1. Baribeau DA, Anagnostou E. {{Social Communication is an Emerging Target for Pharmacotherapy in Autism Spectrum Disorder – A Review of the Literature on Potential Agents}}. {J Can Acad Child Adolesc Psychiatry};2014 (Feb);23(1):20-30.
OBJECTIVE: To review the published literature and registered clinical trials on pharmacologic interventions targeting social communication impairment in Autism Spectrum Disorder (ASD). METHODS: A comprehensive search of several databases (PubMed, MEDLINE, PsycINFO, Clinical trials.gov) was conducted to identify pharmacologic agents that have been, or will be, tested as treatments for social communication impairment in individuals with ASD. Evidence from basic science research supporting rational drug discovery is surveyed. RESULTS: Data from animal models and early clinical trials suggest that novel and existing compounds, including N-methyl-D-aspartate (NMDA) modulators, gamma-aminobutyric acid (GABA) agonists, metabotropic glutamate receptor (mGluR) antagonists and neuropeptides, may enhance social communication/function in ASD. Results from numerous Phase 2 and Phase 3 clinical trials are expected in the near future. CONCLUSIONS: Recent evidence suggests that social communication may be an appropriate target for pharmacologic manipulation. It is hoped that, in combination with behavioural interventions, novel therapeutics may soon be clinically available to help improve social outcomes.
2. Chase A. {{Brain imaging: White matter disruption in autism spectrum disorder is exaggerated by head movements during neuroimaging}}. {Nat Rev Neurol};2014 (Feb 11)
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3. Chiocchetti AG, Haslinger D, Boesch M, Karl T, Wiemann S, Freitag CM, Poustka F, Scheibe B, Bauer JW, Hintner H, Breitenbach M, Kellermann J, Lottspeich F, Klauck SM, Breitenbach-Koller L. {{Protein signatures of oxidative stress response in a patient specific cell line model for autism}}. {Mol Autism};2014 (Feb 10);5(1):10.
BACKGROUND: Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress. METHODS: Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways. RESULTS: The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects’ and the ASD patients’ set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress. CONCLUSIONS: Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins.
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4. Gkogkas CG, Sonenberg N. {{Translational control and autism-like behaviors}}. {Cell Logist};2013 (Jan 1);3(1):e24551.
AUTISM SPECTRUM DISORDERS (ASD) CONSIST OF A SPECTRUM OF NEURODEVELOPMENTAL DISEASES WITH THREE SALIENT FEATURES: reduced social interactions, impaired communication and repetitive/stereotyped behaviors. In a recent study we found that increased eIF4E (eukaryotic initiation factor 4E)-dependent protein synthesis as a result of genetic deletion of Eif4ebp2 (eIF4E-binding protein 2) in mice, stimulates the production of neuroligins (Nlgns, synaptic cell-adhesion molecules important for synapse regulation) and engenders an imbalance of excitatory to inhibitory synaptic transmission (E/I) in CA1 pyramidal neurons. This imbalance is accompanied with deficits in social interaction, communication and repetitive/stereotyped behaviors in Eif4ebp2-/- mice. Using a compound that blocks cap-dependent translation or by knocking down Nlgn1, we restored the E/I balance and reversed the autism-like social deficits.
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5. Haq AU, Ghaziuddin N. {{Maintenance electroconvulsive therapy for aggression and self-injurious behavior in two adolescents with autism and catatonia}}. {J Neuropsychiatry Clin Neurosci};2014 (Jan 1);26(1):64-72.
Frequent aggression toward others and repetitive self-injurious behaviors (SIB) can be features of catatonia in patients with autism. Similar to catatonia secondary to other etiologies, catatonia associated with autism responds well to treatment with benzodiazepines and/or electroconvulsive therapy (ECT). The authors report here on two adolescent patients with autism who presented with severe aggression, one of whom also engaged in repetitive SIB. With ongoing treatment with maintenance ECT, dramatic reduction in aggression and SIB were noted, allowing both patients a reasonable quality of life in their own homes. Attempts to taper off ECT coincided with return of aggression symptoms, although not SIB.
