1. Allemang-Grand R, Ellegood J, Spencer Noakes L, Ruston J, Justice M, Nieman BJ, Lerch JP. {{Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes}}. {Mol Autism}. 2017; 8: 32.
BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain. METHODS: In this study, we examined the neuroanatomy of male and female mice from the Mecp2tm1Hzo, Mecp2tm1.1Bird/J, and Mecp2tm2Bird/J mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions. RESULTS: We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2tm1Hzo brain relative to controls and a decrease in the Mecp2tm1.1Bird/J and Mecp2tm2Bird/J lines. CONCLUSIONS: Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments.
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2. Choque Olsson N, Flygare O, Coco C, Gorling A, Rade A, Chen Q, Lindstedt K, Berggren S, Serlachius E, Jonsson U, Tammimies K, Kjellin L, Bolte S. {{Social Skills Training for Children and Adolescents With Autism Spectrum Disorder: A Randomized Controlled Trial}}. {J Am Acad Child Adolesc Psychiatry}. 2017; 56(7): 585-92.
OBJECTIVE: Social skills group training (SSGT) for children and adolescents with autism spectrum disorder (ASD) is widely applied, but effectiveness in real-world practice has not yet been properly evaluated. This study sought to bridge this gap. METHOD: This 12-week pragmatic randomized controlled trial of SSGT compared to standard care alone was conducted at 13 child and adolescent psychiatry outpatient units in Sweden. Twelve sessions of manualized SSGT (« KONTAKT ») were delivered by regular clinical staff. Participants (N = 296; 88 females and 208 males) were children (n = 172) and adolescents (n = 124) aged 8 to 17 years with ASD without intellectual disability. The primary outcome was the Social Responsiveness Scale rating by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and 3-month follow-up. Moderator analyses were conducted for age and gender. RESULTS: Significant treatment effects on the primary outcome were limited to parent ratings for the adolescent subgroup (posttreatment: -8.3; 95% CI = -14.2 to -1.9; p = .012, effect size [ES] = 0.32; follow-up: -8.6; 95% CI = -15.4 to -1.8; p = .015, ES = 0.33) and females (posttreatment: -8.9; 95% CI = -16.2 to -1.6; p = .019, ES = 0.40). Secondary outcomes indicated moderate effects on adaptive functioning and clinical severity. CONCLUSION: SSGT for children and adolescents with ASD in regular mental health services is feasible and safe. However, the modest and inconsistent effects underscore the importance of continued efforts to improve SSGT beyond current standards. CLINICAL TRIAL REGISTRATION INFORMATION: Social Skills Group Training (« KONTAKT ») for Children and Adolescent With High-functioning Autism Spectrum Disorders; https://clinicaltrials.gov/; NCT01854346.
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3. Darrow SM, Grados M, Sandor P, Hirschtritt ME, Illmann C, Osiecki L, Dion Y, King R, Pauls D, Budman CL, Cath DC, Greenberg E, Lyon GJ, McMahon WM, Lee PC, Delucchi KL, Scharf JM, Mathews CA. {{Autism Spectrum Symptoms in a Tourette’s Disorder Sample}}. {J Am Acad Child Adolesc Psychiatry}. 2017; 56(7): 610-7 e1.
OBJECTIVE: Tourette’s disorder (TD) and autism spectrum disorder (ASD) share clinical features and possibly an overlapping etiology. The aims of this study were to examine ASD symptom rates in participants with TD, and to characterize the relationships between ASD symptom patterns and TD, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). METHOD: Participants with TD (n = 535) and their family members (n =234) recruited for genetic studies reported TD, OCD, and ADHD symptoms and completed the Social Responsiveness Scale Second Edition (SRS), which was used to characterize ASD symptoms. RESULTS: SRS scores in participants with TD were similar to those observed in other clinical samples but lower than in ASD samples (mean SRS total raw score = 51; SD = 32.4). More children with TD met cut-off criteria for ASD (22.8%) than adults with TD (8.7%). The elevated rate in children was primarily due to high scores on the SRS Repetitive and Restricted Behaviors (RRB) subscale. Total SRS scores were correlated with TD (r = 0.27), OCD (r = 0.37), and ADHD (r = 0.44) and were higher among individuals with OCD symptom-based phenotypes than for those with tics alone. CONCLUSION: Higher observed rates of ASD among children affected by TD may in part be due to difficulty in discriminating complex tics and OCD symptoms from ASD symptoms. Careful examination of ASD-specific symptom patterns (social communication vs. repetitive behaviors) is essential. Independent of ASD, the SRS may be a useful tool for identifying patients with TD with impairments in social communication that potentially place them at risk for bullying and other negative sequelae.
