1. Dodero L, Damiano M, Galbusera A, Bifone A, Tsaftsaris SA, Scattoni ML, Gozzi A. {{Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism}}. {PLoS One}. 2013; 8(10): e76655.
BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations.
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2. Garcia-Junco-Clemente P, Chow DK, Tring E, Lazaro MT, Trachtenberg JT, Golshani P. {{Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism}}. {Proc Natl Acad Sci U S A}. 2013.
De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets.
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3. Goodbourn PT, Bosten JM, Bargary G, Hogg RE, Lawrance-Owen AJ, Mollon JD. {{Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia}}. {Genes Brain Behav}. 2013.
Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. We report here a genome-wide association study (GWAS) of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642,758 single-nucleotide polymorphism (SNP) markers. A significant association (P = 7.9 x 10-9 ) was found with the SNP marker rs1797052, situated in the 5′-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the alpha = .005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with NMDA receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements.
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4. Kovac J, Macedoni Luksic M, Trebusak Podkrajsek K, Klancar G, Battelino T. {{Rare Single Nucleotide Polymorphisms in the Regulatory Regions of the Superoxide Dismutase Genes in Autism Spectrum Disorder}}. {Autism Res}. 2013.
Oxidative stress is suspected to be one of the several contributing factors in the etiology of autism spectrum disorder (ASD). We analyzed genes of the superoxide dismutase family (SOD1, SOD2, and SOD3) that are part of a major antioxidative stress system in human in order to detect the genetic variants contributing to the development of ASD. Using the optimized high-resolution melting (HRM) analysis, we identified two rare single nucleotide polymorphisms (SNPs) associated with the etiology of ASD. Both are located in the superoxide dismutase 1 (SOD1) gene and have a minor allele frequency in healthy population approximately 5%. The SNP c.239 + 34A>C (rs2234694) and SNP g.3341C>G (rs36233090) were detected with an odds ratio of 2.65 and P < 0.01. Both are located in the noncoding potentially regulatory regions of the SOD1 gene. This adds to the importance of rare SNPs in the etiology of complex diseases as well as to the importance of noncoding genetic variants analysis with a potential influence on the regulation of gene expression. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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5. Luck AN, Bobst CE, Kaltashov IA, Mason AB. {{Human serum transferrin: Is there a link between autism, high oxalate and iron deficiency anemia?}}. {Biochemistry}. 2013.
It has been previously suggested that high amounts of oxalate in plasma could play a role in autism by binding to the bilobal iron transport protein transferrin (hTF) thereby interfering with iron metabolism by inhibiting iron delivery to cells. By examining the effect of the substitution of oxalate for the physiologically utilized synergistic carbonate anion in each lobe of hTF we sought to provide a molecular basis for or against such a role. Our work clearly shows both qualitatively (6 M urea gels) and quantitatively (kinetic analysis by stop flow spectrofluorimetry) that the presence of oxalate in place of carbonate in each binding site of hTF does indeed greatly interfere with iron removal from each lobe (both in the absence and presence of the specific hTF receptor). However, we also clearly demonstrate that once the iron is bound within each lobe of hTF, neither anion can displace the other. Additionally, as verified by urea gels and electrospray mass spectrometry, formation of completely homogeneous hTF-anion complexes requires that all iron must first be removed and hTF then reloaded with iron in the presence of either carbonate or oxalate. Of significance, experiments described herein show that carbonate is the preferred binding partner, i.e., even if an equal amount of each anion is available during the iron loading process the hTF-carbonate complex is formed.
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6. McCurdy EE, Cole CL. {{Use of a Peer Support Intervention for Promoting Academic Engagement of Students with Autism in General Education Settings}}. {J Autism Dev Disord}. 2013.
Students with autism spectrum disorder (ASD) have been shown to benefit from being educated in general education classrooms that provide interactions with typically developing peers. However, behaviors exhibited by students with ASD frequently lead to their return to segregated special education settings. Evidence-based interventions that are both cost-efficient and easy to use in general education settings are needed. The purpose of this study was to evaluate the effects of a simple peer support intervention on the minor disruptive, off-task behaviors of three elementary students with high-functioning ASD in three different general education classrooms. Results indicated the peer support intervention was effective in reducing the off-task behaviors of the students with ASD in these inclusion settings. Practical implications and directions for future research are discussed.
