1. Aramaki E, Shikata S, Miyabe M, Usuda Y, Asada K, Ayaya S, Kumagaya S. {{Understanding the Relationship between Social Cognition and Word Difficulty. A Language Based Analysis of Individuals with Autism Spectrum Disorder}}. {Methods Inf Med};2015 (Sep 22);54(5)
BACKGROUND: Few quantitative studies have been conducted on the relationship between society and its languages. Individuals with autistic spectrum disorder (ASD) are known to experience social hardships, and a wide range of clinical information about their quality of life has been provided through numerous narrative analyses. However, the narratives of ASD patients have thus far been examined mainly through qualitative approaches. OBJECTIVES: In this study, we analyzed adults with ASD to quantitatively examine the relationship between language abilities and ASD severity scores. METHODS: We generated phonetic transcriptions of speeches by 16 ASD adults at an ASD workshop, and divided the participants into 2 groups according to their Social Responsiveness ScaleTM, 2nd Edition (SRSTM-2) scores (where higher scores represent more severe ASD): Group A comprised high-scoring ASD adults (SRSTM-2 score: >/= 76) and Group B comprised low- and intermediate-scoring ASD adults (SRSTM-2 score: < 76). Using natural language processing (NLP)-based analytical methods, the narratives were converted into numerical data according to four language ability indicators, and the relationships between the language ability scores and ASD severity scores were compared. RESULTS AND DISCUSSION: Group A showed a marginally negative correlation with the level of Japanese word difficulty (p < .10), while the « social cognition » subscale of the SRSTM-2 score showed a significantly negative correlation (p < .05) with word difficulty. When comparing only male participants, Group A demonstrated a significantly lower correlation with word difficulty level than Group B (p < .10). CONCLUSION: Social communication was found to be strongly associated with the level of word difficulty in speech. The clinical applications of these findings may be available in the near future, and there is a need for further detailed study on language metrics designed for ASD adults.
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2. Bearss K, Taylor CA, Aman MG, Whittemore R, Lecavalier L, Miller J, Pritchett J, Green B, Scahill L. {{Using qualitative methods to guide scale development for anxiety in youth with autism spectrum disorder}}. {Autism};2015 (Sep 22)
Anxiety is common in youth with autism spectrum disorder. Despite this common co-occurrence, studies targeting anxiety in this population are hindered by the under-developed state of measures in youth with autism spectrum disorder. Content validity (the extent to which an instrument measures the domain of interest) and an instrument’s relevance to the patient population are key components of measurement development. This article describes the application of qualitative research methods in the initial development of a parent-rated instrument of anxiety symptoms in youth with autism spectrum disorder. Overall, 48 parents of 45 children (aged 3-17 years) with autism spectrum disorder and at least mild anxiety participated in one of six focus groups at two sites (three groups per site). Systematic coding of the focus group transcripts identified broad themes reflecting the situations and events that trigger anxiety in children with autism spectrum disorder, the behavioral manifestations of anxiety in children with autism spectrum disorder, the parent and the child’s own response to anxiety, and broad behavioral patterns that could be associated with anxiety. From the focus group data, investigators generated 52 candidate items for a parent-rating of anxiety in youth with autism spectrum disorder. This report provides a detailed description of these early steps in developing a patient-oriented outcome measure.
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3. Chiu TA, Anagnostou E, Brian J, Chau T, Kushki A. {{Specificity of autonomic arousal to anxiety in children with autism spectrum disorder}}. {Autism Res};2015 (Sep 21)
Anxiety is one of the most concerning comorbidities in autism spectrum disorder (ASD) due to its high prevalence, negative impact on physical and psychological well-being, and interaction with core deficits of ASD. Current assessment and treatment of anxiety, which rely on the observation of behavior and self-reports, are often ineffective as ASD is associated with deficits in communication and diminished introspective ability. In this light, autonomic nervous system (ANS) activity has been suggested as a marker of physiological arousal associated with anxiety. However, physiological arousal measured by ANS indices also occurs with other cognitive and emotional processes, and it is unclear whether anxiety-related arousal can be differentiated from that related to other cognitive processes. To address this gap, we investigated the use of linear and nonlinear classification techniques for differentiating anxiety-related arousal from arousal due to three cognitive processes (attention, inhibitory control, and social cognition) and physical activity based on electrocardiography signal features. Our results indicate that over 80% classification accuracy can be achieved, suggesting that ANS response can be used as a specific marker of anxiety-related arousal in a subgroup of children with ASD who demonstrate an increase in heart rate in response to anxiogenic stimuli. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Jamison TR, Schuttler JO. {{Examining social competence, self-perception, quality of life, and internalizing and externalizing symptoms in adolescent females with and without autism spectrum disorder: a quantitative design including between-groups and correlational analyses}}. {Mol Autism};2015;6:53.
