1. Assouline SG, Foley Nicpon M, Dockery L. {{Predicting the Academic Achievement of Gifted Students with Autism Spectrum Disorder}}. {J Autism Dev Disord};2011 (Nov 22)
We are not well informed regarding the ability-achievement relationship for twice-exceptional individuals (very high cognitive ability and a diagnosed disability, e.g., autism spectrum disorder [ASD]). The research question for this investigation (N = 59) focused on the predictability of achievement among variables related to ability and education in a twice-exceptional sample of students (cognitive ability of 120 [91st percentile], or above, and diagnosed with ASD). We determined that WISC-IV Working Memory and Processing Speed Indices were both significantly positively correlated with achievement in math, reading, and written language. WISC Perceptual Reasoning Index was uniquely predictive of Oral Language test scores. Unexpected findings were that ASD diagnosis, Verbal Comprehension Index, and forms of academic acceleration were not related to the dependent variables.
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2. Bode MK, Mattila ML, Kiviniemi V, Rahko J, Moilanen I, Ebeling H, Tervonen O, Nikkinen J. {{White matter in autism spectrum disorders – evidence of impaired fiber formation}}. {Acta Radiol};2011 (Nov 18)
BackgroundDiffusion tensor imaging (DTI) enables measurements and visualization of the microstructure of neural fiber tracts. The existing literature on autism spectrum disorders (ASDs) and DTI is heterogenous both regarding methodology and results.PurposeTo compare brain white matter of high-functioning individuals with ASDs and controls.Material and MethodsTract-based spatial statistics (TBSS), a voxel-based approach to DTI, was used to compare 27 subjects with ASDs (mean age 14.7 years, range 11.4-17.6 years, 20 boys, 7 girls) and 26 control subjects (mean age 14.5 years, range 11.7-17.3 years, 17 boys, 9 girls). Mean fractional anisotropy (FA) image (skeleton) was created and each subject’s aligned FA data were then projected onto this skeleton. Voxelwise cross-subject statistics on the skeletonized FA data, mean diffusivity (MD), and measures of diffusion direction were calculated. Importantly, the data were corrected across the whole image instead of using ROI-based methods.ResultsThe ASD group showed significantly greater FA (P < 0.05, corrected) in the area containing clusters of optic radiation and the right inferior fronto-occipital fasciculus (iFOF). In the same area, lambda(3) (representing transverse diffusion) was significantly reduced in the ASD group. No age-related changes were found.ConclusionThe results suggest that the reduced transverse diffusion within the iFOF is related to abnormal information flow between the insular salience processing areas and occipital visual areas.
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3. Brookman-Frazee LI, Drahota A, Stadnick N. {{Training Community Mental Health Therapists to Deliver a Package of Evidence-Based Practice Strategies for School-Age Children with Autism Spectrum Disorders: A Pilot Study}}. {J Autism Dev Disord};2011 (Nov 21)
Research on moving evidence-based practice (EBP) intervention strategies to community service settings for children with autism spectrum disorders (ASD) is urgently needed. The current pilot study addresses this need by examining the feasibility, acceptability and preliminary outcomes of training therapists practicing in community mental health (CMH) clinics to deliver a package of EBP strategies aimed to reduce challenging behaviors in school-age children with ASD. Results indicate that CMH therapists participated in both initial and ongoing training, were able to deliver the intervention with fidelity, and perceived the intervention strategies as useful. Parents participated in almost all sessions with their children and remained in therapy when therapists delivered the intervention. Meaningful reductions in child problem behaviors occurred over 5 months providing promising support for the intervention.
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4. Cuccaro ML, Tuchman RF, Hamilton KL, Wright HH, Abramson RK, Haines JL, Gilbert JR, Pericak-Vance M. {{Exploring the Relationship Between Autism Spectrum Disorder and Epilepsy Using Latent Class Cluster Analysis}}. {J Autism Dev Disord};2011 (Nov 22)
Epilepsy co-occurs frequently in autism spectrum disorders (ASD). Understanding this co-occurrence requires a better understanding of the ASD-epilepsy phenotype (or phenotypes). To address this, we conducted latent class cluster analysis (LCCA) on an ASD dataset (N = 577) which included 64 individuals with epilepsy. We identified a 5-cluster solution with one cluster showing a high rate of epilepsy (29%), earlier age at first recognition, and high rates of repetitive object use and unusual sensory interests. We also conducted LCCA on an ASD-epilepsy subset from the overall dataset (N = 64) which yielded three clusters, the largest of which had impairments in language and motor development; the remaining clusters, while not as developmentally impaired were characterized by different levels of repetitive and sensory behaviors.
