1. Aller MI, Pecoraro V, Paternain AV, Canals S, Lerma J. {{Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features}}. {J Neurosci};2015 (Oct 7);35(40):13619-13628.
The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders. SIGNIFICANCE STATEMENT: A genetic overlap exists between autism spectrum disorders (ASD), currently thought to represent a continuum of the same disorder with varying degrees of severity, and other neurodevelopmental and neuropsychiatric endophenotypes. We show that the duplication of a single gene coding for a high-affinity kainate receptor subunit (i.e., grik4) in a limited area of the brain recapitulates behavioral endophenotypes seen in humans diagnosed with autism (anhedonia, depression, anxiety, and altered social interaction), including some humans with GRIK4 duplications. Therefore, it should be possible to use mice overexpressing grik4 to directly address circuit dysfunctions associated with ASDs and test specific treatments of autism-related behaviors.
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2. Ammanuel S, Chan WC, Adler DA, Lakshamanan BM, Gupta SS, Ewen JB, Johnston MV, Marcus CL, Naidu S, Kadam SD. {{Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency}}. {PLoS One};2015;10(10):e0138113.
Sleep problems are commonly reported in Rett syndrome (RTT); however the electroencephalographic (EEG) biomarkers underlying sleep dysfunction are poorly understood. The aim of this study was to analyze the temporal evolution of quantitative EEG (qEEG) biomarkers in overnight EEGs recorded from girls (2-9 yrs. old) diagnosed with RTT using a non-traditional automated protocol. In this study, EEG spectral analysis identified high delta power cycles representing slow wave sleep (SWS) in 8-9h overnight sleep EEGs from the frontal, central and occipital leads (AP axis), comparing age-matched girls with and without RTT. Automated algorithms quantitated the area under the curve (AUC) within identified SWS cycles for each spectral frequency wave form. Both age-matched RTT and control EEGs showed similar increasing trends for recorded delta wave power in the EEG leads along the antero-posterior (AP). RTT EEGs had significantly fewer numbers of SWS sleep cycles; therefore, the overall time spent in SWS was also significantly lower in RTT. In contrast, the AUC for delta power within each SWS cycle was significantly heightened in RTT and remained heightened over consecutive cycles unlike control EEGs that showed an overnight decrement of delta power in consecutive cycles. Gamma wave power associated with these SWS cycles was similar to controls. However, the negative correlation of gamma power with age (r = -.59; p<0.01) detected in controls (2-5 yrs. vs. 6-9 yrs.) was lost in RTT. Poor % SWS (i.e., time spent in SWS overnight) in RTT was also driven by the younger age-group. Incidence of seizures in RTT was associated with significantly lower number of SWS cycles. Therefore, qEEG biomarkers of SWS in RTT evolved temporally and correlated significantly with clinical severity.
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3. Chiu M, Watson S. {{Xerophthalmia and vitamin A deficiency in an autistic child with a restricted diet}}. {BMJ Case Rep};2015;2015
We report the ocular and systemic manifestations of vitamin A deficiency in a child with a complicated medical history including autism and a restricted diet, living in a developed country. This child had significant vitamin A deficiency despite being under long-term medical care, yet the diagnosis was not considered until he had an ophthalmology review for visual deterioration.
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4. De Giacomo A, Craig F, Cristella A, Terenzio V, Buttiglione M, Margari L. {{Can PEP-3 Provide a Cognitive Profile in Children with ASD? A Comparison Between the Developmental Ages of PEP-3 and IQ of Leiter-R}}. {J Appl Res Intellect Disabil};2015 (Oct 6)
BACKGROUND: The assessment of the intelligence quotient (IQ) in children with autism spectrum disorder (ASD) is important to plan a detailed therapeutic-educative programme. The aim of the study was to evaluate the usefulness of the Psychoeducational Profile-third edition (PEP-3) to estimate the general cognitive development of children with ASD. METHOD: We recruited 30 children with ASD assessed with the Leiter International Performance Scale-Revised (Leiter-R) and the PEP-3. We compared the IQ of the Leiter-R with the developmental level (DL) of PEP-3. RESULTS: The findings showed a significant positive correlation between IQ with DL of the cognitive verbal/pre-verbal (P = 0.0005), DL of the area of expressive language (P = 0.0004), DL of the area of receptive language (P = 0.0001), DL of fine motor (P = 0.0066), DL of gross motor (P = 0.0217), DL of visuo-motor imitation (P = 0.02), DL of communication (P = 0.0001) and DL of motor (P = 0.0063). CONCLUSIONS: These findings show that the DLs could be considered as indicators of cognitive functioning in ASD.
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5. Desarkar P, Rajji TK, Ameis SH, Daskalakis ZJ. {{Assessing and Stabilizing Aberrant Neuroplasticity in Autism Spectrum Disorder: The Potential Role of Transcranial Magnetic Stimulation}}. {Front Psychiatry};2015;6:124.