BACKGROUND: Adolescent females with an autism spectrum disorder (ASD) are an understudied population, yet are also quite vulnerable, due to the increased complexities of social interaction and increased risk for internalizing symptoms in adolescence. Most research literature currently focuses on males with ASD, limiting our understanding of social experiences for females with ASD, and thus the potential to better inform supports and intervention to promote social-emotional functioning. This study examined similarities and differences in selected indicators of social-emotional health (social competence, self-perception, quality of life) and problematic behaviors such as externalizing and internalizing symptoms for adolescent females with and without ASD. METHODS: This study employed a quantitative design utilizing correlational analysis as well as t test comparisons to examine selected indicators of social-emotional health and problematic symptoms using the Social Skills Improvement System (SSIS), Youth Quality of Life Instrument (YQOL), and the Self-Perceptions Profile for Adolescents (SPPA) for adolescent females with ASD in relation to their typically developing peers. RESULTS: Significant differences were found between females with and without ASD in terms of their self-ratings of social-emotional health and problematic behaviors. The no-ASD group rated themselves higher across all areas of social-emotional health. Findings also suggest strong relationships between these constructs, especially for females without ASD. Parent reports of autism symptoms and social-emotional health indicated that as symptoms of autism are more severe, so too was the impact on individuals’ social competence. CONCLUSIONS: Adolescent females with ASD perceive themselves as having lower social competence, self-worth, and quality of life and higher levels of internalizing and externalizing symptoms as compared to their typically developing peers. Parent ratings indicate that higher levels of autism symptoms relate to lower levels of social competence. These findings lend support to the postulate that adolescent females with ASD are more vulnerable than their typically developing counterparts due to the compounded impact of ASD symptoms on social-emotional health and the higher risk for internalizing disorders for adolescent girls. Limitations and implications for further research and intervention are discussed.
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5. Kasari C, Dean M, Kretzmann M, Shih W, Orlich F, Whitney R, Landa R, Lord C, King B. {{Children with autism spectrum disorder and social skills groups at school: a randomized trial comparing intervention approach and peer composition}}. {J Child Psychol Psychiatry};2015 (Sep 22)
BACKGROUND: Peer relationships improve for children with autism spectrum disorder (ASD) in clinic-based social skills groups but rarely generalize to real world contexts. This study compares child outcomes of two social skills interventions conducted in schools with children in Kindergarten through fifth grade. METHOD: Children with ASD were randomized to one of two interventions that varied on group composition (mixed typical and ASD vs. all ASD or social difficulties) and intervention approach (didactic SKILLS based vs. activity-based ENGAGE groups). Interventions were implemented at school for 8 weeks (16 sessions) with an 8-week follow-up. Innovative measures of peer nomination and playground peer engagement, as well as teacher reports of child behavior problems and teacher-child relationship were analyzed for 137 children with ASD across four sites. RESULTS: On the primary outcome of social network connections from the peer nomination measure, there was no main effect of treatment, but there were moderator effects. Children with low teacher-child closeness or high conflict improved more in their social connections if they received the SKILLS intervention, whereas children with higher teacher-child closeness improved more if they received the ENGAGE intervention. Only two secondary outcome measures yielded significant effects of treatment. Children in the SKILLS groups increased peer engagement and decreased isolation during recess. Child behavior problems and teacher-child closeness moderated peer engagement such that children with higher behavior problems and lower closeness benefitted more from SKILLS groups. CONCLUSIONS: These findings suggest that social skills groups conducted at school can affect both peer engagement during recess as well as peer acceptability. Child characteristics and teacher-child relationship prior to intervention yield important information on who might benefit from a specific social skills intervention.
