1. Ameis SH, Daskalakis ZJ, Blumberger DM, Desarkar P, Drmic I, Mabbott DJ, Lai MC, Croarkin PE, Szatmari P. {{Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach}}. {J Child Adolesc Psychopharmacol};2017 (Mar 27)
OBJECTIVE: Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented. METHODS: An ongoing protocol will enroll participants aged 16-35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing. CONCLUSIONS: EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD.
Lien vers le texte intégral (Open Access ou abonnement)
2. Kruusvee V, Lyst MJ, Taylor C, Tarnauskaite Z, Bird AP, Cook AG. {{Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders}}. {Proc Natl Acad Sci U S A};2017 (Mar 27)
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the « NCoR/SMRT interaction domain » (NID) of MeCP2 directly contacts transducin-beta like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.
Lien vers le texte intégral (Open Access ou abonnement)
3. Pfaender S, Sauer AK, Hagmeyer S, Mangus K, Linta L, Liebau S, Bockmann J, Huguet G, Bourgeron T, Boeckers TM, Grabrucker AM. {{Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3}}. {Sci Rep};2017 (Mar 27);7:45190.
Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3alphabeta knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract.
Lien vers le texte intégral (Open Access ou abonnement)
4. Stevenson JL, Hart KR. {{Psychometric Properties of the Autism-Spectrum Quotient for Assessing Low and High Levels of Autistic Traits in College Students}}. {J Autism Dev Disord};2017 (Mar 27)
The current study systematically investigated the effects of scoring and categorization methods on the psychometric properties of the Autism-Spectrum Quotient. Four hundred and three college students completed the Autism-Spectrum Quotient at least once. Total scores on the Autism-Spectrum Quotient had acceptable internal consistency and test-retest reliability using a binary or Likert scoring method, but the results were more varied for the subscales. Overall, Likert scoring yielded higher internal consistency and test-retest reliability than binary scoring. However, agreement in categorization of low and high autistic traits was poor over time (except for a median split on Likert scores). The results support using Likert scoring and administering the Autism-Spectrum Quotient at the same time as the task of interest with neurotypical participants.
Lien vers le texte intégral (Open Access ou abonnement)
5. Touzet S, Occelli P, Schroder C, Manificat S, Gicquel L, Stanciu R, Schaer M, Oreve MJ, Speranza M, Denis A, Zelmar A, Falissard B, Georgieff N, Bahrami S, Geoffray MM. {{Impact of the Early Start Denver Model on the cognitive level of children with autism spectrum disorder: study protocol for a randomised controlled trial using a two-stage Zelen design}}. {BMJ Open};2017 (Mar 27);7(3):e014730.
INTRODUCTION: Early intervention for autism spectrum disorder (ASD) in the European French-speaking countries is heterogeneous and poorly evaluated to date. Early intervention units applying the Early Start Denver Model (ESDM) for toddlers and young children with ASD have been created in France and Belgium to improve this situation. It is essential to evaluate this intervention for the political decision-making process regarding ASD interventions in European French-speaking countries. We will evaluate the effectiveness of 12 hours per week ESDM intervention on the cognitive level of children with ASD, over a 2-year period. METHODS AND ANALYSIS: The study will be a multicentre, randomised controlled trial, using a two-stage Zelen design. Children aged 15-36 months, diagnosed with ASD and with a developmental quotient (DQ) of 30 or above on the Mullen Scale of Early Learning (MSEL) will be included. We will use a stratified minimisation randomisation at a ratio 1:2 in favour of the control group. The sample size required is 180 children (120 in the control and 60 in the intervention group). The experimental group will receive 12 hours per week ESDM by trained therapists 10 hours per week in the centre and 2 hours in the toddlers’ natural environment (alternatively by the therapist and the parent). The control group will receive care available in the community. The primary outcome will be the change in cognitive level measured with the DQ of the MSEL scored at 2 years. Secondary outcomes will include change in autism symptoms, behavioural adaptation, communicative and productive language level, sensory profile and parents’ quality of life. The primary analysis will use the intention-to-treat principle. An economic evaluation will be performed. DISSEMINATION: Findings from the study will be disseminated through peer reviewed publications and meetings. TRIAL REGISTRATION NUMBER: NCT02608333 (clinicaltrials.gov); Pre-results.
