1. Amaral DG, Li D, Libero L, Solomon M, Van de Water J, Mastergeorge A, Naigles L, Rogers S, Wu Nordahl C. {{In pursuit of neurophenotypes: The consequences of having autism and a big brain}}. {Autism Res};2017 (Feb 27)
A consensus has emerged that despite common core features, autism spectrum disorder (ASD) has multiple etiologies and various genetic and biological characteristics. The fact that there are likely to be subtypes of ASD has complicated attempts to develop effective therapies. The UC Davis MIND Institute Autism Phenome Project is a longitudinal, multidisciplinary analysis of children with autism and age-matched typically developing controls; nearly 400 families are participating in this study. The overarching goal is to gather sufficient biological, medical, and behavioral data to allow definition of clinically meaningful subtypes of ASD. One reasonable hypothesis is that different subtypes of autism will demonstrate different patterns of altered brain organization or development i.e., different neurophenotypes. In this Commentary, we discuss one neurophenotype that is defined by megalencephaly, or having brain size that is large and disproportionate to body size. We have found that 15% of the boys with autism demonstrate this neurophenotype, though it is far less common in girls. We review behavioral and medical characteristics of the large-brained group of boys with autism in comparison to those with typically sized brains. While brain size in typically developing individuals is positively correlated with cognitive function, the children with autism and larger brains have more severe disabilities and poorer prognosis. This research indicates that phenotyping in autism, like genotyping, requires a very substantial cohort of subjects. Moreover, since brain and behavior relationships may emerge at different times during development, this effort highlights the need for longitudinal analyses to carry out meaningful phenotyping. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Armstrong R, Whitehouse AJ, Scott JG, Copland DA, McMahon KL, Fleming S, Arnott W. {{A Relationship Between Early Language Skills and Adult Autistic-Like Traits: Evidence from a Longitudinal Population-Based Study}}. {J Autism Dev Disord};2017 (Feb 27)
The current study examined the relationship between early language ability and autistic-like traits in adulthood, utilising data from 644 participants from a longitudinal study of the general population. Language performance at 2 years was measured with the Language Development Survey (LDS), and at 20 years the participants completed the Autism-Spectrum Quotient (AQ). Vocabulary size at 2 years was negatively associated with Total AQ score, as well as scores on the Communication, and Social Skills subscales. Adults who had been late talkers were also more likely to have ‘high’ scores on the Communication subscale. This is the first study to show an association between early language ability and autistic-like traits in adulthood.
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3. Bishop-Fitzpatrick L, Smith DaWalt L, Greenberg JS, Mailick MR. {{Participation in recreational activities buffers the impact of perceived stress on quality of life in adults with autism spectrum disorder}}. {Autism Res};2017 (Feb 28)
As the number of adults with autism spectrum disorder (ASD) grows, the need to identify modifiable correlates of positive outcomes and quality of life (QoL) gains in importance. Research indicates that perceived stress is significantly correlated with QoL in adults with ASD. Studies in the general population of individuals without disabilities indicate that greater participation in social and recreational activities may lessen the negative impact of perceived stress on well-being, and this association may also hold among adults with ASD. We hypothesized that: (1) perceived stress would be negatively associated with QoL; and (2) higher frequency of participation in social activities and recreational activities would moderate the relationship between perceived stress and QoL. We used data collected from 60 adults with ASD aged 24-55 and their mothers to address our hypotheses. Findings indicate that adults with ASD with higher perceived stress are likely to have poorer QoL. Furthermore, greater participation in recreational activities buffers the impact of perceived stress on QoL, but no buffering effect was observed for participation in social activities. These findings suggest that interventions and services that provide supports and opportunities for participation in recreational activities may help adults with ASD manage their stress and lead to better QoL. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Datko M, Pineda J, Muller RA. {{Positive effects of neurofeedback on autism symptoms correlate with brain activation during imitation and observation}}. {Eur J Neurosci};2017 (Feb 28)
Autism has been characterized by atypical task-related brain activation and functional connections, coinciding with deficits in sociocommunicative abilities. However, evidence of the brain’s experience-dependent plasticity suggests that abnormal activity patterns may be reversed with treatment. In particular, neurofeedback training, an intervention based on operant conditioning resulting in self-regulation of brain electrical oscillations, has shown increasing promise in addressing abnormalities in brain function and behavior. We examined the effects of >/=20 hours of sensorimotor mu-rhythm based neurofeedback training in children with high functioning autism spectrum disorders (ASD) and a matched control group of typically developing children (ages 8-17). During an fMRI imitation and observation task, the ASD group showed increased activation in regions of the human mirror neuron system following neurofeedback training, as part of a significant interaction between group (ASD vs. controls) and training (pre- vs. post-training). These changes were positively correlated with behavioral improvements in ASD participants, indicating that mu-rhythm neurofeedback training may be beneficial to individuals with ASD. This article is protected by copyright. All rights reserved.
