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Purpose: The aim of the present study was to compare scale and conditional reliability derived from item response theory analyses among the most commonly used, as well as several newly developed, observation, interview, and parent-report autism instruments., Methods: When available, data sets were combined to facilitate large sample evaluation. Scale reliability (internal consistency, average corrected item-total correlations, and model reliability) and conditional reliability estimates were computed for total scores and for measure subscales., Results: Generally good to excellent scale reliability was observed for total scores for all measures, scale reliability was weaker for RRB subscales of the ADOS and ADI-R, reflecting the relatively small number of items for these measures. For diagnostic measures, conditional reliability tended to be very good (> 0.80) in the regions of the latent trait where ASD and non-ASD developmental disability cases would be differentiated. For parent-report scales, conditional reliability of total scores tended to be excellent (> 0.90) across very wide ranges of autism symptom levels, with a few notable exceptions., Conclusions: These findings support the use of all of the clinical observation, interview, and parent-report autism symptom measures examined, but also suggest specific limitations that warrant consideration when choosing measures for specific clinical or research applications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated., Competing Interests: Declaration of interests M.C.-M., S.W.D., and J.L.W. are employees of Altos Labs, Inc. M.C.-M. is a shareholder of Altos Labs, Inc. and Mikrovia, Inc., (Copyright © 2023. Published by Elsevier Inc.)

Objective: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD., Method: Diffusion-weighted MRIs were obtained from same-sex twin pairs (6-15 years of age) in which at least 1 twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain, and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a novel Twin-Pair Difference Score analysis method that produces quantitative estimates of the genetic and environmental contributions to shared covariance between different brain and behavioral traits., Results: Good-quality data were available from 84 twin pairs, 50 ASD pairs (32 concordant for ASD [16 monozygotic; 16 dizygotic], 16 discordant for ASD [3 monozygotic; 13 dizygotic], and 2 pairs in which 1 twin had ASD and the other exhibited some subthreshold symptoms [1 monozygotic; 1 dizygotic]) and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A = 0.80, 95% CI [0.57, 1.02]; A = 0.80 [0.55, 1.04]) and twins concordant for having ASD (A = 0.71 [0.33, 1.09]; A = 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD because Twin-Pair Difference-Score analysis indicated that genetic factors may have contributed to ∼40% to 50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD; for example, our analyses suggested that unique environmental factors may have contributed to ∼10% to 20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule., Conclusion: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted and they participated in the data collection, design, analysis, and/or interpretation of the work., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Insistence on sameness (IS) encompasses a range of behavioral patterns, including resistance to change, routines, and ritualized behaviors, that can be present across social and non-social contexts. Given the breadth of behaviors encompassed by IS, it is important to determine whether this domain is best conceptualized and measured as uni- or a multi-dimensional construct. Therefore, the current study aimed to characterize the structure of IS and explore potentially distinct of patterns of associations between identified IS factors and relevant correlates, including age, sex, IQ, anxiety, social abilities, emotional and behavioral dysregulation, and sensory hypersensitivity. Exploratory graph analysis was conducted using the dimensional assessment of restricted and repetitive behaviors to examine the structure of IS in a sample 1892 autistic youth (M age  = 10.82, SD age  = 4.14; range: 3-18 years; 420 females) recruited from the Simons Foundation Powering Autism Research for Knowledge cohort. Three distinct IS subdomains labeled as IS-Ritualistic/sameness, IS-Routines, and IS-Others (referring to IS behaviors during interactions with others) were identified. Generalized additive models demonstrated that each of the IS subdomains showed a unique pattern of association with key variables. More specifically, while sensory hypersensitivity was significantly associated with IS-Ritualistic/sameness and IS-Routines, it was not associated with IS-Others. Further, while emotional dysregulation was a unique predictor of IS-Ritualistic/sameness (but not IS-Routines or IS-Others), social interaction abilities were a unique predictor of IS-Routines (but not IS-Ritualistic/sameness or IS-Others). Current findings provide preliminary evidence that the IS may encompass several distinct subdomains., (© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Aim: To describe the development and initial psychometric evaluation of a new, freely available measure, the Autism Symptom Dimensions Questionnaire (ASDQ)., Method: After development and revision of an initial 33-item version, informants completed a revised 39-item version of the ASDQ on 1467 children and adolescents (aged 2-17 years), including 104 with autism spectrum disorder (ASD)., Results: The initial 33-item version of the ASDQ had good reliability and construct validity. However, only four specific symptom factors were identified, potentially due to an insufficient number of items. Factor analyses of the expanded instrument identified a general ASD factor and nine specific symptom factors with good measurement invariance across demographic groups. Scales showed good-to-excellent overall and conditional reliability. Exploratory analyses of predictive validity for ASD versus neurotypical and other developmental disability diagnoses indicated good accuracy for population and at-risk contexts., Interpretation: The ASDQ is a free and psychometrically sound informant report instrument with good reliability of measurement across a continuous range of scores and preliminary evidence of predictive validity. The measure may be a useful alternative to existing autism symptom measures but further studies with comparison of clinical diagnoses using criterion-standard instruments are needed., What This Paper Adds: The Autism Symptom Dimensions Questionnaire (ASDQ) is a new, freely available measure of autism symptoms. The ASDQ showed reliable and accurate measurement of autism symptoms. The measure had good screening efficiency for autism spectrum disorder relative to other developmental conditions., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

