1. Baum SH, Stevenson RA, Wallace MT. {{Testing sensory and multisensory function in children with autism spectrum disorder}}. {Journal of visualized experiments : JoVE}. 2015(98).
In addition to impairments in social communication and the presence of restricted interests and repetitive behaviors, deficits in sensory processing are now recognized as a core symptom in autism spectrum disorder (ASD). Our ability to perceive and interact with the external world is rooted in sensory processing. For example, listening to a conversation entails processing the auditory cues coming from the speaker (speech content, prosody, syntax) as well as the associated visual information (facial expressions, gestures). Collectively, the « integration » of these multisensory (i.e., combined audiovisual) pieces of information results in better comprehension. Such multisensory integration has been shown to be strongly dependent upon the temporal relationship of the paired stimuli. Thus, stimuli that occur in close temporal proximity are highly likely to result in behavioral and perceptual benefits – gains believed to be reflective of the perceptual system’s judgment of the likelihood that these two stimuli came from the same source. Changes in this temporal integration are expected to strongly alter perceptual processes, and are likely to diminish the ability to accurately perceive and interact with our world. Here, a battery of tasks designed to characterize various aspects of sensory and multisensory temporal processing in children with ASD is described. In addition to its utility in autism, this battery has great potential for characterizing changes in sensory function in other clinical populations, as well as being used to examine changes in these processes across the lifespan.
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2. Cheaha D, Bumrungsri S, Chatpun S, Kumarnsit E. {{Characterization of in utero valproic acid mouse model of autism by local field potential in the hippocampus and the olfactory bulb}}. {Neuroscience research}. 2015 May 2.
Valproic acid (VPA) mouse model of autism spectrum disorder (ASD) has been characterized mostly by impaired ultrasonic vocalization, poor sociability and increased repetitive self-grooming behavior. However, its neural signaling remained unknown. This study investigated the local field potentials (LFPs) in the dorsal hippocampal CA1 and the olfactory bulb while animals exploring a novel open field. VPA was administered at gestational day 13. The results demonstrated three core features of ASD in male offspring. However, there was no difference in Y-maze performance and locomotor activity. Analysis of hippocampal LFP power revealed significantly increased slow wave (1-4Hz) and high gamma (80-140Hz) oscillations and decreased theta (4-12Hz) activity in VPA mice. In the olfactory bulb, VPA animals showed greater slow wave (1-4Hz) and beta (25-40Hz) activity and lower activity of low gamma (55-80Hz) wave. Regression analysis revealed positive correlations between hippocampal theta power and locomotor speed for both control and VPA-exposed mice. There was no significant difference between groups for modulation index of theta (4-12Hz) phase modulated gamma (30-200Hz) amplitude. These findings characterized VPA mouse model with LFP oscillations that might provide better understanding of neural processing in ASD.
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3. de Vinck-Baroody O, Shui A, Macklin EA, Hyman SL, Leventhal JM, Weitzman C. {{Overweight and Obesity in a Sample of Children With Autism Spectrum Disorder}}. {Academic pediatrics}. 2015 Apr 30.
OBJECTIVE: To determine the prevalence of overweight/obese status in children with autism spectrum disorders (ASD), identify associated characteristics, and develop a model to predict weight status. METHODS: The prevalence of overweight and obesity were determined in 2769 children with ASD enrolled in the Autism Speaks Autism Treatment Network, a collaboration of 17 academic centers, and compared with a national sample matched for age, sex, and race. Associations in the ASD sample between weight status and demographic and clinical variables, such as age, race, head circumference, and adaptive functioning, were tested using ordinal logistic regression. The accuracy of a final model that predicted weight status based on early life variables was evaluated in a validation sample. RESULTS: The prevalence of overweight and obesity were 33.9% and 18.2%, respectively; ASD was associated with a higher risk of obesity (but not overweight) relative to the national sample (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.05-1.28; P = .003). In the adjusted analysis, overweight/obese status was significantly associated with Hispanic ethnicity (OR, 1.99; 95% CI, 1.37-2.89), parental high school education (OR, 1.56; 95% CI, 1.09-2.21), high birth weight (OR, 1.56; 95% CI, 1.11-2.18), macrocephaly (OR, 4.01; 95% CI, 2.96-5.43), and increased somatic symptoms (OR, 1.41; 95% CI, 1.01-1.95). A prediction model designed to have high sensitivity predicted low risk of overweight/obesity accurately, but had low positive predictive value. CONCLUSIONS: The prevalence of obesity in children with ASD was greater than a national sample. Independent associations with increased weight status included known risk factors and macrocephaly and increased level of somatic symptoms. A model based on early life variables accurately predicted low risk of overweight/obesity.
