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Males are diagnosed with autism much more frequently than females, and most research study samples reflect this male predominance. The result is that autistic females are understudied. There is a critical need to increase our understanding of autistic females, both biologically and clinically. The only way to do this is to recruit sex-balanced cohorts in studies so that similarities and differences between males and females can be evaluated in all autism research studies. The purpose of this commentary is to (1) provide historical context about how females came to be under-represented in all research, not just in the field of autism and (2) learn from other areas of health and medicine about the potentially dire consequences of not studying both sexes, and (3) draw attention to the need to recruit sex-balanced cohorts in autism research, particularly in neuroimaging studies.

We used parent report data to investigate video game playing, aggression, and social impairment in adolescents with autism spectrum disorder. Parents of autistic adolescents were more likely to report that their child plays video games as a hobby compared to parents of adolescents with typical development and also reported that their children spent more time playing video games. For autistic participants, we found no differences in aggression levels or social impairment when comparing players versus non-players. However, playing video games "more than average," as compared to "average" was associated with greater aggression and greater social impairment on "awareness" and "mannerisms" subscales. Future studies should focus on how type of video game(s) played is associated with these clinically important variables.

We used parent report data to investigate video game playing, aggression, and social impairment in adolescents with autism spectrum disorder. Parents of autistic adolescents were more likely to report that their child plays video games as a hobby compared to parents of adolescents with typical development and also reported that their children spent more time playing video games. For autistic participants, we found no differences in aggression levels or social impairment when comparing players versus non-players. However, playing video games "more than average," as compared to "average" was associated with greater aggression and greater social impairment on "awareness" and "mannerisms" subscales. Future studies should focus on how type of video game(s) played is associated with these clinically important variables.

Lay abstractResearch has found differences in responding to various sensory stimuli among autistic individuals, which are associated with social and adaptive skills. However, our understanding of sensory profiles in autism has been complicated due to the variable presentation of sensory symptoms. One way to better understand variability in sensory symptoms is to use advanced statistical approaches, such as latent profile analysis, that allow for the identification of more similar sensory classes in otherwise variable groups. We used the Short Sensory Profile to identify homogeneous classes of sensory reactivity in autistic children based on both severity and modality and examined whether sensory classes differed in terms of autism characteristics, adaptive skills, and attention-deficit/hyperactivity disorder symptoms. Based on the pattern of both severity and modality, four sensory classes emerged and were named Moderate/Mixed (35.5%; probable-to-definite differences in all modalities except in movement sensitivity and low energy/weakness), Severe/Mixed (8.5%; definite sensory differences in all modalities except in low energy/weakness), Moderate/Broad (14.6%; probable-to-definite differences in all modalities), and Low/Mixed (41.1%; typical scores in most modalities with probable differences in taste/smell sensitivity, under-responsive/seeks sensation, and auditory filtering). The Severe/Mixed class exhibited greater problems in a variety of areas such as social, adaptive, and attention-deficit/hyperactivity disorder symptoms, whereas the Low/Mixed class showed overall fewer problems. This may provide insight for clinicians and researchers aiming to understand whether autistic children who exhibit distinct sensory patterns are more or less likely to also experience social, adaptive, and/or attention/behavior-related difficulties.

BackgroundWe extended our study of trajectories of intellectual development of autistic individuals in early (mean age 3 years; T1), and middle childhood (mean age 5 years, 7 months; T2) into later middle childhood/preadolescence (mean age 11 years, 6 months; T3) in the longitudinal Autism Phenome Project cohort. Participants included 373 autistic children (115 females).MethodsMultivariate latent class growth analysis was used to identify distinct IQ trajectory subgroups. Baseline and developmental course group differences and predictors of trajectory membership were assessed using linear mixed effects models with repeated measures with pairwise testing, multinomial logistic regression models, and sensitivity analyses.ResultsWe isolated three IQ trajectories between T1 and T3 for autistic youth that were similar to those found in our prior work. These included a group with persistent intellectual disability (ID; 45%), a group with substantial increases in IQ (CHG; 39%), and a group with persistently average or above IQs (P-High; 16%). By T3, the groups did not differ in ADOS-2 calibrated severity scores (CSS), and there were no group differences between Vineland (VABS) communication scores in CHG and P-High. T1-T3 externalizing behaviors declined significantly for CHG, however, there were no significant T3 group differences between internalizing or externalizing symptoms. T1 correlates for CHG and P-High versus ID group membership included higher VABS communication and lower ADOS-2 CSS. A T1 to T2 increase in VABS communication scores and a decline in externalizing predicted CHG versus ID group membership at T3, while T1 to T2 improvement in VABS communication and reduction in ADOS-2 CSS predicted P-High versus ID group membership.ConclusionsAutistic youth exhibit consistent IQ developmental trajectories from early childhood through preadolescence. Factors associated with trajectory group membership may provide clues about prognosis, and the need for treatments that improve adaptive communication and externalizing symptoms.

