1. Badescu GM, Filfan M, Sandu RE, Surugiu R, Ciobanu O, Popa-Wagner A. {{Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism}}. {Rom J Morphol Embryol}. 2016; 57(2): 361-6.
Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11.
2. Cellot G, Maggi L, Di Castro MA, Catalano M, Migliore R, Migliore M, Scattoni ML, Calamandrei G, Cherubini E. {{Premature changes in neuronal excitability account for hippocampal network impairment and autistic-like behavior in neonatal BTBR T+tf/J mice}}. {Sci Rep}. 2016; 6: 31696.
Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments EGABA was positive to Em), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients.
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3. Cheng N, Khanbabaei M, Murari K, Rho JM. {{Disruption of visual circuit formation and refinement in a mouse model of autism}}. {Autism Res}. 2016.
Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi- and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower-level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2016. (c) 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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4. Deckers A, Muris P, Roelofs J, Arntz A. {{A Group-Administered social Skills Training for 8- to 12- Year-Old, high-Functioning Children With Autism Spectrum Disorders: An Evaluation of its Effectiveness in a Naturalistic Outpatient Treatment Setting}}. {J Autism Dev Disord}. 2016.
A social skills training (SST) for high-functioning children with autism spectrum disorders (ASD) was evaluated in an outpatient setting using a combined between- and within-subject design in which SST and a waiting list condition were compared. According to parents and teachers, the SST produced greater improvement of social skills than the waiting list, and these effects were maintained at 3 months follow-up. No between-group effects were found for loneliness, although in general scores on this outcome measure decreased from pre- to follow-up. The effects of SST were unaffected by social anxiety, ADHD symptoms, Theory of Mind, or desire for social interaction. Altogether, SST seems an effective intervention for high-functioning children with ASD that can be applied in daily clinical practice.
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5. Ehrhart F, Coort SL, Cirillo E, Smeets E, Evelo CT, Curfs L. {{New insights in Rett syndrome using pathway analysis for transcriptomics data}}. {Wien Med Wochenschr}. 2016.
The analysis of transcriptomics data is able to give an overview of cellular processes, but requires sophisticated bioinformatics tools and methods to identify the changes. Pathway analysis software, like PathVisio, captures the information about biological pathways from databases and brings this together with the experimental data to enable visualization and understanding of the underlying processes. Rett syndrome is a rare disease, but still one of the most abundant causes of intellectual disability in females. Cause of this neurological disorder is mutation of one single gene, the methyl-CpG-binding protein 2 (MECP2) gene. This gene is responsible for many steps in neuronal development and function. Although the genetic mutation and the clinical phenotype are well described, the molecular pathways linking them are not yet fully elucidated. In this study we demonstrate a workflow for the analysis of transcriptomics data to identify biological pathways and processes which are changed in a Mecp2 -/y mouse model.
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6. Einspieler C, Freilinger M, Marschik PB. {{Behavioural biomarkers of typical Rett syndrome: moving towards early identification}}. {Wien Med Wochenschr}. 2016.
The dynamic course of Rett syndrome (RTT) is still said to begin with a period of apparently normal development although there is mounting evidence that individuals with RTT show behavioural peculiarities and abnormalities during their infancy. Their spontaneous general movements are abnormal from birth onwards. Normal cooing vocalisation and canonical babbling (if at all required) are interspersed with abnormalities such as proto-vowel and proto-consonant alternations produced on ingressive airstream, breathy voice characteristics, and pressed or high-pitched vocalisations. The gestural repertoire is limited. Certain developmental motor and speech-language milestones are not at all acquired or show a significant delay. Besides abnormal blinking, repetitive and/or long lasting tongue protrusion, and bizarre smiling, there are already the first body and/or hand stereotypies during the first year of life. We are currently on a promising way to define a specific set of behavioural biomarkers pinpointing RTT.
