1. Arvidsson O, Gillberg C, Lichtenstein P, Lundstrom S. {{Secular changes in the symptom level of clinically diagnosed autism}}. {J Child Psychol Psychiatry}. 2018.
BACKGROUND: The prevalence of autism has been reported to have increased worldwide. A decrease over time in the number of autism symptoms required for a clinical autism diagnosis would partly help explain this increase. This study aimed to determine whether the symptom level of clinically diagnosed autism cases below age 13 had changed over time. METHODS: Parents of Swedish 9-year old twins (n = 28,118) participated in a telephone survey, in which symptoms and dysfunction/suffering related to neurodevelopmental disorders [including autism, but also attention-deficit/hyperactivity disorder (ADHD), Developmental Coordination Disorder (DCD), and Learning Disabilities (LD)] in their children were assessed over a 10-year period. Survey data was merged with the National Patient Register containing clinically registered autism diagnoses (n = 271). RESULTS: In individuals who had been clinically diagnosed with autism before the age of 13, the symptom score for autism decreased on average 30% over more than a decade in birth cohorts 1992-2002. There was an average decrease of 50% in the autism symptom score from 2004 to 2014 in individuals who were diagnosed with autism at ages 7-12, but there was no decrease in those diagnosed at ages 0-6. CONCLUSIONS: Over time, considerably fewer autism symptoms seemed to be required for a clinical diagnosis of autism, at least for those diagnosed after the preschool years. The findings add support for the notion that the observed increase in autism diagnoses is, at least partly, the by-product of changes in clinical practice, and flag up the need for working in agreement with best practice guidelines.
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2. Batista TH, Giusti-Paiva A, Vilela FC. {{Maternal protein malnutrition induces autism-like symptoms in rat offspring}}. {Nutr Neurosci}. 2018: 1-9.
OBJECTIVE: We tested the correlation between maternal protein malnutrition and autistic-like symptoms using behavioral tests in rodents that measure main behavioral characteristics observed in humans with autism spectrum disorder (ASD). METHODS: Pregnant female rats were fed a normal diet or a hypoproteic diet during gestation and lactation periods. The litters were weighed every 3 days during lactation, and the offspring were tested in behavioral tasks during infancy (postnatal day (PND) 5: quantification of ultrasonic vocalizations; PND 13: homing behavior test) and adolescence (PND 30-32: open field, hole-board, play social behavior, and object recognition tests) in order to capture the prevalence of some of the core and associated symptoms of ASD. RESULTS: Litters of the hypoproteic diet group had a lesser weight gain during lactation. In addition, pups of dams fed with a hypoproteic diet vocalized less compared to those fed with a normal diet, and they showed impaired social discrimination abilities in the homing behavior test. In adolescence, both male and female offspring of the hypoproteic diet group showed no impairment in locomotor activity; however, they exhibited stereotypic behavior in the hole-board test and a decrease in social play behaviors. Male offspring showed increased interest in exploring a familiar object rather than a novel object. CONCLUSION: Our results show that maternal protein malnutrition in rats causes offspring behaviors that resemble core and associated ASD symptoms.
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3. Berg EL, Copping NA, Rivera JK, Pride MC, Careaga M, Bauman MD, Berman RF, Lein PJ, Harony-Nicolas H, Buxbaum JD, Ellegood J, Lerch JP, Wohr M, Silverman JL. {{Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder}}. {Autism Res}. 2018.
Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication.
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4. Brandes-Aitken A, Anguera JA, Rolle CE, Desai SS, Demopoulos C, Skinner SN, Gazzaley A, Marco EJ. {{Characterizing cognitive and visuomotor control in children with sensory processing dysfunction and autism spectrum disorders}}. {Neuropsychology}. 2018; 32(2): 148-60.