A broad range of interests characterized by unusual content and/or intensity, labeled as circumscribed interests (CI), are a core diagnostic feature of autism. Recent evidence suggests that a distinction can be drawn between interests that, although characterized by unusually high intensity and/or inflexibility, are otherwise common in terms of their content (e.g., an interest in movies or animals), labeled as restricted interests (RI), and interests that are generally not salient outside of autism (e.g., an interest in traffic lights or categorization), labeled as unusual interests (UI). The current study aimed to further characterize RI and UI by exploring their association with age, sex, IQ, and social motivation, as well as to examine differences in the adaptive benefits and negative impacts of these two subdomains. Parents of 1892 autistic children and adolescents (M age  = 10.82, SD age  = 4.14; 420 females) completed an online survey including the Dimensional Assessment of Restricted and Repetitive Behaviors and the Social Communication Questionnaire. Both RI and UI were found to be highly frequent. Sex-based differences were observed in the content, but not intensity, of CI such that females were more likely to show interests with a social component. Finally, RI and UI showed distinct patterns of association with age, sex, IQ, and social motivation, as well as metrics of adaptive benefits and negative impacts. Findings afford a more nuanced understanding of sex-based differences in CI and, crucially, provide preliminary evidence that RI and UI represent distinct constructs that should be studied independently in future research., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Hopelessness in parents has implications for parents' own well-being as well as their ability to meet the needs of their children. In the present study, we examined the effect of maladaptive behaviors in children with autism on parental hopelessness, with particular attention to whether parental reflective functioning would moderate the effect of maladaptive behaviors on parental hopelessness. Our sample included 68 parents of children with autism between the ages of 3 and 18. Findings revealed a significant positive relationship between maladaptive behaviors in the children and hopelessness in the parents. Moreover, parental reflective functioning moderated the effect of child maladaptive behaviors on parental hopelessness, such that children's maladaptive behaviors were positively associated with parental hopelessness in parents with low (but not high) reflective functioning. Findings suggest parental reflective functioning may be a protective factor against parental hopelessness, and thus a possible target for interventions for hopelessness in parents whose children with autism exhibit greater maladaptive behaviors., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