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7. Fasano A, Sammartino F, Llinas M, Lozano AM. {{MRI-guided focused ultrasound thalamotomy in fragile X-associated tremor/ataxia syndrome}}. {Neurology}. 2016; 87(7): 736-8.
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8. Gamliel M, Anderson KL, Ebstein RP, Yirmiya N, Mankuta D. {{Paternal HLA-C and Maternal Killer-Cell Immunoglobulin-Like Receptor Genotypes in the Development of Autism}}. {Front Pediatr}. 2016; 4: 76.
Killer-cell immunoglobulin-like receptors (KIRs) are a family of cell surface proteins found on natural killer cells, which are components of the innate immune system. KIRs recognize MHC class I proteins, mainly HLA-C and are further divided into two groups: short-tailed 2/3DS activating receptors and long-tailed 2/3DL inhibitory receptors. Based on the Barker Hypothesis, the origins of illness can be traced back to embryonic development in the uterus, and since KIR:HLA interaction figures prominently in the maternal-fetal interface, we investigated whether specific KIR:HLA combinations may be found in autism spectrum disorders (ASD) children compared with their healthy parents. This study enrolled 49 ASD children from different Israeli families, and their healthy parents. Among the parents, a higher frequency of HLA-C2 allotypes was found in the fathers, while its corresponding ligand 2DS1 was found in higher percentage in the maternal group. However, such skewing in KIR:HLA frequencies did not appear in the ASD children. Additionally, analysis of « overall activation » indicated higher activation in maternal than in paternal cohorts.
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9. Garg S, Heuvelman H, Huson S, Tobin H, Green J. {{Sex bias in autism spectrum disorder in neurofibromatosis type 1}}. {J Neurodev Disord}. 2016; 8: 26.
BACKGROUND: Despite extensive literature, little is known about the mechanisms underlying sex bias in autism spectrum disorder (ASD). This study investigates the sex differences in ASD associated with neurofibromatosis type 1, a single-gene model of syndromic autism. METHODS: We analysed data from n = 194 children aged 4-16 years with neurofibromatosis type 1. Sex differences were evaluated across the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), verbal IQ, Social Responsiveness Scale (SRS) and Conners questionnaires. RESULTS: There was 2.68:1 male:female ratio in children meeting ASD criteria on the deep phenotyping measures. On symptom profile, males with neurofibromatosis type 1 (NF1) + ASD were more impaired on reciprocal social interaction and communication domains of the ADI-R but we found no differences on the restricted, repetitive behaviours (RRBs) domain of the ADI-R and no differences on the social on the ADOS. NF1 ASD males and females were comparable on verbal IQ, and the inattention/hyperactivity domains of the Conners questionnaire. CONCLUSIONS: There is a significant male bias in the prevalence of ASD in NF1. The phenotypic profile of NF1 + ASD cases includes greater social communication impairment in males. We discuss the implications of our findings and the rationale for using NF1 as a model for investigating sex bias in idiopathic ASD.
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10. Glod M, Riby DM, Honey E, Rodgers J. {{Sensory atypicalities in dyads of children with autism spectrum disorder (ASD) and their parents}}. {Autism Res}. 2016.
Sensory atypicalities are a common feature of autism spectrum disorder (ASD). To date, the relationship between sensory atypicalities in dyads of children with ASD and their parents has not been investigated. Exploring these relationships can contribute to an understanding of how phenotypic profiles may be inherited, and the extent to which familial factors might contribute towards children’s sensory profiles and constitute an aspect of the broader autism phenotype (BAP). Parents of 44 children with ASD and 30 typically developing (TD) children, aged between 3 and 14 years, participated. Information about children’s sensory experiences was collected through parent report using the Sensory Profile questionnaire. Information about parental sensory experiences was collected via self-report using the Adolescent/Adult Sensory Profile. Parents of children with ASD had significantly higher scores than parents of TD children in relation to low registration, over responsivity, and taste/smell sensory processing. Similar levels of agreement were obtained within ASD and TD parent-child dyads on a number of sensory atypicalities; nevertheless significant correlations were found between parents and children in ASD families but not TD dyads for sensation avoiding and auditory, visual, and vestibular sensory processing. The findings suggest that there are similarities in sensory processing profiles between parents and their children in both ASD and TD dyads. Familial sensory processing factors are likely to contribute towards the BAP. Further work is needed to explore genetic and environmental influences on the developmental pathways of the sensory atypicalities in ASD. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Goldschmidt J, Song HJ. {{Development of Cooking Skills as Nutrition Intervention for Adults with Autism and Other Developmental Disabilities}}. {J Acad Nutr Diet}. 2016.
