1. Ackerman S, Schoenrbun S, Hudac C, Bernier R. {{Interactive Effects of Prenatal Antidepressant Exposure and Likely Gene Disrupting Mutations on the Severity of Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Aug 02)
To examine the interactive effects of two proposed risk factors which may contribute to symptom severity of Autism Spectrum Disorder (ASD): prenatal antidepressant exposure and likely gene-disrupting (LGD) mutations. Participants included 2748 individuals with ASD from the Simons Simplex Collection. We examined the effects of prenatal antidepressant exposure, maternal depression, presence of an LGD mutation and their interaction on ASD severity. We found a significant interactive effect between antidepressant exposure and the presence of an LGD mutation on ASD severity in the ADOS and ADI-R verbal communication domains. We consider a « two-hit » model in which one variable lays the foundation for an initial risk which is compounded by a second variable.
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2. Amaral CP, Simoes MA, Mouga S, Andrade J, Castelo-Branco M. {{A novel Brain Computer Interface for classification of social joint attention in autism and comparison of 3 experimental setups: A feasibility study}}. {J Neurosci Methods};2017 (Jul 29);290:105-115.
BACKGROUND: We present a novel virtual-reality P300-based Brain Computer Interface (BCI) paradigm using social cues to direct the focus of attention. We combined interactive immersive virtual-reality (VR) technology with the properties of P300 signals in a training tool which can be used in social attention disorders such as autism spectrum disorder (ASD). NEW METHOD: We tested the novel social attention training paradigm (P300-based BCI paradigm for rehabilitation of joint-attention skills) in 13 healthy participants, in 3 EEG systems. The more suitable setup was tested online with 4 ASD subjects. Statistical accuracy was assessed based on the detection of P300, using spatial filtering and a Naive-Bayes classifier. RESULTS: We compared: 1 – g.Mobilab+ (active dry-electrodes, wireless transmission); 2 – g.Nautilus (active electrodes, wireless transmission); 3 – V-Amp with actiCAP Xpress dry-electrodes. Significant statistical classification was achieved in all systems. g.Nautilus proved to be the best performing system in terms of accuracy in the detection of P300, preparation time, speed and reported comfort. Proof of concept tests in ASD participants proved that this setup is feasible for training joint attention skills in ASD. COMPARISON WITH EXISTING METHODS: This work provides a unique combination of ‘easy-to-use’ BCI systems with new technologies such as VR to train joint-attention skills in autism. CONCLUSIONS: Our P300 BCI paradigm is feasible for future Phase I/II clinical trials to train joint-attention skills, with successful classification within few trials, online in ASD participants. The g.Nautilus system is the best performing one to use with the developed BCI setup.
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3. Anderson AH, Carter M, Stephenson J. {{Perspectives of University Students with Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Jul 29)
Students with autism spectrum disorder (ASD) are at heightened risk of post-secondary educational failure and account for approximately 1% of students in post-secondary education. Findings from an on-line survey of students with ASD attending university in Australian are reported in this study. Respondents indicated high rates of academic and non-academic difficulties but low usage of supports. Ratings for supports were idiosyncratic, and some students indicated discomfort from using supports or disclosing their disability. Those students who delayed their disclosure accessed fewer supports and reported a poorer overall university experience. Recommendations were made including the need for better transition support and alternative strengths based approaches that use more flexible and individualised curriculum designs.
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4. Axmon A, Hoglund P, Ahlstrom G. {{Chronic Respiratory Disorders and Their Treatment among Older People with Intellectual Disability and/or Autism Spectrum Disorder in Comparison with the General Population}}. {Healthcare (Basel)};2017 (Aug 01);5(3)
Respiratory disorders are common among people with intellectual disabilities (ID). However, few studies have investigated these disorders among older people with ID. We identified 7936 people, aged 55+ years, with ID and a reference cohort from the general population. Data on diagnoses of chronic respiratory disorders, with a focus on asthma and chronic obstructive pulmonary disease (COPD), were collected, as was information on health care visits due to such disorders. We also added data on the prescription of drugs for obstructive airway diseases. Whereas the risk of having at least one diagnosis of asthma during the study period was similar in the two cohorts, people with ID were less likely than the general population to have been diagnosed with COPD. The same was found for health care visits due to asthma and COPD, respectively. The patterns of drug prescription were similar among people with ID and the general population, with the exception of adrenergics for systemic use, which were more commonly prescribed to people with ID. Thus, older people with ID do not seem to have an increased risk of asthma or COPD. Moreover, the indications are that when diagnosed with any of these disorders, they receive treatment adapted to their particular needs.
