1. Ballantyne CJ, Nunez M, Manoussaki K. {{Visuo-spatial construction trajectories in Fragile X Syndrome (FXS) and Autism Spectrum Disorders (ASD): Evidence of cognitive heterogeneity within neurodevelopmental conditions}}. {Res Dev Disabil}. 2017; 70: 113-25.
BACKGROUND/AIMS: There have been discrepancies reported in visuo-spatial construction ability in children with Autism Spectrum Disorders (ASD), fragile X Syndrome (FXS) and those with a comorbid diagnosis of FXS and ASD (AFXS). This study aimed to provide a better understanding of the visuo-spatial processing styles in these heterogeneous neurodevelopmental disorders. METHODS AND PROCEDURE: Navon-type tasks were used to assess visuo-spatial construction ability across 5 groups of children: typically developing, FXS, AFXS, ASD children who scored low-moderate (HFA) and ASD children that scored severe (LFA) on the Childhood Autism Rating Scale (CARS). Analyses of their developmental trajectories compared the performance of these groups. OUTCOMES AND RESULTS: Each group produced their own distinct trajectory. HFA achieved higher scores from an earlier age than the TD group, while the LFA group’s performance was driven by a bias in local processing. The FXS performance was normalised by using mental age as a predictor while neither mental nor chronological age predicted the AFXS group performance. CONCLUSIONS AND IMPLICATIONS: The study showed unique processing styles. These findings highlight the importance of taking comorbidity and the severity of symptoms within each condition into account in order to understand cognitive abilities and cognitive profiles.
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2. Boone KM, Gracious B, Klebanoff MA, Rogers LK, Rausch J, Coury DL, Keim SA. {{Omega-3 and -6 fatty acid supplementation and sensory processing in toddlers with ASD symptomology born preterm: A randomized controlled trial}}. {Early Hum Dev}. 2017; 115: 64-70.
BACKGROUND: Despite advances in the health and long-term survival of infants born preterm, they continue to face developmental challenges including higher risk for autism spectrum disorder (ASD) and atypical sensory processing patterns. AIMS: This secondary analysis aimed to describe sensory profiles and explore effects of combined dietary docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and gamma-linolenic acid (GLA) supplementation on parent-reported sensory processing in toddlers born preterm who were exhibiting ASD symptoms. STUDY DESIGN: 90-day randomized, double blinded, placebo-controlled trial. SUBJECTS: 31 children aged 18-38months who were born at Lien vers le texte intégral (Open Access ou abonnement)
3. Bruno JL, Romano D, Mazaika P, Lightbody AA, Hazlett HC, Piven J, Reiss AL. {{Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome}}. {Proc Natl Acad Sci U S A}. 2017.
Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences (P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders. Lien vers le texte intégral (Open Access ou abonnement)
4. Bush RA, Connelly CD, Perez A, Barlow H, Chiang GJ. {{Extracting autism spectrum disorder data from the electronic health record}}. {Appl Clin Inform}. 2017; 8(3): 731-41.
BACKGROUND: Little is known about the health care utilization patterns of individuals with pediatric autism spectrum disorder (ASD). OBJECTIVES: Electronic health record (EHR) data provide an opportunity to study medical utilization and track outcomes among children with ASD. Methods: Using a pediatric, tertiary, academic hospital’s Epic EHR, search queries were built to identify individuals aged 2-18 with International Classification of Diseases, Ninth Revision (ICD-9) codes, 299.00, 299.10, and 299.80 in their records. Codes were entered in the EHR using four different workflows: (1) during an ambulatory visit, (2) abstracted by Health Information Management (HIM) for an encounter, (3) recorded on the patient problem list, or (4) added as a chief complaint during an Emergency Department visit. Once individuals were identified, demographics, scheduling, procedures, and prescribed medications were extracted for all patient-related encounters for the period October 2010 through September 2012. RESULTS: There were 100,000 encounters for more than 4,800 unique individuals. Individuals were most frequently identified with an HIM abstracted code (82.6%) and least likely to be identified by a chief complaint (45.8%). Categorical frequency for reported race (2 = 816.5, p < 0.001); payor type (2 = 354.1, p < 0.001); encounter type (2 = 1497.0, p < 0.001); and department (2 = 3722.8, p < 0.001) differed by search query. Challenges encountered included, locating available discrete data elements and missing data. CONCLUSIONS: This study identifies challenges inherent in designing inclusive algorithms for identifying individuals with ASD and demonstrates the utility of employing multiple extractions to improve the completeness and quality of EHR data when conducting research. Lien vers le texte intégral (Open Access ou abonnement)
5. Chen CH, Chen HI, Chien WH, Li LH, Wu YY, Chiu YN, Tsai WC, Gau SS. {{High resolution analysis of rare copy number variants in patients with autism spectrum disorder from Taiwan}}. {Sci Rep}. 2017; 7(1): 11919.
