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1.  The Relationship between Stress and Social Functioning in Adults with Autism Spectrum Disorder and without Intellectual Disability 
Scientific Abstract
Adults with autism spectrum disorder (ASD) face substantial challenges accomplishing basic tasks associated with daily living, which are exacerbated by their broad and pervasive difficulties with social interactions. These challenges put people with ASD at increased risk for psychophysiological distress, which likely factors heavily into social functioning for adults with ASD, as suggested by a growing literature on stress in children that indicates that children with ASD have differential responses to stress than healthy children. We hypothesized that adults with ASD and without intellectual disability (n=38) would experience more stress than healthy volunteers (n=37) and that there would be an inverse relationship between stress and social functioning in individuals with ASD. Baseline, semi-structured interview data from a randomized-controlled trial of two treatments for adults with ASD were used to assess differences in stress between adults with ASD and healthy volunteers and to assess the relationship between stress response and social functioning in adults with ASD. Findings indicate that adults with ASD experience greater perceived and interviewer-observed stress than did healthy volunteers and that stress is significantly related to social functioning in adults with ASD. These findings highlight the role of stress in adult functioning and outcomes and suggest the need to develop and assess treatments designed to target stress and coping in adults with ASD.
doi:10.1002/aur.1433
PMCID: PMC4412754  PMID: 25524571
Emotion regulation; coping; anxiety; adult outcome; pervasive developmental disorder
2.  Atypical Hemispheric Specialization for Faces in Infants At-Risk for Autism Spectrum Disorder 
Behavioral and neuroimaging findings from typically developing infants and children have demonstrated that the right hemisphere becomes specialized for processing faces. Face processing impairments and atypical hemispheric specialization have previously been reported in individuals with autism spectrum disorder (ASD). The goal of this study was to examine the emergence of the right-lateralized face processing network in infants at high-risk for autism (HRA; defined as having an older sibling with ASD) and low-risk comparison (LRC) infants, defined as having no family history of ASD. To investigate the earliest appearance of these features, we examined lateralization of event-related gamma-band coherence (a measure of intra-hemispheric connectivity) to faces during the first year of life. Forty-nine HRA and 46 LRC infants contributed a total of 127 data sets at 6- and/or 12-months. EEG was recorded while infants viewed pictures of either their mother or a stranger. Event-related gamma-band (30-50Hz) phase coherence between anterior-posterior regions for left and right hemispheres was computed. HRA infants showed an aberrant pattern of leftward lateralization of intra-hemispheric coherence by the end of the first year of life, suggesting that the network specialized for face processing may develop atypically in these infants. Further, infants with the greatest leftward asymmetry at 12-months were those that later met diagnostic criteria for ASD, providing support to the growing body of evidence that atypical hemispheric specialization may be an early neurobiological marker for ASD.
Among the many experimental findings that tend to distinguish those with and without autism spectrum disorder (ASD) are face processing deficits, reduced hemispheric specialization, and atypical neurostructural and functional connectivity. To investigate the earliest manifestations of these features, we examined lateralization of event-related gamma-band coherence to faces during the first year of life in infants at high-risk for autism (HRA; defined as having an older sibling with ASD) who were compared low-risk comparison (LRC) infants, defined as having no family history of ASD. Participants included 49 HRA and 46 LRC infants who contributed a total of 127 data sets at 6- and 12-months. EEG was recorded while infants viewed images of familiar/unfamiliar faces. Event-related gamma-band (30-50Hz) phase coherence between anterior-posterior electrode pairs for left and right hemispheres was computed. Developmental trajectories for lateralization of intra-hemispheric coherence were significantly different in HRA and LRC infants: by 12-months HRA infants showed significantly greater leftward lateralization compared to LRC infants who showed rightward lateralization. Preliminary results indicate that infants who later met criteria for ASD were those that showed the greatest leftward lateralization. HRA infants demonstrate an aberrant pattern of leftward lateralization of intra-hemispheric coherence by the end of the first year of life, suggesting that the network specialized for face processing may develop atypically. Further, infants with the greatest leftward asymmetry at 12-months where those that later met criteria for ASD, providing support to the growing body of evidence that atypical hemispheric specialization may be an early neurobiological marker for ASD.
doi:10.1002/aur.1438
PMCID: PMC4412772  PMID: 25808162
autism; EEG coherence; face processing; hemispheric specialization; endophenotype; gamma; infancy
3.  Patterns of Risk for Multiple Co‐Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder 
Autism Research  2015;8(6):771-781.