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5. Bathelt J, Dale N, de Haan M. {{Event-related potential response to auditory social stimuli, parent-reported social communicative deficits and autism risk in school-aged children with congenital visual impairment}}. {Dev Cogn Neurosci};2017 (Jul 19);27:10-18.
Communication with visual signals, like facial expression, is important in early social development, but the question if these signals are necessary for typical social development remains to be addressed. The potential impact on social development of being born with no or very low levels of vision is therefore of high theoretical and clinical interest. The current study investigated event-related potential responses to basic social stimuli in a rare group of school-aged children with congenital visual disorders of the anterior visual system (globe of the eye, retina, anterior optic nerve). Early-latency event-related potential responses showed no difference between the VI and control group, suggesting similar initial auditory processing. However, the mean amplitude over central and right frontal channels between 280 and 320ms was reduced in response to own-name stimuli, but not control stimuli, in children with VI suggesting differences in social processing. Children with VI also showed an increased rate of autistic-related behaviours, pragmatic language deficits, as well as peer relationship and emotional problems on standard parent questionnaires. These findings suggest that vision may be necessary for the typical development of social processing across modalities.
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6. Bhattacherjee A, Mu Y, Winter MK, Knapp JR, Eggimann LS, Gunewardena SS, Kobayashi K, Kato S, Krizsan-Agbas D, Smith PG. {{Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome}}. {Proc Natl Acad Sci U S A};2017 (Jul 31)
Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
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7. Bishop-Fitzpatrick L, Kind AJH. {{A Scoping Review of Health Disparities in Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Jul 29)
Individuals with autism spectrum disorder (ASD) experience increased morbidity and decreased life expectancy compared to the general population, and these disparities are likely exacerbated for those individuals who are otherwise disadvantaged. We conducted a review to ascertain what is known about health and health system quality (e.g., high quality care delivery, adequate care access) disparities in ASD. Nine studies met final inclusion criteria. Seven studies identified racial disparities in access to general medical services for children with ASD. No studies examined disparities in health outcomes or included older adults. We present a model of health disparities (Fundamental Causes Model) that guides future research. Additional work should examine health disparities, and their causal pathways, in ASD, particularly for older adults.
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8. Burnside K, Wright K, Poulin-Dubois D. {{Social motivation and implicit theory of mind in children with autism spectrum disorder}}. {Autism Res};2017 (Aug 01)
According to the social motivation theory of autism, children who develop Autism Spectrum Disorder (ASD) have early deficits in social motivation, which is expressed by decreased attention to social information. These deficits are said to lead to impaired socio-cognitive development, such as theory of mind (ToM). There is little research focused on the relation between social motivation and ToM in this population. The goal of the present study was to investigate the link between one aspect of social motivation, social orienting, and ToM in preschoolers with ASD. It was expected that, in contrast to typically developing (TD) children, children with ASD would show impaired performance on tasks measuring social orienting and ToM. It was also expected that children’s performance on the social orienting tasks would be correlated with their performance on the ToM task. A total of 17 children with ASD and 16 TD children participated in this study. Participants completed two social orienting tasks, a face preference task and a biological motion preference task, as well an implicit false belief task. Results reveal that TD children, but not children with ASD, exhibited social preference as measured by a preference for faces and biological motion. Furthermore, children with ASD tended to perform worse on the ToM task compared to their TD counterparts. Performance on the social motivation tasks and the ToM task tended to be related but only for the TD children. These findings suggest that ToM is multifaceted and that motivational deficits might have downstream effects even on implicit ToM. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Cameron JM, Levandovskiy V, Roberts W, Anagnostou E, Scherer S, Loh A, Schulze A. {{Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder}}. {Int J Mol Sci};2017 (Jul 31);18(8)
Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher’s exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children.