Rare genomic copy number variations (CNVs) (frequency <1%) contribute a part to the genetic underpinnings of autism spectrum disorders (ASD). The study aimed to understand the scope of rare CNV in Taiwanese patients with ASD. We conducted a genome-wide CNV screening of 335 ASD patients (299 males, 36 females) from Taiwan using Affymetrix Genome-Wide Human SNP Array 6.0 and compared the incidence of rare CNV with that of 1093 control subjects (525 males, 568 females). We found a significantly increased global burden of rare CNVs in the ASD group compared to the controls as a whole or when the rare CNVs were classified by the size and types of CNV. Further analysis confirmed the presence of several rare CNVs at regions strongly associated with ASD as reported in the literature in our sample. Additionally, we detected several new private pathogenic CNVs in our samples and five patients carrying two pathogenic CNVs. Our data indicate that rare genomic CNVs contribute a part to the genetic landscape of our ASD patients. These CNVs are highly heterogeneous, and the clinical interpretation of the pathogenic CNVs of ASD is not straightforward in consideration of the incomplete penetrance, varied expressivity, and individual genetic background. Lien vers le texte intégral (Open Access ou abonnement)
6. Chien YL, Chen YJ, Hsu YC, Tseng WI, Gau SS. {{Altered white-matter integrity in unaffected siblings of probands with autism spectrum disorders}}. {Hum Brain Mapp}. 2017.
Despite the evidence of altered white-matter tract property in individuals with autism spectrum disorder (ASD), little is known about their unaffected siblings. This study aimed to investigate white-matter integrity in unaffected siblings of ASD probands. Thirty-nine unaffected siblings (mean age 15.6 +/- 6.0 years; 27 males, 69.2%) and 39 typically developing controls (TDC) (14.2 +/- 5.6 years; 26 males, 66.7%) were assessed with diffusion spectrum images and neuropsychological tests. Using the tract-based automatic analysis and the threshold-free cluster weighted (TFCW) scores, we searched for the segments among 76 tracts with the largest difference over the entire brain compared to TDC. Tract integrity was quantified by calculating the mean generalized fractional anisotropy (mGFA) values of the segments with the largest difference in TFCW scores. Unaffected siblings showed reduced mGFA in the bilateral frontal aslant tracts, the right superior longitudinal fasciculus 2 (SLF2), the frontostriatal tracts from the right dorsolateral and left ventrolateral prefrontal cortices, the thalamic radiations of the left ventral and the right dorsal thalamus, the callosal fibers of the splenium, and the increased mGFA of the callosal fibers of the precuneus and the left inferior longitudinal fasciculus. Among these, reduced right SLF2 mGFA was associated with social awareness deficits; impaired frontostriatal tract was associated with internalizing problems, while right frontal aslant tract integrity was associated with visual memory deficits. In conclusion, unaffected siblings showed the aberrant integrity of several white-matter tracts, which were correlated with clinical symptoms and neurocognitive dysfunction. The altered tract integrity could be further examined in the probands with ASD. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc.
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7. Dixon MR, Belisle J, Munoz BE, Stanley CR, Rowsey KE. {{Teaching metaphorical extensions of private events through rival-model observation to children with autism}}. {J Appl Behav Anal}. 2017.
The study evaluated the efficacy of observational learning using the rival-model technique in teaching three children with autism to state metaphorical statements about emotions when provided a picture, as well as to intraverbally state an appropriate emotion when provided a scenario and corresponding metaphorical emotion. The results provide a preliminary evaluation of how an observational teaching strategy may be effective in teaching children with autism to correctly tact emotions when given metaphors.
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8. Ganz JB, Morin KL, Foster MJ, Vannest KJ, Genc Tosun D, Gregori EV, Gerow SL. {{High-technology augmentative and alternative communication for individuals with intellectual and developmental disabilities and complex communication needs: a meta-analysis}}. {Augment Altern Commun}. 2017: 1-15.