BackgroundIntellectual disability affects approximately one third of individuals with autism spectrum disorder (autism). Yet, a major unresolved neurobiological question is what differentiates autistic individuals with and without intellectual disability. Intelligence quotients (IQs) are highly variable during childhood. We previously identified three subgroups of autistic children with different trajectories of intellectual development from early (2-3½ years) to middle childhood (9-12 years): (a) persistently high: individuals whose IQs remained in the normal range; (b) persistently low: individuals whose IQs remained in the range of intellectual disability (IQ < 70); and (c) changers: individuals whose IQs began in the range of intellectual disability but increased to the normal IQ range. The frontoparietal (FPN) and default mode (DMN) networks have established links to intellectual functioning. Here, we tested whether brain regions within the FPN and DMN differed volumetrically between these IQ trajectory groups in early childhood.MethodsWe conducted multivariate distance matrix regression to examine the brain regions within the FPN (11 regions x 2 hemispheres) and the DMN (12 regions x 2 hemispheres) in 48 persistently high (18 female), 108 persistently low (32 female), and 109 changers (39 female) using structural MRI acquired at baseline. FPN and DMN regions were defined using networks identified in Smith et al. (Proc Natl Acad Sci U S A 106:13040-5, 2009). IQ trajectory groups were defined by IQ measurements from up to three time points spanning early to middle childhood (mean age time 1: 3.2 years; time 2: 5.4 years; time 3: 11.3 years).ResultsThe changers group exhibited volumetric differences in the DMN compared to both the persistently low and persistently high groups at time 1. However, the persistently high group did not differ from the persistently low group, suggesting that DMN structure may be an early predictor for change in IQ trajectory. In contrast, the persistently high group exhibited differences in the FPN compared to both the persistently low and changers groups, suggesting differences related more to concurrent IQ and the absence of intellectual disability.ConclusionsWithin autism, volumetric differences of brain regions within the DMN in early childhood may differentiate individuals with persistently low IQ from those with low IQ that improves through childhood. Structural differences in brain networks between these three IQ-based subgroups highlight distinct neural underpinnings of these autism sub-phenotypes.

Altered amygdala development is implicated in the neurobiology of autism, but little is known about the coordinated development of the brain regions directly connected with the amygdala. Here we investigated the volumetric development of an amygdala-connected network, defined as the set of brain regions with monosynaptic connections with the amygdala, in autism from early to middle childhood. A total of 950 longitudinal structural MRI scans were acquired from 282 children (93 female) with autism and 128 children with typical development (61 female) at up to four time points (mean ages: 39, 52, 64, and 137 months, respectively). Volumes from 32 amygdala-connected brain regions were examined using mixed effects multivariate distance matrix regression. The Social Responsiveness Scale-2 was administered to assess degree of autistic traits and social impairments. The amygdala-connected network exhibited persistent diagnostic differences (p values ≤ 0.03) that increased over time (p values ≤ 0.02). These differences were most prominent in autistics with more impacted social functioning at baseline. This pattern was not observed across regions without monosynaptic amygdala connection. We observed qualitative sex differences. In males, the bilateral subgenual anterior cingulate cortices were most affected, while in females the left fusiform and superior temporal gyri were most affected. In conclusion, (1) autism is associated with widespread alterations to the development of brain regions connected with the amygdala, which were associated with autistic social behaviors; and (2) autistic males and females exhibited different patterns of alterations, adding to a growing body of evidence of sex differences in the neurobiology of autism.SIGNIFICANCE STATEMENT Global patterns of development across brain regions with monosynaptic connection to the amygdala differentiate autism from typical development, and are modulated by social functioning in early childhood. Alterations to brain regions within the amygdala-connected network differed in males and females with autism. Results also indicate larger volumetric differences in regions having monosynaptic connection with the amygdala than in regions without monosynaptic connection.