The present study aimed to examine anxiety profiles among children and adolescents on the autism spectrum. It further aimed to characterize the association between the identified anxiety profiles and key clinical and developmental variables. The Spence Children's Anxiety Scale-Parent Version (SCAS-P) data from a large international pooled sample of 870 caregivers of autistic children and adolescents (M age  = 11.6 years, SD age  = 2.77; 107 females) was used. Latent profile analysis identified a three-anxiety profile solution exhibiting high entropy (0.80) and high latent profile probabilities, with good classification accuracy. Identified profiles fell along the severity spectrum and were named as the mild (n = 498), moderate (n = 272) and severe (n = 100) anxiety profiles. There were no statistically significant differences between the three anxiety profiles in terms of sex distribution. Participants in the mild profile were significantly younger than those in the severe profile, had significantly fewer social communication difficulties than youth in the moderate anxiety profile group and had significantly fewer restricted and repetitive behaviors and lower cognitive functioning scores compared to participants in moderate and severe anxiety profiles. This is the first study to move beyond identifying associations and group-level differences to exploring and identifying characteristics of anxiety-based subgroups at an individual level that differ on key clinical and developmental variables. The subgroups identified in this study are a preliminary, yet important, first step towards informing future assessment and individualized interventions aiming to support young people on the autism spectrum to reduce and manage anxiety. LAY SUMMARY: This study tried to understand if there are subgroups of autistic young people who may have similar anxiety profiles. We found that we could meaningfully group young people into three groups based on how severe the anxiety symptoms their caregivers reported were: a group with low levels of anxiety, those with moderate anxiety, and those with more severe anxiety. We also found that the young people in the mild group were younger, had fewer autism traits and lower levels of intellectual functioning than young people in the other two groups., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Lay Abstract: Despite being highly prevalent among people with autism, restricted and unusual interests remain under-researched and poorly understood. This article confirms that restricted interests are very frequent and varied among children and adolescents with autism. It also further extends current knowledge in this area by characterizing the relationship between the presence, number, and type of restricted interests with chronological age, sex, cognitive functioning, and social and communication symptoms.

The current study aimed to explore the factor structure of a broad range of restricted and repetitive behaviors (RRB) within the autism spectrum. Exploratory structural equation modeling was conducted using individual item-level data from the Diagnostic Interview for Social and Communication Disorders (DISCO). DISCO is a comprehensive semi-structured interview used by clinicians to elicit information from caregivers about the individual's profile of development and behavior. Data from a sample of 226 individuals with a clinical diagnosis of autism spectrum disorder (ASD) (189 males; M age  = 11.82 years, SD age  = 7.87) were analyzed. The six-factor structure provided the most optimal and interpretable fit (comparative fit index = 0.944, Tucker-Lewis index = 0.923, root mean square error of approximation = 0.018). Derived factors were interpreted as repetitive motor behaviors (RMB), unusual sensory and object focused interests (USOI), sensory sensitivity (SS), insistence on sameness (IS), circumscribed interests (CI) and stereotyped language (SL). Age was significantly negatively associated with RMB, USOI and SL but not with SS, IS or CI factor scores. None of the factors were associated with sex. ASD individuals with intellectual disability (ID) had the highest RMB, USOI, SS and SL scores while those without ID had the highest IS and CI scores. Our findings provide preliminary evidence for the utility of the DISCO as a comprehensive measure of several distinct RRB domains in both research and clinical contexts. Importantly, the current investigation highlights crucial areas for measurement development. LAY SUMMARY: The diagnostic Interview for Social and Communication Disorders (DISCO) is a detailed caregiver report clinical interview designed to capture a wide range of key features associated with autism spectrum disorder, including restricted and repetitive behaviors (RRB). This paper provides initial evidence that the DISCO is a promising measure for assessing a wide range of RRB including repetitive motor behaviors, insistence on sameness, circumscribed interests, unusual interests in sensory stimuli, sensory sensitivity and stereotypic language., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Objective: Despite being a core diagnostic feature of autism spectrum disorder (ASD), demographic, developmental and clinical correlates of restricted and repetitive behaviors and interests (RRB) remain poorly characterized. This study aimed to utilize the largest available RRB data set to date to provide a comprehensive characterization of how distinct RRB domains vary according to a range of individual characteristics., Method: Data were obtained from 17,581 children and adolescents with ASD (mean age = 8.24 years, SD age = 4.06) from the Simons Foundation Powering Autism Research for Knowledge cohort. Caregivers completed the Repetitive Behavior Scale-Revised questionnaire as a measure of repetitive motor behaviors, self-injurious behaviors, compulsions, insistence on sameness, and circumscribed interests RRB domains. Caregivers also provided information on children's cognitive functioning, language ability, and social and communication impairments., Results: Male sex was associated with higher severity of repetitive motor behaviors and restricted interests and with lower severity of compulsions and self-injurious behaviors; no sex differences were found for the insistence on sameness domain. Although repetitive motor behaviors showed a mostly linear (negative) association with age, other RRB domains showed more complex and nonlinear pattern of associations. Higher severity of social and communication impairments provided significant independent contribution in predicting higher severity of all RRB domains at the p < .001 level; however, these effects were small (d < 0.25). The strongest of these effects was observed for insistence on sameness (d = 0.24), followed by repetitive motor behaviors (d = 0.21), compulsions (d = 0.17), restricted interests (d = 0.14), and self-injurious behaviors (d = 0.12)., Conclusion: Findings reported here provide further evidence that RRB subdomains show a somewhat distinct pattern of associations with demographic, developmental, and clinical variables, with a key implication that separate consideration of these domains can help to facilitate efforts to understand diverse ASD etiology and to inform the design of effective interventions., (Copyright © 2021. Published by Elsevier Inc.)