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6. Harper-Hill K, Copland D, Arnott W. {{Efficiency of Lexical Access in Children with Autism Spectrum Disorders: Does Modality Matter?}}. {J Autism Dev Disord};2014 (Feb 12)
The provision of visual support to individuals with an autism spectrum disorder (ASD) is widely recommended. We explored one mechanism underlying the use of visual supports: efficiency of language processing. Two groups of children, one with and one without an ASD, participated. The groups had comparable oral and written language skills and nonverbal cognitive abilities. In two semantic priming experiments, prime modality and prime-target relatedness were manipulated. Response time and accuracy of lexical decisions on the spoken word targets were measured. In the first uni-modal experiment, both groups demonstrated significant priming effects. In the second experiment which was cross-modal, no effect for relatedness or group was found. This result is considered in the light of the attentional capacity required for access to the lexicon via written stimuli within the developing semantic system. These preliminary findings are also considered with respect to the use of visual support for children with ASD.
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7. Kuzmanovic B, Schilbach L, Georgescu AL, Kockler H, Santos NS, Shah NJ, Bente G, Fink GR, Vogeley K. {{Dissociating animacy processing in high-functioning autism: Neural correlates of stimulus properties and subjective ratings}}. {Soc Neurosci};2014 (Feb 10)
When movements indicate meaningful actions, even nonbiological objects induce the impression of « having a mind » or animacy. This basic social ability was investigated in adults with high-functioning autism (HFA, n = 13, and matched controls, n = 13) by systematically varying motion properties of simple geometric shapes. Critically, trial-by-trial variations of (1) motion complexity of stimuli, and of (2) participants’ individual animacy ratings were separately correlated with neural activity to dissociate cognitive strategies relying more closely on stimulus analysis vs. subjective experience. Increasing motion complexity did not yield any significant group differences, and in both groups, it correlated with neural activity in regions involved in perceptual and evaluative processing, including the ventral medial prefrontal cortex (mPFC), superior temporal gyrus (STG) and posterior cingulate cortex (PCC). In contrast, although there were no significant behavioral differences between the groups, increasing animacy ratings correlated with neural activity in the insula, STG, amygdala, dorsal mPFC and PCC more strongly in controls than in HFA. These results indicate that in HFA the evaluation of stimulus properties cuing for animacy is intact, while increasing subjective ratings do not seem to be robustly related to social processing, including spontaneous mental state inferences and experience of salience.
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8. Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. {{Economic Burden of Childhood Autism Spectrum Disorders}}. {Pediatrics};2014 (Feb 10)
OBJECTIVE: To estimate the associations between autism spectrum disorder (ASD) diagnoses and service use, caregiver time, and cost outcomes. METHODS: We used national data from the Medical Expenditure Panel Survey linked to the National Health Interview Survey and a study-specific survey to estimate the annual utilization and costs for health care, school, ASD-related therapy, family-coordinated services, as well as caregiver time in children aged 3 to 17 years, with and without parent-reported ASD. Regression analyses estimated the association between ASD diagnosis and cost, controlling for child gender, age, race/ethnicity, insurance status, household income, country region and urban/rural classification, and non-ASD-related illnesses. RESULTS: Children with parent-reported ASD had higher levels of health care office visits and prescription drug use compared with children without ASD (P < .05). A greater proportion of children in the ASD group used special educational services (76% vs 7% in the control group, P < .05). After adjusting for child demographic characteristics and non-ASD-associated illnesses, ASD was associated with $3020 (95% confidence interval [CI]: $1017-$4259) higher health care costs and $14 061 (95% CI: $4390-$24 302) higher aggregate non-health care costs, including $8610 (95% CI: $6595-$10 421) higher school costs. In adjusted analyses, parents who reported that their child had ASD did not have significantly higher out-of-pocket costs or spend more time on caregiving activities compared with control parents. CONCLUSIONS: The economic burden associated with ASD is substantial and can be measured across multiple sectors of our society. Previous analyses that focused on health care underestimated this economic burden, particularly for school systems.
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9. Matsuyoshi D, Kuraguchi K, Tanaka Y, Uchida S, Ashida H, Watanabe K. {{Individual differences in autistic traits predict the perception of direct gaze for males, but not for females}}. {Mol Autism};2014 (Feb 12);5(1):12.