The structure of large-scale intrinsic connectivity networks is atypical in adolescents diagnosed with autism spectrum disorder (ASD or autism). However, the degree to which alterations occur in younger children, and whether these differences vary by sex, is unknown. We utilized structural magnetic resonance imaging (MRI) data from a sex- and age- matched sample of 122 autistic and 122 typically developing (TD) children (2-4 years old) to investigate differences in underlying network structure in preschool-aged autistic children within three large scale intrinsic connectivity networks implicated in ASD: the Socioemotional Salience, Executive Control, and Default Mode Networks. Utilizing structural covariance MRI (scMRI), we report network-level differences in autistic versus TD children, and further report preliminary findings of sex-dependent differences within network topology.

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2-19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism.

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making.

Little is known about the neural substrates underlying early memory functioning. To gain more insight, we examined how toddlers remember newly learned words. Hippocampal and anterior medial-temporal lobe (MTL) processes have been hypothesized to support forming and retaining the association between novel words and their referents, but direct evidence of this connection in early childhood is lacking. We assessed 2-year-olds (n = 38) for their memory of newly learned pseudowords associated with novel objects and puppets. We tested memory for these associations during the same session as learning and after a 1-week delay. We then played these pseudowords, previously known words, and completely novel pseudowords during natural nocturnal sleep, while collecting functional magnetic resonance imaging data. Activation in the left hippocampus and the left anterior MTL for newly learned compared to novel words was associated with same-session memory for these newly learned words only when they were learned as puppet names. Activation for known words was associated with memory for puppet names at the 1-week delay. Activation for newly learned words was also associated with overall productive vocabulary. These results underscore an early developing link between memory mechanisms and word learning in the medial temporal lobe.

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD).Method: The sample included 75 children (ages 9-13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSM-specified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments.Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinically-significant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ

BackgroundCerebral overgrowth is frequently reported in children but not in adults with autism spectrum disorder (ASD). This suggests that early cerebral overgrowth is followed by normalization of cerebral volumes. However, this notion is predicated on cross-sectional research that is vulnerable to sampling bias. For example, autistic individuals with disproportionate megalencephaly, a subgroup with higher rates of intellectual disability and larger cerebral volumes, may be underrepresented in studies of adolescents and adults. Furthermore, extant studies have cohorts that are predominately male, thus limiting knowledge of cerebral growth in females with ASD.MethodsGrowth of total cerebral volume, gray matter (GM) volume, and white matter volume as well as proportion of GM to total cerebral volume were examined in a longitudinal sample comprising 273 boys (199 with ASD) scanned at up to four time points (mean ages = 38, 50, 64, and 137 months, respectively) and 156 girls (95 with ASD) scanned at up to three time points (mean ages = 39, 53, and 65 months, respectively) using mixed-effects modeling.ResultsIn boys with ASD, cerebral overgrowth in the ASD with disproportionate megalencephaly subgroup was predominately driven by increases in GM and persisted throughout childhood without evidence of volumetric regression or normalization. In girls with ASD, cerebral volumes were similar to those in typically developing girls, but growth trajectories of GM and white matter were slower throughout early childhood. The proportion of GM to total cerebral volume declined with age at a slower rate in autistic boys and girls relative to typically developing control subjects.ConclusionsLongitudinal evidence does not support the notion that early brain overgrowth is followed by volumetric regression, at least from early to late childhood.

The Children's Sleep Habits Questionnaire (CSHQ) is often used to assess sleep in children with autism spectrum disorder (ASD), but little is known about its factor structure in younger children with ASD. We evaluated alternative factor structures and measurement invariance for CSHQ items in 2- to 4-year-olds with ASD or typical development (TD). Bifactor models indicated subscales' variance was subsumed by a general factor predominantly reflecting sleep initiation and nighttime awakening items. A factor consisting of 7 of these items was measurement invariant across ASD and TD. Thus, comparisons between young children with ASD and TD is appropriate for a measure composed of 7 CSHQ items relating to sleep initiation and awakenings but not for other CSHQ item composites.

