detect significant amplitude sources in six frequency bands: delta (2-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low gamma (30-60 Hz), and high gamma (60-120 Hz). MEG-derived source maps for each participant were co-registered in standard MNI space, and group-level source maps were obtained for each frequency. For each frequency band, the 10 largest clusters resulting from these t-tests were used as regions of interest (ROIs) for the fMRI functional connectivity analysis. Pairwise BOLD signal correlations were obtained between each pair of these ROIs for each frequency band. Each pairwise correlation was compared between the ASD and TD groups using t-tests. We also constrained these pairwise correlations to known network structures, resulting in a follow-up set of correlation matrices specific to each network we considered. Frequency-specific MEG sources had distinct patterns of fMRI resting state functional connectivity in the ASD group, but perhaps the most significant was a finding of hypoconnectivity between many sources of low and high gamma activity. These novel findings suggest that in ASD there are differences in functionally defined networks as shown in previous fMRI studies, as well as between sets of regions defined by magnetoencephalographic neural oscillatory activity.
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5. Dong T, He J, Wang S, Wang L, Cheng Y, Zhong Y. {{Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes}}. {Proc Natl Acad Sci U S A};2016 (Jul 5);113(27):7644-7649.
The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.
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6. Gross C. {{Defective phosphoinositide metabolism in autism}}. {J Neurosci Res};2016 (Jul 4)
Phosphoinositides are essential components of lipid membranes and crucial regulators of many cellular functions, including signal transduction, vesicle trafficking, membrane receptor localization and activity, and determination of membrane identity. These functions depend on the dynamic and highly regulated metabolism of phosphoinositides and require finely balanced activity of specific phosphoinositide kinases and phosphatases. There is increasing evidence from genetic and functional studies that these enzymes are often dysregulated or mutated in autism spectrum disorders; in particular, phosphoinositide 3-kinases and their regulatory subunits appear to be affected frequently. Examples of autism spectrum disorders with defective phosphoinositide metabolism are fragile X syndrome and autism disorders associated with mutations in the phosphoinositide 3-phosphatase tensin homolog deleted on chromosome 10 (PTEN), but recent genetic analyses also suggest that select nonsyndromic, idiopathic forms of autism may have altered activity of phosphoinositide kinases and phosphatases. Isoform-specific inhibitors for some of the phosphoinositide kinases have already been developed for cancer research and treatment, and a few are being evaluated for use in humans. Altogether, this offers exciting opportunities to explore altered phosphoinositide metabolism as a therapeutic target in individuals with certain forms of autism. This review summarizes genetic and functional studies identifying defects in phosphoinositide metabolism in autism and related disorders, describes published preclinical work targeting phosphoinositide 3-kinases in neurological diseases, and discusses the opportunities and challenges ahead to translate these findings from animal models and human cells into clinical application in humans. (c) 2016 Wiley Periodicals, Inc.
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7. Ide M, Wada M. {{Periodic Visuotactile Stimulation Slowly Enhances the Rubber Hand Illusion in Individuals with High Autistic Traits}}. {Front Integr Neurosci};2016;10:21.
In a rubber hand illusion (RHI) task, synchronous brush stroking of a rubber hand and a participant’s hidden hand induces body ownership of the rubber hand. The effects of spatial distances and temporal lags on the RHI have been extensively examined; however, the effect of periodicity of the stimuli on illusory body ownership has not been examined. Meanwhile, the occurrence of RHI tends to be weak in individuals with autism-spectrum disorders (ASD) and high autistic traits. Preference for stimulus having regularity of tempo is generally observed in individuals with ASD, and thus, periodic stimulation might be more effective to elicit the body ownership illusion in individuals with high autistic traits. Hence, we investigated whether stimulus periodicity influenced RHI as well as its association with participant’s autistic traits. Brush strokes were applied to a participant’s own hand and the rubber hand periodically (2 s) or non-periodically (1-3 s), either synchronously or asynchronously. Two blocks were performed in each condition. We found that periodic stimulation enhanced the spatial updating of tactile sensation induced by RHI in the subsequent block in participants with high autistic traits, whereas both periodic and non-periodic stimulation strongly elicited RHI in blocks 1 and 2. These results indicate that the periodicity of stimulation has different effects based on an individual’s autistic traits. Since individuals with ASD are known to sustain their focus on interoceptive sensations (heartbeats), a periodic stimulation that is potentially correlated with heartbeats might be effective to enhance the visuotactile integration during RHI in individuals with high autistic traits.