The use of mobile technology is ubiquitous in modern society and is rapidly increasing in novel use. The use of mobile devices and software applications (« apps ») as augmentative and alternative communication (AAC) is rapidly expanding in the community, and this is also reflected in the research literature. This article reports the social-communication outcome results of a meta-analysis of single-case experimental research on the use of high-tech AAC, including mobile devices, by individuals with intellectual and developmental disabilities, including autism spectrum disorder. Following inclusion determination, and excluding studies with poor design quality, raw data from 24 publications were extracted and included 89 A-B phase contrasts. Tau-U nonparametric, non-overlap effect size was used to aggregate the results across all studies for an omnibus and moderator analyses. Kendall’s S was calculated for confidence intervals, p-values, and standard error. The omnibus analysis indicated overall low to moderate positive effects on social-communication outcomes for high-tech AAC use by individuals with intellectual and developmental disabilities.
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9. Graf WD, Miller G, Epstein LG, Rapin I. {{Author response: The autism « epidemic »: Ethical, legal, and social issues in a developmental spectrum disorder}}. {Neurology}. 2017; 89(12): 1310-1.
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10. Guerini FR, Bolognesi E, Chiappedi M, Ripamonti E, Ghezzo A, Zanette M, Sotgiu S, Mensi MM, Carta A, Canevini MP, Zanzottera M, Agliardi C, Costa AS, Balottin U, Clerici M. {{HLA-G coding region polymorphism is skewed in autistic spectrum disorders}}. {Brain Behav Immun}. 2017.
Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.
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11. Hara Y, Ago Y, Higuchi M, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K. {{Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism}}. {Horm Behav}. 2017.
Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.
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12. Hebron JS. {{School connectedness and the primary to secondary school transition for young people with autism spectrum conditions}}. {Br J Educ Psychol}. 2017.
BACKGROUND: Young people with autism spectrum conditions (ASC) face many educational challenges, particularly in terms of academic achievement, social inclusion, and mental health. School connectedness is linked to many positive outcomes and may be of particular salience at the primary-secondary school transition, when young people with ASC are expected to cope in new and unfamiliar settings. AIMS: This study explores for the first time school connectedness across the primary to secondary school transition for young people with ASC. SAMPLE: Twenty-eight students with ASC (23 male, five female) and a comparison group of 21 students with no additional needs (16 male, five female) participated. METHODS: A longitudinal design was used to measure school connectedness across transition at four time-points from the end of primary school, into the first and second years of secondary school. Students completed the Psychological Sense of School Membership (Goodenow, 1993, Psychology in the Schools, 30, 79) questionnaire at each time-point, with responses analysed statistically. RESULTS: Students with ASC reported positive levels of school connectedness across transition, although their scores remained lower than those of their typically developing peers. The gap between the two groups narrowed significantly during the first year of secondary school, with students in the ASC group reporting improving levels of school connectedness, although there were non-significant signs of a decline for both groups in the second year. CONCLUSIONS: Transition can be a positive experience for students with ASC. However, their consistently lower levels of school connectedness compared to those of their peers highlight the need for ongoing monitoring and support during secondary education.
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13. Hegarty JP, 2nd, Gu M, Spielman DM, Cleveland SC, Hallmayer JF, Lazzeroni LC, Raman MM, Frazier TW, Phillips JM, Reiss AL, Hardan AY. {{A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder}}. {Prog Neuropsychopharmacol Biol Psychiatry}. 2017.
Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with 1H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.
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14. Hemdi A, Daley D. {{The Effectiveness of a Psychoeducation Intervention delivered via WhatsApp for mothers of children with Autism Spectrum Disorder (ASD) in the Kingdom of Saudi Arabia: A randomized controlled trial}}. {Child Care Health Dev}. 2017.