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5. Denisova K, Zhao G, Wang Z, Goh S, Huo Y, Peterson BS. {{Cortical interactions during the resolution of information processing demands in autism spectrum disorders}}. {Brain Behav};2017 (Feb);7(2):e00596.
INTRODUCTION: Our flexible and adaptive interactions with the environment are guided by our individual representation of the physical world, estimated through sensation and evaluation of available information against prior knowledge. When linking sensory evidence with higher-level expectations for action, the central nervous system (CNS) in typically developing (TD) individuals relies in part on distributed and interacting cortical regions to communicate neuronal signals flexibly across the brain. Increasing evidence suggests that the balance between levels of signal and noise during information processing may be disrupted in individuals with Autism Spectrum Disorders (ASD). METHODS: Participants with and without ASD performed a visuospatial interference task while undergoing functional Magnetic Resonance Imaging (fMRI). We empirically estimated parameters characterizing participants’ latencies and their subtle fluctuations (noise accumulation) over the 16-min scan. We modeled hemodynamic activation and used seed-based analyses of neural coupling to study dysfunction in interference-specific connectivity in a subset of ASD participants who were nonparametrically matched to TD participants on age, male-to-female ratio, and magnitude of movement during the scan. RESULTS: Stochastic patterns of response fluctuations reveal significantly higher noise-to-signal levels and a more random and noisy structure in ASD versus TD participants, and in particular ASD adults who have the greatest clinical autistic deficits. While individuals with ASD show an overall weaker modulation of interference-specific functional connectivity relative to TD individuals, in particular between the seeds of Anterior Cingulate Cortex (ACC) and Inferior Parietal Sulcus (IPS) and the rest of the brain, we found that in ASD, higher uncertainty during the task is linked to increased interference-specific coupling between bilateral anterior insula and prefrontal cortex. CONCLUSIONS: Subtle and informative differences in the structure of experiencing information exist between ASD and TD individuals. Our findings reveal in ASD an atypical capacity to apply previously perceived information in a manner optimal for adaptive functioning, plausibly revealing suboptimal message-passing across the CNS.
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6. Ghirardi L, Brikell I, Kuja-Halkola R, Freitag CM, Franke B, Asherson P, Lichtenstein P, Larsson H. {{The familial co-aggregation of ASD and ADHD: a register-based cohort study}}. {Mol Psychiatry};2017 (Feb 28)
Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77-22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80-32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21-5.85) and full siblings (OR=4.59, 95% CI: 4.39-4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.Molecular Psychiatry advance online publication, 28 February 2017; doi:10.1038/mp.2017.17.