Exciting developments have taken place in the neuroscience research in autism spectrum disorder (ASD), and results from these studies indicate that brain in ASD is associated with aberrant neuroplasticity. Transcranial magnetic stimulation (TMS) has rapidly evolved to become a widely used, safe, and non-invasive neuroscientific tool to investigate a variety of neurophysiological processes, including neuroplasticity. The diagnostic and therapeutic potential of TMS in ASD is beginning to be realized. In this article, we briefly reviewed evidence of aberrant neuroplasticity in ASD, suggested future directions in assessing neuroplasticity using repetitive TMS (rTMS), and discussed the potential of rTMS in rectifying aberrant neuroplasticity in ASD.
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6. Doumas M, McKenna R, Murphy B. {{Postural Control Deficits in Autism Spectrum Disorder: The Role of Sensory Integration}}. {J Autism Dev Disord};2015 (Oct 7)
We investigated the nature of sensory integration deficits in postural control of young adults with ASD. Postural control was assessed in a fixed environment, and in three environments in which sensory information about body sway from visual, proprioceptive or both channels was inaccurate. Furthermore, two levels of inaccurate information were used within each channel (gain 1 and 1.6). ASD participants showed greater postural sway when information from both channels was inaccurate. In addition, control participants’ ellipse area at gain 1.6 was identical to ASD participants’ at gain 1, reflecting hyper-reactivity in ASD. Our results provide evidence for hyper-reactivity in posture-related sensory information, which reflects a general, rather than channel-specific sensory integration impairment in ASD.
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7. Du RY, Yiu CK, Wong VC, McGrath CP. {{Erratum to: Autism Developmental Profiles and Cooperation with Oral Health Screening}}. {J Autism Dev Disord};2015 (Oct 5)
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8. Durkin MS, Elsabbagh M, Barbaro J, Gladstone M, Happe F, Hoekstra RA, Lee LC, Rattazzi A, Stapel-Wax J, Stone WL, Tager-Flusberg H, Thurm A, Tomlinson M, Shih A. {{Autism screening and diagnosis in low resource settings: Challenges and opportunities to enhance research and services worldwide}}. {Autism Res};2015 (Oct 6)
Most research into the epidemiology, etiology, clinical manifestations, diagnosis and treatment of autism is based on studies in high income countries. Moreover, within high income countries, individuals of high socioeconomic status are disproportionately represented among participants in autism research. Corresponding disparities in access to autism screening, diagnosis, and treatment exist globally. One of the barriers perpetuating this imbalance is the high cost of proprietary tools for diagnosing autism and for delivering evidence-based therapies. Another barrier is the high cost of training of professionals and para-professionals to use the tools. Open-source and open access models provide a way to facilitate global collaboration and training. Using these models and technologies, the autism scientific community and clinicians worldwide should be able to work more effectively and efficiently than they have to date to address the global imbalance in autism knowledge and at the same time advance our understanding of autism and our ability to deliver cost-effective services to everyone in need. Autism Res 2015. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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9. Gabriele S, Sacco R, Altieri L, Neri C, Urbani A, Bravaccio C, Riccio MP, Iovene MR, Bombace F, De Magistris L, Persico AM. {{Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children}}. {Autism Res};2015 (Oct 6)
The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Goldenthal MJ, Damle S, Sheth S, Shah N, Melvin J, Jethva R, Hardison H, Marks H, Legido A. {{Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis}}. {Biomark Med};2015 (Oct 6)
AIM: Mitochondrial function studies in autism spectrum disorders (ASD) have detected skeletal muscle mitochondrial enzyme deficiencies in respiratory complex (RC) activities. As a muscle biopsy is expensive and invasive, we assessed RC-I and RC-IV activities in buccal swabs. METHODS: 92 children with ASD and 68 controls were studied with immunocapture for RC-I and microspectrophotometry for RC-IV. RESULTS: Significant RC activity deficiencies were found in 39 (42%) ASD patients (p < 0.01) and more prevalent in more severe cases. Aberrant RC overactivity was seen in 9 children. RC-I/RC-IV activity ratio was significantly increased in 64% of the entire ASD cohort including 76% of those more severely affected (p < 0.05). CONCLUSION: Buccal swab analysis revealed extensive RC abnormalities in ASD providing a noninvasive biomarker to assess mitochondrial function in ASD patients.
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11. Gonzalez-Gronow M, Cuchacovich M, Francos R, Cuchacovich S, Blanco A, Sandoval R, Gomez CF, Valenzuela JA, Ray R, Pizzo SV. {{Catalytic autoantibodies against myelin basic protein (MBP) isolated from serum of autistic children impair in vitro models of synaptic plasticity in rat hippocampus}}. {J Neuroimmunol};2015 (Oct 15);287:1-8.
Autoantibodies from autistic spectrum disorder (ASD) patients react with multiple proteins expressed in the brain. One such autoantibody targets myelin basic protein (MBP). ASD patients have autoantibodies to MBP of both the IgG and IgA classes in high titers, but no autoantibodies of the IgM class. IgA autoantibodies act as serine proteinases and degrade MBP in vitro. They also induce a decrease in long-term potentiation in the hippocampi of rats either perfused with or previously inoculated with this IgA. Because this class of autoantibody causes myelin sheath destruction in multiple sclerosis (MS), we hypothesized a similar pathological role for them in ASD.