BACKGROUND: Mothers of children with autism spectrum disorder (ASD) report high levels of stress and lower levels of well-being than parents of typically developing children. Current interventions for ASD typically focus on working with the child rather than delivering strategies to help support parents. OBJECTIVE: To evaluate the effectiveness of a psychoeducation intervention developed to support mothers of children with ASD in Saudi Arabia. METHOD: Sixty-two mothers (23-52 years) of children (26-78 months) were recruited to a multisite randomized controlled trials of the intervention. The intervention consisted of one face-to-face session (60 min) and four virtual sessions (30 min each) delivered using WhatsApp. Parenting stress was the primary outcome, with secondary outcomes focusing on maternal depression, anxiety, and happiness, and child behaviour problems and ASD symptoms. Data were collected at baseline T1, immediately postintervention T2 and 8-week follow-up T3. RESULTS: One-way analysis of covariance was used at T2 and T3 with T1 scores entered as a covariate. Improvements were found at T2 for stress (F = 234.34, p = .00, and d = -1.52) and depression (F = 195.70, p = .00, and d = -2.14) but not anxiety, and these results were maintained at T3. Changes in child behaviour problems were limited to improvements in hyperactivity at T2 (F = 133.66, p = .00, and d = -1.54). Although changes in stress and depression were statistically significant, change to clinically normal levels was limited to depression. None of the participants had recovered after the intervention (Parent Stress Index Short Form stress scores), whereas 23 mothers (71.87%) in the intervention group had recovered at T2 and 22 (68.75%) at T3 (Hospital Anxiety and Depression Scale depression scores). CONCLUSION: This intervention with WhatsApp support is beneficial but may need to be augmented with other forms of support for mothers of children with ASD including more condensed sessions on stress and interventions targeting anxiety.
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15. Hsiao YJ, Higgins K, Pierce T, Whitby PJS, Tandy RD. {{Parental stress, family quality of life, and family-teacher partnerships: Families of children with autism spectrum disorder}}. {Res Dev Disabil}. 2017; 70: 152-62.
BACKGROUND: Reducing parental stress and improving family quality of Life (FQOL) are continuing concerns for families of children with autism spectrum disorder (ASD). Family-teacher partnerships have been identified as a positive factor to help parents reduce their stress and improve their FQOL. However, the interrelations among parental stress, FQOL, and family-teacher partnerships need to be further examined so as to identify the possible paths to help parents reduce their stress and improve their FQOL. The purpose of this study was to examine the interrelations among these three variables. METHOD: A total of 236 parents of school children with ASD completed questionnaires, which included three measures: (a) the Beach Center Family Quality of Life Scale, (b) the Parental Stress Scale, and (c) the Beach Center Family-Professional Partnerships Scale. The structural equation modeling was used to analyze the interrelations among these three variables. RESULTS: Perceived parental stress had a direct effect on parental satisfaction concerning FQOL and vice versa. Perceived family-teacher partnerships had a direct effect on FQOL, but did not have a direct effect on parental stress. However, family-teacher partnerships had an indirect effect on parental stress through FQOL. CONCLUSIONS AND IMPLICATIONS: Reducing parental stress could improve FQOL for families of children with ASD and vice versa. Strong family-teacher partnerships could help parents of children with ASD improve their FQOL and indirectly reduce their stress.
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16. Jiraanont P, Kumar M, Tang HT, Espinal G, Hagerman PJ, Hagerman RJ, Chutabhakdikul N, Tassone F. {{Size and methylation mosaicism in males with Fragile X syndrome}}. {Expert Rev Mol Diagn}. 2017.
OBJECTIVES: Size and methylation mosaicism are a common phenomenon in Fragile X syndrome (FXS). Here, the authors report a study on twelve fragile X males with atypical mosaicism, seven of whom presented with autism spectrum disorder. METHODS: Southern Blot and PCR analysis was used for CGG allele sizing and methylation. FMR1 mRNA and FMRP expression were measured by qRT-PCR and by Homogeneous Time Resolved Fluorescence methodology respectively. RESULTS: DNA analysis showed atypical size- or methylation-mosaicism with both, full mutation and smaller (normal to premutation) alleles, as well as a combination of methylated and unmethylated alleles. Four individuals carried a deletion of the CGG repeat and portions of the flanking regions. The extent of methylation among the participants was reflected in the lower FMR1 mRNA and FMRP expression levels detected in these subjects. CONCLUSION: Decreased gene expression is likely the main contributor to the cognitive impairment observed in these subjects; although the presence of a normal allele did not appear to compensate for the presence of the full mutation, it correlated with better cognitive function in some but not all of the reported cases emphasizing the complexity of the molecular and clinical profile in FXS.