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10. Cekici H, Sanlier N. {{Current nutritional approaches in managing autism spectrum disorder: A review}}. {Nutr Neurosci};2017 (Aug 01):1-11.
The link between nutrition and autism spectrum disorder (ASD), which is a complex developmental disorder manifesting itself in significant delays or deviation in interaction and communication, has provided a fresh point of view and signals that nutrition may have a role in the aetiology of ASD, as well as play an active role in treatment by alleviating symptoms. OBJECTIVE: In this review study aimed at evaluating, with scientific and concrete proof, the current medical nutrition implementations on ASD, existing medical nutrition therapies have been addressed and their effects on ASD symptoms have been discussed in light of current research. METHODS: We reviewed articles regarding the medical nutritional therapy of autism on current nutritional approaches selected from PubMed, Science Direct, EBSCO, and databases about autism and nutrition. RESULTS: The research put forward that in individuals with ASD, while gluten-free/casein-free and ketogenic diets, camel milk, curcumin, probiotics, and fermentable foods can play a role in alleviating ASD symptoms, consumption of sugar, additives, pesticides, genetically modified organisms, inorganic processed foods, and hard-to-digest starches may aggravate symptoms. DISCUSSION: Further prospective controlled trials with large sample sizes are needed before recommendations can be made regarding the ideal ASD diet. This review emphasizes the value of identifying current nutritional approaches specific to individuals with ASD and integrating their effects on symptoms to the conversation and presents suggestions for future research designed to identify medical nutrition therapies targeting this population to better understand the link between ASD and nutrition.
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11. Doll CA, Vita DJ, Broadie K. {{Fragile X Mental Retardation Protein Requirements in Activity-Dependent Critical Period Neural Circuit Refinement}}. {Curr Biol};2017 (Aug 07);27(15):2318-2330.e2313.
Activity-dependent synaptic remodeling occurs during early-use critical periods, when naive juveniles experience sensory input. Fragile X mental retardation protein (FMRP) sculpts synaptic refinement in an activity sensor mechanism based on sensory cues, with FMRP loss causing the most common heritable autism spectrum disorder (ASD), fragile X syndrome (FXS). In the well-mapped Drosophila olfactory circuitry, projection neurons (PNs) relay peripheral sensory information to the central brain mushroom body (MB) learning/memory center. FMRP-null PNs reduce synaptic branching and enlarge boutons, with ultrastructural and synaptic reconstitution MB connectivity defects. Critical period activity modulation via odorant stimuli, optogenetics, and transgenic tetanus toxin neurotransmission block show that elevated PN activity phenocopies FMRP-null defects, whereas PN silencing causes opposing changes. FMRP-null PNs lose activity-dependent synaptic modulation, with impairments restricted to the critical period. We conclude that FMRP is absolutely required for experience-dependent changes in synaptic connectivity during the developmental critical period of neural circuit optimization for sensory input.
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12. Duan X, Chen H, He C, Long Z, Guo X, Zhou Y, Uddin LQ, Chen H. {{Resting-state functional under-connectivity within and between large-scale cortical networks across three low-frequency bands in adolescents with autism}}. {Prog Neuropsychopharmacol Biol Psychiatry};2017 (Aug 02)
Although evidence is accumulating that autism spectrum disorder (ASD) is associated with disruption of functional connections between and within brain networks, it remains largely unknown whether these abnormalities are related to specific frequency bands. To address this question, network contingency analysis was performed on brain functional connectomes obtained from 213 adolescent participants across nine sites in the Autism Brain Imaging Data Exchange (ABIDE) multisite sample, to determine the disrupted connections between and within seven major cortical networks in adolescents with ASD at Slow-5, Slow-4 and Slow-3 frequency bands and further assess whether the aberrant intra- and inter-network connectivity varied as a function of ASD symptoms. Overall under-connectivity within and between large-scale intrinsic networks in ASD was revealed across the three frequency bands. Specifically, decreased connectivity strength within the default mode network (DMN), between DMN and visual network (VN), ventral attention network (VAN), and between dorsal attention network (DAN) and VAN was observed in the lower frequency band (slow-5, slow-4), while decreased connectivity between limbic network (LN) and frontal-parietal network (FPN) was observed in the higher frequency band (slow-3). Furthermore, weaker connectivity within and between specific networks correlated with poorer communication and social interaction skills in the slow-5 band, uniquely. These results demonstrate intrinsic under-connectivity within and between multiple brain networks within predefined frequency bands in ASD, suggesting that frequency-related properties underlie abnormal brain network organization in the disorder.