Lien vers le texte intégral (Open Access ou abonnement)
6. Van der Hallen R, Vanmarcke S, Noens I, Wagemans J. {{Hierarchical Letters in ASD: High Stimulus Variability Under Different Attentional Modes}}. {J Autism Dev Disord};2017 (Mar 27)
Studies using hierarchical patterns to test global precedence and local-global interference in individuals with ASD have produced mixed results. The current study focused on stimulus variability and locational uncertainty, while using different attentional modes. Two groups of 44 children with and without ASD completed a divided attention task as well as a global and local selective attention task. The results revealed global-to-local and local-to-global interference in ASD, to the same extent as in the TD group. Both groups struggled with the same type of stimuli (i.e., ignoring the global level information) and performed similar in all three tasks. Future studies on (visual) information processing in ASD should pursue the impact of stimulus noise and trial-by-trial uncertainty further.
Lien vers le texte intégral (Open Access ou abonnement)
7. Velasquez F, Qin XA, Reilly MA, Neuhaus E, Estes A, Aylward E, Kleinhans NM. {{Neural correlates of emotional inhibitory control in autism spectrum disorders}}. {Res Dev Disabil};2017 (Mar 27);64:64-77.
Atypical inhibitory function is often present in individuals with autism spectrum disorder (ASD), who may have difficulty suppressing context-inappropriate behaviors. We investigated the neural correlates of inhibition in ASD in response to both emotional and non-emotional stimuli using an fMRI Go/NoGo inhibition task with human faces and letters. We also related neural activation to behavioral dysfunction in ASD. Our sample consisted of 19 individuals with ASD (mean age=25.84) and 22 typically developing (TD) control participants (mean age=29.03). As expected, no group differences in task performance (inhibition accuracy and response time) were found. However, adults with ASD exhibited greater angular gyrus activation in face response inhibition blocks, as well as greater fusiform gyrus activation than controls, in a condition comparing face inhibition to letter inhibition. In contrast, control participants yielded significantly greater anterior cingulate cortex (ACC) activation in letter inhibition blocks. A positive relationship between communication and language impairment and angular gyrus activation during face inhibition was also found. Group activation differences during inhibition tasks in the context of comparable task performance and the relationship between activation and dysfunction highlight brain regions that may be related to ASD-specific dysfunction.
Lien vers le texte intégral (Open Access ou abonnement)
8. Vivanti G, Fanning PA, Hocking DR, Sievers S, Dissanayake C. {{Social Attention, Joint Attention and Sustained Attention in Autism Spectrum Disorder and Williams Syndrome: Convergences and Divergences}}. {J Autism Dev Disord};2017 (Mar 27)
There is limited knowledge on shared and syndrome-specific attentional profiles in autism spectrum disorder (ASD) and Williams syndrome (WS). Using eye-tracking, we examined attentional profiles of 35 preschoolers with ASD, 22 preschoolers with WS and 20 typically developing children across social and non-social dimensions of attention. Children with ASD and those with WS presented with overlapping deficits in spontaneous visual engagement with the target of others’ attention and in sustained attention. Children with ASD showed syndrome-specific abnormalities in monitoring and following a person’s referential gaze, as well as a lack of preferential attention to social stimuli. Children with ASD and WS present with shared as well as syndrome-specific abnormalities across social and non-social dimensions of attention.
Lien vers le texte intégral (Open Access ou abonnement)
9. Wang J, Wang Q, Peng J, Nie D, Zhao F, Kim M, Zhang H, Wee CY, Wang S, Shen D. {{Multi-task diagnosis for autism spectrum disorders using multi-modality features: A multi-center study}}. {Hum Brain Mapp};2017 (Mar 27)
Autism spectrum disorder (ASD) is a neurodevelopment disease characterized by impairment of social interaction, language, behavior, and cognitive functions. Up to now, many imaging-based methods for ASD diagnosis have been developed. For example, one may extract abundant features from multi-modality images and then derive a discriminant function to map the selected features toward the disease label. A lot of recent works, however, are limited to single imaging centers. To this end, we propose a novel multi-modality multi-center classification (M3CC) method for ASD diagnosis. We treat the classification of each imaging center as one task. By introducing the task-task and modality-modality regularizations, we solve the classification for all imaging centers simultaneously. Meanwhile, the optimal feature selection and the modeling of the discriminant functions can be jointly conducted for highly accurate diagnosis. Besides, we also present an efficient iterative optimization solution to our formulated problem and further investigate its convergence. Our comprehensive experiments on the ABIDE database show that our proposed method can significantly improve the performance of ASD diagnosis, compared to the existing methods. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc.