Despite the emphasis of autism spectrum disorders as a continuum of social communication disabilities and the sexual heterogeneity of phenotypic manifestations, whether gaze processing constitutes an autistic endophenotype in both sexes remains unclear. Using the Autism-Spectrum Quotient and a psychophysical approach in a normal population (N = 128), here we demonstrated that individual differences in autistic traits predicted direct-gaze perception for males, but not for females. Our findings suggest that direct-gaze perception may not be taken as a definitive indicator of autistic spectrum, and highlight the importance of sex differences when considering relationships between autistic traits and behaviors.
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10. Puts NA, Wodka EL, Tommerdahl M, Mostofsky SH, Edden RA. {{Impaired tactile processing in children with Autism Spectrum Disorder}}. {J Neurophysiol};2014 (Feb 12)
Impaired responses to tactile stimulation are a commonly reported symptom among children with Autism Spectrum Disorder (ASD). Furthermore, impairments in filtering or habituation to tactile input have been described in ASD. This study measured different aspects of tactile processing to investigate atypical touch sensitivity in children with ASD, methodology that has not been previously used in this population. 68 typically developing children (TDC) and 32 children with ASD (ages 8-12) completed vibrotactile tasks assessing: reaction time (RT); static and dynamic detection threshold (DT); amplitude discrimination with and without single-site adaptation; frequency discrimination (FD); and temporal order judgment (TOJ) with and without concurrent stimulation. Children with ASD showed raised static detection thresholds and an absence of the effect of a dynamically increasing sub-threshold stimulus on static detection threshold. Children with ASD also showed poorer amplitude discrimination than TDC, as well as decreased adaptation. There were no significant differences in FD or TOJ between groups. Differences in the effect of dynamic stimulation on DT suggest impaired feed-forward inhibition in autism, which may be linked to poor sensory filtering. Increased baseline amplitude discrimination thresholds in ASD suggest that lateral inhibitory connections are weaker in ASD, and an absence of the effect of adaptation suggests impaired modulation of lateral inhibitory connections in ASD, which may relate to aberrant habituation. These results suggest a functional deficit in the somatosensory inhibitory system in autism. Understanding the specific mechanisms underlying sensory symptoms in autism may allow for more specific therapeutic or drug- targeting in the near future.
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11. Ruysschaert L, Warreyn P, Wiersema JR, Oostra A, Roeyers H. {{Exploring the Role of Neural Mirroring in Children with Autism Spectrum Disorder}}. {Autism Res};2014 (Feb 10)
Investigating the underlying neural mechanisms of autism spectrum disorder (ASD) has recently been influenced by the discovery of mirror neurons. These neurons, active during both observation and execution of actions, are thought to play a crucial role in imitation and other social-communicative skills that are often impaired in ASD. In the current electroencephalographic study, we investigated mu suppression, indicating neural mirroring in children with ASD between the ages of 24 and 48 months and age-matched typically developing children, during observation of goal-directed actions and non-goal-directed mimicked hand movements, as well as during action execution. Results revealed no significant group differences with significant central mu suppression in the ASD children and control children during both execution and observation of goal-directed actions and during observation of hand movements. Furthermore, no significant correlations between mu suppression on one hand and quality of imitation, age, and social communication questionnaire scores on the other hand were found. These findings challenge the « broken mirror » hypothesis of ASD, suggesting that impaired neural mirroring is not a distinctive feature of ASD. Autism Res 2014, : – . (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Schmitz EA, Banerjee R, Pouw LB, Stockmann L, Rieffe C. {{Better to be equal? Challenges to equality for cognitively able children with autism spectrum disorders in a social decision game}}. {Autism};2014 (Feb 12)
Much controversy surrounds questions about whether humans have an aversion to inequity and how a commitment to equality might play a role in cooperation and other aspects of social interactions. Examining the social decisions of children with autism spectrum disorders provides a fascinating opportunity to explore these issues. Specifically, we evaluated the possibility that children with autism spectrum disorders may be less likely than typically developing children to show a prioritisation of equality. A total of 69 typically developing (mean age 11;6 years) and 57 cognitively able children with autism spectrum disorders (mean age 11;7 years) played a social decision game in which the equality option was pitted against alternatives that varied in instrumental outcomes. Results showed that both groups were more likely to choose the equality option when there was no cost to the self. However, even though children with autism spectrum disorders appeared to view equality as preferable to causing explicit harm to others, they departed from an equality stance when there was an opportunity to increase instrumental gain without any obvious harm to the self or the other. Typically developing children, in contrast, showed similar prioritisation of equality across these contexts. Future research needs to address the question of how differences in the commitment to equality affect children’s social behaviour and relationships in daily life.