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7. Helminen TM, Leppanen JM, Eriksson K, Luoma A, Hietanen JK, Kylliainen A. {{Atypical physiological orienting to direct gaze in low-functioning children with autism spectrum disorder}}. {Autism Res};2017 (Feb 28)
Reduced use of eye contact is a prominent feature in individuals with autism spectrum disorder (ASD). It has been proposed that direct gaze does not capture the attention of individuals with ASD. Experimental evidence is, however, mainly restricted to relatively high-functioning school-aged children or adults with ASD. This study investigated whether 2-5-year-old low-functioning children with severe ASD differ from control children in orienting to gaze stimuli, as measured with the heart rate deceleration response. Responses were measured to computerized presentations of dynamic shifts of gaze direction either toward (direct) or away (averted) from the observing child. The results showed a significant group by gaze direction interaction effect on heart rate responses (permuted P = .004), reflecting a stronger orienting response to direct versus averted gaze in typically developing (N = 17) and developmentally delayed (N = 16) children but not in children with ASD (N = 12). The lack of enhanced orienting response to direct gaze in the ASD group was not caused by a lack of looking at the eye region, as confirmed by eye tracking. The results suggest that direct gaze is not a socially salient, attention-grabbing signal for low-functioning children with ASD. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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8. Jones EJ, Dawson G, Kelly J, Estes A, Jane Webb S. {{Parent-delivered early intervention in infants at risk for ASD: Effects on electrophysiological and habituation measures of social attention}}. {Autism Res};2017 (Feb 28)
Prospective longitudinal studies of infants with older siblings with autism spectrum disorder (ASD) have indicated that differences in the neurocognitive systems underlying social attention may emerge prior to the child meeting ASD diagnostic criteria. Thus, targeting social attention with early intervention might have the potential to alter developmental trajectories for infants at high risk for ASD. Electrophysiological and habituation measures of social attention were collected at 6, 12, and 18 months in a group of high-risk infant siblings of children with ASD (N = 33). Between 9 and 11 months of age, infant siblings received a parent-delivered intervention, promoting first relationships (PFR), (n = 19) or on-going assessment without intervention (n = 14). PFR has been previously shown to increase parental responsivity to infant social communicative cues and infant contingent responding. Compared to infants who only received assessment and monitoring, infants who received the intervention showed improvements in neurocognitive metrics of social attention, as reflected in a greater reduction in habituation times to face versus object stimuli between 6 and 12 months, maintained at 18 months; a greater increase in frontal EEG theta power between 6 and 12 months; and a more comparable P400 response to faces and objects at 12 months. The high-risk infants who received the intervention showed a pattern of responses that appeared closer to the normative responses of two groups of age-matched low-risk control participants. Though replication is necessary, these results suggest that early parent-mediated intervention has the potential to impact the brain systems underpinning social attention in infants at familial risk for ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Jones RA, Downing K, Rinehart NJ, Barnett LM, May T, McGillivray JA, Papadopoulos NV, Skouteris H, Timperio A, Hinkley T. {{Physical activity, sedentary behavior and their correlates in children with Autism Spectrum Disorder: A systematic review}}. {PLoS One};2017;12(2):e0172482.
Autism Spectrum Disorder affects up to 2.5% of children and is associated with harmful health outcomes (e.g. obesity). Low levels of physical activity and high levels of sedentary behaviors may contribute to harmful health outcomes. To systematically review the prevalence and correlates of physical activity and sedentary behaviors in children with Autism Spectrum Disorder, electronic databases (PsycINFO, SPORTDiscus, EMBASE, Medline) were searched from inception to November 2015. The review was registered with PROSPERO (CRD42014013849). Peer-reviewed, English language studies were included. Two reviewers screened potentially relevant articles. Outcomes of interest were physical activity and sedentary behaviour levels and their potential correlates. Data were collected and analysed in 2015. Of 35 included studies, 15 reported physical activity prevalence, 10 reported physical activity correlates, 18 reported sedentary behavior prevalence, and 10 reported sedentary behavior correlates. Estimates of children’s physical activity (34-166 mins/day, average 86 mins/day) and sedentary behavior (126-558 mins/day in screen time, average 271 mins/day; 428-750 mins/day in total sedentary behavior, average 479 mins/day) varied across studies. Age was consistently inversely associated, and sex inconsistently associated with physical activity. Age and sex were inconsistently associated with sedentary behavior. Sample sizes were small. All but one of the studies were classified as having high risk of bias. Few correlates have been reported in sufficient studies to provide overall estimates of associations. Potential correlates in the physical environment remain largely unexamined. This review highlights varying levels of physical activity and sedentary behavior in children with Autism Spectrum Disorder. Research is needed to consistently identify the correlates of these behaviors. There is a critical need for interventions to support healthy levels of these behaviors.