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13. Ford TC, Nibbs R, Crewther DP. {{Glutamate/GABA+ ratio is associated with the psychosocial domain of autistic and schizotypal traits}}. {PLoS One};2017;12(7):e0181961.
BACKGROUND: The autism and schizophrenia spectra overlap to a large degree in the social and interpersonal domains. Similarly, abnormal excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitter concentrations have been reported for both spectra, with the interplay of these neurotransmitters important for cortical excitation to inhibition regulation. This study investigates whether these neurotransmitter abnormalities are specific to the shared symptomatology, and whether the degree of abnormality increases with increasing symptom severity. Hence, the relationship between the glutamate/GABA ratio and autism and schizophrenia spectrum traits in an unmedicated, subclinical population was investigated. METHODS: A total of 37 adults (19 female, 18 male) aged 18-38 years completed the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ), and participated in the resting state proton magnetic resonance spectroscopy study in which sequences specific for quantification of glutamate and GABA+ concentration were applied to a right and left superior temporal voxel. RESULTS: There were significant, moderate, positive relationships between right superior temporal glutamate/GABA+ ratio and AQ, SPQ and AQ+SPQ total scores (p<0.05), SPQ subscales Social Anxiety, No Close Friend, Constricted Affect, Odd Behaviour, Odd Speech, Ideas of Reference and Suspiciousness, and AQ subscales Social Skills, Communication and Attention Switching (p<0.05); increased glutamate/GABA+ coinciding with higher scores on these subscales. Only the relationships between glutamate/GABA+ ratio and Social Anxiety, Constricted Affect, Social Skills and Communication survived multiple comparison correction (p< 0.004). Left superior temporal glutamate/GABA+ ratio reduced with increasing restricted imagination (p<0.05). CONCLUSION: These findings demonstrate evidence for an association between excitatory/inhibitory neurotransmitter concentrations and symptoms that are shared between the autism and schizophrenia spectra. Lien vers le texte intégral (Open Access ou abonnement)
14. Garcia-Pino E, Gessele N, Koch U. {{Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice}}. {J Neurosci};2017 (Aug 02);37(31):7403-7419.
Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (Fmr1 KO), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS.SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS.
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15. Ishizuka K, Fujita Y, Kawabata T, Kimura H, Iwayama Y, Inada T, Okahisa Y, Egawa J, Usami M, Kushima I, Uno Y, Okada T, Ikeda M, Aleksic B, Mori D, Someya T, Yoshikawa T, Iwata N, Nakamura H, Yamashita T, Ozaki N. {{Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders}}. {Transl Psychiatry};2017 (Aug 01);7(8):e1184.
CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
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16. Kamitakahara A, Wu HH, Levitt P. {{Distinct Projection Targets Define Subpopulations of Mouse Brainstem Vagal Neurons that Express the Autism-Associated MET Receptor Tyrosine Kinase}}. {J Comp Neurol};2017 (Jul 31)
Detailed anatomical tracing and mapping of the viscerotopic organization of the vagal motor nuclei has provided insight into autonomic function in health and disease. To further define specific cellular identities, we paired information based on visceral connectivity with a cell-type specific marker of a subpopulation of neurons in the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (nAmb) that express the autism-associated MET receptor tyrosine kinase. As gastrointestinal disturbances are common in children with autism spectrum disorder (ASD), we sought to define the relationship between MET-expressing (MET+) neurons in the DMV and nAmb, and the gastrointestinal tract. Using wholemount tissue staining and clearing, or retrograde tracing in a METEGFP transgenic mouse, we identify three novel subpopulations of EGFP+ vagal brainstem neurons: 1) EGFP+ neurons in the nAmb projecting to the esophagus or laryngeal muscles, 2) EGFP+ neurons in the medial DMV projecting to the stomach, and 3) EGFP+ neurons in the lateral DMV projecting to the cecum and/or proximal colon. Expression of the MET ligand, hepatocyte growth factor (HGF), by tissues innervated by vagal motor neurons during fetal development reveal potential sites of HGF-MET interaction. Furthermore, similar cellular expression patterns of MET in the brainstem of both the mouse and nonhuman primate suggest that MET expression at these sites is evolutionarily conserved. Together, the data suggest that MET+ neurons in the brainstem vagal motor nuclei are anatomically positioned to regulate distinct portions of the gastrointestinal tract, with implications for the pathophysiology of gastrointestinal comorbidities of ASD. This article is protected by copyright. All rights reserved.
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17. Kawada K, Mimori S. {{Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder}}. {Neurochem Res};2017 (Aug 02)
Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.
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18. Kazemi M, Fayyazi-Bordbar MR, Mahdavi-Shahri N. {{Comparative Dermatoglyphic Study between Autistic Patients and Normal People in Iran}}. {Iran J Med Sci};2017 (Jul);42(4):392-396.
Autism is a neurodevelopmental disorder originating from early childhood; nevertheless, its diagnosis is in older ages. In addition to heredity, environmental factors are also of great significance in the etiology of the disease. Dermatoglyphic patterns, albeit varied, remain stable for a lifetime and yield a large number of patterns upon examination. Studies have shown a significant association between dermatoglyphics and some diseases, especially genetic ones. We compared fingerprints between patients with autism and normal individuals in a Fars population living in Khorasan-Razavi Province, Iran, in 2015. The right and left hand fingerprints of 104 autistic individuals (case group; age range=5-15 y) were collected using a fingerprint scanner. The same process was performed for 102 healthy individuals, in the age range of 6 to 25 years. All dermatoglyphic patterns and ridge counts were determined. The data were analyzed using the Mann-Whitney nonparametric test and binomial distribution. There was a significant difference in the distribution of the dermatoglyphic patterns on the right and left thumbs and the index fingers between the case and control groups (P<0.05). The patients had a significantly higher count of loops on their right and left thumbs and their index fingers. A significant decrease in ridge counts for the right and left thumbs and the index fingers was observed in the patients compared to the controls. The results suggested that the patterns were associated with the risk of autism. The patterns may be drawn upon as biometric parameters in the screening of children with autism. Lien vers Pubmed
19. Lawson RP, Mathys C, Rees G. {{Adults with autism overestimate the volatility of the sensory environment}}. {Nat Neurosci};2017 (Jul 31)
Insistence on sameness and intolerance of change are among the diagnostic criteria for autism spectrum disorder (ASD), but little research has addressed how people with ASD represent and respond to environmental change. Here, behavioral and pupillometric measurements indicated that adults with ASD are less surprised than neurotypical adults when their expectations are violated, and decreased surprise is predictive of greater symptom severity. A hierarchical Bayesian model of learning suggested that in ASD, a tendency to overlearn about volatility in the face of environmental change drives a corresponding reduction in learning about probabilistically aberrant events, thus putatively rendering these events less surprising. Participant-specific modeled estimates of surprise about environmental conditions were linked to pupil size in the ASD group, thus suggesting heightened noradrenergic responsivity in line with compromised neural gain. This study offers insights into the behavioral, algorithmic and physiological mechanisms underlying responses to environmental volatility in ASD.
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20. Ligsay A, Van Dijck A, Nguyen DV, Lozano R, Chen Y, Bickel ES, Hessl D, Schneider A, Angkustsiri K, Tassone F, Ceulemans B, Kooy RF, Hagerman RJ. {{A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome}}. {J Neurodev Disord};2017 (Aug 02);9(1):26.
BACKGROUND: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. METHODS: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. RESULTS: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. CONCLUSIONS: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01725152.