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7. Pallett PM, Cohen SJ, Dobkins KR. {{Face and Object Discrimination in Autism, and Relationship to IQ and Age}}. {J Autism Dev Disord}. 2013.
The current study tested fine discrimination of upright and inverted faces and objects in adolescents with Autism Spectrum Disorder (ASD) as compared to age- and IQ-matched controls. Discrimination sensitivity was tested using morphed faces and morphed objects, and all stimuli were equated in low-level visual characteristics (luminance, contrast, spatial frequency make-up). Participants with ASD exhibited slight, non-significant impairments in discrimination sensitivity for faces, yet significantly enhanced discrimination sensitivity for objects. The ASD group also showed a protracted development of face and object inversion effects. Finally, for ASD participants, face sensitivity improved with increasing IQ while object sensitivity improved with age. By contrast, for controls, face sensitivity improved with age, but neither face nor object sensitivity was influenced by IQ. These findings suggest that individuals with ASD follow a qualitatively different path in the development of face and object processing abilities.
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8. Robertson CE, Kravitz DJ, Freyberg J, Baron-Cohen S, Baker CI. {{Slower rate of binocular rivalry in autism}}. {J Neurosci}. 2013; 33(43): 16983-91.
An imbalance between cortical excitation and inhibition is a central component of many models of autistic neurobiology. We tested a potential behavioral footprint of this proposed imbalance using binocular rivalry, a visual phenomenon in which perceptual experience is thought to mirror the push and pull of excitatory and inhibitory cortical dynamics. In binocular rivalry, two monocularly presented images compete, leading to a percept that alternates between them. In a series of trials, we presented separate images of objects (e.g., a baseball and a broccoli) to each eye using a mirror stereoscope and asked human participants with autism and matched control subjects to continuously report which object they perceived, or whether they perceived a mixed percept. Individuals with autism demonstrated a slower rate of binocular rivalry alternations than matched control subjects, with longer durations of mixed percepts and an increased likelihood to revert to the previously perceived object when exiting a mixed percept. Critically, each of these findings was highly predictive of clinical measures of autistic symptomatology. Control « playback » experiments demonstrated that differences in neither response latencies nor response criteria could account for the atypical dynamics of binocular rivalry we observed in autistic spectrum conditions. Overall, these results may provide an index of atypical cortical dynamics that may underlie both the social and nonsocial symptoms of autism.
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9. Robinson EB, Howrigan D, Yang J, Ripke S, Anttila V, Duncan LE, Jostins L, Barrett JC, Medland SE, Macarthur DG, Breen G, O’Donovan MC, Wray NR, Devlin B, Daly MJ, Visscher PM, Sullivan PF, Neale BM. {{Response to ‘Predicting the diagnosis of autism spectrum disorder using gene pathway analysis’}}. {Mol Psychiatry}. 2013.
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10. Sampath S, Bhat S, Gupta S, O’Connor A, West AB, Arking DE, Chakravarti A. {{Defining the Contribution of CNTNAP2 to Autism Susceptibility}}. {PLoS One}. 2013; 8(10): e77906.
Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD). This analysis yielded two SNPs with nominal statistical significance (rs17170073, p = 2.0 x 10(-4); rs2215798, p = 1.6 x 10(-4)) that did not survive multiple testing. In a combined analysis of all families, two highly correlated (r (2) = 0.99) SNPs in intron 14 showed significant association with autism (rs2710093, p = 9.0 x 10(-6); rs2253031, p = 2.5 x 10(-5)). To validate these findings and associations at SNPs from previous autism studies (rs7794745, rs2710102 and rs17236239) we genotyped 2051 additional families (572 multiplex and 1479 simplex). None of these variants were significantly associated with ASD after corrections for multiple testing. The analysis of Mendelian errors within each family did not indicate any segregating deletions. Nevertheless, a study of CNTNAP2 gene expression in brains of autistic patients and of normal controls, demonstrated altered expression in a subset of patients (p = 1.9 x10(-5)). Consequently, this study suggests that although CNTNAP2 dysregulation plays a role in some cases, its population contribution to autism susceptibility is limited.
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11. Spencer D, Marshall J, Post B, Kulakodlu M, Newschaffer C, Dennen T, Azocar F, Jain A. {{Psychotropic Medication Use and Polypharmacy in Children With Autism Spectrum Disorders}}. {Pediatrics}. 2013.