BackgroundCross-sectional diffusion-weighted magnetic resonance imaging studies suggest that young autistic children have alterations in white matter structure that differ from older autistic individuals. However, it is unclear whether these differences result from atypical neurodevelopment or sampling differences between young and older cohorts. Furthermore, the relationship between altered white matter development and longitudinal changes in autism symptoms is unknown.MethodsUsing longitudinal diffusion-weighted magnetic resonance imaging acquired over 2 to 3 time points between the ages of approximately 2.5 to 7.0 years in 125 autistic children and 69 typically developing control participants, we directly tested the hypothesis that autistic individuals have atypical white matter development across childhood. Additionally, we sought to determine whether changes in white matter diffusion parameters were associated with longitudinal changes in autism severity.ResultsAutistic children were found to have slower development of fractional anisotropy in the cingulum bundle, superior longitudinal fasciculus, internal capsule, and splenium of the corpus callosum. Furthermore, in the sagittal stratum, autistic individuals who increased in autism severity over time had a slower developmental trajectory of fractional anisotropy compared with individuals whose autism decreased in severity. In the uncinate fasciculus, autistic individuals who decreased in autism symptom severity also had greater increases in fractional anisotropy with age.ConclusionsThese longitudinal findings indicate that previously reported differences in diffusion-weighted magnetic resonance imaging measures between younger and older autism cohorts are attributable to an atypical developmental trajectory of white matter. Differences in white matter development between individuals whose autism severity increased, remained stable, or decreased suggest that these functional differences are associated with fiber development in the autistic brain.

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD.

BackgroundRecent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD.Materials and methodsWe used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n = 20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at 3 years of age for diagnostic outcome. Three outcome groups were defined (ASD, n = 9; typical development, n = 8; non-typical development, n = 3).ResultsASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e., prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.LimitationsOur study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples.ConclusionThese preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.

ObjectiveThe aims of this study were to identify a subset of children with autism spectrum disorder (ASD) and co-occurring symptoms of psychopathology, and to evaluate associations between this subgroup and biological sex and amygdala volume.MethodParticipants included 420 children (ASD: 91 girls, 209 boys; typically developing controls: 57 girls, 63 boys). Latent profile analysis was used to identify ASD subgroups based on symptoms of psychopathology, adaptive functioning, cognitive development, and autism severity. Differences in the proportions of girls and boys across subgroups were evaluated. Magnetic resonance imaging scans were acquired (346 children); amygdala volumes were evaluated in relation to subgroups and problem behavior scores.ResultsThree ASD subgroups were identified. One group was characterized by high levels of psychopathology and moderate impairment on other measures (High Psychopathology Moderate Impairments [HPMI], comprising 27% of the sample). The other two subgroups had lower symptoms of psychopathology but were differentiated by high and low levels of impairment on other measures. A higher proportion of girls were classified into the HPMI subgroup (40% of girls versus 22% of boys). Relative to controls, amygdala volumes were enlarged only in the HPMI subgroup. There was a positive association between right amygdala volume and internalizing behaviors in girls but not in boys with ASD.ConclusionA higher proportion of girls with ASD faced greater challenges with psychopathology, suggesting a need for closer evaluation and potentially earlier intervention to help improve outcomes. Amygdala enlargement was associated with co-occurring symptoms of psychopathology, and sex-specific correlations with symptoms were observed.

Although individuals with autism spectrum disorder (ASD) have been often shown to display similar memory performance on semantic memory tasks compared to typically developing (TD) children, there is ongoing debate about whether and how their ability to remember specific past events (i.e., episodic memory) is impaired. We assessed a sample of 62 children with ASD and 72 TD children, ranging in age between 8 and 12 years on 2 memory tasks. Participants encoded a series of images and their association with either where they appeared on the screen (item-space association task) or with the color of an image's border (item-color association task). Children with ASD showed worse memory in the item-space association task compared to their TD peers, but comparable memory for the item-color association task. These differences persisted when age, intellectual quotient, and general item recognition memory were accounted for statistically. We interpret these results in light of evidence for specific deficits along the dorsal stream affecting processing of spatiotemporal information in ASD. Autism Res 2020, 13: 1985-1997. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Episodic memory requires the ability to bind contextual details (such as color, location, etc.) to an item or event in order to remember the past with specific detail. Here, we compared children with autism spectrum disorder (ASD) and typically developing (TD) children on tasks examining episodic memory. Children with ASD recalled more poorly previously seen items and their associated space-related details, but they performed comparably to TD children on color details. We discuss the possible mechanisms that contribute to worse spatial processing/recall in ASD.