OBJECTIVE: Children with autism spectrum disorders (ASD) and sensory processing dysfunction (SPD) are reported to show difficulties involving cognitive and visuomotor control. We sought to determine whether performance on computerized, behavioral measures of cognitive control aimed at assessing selective attention, as well as visuomotor abilities differentiated children with ASD (n = 14), SPD (n = 14) and typically developing controls (TDC; n = 28). METHOD: Cognitive control differences were measured by assessing selective attention-based abilities both with and without distracting stimuli, and visuomotor differences were measured by characterizing visuomotor tracking and tracing skills. Performance in cognitive control and visuomotor domains were investigated globally as composite scores, and specifically within each task. RESULTS: Our results indicated that though the ASD group showed the most impaired selective attention performance, the SPD group had intermediate abilities-performing above the ASD group but below the TDC group. Furthermore, both the SPD and ASD groups demonstrated equally impaired visuomotor abilities relative to the TDC group. A correlational analysis between cognitive and visuomotor control suggest a relationship between these overlapping control networks. CONCLUSIONS: This study supports the importance of direct, phenotypic characterizations of control-based abilities in children with ASD and SPD to personalize characterization and treatment interventions for at-risk children. (PsycINFO Database Record
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5. Cai Q, Feng L, Yap KZ. {{Systematic review and meta-analysis of reported adverse events of long-term intranasal oxytocin treatment for autism spectrum disorder}}. {Psychiatry and clinical neurosciences}. 2018; 72(3): 140-51.
Recent studies have suggested oxytocin as a possible drug to treat social deficits caused by autism spectrum disorder (ASD), but the safety of intranasal oxytocin in autistic patients has not been established. The aim of this review was to characterize the side-effect profile of long-term intranasal oxytocin in treatment of ASD compared to placebo. All randomized controlled trials of intranasal oxytocin in the treatment of ASD published before 1 January 2017 that reported safety data were identified from databases, including PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstract. Relevant data from the selected studies were then extracted for meta-analysis to estimate the pooled risk ratio for the most common adverse events. Descriptive analysis of severe adverse events was also conducted. Of the 223 participants in the five included studies, 123 were given oxytocin and 100 were given placebos. Nasal discomfort (14.3%), tiredness (7.2%), irritability (9.0%), diarrhea (4.5%), and skin irritation (4.5%) were the most common adverse events. None of these common adverse events was statistically associated with treatment allocation according to meta-analysis using pooled data (all P-values > 0.1). Five severe adverse events were reported, namely aggression (one in placebo, two in oxytocin) and seizures (one in placebo, one in oxytocin). Results from this systematic review support intranasal oxytocin as well tolerated and safe for use in the ASD population. Larger clinical trials should be conducted to establish the efficacy of intranasal oxytocin as a treatment of ASD.
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6. Danzer E, Hoffman C, D’Agostino JA, Miller JS, Waqar LN, Gerdes M, Bernbaum JC, Rosenthal H, Rintoul NE, Herkert LM, Peranteau WH, Flake AW, Adzick NS, Hedrick HL. {{Rate and Risk Factors Associated with Autism Spectrum Disorder in Congenital Diaphragmatic Hernia}}. {J Autism Dev Disord}. 2018.
To determine the rate and predictors of autism spectrum disorder (ASD) in congenital diaphragmatic hernia (CDH). Between 06/2004 and 09/2015 a total of 110 CDH survivors underwent neurodevelopmental (ND) testing and screening for ASD, followed by a full autism diagnostic evaluation if indicated at our institution. We found a 9 time higher rate of ASD in CDH children compared to the general population (P = 0.0002). Multiple patient-related and clinical variables risk factors of ASD were identified by univariate analysis. However, only short-term and long-term neurodevelopmental delays were strongly associated with ASD in CDH by multivariate comparisons. There is a striking prevalence of ASD in CDH survivors and our findings suggest that all CDH children should be regularly screened for ASD.
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7. Davis TN, Rispoli M. {{Introduction to the Special Issue: Interventions to Reduce Challenging Behavior Among Individuals With Autism Spectrum Disorder}}. {Behav Modif}. 2018: 145445518755349.