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4. Duan G, Chen J, Zhang W, Yu B, Jin Y, Wang Y, Yao M. {{Physical maltreatment of children with autism in Henan province in China: A cross-sectional study}}. {Child abuse & neglect}. 2015 May 6.
The aim of this study was to investigate the frequency of child physical maltreatment (CPM) in children with autism aged 2-5 years in Henan province (China), and to explore the risk factors for severe CPM in these children. This cross-sectional study was performed at the Psychology Clinic of the Third Affiliated Hospital of Zhengzhou University between September 2012 and September 2013 with 180 parents of children with autism. Children and parents had no history of any cognitive therapy. The childhood autism rating scale (CARS) was used to evaluate the severity of autism in children. Data on parental CPM during the past 3 months were collected from parental self-reporting. Logistic regression was used to investigate the risk factors of severe CPM. CPM was self-reported by 88% of the parents of children with autism. One hundred and fifty four of these cases were in the minor CPM group (86%) and 64 in the severe CPM group (36%). Most cases of severe CPM were unlikely to have caused injury. Univariate analyses showed that child’s age (p=.018), age started to speak (p=.043) and CARS score (p=.048) were associated with severe CPM. Child’s age (p=.011) and CARS score (p=.041) were independently associated with severe CPM. The risk of severe CPM increased with age and CARS score. Our findings showed that CPM is widespread in families of children with autism in Central China and more knowledge should be provided to parents of children with autism, particularly in cases of severe autism (those with high CARS scores).
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5. Hanley M, Riby DM, Carty C, Melaugh McAteer A, Kennedy A, McPhillips M. {{The use of eye-tracking to explore social difficulties in cognitively able students with autism spectrum disorder: A pilot investigation}}. {Autism : the international journal of research and practice}. 2015 May 6.
Individuals with autism spectrum disorder do not just ‘grow out of’ their early difficulties in understanding the social world. Even for those who are cognitively able, autism-related difficulties continue into adulthood. Atypicalities attending to and interpreting communicative signals from others can provide barriers to success in education, employment and relationships. In the current study, we use eye-tracking during real social interaction to explore attention to social cues (e.g. face, eyes, mouth) and links to social awareness in a group of cognitively able University students with autism spectrum disorder and typically developing students from the same University. During the interaction, students with autism spectrum disorder showed less eye fixation and more mouth fixation than typically developing students. Importantly, while 63% of typically developing participants reported thinking they were deceived about the true nature of the interaction, only 9% of autism spectrum disorder participants picked up this subtle social signal. We argue that understanding how these social attentional and social awareness difficulties manifest during adulthood is important given the growing number of adults with autism spectrum disorder who are attending higher level education. These adults may be particularly susceptible to drop-out due to demands of coping in situations where social awareness is so important.
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6. Harrop C, Gulsrud A, Shih W, Hovsepyan L, Kasari C. {{Characterizing caregiver responses to restricted and repetitive behaviors in toddlers with autism spectrum disorder}}. {Autism : the international journal of research and practice}. 2015 May 6.