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. LAY SUMMARY: ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self-injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778-1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

BackgroundMultifactorial liability models predict greater dissimilarity in the neural phenotype of autism spectrum disorder (ASD) in female individuals than in male individuals, while gender incoherence and extreme male brain models predict attenuated sex differences in ASD. The amygdala is an informative target to explore these models because it is implicated in both the neurobiology of ASD and sex differences in typical development.MethodsThis study investigated amygdala resting-state functional connectivity in a cohort of 116 children with ASD (36 female) and 58 typically developing children (27 female) 2 to 7 years of age during natural sleep. First, multivariate distance matrix regression assessed global sex and diagnostic differences across the amygdala connectome. Second, univariate general linear models identified regions with mean connectivity differences.ResultsMultivariate distance matrix regression revealed greater differences between typically developing children and those with ASD in females than in males, consistent with multifactorial liability models, and attenuated sex differences in the left amygdala connectome of children with ASD in a pattern consistent with the gender incoherence model. Univariate analysis identified similar sex differences in dorsomedial and ventral prefrontal cortices, lingual gyrus, and posterior cingulate cortex, but also noted that lower amygdala connectivity with superior temporal sulcus is observed across sexes.ConclusionsThis study provides evidence that compared with sex-matched control subjects, ASD manifests differently in the brain at the time of diagnosis and prior to the influence of compensatory mechanisms in male and female children, consistent with multifactorial liability models, and that ASD is associated with reduced sex differences in a pattern consistent with gender incoherence models.

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD).Method: The sample included 75 children (ages 9-13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSM-specified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments.Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinically-significant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ

BACKGROUND:The core symptoms of autism spectrum disorder (ASD) are widely theorized to result from altered brain connectivity. Diffusion-weighted magnetic resonance imaging (DWI) has been a versatile method for investigating underlying microstructural properties of white matter (WM) in ASD. Despite phenotypic and etiological heterogeneity, DWI studies in majority male samples of older children, adolescents, and adults with ASD have largely reported findings of decreased fractional anisotropy (FA) across several commissural, projection, and association fiber tracts. However, studies in preschool-aged children (i.e.,

The Children's Sleep Habits Questionnaire (CSHQ) is often used to assess sleep in children with autism spectrum disorder (ASD), but little is known about its factor structure in younger children with ASD. We evaluated alternative factor structures and measurement invariance for CSHQ items in 2- to 4-year-olds with ASD or typical development (TD). Bifactor models indicated subscales' variance was subsumed by a general factor predominantly reflecting sleep initiation and nighttime awakening items. A factor consisting of 7 of these items was measurement invariant across ASD and TD. Thus, comparisons between young children with ASD and TD is appropriate for a measure composed of 7 CSHQ items relating to sleep initiation and awakenings but not for other CSHQ item composites.

Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Autism Phenome Project is a longitudinal, multidisciplinary study of young children with ASD and age-matched typically developing (TD) controls. Previous analyses of the magnetic resonance imaging data from this cohort have shown that ∼15% of boys with ASD have disproportionate megalencephaly (DM) or brain size to height ratio, that is 1.5 standard deviations above the TD mean. Here, we investigated electrophysiological responses to auditory stimuli of increasing intensity (50-80 dB) in young toddlers (27-48 months old). Analyses included data from 36 age-matched boys, of which 24 were diagnosed with ASD (12 with and 12 without DM; ASD-DM and ASD-N) and 12 TD controls. We found that the two ASD subgroups differed in their electrophysiological response patterns to sounds of increasing intensity. At early latencies (55-115 ms), ASD-N does not show a loudness-dependent response like TD and ASD-DM, but tends to group intensities by soft vs. loud sounds, suggesting differences in sensory sensitivity in this group. At later latencies (145-195 ms), only the ASD-DM group shows significantly higher amplitudes for loud sounds. Because no similar effects were found in ASD-N and TD groups, this may be related to their altered neuroanatomy. These results contribute to the effort to delineate ASD subgroups and further characterize physiological responses associated with observable phenotypes. Autism Res 2019, 12: 1236-1250. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Approximately 15% of boys with ASD have much bigger brains when compared to individuals with typical development. By recording brain waves (electroencephalography) we compared how autistic children, with or without big brains, react to sounds compared to typically developing controls. We found that brain responses in the big-brained group are different from the two other groups, suggesting that they represent a specific autism subgroup.