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12. Gottfried C, Bambini-Junior V, Francis F, Riesgo R, Savino W. {{The Impact of Neuroimmune Alterations in Autism Spectrum Disorder}}. {Front Psychiatry};2015;6:121.
Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity.
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13. Hammer M, Krueger-Burg D, Tuffy LP, Cooper BH, Taschenberger H, Goswami SP, Ehrenreich H, Jonas P, Varoqueaux F, Rhee JS, Brose N. {{Perturbed Hippocampal Synaptic Inhibition and gamma-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism}}. {Cell Rep};2015 (Oct 7)
Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of gamma-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.
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14. Higuchi Y, Uchitomi Y, Fujimori M, Koyama T, Kataoka H, Kitamura Y, Sendo T, Inagaki M. {{Exploring autistic-like traits relating to empathic attitude and psychological distress in hospital pharmacists}}. {Int J Clin Pharm};2015 (Oct 6)
Background Pharmacists are expected to play a key role in modern cancer care. Research suggests that an empathic approach and attitude in medical staff improves the quality of patient care. An empathic attitude and psychological distress are thought to be associated with autistic-like traits, but little is known about such traits. Objective In this study, we aimed to clarify the associations among autistic-like traits, empathic attitude in a medical context, and psychological health in hospital pharmacists. Setting Eligibility criteria for inclusion were certified pharmacists working at hospitals for patient care who returned their questionnaires. Method Eight hundred and twenty-three hospital pharmacists completed a number of self-administered questionnaires anonymously by mail. Main outcome measures Scores were obtained on the Autism-Spectrum Quotient, the Jefferson Scale of Empathy, the General Health Questionnaire-12, and subscales of the Interpersonal Reactivity Index (Perspective Taking, IRI-Empathic Concern, IRIPersonal Distress). We performed correlation and mediation analyses to confirm that the empathy and general health questionnaires were associated with autism-spectrum quotient scores, and with each IRI subscale. Results Complete responses were obtained from 379 pharmacists comprising 151 males (39.8 %) with a mean age of 37.7 +/- 10.8 years (missing data, n = 13) and a median of 11 years after qualification as a pharmacist. Autism-Spectrum Quotient scores were inversely correlated with empathy (r = -0.22, p < 0.001) and positively correlated with general health scores (r = 0.40, p < 0.001). In the models with mediation, the inverse correlation between autism-spectrum quotient and empathy scores was mediated indirectly by IRI-Perspective Taking and IRI-Empathic Concern, and the positive correlation between autism-spectrum quotient and general health was mediated indirectly by IRI-Personal Distress. There were also direct effects, with significant effects of autism-spectrum quotient on empathy and general health scores. Conclusion Our findings suggest that autistic-like traits affect both empathic attitude in a medical context and the psychological health of pharmacists. We recommend that to improve empathy in those with high levels of autistic-like traits, we may need to develop specialized interventions, such as improving communication skills training.
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15. Jacob A, Scott M, Falkmer M, Falkmer T. {{The Costs and Benefits of Employing an Adult with Autism Spectrum Disorder: A Systematic Review}}. {PLoS One};2015;10(10):e0139896.
BACKGROUND: Despite an ambition from adults with Autism Spectrum Disorder (ASD) to be employed, there are limited opportunities for competitive employment for this group. Employment is not only an entitlement enjoyed by others in society, but employing adults with ASD also has economic benefits by decreasing lost productivity and resource costs for this group. Few studies have explored the cost-benefit ratio for employing adults with ASD and even fewer have taken the viewpoint of the employer, particularly applying this situation to ASD. Until such study occurs, employers may continue to be reluctant to employ adults from this group. OBJECTIVE: This review aimed to examine the costs, benefits and the cost-benefit ratio of employing adults with ASD, from a societal perspective and from the perspective of employers. METHODS: Eight databases were searched for scientific studies within defined inclusion criteria. These databases included CINAHL Plus, Cochrane Library, Emerald, Ovid Medline, ProQuest, PsycINFO, Scopus and Web of Science. RESULTS AND CONCLUSION: Enhancing the opportunities for adults with ASD to join the workforce is beneficial from a societal perspective, not only from an inclusiveness viewpoint, but also from a strict economic standpoint. Providing supported employment services for adults with ASD does not only cut the cost compared with providing standard care, it also results in better outcomes for adults with ASD. Despite the fact that ASD was the most expensive group to provide vocational rehabilitation services for, adults with ASD have a strong chance of becoming employed once appropriate measures are in place. Hence, rehabilitation services could be considered as a worthwhile investment. The current systematic review uncovered the fact that very few studies have examined the benefits, the costs and the cost-benefit ratio of employing an adult with ASD from the perspective of employers indicating a need for this topic to be further explored.
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16. Kalus S, King J, Lui E, Gaillard F. {{Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia}}. {J Clin Neurosci};2015 (Oct 1)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X « premutation », defined as 55-200 CGG repeats in the 5′-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The « MCP sign », referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations.