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13. Schwarzkopf DS, Anderson EJ, de Haas B, White SJ, Rees G. {{Larger extrastriate population receptive fields in autism spectrum disorders}}. {J Neurosci};2014 (Feb 12);34(7):2713-2724.
Previous behavioral research suggests enhanced local visual processing in individuals with autism spectrum disorders (ASDs). Here we used functional MRI and population receptive field (pRF) analysis to test whether the response selectivity of human visual cortex is atypical in individuals with high-functioning ASDs compared with neurotypical, demographically matched controls. For each voxel, we fitted a pRF model to fMRI signals measured while participants viewed flickering bar stimuli traversing the visual field. In most extrastriate regions, perifoveal pRFs were larger in the ASD group than in controls. We observed no differences in V1 or V3A. Differences in the hemodynamic response function, eye movements, or increased measurement noise could not account for these results; individuals with ASDs showed stronger, more reliable responses to visual stimulation. Interestingly, pRF sizes also correlated with individual differences in autistic traits but there were no correlations with behavioral measures of visual processing. Our findings thus suggest that visual cortex in ASDs is not characterized by sharper spatial selectivity. Instead, we speculate that visual cortical function in ASDs may be characterized by extrastriate cortical hyperexcitability or differential attentional deployment.
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14. Skewes JC, Jegindo EM, Gebauer L. {{Perceptual inference and autistic traits}}. {Autism};2014 (Feb 12)
Autistic people are better at perceiving details. Major theories explain this in terms of bottom-up sensory mechanisms or in terms of top-down cognitive biases. Recently, it has become possible to link these theories within a common framework. This framework assumes that perception is implicit neural inference, combining sensory evidence with prior perceptual knowledge. Within this framework, perceptual differences may occur because of enhanced precision in how sensory evidence is represented or because sensory evidence is weighted much higher than prior perceptual knowledge. In this preliminary study, we compared these models using groups with high and low autistic trait scores (Autism-Spectrum Quotient). We found evidence supporting the cognitive bias model and no evidence for the enhanced sensory precision model.
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15. Yalcin O. {{Micturition Difficulty and Urinary Retention Associated with Aripiprazole and Citalopram Treatment in a Male Adolescent with Asperger Syndrome}}. {J Child Adolesc Psychopharmacol};2014 (Feb 10)
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16. Zhou Z, Cao M, Guo Y, Zhao L, Wang J, Jia X, Li J, Wang C, Gabriel G, Xue Q, Yi Y, Cui S, Jin Q, Deng T. {{Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus}}. {Nat Commun};2014 (Feb 10);5:3259.
The ribonucleoprotein (RNP) of the influenza A virus is responsible for the transcription and replication of viral RNA in the nucleus. These processes require interplay between host factors and RNP components. Here, we report that the Fragile X mental retardation protein (FMRP) targets influenza virus RNA synthesis machinery and facilitates virus replication both in cell culture and in mice. We demonstrate that FMRP transiently associates with viral RNP and stimulates viral RNP assembly through RNA-mediated interaction with the nucleoprotein. Furthermore, the KH2 domain of FMRP mediates its association with the nucleoprotein. A point mutation (I304N) in the KH2 domain, identified from a Fragile X syndrome patient, disrupts the FMRP-nucleoprotein association and abolishes the ability of FMRP to participate in viral RNP assembly. We conclude that FMRP is a critical host factor used by influenza viruses to facilitate viral RNP assembly. Our observation reveals a mechanism of influenza virus RNA synthesis and provides insights into FMRP functions.