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17. Kida H, Takahashi T, Nakamura Y, Kinoshita T, Hara M, Okamoto M, Okayama S, Nakamura K, Kosai KI, Taniwaki T, Yamashita Y, Matsuishi T. {{Pathogenesis of Lethal Aspiration Pneumonia in Mecp2-null Mouse Model for Rett Syndrome}}. {Sci Rep}. 2017; 7(1): 12032.
Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.
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18. Laidi C, Boisgontier J, Chakravarty MM, Hotier S, d’Albis MA, Mangin JO, Devenyi GA, Delorme R, Bolognani F, Czech C, Bouquet C, Toledano E, Bouvard M, Gras D, Petit J, Mishchenko M, Gaman A, Scheid I, Leboyer M, Zalla T, Houenou J. {{Cerebellar anatomical alterations and attention to eyes in autism}}. {Sci Rep}. 2017; 7(1): 12008.
The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.
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19. Li D, Tomljenovic L, Li Y, Shaw CA. {{Subcutaneous injections of aluminum at vaccine adjuvant levels activate innate immune genes in mouse brain that are homologous with biomarkers of autism}}. {J Inorg Biochem}. 2017; 177: 39-54.
Autism is a neurobehavioral disorder characterized by immune dysfunction. It is manifested in early childhood, during a window of early developmental vulnerability where the normal developmental trajectory is most susceptible to xenobiotic insults. Aluminum (Al) vaccine adjuvants are xenobiotics with immunostimulating and neurotoxic properties to which infants worldwide are routinely exposed. To investigate Al’s immune and neurotoxic impact in vivo, we tested the expression of 17 genes which are implicated in both autism and innate immune response in brain samples of Al-injected mice in comparison to control mice. Several key players of innate immunity, such as cytokines CCL2, IFNG and TNFA, were significantly upregulated, while the nuclear factor-kappa beta (NF-kappaB) inhibitor NFKBIB, and the enzyme controlling the degradation of the neurotransmitter acetylcholine (ACHE), were downregulated in Al-injected male mice. Further, the decrease of the NF-kappaB inhibitor and the consequent increase in inflammatory signals, led to the activation of the NF-kappaB signaling pathway resulting in the release of chemokine MIP-1A and cytokines IL-4 and IL-6. It thus appears that Al triggered innate immune system activation and altered cholinergic activity in male mice, observations which are consistent with those in autism. Female mice were less susceptible to Al exposure as only the expression levels of NF-kappaB inhibitor and TNFA were altered. Regional patterns of gene expression alterations also exhibited gender differences, as frontal cortex was the most affected area in males and cerebellum in females. Thus, Al adjuvant promotes brain inflammation and males appear to be more susceptible to Al’s toxic effects.
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20. Linstead E, Dixon DR, Hong E, Burns CO, French R, Novack MN, Granpeesheh D. {{An evaluation of the effects of intensity and duration on outcomes across treatment domains for children with autism spectrum disorder}}. {Transl Psychiatry}. 2017; 7(9): e1234.
Applied behavior analysis (ABA) is considered an effective treatment for individuals with autism spectrum disorder (ASD), and many researchers have further investigated factors associated with treatment outcomes. However, few studies have focused on whether treatment intensity and duration have differential influences on separate skills. The aim of the current study was to investigate how treatment intensity and duration impact learning across different treatment domains, including academic, adaptive, cognitive, executive function, language, motor, play, and social. Separate multiple linear regression analyses were used to evaluate these relationships. Participants included 1468 children with ASD, ages 18 months to 12 years old, M=7.57 years, s.d.=2.37, who were receiving individualized ABA services. The results indicated that treatment intensity and duration were both significant predictors of mastered learning objectives across all eight treatment domains. The academic and language domains showed the strongest response, with effect sizes of 1.68 and 1.85 for treatment intensity and 4.70 and 9.02 for treatment duration, respectively. These findings are consistent with previous research that total dosage of treatment positively influences outcomes. The current study also expands on extant literature by providing a better understanding of the differential impact that these treatment variables have across various treatment domains.
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21. Machado C, Estevez M, Rodriguez R, Leisman G. {{Letter re: The autism « epidemic »: Ethical, legal, and social issues in a developmental spectrum disorder}}. {Neurology}. 2017; 89(12): 1310.
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22. Martinez-Gonzalez AE, Piqueras JA. {{Validation of the Repetitive Behavior Scale-Revised in Spanish-Speakers Participants with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2017.