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6. Lawson RP, Friston KJ, Rees G. {{A more precise look at context in autism}}. {Proc Natl Acad Sci U S A};2015 (Sep 22);112(38):E5226.
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7. Louwerse A, Eussen ML, Van der Ende J, de Nijs PF, Van Gool AR, Dekker LP, Verheij C, Verheij F, Verhulst FC, Greaves-Lord K. {{ASD Symptom Severity in Adolescence of Individuals Diagnosed with PDD-NOS in Childhood: Stability and the Relation with Psychiatric Comorbidity and Societal Participation}}. {J Autism Dev Disord};2015 (Sep 22)
The current 7-year follow-up study investigated: (1) the stability of ASD severity, and (2) associations of ASD severity in adolescence with (a) childhood and concurrent psychiatric comorbidity, and (b) concurrent societal functioning. The Autism Diagnostic Observation Schedule (ADOS) and the Diagnostic Interview Schedule for Children were administered in childhood (ages 6-12) and in adolescence (ages 12-20) to 72 individuals with a pervasive developmental disorder-not otherwise specified (PDD-NOS). ADOS calibrated severity scores showed a large stability (r = .51). Psychiatric comorbidity in childhood and adolescence were not associated with ASD severity in adolescence. Mental health care use (87 %) and special education needs were high (71 %). Reevaluation of ASD severity and psychiatric comorbidity later in life seem useful when PDD-NOS is diagnosed in childhood.
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8. Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ. {{Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis}}. {Transl Psychiatry};2015;5:e640.
Large placebo responses in many clinical trials limit our capacity to identify effective therapeutics. Although it is often assumed that core behaviors in children with autism spectrum disorders (ASDs) rarely remit spontaneously, there has been limited investigation of the size of the placebo response in relevant clinical trials. These trials also rely on caregiver and clinical observer reports as outcome measures. The objectives of this meta-analysis are to identify the pooled placebo response and the predictors of placebo response in pharmacological and dietary supplement treatment trials for participants with a diagnosis of ASD. Randomized controlled trials (RCTs) in pediatric ASD, conducted between 1980 and August 2014, were identified through a search of Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews and clinicaltrials.gov. RCTs of at least 14 days duration, comparing the treatment response for an oral active agent and placebo using at least one of the common outcome measures, were included. Analysis of 25 data sets (1315 participants) revealed a moderate effect size for overall placebo response (Hedges’ g=0.45, 95% confidence interval (0.34-0.56), P<0.001). Five factors were associated with an increase in response to placebo, namely: an increased response to the active intervention; outcome ratings by clinicians (as compared with caregivers); trials of pharmacological and adjunctive interventions; and trials located in Iran. There is a clear need for the identification of objective measures of change in clinical trials for ASD, such as evaluation of biological activity or markers, and for consideration of how best to deal with placebo response effects in trial design and analyses.
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9. McCormick C, Hepburn S, Young GS, Rogers SJ. {{Sensory symptoms in children with autism spectrum disorder, other developmental disorders and typical development: A longitudinal study}}. {Autism};2015 (Sep 22)
Sensory symptoms are prevalent in autism spectrum disorder but little is known about the early developmental patterns of these symptoms. This study examined the development of sensory symptoms and the relationship between sensory symptoms and adaptive functioning during early childhood. Three groups of children were followed across three time points from 2 to 8 years of age: autism spectrum disorder, developmental delay, and typical development. At each time point, parents filled out questionnaires regarding their child’s sensory symptoms and adaptive functioning. At the initial time point, parents of children with autism spectrum disorder reported more sensory symptoms in their children than parents in the typical development group. Parents in the autism spectrum disorder group reported more sensory symptoms than parents in the developmental delay group within smell, taste, and auditory domains. While the typical development group decreased in reported sensory symptoms across the study period, the clinical groups demonstrated no significant change across assessment points. Sensory symptoms for all groups were not independently predictive of adaptive functioning when verbal mental age was also included in the model. The young age range at the initial assessment and pattern of results suggest that sensory symptoms are present early in the etiology of autism spectrum disorder and other developmental disorders and remain stable over time.
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10. Mosconi MW, Wang Z, Schmitt LM, Tsai P, Sweeney JA. {{The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders}}. {Front Neurosci};2015;9:296.
