1. Alaerts K, Swinnen S, Wenderoth N. {{Sex differences in Autism: A resting-state fMRI investigation of functional brain connectivity in males and females}}. {Soc Cogn Affect Neurosci};2016 (Mar 17)
Autism spectrum disorders (ASD) are far more prevalent in males than in females. Little is known however about the differential neural expression of ASD in males and females.We used a resting-state fMRI-dataset comprising 42 males/ 42 females with ASD and 75 male/ 75 female typical-controls to examine whether autism-related alterations in intrinsic functional connectivity are similar or different in males and females, and particularly whether alterations reflect ‘neural masculinization’, as predicted by the Extreme Male Brain theory.Males and females showed a differential neural expression of ASD, characterized by highly consistent patterns of hypo-connectivity in males with ASD (compared to typical males), and hyper-connectivity in females with ASD (compared to typical females). Interestingly, patterns of hyper-connectivity in females with ASD reflected a shift towards the (high) connectivity levels seen in typical males (neural masculinization), whereas patterns of hypo-connectivity observed in males with ASD reflected a shift towards the (low) typical feminine connectivity patterns (neural feminization).Our data support the notion that ASD is a disorder of sexual differentiation rather than a disorder characterized by masculinization in both genders. Future work is needed to identify underlying factors such as sex hormonal alterations that drive these sex-specific neural expressions of ASD.
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2. Buckley AW, Holmes GL. {{Epilepsy and Autism}}. {Cold Spring Harb Perspect Med};2016 (Mar 17)
Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under- or overconnected or have a mixture of over- and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge.
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3. Elrod MG, Nylund CM, Susi AL, Gorman GH, Hisle-Gorman E, Rogers DJ, Erdie-Lalena C. {{Prevalence of Diagnosed Sleep Disorders and Related Diagnostic and Surgical Procedures in Children with Autism Spectrum Disorders}}. {J Dev Behav Pediatr};2016 (Mar 14)
OBJECTIVE: Sleep disorders are common and important comorbid conditions in children with autism spectrum disorder (ASD) and can contribute to cognitive and behavioral problems. Sleep-disordered breathing (SDB) is a diagnosable and treatable cause of behavioral problems in children. We aimed to quantify the relative risk for children with ASD versus controls of being diagnosed with sleep disorders including SDB and undergoing related diagnostic and surgical procedures. METHOD: This retrospective case-cohort study included 48,762 children with ASD aged 2 to 18 years enrolled in the military health system (MHS) from 2000 to 2013. Children with ASD were matched 1:5 by birthdate, sex, and enrollment time to children without an ASD diagnosis. The MHS database was queried for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for sleep disorders or ICD-9-CM and Current Procedural Terminology codes for diagnostic and surgical procedures. Relative risks (RR) and 95% confidence intervals (CI) were determined with binary Poisson regression conditional on the match and adjusting for confounders. RESULTS: Children with ASD were at higher risk of receiving any sleep disorder diagnosis (RR: 1.97 [95% CI, 1.91-2.02]) including SDB (RR: 1.96 [95% CI, 1.88-2.05]). Children with ASD also were at increased risk of undergoing polysomnography (RR: 3.74 [95% CI, 3.56-3.93]) and sleep disorder-related surgery (RR: 1.50 [95% CI, 1.46-1.54]). CONCLUSION: Children with ASD are more likely to be given a sleep disorder diagnosis including SDB and are more likely to undergo related diagnostic and surgical procedures compared with controls without ASD.
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4. Field SS. {{Nutrition and Autism: Intervention Compared with Identification}}. {Adv Nutr};2016 (Mar);7(2):420-421.
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5. Hage A, Banaschewski T, Buitelaar JK, Dijkhuizen RM, Franke B, Lythgoe DJ, Mechler K, Williams SC, Dittmann RW. {{Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) – study protocol for a randomised controlled trial}}. {Trials};2016;17(1):141.
BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer’s dementia in a number of countries. METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children’s Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.
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6. Hawkes N. {{People with autism die 16 years earlier on average, says charity}}. {BMJ};2016;352:i1615.
7. Hupen P, Groen Y, Gaastra GF, Tucha L, Tucha O. {{Performance Monitoring in Autism Spectrum Disorders: A Systematic Literature Review of Event-Related Potential Studies}}. {Int J Psychophysiol};2016 (Mar 12)
Autism spectrum disorder (ASD) is marked by impairments in social-emotional situations, executive functioning, and behavioral regulation. These symptoms may be related to deficits in performance monitoring, i.e., the ability to observe and evaluate one’s own behavior and performance which is necessary for the regulation of future behavior. The present literature review investigated electroencephalic correlates of performance monitoring in ASD. Event-related potentials (ERPs) considered in this review included internal performance monitoring components (error-related negativity, error positivity), external performance monitoring components (feedback-related negativity, feedback-P3), and observational performance monitoring components (observer error-related negativity, observer feedback-related negativity). The majority of studies point to reduced internal performance monitoring in ASD. External performance monitoring in reward-processing paradigms, where rewards are independent of performance, seems to be intact in ASD. So far, no studies have investigated the observer error-related negativity in ASD. Available data on the observer feedback-related negativity are inconclusive, since only two studies with differential study results investigated this construct in ASD. In general, results suggest that individuals with ASD have problems with internal performance monitoring and with learning from external, abstract feedback. In contrast, the processing of external, concrete feedback seems to be largely intact in ASD.