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4. Dubois M, Cousin E, Chouklati K, Bruneau B, Proisy M. {{Scurvy in a 3-year-old autistic girl: Whole-body magnetic resonance imaging findings}}. {Diagn Interv Imaging}. 2017.
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5. Engelhardt CR, Mazurek MO, Hilgard J. {{Pathological game use in adults with and without Autism Spectrum Disorder}}. {PeerJ}. 2017; 5: e3393.
This study tested whether adults with autism spectrum disorder (ASD) are at higher risk for pathological game use than typically developing (TD) adults. Participants included 119 adults with and without ASD. Participants completed measures assessing daily hours of video game use, percent of free time spent playing video games, and symptoms of pathological game use. The results indicated that adults with ASD endorsed more symptoms of video game pathology than did TD adults. This relationship was strong, enjoying 300,000-to-1 odds in Bayesian model comparison. Results also showed that adults with ASD spent more daily hours playing video games and spent a higher percent of their free time playing video games than did TD adults. Even after adjustment for these differences in daily video game hours and proportion of free time spent on games, model comparisons found evidence for a difference in game pathology scores associated with ASD status. Additionally, escapism motives for playing video games was associated with game pathology scores in both ASD and TD adults, replicating and extending a previous report. In conclusion, the risk for pathological game use appears larger in adults with ASD compared with TD adults. These findings point to pathological game use as a potentially important focus of clinical attention in adults with ASD.
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6. Fassbender C, Mukherjee P, Schweitzer JB. {{Reprint of: Minimizing noise in pediatric task-based functional MRI; Adolescents with developmental disabilities and typical development}}. {Neuroimage}. 2017; 154: 230-9.
Functional Magnetic Resonance Imaging (fMRI) represents a powerful tool with which to examine brain functioning and development in typically developing pediatric groups as well as children and adolescents with clinical disorders. However, fMRI data can be highly susceptible to misinterpretation due to the effects of excessive levels of noise, often related to head motion. Imaging children, especially with developmental disorders, requires extra considerations related to hyperactivity, anxiety and the ability to perform and maintain attention to the fMRI paradigm. We discuss a number of methods that can be employed to minimize noise, in particular movement-related noise. To this end we focus on strategies prior to, during and following the data acquisition phase employed primarily within our own laboratory. We discuss the impact of factors such as experimental design, screening of potential participants and pre-scan training on head motion in our adolescents with developmental disorders and typical development. We make some suggestions that may minimize noise during data acquisition itself and finally we briefly discuss some current processing techniques that may help to identify and remove noise in the data. Many advances have been made in the field of pediatric imaging, particularly with regard to research involving children with developmental disorders. Mindfulness of issues such as those discussed here will ensure continued progress and greater consistency across studies.
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7. Frazier TW, Strauss M, Klingemier EW, Zetzer EE, Hardan AY, Eng C, Youngstrom EA. {{A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism}}. {J Am Acad Child Adolesc Psychiatry}. 2017; 56(7): 546-55.
OBJECTIVE: Numerous studies have identified abnormal gaze in individuals with autism. However, only some findings have been replicated, the magnitude of effects is unclear, and the pattern of gaze differences across stimuli remains poorly understood. To address these gaps, a comprehensive meta-analysis of autism eye-tracking studies was conducted. METHOD: PubMed and a manual search of 1,132 publications were used to identify studies comparing looking behavior to social and/or nonsocial stimuli between individuals with autism and controls. Sample characteristics, eye-tracking methods, stimulus features, and regions of interest (ROIs) were coded for each comparison within each study. Multivariate mixed-effects meta-regression analyses examined the impact of study methodology, stimulus features, and ROI on effect sizes derived from comparisons using gaze-fixation metrics. RESULTS: The search yielded 122 independent studies with 1,155 comparisons. Estimated effect sizes tended to be small to medium but varied substantially across stimuli and ROIs. Overall, nonsocial ROIs yielded larger effect sizes than social ROIs; however, eye and whole-face regions from stimuli with human interaction produced the largest effects (Hedges g = 0.47 and 0.50, respectively). Studies with weaker study designs or reporting yielded larger effects, but key effects remained significant and medium in size, even for high-rigor designs. CONCLUSION: Individuals with autism show a reliable pattern of gaze abnormalities that suggests a basic problem with selecting socially relevant versus irrelevant information for attention and that persists across ages and worsens during perception of human interactions. Aggregation of gaze abnormalities across stimuli and ROIs could yield clinically useful risk assessment and quantitative, objective outcome measurements.