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17. Kauschke C, van der Beek B, Kamp-Becker I. {{Narratives of Girls and Boys with Autism Spectrum Disorders: Gender Differences in Narrative Competence and Internal State Language}}. {J Autism Dev Disord};2015 (Oct 5)
Since gender differences in the symptomatology of autism spectrum disorder (ASD) are not well understood, the current study examines the communicative skills of males and females with ASD. Narrative competence and internal state language (ISL) was investigated using narrations elicited by a wordless picture book. 11 girls and 11 boys with ASD and 11 typically developing girls were individually matched. Although results demonstrate largely comparable narrative skills across groups, the groups differed with respect to the size and use of ISL: Girls with ASD verbalized and motivated internal states more often than boys, and both groups with ASD fell behind typically developing children in production of affective words. Implications for the clinical presentation of males and females with ASD are discussed.
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18. Lin IF, Mochida T, Asada K, Ayaya S, Kumagaya S, Kato M. {{Atypical delayed auditory feedback effect and Lombard effect on speech production in high-functioning adults with autism spectrum disorder}}. {Front Hum Neurosci};2015;9:510.
Individuals with autism spectrum disorder (ASD) show impaired social interaction and communication, which may be related to their difficulties in speech production. To investigate the mechanisms of atypical speech production in this population, we examined feedback control by delaying the auditory feedback of their own speech, which degraded speech fluency. We also examined feedforward control by adding loud pink noise to the auditory feedback, which led to increased vocal effort in producing speech. The results of Japanese speakers show that, compared with neurotypical (NT) individuals, high-functioning adults with ASD (including Asperger’s disorder, autistic disorder, and pervasive developmental disorder not otherwise specified) were more affected by delayed auditory feedback but less affected by external noise. These findings indicate that, in contrast to NT individuals, those with ASD relied more on feedback control than on feedforward control in speech production, which is consistent with the hypothesis that this population exhibits attenuated Bayesian priors.
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19. Neufeld J, Ioannou C, Korb S, Schilbach L, Chakrabarti B. {{Spontaneous Facial Mimicry is Modulated by Joint Attention and Autistic Traits}}. {Autism Res};2015 (Oct 7)
Joint attention (JA) and spontaneous facial mimicry (SFM) are fundamental processes in social interactions, and they are closely related to empathic abilities. When tested independently, both of these processes have been usually observed to be atypical in individuals with autism spectrum conditions (ASC). However, it is not known how these processes interact with each other in relation to autistic traits. This study addresses this question by testing the impact of JA on SFM of happy faces using a truly interactive paradigm. Sixty-two neurotypical participants engaged in gaze-based social interaction with an anthropomorphic, gaze-contingent virtual agent. The agent either established JA by initiating eye contact or looked away, before looking at an object and expressing happiness or disgust. Eye tracking was used to make the agent’s gaze behavior and facial actions contingent to the participants’ gaze. SFM of happy expressions was measured by Electromyography (EMG) recording over the Zygomaticus Major muscle. Results showed that JA augments SFM in individuals with low compared with high autistic traits. These findings are in line with reports of reduced impact of JA on action imitation in individuals with ASC. Moreover, they suggest that investigating atypical interactions between empathic processes, instead of testing these processes individually, might be crucial to understanding the nature of social deficits in autism. Autism Res 2015. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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20. Oien R, Eisemann MR. {{Brief Report: Parent-Reported Problems Related to Communication, Behavior and Interests in Children with Autistic Disorder and Their Impact on Quality of Life}}. {J Autism Dev Disord};2015 (Oct 5)
Parents of children with Autism spectrum disorders often report elevated levels of stress, depression and anxiety compared to parents of children with other developmental disorders. The present study investigated experiences of mothers of children with autistic disorder, both boys and girls. The results show that mothers report problems related to communication, behavior and interests of their child, which impact their quality of life. There were also differences between boys and girls.
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21. Oswald TM, Winter-Messiers MA, Gibson B, Schmidt AM, Herr CM, Solomon M. {{Sex Differences in Internalizing Problems During Adolescence in Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Oct 5)
We hypothesized that the double hit conferred by sex and diagnosis increases the risk for internalizing disorders in adolescent females with autism spectrum disorder (ASD). In a sample of 32 adolescents with ASD and 32 controls, we examined the effects of sex, diagnostic factors, and developmental stages on depression and anxiety. A 3-way interaction revealed that females with ASD exhibited greater depressive symptoms than males with ASD and female controls particularly during early adolescence; therefore, females with ASD might have a unique combination of genetic, hormonal, and psychosocial vulnerabilities that heighten their risk for depression during early adolescence. Additionally, the ASD group reported high levels of separation anxiety and panic in late adolescence, possibly indicating atypical development of independence.
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22. Park CY, Halevy T, Lee DR, Sung JJ, Lee JS, Yanuka O, Benvenisty N, Kim DW. {{Reversion of FMR1 Methylation and Silencing by Editing the Triplet Repeats in Fragile X iPSC-Derived Neurons}}. {Cell Rep};2015 (Oct 13);13(2):234-241.