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8. Jones EJ, Venema K, Earl R, Lowy R, Barnes K, Estes A, Dawson G, Webb SJ. {{Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: a longitudinal prospective study of infants at high familial risk}}. {J Neurodev Disord};2016;8:7.
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the population and close to 20 % of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. METHODS: In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months and investigated the relationship to ASD outcome at 24 months. RESULTS: High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. CONCLUSIONS: These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning.
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9. Kargas N, Lopez B, Morris P, Reddy V. {{Relations Among Detection of Syllable Stress, Speech Abnormalities, and Communicative Ability in Adults With Autism Spectrum Disorders}}. {J Speech Lang Hear Res};2016 (Mar 17):1-10.
Purpose: To date, the literature on perception of affective, pragmatic, and grammatical prosody abilities in autism spectrum disorders (ASD) has been sparse and contradictory. It is interesting to note that the primary perception of syllable stress within the word structure, which is crucial for all prosody functions, remains relatively unexplored in ASD. Thus, in the current study, we explored syllable stress perception sensitivity and its relationship to speech production abnormalities and communicative ability in adults with ASD. Method: A same-different syllable stress perception task using pairs of identical 4-syllable words was delivered to 42 adults with/without high-functioning ASD, matched for age, to investigate primary speech perception ability in ASD. Speech production and communicative ability in ASD was measured using the Autism Diagnostic Observation Schedule (Lord et al., 2000). Results: As predicted, the results showed that adults with ASD were less sensitive in making judgments about syllable stress relative to controls. Also, partial correlations revealed a key association of speech production abnormalities with stress perception sensitivity, rather than communicative ability. Conclusions: Our findings provide empirical evidence for deficits on primary syllable stress perception in ASD and its role on sociocommunicative difficulties. This information could facilitate the development of effective interventions for speech and language therapy and social communication.
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10. Nakamura T, Arima-Yoshida F, Sakaue F, Nasu-Nishimura Y, Takeda Y, Matsuura K, Akshoomoff N, Mattson SN, Grossfeld PD, Manabe T, Akiyama T. {{PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking}}. {Nat Commun};2016;7:10861.
Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface gamma-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3zeta/theta form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.
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11. Ruparelia K, Abubakar A, Badoe E, Bakare M, Visser K, Chugani DC, Chugani HT, Donald KA, Wilmshurst JM, Shih A, Skuse D, Newton CR. {{Autism Spectrum Disorders in Africa: Current Challenges in Identification, Assessment, and Treatment: A Report on the International Child Neurology Association Meeting on ASD in Africa, Ghana, April 3-5, 2014}}. {J Child Neurol};2016 (Mar 15)
Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed.
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12. Saresella M, Piancone F, Marventano I, Zoppis M, Hernis A, Zanette M, Trabattoni D, Chiappedi M, Ghezzo A, Canevini MP, la Rosa F, Esposito S, Clerici M. {{Multiple Inflammasome Complexes are Activated in Autistic Spectrum Disorders}}. {Brain Behav Immun};2016 (Mar 12)
BACKGROUND: Inflammasomes are multimeric protein platforms involved in the regulation of inflammatory responses whose activity results in the production of proinflammatory cytokines. Because neuroinflammation is observed in autistic spectrum disorders (ASD), a neurologic condition of childhood resulting in a complex behavioural impairment, we analyzed the inflammasomes activity in ASD. Additionally we verified whether alterations of the gastrointestinal (GI) barriers might play a role in inflammasomes activation. METHODS: The activity of the inflammasomes, the concentration of the inflammasomes-derived proinflammatory cytokines interleukin (IL)-1beta and IL-18, and serum parameters of GI damage were analyzed in 25 ASD children, 23 healthy siblings (HS) and 30 unrelated age-matched healthy controls (HC). RESULTS: A significant upregulation of the AIM2 and the NLRP3 inflammasomes and an increased production of IL-1betaand IL-18 that was associated with a consistent reduction of IL-33, an anti inflammation cytokine were observed in ASD alone. Notably, in a possible immune-mediated attempt to dampen inflammation, IL-37, a suppressor of innate inflammatory responses, was significantly augmented in these same children. Finally, intestinal fatty acid binding protein (IFABP), an index of altered GI permeability, was significantly increased in serum of ASD and HS. CONCLUSIONS: These results show that the inflammasomes are activated in ASD and shed light on the molecular mechanisms responsible for ASD-associated neuroinflammation. The observation that GI alterations could be present as well in ASD offers a possible link between such alterations and neuroinflammation. Therapeutic strategies targeting inflammasome activation could be useful in ASD.