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12. Heinicke MR, Carr JE, Pence ST, Zias DR, Valentino AL, Falligant JM. {{Assessing the efficacy of pictorial preference assessments for children with developmental disabilities}}. {J Appl Behav Anal}. 2016.
Past research has demonstrated that pictorial preference assessments can predict subsequent reinforcement effects for individuals with developmental disabilities only when access to the selected stimulus is provided contingent on a pictorial selection. The purpose of the present investigation was to assess more comprehensively the feasibility of the pictorial format with children with developmental disabilities. In Experiment 1, prerequisite skill assessments were conducted, and the role of a contingent reinforcer was assessed by comparing the results from the pictorial assessment without contingent access to a reinforcer assessment. If contingent access was found to be necessary, the effects of schedule thinning were evaluated to determine whether a pictorial format could be made more practical in Experiment 2. The pictorial format without contingent access was successful with only some participants. However, schedule thinning was found to be an effective method to establish conditioned reinforcement properties for pictorial stimuli to create a more practical assessment for a subset of participants.
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13. Kosaki Y, Watanabe S. {{Impaired Pavlovian predictive learning between temporally phasic but not static events in autism-model strain mice}}. {Neurobiol Learn Mem}. 2016.
Autism-spectrum disorder (ASD) is a multi-aspect developmental disorder characterised by various social and non-social behavioural abnormalities. Using BTBR T+ tf mouse strain (BTBR), a promising animal model displaying a number of behavioural and neural characteristics associated with ASD, we tested the hypothesis that at the core of various symptoms of ASD lies a fundamental deficit in predictive learning between events. In five experiments, we conducted a variety of Pavlovian conditioning tasks, some requiring the establishment of associations between temporally phasic events and others involving static events. BTBR mice were impaired in the acquisition of conditioned magazine approach responses with an appetitive unconditioned stimulus (US) (Experiment 1) and conditioned freezing with an electric shock US (Experiment 2). Both of these tasks had temporally phasic conditioned stimuli (CSs). Conversely, these mice showed normal acquisition of conditioned place preference (CPP), whether the US was a systemic injection of methamphetamine (Experiment 3A) or the presence of food (Experiment 3B). Experiment 4 showed normal acquisition of conditioned taste aversion (CTA) to a flavour-taste compound CS, although BTBR mice still exhibited an abnormal stimulus selection when learning for each element of the compound CS was assessed separately. Experiment 5 revealed a weaker latent inhibition of CTA in BTBR mice. The BTBR mouse’s impaired predictive learning between phasic events and intact associations between static events are discussed in terms of dysfunctional contingency-based, but not contiguity-based learning, which may accompany abnormal selective attention to relevant cues. We propose that such dysfunctional contingency learning mechanisms may underlie the development of various social and non-social symptoms of ASD.
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14. Lee IJ, Chen CH, Lin LY. {{Applied Cliplets-based half-dynamic videos as intervention learning materials to attract the attention of adolescents with autism spectrum disorder to improve their perceptions and judgments of the facial expressions and emotions of others}}. {Springerplus}. 2016; 5(1): 1211.