The prevalence of autism spectrum disorder (ASD) is on the rise. In addition to the social communication skill deficits and restrictive repetitive behaviors and interests, many individuals with ASD engage in challenging behavior. Challenging behavior is associated with a multitude of negative outcomes. Challenging behavior may cause harm to the individual with ASD as well as limit opportunities for educational, vocational, and social participation and development. In addition, caregivers experience high stress and low quality of mental health. As a result, challenging behavior warrants intervention that is specifically tailored to the unique characteristics of individuals with ASD. The purpose of this Special Issue is to showcase recent research in the treatment of challenging behavior for individuals with ASD. This two-part Special Issue contains 12 studies that range from systematic and quality reviews of the intervention literature, to innovative treatment approaches, to studies that develop and evaluate treatments for restrictive and repetitive behaviors and interests.
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8. Kohls G, Antezana L, Mosner MG, Schultz RT, Yerys BE. {{Altered reward system reactivity for personalized circumscribed interests in autism}}. {Mol Autism}. 2018; 9: 9.
Background: Neurobiological research in autism spectrum disorders (ASD) has paid little attention on brain mechanisms that cause and maintain restricted and repetitive behaviors and interests (RRBIs). Evidence indicates an imbalance in the brain’s reward system responsiveness to social and non-social stimuli may contribute to both social deficits and RRBIs. Thus, this study’s central aim was to compare brain responsiveness to individual RRBI (i.e., circumscribed interests), with social rewards (i.e., social approval), in youth with ASD relative to typically developing controls (TDCs). Methods: We conducted a 3T functional magnetic resonance imaging (fMRI) study to investigate the blood-oxygenation-level-dependent effect of personalized circumscribed interest rewards versus social rewards in 39 youth with ASD relative to 22 TDC. To probe the reward system, we employed short video clips as reinforcement in an instrumental incentive delay task. This optimization increased the task’s ecological validity compared to still pictures that are often used in this line of research. Results: Compared to TDCs, youth with ASD had stronger reward system responses for CIs mostly within the non-social realm (e.g., video games) than social rewards (e.g., approval). Additionally, this imbalance within the caudate nucleus’ responsiveness was related to greater social impairment. Conclusions: The current data support the idea of reward system dysfunction that may contribute to enhanced motivation for RRBIs in ASD, accompanied by diminished motivation for social engagement. If a dysregulated reward system indeed supports the emergence and maintenance of social and non-social symptoms of ASD, then strategically targeting the reward system in future treatment endeavors may allow for more efficacious treatment practices that help improve outcomes for individuals with ASD and their families.
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9. Loth E, Garrido L, Ahmad J, Watson E, Duff A, Duchaine B. {{Facial expression recognition as a candidate marker for autism spectrum disorder: how frequent and severe are deficits?}}. {Mol Autism}. 2018; 9: 7.
Background: Impairments in social communication are a core feature of Autism Spectrum Disorder (ASD). Because the ability to infer other people’s emotions from their facial expressions is critical for many aspects of social communication, deficits in expression recognition are a plausible candidate marker for ASD. However, previous studies on facial expression recognition produced mixed results, which may be due to differences in the sensitivity of the many tests used and/or the heterogeneity among individuals with ASD. To ascertain whether expression recognition may serve as a diagnostic marker (which distinguishes people with ASD from a comparison group) or a stratification marker (which helps to divide ASD into more homogeneous subgroups), a crucial first step is to move beyond identification of mean group differences and to better understand the frequency and severity of impairments. Methods: This study tested 46 individuals with ASD and 52 age- and IQ-matched typically developing (TD) participants on the Films Expression Task, which combines three key features of real-life expression recognition: naturalistic facial expressions, a broad range of simple and complex emotions, and short presentation time. Test-retest reliability was assessed in 28 individuals who did not participate in the main study and revealed acceptable reliability (ICC r = .74). Results: Case-control comparisons showed highly significant mean group differences for accuracy (p = 1.1 x 10(- 10)), with an effect size (Cohen’s d = 1.6), more than twice as large as the mean effect size reported in a previous meta-analysis (Uljarevic and Hamilton, 2012, J Autism Dev Disord). The ASD group also had significantly increased mean reaction times overall (p = .00015, d = .83) and on correct trials (p = .0002, d = .78). However, whereas 63% of people with ASD showed severe deficits (they performed below two standard deviations of the TD mean, a small subgroup (15.3%) performed normally (within one standard deviation of the mean). Conclusion: These findings indicate that the majority of people with ASD have severe expression recognition deficits and that the Films Expression Test is a sensitive task for biomarker research in ASD. Future work is needed to establish whether ASD subgroups with and without expression recognition deficits differ from one another in terms of their symptom profile or neurobiological underpinnings.