Children with autism spectrum disorder (ASD) may present with multiple medical conditions in addition to ASD symptoms. This study investigated whether there are predictive patterns of medical conditions that co‐occur with ASD, which could inform medical evaluation and treatment in ASD, as well as potentially identify etiologically meaningful subgroups. Medical history data were queried in the multiplex family Autism Genetic Resource Exchange (AGRE). Fourteen medical conditions were analyzed. Replication in the Simons Simplex Collection (SSC) was attempted using available medical condition data on gastrointestinal disturbances (GID), sleep problems, allergy and epilepsy. In the AGRE cohort, no discrete clusters emerged among 14 medical conditions. GID and seizures were enriched in unaffected family members, and together with sleep problems, were represented in both AGRE and SSC. Further analysis of these medical conditions identified predictive co‐occurring patterns in both samples. For a child with ASD, the presence of GID predicts sleep problems and vice versa, with an approximately 2‐fold odds ratio in each direction. These risk patterns were replicated in the SSC sample, and in addition, there was increased risk for seizures and sleep problems to co‐occur with GID. In these cohorts, seizure alone was not predictive of the other conditions co‐occurring, but behavioral impairments were more severe as the number of co‐occurring medical symptoms increased. These findings indicate that interdisciplinary clinical care for children with ASD will benefit from evaluation for specific patterns of medical conditions in the affected child and their family members. Autism Res 2015, 8: 771–781. © 015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
doi:10.1002/aur.1492
PMCID: PMC4736680  PMID: 26011086
gastrointestinal disturbances; sleep; seizure; medical symptoms
4.  Time reproduction performance is associated with age and working memory in high functioning youth with autism spectrum disorder 
Lay Abstract
Temporal processing refers to our ability to “sense” or register the passage of time and to use that information to guide behavior. There is evidence that children with autism spectrum disorders (ASD) differ from children without ASD in their ability to process temporal information. Prior research has shown that age and working memory (the ability to hold and manipulate information in short-term memory storage) impact performance on temporal processing tasks in typically developing children, but it is not known whether there are similar associations in youth with ASD. It is also known that children with high levels of inattention and hyperactivity/impulsivity, who do not have ASD, tend to perform more poorly on measures of temporal processing. Our study examined the effects of working memory, age, and inattention/hyperactivity on the accuracy and consistency of temporal processing in 27 high-functioning youth with ASD and 25 youth without ASD. Our results show that youth with ASD are less accurate and less consistent in their ability to estimate time intervals, relative to typically developing youth. The difference in accuracy between the groups is more pronounced at younger ages, while working memory has a differential effect on consistency. Within the ASD group, inattention/hyperactivity was not associated with either accuracy or consistency. This study shows for the first time that both age and working memory affect how youth with and without ASD perceive and represent the passage of time.
Scientific Abstract
Impaired temporal processing has historically been viewed as a hallmark feature of attention-deficit/hyperactivity disorder (ADHD). Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD.
Twenty-seven high functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9–17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 seconds. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity.
A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer working memory performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency.
This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.
doi:10.1002/aur.1401
PMCID: PMC4312276  PMID: 25078724
5.  Longitudinal Volumetric Brain Changes in Autism Spectrum Disorder Ages 6–35 Years 
LAY ABSTRACT
Since the impairments associated with autism spectrum disorder (ASD) tend to persist or worsen from childhood into adulthood, it is of critical importance to examine how the brain develops over this growth epoch. We report initial findings on whole and regional longitudinal brain development in 100 male participants with ASD (226 high-quality MRI scans) compared to 56 typically developing male controls (TDCs) (117 high-quality scans) from childhood into adulthood, for a total of 156 participants scanned over an eight-year period. We provide volumetric growth curves for the entire brain, total gray matter (GM), frontal GM, temporal GM, parietal GM, occipital GM, total cortical white matter (WM), corpus callosum, caudate, thalamus, total cerebellum, and total ventricles. Mean volume of cortical WM was reduced significantly. Decreases in regional mean volumes in the ASD sample were most often due to decreases during late adolescence and adulthood. The growth curve of whole-brain volume showed increased volumes in young children with autism and subsequently decreased during adolescence to meet the TDC curve between 10 and 15 years of age. The volume of many structures continued to decline atypically into adulthood in the ASD sample. The data suggest that ASD is a dynamic disorder with complex changes in whole and regional brain volumes that change over time from childhood into adulthood.
