1. Aguilar-Valles A, Matta-Camacho E, Khoutorsky A, Gkogkas C, Nader K, Lacaille JC, Sonenberg N. {{Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2}}. {J Neurosci}. 2015; 35(31): 11125-32.
Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (Eif4ebp2), encoding the suppressor of mRNA translation initiation 4E-BP2, leads to an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 reverses the autistic phenotypes in several ASD mouse models. Importantly, these receptors control synaptic physiology via activation of mRNA translation. We investigated the potential reversal of autistic-like phenotypes in Eif4ebp2(-/-) mice by using antagonists of mGluR1 (JNJ16259685) or mGluR5 (fenobam). Augmented hippocampal mGluR-induced long-term depression (LTD; or chemically induced mGluR-LTD) in Eif4ebp2(-/-) mice was rescued by mGluR1 or mGluR5 antagonists. While rescue by mGluR5 inhibition occurs through the blockade of a protein synthesis-dependent component of LTD, normalization by mGluR1 antagonists requires the activation of protein synthesis. Synaptically induced LTD was deficient in Eif4ebp2(-/-) mice, and this deficit was not rescued by group I mGluR antagonists. Furthermore, a single dose of mGluR1 (0.3 mg/kg) or mGluR5 (3 mg/kg) antagonists in vivo reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2(-/-) mice. Our results demonstrate that Eif4ebp2(-/-) mice serve as a relevant model to test potential therapies for ASD symptoms. In addition, we provide substantive evidence that the inhibition of mGluR1/mGluR5 is an effective treatment for physiological and behavioral alterations caused by exacerbated mRNA translation initiation. SIGNIFICANCE STATEMENT: Exacerbated mRNA translation during brain development is associated with several autism spectrum disorders (ASDs). We recently demonstrated that the deletion of a negative regulator of mRNA translation initiation, the eukaryotic initiation factor 4E-binding protein 2, leads to ASD-like behaviors and increased excitatory synaptic activity. Here we demonstrated that autistic behavioral and electrophysiological phenotypes can be treated in adult mice with antagonists of group I metabotropic glutamate receptors (mGluRs), which have been previously used in other ASD models (i.e., fragile X syndrome). These findings support the use of group I mGluR antagonists as a potential therapy that extends to autism models involving exacerbated mRNA translation initiation.
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2. Billeci L, Tonacci A, Tartarisco G, Ruta L, Pioggia G, Gangemi S. {{Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review}}. {Am J Clin Dermatol}. 2015.
BACKGROUND: Atopic dermatitis (AD) is an allergic disorder caused by both immunological dysregulation and epidermal barrier defect. Several studies have investigated the association between AD and mental health disorders. Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions characterized by impairments in social communication and restricted, stereotyped interests and behaviors. The concurrent increased prevalence of AD and ASD in the last decades has led many scientists to investigate the relationship between the two diseases. OBJECTIVE: The aim of this systematic review was to examine the association between AD and ASD. METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed and ScienceDirect were searched up to March 2015 for all reports examining the association between ASD and AD. Descriptive statistics of the studies are reported. RESULTS: The review included 18 studies assessing the association between ASD and AD. Of these studies, two focused on ASD in relation to AD alone, 14 discussed ASD in relation to both AD and other atopic disorders, and two evaluated AD in parents of children with ASD. Most of these studies found a positive association between the two disorders, although there were some studies going in the opposite direction. The entity of the association is somewhat inconsistent among the different studies given that the frequencies of AD in ASD compared with a control group ranged from 7 to 64.2 %. In addition, odds ratios (ORs) or hazard ratios (HRs) gave different results as three studies found a weak association with an OR below 2 and a nonsignificant p value, and three other studies found a moderate or strong association with an OR ranging from 1.52 to 7.17 and a significant p value. When all atopic disorders were considered when evaluating the risk of ASD, the association was strong with an HR of 3.4 or an OR of 1.24 and p < 0.001. CONCLUSIONS: Overall, the results of this systematic review seem to reveal an association between ASD and AD, suggesting that subjects with ASD have an increased risk of presenting with AD compared with typically developing controls, and vice versa. This association is supported by clinical/epidemiological aspects, shared genetic background and common immunological and autoimmune processes. However, the variability in study population and design, and the presence of other risk factors acting as confounding factors, sometimes contribute to inconsistent results. Further studies are needed to clarify the underlying pathophysiologic mechanism explaining the association between ASD and AD and to explore the causal association between the two conditions.