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Here, we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.
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23. Payakachat N, Tilford JM, Ungar WJ. {{National Database for Autism Research (NDAR): Big Data Opportunities for Health Services Research and Health Technology Assessment}}. {Pharmacoeconomics};2015 (Oct 7)
The National Database for Autism Research (NDAR) is a US National Institutes of Health (NIH)-funded research data repository created by integrating heterogeneous datasets through data sharing agreements between autism researchers and the NIH. To date, NDAR is considered the largest neuroscience and genomic data repository for autism research. In addition to biomedical data, NDAR contains a large collection of clinical and behavioral assessments and health outcomes from novel interventions. Importantly, NDAR has a global unique patient identifier that can be linked to aggregated individual-level data for hypothesis generation and testing, and for replicating research findings. As such, NDAR promotes collaboration and maximizes public investment in the original data collection. As screening and diagnostic technologies as well as interventions for children with autism are expensive, health services research (HSR) and health technology assessment (HTA) are needed to generate more evidence to facilitate implementation when warranted. This article describes NDAR and explains its value to health services researchers and decision scientists interested in autism and other mental health conditions. We provide a description of the scope and structure of NDAR and illustrate how data are likely to grow over time and become available for HSR and HTA.
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24. Pelly L, Vardy C, Fernandez B, Newhook LA, Chafe R. {{Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador}}. {CMAJ Open};2015 (Jul-Sep);3(3):E276-280.
BACKGROUND: Recent studies have reported increased prevalence for autism spectrum disorders in a number of geographical locations. Our objective was to determine the incidence and 1-year cohort prevalence for autism spectrum disorders in children less than 15 years of age and living in the Avalon Peninsula at the time of diagnosis. METHODS: Retrospective and prospective data were obtained from the Janeway Children’s Health and Rehabilitation Centre (St. John’s), including the identification and specific diagnosis for all children assessed for autism spectrum disorder from 2006 to 2010. Additional clinic data were reviewed to update the data until the end of 2013. RESULTS: From 2006 to 2010, 272 children had a diagnosis of autism spectrum disorder, averaging 54 new cases per year. The incidence of new cases increased from 10.1 to 16.7 cases per 10 000 per year from 2006 to 2010. At the end of 2013, the prevalence among children born in 2006 was 1 case of autism spectrum disorder per 46 children or 215.77 per 10 000. INTERPRETATION: We found higher rates of autism spectrum disorder than previously reported for this population. The prevalence in this region is also high when compared with other global populations. The high rate of diagnosis supports the need for a provincial autism spectrum disorder registry and further research on autism spectrum disorder within this population.
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25. Raina SK, Kashyap V, Bhardwaj AK, Kumar D, Chander V. {{Prevalence of autism spectrum disorders among children (1-10 years of age) – Findings of a mid-term report from Northwest India}}. {J Postgrad Med};2015 (Oct-Dec);61(4):243-246.
BACKGROUND: India is the second most populous country of the world. A large portion of the population of this country is below 20 years of age but still there is a paucity of information about the prevalence and incidence of many developmental disorders. This study was planned to estimate the prevalence of autism spectrum disorders (ASDs) in the selected areas (tribal, rural, and urban) of a northern state of India, Himachal Pradesh. METHODS: A cross-sectional two-phase study was conducted covering all the children in the range of 1-10 years of age. Phase one included screening of all the children in the age group of 1-10 years, with the help of an indigenous assessment tool for autism. The sociodemographic profile of the participants was also recorded during phase one. Phase two involved the clinical evaluation of individuals who were suspected of autism on screening. RESULTS: The results show a prevalence rate of 0.9/1000. The highest prevalence rate was observed in the rural area. CONCLUSIONS: Socioeconomic status (SES) may be one of the fundamental indicators for ASDs in India.
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26. Ratto AB, Anthony BJ, Kenworthy L, Armour AC, Dudley K, Anthony LG. {{Are Non-intellectually Disabled Black Youth with ASD Less Impaired on Parent Report than Their White Peers?}}. {J Autism Dev Disord};2015 (Oct 6)
There is a lack of research examining differences in functioning in autism spectrum disorder (ASD) across ethnicity, particularly among those without intellectual disability (ID). This study investigated ethnic differences in parent-reported impairment in executive function, adaptive behavior, and social-emotional functioning. White and Black youth (n = 64; ages 6-17) with ASD without ID were compared on each of these domains. Black youth had significantly lower levels of impairment on all three domains. Findings may reflect better daily functioning among Black youth with ASD and/or cultural differences in parent response to questionnaires. Regardless, these findings raise concern about the sensitivity of commonly used measures for Black children with ASD and the impact of culture on daily functioning and symptom manifestation.
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27. Rommelse N, Langerak I, van der Meer J, de Bruijn Y, Staal W, Oerlemans A, Buitelaar J. {{Intelligence May Moderate the Cognitive Profile of Patients with ASD}}. {PLoS One};2015;10(10):e0138698.