The present study examined language trajectories and placement outcomes for children with autism spectrum disorder (ASD) receiving early intensive behavioral intervention (EIBI). Language measures were collected at baseline and 6, 12, 18, 24, and 36 months or until exit from EIBI in 131 children with ASD. Growth models estimated overall and subgroup language trajectories. Overall, children receiving EIBI showed substantial increases in language relative to normative expectations. Earlier age at EIBI start, higher baseline cognitive function, and lower baseline ASD severity predicted better language trajectories. Although there was significant variability in language trajectories and educational outcomes, most children showed significant increases in language scores, relative to normative expectations. Additional research, in more representative samples, is needed to understand this variability., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Deficits in social skills are common in children with Autism Spectrum Disorder (ASD), and there is an urgent need for effective social skills interventions, especially for improving interactions with typically developing peers. This study examined the effects of a naturalistic behavioral social skills intervention in improving social initiations to peers through a randomized controlled trial. Analyses of multimethod, multi-informant measures indicated that children in the active group (SIMI) demonstrated greater improvement in the types of initiations which were systematically prompted and reinforced during treatment (i.e., behavior regulation). Generalization to joint attention and social interaction initiation types, as well as collateral gains in broader social functioning on clinician- and parent-rated standardized measures were also observed., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Restricted and repetitive behaviors (RRB) in autism spectrum disorder (ASD) encompass several distinct domains. However, commonly used general ASD measures provide broad RRB scores rather than assessing separate RRB domains. The main objective of the current investigation was to conduct a psychometric evaluation of the ability of the Social Responsiveness Scale (SRS-2), the Social Communication Questionnaire (SCQ), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to capture different RRB constructs., Methods: Exploratory Structural Equation Modeling (ESEM) was conducted using individual item-level data from the SRS-2, SCQ, ADI-R and the ADOS. Data were obtained from five existing publicly available databases. For the SRS-2, the final sample consisted of N = 16,761 individuals (M age  = 9.43, SD = 3.73; 18.5% female); for the SCQ, of N = 15,840 (M age  = 7.99, SD = 4.06; 18.1% female); for the ADI-R, of N = 8985 (M age  = 8.86, SD = 4.68; 19.4% female); and for the ADOS, of N = 6314 (M age  = 12.29, SD = 6.79; 17.7% female)., Results: The three-factor structure provided the most optimal and interpretable fit to data for all measures (comparative fit index ≥ .983, Tucker Lewis index ≥ .966, root mean square error of approximation ≤ .028). Repetitive-motor behaviors, insistence on sameness and unusual or circumscribed interests factors emerged across all instruments. No acceptable fit was identified for the ADOS., Limitations: The five datasets used here afforded a large as well as wide distribution of the RRB item scores. However, measures used for establishing convergent and divergent validity were only available for a portion of the sample., Conclusions: Reported findings offer promise for capturing important RRB domains using general ASD measures and highlight the need for measurement development.

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABA A receptor densities can identify objective molecular markers in ASD. We measured both total GABA A receptor densities by using [ 18 F]flumazenil positron emission tomography ([ 18 F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy ( 1 H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABA A receptor densities between ASD and TD groups. However, 1 H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

Lay Abstract: In this study, we examined parental reflective functioning using the Parental Developmental Interview when parents were talking about their interactions with their child with autism versus the child's typically developing siblings. Our sample included 30 parents who had a child between the ages of 3 and 18 years with a clinical diagnosis of autism spectrum disorder and at least one typically developing child. Findings indicated that parents exhibited significantly higher reflective functioning when interacting with their child with autism spectrum disorder versus the typically developing siblings, and the difference was moderated by parental self-efficacy.