SCIENTIFIC ABSTRACT
Since the impairments associated with autism spectrum disorder (ASD) tend to persist or worsen from childhood into adulthood, it is of critical importance to examine how the brain develops over this growth epoch. We report initial findings on whole and regional longitudinal brain development in 100 male participants with ASD (226 high-quality MRI scans; mean inter-scan interval 2.7 years) compared to 56 typically developing male controls (TDCs) (117 high-quality scans; mean inter-scan interval 2.6 years) from childhood into adulthood, for a total of 156 participants scanned over an eight-year period. This initial analysis includes between one and three high-quality scans per participant that have been processed and segmented to date, with 21% having one scan, 27% with two scans and 52% with three scans in the ASD sample; corresponding percentages for the TDC sample are 30%, 30%, and 40%. The proportion of participants with multiple scans (79% of ASDs and 68% of TDCs) was high in comparison to that of large longitudinal neuroimaging studies of typical development. We provide volumetric growth curves for the entire brain, total gray matter (GM), frontal GM, temporal GM, parietal GM, occipital GM, total cortical white matter (WM), corpus callosum, caudate, thalamus, total cerebellum, and total ventricles. Mean volume of cortical WM was reduced significantly. Mean ventricular volume was increased in the ASD sample relative to the TDCs across the broad age range studied. Decreases in regional mean volumes in the ASD sample most often were due to decreases during late adolescence and adulthood. The growth curve of whole brain volume over time showed increased volumes in young children with autism, and subsequently decreased during adolescence to meet the TDC curve between 10 and 15 years of age. The volume of many structures continued to decline atypically into adulthood in the ASD sample. The data suggest that ASD is a dynamic disorder with complex changes in whole and regional brain volumes that change over time from childhood into adulthood.
doi:10.1002/aur.1427
PMCID: PMC4344386  PMID: 25381736
adolescents; adults; children; growth curve; mixed effects; MRI; variance
6.  Left-Hemispheric Microstructural Abnormalities in Children With High Functioning Autism Spectrum Disorder 
Current theories of the neurobiological basis of Autism Spectrum Disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used Diffusion Tensor Imaging to investigate the microstructural properties of the white matter that mediates inter-regional connectivity in 36 high-functioning children with ASD (HF-ASD), as compared to 37 controls. By employing an atlas-based analysis using LDDMM registration, a widespread, but left-lateralized pattern of abnormalities was revealed. The Mean Diffusivity (MD) of water in the white matter of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical white matter. Across diagnostic groups there was a significant effect of age on left hemisphere MD, with a similar reduction in MD during childhood in both TD and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination, and may reflect increased short-range cortico-cortical connections subsequent to early white matter overgrowth. These findings also highlight left hemispheric connectivity as relevant to the pathophysiology of ASD, and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread, and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD.
doi:10.1002/aur.1413
PMCID: PMC4344401  PMID: 25256103
7.  New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures 
Autism Research  2015;8(5):522-533.
Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP. Autism Res 2015, 8: 522–533. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
doi:10.1002/aur.1466
PMCID: PMC4690162  PMID: 25959701
broader autism phenotype; informant interview; self-report interview; interrater reliability; retest reliability
8.  Predicting Health Utilities for Children with Autism Spectrum Disorders 
Scientific Abstract
Comparative effectiveness of interventions for children with ASDs that incorporates costs is lacking due to the scarcity of information on health utility scores or preference-weighted outcomes typically used for calculating quality-adjusted life years (QALYs). This study created algorithms for mapping clinical and behavioral measures for children with ASDs to health utility scores. The algorithms could be useful for estimating the value of different interventions and treatments used in the care of children with ASDs. Participants were recruited from two Autism Treatment Network sites. Health utility data based on the HUI3 for the child was obtained from the primary caregiver (proxy-reported) through a survey (N=224). During the initial clinic visit, proxy-reported measures of the Child Behavior Checklist, Vineland II Adaptive Behavior Scales, and the PedsQL 4.0 (start measures) were obtained and then merged with the survey data. Nine mapping algorithms were developed using the HUI3 scores as dependent variables in ordinary least squares regressions along with the start measures, the Autism Diagnostic Observation Schedule to measure severity, child age, and cognitive ability as independent predictors. In-sample cross-validation was conducted to evaluate predictive accuracy. Multiple imputation techniques were used for missing data. The average age for children with ASDs in this study was 8.4 (SD=3.5) years. Almost half of the children (47%) had cognitive impairment (IQ<=70). Total scores for all of the outcome measures were significantly associated with the HUI3 score. The algorithms can be applied to clinical studies containing start measures of children with ASDs to predict QALYs gained from interventions.
doi:10.1002/aur.1409
PMCID: PMC4270935  PMID: 25255789
mapping; predictive algorithms; equating measure; autism; health utilities; clinical measure; behavioral measure; quality of life measure
9.  Overlap Between Autism Spectrum Disorders and Attention Deficit Hyperactivity Disorder: Searching for Distinctive/Common Clinical Features 
Autism Research  2015;8(3):328-337.