OBJECTIVE:The objectives of this study were to examine rates and predictors of psychotropic use and multiclass polypharmacy among commercially insured children with autism spectrum disorders (ASD).METHODS:This retrospective observational study used administrative medical and pharmacy claims data linked with health plan enrollment and sociodemographic information from 2001 to 2009. Children with ASD were identified by using a validated ASD case algorithm. Psychotropic polypharmacy was defined as concurrent medication fills across >/=2 classes for at least 30 days. Multinomial logistic regression was used to model 5 categories of psychotropic use and multiclass polypharmacy.RESULTS:Among 33 565 children with ASD, 64% had a filled prescription for at least 1 psychotropic medication, 35% had evidence of psychotropic polypharmacy (>/=2 classes), and 15% used medications from >/=3 classes concurrently. Among children with polypharmacy, the median length of polypharmacy was 346 days. Older children, those who had a psychiatrist visit, and those with evidence of co-occurring conditions (seizures, attention-deficit disorders, anxiety, bipolar disorder, or depression) had higher odds of psychotropic use and/or polypharmacy.CONCLUSIONS:Despite minimal evidence of the effectiveness or appropriateness of multidrug treatment of ASD, psychotropic medications are commonly used, singly and in combination, for ASD and its co-occurring conditions. Our results indicate the need to develop standards of care around the prescription of psychotropic medications to children with ASD.
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12. Takeuchi A, Ogino T, Hanafusa K, Morooka T, Oka M, Yorifuji T, Ohtsuka Y. {{Inhibitory Function and Working Memory in Attention Deficit/Hyperactivity Disorder and Pervasive Developmental Disorders:Does a Continuous Cognitive Gradient Explain ADHD and PDD Traits?}}. {Acta Med Okayama}. 2013; 67(5): 293-303.
To clarify the relationship between attention deficit/hyperactivity disorder (AD/HD) and pervasive developmental disorders (PDD), we investigated the common features and differences of these disorders in neuropsychological profiles. The subjects were 4 groups of Japanese boys aged 6 to 15 years, categorized by diagnosis:AD/HD (n20), PDD with comorbid AD/HD (PDD:n16), PDD without comorbid AD/HD (PDD:n8), and typically developing (n60). We evaluated executive function (EF) through verbal and visuospatial memory tasks, the Go/NoGo task, and the color-word matching Stroop task. We performed a categorical analysis to estimate the effects of the 3 disorders on EF and a dimensional analysis to estimate the effects of symptom scales on EF. We found that the AD/HD and PDD subjects had negative effects on verbal working memory and intra-individual response variability. The severity of these impairments was positively correlated with the inattentiveness score. The subjects with a PDD or PDD diagnosis had poorer scores on interference control;the severity of this impairment was correlated with the PDD symptom score. Impairments in visuospatial working memory were detected in the AD/HD and PDD groups but not in the PDD group. Impairments in inhibition of the pre-potent response were noted in all 3 categories. AD/HD and PDD share neuropsychological features, though each disorder has a specific impairment pattern. Our findings partially support the idea that AD/HD and PDD are on a spectrum.
13. Tanaka JW, Sung A. {{The « Eye Avoidance » Hypothesis of Autism Face Processing}}. {J Autism Dev Disord}. 2013.
Although a growing body of research indicates that children with autism spectrum disorder (ASD) exhibit selective deficits in their ability to recognize facial identities and expressions, the source of their face impairment is, as yet, undetermined. In this paper, we consider three possible accounts of the autism face deficit: (1) the holistic hypothesis, (2) the local perceptual bias hypothesis and (3) the eye avoidance hypothesis. A review of the literature indicates that contrary to the holistic hypothesis, there is little evidence to suggest that individuals with autism do perceive faces holistically. The local perceptual bias account also fails to explain the selective advantage that ASD individuals demonstrate for objects and their selective disadvantage for faces. The eye avoidance hypothesis provides a plausible explanation of face recognition deficits where individuals with ASD avoid the eye region because it is perceived as socially threatening. Direct eye contact elicits a increased physiological response as indicated by heightened skin conductance and amygdala activity. For individuals with autism, avoiding the eyes is an adaptive strategy, however, this approach interferes with the ability to process facial cues of identity, expressions and intentions, exacerbating the social challenges for persons with ASD.