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10. Michaelsen-Preusse K, Feuge J, Korte M. {{Imbalance of synaptic actin dynamics as a key to fragile X syndrome?}}. {The Journal of physiology}. 2018.
Our experiences and memories define who we are, and evidence has accumulated that memory formation is dependent on functional and structural adaptations of synaptic structures in our brain. Especially dendritic spines, the postsynaptic compartments of synapses show a strong structure-to-function relationship and a high degree of structural plasticity. Although the molecular mechanisms are not completely understood, it is known that these modifications are highly dependent on the actin cytoskeleton, the major cytoskeletal component of the spine. Given the crucial involvement of actin in these mechanisms, dysregulations of spine actin dynamics (reflected by alterations in dendritic spine morphology) can be found in a variety of neurological disorders ranging from schizophrenia to several forms of autism spectrum disorders such as fragile X syndrome (FXS). FXS is caused by a single mutation leading to an inactivation of the X-linked fragile X mental retardation 1 gene and loss of its gene product, the RNA-binding protein fragile X mental retardation protein 1 (FMRP), which normally can be found both pre- and postsynaptically. FMRP is involved in mRNA transport as well as regulation of local translation at the synapse, and although hundreds of FMRP-target mRNAs could be identified only a very few interactions between FMRP and actin-regulating proteins have been reported and validated. In this review we give an overview of recent work by our lab and others providing evidence that dysregulated actin dynamics might indeed be at the very base of a deeper understanding of neurological disorders ranging from cognitive impairment to the autism spectrum.
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11. Montazeri F, de Bildt A, Dekker V, Anderson GM. {{Network Analysis of Anxiety in the Autism Realm}}. {J Autism Dev Disord}. 2018.
The anxiety and autism realms are each complicated and heterogeneous, and relationships between the two areas are especially complex. Network analysis offers a promising approach to the phenotypic complexities of typical and atypical human behavior. The Revised Children’s Anxiety and Depression Scale (RCADS) was used to assess anxiety in 126 high-functioning 9-13 year-olds with ASDs. Network graphs of Autism Diagnostic Observation Schedule items and RCADS anxiety total score, social, generalized, panic and separation anxiety subscores consistently found the anxiety node (score) to be highly peripheral. Also, the networks of RCADS anxiety items themselves were similar for the ASDs group and a general population comparison group (n = 2017). The results suggest anxiety is not a central part of autism and that anxiety is dynamically similar (aspects of anxiety relate to one another in a similar manner) in high-functioning autism and the general population.
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12. Oerlemans AM, Rommelse NNJ, Buitelaar JK, Hartman CA. {{Examining the intertwined development of prosocial skills and ASD symptoms in adolescence}}. {Eur Child Adolesc Psychiatry}. 2018.
Autism spectrum disorder (ASD) and reduced prosocial behaviour are strongly intertwined. However, social interactions with peers may be increasingly practiced over the course of development and may instigate a reduction in ASD symptoms and vice versa. We, therefore, sought to determine if, during adolescence, possible improvements in prosocial behaviours and ASD symptoms may benefit one another over time. Participants were 2773 adolescents from the Tracking Adolescents’ Individual Lives Survey (TRAILS) cohorts. Measurements took place over three waves (mean ages: 11.1, 13.4, and 16.2 years). Longitudinal associations between teacher-rated classroom prosocial skills and parent-rated ASD symptoms were examined using the random intercept cross-lagged panel model (RI-CLPM). In addition to estimating the stable, between-person associations, the dynamical effects between prosocial skills and ASD symptoms over time were estimated at the within-person level. At the between-person level, prosocial skills and ASD symptoms were substantially negatively correlated. At the within-person level, a small and unexpected positive cross-lagged effect from wave 1 ASD symptoms on wave 2 prosocial skills was observed. We added to the existing literature by showing that, in addition to replicating the already firmly established between-person association between low prosocial skills and ASD, within-person gains in prosocial skills do not lead to subsequent reduction of ASD symptoms, and reductions in ASD symptoms do not lead to subsequent enhancement of prosocial skills. We, therefore, conclude from our findings that the inverse association between autistic symptoms and prosocial skills in adolescence is highly stable.