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13. Solignac I. {{[A girl with foetal valproate syndrome and autism spectrum disorder]}}. {Tijdschr Psychiatr};2016;58(3):228-231.
We study the case of a 12-year-old girl who, following intra-uterine exposure to valproate, was diagnosed with foetal valproate syndrome, characterised at birth by dysmorphic features. The use of valproate during pregnancy (because of epilepsy or bipolar disorder) can cause not only structural defects in the growing foetus, but also problems in cognitive development and in adaptive and emotional/behavioural functioning in later life. We evaluate these domains of development in our discussion and suggest several other drugs, less harmful than valproate, which can be used to treat epilepsy or bipolar disorder during pregnancy.
14. Volker MA, Dua EH, Lopata C, Thomeer ML, Toomey JA, Smerbeck AM, Rodgers JD, Popkin JR, Nelson AT, Lee GK. {{Factor Structure, Internal Consistency, and Screening Sensitivity of the GARS-2 in a Developmental Disabilities Sample}}. {Autism Res Treat};2016;2016:8243079.
The Gilliam Autism Rating Scale-Second Edition (GARS-2) is a widely used screening instrument that assists in the identification and diagnosis of autism. The purpose of this study was to examine the factor structure, internal consistency, and screening sensitivity of the GARS-2 using ratings from special education teaching staff for a sample of 240 individuals with autism or other significant developmental disabilities. Exploratory factor analysis yielded a correlated three-factor solution similar to that found in 2005 by Lecavalier for the original GARS. Though the three factors appeared to be reasonably consistent with the intended constructs of the three GARS-2 subscales, the analysis indicated that more than a third of the GARS-2 items were assigned to the wrong subscale. Internal consistency estimates met or exceeded standards for screening and were generally higher than those in previous studies. Screening sensitivity was .65 and specificity was .81 for the Autism Index using a cut score of 85. Based on these findings, recommendations are made for instrument revision.
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15. Wink LK, Badran I, Pedapati EV, Sorensen R, Benton SC, Johnson MC, Wissel G, Erickson CA. {{Clozapine for Drug-Refractory Irritability in Individuals with Developmental Disability}}. {J Child Adolesc Psychopharmacol};2016 (Mar 17)
OBJECTIVES: In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population. METHODS: Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale (CGI-I). RESULTS: One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 +/- 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 +/- 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or « much improved. » CONCLUSION: These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.
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16. Yakubova G, Hughes EM, Shinaberry M. {{Learning with Technology: Video Modeling with Concrete-Representational-Abstract Sequencing for Students with Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Mar 17)
The purpose of this study was to determine the effectiveness of a video modeling intervention with concrete-representational-abstract instructional sequence in teaching mathematics concepts to students with autism spectrum disorder (ASD). A multiple baseline across skills design of single-case experimental methodology was used to determine the effectiveness of the intervention on the acquisition and maintenance of addition, subtraction, and number comparison skills for four elementary school students with ASD. Findings supported the effectiveness of the intervention in improving skill acquisition and maintenance at a 3-week follow-up. Implications for practice and future research are discussed.
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17. Zahorakova D, Lelkova P, Gregor V, Magner M, Zeman J, Martasek P. {{MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning}}. {J Hum Genet};2016 (Mar 17)
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.Journal of Human Genetics advance online publication, 17 March 2016; doi:10.1038/jhg.2016.19.
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18. Zhou Y, Shi L, Cui X, Wang S, Luo X. {{Functional Connectivity of the Caudal Anterior Cingulate Cortex Is Decreased in Autism}}. {PLoS One};2016;11(3):e0151879.
The anterior cingulate cortex (ACC) is frequently reported to have functionally distinct sub-regions that play key roles in different intrinsic networks. However, the contribution of the ACC, which is connected to several cortical areas and the limbic system, to autism is not clearly understood, although it may be involved in dysfunctions across several distinct but related functional domains. By comparing resting-state fMRI data from persons with autism and healthy controls, we sought to identify the abnormalities in the functional connectivity (FC) of ACC sub-regions in autism. The analyses found autism-related reductions in FC between the left caudal ACC and the right rolandic operculum, insula, postcentral gyrus, superior temporal gyrus, and the middle temporal gyrus. The FC (z-scores) between the left caudal ACC and the right insula was negatively correlated with the Stereotyped Behaviors and Restricted Interests scores of the autism group. These findings suggest that the caudal ACC is recruited selectively in the pathomechanism of autism.