BACKGROUND: Autism spectrum disorders (ASD) are characterized by a reduced ability to understand the emotional expressions on other people’s faces. Increasing evidence indicates that children with ASD might not recognize or understand crucial nonverbal behaviors, which likely causes them to ignore nonverbal gestures and social cues, like facial expressions, that usually aid social interaction. OBJECTIVE: In this study, we used software technology to create half-static and dynamic video materials to teach adolescents with ASD how to become aware of six basic facial expressions observed in real situations. METHODS: This intervention system provides a half-way point via a dynamic video of a specific element within a static-surrounding frame to strengthen the ability of the six adolescents with ASD to attract their attention on the relevant dynamic facial expressions and ignore irrelevant ones. RESULTS: Using a multiple baseline design across participants, we found that the intervention learning system provided a simple yet effective way for adolescents with ASD to attract their attention on the nonverbal facial cues; the intervention helped them better understand and judge others’ facial emotions. CONCLUSION: We conclude that the limited amount of information with structured and specific close-up visual social cues helped the participants improve judgments of the emotional meaning of the facial expressions of others.
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15. Liu L, Zhang D, Rodzinka-Pasko JK, Li YM. {{Environmental risk factors for autism spectrum disorders}}. {Nervenarzt}. 2016.
BACKGROUND: Autism spectrum disorders (ASD) are syndromes that are predominantly defined by behavioral features such as impaired social interactions, restricted verbal and nonverbal communication, and repetitive or stereotyped behavior. In the past few decades, the reported prevalence of ASD has increased dramatically. This growth can be partially explained by an increased level of awareness of the problem among professionals and better diagnostic methods. Nevertheless, underpinning causes of ASD have not yet been detailed and explained. It is suggested that rather than having a single causative factor, ASD pathogenesis is influenced by environmental or genetic factors, or a combination of both. The aims of this review are to describe the environmental risk factors associated with ASD so as to provide a reference basis for current and future clinical and experimental work. MATERIALS AND METHODS: On the basis of a PubMed search, we review the existing knowledge on environmental factors associated with ASD. RESULTS: A series of environmental factors have been repeatedly reported as risk factors for ASD in existing studies. CONCLUSION: Air pollution, organic toxicants, seasonal factors, psychological stress, migration, birth order, and nutrition may have a close relationship with the incidence of ASD.
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16. Luleci NE, Hidiroglu S, Karavus M, Celik S, Cetiner D, Koc E, Kasikci TG, Sadirvan YH, Karavus A, Topuzoglu A. {{A study exploring the autism awareness of first grade nursing and medical students in Istanbul, Turkey}}. {J Pak Med Assoc}. 2016; 66(8): 916-21.
OBJECTIVE: To assess the level of awareness about childhood autism among first-grade nursing and medical students. METHODS: The descriptive study was conducted at Marmara University, Istanbul, Turkey, in December 2012, and comprised first-grade nursing and medical students. Data was collected using a self-administered questionnaire. Association between categorical variables was determined and p<0.05 was considered statistically significant. RESULTS: Of the 175 students, 138(78.9%) were aware of autism, 14(8%) of them being highly aware and 124(70.9%) moderately aware, whereas 37(21.1%) were not aware. There was a significant difference in the awareness level as far as gender was concerned as 102(82.9%) females and 36(69.2%) males were aware (p=0.043). Moreover, 104(59.4%) participants were aware that autism was a neurodevelopmental disorder, 62(67.4%) of them being nursing and 42(50.6%) being medical students (p<0.05). CONCLUSIONS: First-grade medical and nursing students could be considered relatively well aware of autism as their awareness level was in between that of the general public and healthcare professionals. Lien vers Pubmed
17. Majumder P, Chu JF, Chatterjee B, Swamy KB, Shen CJ. {{Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP}}. {Acta Neuropathol}. 2016.