BACKGROUND: The intelligence of individuals with Autism Spectrum Disorder (ASD) varies considerably. The pattern of cognitive deficits associated with ASD may differ depending on intelligence. We aimed to study the absolute and relative severity of cognitive deficits in participants with ASD in relation to IQ. METHODS: A total of 274 children (M age = 12.1, 68.6% boys) participated: 30 ASD and 22 controls in the below average Intelligence Quotient (IQ) group (IQ<85), 57 ASD and 54 controls in the average IQ group (85<IQ<115) and 41 ASD and 70 controls in the above average IQ group (IQ>115). Matching for age, sex, Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ) and VIQ-PIQ difference was performed. Speed and accuracy of social cognition, executive functioning, visual pattern recognition and basic processing speed were examined per domain and as a composite score. RESULTS: The composite score revealed a trend significant IQ by ASD interaction (significant when excluding the average IQ group). In absolute terms, participants with below average IQs performed poorest (regardless of diagnosis). However, in relative terms, above average intelligent participants with ASD showed the most substantial cognitive problems (particularly for social cognition, visual pattern recognition and verbal working memory) since this group differed significantly from the IQ-matched control group (p < .001), whereas this was not the case for below-average intelligence participants with ASD (p = .57). CONCLUSIONS: In relative terms, cognitive deficits appear somewhat more severe in individuals with ASD and above average IQs compared to the below average IQ patients with ASD. Even though high IQ ASD individuals enjoy a certain protection from their higher IQ, they clearly demonstrate cognitive impairments that may be targeted in clinical assessment and treatment. Conversely, even though in absolute terms ASD patients with below average IQs were clearly more impaired than ASD patients with average to above average IQs, the differences in cognitive functioning between participants with and without ASD on the lower end of the IQ spectrum were less pronounced. Clinically this may imply that cognitive assessment and training of cognitive skills in below average intelligent children with ASD may be a less fruitful endeavour. These findings tentatively suggest that intelligence may act as a moderator in the cognitive presentation of ASD, with qualitatively different cognitive processes affected in patients at the high and low end of the IQ spectrum.
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28. Sharer EA, Mostofsky SH, Pascual-Leone A, Oberman LM. {{Isolating Visual and Proprioceptive Components of Motor Sequence Learning in ASD}}. {Autism Res};2015 (Oct 7)
In addition to defining impairments in social communication skills, individuals with autism spectrum disorder (ASD) also show impairments in more basic sensory and motor skills. Development of new skills involves integrating information from multiple sensory modalities. This input is then used to form internal models of action that can be accessed when both performing skilled movements, as well as understanding those actions performed by others. Learning skilled gestures is particularly reliant on integration of visual and proprioceptive input. We used a modified serial reaction time task (SRTT) to decompose proprioceptive and visual components and examine whether patterns of implicit motor skill learning differ in ASD participants as compared with healthy controls. While both groups learned the implicit motor sequence during training, healthy controls showed robust generalization whereas ASD participants demonstrated little generalization when visual input was constant. In contrast, no group differences in generalization were observed when proprioceptive input was constant, with both groups showing limited degrees of generalization. The findings suggest, when learning a motor sequence, individuals with ASD tend to rely less on visual feedback than do healthy controls. Visuomotor representations are considered to underlie imitative learning and action understanding and are thereby crucial to social skill and cognitive development. Thus, anomalous patterns of implicit motor learning, with a tendency to discount visual feedback, may be an important contributor in core social communication deficits that characterize ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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29. Skorich DP, May AR, Talipski LA, Hall MH, Dolstra AJ, Gash TB, Gunningham BH. {{Is Social Categorization the Missing Link Between Weak Central Coherence and Mental State Inference Abilities in Autism? Preliminary Evidence from a General Population Sample}}. {J Autism Dev Disord};2015 (Oct 5)
We explore the relationship between the ‘theory of mind’ (ToM) and ‘central coherence’ difficulties of autism. We introduce covariation between hierarchically-embedded categories and social information-at the local level, the global level, or at both levels simultaneously-within a category confusion task. We then ask participants to infer the mental state of novel category members, and measure participants’ autism-spectrum quotient (AQ). Results reveal a positive relationship between AQ and the degree of local/global social categorization, which in turn predicts the pattern of mental state inferences. These results provide preliminary evidence for a causal relationship between central coherence and ToM abilities. Implications with regard to ToM processes, social categorization, intervention, and the development of a unified account of autism are discussed.
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30. Tye C, Farroni T, Volein A, Mercure E, Tucker L, Johnson MH, Bolton PF. {{Autism diagnosis differentiates neurophysiological responses to faces in adults with tuberous sclerosis complex}}. {J Neurodev Disord};2015;7:33.