Local gyrification index (LGI), a metric quantifying cortical folding, was evaluated in 105 boys with autism spectrum disorder (ASD) and 49 typically developing (TD) boys at 3 and 5 years-of-age. At 3 years-of-age, boys with ASD had reduced gyrification in the fusiform gyrus compared with TD boys. A longitudinal evaluation from 3 to 5 years revealed that while TD boys had stable/decreasing LGI, boys with ASD had increasing LGI in right inferior temporal gyrus, right inferior frontal gyrus, right inferior parietal lobule, and stable LGI in left lingual gyrus. LGI was also examined in a previously defined neurophenotype of boys with ASD and disproportionate megalencephaly. At 3 years-of-age, this subgroup exhibited increased LGI in right dorsomedial prefrontal cortex, cingulate cortex, and paracentral cortex, and left cingulate cortex and superior frontal gyrus relative to TD boys and increased LGI in right paracentral lobule and parahippocampal gyrus, and left precentral gyrus compared with boys with ASD and normal brain size. In summary, this study identified alterations in the pattern and development of LGI during early childhood in ASD. Distinct patterns of alterations in subgroups of boys with ASD suggests that multiple neurophenotypes exist and boys with ASD and disproportionate megalencephaly should be evaluated separately.

To advance what is known about how emotions affect memory in autism spectrum disorder (ASD), we examined emotional false memory for negative, positive, and neutrally valenced photographs comprising scripts of everyday events in a verbal IQ-case matched sample of youth ages 8-14 with ASD (N = 38) and typical development (TYP, N = 38). The groups exhibited many similarities. Their task performance during a recognition task including previously seen and unseen photographs was largely comparable. They evidenced high hit rates for previously viewed photographs, and low false alarm rates for lure photographs that were inconsistent with the scripts. Both ASD and TYP groups showed relatively higher false alarms for lure photographs depicting previously unseen causes of scenario outcomes (causal errors) compared to errors for script-consistent lure photographs that showed extra potentially related events (gap-filling errors). In both groups, task performance was associated with verbal working memory, but not attention deficit hyperactivity, anxiety, or depression symptoms. However, the ASD group made more causal and gap-filling errors on negative and positive, but not neutral, lures compared to TYP, indicating that viewing emotionally valenced stimuli made it harder to discriminate previously seen and unseen photographs. For the ASD group, task performance was associated with compulsive, ritualistic, and sameness behaviors and stereotypic and restricted interests. Findings suggest that the integration of cognition and emotion in ASD is altered and associated with the presence of repetitive behaviors. The impact of these results on the lives of individuals with ASD and implications for psychosocial interventions are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but methodological challenges have hindered assessments of this possibility in humans. Here, we delivered a previously learned song and a novel song to 2-year-old toddlers during natural nocturnal sleep and, using functional magnetic resonance imaging, found that hippocampal activation was stronger for the learned song compared with the novel song. This was true regardless of whether the song was presented intact or backwards. Toddlers who remembered where and in the presence of which toy character they heard the song exhibited stronger hippocampal activation for the song. The results establish that hippocampal activation in toddlers reflects past experiences, persists despite some alteration of the stimulus, and is associated with behavior. This research sheds light on early hippocampal and memory functioning and offers an approach to interrogate the neural substrates of early memory.

Children with autism vary widely in their language abilities, yet the neural correlates of this language variability remain unclear, especially early in development. Diffusion tensor imaging (DTI) was used to examine diffusivity measures along the length of 18 major fiber tracts in 104 preschool-aged boys with autism spectrum disorder (ASD). The boys were assigned to subgroups according to their level of language development (Low: no/low language, Middle: small vocabulary, High: large vocabulary and grammar), based on their raw scores on the expressive language (EL) and receptive language (RL) sections of the Mullen Scales of Early Learning (MSEL). Results indicate that the subgroups differed in fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) along the inferior longitudinal fasciculus (ILF) in both hemispheres. Moreover, FA correlated significantly with Mullen EL and RL raw scores, but not ADOS severity score, along the left and right ILF. Subgroups also differed in MD (but not FA) along the left superior longitudinal fasiculus and left corticospinal tract, but these differences were not correlated with language scores. These findings suggest that white matter microstructure in the left and right ILF varies in relation to lexical development in young males with ASD. The findings also support the use of raw scores on language-relevant standardized tests for assessing early language-brain relationships. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1107-1119. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