For proper mammalian brain development and functioning, the translation of many neuronal mRNAs needs to be repressed without neuronal activity stimulations. We have discovered that the expression of a subclass of neuronal proteins essential for neurodevelopment and neuron plasticity is co-regulated at the translational level by TDP-43 and the Fragile X Syndrome protein FMRP. Using molecular, cellular and imaging approaches, we show that these two RNA-binding proteins (RBP) co-repress the translation initiation of Rac1, Map1b and GluR1 mRNAs, and consequently the hippocampal spinogenesis. The co-repression occurs through binding of TDP-43 to mRNA(s) at specific UG/GU sequences and recruitment of the inhibitory CYFIP1-FMRP complex by its glycine-rich domain. This novel regulatory scenario could be utilized to silence a significant portion of around 160 common target mRNAs of the two RBPs. The study establishes a functional/physical partnership between FMRP and TDP-43 that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases.
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18. Marshall D, Wright B, Allgar V, Adamson J, Williams C, Ainsworth H, Cook L, Varley D, Hackney L, Dempster P, Ali S, Trepel D, Collingridge Moore D, Littlewood E, McMillan D. {{Social Stories in mainstream schools for children with autism spectrum disorder: a feasibility randomised controlled trial}}. {BMJ Open}. 2016; 6(8): e011748.
OBJECTIVES: To assess the feasibility of recruitment, retention, outcome measures and intervention training/delivery among teachers, parents and children. To calculate a sample size estimation for full trial. DESIGN: A single-centre, unblinded, cluster feasibility randomised controlled trial examining Social Stories delivered within a school environment compared with an attentional control. SETTING: 37 primary schools in York, UK. PARTICIPANTS: 50 participants were recruited and a cluster randomisation approach by school was examined. Participants were randomised into the treatment group (n=23) or a waiting list control group (n=27). OUTCOME MEASURES: Acceptability and feasibility of the trial, intervention and of measurements required to assess outcomes in a definitive trial. RESULTS: An assessment of the questionnaire completion rates indicated teachers would be most appropriate to complete the primary outcome measure. 2 outcome measures: the Social Responsiveness Scale (SRS)-2 and a goal-based measure showed both the highest levels of completion rates (above 80%) at the primary follow-up point (6 weeks postintervention) and captured relevant social and behaviour outcomes. Power calculations were based on these 2 outcome measures leading to a total proposed sample size of 180 participant groups. CONCLUSIONS: Results suggest that a future trial would be feasible to conduct and could inform the policy and practice of using Social Stories in mainstream schools. TRIAL REGISTRATION NUMBER: ISRCTN96286707; Results.
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19. Mychasiuk R, Rho JM. {{Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder}}. {Autism Res}. 2016.
Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder characterized by hallmark behavioral features. The spectrum of disorders that fall within the ASD umbrella encompass a distinct but overlapping symptom complex that likely results from an array of molecular and genetic aberrations rather than a single genetic mutation. The ketogenic diet (KD) is a high-fat low-carbohydrate anti-seizure and neuroprotective diet that has demonstrated efficacy in the treatment of ASD-like behaviors in animal and human studies. We investigated changes in mRNA and gene expression in the BTBR mouse model of ASD that may contribute to the behavioral phenotype. In addition, we sought to examine changes in gene expression following KD treatment in BTBR mice. Despite significant behavioral abnormalities, expression changes in BTBR mice did not differ substantially from controls; only 33 genes were differentially expressed in the temporal cortex, and 48 in the hippocampus. Examination of these differentially expressed genes suggested deficits in the stress response and in neuronal signaling/communication. After treatment with the KD, both brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development. Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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20. Prat CS, Stocco A, Neuhaus E, Kleinhans NM. {{Basal ganglia impairments in autism spectrum disorder are related to abnormal signal gating to prefrontal cortex}}. {Neuropsychologia}. 2016; 91: 268-81.
