1. Ament K, Mejia A, Buhlman R, Erklin S, Caffo B, Mostofsky S, Wodka E. {{Evidence for Specificity of Motor Impairments in Catching and Balance in Children with Autism}}. {J Autism Dev Disord};2014 (Sep 18)
To evaluate evidence for motor impairment specificity in autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Children completed performance-based assessment of motor functioning (Movement Assessment Battery for Children: MABC-2). Logistic regression models were used to predict group membership. In the models comparing typically developing and developmental disability (DD), all three MABC subscale scores were significantly negatively associated with having a DD. In the models comparing ADHD and ASD, catching and static balance items were associated with ASD group membership, with a 1 point decrease in performance increasing odds of ASD by 36 and 39 %, respectively. Impairments in motor skills requiring the coupling of visual and temporal feedback to guide and adjust movement appear specifically deficient in ASD.
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2. Byars SG, Stearns SC, Boomsma JJ. {{Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects}}. {Proc Biol Sci};2014 (Nov 7);281(1794)
Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark’s roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean +/- 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691-4090 g; length, 52.8-54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891-3290 g; 49.7-51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.
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3. Casenhiser DM, Binns A, McGill F, Morderer O, Shanker SG. {{Measuring and Supporting Language Function for Children with Autism: Evidence from a Randomized Control Trial of a Social-Interaction-Based Therapy}}. {J Autism Dev Disord};2014 (Sep 19)
In a report of the effectiveness of MEHRIT, a social-interaction-based intervention for autism, Casenhiser et al. (Autism 17(2):220-241, 2013) failed to find a significant advantage for language development in the treatment group using standardized language assessments. We present the results from a re-analysis of their results to illustrate the importance of measuring communicative language acts (formally called « speech acts »). Reanalysis confirmed that children in the MEHRIT group outperformed the community treatment group on measures of MLUm, number of utterances produced, and various speech act categories. The study underscores the importance of functional language measures in guiding and evaluating treatment for children with autism, and suggests that MEHRIT is effective in improving children’s use of language during parent-child interactions.
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4. Deriziotis P, O’Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, Gerdts J, Shendure J, Eichler EE, Fisher SE. {{De novo TBR1 mutations in sporadic autism disrupt protein functions}}. {Nat Commun};2014;5:4954.
Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.
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5. Durrleman S, Hippolyte L, Zufferey S, Iglesias K, Hadjikhani N. {{Complex syntax in autism spectrum disorders: a study of relative clauses}}. {Int J Lang Commun Disord};2014 (Sep 19)
BACKGROUND: The few studies that have evaluated syntax in autism spectrum disorder (ASD) have yielded conflicting findings: some suggest that once matched on mental age, ASD and typically developing controls do not differ for grammar, while others report that morphosyntactic deficits are independent of cognitive skills in ASD. There is a need for a better understanding of syntax in ASD and its relation to, or dissociation from, nonverbal abilities. AIMS: Syntax in ASD was assessed by evaluating subject and object relative clause comprehension in adolescents and adults diagnosed with ASD with a performance IQ within the normal range, and with or without a history of language delay. METHODS & PROCEDURES: Twenty-eight participants with ASD (mean age 21.8) and 28 age-matched controls (mean age 22.07) were required to point to a character designated by relative clauses that varied in syntactic complexity. OUTCOMES & RESULTS: Scores indicate that participants with ASD regardless of the language development history perform significantly worse than age-matched controls with object relative clauses. In addition, participants with ASD with a history of language delay (diagnosed with high-functioning autism in the DSM-IV-TR) perform worse on subject relatives than ASD participants without language delay (diagnosed with Asperger syndrome in the DSM-IV-TR), suggesting that these two groups do not have equivalent linguistic abilities. Performance IQ has a positive impact on the success of the task for the population with ASD. CONCLUSIONS & IMPLICATIONS: This study reveals subtle grammatical difficulties remaining in adult individuals with ASD within normal IQ range as compared with age-matched peers. Even in the absence of a history of language delay in childhood, the results suggest that a slight deficit may nevertheless be present and go undetected by standardized language assessments. Both groups with and without language delay have a similar global performance on relative clause comprehension; however, the study also indicates that the participants with reported language delay show more difficulty with subject relatives than the participants without language delay, suggesting the presence of differences in linguistic abilities between these subgroups of ASD.