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs., Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity., Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated., Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors., Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD., Competing Interests: None declared., (© 2020 Joule Inc. or its licensors)

This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Parents of children diagnosed with autism spectrum disorder (ASD) report higher levels of stress and other negative affective states than parents of typically developing children. One important resource in managing these heightened levels of negative affect is emotion regulation, which in turn depends upon the ability to recognize and understand one's own and others' mental states (referred to as mentalization or reflective functioning). In this study, parents of children with ASD either participated in a mentalization-based group intervention (N = 36) or a delayed treatment (N = 28). Compared to delayed treatment participants, parents in the mentalization-based group had increases in reflective functioning and in the belief that emotions can change. Moreover, they reported decreased behavioral and emotional symptoms in their children, and greater parental self-efficacy. These preliminary findings support previous studies, which have shown that mentalization-based interventions for parents lead to positive outcomes, and suggest that these findings may apply to a diverse population of parents such as those of children with broader autism phenotype or children with different neurological disorders. Further studies to evaluate the effects of the intervention are recommended. Autism Res 2019, 12: 1077-1086. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, parents of children with ASD participated in a group intervention designed to increase their awareness of mental states (their own and their children's) and to enhance their emotion regulation. Compared to delayed treatment parents, those in the intervention group showed increased awareness of developmental states, and reported increased belief that emotions can change and decreased levels of behavioral and emotional symptoms in their children., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues (eg, cerebrospinal fluid [CSF]) by which to identify markers of disease and targets for treatment. Here, we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. Ann Neurol 2018;84:611-615., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD ( N  = 112)., Findings: Anandamide concentrations significantly differentiated ASD cases ( N  = 59) from controls ( N  = 53), such that children with lower anandamide concentrations were more likely to have ASD ( p  = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children ( p  = 0.034)., Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD., Competing Interests: All research procedures were approved by the Stanford University Institutional Review Board prior to participant enrollment. Participants’ parents provided written consent prior to initiation of any experimental procedures, and written assent was obtained from participants when appropriate (e.g., children ≥ 7 years of age and deemed intellectually capable).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension., Methods: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day., Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks., Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

This study's objective was to assess maintenance of treatment effects 3 months after completion of a 12-week Pivotal Response Treatment (PRT) parent education group. Families who completed the active treatment (N = 23) were followed for an additional 12 weeks to measure changes in language and cognitive skills. Results indicated a significant improvement in frequency of functional utterances, with maintenance at 3-month follow-up [F(2, 21): 5.9, p = .009]. Children also made significant gains on the Vineland Communication Domain Standard Score [F(2, 12):11.74, p = .001] and the Mullen Scales of Early Learning Composite score [F(1, 20) = 5.43, p = .03]. These results suggest that a brief PRT parent group intervention can lead to improvements in language and cognitive functioning that are maintained 12 weeks post treatment.

Background: With rates of autism diagnosis continuing to rise, there is an urgent need for effective and efficient service delivery models. Pivotal Response Treatment (PRT) is considered an established treatment for autism spectrum disorder (ASD); however, there have been few well-controlled studies with adequate sample size. The aim of this study was to conduct a randomized controlled trial to evaluate PRT parent training group (PRTG) for targeting language deficits in young children with ASD., Methods: Fifty-three children with autism and significant language delay between 2 and 6 years old were randomized to PRTG (N = 27) or psychoeducation group (PEG; N = 26) for 12 weeks. The PRTG taught parents behavioral techniques to facilitate language development. The PEG taught general information about ASD (clinical trial NCT01881750; http://www.clinicaltrials.gov)., Results: Analysis of child utterances during the structured laboratory observation (primary outcome) indicated that, compared with children in the PEG, children in the PRTG demonstrated greater improvement in frequency of utterances (F(2, 43) = 3.53, p = .038, d = 0.42). Results indicated that parents were able to learn PRT in a group format, as the majority of parents in the PRTG (84%) met fidelity of implementation criteria after 12 weeks. Children also demonstrated greater improvement in adaptive communication skills (Vineland-II) following PRTG and baseline Mullen visual reception scores predicted treatment response to PRTG., Conclusions: This is the first randomized controlled trial of group-delivered PRT and one of the largest experimental investigations of the PRT model to date. The findings suggest that specific instruction in PRT results in greater skill acquisition for both parents and children, especially in functional and adaptive communication skills. Further research in PRT is warranted to replicate the observed results and address other core ASD symptoms., (© 2014 Association for Child and Adolescent Mental Health.)