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3. Chandrasekhar T, Sikich L. {{Challenges in the diagnosis and treatment of depression in autism spectrum disorders across the lifespan}}. {Dialogues Clin Neurosci}. 2015; 17(2): 219-27.
Diagnosis and treatment of comorbid neuropsychiatric illness is often a secondary focus of treatment in individuals with autism spectrum disorder (ASD), given that substantial impairment may be caused by core symptoms of ASD itself. However, psychiatric comorbidities, including depressive disorders, are common and frequently result in additional functional impairment, treatment costs, and burden on caregivers. Clinicians may struggle to appropriately diagnose depression in ASD due to communication deficits, atypical presentation of depression in ASD, and lack of standardized diagnostic tools. Specific risk and resilience factors for depression in ASD across the lifespan, including level of functioning, age, family history, and coping style, have been suggested, but require further study. Treatment with medications or psychotherapy may be beneficial, though more research is required to establish guidelines for management of symptoms. This review will describe typical presentations of depression in individuals with ASD, review current information on the prevalence, assessment, and treatment of comorbid depression in individuals with ASD, and identify important research gaps.
4. Chiang HL, Gau SS. {{Comorbid psychiatric conditions as mediators to predict later social adjustment in youths with autism spectrum disorder}}. {J Child Psychol Psychiatry}. 2015.
BACKGROUND: Individuals with autism spectrum disorder (ASD) experience long-term social impairment and their comorbid psychiatric conditions negatively impact adaptive functioning. The aims of the study are to investigate whether comorbid psychopathologies, such as anxiety/depression, inattention, hyperactivity/impulsivity, and oppositional behaviors, mediated the link between autistic symptoms and social maladjustment. METHOD: One hundred and twenty-four youths diagnosed with a clinical diagnosis of DSM-IV ASD (mean age, 10.6 +/- 3.3 years) participated in this longitudinal study. They were assessed using semistructured diagnostic interviews on ASD and other psychiatric conditions at recruitment. Follow-up interviews took place approximately 3 years later (37.59 +/- 15 months) while the parents reported to the Social Adjustment Inventory for Children and Adolescents on their children’s social adjustment. Mediation models were used to examine the mediating effect of comorbid psychopathologies on social adjustment. RESULTS: Youths with ASD had worse school, peer, and home functions than controls at follow-up assessment. In general, comorbid psychiatric conditions mediated the link between autistic symptoms and different domains of social adjustment, independent of age, sex, and full-scale IQ. Additionally, we found specific mediating effects of anxiety/depression and inattention on school functions; anxiety/depression on peer relationships; and oppositional behaviors on home behaviors. CONCLUSION: Early comorbid psychopathologies may further impair later social adjustment in youths with ASD and an early identification and intervention of these comorbid conditions are suggested.
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5. Jarvinen A, Ng R, Crivelli D, Neumann D, Arnold AJ, Woo-VonHoogenstyn N, Lai P, Trauner D, Bellugi U. {{Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder}}. {Dev Psychobiol}. 2015.
Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD. (c) 2015 Wiley Periodicals, Inc. Dev Psychobiol.
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6. Klabunde M, Saggar M, Hustyi KM, Kelley RG, Reiss AL, Hall SS. {{Examining the neural correlates of emergent equivalence relations in fragile X syndrome}}. {Psychiatry Res}. 2015.
The neural mechanisms underlying the formation of stimulus equivalence relations are poorly understood, particularly in individuals with specific learning impairments. As part of a larger study, we used functional magnetic resonance imaging (fMRI) while participants with fragile X syndrome (FXS), and age- and IQ-matched controls with intellectual disability, were required to form new equivalence relations in the scanner. Following intensive training on matching fractions to pie charts (A=B relations) and pie charts to decimals (B=C relations) outside the scanner over a 2-day period, participants were tested on the trained (A=B, B=C) relations, as well as emergent symmetry (i.e., B=A and C=B) and transitivity/equivalence (i.e., A=C and C=A) relations inside the scanner. Eight participants with FXS (6 female, 2 male) and 10 controls, aged 10-23 years, were able to obtain at least 66.7% correct on the trained relations in the scanner and were included in the fMRI analyses. Across both groups, results showed that the emergence of symmetry relations was correlated with increased brain activation in the left inferior parietal lobule, left postcentral gyrus, and left insula, broadly supporting previous investigations of stimulus equivalence research in neurotypical populations. On the test of emergent transitivity/equivalence relations, activation was significantly greater in individuals with FXS compared with controls in the right middle temporal gyrus, left superior frontal gyrus and left precuneus. These data indicate that neural execution was significantly different in individuals with FXS than in age- and IQ-matched controls during stimulus equivalence formation. Further research concerning how gene-brain-behavior interactions may influence the emergence of stimulus equivalence in individuals with intellectual disabilities is needed.