Recent studies support several overlapping traits between autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD), assuming the existence of a combined phenotype. The aim of our study was to evaluate the common or distinctive clinical features between ASD and ADHD in order to identify possible different phenotypes that could have a clinical value. We enrolled 181 subjects divided into four diagnostic groups: ADHD group, ASD group, ASD+ADHD group (that met diagnostic criteria for both ASD and ADHD), and control group. Intelligent quotient (IQ), emotional and behavior problems, ADHD symptoms, ASD symptoms, and adaptive behaviors were investigated through the following test: Wechsler Intelligence Scale for Children, Wechsler Preschool and Primary Scale of Intelligence or Leiter International Performances Scale Revised, Child Behavior Checklist, Conners' Rating Scales-Revised, SNAP-IV Rating Scale, the Social Communication Questionnaire, Vineland Adaptive Behavior Scales. The ASD+ADHD group differs from ADHD or ASD in some domains such as lower IQ mean level and a higher autistic symptoms severity. However, the ASD+ADHD group shares inattention and hyperactivity deficit and some emotional and behavior problems with the ADHD group, while it shares adaptive behavior impairment with ASD group. These findings provide a new understanding of clinical manifestation of ASD+ADHD phenotype, they may also inform a novel treatment target. Autism Res 2015, 8: 328–337. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
doi:10.1002/aur.1449
PMCID: PMC4654237  PMID: 25604000
autism spectrum disorders; attention deficit hyperactivity disorder; overlapping; intelligent quotient; emotional and behavior problems; ADHD symptoms; ASD symptoms; adaptive behaviors
10.  A Genotype Resource for Postmortem Brain Samples from the Autism Tissue Program 
The Autism Tissue Program (ATP), a science program of Autism Speaks, provides researchers with access to well-characterized postmortem brain tissues. Researchers access these tissues through a peer-reviewed, project-based approval process, and obtain related clinical information from a secure, online informatics portal. However, few of these samples have DNA banked from other sources (such as a blood sample from the same individual), hindering genotype–phenotype correlation and interpretation of gene expression data derived fromthe banked brain tissue. Here, we describe an initiative to extract DNA from Brodmann Area 19, and genotype these samples using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Human1M-Duo DNA Analysis BeadChip genome-wide microarray technologies. We additionally verify reported gender, and infer ethnic background from the single nucleotide polymorphism data. We have also used a rigorous, multiple algorithm approach to identify genomic copy number variation (CNV) from these array data. Following an initial proof of principle study using two samples, 52 experimental samples, consisting of 27 subjects with confirmed or suspected autism and related disorders, 5 subjects with cytogenetically visible duplications of 15q, 2 with epilepsy and 18 age-matched normal controls were processed, yielding high-quality genotype data in all cases. The genotype and CNV data are provided via the ATP informatics portal as a resource for the autism research community.
doi:10.1002/aur.173
PMCID: PMC4605268  PMID: 21254448
autism; autism spectrum disorder; brain; brodmann area 19; copy number variation; genome-wide; microarray; single nucleotide polymorphism
11.  Risperidone and the 5-HT2A receptor antagonist, M100907 improve probabilistic reversal learning in BTBR T+ tf/J mice 
Lay Abstract
Restricted interests and repetitive behaviors in autism can lead to an ‘insistence on sameness’ for routines and decision-making. The ability to adapt choice patterns when external contingencies change is commonly referred to as cognitive flexibility. To date, there are limited options for treating cognitive inflexibility in autism. Risperidone, an atypical antipsychotic, is approved to treat irritability in autism, but less is known of whether it is effective in treating cognitive inflexibility. Risperidone acts at multiple receptors although only actions at a subset of these receptors may be beneficial for cognitive flexibility. 5HT2A receptor blockade represents one pharmacological action of risperidone. Rodent studies have shown that 5HT2A receptor antagonists improve attention and cognitive flexibility. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved cognitive flexibility in the BTBR mouse model of autism. The BTBR mouse compared to C57BL/6J (B6) mice exhibit a deficit in reversing learned choice patterns comparable to that in individuals with autism. The present experiments used a two-choice probabilistic reversal learning test in which the ‘correct’ choice was reinforced on 80% of trials and the ‘incorrect’ choice reinforced on 20% of trials. After initial acquisition, the contingencies were reversed. Both risperidone and M100907 improved probabilistic reversal learning performance in BTBR mice. The same treatments did not improve reversal learning in B6 mice. Because risperidone can often lead to unwanted side effects, treatment with a 5HT2A receptor antagonist may offer an alternative for improving cognitive flexibility in individuals with autism.