The changes in the diagnostic classification of the pervasive developmental disorders from the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) to DSM-5 are expected to affect patients with autism, their families, as well as clinicians and researchers in the field of autism. This article reviews the new DSM-5 diagnostic criteria for Autism Spectrum Disorder (ASD) and Social Communication Disorder (SCD), and discusses potential consequences in the perspectives of major stakeholders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change., Methods: Twenty-three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures., Results: Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance., Conclusion: This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence., (© 2013.)

Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range=8-17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Reasons for the underutilization of genetics services by families of children with autism spectrum disorders (ASD) are not well understood. We report the identification of factors associated with this underuse. Survey-based study of parents and/or guardians of children with ASD. One hundred fifty-five families completed the questionnaire. Thirty-one of 155 (20%) children had seen a genetics professional. Forty-nine of 154 (32%) children had undergone genetic testing. Parents whose child saw a genetics professional were more likely to 1) Have a primary provider refer for or suggest a genetics evaluation 2) Have asked for a referral, and/or 3) Know another person with a genetic cause of ASD. amilies of children with ASD who have not received genetics services are less aware of their availability and utility. They are also less likely to have their provider recommend a clinical genetics evaluation. Efforts should be taken to increase awareness of both health providers and parents regarding the usefulness of genetics services for ASD.

A growing body of literature has identified size reductions of the corpus callosum (CC) in autism. However, to our knowledge, no published studies have reported on the growth of CC volumes in youth with autism. Volumes of the total CC and its sub-divisions were obtained from 23 male children with autism and 23 age- and gender-matched controls at baseline and 2-year follow-up. Persistent reductions in total CC volume were observed in participants with autism relative to controls. Only the rostral body subdivision showed a normalization of size over time. Persistent reductions are consistent with the diagnostic stability and life-long impairment observed in many individuals with autism. Multi-modal imaging studies are needed to identify specific fiber tracks contributing to CC reductions.

Background: An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism., Methods: This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale., Results: Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96)., Conclusions: Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment., Methods: We use voxel-based morphometry along with a novel multivariate pattern analysis approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants., Results: Despite modest voxel-based morphometry differences, multivariate pattern analysis revealed that the groups could be distinguished with accuracies of approximately 90% based on gray matter in the posterior cingulate cortex, medial prefrontal cortex, and bilateral medial temporal lobes-regions within the default mode network. Abnormalities in the posterior cingulate cortex were associated with impaired Autism Diagnostic Interview communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between groups with accuracies between 81% and 90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy., Conclusions: Multiple brain regions, including those belonging to the default mode network, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural magnetic resonance imaging data may contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of targeted early interventions., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cortical and central white matter (WM) volumes were measured to assess short- and long-range connectivity in autism, respectively. Subjects included 23 boys with autism and 23 matched controls, all without intellectual disability. Magnetic resonance imaging data obtained at 1.5 T were analyzed using BRAINS2 software (University of Iowa, Iowa City, IA, USA). Central WM volume was quantified by subtracting cortical from supratentorial WM volumes. Reduced central WM volume was observed in the autism group. IQ was higher in controls with no observed correlations between WM volumes and IQ. This preliminary evidence of reduced central WM volume in autism suggests abnormal long-range connectivity., (© 2010 The Authors. Psychiatry and Clinical Neurosciences © 2010 Japanese Society of Psychiatry and Neurology.)

Objective: There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD., Method: Thirty-four children and adolescents with ASD (age range 8-17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10 mg), followed by a 10-week open label trial for placebo nonresponders., Results: The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups)., Conclusions: The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures.

The number of children diagnosed with autism spectrum disorders is increasing, necessitating the development of efficient treatment models. Research has demonstrated that parent-delivered behavioral interventions are a viable treatment model; however, little research has focused on teaching parents in groups. The aim of this study was to demonstrate that parents can learn Pivotal Response Training (PRT) in group therapy, resulting in correlated gains in children's language. Baseline and post-treatment data were obtained and examined for changes in (a) parent fidelity of PRT implementation, and (b) child functional verbal utterances. Significant differences were observed for both variables. These findings suggest that parents can learn PRT in a group format, resulting in correlated child language gains, thus future controlled studies are warranted.