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21. Mackay BA, Shochet IM, Orr JA. {{A Pilot Randomised Controlled Trial of a School-Based Resilience Intervention to Prevent Depressive Symptoms for Young Adolescents with Autism Spectrum Disorder: A Mixed Methods Analysis}}. {J Autism Dev Disord};2017 (Aug 02)
Despite increased depression in adolescents with Autism Spectrum Disorder (ASD), effective prevention approaches for this population are limited. A mixed methods pilot randomised controlled trial (N = 29) of the evidence-based Resourceful Adolescent Program-Autism Spectrum Disorder (RAP-A-ASD) designed to prevent depression was conducted in schools with adolescents with ASD in years 6 and 7. Quantitative results showed significant intervention effects on parent reports of adolescent coping self-efficacy (maintained at 6 month follow-up) but no effect on depressive symptoms or mental health. Qualitative outcomes reflected perceived improvements from the intervention for adolescents’ coping self-efficacy, self-confidence, social skills, and affect regulation. Converging results remain encouraging given this population’s difficulties coping with adversity, managing emotions and interacting socially which strongly influence developmental outcomes.
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22. Mandak K, Light J. {{Family-centered Services for Children with ASD and Limited Speech: The Experiences of Parents and Speech-language Pathologists}}. {J Autism Dev Disord};2017 (Jul 29)
Although family-centered services have long been discussed as essential in providing successful services to families of children with autism spectrum disorder (ASD), ideal implementation is often lacking. This study aimed to increase understanding of how families with children with ASD and limited speech receive services from speech-language pathologists (SLPs). 99 parents of children with ASD and limited speech and 211 SLPs who served children with ASD and limited speech completed questionnaires measuring their experiences with the provision of family-centered services. Findings revealed that parents and SLPs differed in their views on the degree to which family-centered services were being implemented. Clinical implications and future research directions are discussed in order to promote continued growth in the acquisition of family-centered skills.
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23. Maughan AL, Weiss JA. {{Parental Outcomes Following Participation in Cognitive Behavior Therapy for Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Aug 01)
Children with autism spectrum disorder (ASD) benefit from parent involvement in their therapy, and there is evidence that this involvement may improve parent functioning as well. We examined changes in parent mental health, parenting, and expressed emotion, following participation in a randomized controlled trial of cognitive behavior therapy for 57 children with ASD. Post-intervention, improvements occurred in the treatment group in parent depression and emotion regulation, compared to waitlisted parents. Treatment effects also occurred across all parents in depression, emotion regulation, perceptions of their children and mindful parenting. Though preliminary, these results have implications for intervention development and evaluation by focusing on parent outcomes in child treatment.
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24. Murphy SM, Chowdhury U, White SW, Reynolds L, Donald L, Gahan H, Iqbal Z, Kulkarni M, Scrivener L, Shaker-Naeeni H, Press DA. {{Cognitive Behaviour Therapy Versus a Counselling Intervention for Anxiety in Young People with High-Functioning Autism Spectrum Disorders: A Pilot Randomised Controlled Trial}}. {J Autism Dev Disord};2017 (Aug 02)
The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12-18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements in participants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults.
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25. Neufeld J, Kuja-Halkola R, Mevel K, Cauvet E, Fransson P, Bolte S. {{Alterations in resting state connectivity along the autism trait continuum: a twin study}}. {Mol Psychiatry};2017 (Aug 01)
Autism spectrum disorder (ASD) has been found to be associated with alterations in resting state (RS) functional connectivity, including areas forming the default mode network (DMN) and salience network (SN). However, insufficient control for confounding genetic and environmental influences and other methodological issues limit the generalizability of previous findings. Moreover, it has been hypothesized that ASD might be marked by early hyper-connectivity followed by later hypo-connectivity. To date, only a few studies have explicitly tested age-related influences on RS connectivity alterations in ASD. Using a within-twin pair design (N=150 twins; 8-23 years), we examined altered RS connectivity between core regions of the DMN and SN in relation to autistic trait severity and age in a sample of monozygotic (MZ) and dizygotic (DZ) twins showing typical development, ASD or other neurodevelopmental conditions. Connectivity between core regions of the SN was stronger in twins with higher autistic traits compared to their co-twins. This effect was significant both in the total sample and in MZ twins alone, highlighting the effect of non-shared environmental factors on the link between SN-connectivity and autistic traits. While this link was strongest in children, we did not identify differences between age groups for the SN. In contrast, connectivity between core hubs of the DMN was negatively correlated with autistic traits in adolescents and showed a similar trend in adults but not in children. The results support hypotheses of age-dependent altered RS connectivity in ASD, making altered SN and DMN connectivity promising candidate biomarkers for ASD.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.160.
