1. Beebe K, Wang Y, Kulesza RJ. {{Distribution of Fragile X Mental Retardation Protein in the Human Auditory Brainstem}}. {Neuroscience};2014 (May 14)
Fragile X mental retardation protein (FMRP) binds select mRNAs, functions in intracellular transport of these mRNAs and represses their translation. FMRP is highly expressed in neurons and lack of FMRP has been shown to result in dendritic dysmorphology and altered synaptic function. FMRP is known to interact with mRNAs for the Kv3.1b potassium channel which is required for neurons to fire action potentials at high rates with remarkable temporal precision. Auditory brainstem neurons are known for remarkably high spike rates and expression of Kv3.1b potassium channels. Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X mental retardation 1 gene (Fmr1) resulting in decreased expression of FMRP and subsequent intellectual disability, seizures, attention deficit and hypersensitivity to auditory and other sensory stimuli. We therefore hypothesize that the auditory difficulties in FXS result, at least in part, from dysfunction of auditory brainstem neurons. To examine this hypothesis, we have studied normal human brainstem tissue with immunohistochemical techniques and confocal microscopy. Our results demonstrate that FMRP is widely expressed in cell bodies and dendritic arbors of neurons in the human cochlear nucleus and superior olivary complex and also further that coincidence detector neurons of the medial superior olive colocalization of FMRP and Kv3.1b. We interpret these observations to suggest that the lower auditory brainstem is a potential site of dysfunction in FXS.
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2. Crepel A, De Wolf V, Brison N, Ceulemans B, Walleghem D, Peuteman G, Lambrechts D, Steyaert J, Noens I, Devriendt K, Peeters H. {{Association of CDH11 with non-syndromic ASD}}. {Am J Med Genet B Neuropsychiatr Genet};2014 (May 19)
We report a sporadic patient with Autism Spectrum Disorder (ASD), mild intellectual disability and attention deficit hyperactivity disorder (ADHD) with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)ins(4;5)(q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. Since genetic evidence points towards a role for cadherins in ASD, we studied the possible contribution of CDH11 to ASD. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group [P = 0.0049 (Chi-square = 7.90 1 df) and O.R. 3.88 C.I. = 1.403-10.733]. There was no association for C/T versus T/T [P = 0.6772 (Chi-square = 0.17 1 df)] nor was there association at the allelic level [P = 0.4373 (Chi-square = 0.6 1 df)]. In addition to the association of common variants in CDH11 with ASD, we studied the possible contribution of rare variants by sequencing CDH11 in 247 patients, and found three novel variants in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. In conclusion, the data provide evidence for the involvement of CDH11 in ASD which is consistent with the association of other cadherins with ASD and neuropsychiatric diseases. (c) 2014 Wiley Periodicals, Inc.
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3. Egawa J, Watanabe Y, Shibuya M, Endo T, Sugimoto A, Igeta H, Nunokawa A, Inoue E, Someya T. {{Resequencing and association analysis of OXTR with autism spectrum disorder in a Japanese population}}. {Psychiatry Clin Neurosci};2014 (May 19)
AIM: The oxytocin receptor (OXTR) is implicated in the pathophysiology of autism spectrum disorder (ASD). A recent study found a rare non-synonymous OXTR gene variation, rs35062132 (R376G), associated with ASD in a Japanese population. To investigate association between rare non-synonymous OXTR variations and ASD, we resequenced OXTR and performed association analysis with ASD in a Japanese population. METHODS: We resequenced the OXTR coding region in 213 ASD patients. Rare non-synonymous OXTR variations detected by resequencing were genotyped in 213 patients and 667 controls. RESULTS: We detected three rare non-synonymous variations: rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G>T (R150S). However, there was no significant association between these rare non-synonymous variations and ASD. CONCLUSIONS: Our present study does not support contribution of rare non-synonymous OXTR variations to ASD susceptibility in the Japanese population.
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4. Engineer CT, Centanni TM, Im KW, Rahebi KC, Buell EP, Kilgard MP. {{Degraded speech sound processing in a rat model of fragile X syndrome}}. {Brain Res};2014 (May 20);1564:72-84.
Fragile X syndrome is the most common inherited form of intellectual disability and the leading genetic cause of autism. Impaired phonological processing in fragile X syndrome interferes with the development of language skills. Although auditory cortex responses are known to be abnormal in fragile X syndrome, it is not clear how these differences impact speech sound processing. This study provides the first evidence that the cortical representation of speech sounds is impaired in Fmr1 knockout rats, despite normal speech discrimination behavior. Evoked potentials and spiking activity in response to speech sounds, noise burst trains, and tones were significantly degraded in primary auditory cortex, anterior auditory field and the ventral auditory field. Neurometric analysis of speech evoked activity using a pattern classifier confirmed that activity in these fields contains significantly less information about speech sound identity in Fmr1 knockout rats compared to control rats. Responses were normal in the posterior auditory field, which is associated with sound localization. The greatest impairment was observed in the ventral auditory field, which is related to emotional regulation. Dysfunction in the ventral auditory field may contribute to poor emotional regulation in fragile X syndrome and may help explain the observation that later auditory evoked responses are more disturbed in fragile X syndrome compared to earlier responses. Rodent models of fragile X syndrome are likely to prove useful for understanding the biological basis of fragile X syndrome and for testing candidate therapies.