The validity of Asperger disorder as a distinct syndrome from autism is unclear partly because of the paucity of differentiating neurobiological evidence. Frontal lobe cortical folding between these disorders was compared using the gyrification index. Twenty-three boys underwent structural magnetic resonance imaging: 6 with high-functioning autism, 9 with Asperger disorder, and 8 controls. Using the first coronal slice anterior to the corpus callosum, total and outer cortical contours were traced to calculate the gyrification index. This index was also calculated for superior and inferior regions to examine dorsolateral prefrontal and orbitofrontal cortices, respectively. Analysis of variance revealed differences in the left inferior gyrification index, which was higher in the autism group compared with Asperger and control groups. There were no differences in age, intelligence quotient, and brain volume. These preliminary findings suggest that cortical folding may be abnormally high in the frontal lobe in autism but not Asperger disorder, suggesting distinct frontal lobe neuropathology.

The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5±3.4years; full-scale IQ=103.6±13.4) and 19 healthy controls (mean age=13.7±3.0years; full-scale IQ=103.9±10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism., Method: PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements., Results: Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons., Conclusions: Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.

The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications.

Background: Autism is a developmental neurobiologic disorder associated with structural and functional abnormalities in several brain regions including the cerebral cortex. This longitudinal study examined developmental changes in brain volume and cortical thickness (CT) using magnetic resonance imaging (MRI) in children with autism., Methods: MRI scans and behavioral measures were obtained at baseline and after a 30-month interval in a sample of male subjects with autism (n = 18) and healthy age-, and sex-matched control subjects (n = 16) between ages 8 and 12 years at baseline., Results: No differences in brain volumes were observed between the autism and control subjects at baseline or follow-up. However, differences in total gray matter volumes were observed over time with significantly greater decreases in the autism group compared with control subjects. Differences in CT were observed over time with greater decreases in the autism group compared with control subjects in several brain regions including the frontal lobe. When accounting for multiple comparisons, differences between the two groups became nonsignificant except for changes in occipital CT. Furthermore, associations were observed between several clinical features and changes in CT with greater thinning of the cortex being correlated with more severe symptomatology., Conclusions: Findings from this study provide preliminary evidence for age-related changes in gray matter volume and CT in children with autism that are associated with symptoms severity. Future longitudinal studies of larger sample sizes are needed to evaluate developmental changes and examine the relationships between structural abnormalities and clinical expressions of the disorder.

Background: Although several studies have examined brainstem volume in autism, results have been mixed and no investigation has specifically measured gray- and white-matter structures. The aim of this investigation was to assess gray- and white-matter volumes in children with autism., Method: Subjects included 22 right-handed, non-mentally retarded boys with autism and 22 gender- and age-matched controls. Magnetic resonance imaging (MRI) scans were obtained using a 1.5-T scanner and volumetric measurements were performed using the BRAINS2 software package. Gray- and white-matter volumes were measured using a semi-automated segmentation process., Results: There were no significant differences in age and total brain volume (TBV) between the two groups but full-scale IQ was higher in controls. A decrease in brainstem gray-matter volume was observed in the autism group before and after controlling for TBV. No significant differences were observed in white-matter volume. A significant relationship was observed between brainstem gray-matter volume and oral sensory sensitivity as measured by the Sensory Profile Questionnaire (SPQ)., Conclusions: Findings from this study are suggestive of brainstem abnormalities in autism involving gray-matter structures with evidence supporting the existence of a relationship between these alterations and sensory deficits. These results are consistent with previous investigations and support the existence of disturbances in brainstem circuitry thought to be implicated in the sensory dysfunction observed in autism.

The corpus callosum has recently been considered as an index of interhemispheric connectivity. This study applied a novel volumetric method to examine the size of the corpus callosum in 32 individuals with autism and 34 age-, gender- and IQ-matched controls and to investigate the relationship between this structure and cognitive measures linked to interhemispheric functioning. Participants with autism displayed reductions in total corpus callosum volume and in several of its subdivisions. Relationships were also observed between volumetric alterations and performance on several cognitive tests including the Tower of Hanoi test. These findings provide further evidence for anatomical alterations in the corpus callosum in autism, but warrant additional studies examining the relationship of this structure and specific measures of interhemispheric connectivity.