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26. Ruparelia K, Manji K, Abubakar A, Newton CR. {{Investigating the Evidence of Behavioral, Cognitive, and Psychiatric Endophenotypes in Autism: A Systematic Review}}. {Autism Res Treat};2017;2017:6346912.
Substantial evidence indicates that parents of autistic individuals often display milder forms of autistic traits referred to as the broader autism phenotype (BAP). To determine if discrete endophenotypes of autism can be identified, we reviewed the literature to assess the evidence of behavioral, cognitive, and psychiatric profiles of the BAP. A systematic review was conducted using EMBASE, MEDLINE, PsycINFO, PsycEXTRA, and Global Health. Sixty papers met our inclusion criteria and results are discussed according to the proportion of studies that yield significant deficits per domain. The behavioral, cognitive, and psychiatric endophenotypes in parents of autistic probands are still not clarified; however, evidence suggests mild social/communication deficits, rigid/aloof personality traits, and pragmatic language difficulties as the most useful sociobehavioral candidate endophenotype traits. The existence of deficits in the cognitive domain does suggest familial vulnerability for autism. Furthermore, increased depressed mood and anxiety can also be useful markers; however, findings should be interpreted with caution because of the small number of studies in such heterogeneously broad domains and several methodological limitations.
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27. Shpigler HY, Saul MC, Corona F, Block L, Cash Ahmed A, Zhao SD, Robinson GE. {{Deep evolutionary conservation of autism-related genes}}. {Proc Natl Acad Sci U S A};2017 (Jul 31)
E. O. Wilson proposed in Sociobiology that similarities between human and animal societies reflect common mechanistic and evolutionary roots. When introduced in 1975, this controversial hypothesis was beyond science’s ability to test. We used genomic analyses to determine whether superficial behavioral similarities in humans and the highly social honey bee reflect common molecular mechanisms. Here, we report that gene expression signatures for individual bees unresponsive to various salient social stimuli are significantly enriched for autism spectrum disorder-related genes. These signatures occur in the mushroom bodies, a high-level integration center of the insect brain. Furthermore, our finding of enrichment was unique to autism spectrum disorders; brain gene expression signatures from other honey bee behaviors do not show this enrichment, nor do datasets from other human behavioral and health conditions. These results demonstrate deep conservation for genes associated with a human social pathology and individual differences in insect social behavior, thus providing an example of how comparative genomics can be used to test sociobiological theory.
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28. Siegel JJ, Chitwood RA, Ding JM, Payne C, Taylor W, Gray R, Zemelman BV, Johnston D. {{Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain}}. {J Neurosci};2017 (Aug 02);37(31):7305-7317.
Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain.SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC function. The results suggest that at least some FX-specific neurological defects can be rescued in the adult FX brain after development.