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5. Dowd AM, McGinley JL, Taffe JR, Rinehart NJ. {{Do Planning and Visual Integration Difficulties Underpin Motor Dysfunction in Autism? A Kinematic Study of Young Children with Autism}}. {J Autism Dev Disord};2011 (Nov 22)
This paper examines the upper-limb movement kinematics of young children (3-7 years) with high-functioning autism using a point-to-point movement paradigm. Consistent with prior findings in older children, a difference in movement preparation was found in the autism group (n = 11) relative to typically developing children. In contrast to typically developing children, the presence of a visual distractor in the movement task did not appear to impact on early movement planning or execution in children with autism, suggesting that this group were not considering all available environmental cues to modulate movement. The findings from this study are consistent with the possibility that autism is associated with a difficulty using visual information to prime alternative movements in a responsive way to environmental demands.
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6. Grynszpan O, Nadel J, Martin JC, Simonin J, Bailleul P, Wang Y, Gepner D, Le Barillier F, Constant J. {{Self-Monitoring of Gaze in High Functioning Autism}}. {J Autism Dev Disord};2011 (Nov 21)
Atypical visual behaviour has been recently proposed to account for much of social misunderstanding in autism. Using an eye-tracking system and a gaze-contingent lens display, the present study explores self-monitoring of eye motion in two conditions: free visual exploration and guided exploration via blurring the visual field except for the focal area of vision. During these conditions, thirteen students with High Functioning Autism Spectrum Disorders (HFASD) and fourteen typical individuals were presented naturalistic and interactive social stimuli using virtual reality. Fixation data showed a weaker modulation of eye movements according to the conditions in the HFASD group, thus suggesting impairments in self-monitoring of gaze. Moreover, the gaze-contingent lens induced a visual behaviour whereby social understanding scores were correlated with the time spent gazing at faces. The device could be useful for treating gaze monitoring deficiencies in HFASD.
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7. Lee HY, Ge WP, Huang W, He Y, Wang GX, Rowson-Baldwin A, Smith SJ, Jan YN, Jan LY. {{Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile x mental retardation protein}}. {Neuron};2011 (Nov 17);72(4):630-642.
How transmitter receptors modulate neuronal signaling by regulating voltage-gated ion channel expression remains an open question. Here we report dendritic localization of mRNA of Kv4.2 voltage-gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by fragile X mental retardation protein (FMRP) linked to fragile X syndrome (FXS), the most common heritable mental retardation. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice and in neurons expressing Kv4.2-3’UTR that binds FMRP. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation induced by moderate stimuli. Surprisingly, recovery of Kv4.2 after N-methyl-D-aspartate receptor (NMDAR)-induced degradation also requires FMRP, likely due to NMDAR-induced FMRP dephosphorylation, which turns off FMRP suppression of Kv4.2. Our study of FMRP regulation of Kv4.2 deepens our knowledge of NMDAR signaling and reveals a FMRP target of potential relevance to FXS.
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8. Lu AT, Yoon J, Geschwind DH, Cantor RM. {{QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders}}. {Mol Psychiatry};2011 (Nov 22)
Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P<0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.Molecular Psychiatry advance online publication, 22 November 2011; doi:10.1038/mp.2011.155.