Restricted and repetitive behaviors are a core feature of autism spectrum disorder. This descriptive study documented the presence of restricted and repetitive behaviors in 85 toddlers with autism spectrum disorder as they interacted with their caregiver in a play interaction. For each child restricted and repetitive behavior, a caregiver response/non-response was coded. Caregiver responses were rated as successful or unsuccessful. In all, 83 toddlers demonstrated at least one restricted and repetitive behavior in 10 min. The most common child restricted and repetitive behavior was repetitive object use with 72 children displaying at least one instance of this category of restricted and repetitive behavior. Overall, caregivers responded to fewer than half of their child’s restricted and repetitive behaviors, and caregiver response varied by child restricted and repetitive behavior type. The most common response was redirection. Success varied by child restricted and repetitive behavior type and caregiver response-redirections were most successful for child verbal and motor restricted and repetitive behaviors, whereas physical or verbal responses were rated more successful for repetitive object use and visual restricted and repetitive behaviors. This study represents the first attempt to characterize how caregivers respond to restricted and repetitive behaviors. Toddlers with autism spectrum disorder are already demonstrating a variety of restricted and repetitive behaviors within the context of a free play sessions, and caregivers differentially and naturally respond to them.
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7. Ifrim MF, Williams KR, Bassell GJ. {{Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2015 May 6;35(18):7116-30.
Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3’UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3’UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS.
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8. Keen D, Webster A, Ridley G. {{How well are children with autism spectrum disorder doing academically at school? An overview of the literature}}. {Autism : the international journal of research and practice}. 2015 May 6.
The academic achievement of individuals with autism spectrum disorder has received little attention from researchers despite the importance placed on this by schools, families and students with autism spectrum disorder. Investigating factors that lead to increased academic achievement thus would appear to be very important. A review of the literature was conducted to identify factors related to the academic achievement of children and adolescents with autism spectrum disorder. A total of 19 studies were identified that met the inclusion criteria for the review. Results indicated that many individuals demonstrate specific areas of strength and weakness and there is a great deal of variability in general academic achievement across the autism spectrum. Adolescents and individuals with lower IQ scores were underrepresented, and few studies focused on environmental factors related to academic success. The importance of individualised assessments that profile the relative strengths and weaknesses of children and adolescents to aid in educational programming was highlighted. Further research on child-related and environmental factors that predict academic achievement is needed.
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9. Lambert-Brown BL, McDonald NM, Mattson WI, Martin KB, Ibanez LV, Stone WL, Messinger DS. {{Positive Emotional Engagement and Autism Risk}}. {Developmental psychology}. 2015 May 4.
Positive emotional engagement develops in the context of face-to-face interactions during the first 6 months of life. Deficits in emotional engagement are characteristic of autism spectrum disorder (ASD) and may characterize the younger siblings of children with ASD (high-risk siblings). High-risk siblings are likely to exhibit a broad range of positive emotional engagement that may or may not be associated with ASD outcomes. We examined positive emotional engagement (i.e., smiling rate and contingent responsiveness to the partner’s smile) during the infant-parent interaction episodes of the face-to-face/still face protocol at 6 months of age. The sample included 43 high-risk infant siblings, 11 of whom went on to an ASD diagnosis, and 25 low-risk siblings with no family history of ASD. Low-risk siblings and high-risk siblings without ASD showed the typical still-face effect (i.e., decreases in smiling rate after period of parental nonresponsiveness), but high-risk siblings with later ASD outcomes did not show this decrease. Although high-risk siblings without an ASD diagnosis were less likely to respond to their parents’ smiles than were low-risk siblings, the children with eventual ASD did not differ from the other groups in contingent responsiveness. Findings suggest that subtle differences in positive emotional engagement are present in the early development of high-risk siblings but are not consistently associated with ASD outcomes. (PsycINFO Database Record
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10. Manning C, Tibber MS, Charman T, Dakin SC, Pellicano E. {{Enhanced integration of motion information in children with autism}}. {The Journal of neuroscience : the official journal of the Society for Neuroscience}. 2015 May 6;35(18):6979-86.