A consensus has emerged that despite common core features, autism spectrum disorder (ASD) has multiple etiologies and various genetic and biological characteristics. The fact that there are likely to be subtypes of ASD has complicated attempts to develop effective therapies. The UC Davis MIND Institute Autism Phenome Project is a longitudinal, multidisciplinary analysis of children with autism and age-matched typically developing controls; nearly 400 families are participating in this study. The overarching goal is to gather sufficient biological, medical, and behavioral data to allow definition of clinically meaningful subtypes of ASD. One reasonable hypothesis is that different subtypes of autism will demonstrate different patterns of altered brain organization or development i.e., different neurophenotypes. In this Commentary, we discuss one neurophenotype that is defined by megalencephaly, or having brain size that is large and disproportionate to body size. We have found that 15% of the boys with autism demonstrate this neurophenotype, though it is far less common in girls. We review behavioral and medical characteristics of the large-brained group of boys with autism in comparison to those with typically sized brains. While brain size in typically developing individuals is positively correlated with cognitive function, the children with autism and larger brains have more severe disabilities and poorer prognosis. This research indicates that phenotyping in autism, like genotyping, requires a very substantial cohort of subjects. Moreover, since brain and behavior relationships may emerge at different times during development, this effort highlights the need for longitudinal analyses to carry out meaningful phenotyping. Autism Res 2017, 10: 711-722. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

BackgroundMagnetic resonance imaging (MRI) has been widely used in studies evaluating the neuropathology of autism spectrum disorder (ASD). Studies are often limited, however, to higher functioning individuals with ASD. MRI studies of individuals with ASD and comorbid intellectual disability (ID) are lacking, due in part to the challenges of acquiring images without the use of sedation.MethodsUtilizing principles of applied behavior analysis (ABA), we developed a protocol for acquiring structural MRI scans in school-aged children with ASD and intellectual impairment. Board certified behavior analysts worked closely with each child and their parent(s), utilizing behavior change techniques such as pairing, shaping, desensitization, and positive reinforcement, through a series of mock scanner visits to prepare the child for the MRI scan. An objective, quantitative assessment of motion artifact in T1- and diffusion-weighted scans was implemented to ensure that high-quality images were acquired.ResultsThe sample consisted of 17 children with ASD who are participants in the UC Davis Autism Phenome Project, a longitudinal MRI study aimed at evaluating brain developmental trajectories from early to middle childhood. At the time of their initial scan (2-3.5 years), all 17 children had a diagnosis of ASD and development quotient (DQ)

ObjectiveThe objective of this study was to determine whether functional connectivity of the amygdala is altered in preschool-age children with autism spectrum disorder (ASD) and to assess the clinical relevance of observed alterations in amygdala connectivity.MethodA resting-state functional connectivity magnetic resonance imaging study of the amygdala (and a parallel study of primary visual cortex) was conducted in 72 boys (mean age 3.5 years; n = 43 with ASD; n = 29 age-matched controls).ResultsThe ASD group showed significantly weaker connectivity between the amygdala and several brain regions involved in social communication and repetitive behaviors, including bilateral medial prefrontal cortex, temporal lobes, and striatum (p < .05, corrected). Weaker connectivity between the amygdala and frontal and temporal lobes was significantly correlated with increased autism severity in the ASD group (p < .05). In a parallel analysis examining the functional connectivity of primary visual cortex, the ASD group showed significantly weaker connectivity between visual cortex and sensorimotor regions (p < .05, corrected). Weaker connectivity between visual cortex and sensorimotor regions was not correlated with core autism symptoms, but instead was correlated with increased sensory hypersensitivity in the visual/auditory domain (p < .05).ConclusionThese findings indicate that preschool-age children with ASD have disrupted functional connectivity between the amygdala and regions of the brain important for social communication and language, which might be clinically relevant because weaker connectivity was associated with increased autism severity. Moreover, although amygdala connectivity was associated with behavioral domains that are diagnostic of ASD, altered connectivity of primary visual cortex was related to sensory hypersensitivity.