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10. Oh DH, Kim IB, Kim SH, Ahn DH. {{Predicting Autism Spectrum Disorder Using Blood-based Gene Expression Signatures and Machine Learning}}. {Clin Psychopharmacol Neurosci};2017 (Feb 28);15(1):47-52.
Objective: The aim of this study was to identify a transcriptomic signature that could be used to classify subjects with autism spectrum disorder (ASD) compared to controls on the basis of blood gene expression profiles. The gene expression profiles could ultimately be used as diagnostic biomarkers for ASD. Methods: We used the published microarray data (GSE26415) from the Gene Expression Omnibus database, which included 21 young adults with ASD and 21 age- and sex-matched unaffected controls. Nineteen differentially expressed probes were identified from a training dataset (n=26, 13 ASD cases and 13 controls) using the limma package in R language (adjusted p value 0.05) and were further analyzed in a test dataset (n=16, 8 ASD cases and 8 controls) using machine learning algorithms. Results: Hierarchical cluster analysis showed that subjects with ASD were relatively well-discriminated from controls. Based on the support vector machine and K-nearest neighbors analysis, validation of 19-DE probes with a test dataset resulted in an overall class prediction accuracy of 93.8% as well as a sensitivity and specificity of 100% and 87.5%, respectively. Conclusion: The results of our exploratory study suggest that the gene expression profiles identified from the peripheral blood samples of young adults with ASD can be used to identify a biological signature for ASD. Further study using a larger cohort and more homogeneous datasets is required to improve the diagnostic accuracy.
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11. Skuk VG, Palermo R, Broemer L, Schweinberger SR. {{Autistic Traits are Linked to Individual Differences in Familiar Voice Identification}}. {J Autism Dev Disord};2017 (Feb 28)
Autistic traits vary across the general population, and are linked with face recognition ability. Here we investigated potential links between autistic traits and voice recognition ability for personally familiar voices in a group of 30 listeners (15 female, 16-19 years) from the same local school. Autistic traits (particularly those related to communication and social interaction) were negatively correlated with voice recognition, such that more autistic traits were associated with fewer familiar voices identified and less ability to discriminate familiar from unfamiliar voices. In addition, our results suggest enhanced accessibility of personal semantic information in women compared to men. Overall, this study establishes a detailed pattern of relationships between voice identification performance and autistic traits in the general population.
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12. Zhou LT, Ye SH, Yang HX, Zhou YT, Zhao QH, Sun WW, Gao MM, Yi YH, Long YS. {{A novel role of fragile X mental retardation protein in pre-mRNA alternative splicing through RNA-binding protein 14}}. {Neuroscience};2017 (Feb 28)
Fragile X mental retardation protein (FMRP)an important RNA-binding protein responsible for fragile X syndrome, is involved in posttranscriptional control of gene expression that links with brain development and synaptic functions. Here, we reveal a novel role of FMRP in pre-mRNA alternative splicing, a general event of posttranscriptional regulation. Using co-immunoprecipitation and immunofluorescence assays, we identified that FMRP interacts with an alternative-splicing-associated protein RNA-binding protein 14 (RBM14) in a RNA-dependent fashion, and the two proteins partially colocalize in the nuclei of hippocampal neurons. We show that the relative skipping/inclusion ratio of the micro-exon L in the Protrudin gene and exon 10 in the Tau gene decreased in the hippocampus of Fmr1 knockout (KO) mice. Knockdown of either FMRP or RBM14 alters the relative skipping/inclusion ratio of Protrudin and Tau in cultured Neuro-2a cells, similar to that in the Fmr1 KO mice. Furthermore, overexpression of FMRP leads to an opposite pattern of the splicing, which can be offset by RBM14 knockdown. RNA immunoprecipitation assays indicate that FMRP promotes RBM14’s binding to the mRNA targets. In addition, overexpression of the long form of Protrudin or the short form of Tau promotes protrusion growth of the retinoic acid-treated, neuronal-differentiated Neuro-2a cells. Together, these data suggest a novel function of FMRP in the regulation of pre-mRNA alternative splicing through RBM14 that may be associated with normal brain function and FMRP-related neurological disorders.