Restricted and repetitive behavior (RRB) is one of the two key diagnostic features of autism spectrum disorder (ASD). DSM-5 highlights the importance of severity-based diagnostic modifiers assigned on the basis of intensity of needed supports. Therefore, there is a need for available measures that assess the severity of RRB. The repetitive behavior scale-revised (RBS-R) is probably the most used informant-based rating scale for the assessment of RRB and interests observed in ASD. The present study examined the psychometric properties of the Spanish version of the RBS-R in a sample of 233 participants with ASD, aged 3 to 63 years. Results revealed a six-factor model, good internal consistency, and concurrent-divergent validity. These findings suggest the utility of the Spanish version of RBS-R.
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23. Michetti C, Caruso A, Pagani M, Sabbioni M, Medrihan L, David G, Galbusera A, Morini M, Gozzi A, Benfenati F, Scattoni ML. {{The Knockout of Synapsin II in Mice Impairs Social Behavior and Functional Connectivity Generating an ASD-like Phenotype}}. {Cereb Cortex}. 2017; 27(10): 5014-23.
Autism spectrum disorders (ASD) and epilepsy are neurodevelopmental conditions that appear with high rate of co-occurrence, suggesting the possibility of a common genetic basis. Mutations in Synapsin (SYN) genes, particularly SYN1 and SYN2, have been recently associated with ASD and epilepsy in humans. Accordingly, mice lacking Syn1 or Syn2, but not Syn3, experience epileptic seizures and display autistic-like traits that precede the onset of seizures. Here, we analyzed social behavior and ultrasonic vocalizations emitted in 2 social contexts by SynI, SynII, or SynIII mutants and show that SynII mutants display the most severe ASD-like phenotype. We also show that the behavioral SynII phenotype correlates with a significant decrease in auditory and hippocampal functional connectivity as measured with resting state functional magnetic resonance imaging (rsfMRI). Taken together, our results reveal a permissive contribution of Syn2 to the expression of normal socio-communicative behavior, and suggest that Syn2-mediated synaptic dysfunction can lead to ASD-like behavior through dysregulation of cortical connectivity.
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24. Nadeem A, Ahmad SF, Attia SM, Bakheet SA, Al-Harbi NO, Al-Ayadhi LY. {{Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children}}. {Brain Behav Immun}. 2017.
Millions of children are affected by different neurodevelopmental disorders, out of which autism spectrum disorder (ASD) poses a major hurdle to normal life style due to associated behavioral abnormalities. Several studies have shown an increased expression/release of Th17 related cytokine, IL-17A in ASD. IL-17A may enhance neuroinflammation via its IL-17A receptor, i.e. IL-17RA expressed in immune cells (such as monocytes) of autistic children. Increased oxidative stress has been implicated in a number of neuropsychiatric disorders including ASD. However, whether IL-17A/IL-17RA signaling contributes to oxidative inflammation in monocytes of autistic children has not been explored previously. With this background, we performed this study in peripheral monocytes of ASD patients and age-matched typically developing children. Our study shows that ASD individuals have increased IL-17RA expression in monocytes which is associated with increased nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) pathway and inducible nitric oxide synthase (iNOS)/nitrotyrosine expression as compared to typically developing children. Moreover, in vitro activation of IL-17 receptor by IL-17A in monocytes isolated from ASD individuals leads to enhanced iNOS expression via NFkappaB pathway. IL-17RA antibody treatment in vitro reversed IL-17A-induced increase in NFkappaB and iNOS/nitrotyrosine expression in monocytes isolated from ASD subjects. These data connect increased IL-17A/IL-17RA signaling in ASD patients with enhanced oxidative inflammation in monocytes. Therefore, IL-17 receptor signaling in monocytes may potentiate the effects of IL-17A released by other immune cells and may aggravate neuroinflammation in ASD. Our study further suggests that blockade of IL-17A/IL-17 receptor signaling may be beneficial in the children with ASD.
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25. Operto FF, Martino F, Rinaldi A, Cerracchio A, Salvati G, Orza M, Lembo C, Panzarino G, Di Paolantonio C, Verrotti A, Farello G, Coppola G. {{Long-term outcome of autistic spectrum disorder: a retrospective case study in a southern italian region}}. {Ital J Pediatr}. 2017; 43(1): 83.
BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, characterized by impaired social communication and restricted and repetitive behaviours, as well as associated features including intellectual disability and impaired sensorimotor function. Despite a growing interest in this devastating disorder for families and young parents, there are no certainties as regards its aetiology, although a significant genetic background is considered to be important. Since there is little information about the social adaptation and quality of life of patients with Autism Spectrum Disorder, we decided to study and evaluate the long-term outcome and quality of life in a sample of children, adolescent and young adults. METHODS: This is a case study of subjects diagnosed with ASD and followed by clinics and rehabilitation centers in Campania region, in the south of Italy. The study sample was composed by 110 patients (83 males, 27 females), aged between 8.1 and 28.0 years (mean 20.6; median 21.2; SD +/- 4.85), recruited in 8 rehabilitation centers of Campania region. A follow-up interview was performed by means of a questionnaire administered to the parents/caregivers of patients at a mean age of their son/daughter of 20.6 years (median 21.2 years; range 8.1-28.0). RESULTS: Reports from parents or caregivers show an overall improvement with regard to social and adaptive abilities in a group of teen-agers and young adults with ASD. Major concerns on significant quality of life parameters such as independent living, work experiences, friendships and relationships, accommodation type, recreational activities and personal autonomy were persisting. CONCLUSIONS: The present study shows an overall improvement with regard to social and adaptive abilities in a large number of subjects. Considerable problems are related to autonomy, employment opportunities and social relationships of these patients. Parents need more recreational activities and continuous support with facilities for families.
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26. Slawson D. {{No Increased Risk of ASD, ADHD, or SGA with First-Trimester Antidepressant Use}}. {Am Fam Physician}. 2017; 96(4): 261-2.
27. Smith-Hicks CL, Gupta S, Ewen JB, Hong M, Kratz L, Kelley R, Tierney E, Vaurio R, Bibat G, Sanyal A, Yenokyan G, Brereton N, Johnston MV, Naidu S. {{Randomized open-label trial of dextromethorphan in Rett syndrome}}. {Neurology}. 2017.
OBJECTIVE: To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome. METHODS: We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist-Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity. RESULTS: Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale. CONCLUSIONS: Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.
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28. Solomon M, Hogeveen J, Libero L, Nordahl C. {{An altered scaffold for information processing: Cognitive control development in adolescents with autism}}. {Biol Psychiatry Cogn Neurosci Neuroimaging}. 2017; 2(6): 464-75.
We investigated how cognitive neuroscientific studies during the last decade have advanced understanding of cognitive control from adolescence to young adulthood in individuals with autism spectrum disorder (ASD). To do so, we conducted a selective review of the larger structural, resting state, and diffusion imaging studies of brain regions and networks related to cognitive control that have been conducted since 2007 in individuals with ASD and typical development (TYP) ages 10 to 30 years that examined how these regions and networks support behavioral and task-based fMRI performance on tasks assessing cognitive control during this period. Longitudinal structural studies reveal overgrowth of the anterior cingulate (ACC) and slower white matter development in the parietal cortex in adolescents with ASD versus TYP. Cross-sectional studies of the salience, executive control and default mode resting state functional connectivity networks, which mediate cognitive control, demonstrate patterns of connectivity that differ from TYP through adolescence. Finally, white matter tracts underlying these control-related brain regions continue to show reduced diffusion properties compared to TYP. It is thus not surprising that cognitive control tasks performance improves less during adolescence in ASD versus TYP. This review illustrates that a cognitive neuroscientific approach produces insights about the mechanisms of persistent cognitive control deficits in individuals with ASD from adolescence into young adulthood not apparent with neuropsychological methods alone, and draws attention to the great need for longitudinal studies of this period in those with ASD. Further investigation of ACC and fronto-parietal neural circuits may help specify pathophysiology and treatment options.
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29. Tomeny TS, Vargo CJ, El-Toukhy S. {{Geographic and demographic correlates of autism-related anti-vaccine beliefs on Twitter, 2009-15}}. {Soc Sci Med}. 2017; 191: 168-75.