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8. Khan S, Hashmi JA, Mamashli F, Bharadwaj HM, Ganesan S, Michmizos KP, Kitzbichler MG, Zetino M, Garel KL, Hamalainen MS, Kenet T. {{Altered Onset Response Dynamics in Somatosensory Processing in Autism Spectrum Disorder}}. {Front Neurosci};2016;10:255.
Abnormalities in cortical connectivity and evoked responses have been extensively documented in autism spectrum disorder (ASD). However, specific signatures of these cortical abnormalities remain elusive, with data pointing toward abnormal patterns of both increased and reduced response amplitudes and functional connectivity. We have previously proposed, using magnetoencephalography (MEG) data, that apparent inconsistencies in prior studies could be reconciled if functional connectivity in ASD was reduced in the feedback (top-down) direction, but increased in the feedforward (bottom-up) direction. Here, we continue this line of investigation by assessing abnormalities restricted to the onset, feedforward inputs driven, component of the response to vibrotactile stimuli in somatosensory cortex in ASD. Using a novel method that measures the spatio-temporal divergence of cortical activation, we found that relative to typically developing participants, the ASD group was characterized by an increase in the initial onset component of the cortical response, and a faster spread of local activity. Given the early time window, the results could be interpreted as increased thalamocortical feedforward connectivity in ASD, and offer a plausible mechanism for the previously observed increased response variability in ASD, as well as for the commonly observed behaviorally measured tactile processing abnormalities associated with the disorder.
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9. Kharrat M, Hsairi I, Doukali H, Fendri-Kriaa N, Kammoun H, Ammar-Keskes L, Triki C, Fakhfakh F. {{Phenotypic variability in two infants sharing the same MECP2 mutation: evidence of chromosomal rearrangements and high sister-chromatid exchange levels in Rett syndrome}}. {Acta Neurol Belg};2016 (Jul 5)
Rett syndrome (RTT) whose major cause is the mutations in the X-linked MECP2 gene is a genetic disease that affects females. We screened two RTT patients using cytogenetic studies and in silico analysis as well as molecular analysis by the direct sequencing of MECP2. The cytogenetic results showed that although patient A was karyotypically normal, patient B showed chromosomal abnormalities, including chromosomal breakage in both chromosomes 2 and 5. In addition, chromosome 9 was detected on heteromorphic pattern (9ph+). A significant increase in sister-chromatid exchange (SCE) frequency was also observed in this patient. Although both patients were karyotypically different, they share the same MeCP2 mutation (p.P152R) which was predicted to be deleterious. To our knowledge, we describe the first association between MECP2 mutation, chromosomal abnormalities and high SCE frequency, which further validates the importance of the thorough chromosomal and molecular analyses that should be performed on the suspected RTT cases.
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10. 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 (Jun 18)
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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11. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC, Beltrao-Braga PC, Trujillo CA, Mendes AP, Padmanabhan K, Nunez Y, Ou J, Ghosh H, Wright R, Brennand KJ, Pierce K, Eichenfield L, Pramparo T, Eyler LT, Barnes CC, Courchesne E, Geschwind DH, Gage FH, Wynshaw-Boris A, Muotri AR. {{Altered proliferation and networks in neural cells derived from idiopathic autistic individuals}}. {Mol Psychiatry};2016 (Jul 5)
Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a beta-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.Molecular Psychiatry advance online publication, 5 July 2016; doi:10.1038/mp.2016.95.