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7. Maurin T, Melko M, Abekhoukh S, Khalfallah O, Davidovic L, Jarjat M, D’Antoni S, Catania MV, Moine H, Bechara E, Bardoni B. {{The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum}}. {Nucleic Acids Res}. 2015.
Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by the silencing of the FMR1 gene encoding an RNA-binding protein (FMRP) mainly involved in translational control. We characterized the interaction between FMRP and the mRNA of GRK4, a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase super-family, both in vitro and in vivo. While the mRNA level of GRK4 is unchanged in the absence or in the presence of FMRP in different regions of the brain, GRK4 protein level is increased in Fmr1-null cerebellum, suggesting that FMRP negatively modulates the expression of GRK4 at the translational level in this brain region. The C-terminal region of FMRP interacts with a domain of GRK4 mRNA, that we called G4RIF, that is folded in four stem loops. The SL1 stem loop of G4RIF is protected by FMRP and is part of the S1/S2 sub-domain that directs translation repression of a reporter mRNA by FMRP. These data confirm the role of the G4RIF/FMRP complex in translational regulation. Considering the role of GRK4 in GABAB receptors desensitization, our results suggest that an increased GRK4 levels in FXS might contribute to cerebellum-dependent phenotypes through a deregulated desensitization of GABAB receptors.
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8. Peters LC, Thompson RH. {{Teaching children with autism to respond to conversation partners’ interest}}. {J Appl Behav Anal}. 2015.
Successful conversation requires that the speaker’s behavior is sensitive to nonvocal listener responses. We observed children with autism spectrum disorder during conversation probes in which a listener periodically displayed nonvocal cues that she was uninterested in the conversation. We used behavioral skills training to teach conversation skills. First, we taught participants to tact nonvocal listener behavior (interested or uninterested), but this was insufficient to improve responding aimed at regaining listener interest. Participants were then taught to ask a question (Experiments 1 and 2) or change the topic (Experiment 2) when the listener was uninterested. Responding persisted over time and with changes in the stimulus conditions. The behavior change was also deemed socially valid by blind observers. In Experiment 3, participants learned to shift to the other trained response when exposed to extinction. This study illustrates a set of procedures for bringing speaker behavior under control of nonvocal listener cues.
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9. Srinivasan SM, Park IK, Neelly LB, Bhat AN. {{A comparison of the effects of rhythm and robotic interventions on repetitive behaviors and affective states of children with Autism Spectrum Disorder (ASD)}}. {Res Autism Spectr Disord}. 2015; 18: 51-63.
Repetitive behaviors and poor affect regulation are commonly seen in children with Autism Spectrum Disorder (ASD). We compared the effects of two novel interventions – rhythm and robotic therapies, with those of a standard-of-care intervention, on the repetitive behaviors and affective states of 36 children with ASD between 5 and 12 years using a randomized controlled trial design. We coded for frequencies of sensory, negative, and stereotyped behaviors and the duration of positive, negative, and interested affective states in children during early, mid, and late training sessions. In terms of repetitive behaviors, in the early session, the rhythm and robot groups engaged in greater negative behaviors, whereas the comparison group engaged in greater sensory behaviors. With training, the rhythm group reduced negative behaviors whereas there were no training-related changes in the other groups. In terms of affective states, the rhythm and robot groups showed greater negative affect, whereas the comparison group demonstrated greater interested affect across all sessions. With training, the rhythm group showed a reduction in negative affect and an increase in interested affect whereas the robot group showed a reduction in positive affect. Overall, it appears that rhythm-based interventions are socially engaging treatment tools to target core impairments in autism.
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10. Taghizadeh N, Davidson A, Williams K, Story D. {{Autism spectrum disorder (ASD) and its perioperative management}}. {Paediatr Anaesth}. 2015.