This study examines temporal trends, geographic distribution, and demographic correlates of anti-vaccine beliefs on Twitter, 2009-2015. A total of 549,972 tweets were downloaded and coded for the presence of anti-vaccine beliefs through a machine learning algorithm. Tweets with self-disclosed geographic information were resolved and United States Census data were collected for corresponding areas at the micropolitan/metropolitan level. Trends in number of anti-vaccine tweets were examined at the national and state levels over time. A least absolute shrinkage and selection operator regression model was used to determine census variables that were correlated with anti-vaccination tweet volume. Fifty percent of our sample of 549,972 tweets collected between 2009 and 2015 contained anti-vaccine beliefs. Anti-vaccine tweet volume increased after vaccine-related news coverage. California, Connecticut, Massachusetts, New York, and Pennsylvania had anti-vaccination tweet volume that deviated from the national average. Demographic characteristics explained 67% of variance in geographic clustering of anti-vaccine tweets, which were associated with a larger population and higher concentrations of women who recently gave birth, households with high income levels, men aged 40 to 44, and men with minimal college education. Monitoring anti-vaccination beliefs on Twitter can uncover vaccine-related concerns and misconceptions, serve as an indicator of shifts in public opinion, and equip pediatricians to refute anti-vaccine arguments. Real-time interventions are needed to counter anti-vaccination beliefs online. Identifying clusters of anti-vaccination beliefs can help public health professionals disseminate targeted/tailored interventions to geographic locations and demographic sectors of the population.
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30. van Tilborg E, Achterberg EJM, van Kammen CM, van der Toorn A, Groenendaal F, Dijkhuizen RM, Heijnen CJ, Vanderschuren L, Benders M, Nijboer CHA. {{Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury}}. {Glia}. 2017.
Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.
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31. Weir RK, Bauman MD, Jacobs B, Schumann CM. {{Protracted dendritic growth in the typically developing human amygdala and increased spine density in young ASD brains}}. {J Comp Neurol}. 2017.
The amygdala is a medial temporal lobe structure implicated in social and emotional regulation. In typical development (TD), the amygdala continues to increase volumetrically throughout childhood and into adulthood, while other brain structures are stable or decreasing in volume. In autism spectrum disorder (ASD), the amygdala undergoes rapid early growth, making it volumetrically larger in children with ASD compared to TD children. Here we explore: 1) if dendritic arborization in the amygdala follows the pattern of protracted growth in TD and early overgrowth in ASD and 2), if spine density in the amygdala in ASD cases differs from TD from youth to adulthood. The amygdala from 32 postmortem human brains (7-46 years of age) was stained using a Golgi-Kopsch impregnation. Ten principal neurons per case were selected in the lateral nucleus and traced using Neurolucida software in their entirety. We found that both ASD and TD individuals show a similar pattern of increasing dendritic length with age well into adulthood. However, spine density is i) greater in young ASD cases compared to age-matched TD controls (<18 years old) and ii) decreases in the amygdala as people with ASD age into adulthood, a phenomenon not found in typical development. Therefore, by adulthood, there is no observable difference in spine density in the amygdala between ASD and TD age-matched adults (>/=18 years old). Our findings highlight the unique growth trajectory of the amygdala and suggest that spine density may contribute to aberrant development and function of the amygdala in children with ASD. This article is protected by copyright. All rights reserved.
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32. Westwood H, Mandy W, Tchanturia K. {{The association between symptoms of autism and neuropsychological performance in females with Anorexia Nervosa}}. {Psychiatry Res}. 2017.
The aim of this study was to investigate the relationship between symptoms of autism spectrum disorder (ASD) and performance on measures of set-shifting and central coherence in a sample of females with anorexia nervosa (AN). Ninety-nine females aged 12-47, recruited from inpatient and day patient eating disorder services, were assessed with the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2), as well as the Wechsler Abbreviated Scale of Intelligence, 2nd edition (WASI-II); Wisconsin Card Sorting Test (WCST); Rey-Osterrieth Complex Figure Test (ROCFT) and self-report questionnaires assessing eating disorder pathology, depression, cognitive rigidity and attention to detail. Individuals scoring above clinical cut-off on the ADOS-2 (N = 35) reported significantly higher levels of cognitive rigidity than those with lower levels of ASD symptoms but there was no difference between groups on self-reported attention to detail. There group with high levels of ASD symptoms also made significantly more perseverative errors on the WCST but there was no association between ASD symptoms and performance on the ROCFT. The group who scored above cut-off on the ADOS-2 were significantly younger than the sub-clinical groups. The presence of symptoms associated with ASD appears to be related to increased cognitive rigidity in females with AN.