To judge the overall direction of a shoal of fish or a crowd of people, observers must integrate motion signals across space and time. The limits on our ability to pool motion have largely been established using the motion coherence paradigm, in which observers report the direction of coherently moving dots amid randomly moving noise dots. Poor performance by autistic individuals on this task has widely been interpreted as evidence of disrupted integrative processes. Critically, however, motion coherence thresholds are not necessarily limited only by pooling. They could also be limited by imprecision in estimating the direction of individual elements or by difficulties segregating signal from noise. Here, 33 children with autism 6-13 years of age and 33 age- and ability-matched typical children performed a more robust task reporting mean dot direction both in the presence and the absence of directional variability alongside a standard motion coherence task. Children with autism were just as sensitive to directional differences as typical children when all elements moved in the same direction (no variability). However, remarkably, children with autism were more sensitive to the average direction in the presence of directional variability, providing the first evidence of enhanced motion integration in autism. Despite this improved averaging ability, children with autism performed comparably to typical children in the motion coherence task, suggesting that their motion coherence thresholds may be limited by reduced segregation of signal from noise. Although potentially advantageous under some conditions, increased integration may lead to feelings of « sensory overload » in children with autism.
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11. Ochs E. {{Corporeal Reflexivity and Autism}}. {Integrative psychological & behavioral science}. 2015 May 6.
Ethnographic video recordings of high functioning children with autism or Aspergers Syndrome in everyday social encounters evidence their first person perspectives. High quality visual and audio data allow detailed analysis of children’s bodies and talk as loci of reflexivity. Corporeal reflexivity involves displays of awareness of one’s body as an experiencing subject and a physical object accessible to the gaze of others. Gaze, demeanor, actions, and sotto voce commentaries on unfolding situations indicate a range of moment-by-moment reflexive responses to social situations. Autism is associated with neurologically based motor problems (e.g. delayed action-goal coordination, clumsiness) and highly repetitive movements to self-soothe. These behaviors can provoke derision among classmates at school. Focusing on a 9-year-old girl’s encounters with peers on the playground, this study documents precisely how autistic children can become enmeshed as unwitting objects of stigma and how they reflect upon their social rejection as it transpires. Children with autism spectrum disorders in laboratory settings manifest diminished understandings of social emotions such as embarrassment, as part of a more general impairment in social perspective-taking. Video ethnography, however, takes us further, into discovering autistic children’s subjective sense of vulnerability to the gaze of classmates.
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12. Penner M, Rayar M, Bashir N, Roberts SW, Hancock-Howard RL, Coyte PC. {{Cost-Effectiveness Analysis Comparing Pre-diagnosis Autism Spectrum Disorder (ASD)-Targeted Intervention with Ontario’s Autism Intervention Program}}. {J Autism Dev Disord}. 2015 May 5.
Novel management strategies for autism spectrum disorder (ASD) propose providing interventions before diagnosis. We performed a cost-effectiveness analysis comparing the costs and dependency-free life years (DFLYs) generated by pre-diagnosis intensive Early Start Denver Model (ESDM-I); pre-diagnosis parent-delivered ESDM (ESDM-PD); and the Ontario Status Quo (SQ). The analyses took government and societal perspectives to age 65. We assigned probabilities of Independent, Semi-dependent or Dependent living based on projected IQ. Costs per person (in Canadian dollars) were ascribed to each living setting. From a government perspective, the ESDM-PD produced an additional 0.17 DFLYs for $8600 less than SQ. From a societal perspective, the ESDM-I produced an additional 0.53 DFLYs for $45,000 less than SQ. Pre-diagnosis interventions targeting ASD symptoms warrant further investigation.
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13. Rajan-Babu IS, Law HY, Yoon CS, Lee CG, Chong SS. {{Simplified strategy for rapid first-line screening of fragile X syndrome: closed-tube triplet-primed PCR and amplicon melt peak analysis}}. {Expert reviews in molecular medicine}. 2015;17:e7.