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29. Sturner R, Howard B, Bergmann P, Morrel T, Landa R, Walton K, Marks D. {{Accurate Autism Screening at the 18-Month Well-Child Visit Requires Different Strategies than at 24 Months}}. {J Autism Dev Disord};2017 (Jul 31)
Accuracy of autism screening using M-CHAT plus the follow-up interview (M-CHAT/F) for children screened positive at 18-months was compared to screening at 24-months. Formal ASD testing was criterion for a community sample of M-CHAT positive children (n = 98), positive predictive value (PPV) was 0.40 for the M-CHAT and 0.58 for the M-CHAT/F. MCHAT/F PPV was 0.69 among children 20+ months compared to 0.36 for <20 months. Multivariate analyses incorporating data from the Ages and Stages Questionnaire, MacArthur-Bates Communicative Development Inventory, M-CHAT and M-CHAT/F results, and M-CHAT items suggest language variables carry greatest relative importance in contributing to an age-based algorithm with potential to improve PPV for toddlers <20 months to the same level as observed in older toddlers. Lien vers le texte intégral (Open Access ou abonnement)
30. Thomson SR, Seo SS, Barnes SA, Louros SR, Muscas M, Dando O, Kirby C, Wyllie DJA, Hardingham GE, Kind PC, Osterweil EK. {{Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome}}. {Neuron};2017 (Aug 02);95(3):550-563.e555.
Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1-/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1-/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1-/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.
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31. Van Etten HM, Kaur M, Srinivasan SM, Cohen SJ, Bhat A, Dobkins KR. {{Increased Prevalence of Unusual Sensory Behaviors in Infants at Risk for, and Teens with, Autism Spectrum Disorder}}. {J Autism Dev Disord};2017 (Aug 02)
The current study investigated the prevalence and pattern of unusual sensory behaviors (USBs) in teens with Autism Spectrum Disorder (ASD) and infants (3-36 months) at risk for ASD. From two different sites (UCSD and UConn), caregivers of infants at high (n = 32) and low risk (n = 33) for ASD, and teenagers with (n = 12) and without ASD (n = 11), completed age-appropriate Sensory Profile questionnaires (Infant/Toddler Sensory Profile; Dunn 2002; Adolescent/Adult Sensory Profile; Brown and Dunn 2002). The results show that high-risk infants and teenagers with ASD exhibit higher-than-typical prevalence of USBs. Results of our distribution analyses investigating the direction of sensory atypicalities (greater-than-typical vs. less-than-typical) revealed a fair degree of consistency amongst teens, however, USB patterns were more varied in high-risk infants.
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32. Wade J, Weitlauf A, Broderick N, Swanson A, Zhang L, Bian D, Sarkar M, Warren Z, Sarkar N. {{A Pilot Study Assessing Performance and Visual Attention of Teenagers with ASD in a Novel Adaptive Driving Simulator}}. {J Autism Dev Disord};2017 (Jul 29)
Individuals with Autism Spectrum Disorder (ASD), compared to typically-developed peers, may demonstrate behaviors that are counter to safe driving. The current work examines the use of a novel simulator in two separate studies. Study 1 demonstrates statistically significant performance differences between individuals with (N = 7) and without ASD (N = 7) with regards to the number of turning-related driving errors (p < 0.01). Study 2 shows that both the performance-based feedback group (N = 9) and combined performance- and gaze-sensitive feedback group (N = 8) achieved statistically significant reductions in driving errors following training (p < 0.05). These studies are the first to present results of fine-grained measures of visual attention of drivers and an adaptive driving intervention for individuals with ASD. Lien vers le texte intégral (Open Access ou abonnement)
33. Yamasue H, Domes G. {{Oxytocin and Autism Spectrum Disorders}}. {Curr Top Behav Neurosci};2017 (Aug 02)
Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose core symptoms include deficits in social interaction and communication besides restricted and repetitive behaviors. Although ASD is highly prevalent, affecting 1/100 in the general population, no medication for the core symptoms has been established. Therefore, the disorder is considered a huge unmet medical need and a heavy burden on individuals with ASD, their families, and entire society. Oxytocin is expected to be a potential therapeutic resource for the social core symptoms of ASD, since this neuropeptide can modulate human social behavior and cognition. This review article provides an overview of both experimental and clinical studies on effects of oxytocin administration on behavior, neural underpinnings, and symptomatology of ASD. Although the number of studies is increasing, several issues remain for further development of clinical application of the neuropeptide. The issues include optimization of administration route, doses, treatment duration, interval of administrations, and timing of starting treatment. Additional issues involve investigating neurobiological mechanisms of treatment and developing a reliable tool to accurately and objectively assess longitudinal changes in the core symptoms of ASD. Some of these issues are discussed in this review.