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12. Meiring M, Seabi J, Amod Z, Vorster A, Kern A. {{Transition for Adolescents with Autism Spectrum Disorder: South African Parent and Professional Perspectives}}. {Front Psychiatry};2016;7:93.
Adolescents with autism and their families experience a significant increase in the number of challenges encountered when leaving the structure of the formal education system. The purpose of this study was to gain an understanding of the factors parents and professionals regard as important in preparing for transition of adolescents with autism spectrum disorder (ASD) to adulthood, vocational, and residential arrangements. Semistructured interviews were conducted with 14 participants (i.e., 7 parents and 7 professionals) who were involved with adolescents with ASD in Johannesburg, South Africa. The findings revealed that there was a need for advocacy on behalf of learners with ASD transitioning into adult working and living environments. The responses of the participants highlighted needs for curriculum transformation from basic literacy skills to development and teaching of functional self-help and daily living skills. The results also indicated lack of planning and the absence of service facilities for adolescents with autism post-school. There was a general feeling of fear and uncertainty when the participants thought about transition of adolescents with autism and their future. However, there was also a sense of hope and optimism. Transition of adolescents with autism into adulthood is a challenging and stressful time for parents and professionals involved in trying to prepare them. With appropriate attention and support structures, individuals with autism can attain a reasonable quality of life, including residential, employment, and social opportunities.
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13. Prakash S, Pai VK, Dhar M, Kumar AA. {{Premedication in an autistic, combative child: Challenges and nuances}}. {Saudi J Anaesth};2016 (Jul-Sep);10(3):339-341.
Children with autistic spectrum disorders are often encountered in anesthesia practice mainly for outdoor procedural sedation or anesthesia in endoscopy and magnetic resonance imaging suites. We describe a case of a 7-year-old autistic boy who required management of dental caries. He had a phobia to intravenous cannulation, displayed increasing anxiety and became combative on the day of surgery. With parental involvement and distraction, we succeeded in giving oral midazolam by concealing it, with the intent of avoiding intramuscular injection or unnecessary restraint. Lack of knowledge about the medical condition of such a patient can lead to inadequate preoperative preparation and use of restraint on the patient, which might cause anxiety or panic attacks in the operative room. To effectively manage children with special needs one needs to have clear guidelines on the management of uncooperative children, involve parents perioperatively, plan ahead with an emphasis on perioperative analgesia and sometimes incorporate the ethical use of restraint.
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14. Radley KC, Dart EH, Moore JW, Battaglia AA, LaBrot ZC. {{Promoting Accurate Variability of Social Skills in Children With Autism Spectrum Disorder}}. {Behav Modif};2016 (Jul 5)
Restricted and repetitive behavior is a central feature of autism spectrum disorder (ASD), with such behaviors often resulting in lack of reinforcement in social contexts. The present study investigated training multiple exemplars of target behaviors and the utilization of lag schedules of reinforcement in the context of social skills training to promote appropriate and varied social behavior in children with ASD. Five participants with ASD between the ages of 7 and 9 attended a twice-weekly social skills group for 8 weeks. A multiple probe design across skills was utilized to assess intervention effects. During baseline, participants demonstrated low levels of skill accuracy and low appropriate variability in responding. During continuous reinforcement with one trained exemplar, skill accuracy increased while appropriate variability remained low. Training of three exemplars of target skills resulted in minimal improvements in appropriate variability. Introduction of a Lag 2 schedule with three trained exemplars was generally associated with increased appropriate variability. Further appropriate variability was observed during Lag 4 with three trained exemplars. Limitations and implications are discussed.
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15. Tamas G, Kovacs N, Varga NA, Barsi P, Eross L, Molnar MJ, Balas I. {{Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report}}. {Neurol Neurochir Pol};2016 (Jul-Aug);50(4):303-308.
We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.