Research on the biological basis of autism spectrum disorder has yielded a list of brain abnormalities that are arguably as diverse as the set of behavioral symptoms that characterize the disorder. Among these are patterns of abnormal cortical connectivity and abnormal basal ganglia development. In attempts to integrate the existing literature, the current paper tests the hypothesis that impairments in the basal ganglia’s function to flexibly select and route task-relevant neural signals to the prefrontal cortex underpins patterns of abnormal synchronization between the prefrontal cortex and other cortical processing centers observed in individuals with autism spectrum disorder (ASD). We tested this hypothesis using a Dynamic Causal Modeling analysis of neuroimaging data collected from 16 individuals with ASD (mean age=25.3 years; 6 female) and 17 age- and IQ-matched neurotypical controls (mean age=25.6, 6 female), who performed a Go/No-Go test of executive functioning. Consistent with the hypothesis tested, a random-effects Bayesian model selection procedure determined that a model of network connectivity in which basal ganglia activation modulated connectivity between the prefrontal cortex and other key cortical processing centers best fit the data of both neurotypicals and individuals with ASD. Follow-up analyses suggested that the largest group differences were observed for modulation of connectivity between prefrontal cortex and the sensory input region in the occipital lobe [t(31)=2.03, p=0.025]. Specifically, basal ganglia activation was associated with a small decrease in synchronization between the occipital region and prefrontal cortical regions in controls; however, in individuals with ASD, basal ganglia activation resulted in increased synchronization between the occipital region and the prefrontal cortex. We propose that this increased synchronization may reflect a failure in basal ganglia signal gating mechanisms, resulting in a non-selective copying of signals to prefrontal cortex. Such a failure to prioritize and filter signals to the prefrontal cortex could result in the pervasive impairments in cognitive flexibility and executive functioning that characterize autism spectrum disorder, and may offer a mechanistic explanation of some of the observed abnormalities in patterns of cortical synchronization in ASD.
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21. Ravi S, Chandrasekaran V, Kattimani S, Subramanian M. {{Maternal and birth risk factors for children screening positive for autism spectrum disorders on M-CHAT-R}}. {Asian J Psychiatr}. 2016; 22: 17-21.
This study was carried out to screen children aged 16-30 months, attending pediatric outpatient department of JIPMER, Puducherry, during June to August 2014, for ASD using modified checklist for autism in toddlers-revised (MCHAT-R) and to find association between maternal, birth and postnatal risk factors with risk of ASD. A total of 350 mother-child pairs with children aged between 16 and 30 months were recruited. M-CHAT-R was administered to all mothers to screen for ASD along with risk checklist. Based on screen result children were classified as ASD (high risk) and no ASD (low and medium risk) group. The association between risk factors and screen positivity for ASD was studied using odds ratio. According to our study, 33 (9.4%) screened positive for ASD. Mean age was 21 months. High mean paternal age at birth (P value 0.025), need for resuscitation at birth (OR 3.4, 95% CI 1.47-8.10), NICU stay >12h (OR 4.7, 95% CI 2.26-9.94), late initiation of breastfeeding (OR 3.9, 95% CI 1.83-8.39), neonatal seizures (OR 11.8, 95% CI 5.38-26.25) were associated with screen positivity for ASD. After adjusting for confounding, neonatal seizures, and maternal concern about child development were associated with increased odds of screening positive for ASD whereas exclusive breast feeding in the first 6 months of life is associated with decreased odds. Screening for ASD in children with above risk factors might help in early initiation of remedial interventions.
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22. Rijlaarsdam J, van IMH, Verhulst FC, Jaddoe VW, Felix JF, Tiemeier H, Bakermans-Kranenburg MJ. {{Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation and child autistic traits: The moderating role of OXTR rs53576 genotype}}. {Autism Res}. 2016.