Premutation and full-mutation hyperexpansion of CGG-triplets in the X-linked Fragile X Mental Retardation 1 (FMR1) gene have been implicated in fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome (FXS), respectively. The currently available molecular diagnostic tests are either costly or labour-intensive, which prohibits their application as a first-line FMR1 test in large-scale population-based screening programs. In this study, we demonstrate the utility of a simplified closed-tube strategy for rapid first-line screening of FXS based on melt peak temperature (T m) analysis of direct triplet-primed polymerase chain reaction amplicons (dTP-PCR MCA). In addition, we also evaluated the correlation between T m and CGG-repeat size based on capillary electrophoresis (CE) of dTP-PCR amplicons. The assays were initially tested on 29 FMR1 reference DNA samples, followed by a blinded validation on 107 previously characterised patient DNA samples. The dTP-PCR MCA produced distinct melt profiles of higher T m for samples carrying an expanded allele. Among the samples tested, we also observed a good correlation between T m and CGG-repeat size. In the blinded validation study, dTP-PCR MCA accurately classified all normal and expansion carriers, and the FMR1 genotypic classification of all samples was completely concordant with the previously determined genotypes as well as the dTP-PCR CE results. This simple and cost-effective MCA-based assay may be useful as a first-line FXS screening tool that could rapidly screen out the large majority of unaffected individuals, thus minimising the number of samples that need to be analysed by Southern blot analysis.
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14. Rietveld L, Stuss DP, McPhee D, Delaney KR. {{Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice}}. {Frontiers in cellular neuroscience}. 2015;9:145.
Rett syndrome (RTT) is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The heterozygous female brain consists of mosaic of neurons containing both wild-type MeCP2 (MeCP2+) and mutant MeCP2 (MeCP2-). Three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2(+/-) ) and wild-type (Mecp2(+/+) ) female mice ( > 6 mo.) from the Mecp2(tm1.1Jae) line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 mum from the cell body and on average three fewer branch points, specifically loss in the second and third branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo.) and X-chromosome inactivation (XCI) ratios (12-56%). On average, MeCP2- somata and nuclei were 15 and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT) was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.
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15. Sun X, Allison C, Matthews FE, Zhang Z, Auyeung B, Baron-Cohen S, Brayne C. {{Exploring the Underdiagnosis and Prevalence of Autism Spectrum Conditions in Beijing}}. {Autism research : official journal of the International Society for Autism Research}. 2015 May 6.
Previous studies reported that the prevalence of Autism Spectrum Conditions (ASC) in mainland China is much lower than estimates from developed countries (around 1%). The aim of the study is to apply current screening and standardized diagnostic instruments to a Chinese population to establish a prevalence estimate of ASC in an undiagnosed population in mainland China. We followed the design development used previously in the UK published in 2009 by Baron-Cohen and colleagues. The Mandarin Childhood Autism Spectrum Test (CAST) was validated by screening primary school pupils (n = 737 children age 6-10 years old) in Beijing and by conducting diagnostic assessments using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. The prevalence estimate was generated after adjusting and imputing for missing values using the inverse probability weighting. Response was high (97%). Using the UK cutoff (>/=15), CAST performance has 84% sensitivity and 96% specificity (95% confidence interval [CI]: 46, 98, and 96, 97, respectively). Six out of 103 children, not previously diagnosed, were found to the meet diagnostic criteria (8.5 after adjustment, 95% CI: 1.6, 15.4). The preliminary prevalence in an undiagnosed primary school population in mainland China was 119 per 10,000 (95% CI: 53, 265). The utility of CAST is acceptable as a screening instrument for ASC in large epidemiological studies in China. Using a comparable method, the preliminary prevalence estimate of ASC in mainland China is similar to that of those from developed countries. Autism Res 2015, : -. (c) 2015 The Authors. Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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16. Talbott EO, Arena VC, Rager JR, Clougherty JE, Michanowicz DR, Sharma RK, Stacy SL. {{Fine particulate matter and the risk of autism spectrum disorder}}. {Environmental research}. 2015 May 6;140:414-20.