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9. Mercier F, Kwon YC, Douet V. {{Hippocampus/amygdala alterations, loss of heparan sulfates, fractones and ventricle wall reduction in adult BTBR T+ tf/J mice, animal model for autism}}. {Neurosci Lett};2011 (Nov 10)
Multiple studies converge to implicate alterations of the hippocampus and amygdala in the pathology of autism. We have previously reported anatomical alterations of the meninges, vasculature and fractones, the specialized extracellular matrix (ECM) of the subventricular zone, in the forebrain of adult BTBR T+ tf/J mice, animal model for autism. Here, we used bisbenzidine cell nucleus staining and dual immunofluorescence histochemistry for laminin and N-sulfated heparan sulfate proteoglycans (NS-HSPG) to examine a series of brain sections containing the amygdala and hippocampus in the adult BTBR T+ tf/j mouse. We observed an excessive separation of the two hippocampi, a modified trajectory of the meninges leading to a shrunken choroid plexus in the lateral ventricle, a shorter granular layer of the dentate gyrus, and a reduced size of the amygdala nuclei. The lateral ventricle near the amygdala, and the third ventricle were shrunken. The number and size of fractones, and their immunoreactivity for NS-HSPG, were reduced throughout the third and lateral ventricles walls. Enlarged blood vessels were found at the endopiriform cortex/amygdala interface. These results show anatomical alterations of the hippocampal/amygdala that are associated with defects of the choroid plexus/ventricular system and the ECM in the BTBR T+ TF/J mouse. Similar alterations of the hippocampus/amygdala axis in humans with autism to these observed in BTBR T+ tf/J mice make this animal model highly valuable for the study of autism. Moreover, the meningo/vascular and ECM alterations in BTBR T+ Tf/J mice suggest a possible role of the brain connective tissue in autism.
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10. Meyza KZ, Blanchard DC, Pearson BL, Pobbe RL, Blanchard RJ. {{Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice: A strong model of autism}}. {Behav Brain Res};2011 (Nov 12)
BTBR T+tf/J (BTBR) mice show abnormal social, communicatory, and repetitive/stereotyped behaviors paralleling many of the symptoms of autism spectrum disorders. BTBR also show agenesis of the corpus callosum (CC) suggesting major perturbations of growth or guidance factors in the dorsal forebrain [1]. Heparan sulfate (HS) is a polysaccaride found in the brain and other animal tissues. It binds to a wide variety of ligands and through these ligands modulates a number of biological processes, including cell proliferation and differentiation, migration and guidance. It is aggregated on fractal-like structures (fractones) in the subventricular zone (SVZ), that may be visualized by laminin immunoreactivity (LAM-ir), as well as by HS immunoreactivity (HS-ir). We report that the lateral ventricles of BTBR mice were drastically reduced in area compared to C57BL/6J (B6) mice while the BTBR SVZ was significantly shorter than that of B6. In addition to much smaller fractones for BTBR, both HS and LAM-ir associated with fractones were significantly reduced in BTBR, and their anterior-posterior distributions were also altered. Finally, the ratio of HS to LAM in individual fractones was significantly higher in BTBR than in B6 mice. These data, in agreement with other findings linking HS to callosal development, suggest that variations in the quantity and distribution of HS in the SVZ of the lateral ventricles may be important modulators of the brain structural abnormalities of BTBR mice, and, potentially, contribute to the behavioral pathologies of these animals.
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11. Mori T, Mori K, Fujii E, Toda Y, Miyazaki M, Harada M, Hashimoto T, Kagami S. {{Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study}}. {Brain Dev};2011 (Nov 16)
PURPOSE: To evaluate the GABA(A) receptor in the autistic brain, we performed (123)I-IMZ SPECT in patients with ASD. We compared (123)I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings. SUBJECTS AND METHODS: The subjects consisted of 24 patients with ASD (mean age, 7.3+/-3.5years), including 9 with autistic disorder (mean age, 7.0+/-3.7years) and 15 with Asperger’s disorder (mean age, 7.5+/-3.2years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8+/-3.6years) without intellectual delay as a control group. For an objective evaluation of the (123)I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically. RESULTS: In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of (123)I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings. CONCLUSION: The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of (123)I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).
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12. Philip RC, Dauvermann MR, Whalley HC, Baynham K, Lawrie SM, Stanfield AC. {{A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders}}. {Neurosci Biobehav Rev};2011 (Nov 11)
Recent years have seen a rapid increase in the investigation of autism spectrum disorders (ASD) through the use of functional magnetic resonance imaging (fMRI). We carried out a systematic review and ALE meta-analysis of fMRI studies of ASD. A disturbance to the function of social brain regions is among the most well replicated finding. Differences in social brain activation may relate to a lack of preference for social stimuli as opposed to a primary dysfunction of these regions. Increasing evidence points towards a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to changing task demands in ASD. Limitations of the literature to date include the use of small sample sizes and the restriction of investigation to primarily high functioning males with autism.