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13. Rezaei M, Moradi A, Tehrani-Doost M, Hassanabadi H, Khosroabadi R. {{Effects of Combining Medication and Pivotal Response Treatment on Aberrant Behavior in Children with Autism Spectrum Disorder}}. {Children (Basel, Switzerland)}. 2018; 5(2).
Abstract: The purpose of this study was to investigate the effects of combined risperidone (RIS) and pivotal response treatment (PRT) on children with autism spectrum disorder (ASD). A total of 34 children diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) (mean age of 12.36 years) were randomly assigned to either of two groups; the first group (n = 17) received combined PRT-RIS while the second group (n = 17) received RIS only. Behavioral problems were evaluated with the Aberrant Behavior Checklist (ABC), whereas global improvement (GI) was measured with the Clinical Global Impressions (CGI). Assessment of ABC was performed before intervention, after intervention (12 weeks), and following 3 months of the intervention (follow-up). Total ABC scores were seen to decrease in both groups after 3 months, as compared with the scores prior to the interventions. Also, in both groups, mean scores of behavioral problems after the intervention were not significantly different from those prior to the intervention, in all subscales but the inappropriate speech (p < 0.001). However, both groups showed significant differences in mean scores of ABC subscales in both of the post-intervention evaluation stages. It was concluded that the combination of behavioral and drug interventions can further improve behavioral problems, ultimately improving patient's communication and social skills. Lien vers le texte intégral (Open Access ou abonnement)
14. Rochette AC, Soulieres I, Berthiaume C, Godbout R. {{NREM sleep EEG activity and procedural memory: A comparison between young neurotypical and autistic adults without sleep complaints}}. {Autism Res}. 2018.
Delta EEG activity (0.75-3.75 Hz) during non-Rapid eye movement (NREM) sleep reflects the thalamo-cortical system contribution to memory consolidation. The functional integrity of this system is thought to be compromised in the Autism spectrum disorder (ASD). This lead us to investigate the topography of NREM sleep Delta EEG activity in young adults with ASD and typically-developed individuals (TYP). The relationship between Delta EEG activity and sensory-motor procedural information was also examined using a rotary pursuit task. Two dependent variables were computed: a learning index (performance increase across trials) and a performance index (average performance for all trials). The ASD group showed less Delta EEG activity during NREM sleep over the parieto-occipital recording sites compared to the TYP group. Delta EEG activity dropped more abruptly from frontal to posterior regions in the ASD group. Both groups of participants learned the task at a similar rate but the ASD group performed less well in terms of contact time with the target. Delta EEG activity during NREM sleep, especially during stage 2, correlated positively with the learning index for electrodes located all over the cortex in the TYP group, but only in the frontal region in the ASD group. Delta EEG activity, especially during stage 2, correlated positively with the performance index, but in the ASD group only. These results reveal an atypical thalamo-cortical functioning over the parieto-occipital region in ASD. They also point toward an atypical relationship between the frontal area and the encoding of sensory-motor procedural memory in ASD. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Slow EEG waves recorded from the scalp during sleep are thought to facilitate learning and memory during daytime. We compared these EEG waves in young autistic adults to typically-developing young adults. We found less slow EEG waves in the ASD group and the pattern of relationship with memory differed between groups. This suggests atypicalities in the way sleep mechanisms are associated with learning and performance in a sensory-motor procedural memory task in ASD individuals.
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15. Ruan ZL, Liu L, Strodl E, Fan LJ, Yin XN, Wen GM, Sun DL, Xian DX, Jiang H, Jing J, Jin Y, Wu CA, Chen WQ. {{Antenatal Training with Music and Maternal Talk Concurrently May Reduce Autistic-Like Behaviors at around 3 Years of Age}}. {Frontiers in psychiatry}. 2017; 8: 305.