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8. Luyster RJ, Bick J, Westerlund A, Nelson CA, 3rd. {{Testing the effects of expression, intensity and age on emotional face processing in ASD}}. {Neuropsychologia}. 2017.
Individuals with autism spectrum disorder (ASD) commonly show global deficits in the processing of facial emotion, including impairments in emotion recognition and slowed processing of emotional faces. Growing evidence has suggested that these challenges may increase with age, perhaps due to minimal improvement with age in individuals with ASD. In the present study, we explored the role of age, emotion type and emotion intensity in face processing for individuals with and without ASD. Twelve- and 18-22- year-old children with and without ASD participated. No significant diagnostic group differences were observed on behavioral measures of emotion processing for younger versus older individuals with and without ASD. However, there were significant group differences in neural responses to emotional faces. Relative to TD, at 12 years of age and during adulthood, individuals with ASD showed slower N170 to emotional faces. While the TD groups’ P1 latency was significantly shorter in adults when compared to 12 year olds, there was no significant age-related difference in P1 latency among individuals with ASD. Findings point to potential differences in the maturation of cortical networks that support visual processing (whether of faces or stimuli more broadly), among individuals with and without ASD between late childhood and adulthood. Finally, associations between ERP amplitudes and behavioral responses on emotion processing tasks suggest possible neural markers for emotional and behavioral deficits among individuals with ASD.
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9. Mak ASL, Chiu ATG, Leung GKC, Mak CCY, Chu YWY, Mok GTK, Tang WF, Chan KYK, Tang MHY, Lau Yim ET, So KW, Tao VQ, Fung CW, Wong VCN, Uddin M, Lee SL, Marshall CR, Scherer SW, Kan ASY, Chung BHY. {{Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10}}. {Mol Autism}. 2017; 8: 31.
BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3′ exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings.
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10. Martzoukou M, Papadopoulou D, Kosmidis MH. {{The Comprehension of Syntactic and Affective Prosody by Adults with Autism Spectrum Disorder Without Accompanying Cognitive Deficits}}. {J Psycholinguist Res}. 2017.
The present study investigates the comprehension of syntactic and affective prosody in adults with autism spectrum disorder without accompanying cognitive deficits (ASD w/o cognitive deficits) as well as age-, education- and gender-matched unimpaired adults, while processing orally presented sentences. Two experiments were conducted: (a) an on-line sentence completion task containing local subject/object ambiguities and (b) an affective prosody task exploring the comprehension of six emotions. The syntactic prosody task revealed that the experimental group performed similar to the control group on the fillers and the object condition. On the other hand, the ASD w/o cognitive deficits group manifested lower accuracy compared to the unimpaired controls in the subject reading condition, as well as slower reaction times in all conditions. In the affective prosody task, the experimental group performed significantly worse than the controls in the recognition of the emotion of surprise, whereas no differences between the experimental and the control group were attested in the recognition of all other emotions. A positive correlation was found between the two tasks in the ASD w/o cognitive deficits group. Thus, individuals with ASD w/o cognitive deficits face slight difficulties with the decoding of prosody, both the syntactic and the affective one. More specifically, these difficulties are attested in the most difficult conditions, i.e. the subject reading and the emotion of surprise.
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11. 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.
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 prefrontal cortex (PFC) dependent task. We then use conditional knockout (cKO) mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of non-learners and a delay in the onset of learning in both FX and cKO 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 (cON) mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued post-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 STATEMENTThe absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models prefrontal cortex (PFC) dysfunction in 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 post development.
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12. Vermeulen K, Egger JIM, Janzing JGE, van Dongen L, van Bokhoven H, Kleefstra T, Staal WG. {{The Context of Symptom Measures: Interpretation and Clinical Diagnosis of Autism Spectrum Disorders in Intellectual Disabilities}}. {J Am Acad Child Adolesc Psychiatry}. 2017; 56(7): 618-9.