Scientific Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating ‘higher-order’ RRBs, e.g. cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist improved probabilistic reversal learning performance in the BTBR T+ tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects.
doi:10.1002/aur.1395
PMCID: PMC4230321  PMID: 24894823
autism; cognitive flexibility; BTBR; reversal learning; serotonin; risperidone
12.  Specific impairment of face processing abilities in children with autism spectrum disorder using the Let’s Face It! Skills Battery 
Although it has been well established that individuals with autism exhibit difficulties in their face recognition abilities, it has been debated whether this deficit reflects a category-specific impairment of faces or a general perceptual bias toward the local level information in a stimulus. In this study, the Let’s Face It! Skills Battery (Tanaka & Schultz, 2008) of developmental face and object processing measures was administered to a large sample of children diagnosed with autism spectrum disorder (ASD) and typical developing (TD) children. The main finding was that when matched for age and IQ, individuals with ASD were selectively impaired in their ability to recognize faces across changes in orientation, expression and featural information. In a face discrimination task, ASD participants showed a preserved ability to discriminate featural and configural information in the mouth region of a face, but were compromised in their ability to discriminate featural and configural information in the eyes. On object processing tasks, ASD participants demonstrated a normal ability to recognize automobiles across changes in orientation and a superior ability to discriminate featural and configural information in houses. These findings indicate that the face processing deficits in ASD are not due to a local processing bias, but reflect a category-specific impairment of faces characterized by a failure to form view-invariant face representations and discriminate information in the eye region of the face.
doi:10.1002/aur.56
PMCID: PMC4589218  PMID: 19360688
13.  Male gender bias in autism and pediatric autoimmunity 
Lay Abstract
Males have a higher incidence of autism than females by approximately 4 to 1. Similarly, males have a higher incidence of some pediatric autoimmune diseases as compared to females. The basis for these disparities is largely unknown. In recent years there is growing evidence that immune and autoimmune dysregulation may be involved in autism. It is suggested here that the hormonal and immune processes that may contribute to a male preponderance in some pediatric autoimmune disorders may play a role in the male preponderance in autism.
Scientific Abstract
Male bias in both autism and pediatric autoimmune disease is thought to involve hormonal perturbations in pregnancy or early childhood in the context of genetic control. These early molecular events, at a time of rapid development, are intimately linked to concurrent development in the brain and immune system. It is suggested here that these early regulatory events may overlap between autism and autoimmunity in determining male sex bias and may provide evidence of an etiological link between autism, immune dysregulation, and autoimmune disease.
doi:10.1002/aur.1227
PMCID: PMC4530611  PMID: 22431266
14.  Family-Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder 
The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted p=0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5′ untranslated region in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5′UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.
doi:10.1002/aur.1383
PMCID: PMC4134733  PMID: 24753316
Autism; serotonin; gene expression; HTR2A; rs6311; monoamine
15.  Susceptibility to distraction in autism spectrum disorder: Probing the integrity of oscillatory alpha-band suppression mechanisms 
Scientific Abstract
When attention is directed to one information stream over another, the brain can be configured in advance to selectively process the relevant stream and suppress potentially distracting inputs. One key mechanism of suppression is through the deployment of anticipatory alpha-band (~10Hz) oscillatory activity, with greater alpha-band power observed in cortical regions that will ultimately process the distracting stream. Atypical attention has been implicated in autism spectrum disorder (ASD), including greater interference by distracting task-irrelevant inputs. Here we tested the integrity of these alpha-band mechanisms in ASD using an intersensory attention task. EEG was recorded while participants were cued on a trial-by-trial basis to selectively deploy attention to the visual or auditory modality in anticipation of a target within the cued modality. Whereas typically developing children showed the predicted alpha-band modulation, with increased alpha-band power over parieto-occipital scalp when attention was deployed to the auditory compared to the visual modality, this differential pattern was entirely absent at the group level in the ASD cohort. Further, only the ASD group showed impaired performance due to the presence of task-irrelevant sensory information. These data suggest that impaired modulation of alpha-band activity plays a role in increased distraction from extraneous sensory inputs in ASD.
doi:10.1002/aur.1374
PMCID: PMC4183200  PMID: 24678054
Autism; EEG; Oscillations; Attention
16.  Brain Function Differences in Language Processing in Children and Adults with Autism 
Comparison of brain function between children and adults with autism provides an understanding of the effects of the disorder and associated maturational differences on language processing. Functional imaging (functional magnetic resonance imaging) was used to examine brain activation and cortical synchronization during the processing of literal and ironic texts in 15 children with autism, 14 children with typical development, 13 adults with autism, and 12 adult controls. Both the children and adults with autism had lower functional connectivity (synchronization of brain activity among activated areas) than their age and ability comparison group in the left hemisphere language network during irony processing, and neither autism group had an increase in functional connectivity in response to increased task demands. Activation differences for the literal and irony conditions occurred in key language-processing regions (left middle temporal, left pars triangularis, left pars opercularis, left medial frontal, and right middle temporal). The children and adults with autism differed from each other in the use of some brain regions during the irony task, with the adults with autism having activation levels similar to those of the control groups. Overall, the children and adults with autism differed from the adult and child controls in (a) the degree of network coordination, (b) the distribution of the workload among member nodes, and (3) the dynamic recruitment of regions in response to text content. Moreover, the differences between the two autism age groups may be indicative of positive changes in the neural function related to language processing associated with maturation and/or educational experience.
doi:10.1002/aur.1291
PMCID: PMC4492467  PMID: 23495230
fMRI; language processing; development; functional connectivity
17.  The Neuropsychology of Male Adults With High-Functioning Autism or Asperger Syndrome† 
Autism Research  2014;7(5):568-581.