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6. Edgar JC, Heiken K, Chen YH, Herrington JD, Chow V, Liu S, Bloy L, Huang M, Pandey J, Cannon KM, Qasmieh S, Levy SE, Schultz RT, Roberts TP. {{Resting-State Alpha in Autism Spectrum Disorder and Alpha Associations with Thalamic Volume}}. {J Autism Dev Disord};2014 (Sep 18)
Alpha circuits (8-12 Hz), necessary for basic and complex brain processes, are abnormal in autism spectrum disorder (ASD). The present study obtained estimates of resting-state (RS) alpha activity in children with ASD and examined associations between alpha activity, age, and clinical symptoms. Given that the thalamus modulates cortical RS alpha rhythms, associations between thalamic structure and alpha activity were examined. RS magnetoencephalography was obtained from 47 typically-developing children (TDC) and 41 children with ASD. RS alpha activity was measured using distributed source localization. Left and right thalamic volume measurements were also obtained. In both groups, the strongest alpha activity was observed in Calcarine Sulcus regions. In Calcarine regions, only TDC showed the expected association between age and alpha peak frequency. ASD had more alpha activity than TDC in regions bordering the Central Sulcus as well as parietal association cortices. In ASD, whereas greater left Central Sulcus relative alpha activity was associated with higher Social Responsiveness Scale (SRS) scores, greater Calcarine region relative alpha activity was associated with lower SRS scores. Although thalamic volume group differences were not observed, relationships between thalamic volume and Calcarine alpha power were unique to TDC. The present study also identified a failure to shift peak alpha frequency as a function of age in primary alpha-generating areas in children with ASD. Findings suggested that increased RS alpha activity in primary motor and somatosensory as well as parietal multimodal areas-with increased alpha thought to reflect greater inhibition-might impair the ability to identify or interpret social cues. Finally, to our knowledge, this is the first study to report associations between thalamic volume and alpha power, an association observed only in TDC. The lack of thalamic and alpha associations in ASD suggests thalamic contributions to RS alpha abnormalities in ASD.
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7. Herrington JD, Riley ME, Grupe DW, Schultz RT. {{Successful Face Recognition is Associated with Increased Prefrontal Cortex Activation in Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Sep 19)
This study examines whether deficits in visual information processing in autism-spectrum disorder (ASD) can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities in ASD.
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8. Huang CY, Chen KL. {{Response to the Letter to the Editor: Impacts of Autistic Behaviors, Emotional and Behavioral Problems on Parenting Stress in Caregivers of Children with Autism: Errors and Discrepancies}}. {J Autism Dev Disord};2014 (Sep 19)
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9. Kronenberg LM, Slager-Visscher K, Goossens PJ, van den Brink W, van Achterberg T. {{Everyday life consequences of substance use in adult patients with a substance use disorder (SUD) and co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD): a patient’s perspective}}. {BMC Psychiatry};2014;14(1):264.
BACKGROUND: Although the prevalence of substance use disorder (SUD) with co-occurring attention deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) is relatively high in adult patients, there is hardly any knowledge about these dual diagnoses. A recent study reported met- and unmet needs for several life domains regarding these patient groups. To improve treatment, it is necessary to identify the everyday life consequences of SUD and co-occurring ADHD or ASD in adult patients. METHODS: Qualitative study using in-depth interviews. 11 SUD + ADHD and 12 SUD + ASD patients participated in the study. The interview transcripts were coded and analysed according to the seven steps for descriptive phenomenology by Colaizzi. RESULTS: Both patients with ADHD and patients with ASD can get caught in a jumble of thoughts and emotions which can often lead to agitation and impulsivity in the case of ADHD or passivity and melancholia in the case of ASD with co-occurring SUD in both cases. Initially substance use ameliorates the symptoms and related problems, but both patient groups can later experience even greater problems: difficulties with the structuring of daily life due to a lack of planning (SUD + ADHD) or due to a lack of initiative (SUD + ASD). Both groups indicate that structure helps them function better. They also recognize that substance use disorganizes their lives and that an absence of structure contributes to substance use in what becomes a vicious circle which needs to be broken for effective treatment and care. CONCLUSIONS: This study provides insight into the daily life consequences of SUD with a co-occurring ADHD or ASD. Substance use is reported to solve some ADHD- or ASD-related problems in the short run but have negative consequences in the long run (i.e., contribute to already impaired cognitive functioning). Insight is provided into what clinicians can do to break this vicious circle and thus help ADHD patients to refrain from action and ASD patients to take action.