Antenatal training through music and maternal talk to the unborn fetus is a topic of general interest for parents-to-be in China, but we still lack a comprehensive assessment of their effects on the development of autistic-like behaviors during early childhood. During 2014-2016, 34,749 parents of children around the age of 3 years who were enrolled at kindergarten in the Longhua district of Shenzhen participated in this study. Self-administered questionnaires regarding demographics, antenatal music training, and maternal talk to the fetus during pregnancy were completed by the children’s primary caregivers. Autistic-like behaviors were assessed using the Autism Behavioral Checklist. Tobit regression analyses revealed that antenatal music training and maternal talk to the fetus was associated with a reduction in autistic-like behaviors in children, with a dose-dependent relationship. Furthermore, factorial analysis of covariance indicated a significant interaction effect between antenatal music training and maternal talk to the fetus on the autistic-like behaviors and found that children who often experienced antenatal music training and maternal talk concurrently had the lowest risk of autistic-like behaviors, while children who were never exposed to maternal talk and only sometimes experienced antenatal music training had the highest risk. Our results suggest that antenatal training through both music and maternal talk to the unborn fetus might reduce the risk of children’s autistic-like behaviors at around 3 years of age.
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16. Rubenstein E, Wiggins LD, Schieve LA, Bradley C, DiGuiseppi C, Moody E, Pandey J, Pretzel RE, Howard AG, Olshan AF, Pence BW, Daniels J. {{Associations between parental broader autism phenotype and child autism spectrum disorder phenotype in the Study to Explore Early Development}}. {Autism}. 2018: 1362361317753563.
The autism spectrum disorder phenotype varies by social and communication ability and co-occurring developmental, behavioral, and medical conditions. Etiology is also diverse, with myriad potential genetic origins and environmental risk factors. Examining the influence of parental broader autism phenotype-a set of sub-clinical characteristics of autism spectrum disorder-on child autism spectrum disorder phenotypes may help reduce heterogeneity in potential genetic predisposition for autism spectrum disorder. We assessed the associations between parental broader autism phenotype and child phenotype among children of age 30-68 months enrolled in the Study to Explore Early Development (N = 707). Child autism spectrum disorder phenotype was defined by a replication of latent classes derived from multiple developmental and behavioral measures: Mild Language Delay with Cognitive Rigidity, Mild Language and Motor Delay with Dysregulation (e.g. anxiety/depression), General Developmental Delay, and Significant Developmental Delay with Repetitive Motor Behaviors. Scores on the Social Responsiveness Scale-Adult measured parent broader autism phenotype. Broader autism phenotype in at least one parent was associated with a child having increased odds of being classified as mild language and motor delay with dysregulation compared to significant developmental delay with repetitive motor behaviors (odds ratio: 2.44; 95% confidence interval: 1.16, 5.09). Children of parents with broader autism phenotype were more likely to have a phenotype qualitatively similar to broader autism phenotype presentation; this may have implications for etiologic research.
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17. Sare RM, Song A, Loutaev I, Cook A, Maita I, Lemons A, Sheeler C, Smith CB. {{Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome}}. {Front Mol Neurosci}. 2017; 10: 452.
Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is also highly associated with autism spectrum disorders (ASD). It is caused by expansion of a CGG repeat sequence on the X chromosome resulting in silencing of the FMR1 gene. This is modeled in the mouse by deletion of Fmr1 (Fmr1 KO). Fmr1 KO mice recapitulate many of the behavioral features of the disorder including seizure susceptibility, hyperactivity, impaired social behavior, sleep problems, and learning and memory deficits. The mammalian target of rapamycin pathway (mTORC1) is upregulated in Fmr1 KO mice and is thought to be important for the pathogenesis of this disorder. We treated Fmr1 KO mice chronically with an mTORC1 inhibitor, rapamycin, to determine if rapamycin treatment could reverse behavioral phenotypes. We performed open field, zero maze, social behavior, sleep, passive avoidance, and audiogenic seizure testing. We found that pS6 was upregulated in Fmr1 KO mice and normalized by rapamycin treatment, but, except for an anxiogenic effect, it did not reverse any of the behavioral phenotypes examined. In fact, rapamycin treatment had an adverse effect on sleep and social behavior in both control and Fmr1 KO mice. These results suggest that targeting the mTOR pathway in FXS is not a good treatment strategy and that other pathways should be considered.