Autism Spectrum Disorder (ASD) is diagnosed on the basis of behavioral symptoms, but cognitive abilities may also be useful in characterizing individuals with ASD. One hundred seventy-eight high-functioning male adults, half with ASD and half without, completed tasks assessing IQ, a broad range of cognitive skills, and autistic and comorbid symptomatology. The aims of the study were, first, to determine whether significant differences existed between cases and controls on cognitive tasks, and whether cognitive profiles, derived using a multivariate classification method with data from multiple cognitive tasks, could distinguish between the two groups. Second, to establish whether cognitive skill level was correlated with degree of autistic symptom severity, and third, whether cognitive skill level was correlated with degree of comorbid psychopathology. Fourth, cognitive characteristics of individuals with Asperger Syndrome (AS) and high-functioning autism (HFA) were compared. After controlling for IQ, ASD and control groups scored significantly differently on tasks of social cognition, motor performance, and executive function (P's < 0.05). To investigate cognitive profiles, 12 variables were entered into a support vector machine (SVM), which achieved good classification accuracy (81%) at a level significantly better than chance (P < 0.0001). After correcting for multiple correlations, there were no significant associations between cognitive performance and severity of either autistic or comorbid symptomatology. There were no significant differences between AS and HFA groups on the cognitive tasks. Cognitive classification models could be a useful aid to the diagnostic process when used in conjunction with other data sources—including clinical history. Autism Res 2014, 7: 568–581. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
doi:10.1002/aur.1394
PMCID: PMC4489335  PMID: 24903974
autism spectrum disorder; cognitive profiles; autistic symptomatology; comorbid psychopathology; support vector machine classification; autistic subtypes
18.  Mice exposed to diagnostic ultrasound in utero are less social and more active in social situations relative to controls 
Clinical use of diagnostic ultrasound imaging during pregnancy has a long history of safety and diagnostic utility, as supported by numerous human case reports and epidemiological studies. However, there exist in vivo studies linking large but clinically relevant doses of ultrasound applied to mouse fetuses in utero to altered learning, memory, and neuroanatomy of those mice. Also, there exists a well-documented significant increase in the likelihood of non-right handedness in boys exposed to diagnostic ultrasound in utero, potentially relevant given the increased prevalence of autism in males, and some reports of excess non-right-handedness in this population. Motivated by these observations, we applied 30 minutes of diagnostic ultrasound to pregnant mice at embryonic day 14.5 and assayed the social behavior of their male pups three weeks after their birth. The ultrasound-exposed pups were significantly (p < 0.01) less interested in social interaction than sham-exposed pups in a 3-chamber sociability test. In addition, they demonstrated significantly (p < 0.05) more activity relative to the sham-exposed pups, but only in the presence of an unfamiliar mouse. These results suggest that fetal exposure to diagnostic ultrasound applied in utero can alter typical social behaviors in young mice that may be relevant for autism. There exist meaningful differences between the exposure of diagnostic ultrasound to mice versus humans that require further exploration before this work can usefully inform clinical practice. Future work should address these differences as well as clarify the extent, mechanisms, and functional effects of diagnostic ultrasound’s interaction with the developing brain.
doi:10.1002/aur.1349
PMCID: PMC4025980  PMID: 24249575
diagnostic ultrasound; mouse social behavior; autistic-like behavior; risk factor
19.  Identification of Chromosome 7 Inversion Breakpoints in an Autistic Family Narrows Candidate Region for Autism Susceptibility 
Chromosomal breaks and rearrangements have been observed in conjunction with autism and autistic spectrum disorders. A chromosomal inversion has been previously reported in autistic siblings, spanning the region from approximately 7q22.1 to 7q31. This family is distinguished by having multiple individuals with autism and associated disabilities. The region containing the inversion has been strongly implicated in autism by multiple linkage studies, and has been particularly associated with language defects in autism as well as in other disorders with language components. Mapping of the inversion breakpoints by FISH has localized the inversion to the region spanning approximately 99–108.75Mb of chromosome 7. The proximal breakpoint has the potential to disrupt either the coding sequence or regulatory regions of a number of cytochrome P450 genes while the distal region falls in a relative gene desert. Copy number variant analysis of the breakpoint regions detected no duplication or deletion that could clearly be associated with disease status. Association analysis in our autism data set using single nucleotide polymorphisms located near the breakpoints showed no significant association with proximal breakpoint markers, but has identified markers near the distal breakpoint (~108–110Mb) with significant associations to autism. The chromosomal abnormality in this family strengthens the case for an autism susceptibility gene in the chromosome 7q22-31 region and targets a candidate region for further investigation.