LAY ABSTRACT: The gene encoding the oxytocin receptor (OXTR), localized on chromosome 3p25, is considered a promising candidate for explaining genetic vulnerability to autistic traits. Although several lines of evidence implicate OXTR SNP rs53576 (G/A) variation in social behavior, findings have been inconsistent, possibly because DNA methylation after stress exposure was eliminated from consideration. This study investigated the main and interactive effects of OXTR rs53576 genotype, stress exposure, and OXTR methylation on child autistic traits. Prenatal maternal stress exposure, but not OXTR rs53576 genotype and OXTR methylation, showed a main effect on child autistic traits. For child autistic traits in general and social communication problems in particular, we observed a significant OXTR rs53576 genotype by OXTR methylation interaction. More specifically, OXTR methylation levels were positively associated with social problems for OXTR rs53576 G-allele homozygous children but not for A-allele carriers. These results highlight the importance of incorporating epi-allelic information and support the role of OXTR methylation in child autistic traits. SCIENTIFIC ABSTRACT: Findings of studies investigating OXTR SNP rs53576 (G-A) variation in social behavior have been inconsistent, possibly because DNA methylation after stress exposure was eliminated from consideration. Our goal was to examine OXTR rs53576 allele-specific sensitivity for neonatal OXTR DNA methylation in relation to (1) a prenatal maternal stress composite, and (2) child autistic traits. Prospective data from fetal life to age 6 years were collected in a total of 743 children participating in the Generation R Study. Prenatal maternal stress exposure was uniquely associated with child autistic traits but was unrelated to OXTR methylation across both OXTR rs53576 G-allele homozygous children and A-allele carriers. For child autistic traits in general and social communication problems in particular, we observed a significant OXTR rs53576 genotype by OXTR methylation interaction in the absence of main effects, suggesting that opposing effects cancelled each other out. Indeed, OXTR methylation levels were positively associated with social problems for OXTR rs53576 G-allele homozygous children but not for A-allele carriers. These results highlight the importance of incorporating epi-allelic information and support the role of OXTR methylation in child autistic traits. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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23. Ronen GM, Rosenbaum PL. {{Rett Syndrome Turns 50: Themes From a Chronicle: Medical Perspectives and the Human Face of Rett Syndrome}}. {Pediatr Neurol}. 2016; 61: 3-10.
BACKGROUND: Fifty years ago Andreas Rett first described in great detail what came to be known as « Rett syndrome. » Understanding girls and women with this syndrome and their families helped in many ways to revolutionize modern neurodevelopmental medicine. For some people the identification of the genetic underpinning of the syndrome and the ongoing biological research into this condition represented the peak of the scientific accomplishments in Rett syndrome. For others, it was developments in clinical research methodologies that were especially important. Above all, the patient- and family-oriented empathetic and collaborative approach to care by professionals collaborating with families has led to immense achievements, both scientific and humanistic. AIM: The aim of this narrative was to describe the medical and personal life story of a young woman with Rett syndrome and to offer a history that highlights developments in the unraveling of this condition from its initial recognition to our current understanding. CONCLUSION: We believe that much can be learned from the humanistic style of care provision combined with the best possible level of assisted autonomy and life enjoyment of the young woman with Rett syndrome. In addition, the approach to collaborative research by dedicated and often charitable leaders in the field can teach us many important lessons about the ethics of clinical and health services research.
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24. Rosenblau G, Kliemann D, Dziobek I, Heekeren HR. {{Emotional prosody processing in Autism Spectrum Disorder}}. {Soc Cogn Affect Neurosci}. 2016.
Individuals with Autism Spectrum Disorder (ASD) are characterized by severe deficits in social communication, whereby the nature of their impairments in emotional prosody processing have yet to be specified. Here, we investigated emotional prosody processing in individuals with ASD and controls with novel, lifelike behavioral and neuroimaging paradigms. Compared to controls, individuals with ASD showed reduced emotional prosody recognition accuracy on a behavioral task. On the neural level, individuals with ASD displayed reduced activity of the STS, insula and amygdala for complex vs. basic emotions compared to controls. Moreover, the coupling between the STS and amygdala for complex vs. basic emotions was reduced in the ASD group. Finally, groups differed with respect to the relationship between brain activity and behavioral performance. Brain activity during emotional prosody processing was more strongly related to prosody recognition accuracy in ASD participants. In contrast, the coupling between STS and anterior cingulate cortex (ACC) activity predicted behavioral task performance more strongly in the control group. These results provide evidence for aberrant emotional prosody processing of individuals with ASD. They suggest that the differences in the relationship between the neural and behavioral level of individuals with ASD may account for their observed deficits in social communication.