Autism spectrum disorder (ASD) is now diagnosed in more than 1 in 100 children, so it is not surprising that anesthetists are increasingly providing care for children with this diagnosis. The diagnostic classification for ASD has recently changed and our understanding of the causes and management of ASD are also changing rapidly. This review provides a timely update to increase understanding and awareness of the problems that children with ASD experience, and to minimize perioperative problems. Current literature on premedication and the increasing use of alpha-2 agonists such as clonidine and dexmedetomidine as well as the use of old favorites midazolam and ketamine is reviewed. Some simple strategies that will improve care and decrease anxiety, like social stories, the use of tablet computers, other comfort items or games for distraction, and using favorite drinks to disguise the bitter taste of medications, are described. Remember, the parents are their child’s expert and will know what agitates and settles them. Talking to them prior to the day of the procedure is ideal. The importance of staff training and having a clinical practice guideline available at every institution cannot be overstated.
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11. Tang J, Falkmer M, Horlin C, Tan T, Vaz S, Falkmer T. {{Face Recognition and Visual Search Strategies in Autism Spectrum Disorders: Amending and Extending a Recent Review by Weigelt et al}}. {PLoS One}. 2015; 10(8): e0134439.
The purpose of this review was to build upon a recent review by Weigelt et al. which examined visual search strategies and face identification between individuals with autism spectrum disorders (ASD) and typically developing peers. Seven databases, CINAHL Plus, EMBASE, ERIC, Medline, Proquest, PsychInfo and PubMed were used to locate published scientific studies matching our inclusion criteria. A total of 28 articles not included in Weigelt et al. met criteria for inclusion into this systematic review. Of these 28 studies, 16 were available and met criteria at the time of the previous review, but were mistakenly excluded; and twelve were recently published. Weigelt et al. found quantitative, but not qualitative, differences in face identification in individuals with ASD. In contrast, the current systematic review found both qualitative and quantitative differences in face identification between individuals with and without ASD. There is a large inconsistency in findings across the eye tracking and neurobiological studies reviewed. Recommendations for future research in face recognition in ASD were discussed.
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12. Vabalas A, Freeth M. {{Brief Report: Patterns of Eye Movements in Face to Face Conversation are Associated with Autistic Traits: Evidence from a Student Sample}}. {J Autism Dev Disord}. 2015.
The current study investigated whether the amount of autistic traits shown by an individual is associated with viewing behaviour during a face-to-face interaction. The eye movements of 36 neurotypical university students were recorded using a mobile eye-tracking device. High amounts of autistic traits were neither associated with reduced looking to the social partner overall, nor with reduced looking to the face. However, individuals who were high in autistic traits exhibited reduced visual exploration during the face-to-face interaction overall, as demonstrated by shorter and less frequent saccades. Visual exploration was not related to social anxiety. This study suggests that there are systematic individual differences in visual exploration during social interactions and these are related to amount of autistic traits.
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13. Zappella M, Einspieler C, Bartl-Pokorny KD, Krieber M, Coleman M, Bolte S, Marschik PB. {{What do home videos tell us about early motor and socio-communicative behaviours in children with autistic features during the second year of life – An exploratory study}}. {Early Hum Dev}. 2015; 91(10): 569-75.
BACKGROUND: Little is known about the first half year of life of individuals later diagnosed with autism spectrum disorders (ASD). There is even a complete lack of observations on the first 6months of life of individuals with transient autistic behaviours who improved in their socio-communicative functions in the pre-school age. AIM: To compare early development of individuals with transient autistic behaviours and those later diagnosed with ASD. STUDY DESIGN: Exploratory study; retrospective home video analysis. SUBJECTS: 18 males, videoed between birth and the age of 6months (ten individuals later diagnosed with ASD; eight individuals who lost their autistic behaviours after the age of 3 and achieved age-adequate communicative abilities, albeit often accompanied by tics and attention deficit). METHOD: The detailed video analysis focused on general movements (GMs), the concurrent motor repertoire, eye contact, responsive smiling, and pre-speech vocalisations. RESULTS: Abnormal GMs were observed more frequently in infants later diagnosed with ASD, whereas all but one infant with transient autistic behaviours had normal GMs (p<0.05). Eye contact and responsive smiling were inconspicuous for all individuals. Cooing was not observable in six individuals across both groups. CONCLUSIONS: GMs might be one of the markers which could assist the earlier identification of ASD. We recommend implementing the GM assessment in prospective studies on ASD.