The Autism Phenome Project is the largest, single site, longitudinal magnetic resonance imaging (MRI) study of young children with autism spectrum disorder (ASD). Previous analyses from this cohort have shown that the children with autism have a total brain volume at time 1 (∼3 years of age) that is 6% larger than typically developing (TD) children. This finding is driven primarily by 15% of the boys with ASD that have disproportionate megalencephaly (ASD-DM) or brain size that is 1.5 standard deviations above what would be expected for the child's height. In the current study, cerebral cortical grey matter volume, thickness, and surface area were assayed from MRI scans of 112, 3-year-old boys with ASD and 50 age-matched TD boys. The boys with ASD-DM (n = 17) were analyzed separately from the boys with normal brain size (ASD-N, n = 95). Previous studies of cortical thickness and surface area for ASD children in this age range have come to diametrically different conclusions concerning the significance of cortical thickness vs. surface area. Current analyses indicate that cortical thickness was comparable across the ASD and TD groups. However, surface area was significantly greater in the ASD group compared to the TD group. This result was driven largely by the children with ASD-DM. Even in the ASD-DM group, not all cortical regions demonstrated increased surface area. These results provide strong evidence that the early cortical overgrowth associated with ASD is due primarily to increased surface area and not to increased cortical thickness.

BackgroundAbnormalities in the corpus callosum have been reported in individuals with autism spectrum disorder (ASD), but few studies have evaluated young children. Sex differences in callosal organization and diffusion characteristics have also not been evaluated fully in ASD.MethodsStructural and diffusion-weighted images were acquired in 139 preschool-aged children with ASD (112 males/27 females) and 82 typically developing (TD) controls (53 males/29 females). Longitudinal scanning at two additional annual time points was carried out in a subset of these participants. Callosal organization was evaluated using two approaches: 1) diffusion tensor imaging (DTI) tractography to define subregions based on cortical projection zones and 2) as a comparison to previous studies, midsagittal area analysis using Witelson subdivisions. Diffusion measures of callosal fibers were also evaluated.ResultsAnalyses of cortical projection zone subregions revealed sex differences in the patterns of altered callosal organization. Relative to their sex-specific TD counterparts, both males and females with ASD had smaller regions dedicated to fibers projecting to superior frontal cortex, but patterns differed in callosal subregions projecting to other parts of frontal cortex. While males with ASD had a smaller callosal region dedicated to the orbitofrontal cortex, females with ASD had a smaller callosal region dedicated to the anterior frontal cortex. There were also sex differences in diffusion properties of callosal fibers. While no alterations were observed in males with ASD relative to TD males, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were all increased in females with ASD relative to TD females. Analyses of Witelson subdivisions revealed a decrease in midsagittal area of the corpus callosum in both males and females with ASD but no regional differences in specific subdivisions. Longitudinal analyses revealed no diagnostic or sex differences in the growth rate or change in diffusion measures of the corpus callosum from 3 to 5 years of age.ConclusionsThere are sex differences in the pattern of altered corpus callosum neuroanatomy in preschool-aged children with ASD.

[This corrects the article DOI: 10.1186/s13229-015-0005-4.].

Brain development occurs rapidly during the first few years of life involving region-specific changes in both gray matter and white matter. Due to the inherent difficulties in acquiring magnetic resonance imaging data in young children, little is known about the properties of white matter in typically developing toddlers. In the context of an ongoing study of young children with autism spectrum disorder, we collected diffusion-weighted imaging data during natural nocturnal sleep in a sample of young (mean age=35months) typically developing male and female (n=41 and 25, respectively) children. Axial diffusivity, radial diffusivity, mean diffusivity and fractional anisotropy were measured at 99 points along the length of 18 major brain tracts. Influences of hemisphere, age, sex, and handedness were examined. We find that diffusion properties vary significantly along the length of the majority of tracks. We also identify hemispheric and sex differences in diffusion properties in several tracts. Finally, we find the relationship between age and diffusion parameters changes along the tract length illustrating variability in age-related white-matter development at the tract level.

We describe a protocol with which we achieved a 93% success rate in acquiring high quality MRI scans without the use of sedation in 2.5-4.5 year old children with autism, developmental delays, and typical development. Our main strategy was to conduct MRIs during natural nocturnal sleep in the evenings after the child's normal bedtime. Alternatively, with some older and higher functioning children, the MRI was conducted while the child was awake and watching a video. Both strategies relied heavily on the creation of a child and family friendly MRI environment and the involvement of parents as collaborators in the project. Scanning very young children with autism, typical development, and developmental delays without the use of sedation or anesthesia was possible in the majority of cases.