doi:10.1002/aur.96
PMCID: PMC4441209  PMID: 19877165
molecular genetics; paracentric inversion; fluorescent in situ hybridization (FISH); genome-wide association study (GWAS)
20.  Variants in Several Genomic Regions Associated with Asperger Disorder 
Asperger disorder (ASP) is one of the autism spectrum disorders (ASD) and is differentiated from autism largely on the absence of clinically significant cognitive and language delays. Analysis of a homogenous subset of families with ASP may help to address the corresponding effect of genetic heterogeneity on identifying ASD genetic risk factors. To examine the hypothesis that common variation is important in ASD, we performed a genome-wide association study (GWAS) in 124 ASP families in a discovery data set and 110 ASP families in a validation data set. We prioritized the top 100 association results from both cohorts by employing a ranking strategy. Novel regions on 5q21.1 (P = 9.7 × 10−7) and 15q22.1–q22.2 (P = 7.3 × 10−6) were our most significant findings in the combined data set. Three chromosomal regions showing association, 3p14.2 (P = 3.6 × 10−6), 3q25–26 (P = 6.0 × 10−5) and 3p23 (P = 3.3 × 10−4) overlapped linkage regions reported in Finnish ASP families, and eight association regions overlapped ASD linkage areas. Our findings suggest that ASP shares both ASD-related genetic risk factors, as well as has genetic risk factors unique to the ASP phenotype.
doi:10.1002/aur.158
PMCID: PMC4435556  PMID: 21182207
asperger; susceptibility; genetics
21.  Rumination and Perceived Impairment Associated with Depressive Symptoms in a Verbal Adolescent-Adult ASD Sample 
The aim of this study was to examine the association between depressive symptoms and several psychosocial constructs (insight into autism symptoms, rumination, desire for social interaction, and satisfaction with social support) that may play a role in the development or maintenance of depression in verbally fluent adolescents and adults with ASD. Participants included 50 individuals with ASD and verbal IQ >= 70, aged 16-35 (sample size varied by measure). Elevated depressive symptoms on the Beck Depression Inventory, 2nd edition, were associated with greater self-perceived autism-related impairments (n=48), greater rumination (n=21), and lower perceived social support (n=37). Rumination tended to moderate the association between self-perceived autism symptoms and BDI-II scores (n=21), and was significantly associated with ASD-related Insistence on Sameness behaviors (n=18). An unexpected relationship between depressive features and social participation and motivation will need to be clarified by longitudinal research. These and similar findings contribute to our understanding of the phenomenology of depression in ASD, which is critical to the development of practical prevention and treatment.
doi:10.1002/aur.1377
PMCID: PMC4429601  PMID: 24802136
autism spectrum disorders; depression; rumination; insight; social motivation; social support
22.  Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas 
Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals’ genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum’s role in autism.
doi:10.1002/aur.1344
PMCID: PMC4418792  PMID: 24151012
animal models; neuroimaging; neuroanatomy; structural MRI; genetics
23.  Investigation of Maternal Genotype Effects in Autism by Genome-Wide Association 
Lay Abstract
Autism spectrum disorders (ASDs) are pervasive developmental disorders which have both a genetic and environmental component. One source of the environmental component is the in utero (prenatal) environment. The maternal genome can potentially contribute to the risk of autism in children by altering this prenatal environment.
In this study, the possibility of maternal genotype effects was explored by looking for common variants (single nucleotide polymorphisms, or SNPs) in the maternal genome associated with increased risk of autism in children. We performed a case/control genome-wide association study (GWAS) using mothers of probands as cases and either fathers of probands or normal females as controls, using two collections of families with autism.
We did not identify any SNP that reached significance and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles each carrying a small effect. This suggested that if there is a contribution to autism risk through common-variant maternal genetic effects, it may be the result of multiple loci of small effects. We did not investigate rare variants in this study.
Scientific Abstract
Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings.
In this study, the possibility of maternal genotype effects was examined by looking for common variants (single nucleotide polymorphisms, or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study (GWAS) was performed using mothers of probands as cases and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange (AGRE) and Illumina Genotype Control Database (iCon) were used as our discovery cohort (n=1616). The same analysis was then replicated on Simon Simplex Collection (SSC) and Study of Addiction: Genetics and Environment (SAGE) datasets (n=2732).