The causes of autism spectrum disorder (ASD) are not well known. Recent investigations have suggested that air pollution, including PM2.5, may play a role in the onset of this condition. The objective of the present work was to investigate the association between prenatal and early childhood exposure to fine particulate matter (PM2.5) and risk for childhood ASD. A population-based case-control study was conducted in children born between January 1, 2005 and December 31, 2009 in six counties in Southwestern Pennsylvania. ASD cases were recruited from specialty autism clinics, local pediatric practices, and school-based special needs services. ASD cases were children who scored 15 or above on the Social Communication Questionnaire (SCQ) and had written documentation of an ASD diagnosis. Controls were children without ASD recruited from a random sample of births from the Pennsylvania state birth registry and frequency matched to cases on birth year, gender, and race. A total of 217 cases and 226 controls were interviewed. A land use regression (LUR) model was used to create person- and time-specific PM2.5 estimates for individual (pre-pregnancy, trimesters one through three, pregnancy, years one and two of life) and cumulative (starting from pre-pregnancy) key developmental time periods. Logistic regression was used to investigate the association between estimated exposure to PM2.5 during key developmental time periods and risk of ASD, adjusting for mother’s age, education, race, and smoking. Adjusted odds ratios (AOR) were elevated for specific pregnancy and postnatal intervals (pre-pregnancy, pregnancy, and year one), and postnatal year two was significant, (AOR=1.45, 95% CI=1.01-2.08). We also examined the effect of cumulative pregnancy periods; noting that starting with pre-pregnancy through pregnancy, the adjusted odds ratios are in the 1.46-1.51 range and significant for pre-pregnancy through year 2 (OR=1.51, 95% CI=1.01-2.26). Our data indicate that both prenatal and postnatal exposures to PM2.5 are associated with increased risk of ASD. Future research should include multiple pollutant models and the elucidation of the biological mechanism for PM2.5 and ASD.
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17. Theoharides TC, Stewart JM, Panagiotidou S, Melamed I. {{Mast cells, brain inflammation and autism}}. {European journal of pharmacology}. 2015 May 1.
Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Mast cells (MCs) are located perivascularly close to neurons and microglia, primarily in the leptomeninges, thalamus, hypothalamus and especially the median eminence. Corticotropin-releasing factor (CRF) is secreted from the hypothalamus under stress and, together with neurotensin (NT), can stimulate brain MCs to release inflammatory and neurotoxic mediators that disrupt the blood-brain barrier (BBB), stimulate microglia and cause focal inflammation. CRF and NT synergistically stimulate MCs and increase vascular permeability; these peptides can also induce each other’s surface receptors on MCs leading to autocrine and paracrine effects. As a result, brain MCs may be involved in the pathogenesis of « brain fog, » headaches, and autism spectrum disorders (ASDs), which worsen with stress. CRF and NT are significantly increased in serum of ASD children compared to normotypic controls further strengthening their role in the pathogenesis of autism. There are no clinically affective treatments for the core symptoms of ASDs, but pilot clinical trials using natural-antioxidant and anti-inflammatory molecules reported statistically significant benefit.
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18. Tint A, Weiss JA. {{Family wellbeing of individuals with autism spectrum disorder: A scoping review}}. {Autism : the international journal of research and practice}. 2015 May 6.
Families play an important role in supporting individuals with autism spectrum disorder across the lifespan. Indicators of family wellbeing can help to establish benchmarks for service provision and evaluation; however, a critical first step is a clear understanding of the construct in question. The purpose of the current scoping review was to (a) summarize current conceptualizations and measurements of family wellbeing, (b) synthesize key findings, and (c) highlight gaps and limitations in the extant literature. A final review of 86 articles highlighted the difficulty of synthesizing findings of family wellbeing in the autism spectrum disorder literature due to varied measurement techniques and the limited use of a common theoretical direction. Considerations for future research are presented with an eye toward policy relevance.
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19. Vogt D, Cho KK, Lee AT, Sohal VS, Rubenstein JL. {{The Parvalbumin/Somatostatin Ratio Is Increased in Pten Mutant Mice and by Human PTEN ASD Alleles}}. {Cell reports}. 2015 Apr 28.
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST+ interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV+ projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.