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10. Liew SM, Thevaraja N, Hong RY, Magiati I. {{The Relationship Between Autistic Traits and Social Anxiety, Worry, Obsessive-Compulsive, and Depressive Symptoms: Specific and Non-specific Mediators in a Student Sample}}. {J Autism Dev Disord};2014 (Sep 19)
The high prevalence of anxiety symptoms in individuals with autism spectrum disorders has now been well documented. There is also a positive relationship between autistic traits and anxiety symptoms in unselected samples and individuals with anxiety disorders have more autistic traits compared to those without. Less is known, however, regarding which elements of autistic traits (i.e., social versus non-social/behavioral) or which other variables may mediate this relationship. This study investigated the shared and specific role of five autistic-trait related mediators (social problem-solving, social competence, teasing experiences, prevention from/punishment for preferred repetitive behaviors and aversive sensory experiences) in a non-clinical sample of 252 university students. Autistic traits positively correlated with both anxiety and depressive symptoms. Social competence mediated the relationship between autistic traits and social anxiety symptoms only, while only prevention from preferred repetitive behaviors and frequent aversive sensory experiences mediated the relationship between autistic traits, worry and obsessive-compulsive symptoms. Replication of these findings is required in longitudinal studies and with clinical samples. Limitations of the study are discussed and possible implications for intervention are tentatively suggested.
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11. Liu X, Takumi T. {{Genomic and genetic aspects of autism spectrum disorder}}. {Biochem Biophys Res Commun};2014 (Sep 19);452(2):244-253.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.
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12. Macedoni-Luksic M, Gosar D, Bjorklund G, Orazem J, Kodric J, Lesnik-Musek P, Zupancic M, France-Stiglic A, Sesek-Briski A, Neubauer D, Osredkar J. {{Levels of Metals in the Blood and Specific Porphyrins in the Urine in Children with Autism Spectrum Disorders}}. {Biol Trace Elem Res};2014 (Sep 19)
The aim of the present study was to determine the levels of metals in blood (zinc (Zn), copper (Cu), aluminium (Al), lead (Pb) and mercury (Hg)), as well as the specific porphyrin levels in the urine of patients with autism spectrum disorder (ASD) compared with patients with other neurological disorders. The study was performed in a group of children with ASD (N = 52, average age = 6.2 years) and a control group of children with other neurological disorders (N = 22, average age = 6.6 years), matched in terms of intellectual abilities (Mann-Whitney U = 565.0, p = 0.595). Measurement of metals in blood was performed by atomic absorption spectrometry, while the HPLC method via a fluorescence detector was used to test urinary porphyrin levels. Results were compared across groups using a multivariate analysis of covariance (MANCOVA). In addition, a generalized linear model was used to establish the impact of group membership on the blood Cu/Zn ratio. In terms of blood levels of metals, no significant difference between the groups was found. However, compared to the control group, ASD group had significantly elevated blood Cu/Zn ratio (Wald chi 2 = 6.6, df = 1, p = 0.010). Additionally, no significant difference between the groups was found in terms of uroporphyrin I, heptacarboxyporphyrin I, hexacarboxyporphyrin and pentacarboxyporphyrin I. However, the levels of coproporphyrin I and coproporphyrin III were lower in the ASD group compared to the controls. Due to observed higher Cu/Zn ratio, it is suggested to test blood levels of Zn and Cu in all autistic children and give them a Zn supplement if needed.
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13. Miller HL, Ragozzino ME, Cook EH, Sweeney JA, Mosconi MW. {{Cognitive Set Shifting Deficits and Their Relationship to Repetitive Behaviors in Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Sep 19)
The neurocognitive impairments associated with restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD) are not yet clear. Prior studies indicate that individuals with ASD show reduced cognitive flexibility, which could reflect difficulty shifting from a previously learned response pattern or a failure to maintain a new response set. We examined different error types on a test of set-shifting completed by 60 individuals with ASD and 55 age- and nonverbal IQ-matched controls. Individuals with ASD were able to initially shift sets, but they exhibited difficulty maintaining new response sets. Difficulty with set maintenance was related to increased severity of RRBs. General difficulty maintaining new response sets and a heightened tendency to revert to old preferences may contribute to RRBs.
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14. Sabers A, Bertelsen FC, Scheel-Kruger J, Nyengaard JR, Moller A. {{Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism}}. {Neurosci Lett};2014 (Sep 19);580:12-16.