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18. Sears JC, Broadie K. {{Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling}}. {Front Mol Neurosci}. 2017; 10: 440.
Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans-synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the activity-dependent repression of translation. In the well-characterized Drosophila neuromuscular junction (NMJ) model, developmental synaptogenesis and activity-dependent synaptic remodeling both require extracellular matrix metalloproteinase (MMP) enzymes interacting with the heparan sulfate proteoglycan (HSPG) glypican dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, with FXS synaptogenic defects alleviated by both MMP and HSPG reduction. This new mechanistic axis spanning from activity to FMRP to HSPG-dependent MMP regulation modulates activity-dependent synaptogenesis. We discuss future directions for these mechanisms, and intersecting research priorities for FMRP in glial and signaling interactions.
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19. Stavropoulos KK, Carver LJ. {{Oscillatory rhythm of reward: anticipation and processing of rewards in children with and without autism}}. {Mol Autism}. 2018; 9: 4.
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, and multiple theories have emerged concerning core social deficits. While the social motivation hypothesis proposes that deficits in the social reward system cause individuals with ASD to engage less in social interaction, the overly intense world hypothesis (sensory over-responsivity) proposes that individuals with ASD find stimuli to be too intense and may have hypersensitivity to social interaction, leading them to avoid these interactions. Methods: EEG was recorded during reward anticipation and reward processing. Reward anticipation was measured using alpha asymmetry, and post-feedback theta was utilized to measure reward processing. Additionally, we calculated post-feedback alpha suppression to measure attention and salience. Participants were 6- to 8-year-olds with (N = 20) and without (N = 23) ASD. Results: Children with ASD showed more left-dominant alpha suppression when anticipating rewards accompanied by nonsocial stimuli compared to social stimuli. During reward processing, children with ASD had less theta activity than typically developing (TD) children. Alpha activity after feedback showed the opposite pattern: children with ASD had greater alpha suppression than TD children. Significant correlations were observed between behavioral measures of autism severity and EEG activity in both the reward anticipation and reward processing time periods. Conclusions: The findings provide evidence that children with ASD have greater approach motivation prior to nonsocial (compared to social) stimuli. Results after feedback suggest that children with ASD evidence less robust activity thought to reflect evaluation and processing of rewards (e.g., theta) compared to TD children. However, children with ASD evidence greater alpha suppression after feedback compared to TD children. We hypothesize that post-feedback alpha suppression reflects general cognitive engagement-which suggests that children with ASD may experience feedback as overly intense. Taken together, these results suggest that aspects of both the social motivation hypothesis and the overly intense world hypothesis may be occurring simultaneously.
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20. Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A, Kusamori K, Katsumi H, Yutani R, Sakane T, Yamamoto A. {{Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application}}. {Molecular pharmaceutics}. 2018; 15(3): 1105-11.
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.
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21. Torske T, Naerland T, Oie MG, Stenberg N, Andreassen OA. {{Metacognitive Aspects of Executive Function Are Highly Associated with Social Functioning on Parent-Rated Measures in Children with Autism Spectrum Disorder}}. {Frontiers in behavioral neuroscience}. 2017; 11: 258.