We did not identify any SNP that reached genome-wide significance (p<10−8) and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect.
doi:10.1002/aur.1363
PMCID: PMC3989385  PMID: 24574247
maternal genotype effect; autism; GWAS; AGRE; SSC
24.  Autism-related Neuroligin-3 Mutation Alters Social Behavior and Spatial Learning 
LAY ABSTRACT
Mutations in neuroligin genes have been identified in association with autism. This manuscript provides characterization of a specific mutation in the neuroligin-3 gene that has been associated with autism in two brothers. The resulting autism model has alterations in social and cognitive function reminiscent of autism in patients. This model will be useful to understand the role of neuroligin dysfunction as a rare cause of autism.
SCIENTIFIC ABSTRACT
Multiple candidate genes have been identified for autism spectrum disorders. While some of these genes reach genome-wide significance, others, such as the R451C point mutation in the synaptic cell adhesion molecule neuroligin-3, appear to be rare. Interestingly, two brothers with the same R451C point mutation in neuroligin-3 present clinically on seemingly disparate sides of the autism spectrum. These clinical findings suggest genetic background may play a role in modifying the penetrance of a particular autism-associated mutation. Animal models may contribute additional support for such mutations as functionally relevant and can provide mechanistic insights. Previously, in collaboration with the Südhof laboratory, we reported that mice with an R451C substitution in neuroligin-3 displayed social deficits and enhanced spatial learning. While some of these behavioral abnormalities have since been replicated independently in the Südhof laboratory, observations from the Crawley laboratory failed to replicate these findings in a similar neuroligin-3 mutant mouse model and suggested that genetic background may contribute to variation in observations across laboratories. Therefore we sought to replicate our findings in the neuroligin-3 R451C point mutant knockin mouse model (NL3R451C) in a different genetic background. We backcrossed our NL3R451C mouse line onto a 129S2/SvPasCrl genetic background and repeated a subset of our previous behavioral testing. NL3R451C mice on a 129S2/SvPasCrl displayed social deficits, enhanced spatial learning, and increased locomotor activity. These data extend our previous findings that NL3R451C mice exhibit autism-relevant behavioral abnormalities and further suggest that different genetic backgrounds can modify this behavioral phenotype through epistatic genetic interactions.
doi:10.1002/aur.1362
PMCID: PMC3989414  PMID: 24619977
25.  Two to ten years: Developmental trajectories of joint attention in children with ASD who received targeted social communication interventions 
Lay Abstract
This study follows 40 children who were participants in a randomized controlled early intervention trial (Kasari et al., 2006, 2008, 2012) from early childhood (2–5 years of age) to elementary school age (8–10 years). The growth trajectories of social-communication and language outcomes in these children were estimated based on 5 time points during that period. The children were grouped by diagnosis at the last follow-up (Autism, ASD, No Diagnosis) and by their original treatment group assignment (Joint attention, Symbolic Play, Control), and differences between these groups evaluated. Results showed that joint attention skills of coordinated joint looking and showing increased over time and pointing to share interest increased over the first year measured and decreased thereafter. These trajectories were influenced by both original treatment assignment and diagnostic status at the follow-up. In addition, a cross-lagged panel analysis suggests a causal relationship between early pointing and later language development. This study highlights the longitudinal and developmental importance of measures of early core deficits in autism and suggests that both treatment and ASD symptomatology may influence growth in these skills over time.
Scientific Abstract
This study follows 40 children who were participants in a randomized controlled early intervention trial (Kasari et al., 2006, 2008, 2012) from early childhood (2–5 years of age) to elementary school age (8–10 years). To fully utilize the available longitudinal data, the general linear mixed model (GLMM) was the primary analytical approach. The growth trajectories of joint attention skills (pointing, coordinated joint looking and showing) and expressive language outcomes in these children were estimated based on 5 time points during the measurement period. The children were grouped by diagnosis at the last follow-up (Autism, ASD, No Diagnosis) and by their original treatment group assignment (Joint Attention, Symbolic Play, Control), and differences between these groups evaluated. Results showed that joint attention skills of coordinated joint looking and showing increased over time and pointing to share interest increased over the first year measured and decreased thereafter. These trajectories were influenced by both original treatment assignment and diagnostic status at the follow-up. In addition, a cross-lagged panel analysis revealed a causal relationship between early pointing and later language development. This study highlights the longitudinal and developmental importance of measures of early core deficits in autism and suggests that both treatment and ASD symptomatology may influence growth in these skills over time.
doi:10.1002/aur.1360
PMCID: PMC4036529  PMID: 24550145
early intervention; social-communication

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