Objective: Attention-deficit/hyperactivity disorder (ADHD) affects 3%-5% of typical school-age children. However, considerably higher rates of ADHD (15%-25%) are observed in children with intellectual disability and autism. Studies of psychostimulants in the latter two populations have found poorer response rates compared to typically developing children. In addition, evidence suggests that children with developmental disabilities experience higher rates of adverse events. Guanfacine, an alpha2-adrenergic receptor agonist, has shown some promise as an alternative to psychostimulants., Methods: The present study involved a double-blind, placebo-controlled, crossover trial of guanfacine in 11 children (ages 5-9 years) with developmental disabilities and symptoms of inattention/overactivity. The 6-week trial involved a maximum dose of 3 mg/day of guanfacine., Results: Significant benefits were observed on the Hyperactivity subscale of the parent and teacher Aberrant Behavior Checklist (ABC) and Global Improvement Ratings. No gains were noted on other ABC subscales. Five of the 11 subjects (45%) were judged to be responders based on a 50% decrease in the ABC Hyperactivity subscale score between the placebo and guanfacine conditions. Several side effects were reported, including drowsiness and irritability., Conclusion: While guanfacine appears to be an alternative to psychostimulants among children with developmental disabilities, clinicians need to remain vigilant to the possibility of side effects.

Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different.

Recent evidence has implicated the orbitofrontal cortex (OFC) in the pathophysiology of social deficits in autism. An MRI-based morphometric study of the OFC was conducted involving 11 children with autism (age range 8.1-12.7 years) and 18 healthy, age-matched controls (age range 8.9-12.8 years). Decreased grey matter volume in the right lateral OFC in the patient group was found, and correlations were observed between social deficits and white, but not grey, matter structures of the OFC. These findings support the role of OFC in autism and warrant further investigations of this structure using structural and functional methodologies.

This study was conducted to examine the volume of the thalamus in autism and to investigate the effect of brain size on this structure in an attempt to replicate, in a larger sample, findings from a previous study reporting the existence of a relationship between brain volume and thalamus in healthy controls but not in individuals with autism. Additionally, the relationships between thalamic volumes and clinical features were examined. Volumetric measurements of the right and left thalamic nuclei were performed on MRI scans obtained from 40 high-functioning individuals with autism (age range: 8-45 years) and 41 healthy controls (age range: 9-43 years). No differences were observed between the two groups for unadjusted thalamic volumes. However, the expected linear relationship between TBV and thalamic volume was not observed in individuals with autism. Furthermore, no correlations were observed between thalamic volumes and clinical features. Findings from this larger study are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder.

The orbitofrontal cortex is involved in multiple psychologic functions, such as emotional and cognitive processing, learning, and social behavior. These functions are variably impaired in individuals with autism. The present study examined the size of the orbitofrontal cortex, and its medial and lateral subdivisions, using magnetic resonance imaging (MRI) scans obtained from 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any of the orbitofrontal cortex measurements. However, when compared with controls, a smaller right lateral orbitofrontal cortex was observed in children and adolescents with autism, whereas a larger right lateral orbitofrontal cortex was found in adult patients. Interestingly, a positive relationship was found in the patient group between circumscribed interests and all orbitofrontal cortex structures. The present study suggests the absence of global volumetric abnormalities in the orbitofrontal cortex in autism and indicates that the functional disturbances in this structure might not be related to anatomic alterations.

Objective: The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder., Method: Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy comparison subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes., Results: Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes., Conclusions: These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.

The objective of this investigation was to examine the existence of minor physical anomalies (MPA) in autism. The interorbital and interlens distances were measured on MRI scans obtained from a sample of 40 non-mentally retarded individuals with autism and 41 healthy controls. No differences were observed between the two groups on any measurements. However, when the analysis was conducted using a split median procedure, individuals with autism and either low FSIQ, PIQ, or VIQ had shorter interorbital distances when compared to controls. Hypotelorism is a MPA that may be present in a subgroup of individuals with autism. Additional research is warranted using large sample sizes with a wide range of intellectual functioning.