The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients’ sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.
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11. Navot N, Jorgenson AG, Vander Stoep A, Toth K, Webb SJ. {{Family planning and family vision in mothers after diagnosis of a child with autism spectrum disorder}}. {Autism};2015 (Sep 22)
The diagnosis of a child with autism has short- and long-term impacts on family functioning. With early diagnosis, the diagnostic process is likely to co-occur with family planning decisions, yet little is known about how parents navigate this process. This study explores family planning decision making process among mothers of young children with autism spectrum disorder in the United States, by understanding the transformation in family vision before and after the diagnosis. A total of 22 mothers of first born children, diagnosed with autism between 2 and 4 years of age, were interviewed about family vision prior to and after their child’s diagnosis. Grounded Theory method was used for data analysis. Findings indicated that coherence of early family vision, maternal cognitive flexibility, and maternal responses to diagnosis were highly influential in future family planning decisions. The decision to have additional children reflected a high level of adaptability built upon a solid internalized family model and a flexible approach to life. Decision to stop childrearing reflected a relatively less coherent family model and more rigid cognitive style followed by ongoing hardship managing life after the diagnosis. This report may be useful for health-care providers in enhancing therapeutic alliance and guiding family planning counseling.
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12. Schmunk G, Boubion BJ, Smith IF, Parker I, Gargus JJ. {{Shared functional defect in IPR-mediated calcium signaling in diverse monogenic autism syndromes}}. {Transl Psychiatry};2015;5:e643.
Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca2+ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD-fragile X and tuberous sclerosis TSC1 and TSC2 syndromes-display depressed Ca2+ release through inositol trisphosphate receptors (IP3Rs). This was apparent in Ca2+ signals evoked by G protein-coupled receptors and by photoreleased IP3 at the levels of both global and local elementary Ca2+ events, suggesting fundamental defects in IP3R channel activity in ASD. Given the ubiquitous involvement of IP3R-mediated Ca2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP3R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca2+ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.
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13. Singer L. {{Thoughts about sex and gender differences from the next generation of autism scientists}}. {Mol Autism};2015;6:52.
According to the CDC, males are four times more likely to be diagnosed with autism than females. New studies have shown that girls need a higher burden of genetic mutation to be diagnosed with autism than males. These findings are leading researchers to a new avenue of investigation called the female protective effect. This theory holds that even when females carry mutations in autism-linked genes, the effect of the mutations is prevented when the level of genetic disruption is low. Understanding the biology behind this protective effect and studying females independently from males could lead to major advancements in the prevention and treatment of ASD in both males and females.
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14. Telias M, Mayshar Y, Amit A, Ben-Yosef D. {{Molecular mechanisms regulating impaired neurogenesis of fragile X syndrome human embryonic stem cells}}. {Stem Cells Dev};2015 (Sep 22)
Fragile X Syndrome (FXS) is the most common form of inherited cognitive impairment. It is caused by developmental inactivation of the FMR1gene and its encoded protein FMRP, which plays pivotal roles in brain development and function. In FXS embryos with full FMR1 mutation, FMRP is expressed during early embryogenesis and is gradually down-regulated at the third trimester of pregnancy. FX-human embryonic stem cells (FX-hESCs), derived from FX human blastocysts, demonstrate the same pattern of developmentally-regulated FMR1 inactivation when subjected to in-vitro neural differentiation. In this study, we used this in-vitro human platform to explore the molecular mechanisms downstream to FMRP in the context of early human embryonic neurogenesis. Our results show a novel role for the SOX superfamily of transcription factors, specifically for SOX2 and SOX9, which could explain the reduced and delayed neurogenesis observed in FX cells. In addition, we assess in this study the ‘GSK3beta theory of FXS’ for the first time in a human-based model. We found no evidence for a pathological increase in GSK3beta levels upon cellular loss of FMRP, in contrast to what was found in the brain of FMR1 knock-out mice. Our study adds novel data on potential downstream targets of FMRP, and highlights the importance of the FX-hESCs in-vitro neural differentiation system.
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15. Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, Itoh M, Uesaka M, Imamura T, Nakahata Y, Yamashita Y, Abe T, Takamori S, Nakashima K. {{miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes}}. {Cell Rep};2015 (Sep 22);12(11):1887-1901.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR), which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.