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20. Wolff JJ, Gerig G, Lewis JD, Soda T, Styner MA, Vachet C, Botteron KN, Elison JT, Dager SR, Estes AM, Hazlett HC, Schultz RT, Zwaigenbaum L, Piven J, Network I. {{Altered corpus callosum morphology associated with autism over the first 2 years of life}}. {Brain : a journal of neurology}. 2015 May 3.
Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology.
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21. Xiang J, Korostenskaja M, Molloy C, deGrauw X, Leiken K, Gilman C, Meinzen-Derr J, Fujiwara H, Rose DF, Mitchell T, Murray DS. {{Multi-frequency localization of aberrant brain activity in autism spectrum disorder}}. {Brain & development}. 2015 Apr 27.
OBJECTIVE: The abnormality of intrinsic brain activity in autism spectrum disorders (ASDs) is still inconclusive. Contradictory results have been found pointing towards hyper-activity or hypo-activity in various brain regions. The present research aims to investigate the spatial and spectral signatures of aberrant brain activity in an unprecedented frequency range of 1-2884Hz at source levels in ASD using newly developed methods. MATERIALS AND METHODS: Seven ASD subjects and age- and gender-matched controls were studied using a high-sampling rate magnetoencephalography (MEG) system. Brain activity in delta (1-4Hz), theta (4-8Hz), alpha (8-12Hz), beta (12-30Hz), low gamma (30-55Hz), high gamma (65-90Hz), ripples (90-200Hz), high-frequency oscillations (HFOs, 200-1000Hz), and very high-frequency oscillations (VHFOs, 1000-2884Hz) was volumetrically localized and measured using wavelet and beamforming. RESULTS: In comparison to controls, ASD subjects had significantly higher odds of alpha activity (8-12Hz) in the sensorimotor cortex (mu rhythm), and generally high-frequency activity (90-2884Hz) in the frontal cortex. The source power of HFOs (200-1000Hz) in the frontal cortex in ASD was significantly elevated as compared with controls. CONCLUSION: The results suggest that ASD has significantly altered intrinsic brain activity in both low- and high-frequency ranges. Increased intrinsic high-frequency activity in the frontal cortex may play a key role in ASD.
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22. Yang Z, Matsumoto A, Nakayama K, Jimbo EF, Kojima K, Nagata KI, Iwamoto S, Yamagata T. {{Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients}}. {Brain & development}. 2015 May 6.
BACKGROUND: The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B). METHODS: We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened. RESULTS: Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2, and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p=0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (www.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods. CONCLUSION: Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD.
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23. Zaidel A, Goin-Kochel RP, Angelaki DE. {{Self-motion perception in autism is compromised by visual noise but integrated optimally across multiple senses}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2015 May 4.
Perceptual processing in autism spectrum disorder (ASD) is marked by superior low-level task performance and inferior complex-task performance. This observation has led to theories of defective integration in ASD of local parts into a global percept. Despite mixed experimental results, this notion maintains widespread influence and has also motivated recent theories of defective multisensory integration in ASD. Impaired ASD performance in tasks involving classic random dot visual motion stimuli, corrupted by noise as a means to manipulate task difficulty, is frequently interpreted to support this notion of global integration deficits. By manipulating task difficulty independently of visual stimulus noise, here we test the hypothesis that heightened sensitivity to noise, rather than integration deficits, may characterize ASD. We found that although perception of visual motion through a cloud of dots was unimpaired without noise, the addition of stimulus noise significantly affected adolescents with ASD, more than controls. Strikingly, individuals with ASD demonstrated intact multisensory (visual-vestibular) integration, even in the presence of noise. Additionally, when vestibular motion was paired with pure visual noise, individuals with ASD demonstrated a different strategy than controls, marked by reduced flexibility. This result could be simulated by using attenuated (less reliable) and inflexible (not experience-dependent) Bayesian priors in ASD. These findings question widespread theories of impaired global and multisensory integration in ASD. Rather, they implicate increased sensitivity to sensory noise and less use of prior knowledge in ASD, suggesting increased reliance on incoming sensory information.