Autism Spectrum Disorder (ASD) is characterized by social dysfunction. Even though executive dysfunction has been recognized as important in understanding ASD, the findings are inconsistent. This might be due to different definitions of executive function (EF), which part of EF that has been studied, structured vs. unstructured tasks, inclusion of different moderators (age, IQ, sex) and different diagnostic categories within the spectrum. The main finding is that people with ASD have more EF difficulties than normal controls and more difficulties on open-end tasks than on structured cognitive tasks. Since some EF difficulties may not be observable in a laboratory setting, informant measures might have higher ecological validity than neuropsychological tests. Evidence suggests that executive dysfunctions are associated with social impairments, but few studies have investigated the details of this relationship, and it remains unclear what types of EF deficits are relevant for the social problems of individuals with ASD. Here we investigated which EF domains were associated with various domains of social function on parent-rated measures. A total of 86 children and adolescents with a diagnosis of ASD were included and tested for general cognitive abilities. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Social Responsiveness Scale (SRS). Multiple regression analysis revealed significant associations between SRS scores and age, sex, total IQ and the BRIEF indexes. The Metacognition Index from the BRIEF added significantly to the prediction of the SRS total score and the subscales Social Communication, Social Motivation and Autistic Mannerisms. The findings suggest that metacognitive aspects of EF are of particular importance for social abilities in children and adolescents with ASD. Earlier research has shown that typically developing (TD) children have a different relationship between EF and social function than children with ASD. They found that in TD children the EF domain related to behavioral regulation was most important to social function. The results from the current study may have implications for understanding the cognitive components of the social problems that define ASD, and may be relevant in developing more targeted clinical EF interventions related to core ASD dysfunctions.
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22. Ummer-Christian R, Iacono T, Grills N, Pradhan A, Hughes N, Gussy M. {{Access to dental services for children with intellectual and developmental disabilities – A scoping review}}. {Res Dev Disabil}. 2018; 74: 1-13.
BACKGROUND: Children with Intellectual and Developmental Disabilities (IDD) face considerable challenges in participating in dental services. These challenges include resource constraints and inadequate skills of health service providers to work with this population. AIM: The aim was to scope published studies that addressed access to dental services for children with IDD in order to determine the extent to which various barriers have been researched, using an access framework derived from the literature. Access was defined to include the six dimensions of accessibility, availability, affordability, accommodation, acceptability, and appropriateness. METHOD: Arksey and O’Malley’s scoping review framework was used. Relevant databases (e.g., Medline) were searched for all empirical studies conducted from January 2000 to February 2017 that met inclusion criteria. Data were extracted along the six dimensions of the access framework. RESULTS: Sixteen international studies were identified which indicated common key barriers to dental service use: the difficulties of physical inaccessibility, lack of access to information among carers, lack of knowledge of disability issues, and low experience and skills in caring for children with IDD among dental practitioners. CONCLUSIONS: Key recommendations made were exploring dental practitioners’ understanding of disability legislation and developing training for practitioners to expand on issues specific to IDD.
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23. Verhoeff ME, Blanken LME, Kocevska D, Mileva-Seitz VR, Jaddoe VWV, White T, Verhulst F, Luijk M, Tiemeier H. {{The bidirectional association between sleep problems and autism spectrum disorder: a population-based cohort study}}. {Mol Autism}. 2018; 9: 8.
Background: Sleep difficulties are prevalent in children with autism spectrum disorder (ASD). The temporal nature of the association between sleep problems and ASD is unclear because longitudinal studies are lacking. Our aim is to clarify whether sleep problems precede and worsen autistic traits and ASD or occur as a consequence of the disorder. Methods: Repeated sleep measures were available at 1.5, 3, 6, and 9 years of age in 5151 children participating in the Generation R Study, a large prospective birth cohort in the Netherlands. Autistic traits were determined with the Pervasive Developmental Problems score (PDP) of the Child Behavior Checklist (CBCL) at 1.5 and 3 years and the Social Responsiveness Scale (SRS) at 6 years. This cohort included 81 children diagnosed with ASD. Results: Sleep problems in early childhood were prospectively associated with a higher SRS score, but not when correcting for baseline PDP score. By contrast, a higher SRS score and an ASD diagnosis were associated with more sleep problems at later ages, even when adjusting for baseline sleep problems. Likewise, a trajectory of increasing sleep problems was associated with ASD. Conclusions: Sleep problems and ASD are not bidirectionally associated. Sleep problems do not precede and worsen autistic behavior but rather co-occur with autistic traits in early childhood. Over time, children with ASD have an increase in sleep problems, whereas typically developing children have a decrease in sleep problems. Our findings suggest that sleep problems are part of the construct ASD.
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24. Yoo Y, Cho J, Choi M. {{Reply to « a novel mutation in the transmembrane 6 domain of GABBR2 leads to a rett-like phenotype »}}. {Annals of neurology}. 2018; 83(2): 439.