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5. Johnson N, Bree O, Lalley EE, Rettler K, Grande P, Gani MO, Ahamed SI. {{Effect of a Social Script iPad Application for Children With Autism Going to Imaging}}. {J Pediatr Nurs};2014 (Apr 27)
This randomized controlled trial feasibility study tested the effectiveness of an iPad(R) application (app) social script intervention for children with autism spectrum disorder (ASD) going to imaging and their parent (n=32 parent/child dyads). Parents of the children exposed to the app (n=16) had lower state anxiety compared to the parents whose children were not exposed to the app (n=16) (effect size 0.33). Children exposed to the app had fewer externalized challenging behaviors than the control group (effect size 0.56). The results demonstrate feasibility and efficacy of the intervention. Further study of the iPad app is warranted.
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6. Koolen S, Vissers CT, Egger JI, Verhoeven L. {{How Stimulus and Task Complexity Affect Monitoring in High-Functioning Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (May 18)
The present study examined whether individuals with autism spectrum disorder (ASD) are able to update and monitor working memory representations of visual input, and whether performance is influenced by stimulus and task complexity. 15 high-functioning adults with ASD and 15 controls were asked to allocate either elements of abstract figures or semantically meaningful pictures to the correct category, according to a certain set of rules. In general, the groups did not differ on measures of intelligence, working memory, attention, fluency and memory. For the monitoring of allocation of abstract figures, a similar pattern of reaction times was found for ASD and control participants. For the monitoring of allocation of semantically meaningful pictures, a different response pattern was found, with a stronger increase in response times for the ASD than for the control group when the number of categories increased. This suggests that participants with ASD are able to monitor working memory representations, but suffer under more complex circumstances.
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7. Libero LE, Stevens CE, Jr., Kana RK. {{Attribution of emotions to body postures: An independent component analysis study of functional connectivity in autism}}. {Hum Brain Mapp};2014 (May 16)
The ability to interpret others’ body language is a vital skill that helps us infer their thoughts and emotions. However, individuals with autism spectrum disorder (ASD) have been found to have difficulty in understanding the meaning of people’s body language, perhaps leading to an overarching deficit in processing emotions. The current fMRI study investigates the functional connectivity underlying emotion and action judgment in the context of processing body language in high-functioning adolescents and young adults with autism, using an independent components analysis (ICA) of the fMRI time series. While there were no reliable group differences in brain activity, the ICA revealed significant involvement of occipital and parietal regions in processing body actions; and inferior frontal gyrus, superior medial prefrontal cortex, and occipital cortex in body expressions of emotions. In a between-group analysis, participants with autism, relative to typical controls, demonstrated significantly reduced temporal coherence in left ventral premotor cortex and right superior parietal lobule while processing emotions. Participants with ASD, on the other hand, showed increased temporal coherence in left fusiform gyrus while inferring emotions from body postures. Finally, a positive predictive relationship was found between empathizing ability and the brain areas underlying emotion processing in ASD participants. These results underscore the differential role of frontal and parietal brain regions in processing emotional body language in autism. Hum Brain Mapp, 2014. (c) 2014 Wiley Periodicals, Inc.
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8. Mostafa GA, El-Sherif DF, Al-Ayadhi LY. {{Systemic auto-antibodies in children with autism}}. {J Neuroimmunol};2014 (Apr 26)
Autoimmunity to central nervous system may have a role in the pathogenesis of autism. A subset of anti-ds-DNA antibodies has been recently proved to be pathogenic to the brain as well as to the kidney. Due to the paucity of studies investigating the frequency of systemic auto-antibodies in autism, we are the first to investigate the frequency of anti-ds-DNA antibodies in a group of autistic children. The seropositivity of anti-nuclear antibodies (ANA) was also investigated. Serum anti-ds-DNA antibodies and ANA were measured in 100 autistic children, aged between 4 and 11years, in comparison to 100 healthy-matched children. The seropositivity of anti-ds-DNA antibodies and ANA in autistic children was 34% and 25%, respectively. In addition, 42% of autistic children were seropositive for anti-ds-DNA antibodies and/or ANA. The frequencies of anti-ds-DNA antibodies and ANA in autistic children were significantly higher than that in healthy children (4% and 2%, respectively), (P<0.001 and P<0.001, respectively). Autistic children with a family history of autoimmunity (45%) had significantly higher frequency of serum anti-ds-DNA antibodies (48.9%) than patients without such a history (21.8%), P=0.008. There was a significant positive association between the seropositivity of anti-ds-DNA antibodies and ANA (P<0.001). In conclusion, anti-ds-DNA antibodies and ANA were found in the sera of a subgroup of autistic children. However, replication studies of larger samples are warranted to validate whether these antibodies are a mere association or have a pathogenic role in some autistic children.
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9. Speirs SJ, Rinehart NJ, Robinson SR, Tonge BJ, Yelland GW. {{Efficacy of Cognitive Processes in Young People with High-Functioning Autism Spectrum Disorder Using a Novel Visual Information-Processing Task}}. {J Autism Dev Disord};2014 (May 17)
Autism spectrum disorders (ASD) are characterised by a unique pattern of preserved abilities and deficits within and across cognitive domains. The Complex Information Processing Theory proposes this pattern reflects an altered capacity to respond to cognitive demands. This study compared how complexity induced by time constraints on processing affect cognitive function in individuals with ASD and typically-developing individuals. On a visual information-processing task, the Subtle Cognitive Impairment Test, both groups exhibited sensitivity to time-constraints. Further, 65 % of individuals with ASD demonstrated deficits in processing efficiency, possibly attributable to the effects of age and clinical comorbidities, like attention deficit hyperactivity disorder. These findings suggest that for some ASD individuals there are significant impairments in processing efficiency, which may have implications for education and interventions.