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13. Pobbe RL, Pearson BL, Defensor EB, Bolivar VJ, Young WS, 3rd, Lee HJ, Blanchard DC, Blanchard RJ. {{Oxytocin receptor knockout mice display deficits in the expression of autism-related behaviors}}. {Horm Behav};2011 (Nov 9)
A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the ability to synthesize the oxytocin receptor itself, Oxtr knockout (KO) mice, as compared to their wild-type (WT) littermates. In the visible burrow system, Oxtr KO mice showed robust reductions in frontal approach, huddling, allo-grooming, and flight, with more time spent alone, and in self-grooming, as compared to WT. These results were corroborated in the three-chambered test: unlike WT, Oxtr KO mice failed to spend more time in the side of the test box containing an unfamiliar CD-1 mouse. In the social proximity test, Oxtr KO mice showed clear reductions in nose to nose and anogenital sniff behaviors oriented to an unfamiliar C57BL/6J (B6) mouse. In addition, our study revealed no differences between Oxtr WT and KO genotypes in the occurrence of motor and cognitive stereotyped behaviors. A significant genotype effect was found in the scent marking analysis, with Oxtr KO mice showing a decreased number of scent marks, as compared to WT. Overall, the present data indicate that the profile for Oxtr KO mice, including consistent social deficits, and reduced levels of communication, models multiple components of the ASD phenotype.
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14. Seneff S, Davidson R, Mascitelli L. {{Might cholesterol sulfate deficiency contribute to the development of autistic spectrum disorder?}}. {Med Hypotheses};2011 (Nov 16)
Autism is a condition characterized by impaired cognitive and social skills, often associated with compromised immune function. There has been considerable concern recently that the incidence of autism is alarmingly on the rise, especially in Western nations, and environmental factors are increasingly suspected to play a role. In this paper, we propose a novel hypothesis for a principle cause of autism, namely insufficient supply of cholesterol sulfate to the fetus during gestation and the infant postnatally. We hypothesize that main contributory factors are insufficient sun exposure and insufficient dietary sulfur, for both the mother and the affected child. A novel contribution is the theory that endothelial nitric oxide synthase produces not only nitric oxide but also sulfate, and that sulfate production is stimulated by sunlight. We further hypothesize that the sulfur shortage manifests as an impaired immune response, including an increased susceptibility to eczema and asthma. Proposed corrective measures involve increased dietary sulfur intake for both the mother and the child, and increased sun exposure.
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15. Tomljenovic L, Shaw CA. {{Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?}}. {J Inorg Biochem};2011 (Nov);105(11):1489-1499.
Autism spectrum disorders (ASD) are serious multisystem developmental disorders and an urgent global public health concern. Dysfunctional immunity and impaired brain function are core deficits in ASD. Aluminum (Al), the most commonly used vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator. Hence, adjuvant Al has the potential to induce neuroimmune disorders. When assessing adjuvant toxicity in children, two key points ought to be considered: (i) children should not be viewed as « small adults » as their unique physiology makes them much more vulnerable to toxic insults; and (ii) if exposure to Al from only few vaccines can lead to cognitive impairment and autoimmunity in adults, is it unreasonable to question whether the current pediatric schedules, often containing 18 Al adjuvanted vaccines, are safe for children? By applying Hill’s criteria for establishing causality between exposure and outcome we investigated whether exposure to Al from vaccines could be contributing to the rise in ASD prevalence in the Western world. Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades (Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The application of the Hill’s criteria to these data indicates that the correlation between Al in vaccines and ASD may be causal. Because children represent a fraction of the population most at risk for complications following exposure to Al, a more rigorous evaluation of Al adjuvant safety seems warranted.
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16. Vasa RA, Ranta M, Huisman TA, Pinto PS, Tillman RM, Mostofsky SH. {{Normal Rates of Neuroradiological Findings in Children with High Functioning Autism}}. {J Autism Dev Disord};2011 (Nov 22)
Magnetic resonance imaging (MRI) has been used to analyze highly specific volumetric and morphological features of the brains of individuals with autism spectrum disorder (ASD). To date, there are few comprehensive studies examining the prevalence of neuroradiologic findings seen on routine MRI scans in children with ASD. This study examined the prevalence of neuroradiologic findings in children with high functioning ASD, and compared these rates to those in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and children who are typically developing (TD). Results showed that approximately 90% of children had normal MRI scans. There was no significant effect of diagnosis on the total number of neuroradiological findings or the number of specific brain findings. Implications and future research directions are discussed.