BACKGROUND: Autism spectrum disorder (ASD) is a common and highly heritable neurodevelopmental disorder that is likely to be the outcome of complex aetiological mechanisms. One strategy to provide insight is to study ASD within tuberous sclerosis complex (TSC), a rare disorder with a high incidence of ASD, but for which the genetic cause is determined. Individuals with ASD consistently demonstrate face processing impairments, but these have not been examined in adults with TSC using event-related potentials (ERPs) that are able to capture distinct temporal stages of processing. METHODS: For adults with TSC (n = 14), 6 of which had a diagnosis of ASD, and control adults (n = 13) passively viewed upright and inverted human faces with direct or averted gaze, with concurrent EEG recording. Amplitude and latency of the P1 and N170 ERPs were measured. RESULTS: Individuals with TSC + ASD exhibited longer N170 latencies to faces compared to typical adults. Typical adults and adults with TSC-only exhibited longer N170 latency to inverted versus upright faces, whereas individuals with TSC + ASD did not show latency differences according to face orientation. In addition, individuals with TSC + ASD showed increased N170 latency to averted compared to direct gaze, which was not demonstrated in typical adults. A reduced lateralization was shown for the TSC + ASD groups on P1 and N170 amplitude. CONCLUSIONS: The findings suggest that individuals with TSC + ASD may have similar electrophysiological abnormalities to idiopathic ASD and are suggestive of developmental delay. Identifying brain-based markers of ASD that are similar in TSC and idiopathic cases is likely to help elucidate the risk pathways to ASD.
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31. Tzur G. {{Thinking in three dimensions: a different point of view for understanding autism}}. {Front Hum Neurosci};2015;9:484.
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32. Unterrainer JM, Rauh R, Rahm B, Hardt J, Kaller CP, Klein C, Paschke-Muller M, Biscaldi M. {{Development of Planning in Children with High-Functioning Autism Spectrum Disorders and/or Attention Deficit/Hyperactivity Disorder}}. {Autism Res};2015 (Oct 7)
Planning impairment is often observed in children with high-functioning autism spectrum disorders (ASD), but attempts to differentiate planning in ASD from children with attention deficit hyperactivity disorder (ADHD) and typically developing children (TD) have yielded inconsistent results. This study examined differences between these groups by focusing on development and analyzing performance in searching ahead several steps (« search depth ») in addition to commonly used global performance measures in planning. A cross-sectional consecutive sample of 83 male patients (6-13 years), subgrouped as ASD without (ASD-, n = 18) or with comorbid ADHD (ASD+, n = 23), ADHD only (n = 42) and n = 42 TD children (6-13 years) were tested with the Tower-of-London-task. For global performance, ASD+ showed the lowest accuracy in younger children, but similar performance as TD at older ages, suggesting delayed development. Typically, a prolongation of planning time with increasing problem difficulty is observed in older children as compared to younger children. Here, this was most pronounced in ASD-, but under-expressed in ADHD. In contrast to global performance, effects of search depth were independent of age. ASD-, but not ASD+, showed increased susceptibility to raised demands on mentally searching ahead, along with the longest planning times. Thus, examining both global and search depth performance across ages revealed discernible patterns of planning between groups. Notably, the potentially detrimental impact of two diagnosed disorders does not add up in ASD+ in this task. Rather, our results suggest paradoxical enhancement of performance, ostensibly attributable to disruption of behavioral rigidity through increased impulsivity, which did not take place in ASD-. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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33. Ure AM, Treyvaud K, Thompson DK, Pascoe L, Roberts G, Lee KJ, Seal ML, Northam E, Cheong JL, Hunt RW, Inder T, Doyle LW, Anderson PJ. {{Neonatal brain abnormalities associated with autism spectrum disorder in children born very preterm}}. {Autism Res};2015 (Oct 7)
Very preterm (VP) survivors are at increased risk of autism spectrum disorder (ASD) compared with term-born children. This study explored whether neonatal magnetic resonance (MR) brain features differed in VP children with and without ASD at 7 years. One hundred and seventy-two VP children (<30 weeks’ gestation or <1250 g birth weight) underwent structural brain MR scans at term equivalent age (TEA; 40 weeks’ gestation +/-2 weeks) and were assessed for ASD at 7 years of age. The presence and severity of white matter, cortical gray matter, deep nuclear gray matter, and cerebellar abnormalities were assessed, and total and regional brain volumes were measured. ASD was diagnosed using a standardized parent report diagnostic interview and confirmed via an independent assessment. Eight VP children (4.7%) were diagnosed with ASD. Children with ASD had more cystic lesions in the cortical white matter at TEA compared with those without ASD (odds ratio [OR] 8.7, 95% confidence interval [CI] 1.5, 51.3, P = 0.02). There was also some evidence for smaller cerebellar volumes in children with ASD compared with those without ASD (OR = 0.82, CI = 0.66, 1.00, P = 0.06). Overall, the results suggest that VP children with ASD have different brain structure in the neonatal period compared with those who do not have ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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34. Walsh JA, Creighton SE, Rutherford MD. {{Emotion Perception or Social Cognitive Complexity: What Drives Face Processing Deficits in Autism Spectrum Disorder?}}. {J Autism Dev Disord};2015 (Oct 6)
Some, but not all, relevant studies have revealed face processing deficits among those with autism spectrum disorder (ASD). In particular, deficits are revealed in face processing tasks that involve emotion perception. The current study examined whether either deficits in processing emotional expression or deficits in processing social cognitive complexity drive face processing deficits in ASD. We tested adults with and without ASD on a battery of face processing tasks that varied with respect to emotional expression processing and social cognitive complexity. Results revealed significant group differences on tasks involving emotional expression processing, but typical performance on a non-emotional but socially complex task. These results support an emotion processing rather than a social complexity explanation for face processing deficits in ASD.