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25. Somekh J, Peleg M, Eran A, Koren I, Feiglin A, Demishtein A, Shiloh R, Heiner M, Kong SW, Elazar Z, Kohane I. {{A Model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease}}. {J Biomed Inform}. 2016.
We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model’s self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions.
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26. Tsur E, Friger M, Menashe I. {{The Unique Evolutionary Signature of Genes Associated with Autism Spectrum Disorder}}. {Behav Genet}. 2016.
Autism spectrum disorder (ASD) is a common heritable neurodevelopmental disorder, which is characterized by communication and social deficits that reduce the reproductive fitness of individuals with the disorder. Here, we studied the genomic characteristics of 651 ASD genes in a whole-exome sequencing dataset, to search for traces of the evolutionary forces that helped maintain ASD in the human population. We show that ASD genes are ~65 longer and ~20 % less variable than non-ASD genes. The mutational shortage in ASD genes was particularly eminent when considering only deleterious genetic variations, which is a hallmark of negative selection. We further show that these genomic characteristics are unique to ASD genes, as compared with brain-specific genes or with genes of other diseases. Our findings suggest that ASD genes have evolved under complex evolutionary forces, which have left a unique signature that can be used to identify new candidate ASD genes.
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27. Tylee DS, Espinoza AJ, Hess JL, Tahir MA, McCoy SY, Rim JK, Dhimal T, Cohen OS, Glatt SJ. {{RNA sequencing of transformed lymphoblastoid cells from siblings discordant for autism spectrum disorders reveals transcriptomic and functional alterations: Evidence for sex-specific effects}}. {Autism Res}. 2016.
Genome-wide expression studies of samples derived from individuals with autism spectrum disorder (ASD) and their unaffected siblings have been widely used to shed light on transcriptomic differences associated with this condition. Females have historically been under-represented in ASD genomic studies. Emerging evidence from studies of structural genetic variants and peripheral biomarkers suggest that sex-differences may exist in the biological correlates of ASD. Relatively few studies have explicitly examined whether sex-differences exist in the transcriptomic signature of ASD. The present study quantified genome-wide expression values by performing RNA sequencing on transformed lymphoblastoid cell lines and identified transcripts differentially expressed between same-sex, proximal-aged sibling pairs. We found that performing separate analyses for each sex improved our ability to detect ASD-related transcriptomic differences; we observed a larger number of dysregulated genes within our smaller set of female samples (n = 12 sibling pairs), as compared with the set of male samples (n = 24 sibling pairs), with small, but statistically significant overlap between the sexes. Permutation-based gene-set analyses and weighted gene co-expression network analyses also supported the idea that the transcriptomic signature of ASD may differ between males and females. We discuss our findings in the context of the relevant literature, underscoring the need for future ASD studies to explicitly account for differences between the sexes. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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28. Yuen RK, Merico D, Cao H, Pellecchia G, Alipanahi B, Thiruvahindrapuram B, Tong X, Sun Y, Cao D, Zhang T, Wu X, Jin X, Zhou Z, Liu X, Nalpathamkalam T, Walker S, Howe JL, Wang Z, MacDonald JR, Chan A, D’Abate L, Deneault E, Siu MT, Tammimies K, Uddin M, Zarrei M, Wang M, Li Y, Wang J, Yang H, Bookman M, Bingham J, Gross SS, Loy D, Pletcher M, Marshall CR, Anagnostou E, Zwaigenbaum L, Weksberg R, Fernandez BA, Roberts W, Szatmari P, Glazer D, Frey BJ, Ring RH, Xu X, Scherer SW. {{Genome-wide characteristics of de novo mutations in autism}}. {NPJ Genom Med}. 2016; 1: 160271-1602710.
De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10-10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10-13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10-24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10-9; OR=1.84), of which 15.6% (p=4.3×10-3) and 22.5% (p=7.0×10-5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