The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.
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15. Wegiel J, Flory M, Kuchna I, Nowicki K, Ma S, Imaki H, Cohen IL, London E, Wisniewski T, Brown W. {{Stereological study of the neuronal number and volume of 38 brain subdivisions of subjects diagnosed with autism reveals significant alterations restricted to the striatum, amygdala and cerebellum}}. {Acta Neuropathol Commun};2014 (Sep 18);2(1):141.
IntroductionA total of 38 brain cytoarchitectonic subdivisions, representing subcortical and cortical structures, cerebellum, and brainstem, were examined in 4- to 60-year-old subjects diagnosed with autism and control subjects (a) to detect a global pattern of developmental abnormalities and (b) to establish whether the function of developmentally modified structures matches the behavioral alterations that are diagnostic for autism. The volume of cytoarchitectonic subdivisions, neuronal numerical density, and total number of neurons per region of interest were determined in 14 subjects with autism and 14 age-matched controls by using unbiased stereological methods.ResultsThe study revealed that significant differences between the group of subjects with autism and control groups are limited to a few brain regions, including the cerebellum and some striatum and amygdala subdivisions. In the group of individuals with autism, the total number and numerical density of Purkinje cells in the cerebellum were reduced by 25% and 24%, respectively. In the amygdala, significant reduction of neuronal density was limited to the lateral nucleus (by 12%). Another sign of the topographic selectivity of developmental alterations in the brain of individuals with autism was an increase in the volumes of the caudate nucleus and nucleus accumbens by 22% and 34%, respectively, and the reduced numerical density of neurons in the nucleus accumbens and putamen by 15% and 13%, respectively.ConclusionsThe observed pattern of developmental alterations in the cerebellum, amygdala and striatum is consistent with the results of magnetic resonance imaging studies and their clinical correlations, and of some morphometric studies that indicate that detected abnormalities may contribute to the social and communication deficits, and repetitive and stereotypical behaviors observed in individuals with autism.
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16. Wheeler AC, Mussey J, Villagomez A, Bishop E, Raspa M, Edwards A, Bodfish J, Bann C, Bailey DB, Jr. {{DSM-5 Changes and the Prevalence of Parent-Reported Autism Spectrum Symptoms in Fragile X Syndrome}}. {J Autism Dev Disord};2014 (Sep 19)
We used survey methodology to assess parent-reported autism symptomology in 758 individuals (639 males; 119 females) with fragile X syndrome (FXS). Caregivers reported whether their child with FXS had been diagnosed with an autism spectrum disorder (ASD) and endorsed symptoms based on a list of observable behaviors related to ASD diagnoses. Symptom counts were categorized based on DSM-IV-TR and DSM-5 criteria. Based on behavioral symptoms endorsed by caregivers, 38.7 % of males and 24.7 % of females met criteria for DSM-IV-TR diagnosis of autistic disorder. Significantly fewer males (27.8 %) and females (11.3 %) met criteria for ASD based on DSM-5 criteria. Although 86.4 % of males and 61.7 % of females met criteria for the restricted and repetitive behavior domain for DSM-5, only 29.4 % of males and 13.0 % of females met criteria for the social communication and interaction (SCI) domain. Relaxing the social communication criteria by one symptom count led to a threefold increase in those meeting criteria for ASD, suggesting the importance of subthreshold SCI symptoms for individuals with FXS in ASD diagnoses. Findings suggest important differences in the way ASD may be conceptualized in FXS based on the new DSM-5 criteria.
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17. Wolfberg P, DeWitt M, Young GS, Nguyen T. {{Integrated Play Groups: Promoting Symbolic Play and Social Engagement with Typical Peers in Children with ASD Across Settings}}. {J Autism Dev Disord};2014 (Sep 18)
Children with autism spectrum disorders (ASD) face pervasive challenges in symbolic and social play development. The Integrated Play Groups (IPG) model provides intensive guidance for children with ASD to participate with typical peers in mutually engaging experiences in natural settings. This study examined the effects of a 12-week IPG intervention on the symbolic and social play of 48 children with ASD using a repeated measures design. The findings revealed significant gains in symbolic and social play that generalized to unsupported play with unfamiliar peers. Consistent with prior studies, the outcomes provide robust and compelling evidence that further validate the efficacy of the IPG model. Theoretical and practical implications for maximizing children’s developmental potential and social inclusion in play are discussed.