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35. Yirmiya N, Seidman I, Koren-Karie N, Oppenheim D, Dolev S. {{Stability and change in resolution of diagnosis among parents of children with autism spectrum disorder: Child and parental contributions}}. {Dev Psychopathol};2015 (Nov);27(4 Pt 1):1045-1057.
The contribution of change over time in parent and child characteristics to parents’ resolution of child’s diagnosis was examined among 78 mothers and fathers of children with autism spectrum disorder. Children’s characteristics (e.g., mental age and severity of symptoms), parental characteristics (e.g., attachment-related anxiety and stress level), and parents’ resolution of their child’s diagnosis (resolved vs. unresolved) were examined at Time 1, and reassessed 3 years later at Time 2. Results indicated a deferential contribution of change in parent and child characteristics among mothers and fathers. An increase in child symptom severity and in maternal attachment-related anxiety, as well as longer durations of time since receiving the diagnosis, significantly predicted maternal resolved status at Time 2. Conversely, none of the changes in children’s or paternal characteristics predicted paternal resolved status at Time 2. Results are discussed in relation to child and parental contributions to resolution, the differences in the adjustment and well-being of mothers and fathers of children with autism spectrum disorder, parental growth following receiving the diagnosis, and the need for intervention components specific to parental resolution and attachment-related anxiety.
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36. Young HE, Falco RA, Hanita M. {{Randomized, Controlled Trial of a Comprehensive Program for Young Students with Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Oct 5)
This randomized, controlled trial, comparing the Comprehensive Autism Program (CAP) and business as usual programs, studied outcomes for 3-5 year old students with autism spectrum disorder (ASD). Participants included 84 teachers and 302 students with ASD and their parents. CAP utilized specialized curricula and training components to implement specific evidence-based practices both at school and home. A comprehensive set of outcome areas was studied. Hierarchical linear modeling was used to estimate the treatment impact. CAP had small positive impacts on the students’ receptive language (effect size of .13) and on their social skills as rated by teachers (effect size of .19). Treatment effects were moderated by severity of ASD.
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37. Zalla T, Sperduti M. {{The sense of agency in autism spectrum disorders: a dissociation between prospective and retrospective mechanisms?}}. {Front Psychol};2015;6:1278.
While a large number of studies have reported impairments in social and interpersonal abilities in individuals with autism spectrum disorder (ASD), relatively few studies have focused on self-related knowledge in this population. One of the processes implicated in the physical dimension of the Self is the sense of agency (SoA), i.e., the experience of initiating and controlling one’s own actions and producing desired changes in the world via these actions. So far, the few studies investigating SoA in ASD have reported contrasting results, with some showing spared, others impaired SoA. Here, we review the existing literature and suggest that the distinction between prospective and retrospective mechanisms of the SoA might help reconcile the existing findings. In the light of a multi-componential model of SoA, we propose the view that a specific impairment at the level of prospective mechanisms acting on internal agency signals (i.e., the intention, action selection, or command produced to achieve the goal) may be responsible for the reduced SoA in ASD, along with spared retrospective mechanisms. Future research should shed light on the impact of abnormal SoA on social and self-related dysfunctions in ASD.
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38. Zhang L, Tang J, Dong Y, Ji Y, Tao R, Liang Z, Chen J, Wu Y, Wang K. {{Similarities and Differences in Decision-Making Impairments between Autism Spectrum Disorder and Schizophrenia}}. {Front Behav Neurosci};2015;9:259.
Although individuals with autism spectrum disorders (ASD) and schizophrenia (SCH) share overlapping characteristics and may perform similarly on many cognitive tasks, cognitive dysfunctions common to both disorders do not necessarily share the same underlying mechanisms. Decision-making is currently a major research interest for both ASD and SCH. The aim of the present study was to make direct comparisons of decision-making and disorder-specific underlying neuropsychological mechanisms between the two disorders. Thirty-seven participants with ASD, 46 patients with SCH, and 80 healthy controls (HC) were assessed with the Iowa Gambling Task (IGT), which measures decision-making under ambiguity, and the Game of Dice Task (GDT), which measures decision-making under risk. The results revealed that both the ASD and SCH groups had deficits for both the IGT and the GDT compared with the HC. More importantly, in the IGT, participants with ASD displayed a preference for deck A, indicating that they had more sensitivity to the magnitude of loss than to the frequency of loss, whereas patients with SCH displayed a preference for deck B, indicating that they showed more sensitivity to the frequency of loss than to the magnitude of loss. In the GDT, the impaired performance might be due to the deficits in executive functions in patients with SCH, whereas the impaired performance might be due to the deficits in feedback processing in participants with ASD. These findings demonstrate that there are similar impairments in decision-making tasks between ASD and SCH; however, these two disorders may have different impairment mechanisms.