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16. Ueyama Y. {{A Bayesian Model of the Uncanny Valley Effect for Explaining the Effects of Therapeutic Robots in Autism Spectrum Disorder}}. {PLoS One};2015;10(9):e0138642.
One of the core features of autism spectrum disorder (ASD) is impaired reciprocal social interaction, especially in processing emotional information. Social robots are used to encourage children with ASD to take the initiative and to interact with the robotic tools to stimulate emotional responses. However, the existing evidence is limited by poor trial designs. The purpose of this study was to provide computational evidence in support of robot-assisted therapy for children with ASD. We thus propose an emotional model of ASD that adapts a Bayesian model of the uncanny valley effect, which holds that a human-looking robot can provoke repulsion and sensations of eeriness. Based on the unique emotional responses of children with ASD to the robots, we postulate that ASD induces a unique emotional response curve, more like a cliff than a valley. Thus, we performed numerical simulations of robot-assisted therapy to evaluate its effects. The results showed that, although a stimulus fell into the uncanny valley in the typical condition, it was effective at avoiding the uncanny cliff in the ASD condition. Consequently, individuals with ASD may find it more comfortable, and may modify their emotional response, if the robots look like deformed humans, even if they appear « creepy » to typical individuals. Therefore, we suggest that our model explains the effects of robot-assisted therapy in children with ASD and that human-looking robots may have potential advantages for improving social interactions in ASD.
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17. Wang H, Liang S, Wang M, Gao J, Sun C, Wang J, Xia W, Wu S, Sumner SJ, Zhang F, Wu L. {{Potential serum biomarkers from a metabolomics study of autism}}. {J Psychiatry Neurosci};2015 (Sep 22);40(5):140009.
BACKGROUND: Early detection and diagnosis are very important for autism. Current diagnosis of autism relies mainly on some observational questionnaires and interview tools that may involve a great variability. We performed a metabolomics analysis of serum to identify potential biomarkers for the early diagnosis and clinical evaluation of autism. METHODS: We analyzed a discovery cohort of patients with autism and participants without autism in the Chinese Han population using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS) to detect metabolic changes in serum associated with autism. The potential metabolite candidates for biomarkers were individually validated in an additional independent cohort of cases and controls. We built a multiple logistic regression model to evaluate the validated biomarkers. RESULTS: We included 73 patients and 63 controls in the discovery cohort and 100 cases and 100 controls in the validation cohort. Metabolomic analysis of serum in the discovery stage identified 17 metabolites, 11 of which were validated in an independent cohort. A multiple logistic regression model built on the 11 validated metabolites fit well in both cohorts. The model consistently showed that autism was associated with 2 particular metabolites: sphingosine 1-phosphate and docosahexaenoic acid. LIMITATIONS: While autism is diagnosed predominantly in boys, we were unable to perform the analysis by sex owing to difficulty recruiting enough female patients. Other limitations include the need to perform test-retest assessment within the same individual and the relatively small sample size. CONCLUSION: Two metabolites have potential as biomarkers for the clinical diagnosis and evaluation of autism.
18. Yamasue H. {{Promising evidence and remaining issues regarding the clinical application of oxytocin in autism spectrum disorders}}. {Psychiatry Clin Neurosci};2015 (Sep 22)
Oxytocin is a potential therapeutic for the core symptoms of autism spectrum disorder (ASD), which is currently untreatable with pharmacotherapy. Previous clinical trials of a single dose of oxytocin have consistently reported significantly positive effects on various experimental measures associated with the core symptoms of ASD. These studies used various experimental measures as surrogate endpoints of the trials. However, to date, randomized clinical trials of continual administration of oxytocin have failed to reveal significant positive effects on clinically meaningful endpoints, such as how those with ASD interact during interpersonal interactions.. This article reviews both the negative and positive effects of oxytocin on the core symptoms of ASD and their surrogate markers. Some unresolved and critical issues on the development of oxytocin as a new therapeutic have been extracted: optimization of dose, duration of oxytocin treatment, and the development of objective and reliable measurements of clinically meaningful endpoints for the core symptoms of ASD. Furthermore, optimization to intranasal delivery system and careful consideration of how individuals respond differently to treatments should be addressed in future studies.
