Autism-associated brain differences can be observed in utero using MRI.

Developmental changes that occur before birth are thought to be associated with the development of autism spectrum disorders. Identifying anatomical predictors of early brain development may contribute to our understanding of the neurobiology of autism spectrum disorders and allow for earlier and more effective identification and treatment of autism spectrum disorders. In this study, we used retrospective clinical brain magnetic resonance imaging data from fetuses who were diagnosed with autism spectrum disorders later in life (prospective autism spectrum disorders) in order to identify the earliest magnetic resonance imaging-based regional volumetric biomarkers. Our results showed that magnetic resonance imaging-based autism spectrum disorder biomarkers can be found as early as in the fetal period and suggested that the increased volume of the insular cortex may be the most promising magnetic resonance imaging-based fetal biomarker for the future emergence of autism spectrum disorders, along with some additional, potentially useful changes in regional volumes and hemispheric asymmetries.

Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers.

Small Nucleus Accumbens and Large Cerebral Ventricles in Infants and Toddlers Prior to Receiving Diagnoses of Autism Spectrum Disorder.

Early interventions for autism spectrum disorder (ASD) are increasingly available, while only 42-50% of ASD children are diagnosed before 3 years old (YO). To identify neuroimaging biomarkers for early ASD diagnosis, we evaluated surface- and voxel-based brain morphometry in participants under 3YO who were later diagnosed with ASD. Magnetic resonance imaging data were retrospectively obtained from patients later diagnosed with ASD at Boston Children's Hospital. The ASD participants with comorbidities such as congenital disorder, epilepsy, and global developmental delay/intellectual disability were excluded from statistical analyses. Eighty-five structural brain magnetic resonance imaging images were collected from 81 participants under 3YO and compared with 45 images from 45 gender- and age-matched nonautistic controls (non-ASD). Using an Infant FreeSurfer pipeline, 236 regionally distributed measurements were extracted from each scan. By t-tests and linear mixed models, the smaller nucleus accumbens and larger bilateral lateral, third, and fourth ventricles were identified in the ASD group. Vertex-wise t-statistical maps showed decreased thickness in the caudal anterior cingulate cortex and increased thickness in the right medial orbitofrontal cortex in ASD. The smaller bilateral accumbens nuclei and larger cerebral ventricles were independent of age, gender, or gestational age at birth, suggesting that there are MRI-based biomarkers in prospective ASD patients before they receive the diagnosis and that the volume of the nucleus accumbens and cerebral ventricles can be key MRI-based early biomarkers to predict the emergence of ASD.

Multilevel hybrid principal components analysis for region-referenced functional electroencephalography data.

Electroencephalography experiments produce region-referenced functional data representing brain signals in the time or the frequency domain collected across the scalp. The data typically also have a multilevel structure with high-dimensional observations collected across multiple experimental conditions or visits. Common analysis approaches reduce the data complexity by collapsing the functional and regional dimensions, where event-related potential (ERP) features or band power are targeted in a pre-specified scalp region. This practice can fail to portray more comprehensive differences in the entire ERP signal or the power spectral density (PSD) across the scalp. Building on the weak separability of the high-dimensional covariance process, the proposed multilevel hybrid principal components analysis (M-HPCA) utilizes dimension reduction tools from both vector and functional principal components analysis to decompose the total variation into between- and within-subject variance. The resulting model components are estimated in a mixed effects modeling framework via a computationally efficient minorization-maximization algorithm coupled with bootstrap. The diverse array of applications of M-HPCA is showcased with two studies of individuals with autism. While ERP responses to match vs mismatch conditions are compared in an audio odd-ball paradigm in the first study, short-term reliability of the PSD across visits is compared in the second. Finite sample properties of the proposed methodology are studied in extensive simulations.

Erratum to: A computer-generated animated face stimulus set for psychophysiological research.

Erratum to: Behav Res. DOI 10.3758/s13428-014-0491-x. The affiliations for four authors were erroneously printed. The correct affiliation for Adam Naples and James C. McPartland is: Yale Child Study Center, 230 South Frontage Road, New Haven 06520, CT, USA. The correct affiliation for Raphael Bernier and Anna Kresse is: University of Washington, Seattle, WA, USA.

A computer-generated animated face stimulus set for psychophysiological research.

Human faces are fundamentally dynamic, but experimental investigations of face perception have traditionally relied on static images of faces. Although naturalistic videos of actors have been used with success in some contexts, much research in neuroscience and psychophysics demands carefully controlled stimuli. In this article, we describe a novel set of computer-generated, dynamic face stimuli. These grayscale faces are tightly controlled for low- and high-level visual properties. All faces are standardized in terms of size, luminance, location, and the size of facial features. Each face begins with a neutral pose and transitions to an expression over the course of 30 frames. Altogether, 222 stimuli were created, spanning three different categories of movement: (1) an affective movement (fearful face), (2) a neutral movement (close-lipped, puffed cheeks with open eyes), and (3) a biologically impossible movement (upward dislocation of eyes and mouth). To determine whether early brain responses sensitive to low-level visual features differed between the expressions, we measured the occipital P100 event-related potential, which is known to reflect differences in early stages of visual processing, and the N170, which reflects structural encoding of faces. We found no differences between the faces at the P100, indicating that different face categories were well matched on low-level image properties. This database provides researchers with a well-controlled set of dynamic faces, controlled for low-level image characteristics, that are applicable to a range of research questions in social perception.

Mind the Gap: Executive Function Is Associated with the Discrepancy Between Cognitive and Adaptive Functioning in Autistic Children Without Cognitive Delay.

Adaptive functioning is central to autistic individuals' independence and well-being. However, autism spectrum disorder (ASD) is associated with poor adaptive functioning, even in the absence of cognitive delays or deficits. This study examined how age and executive function associate with adaptive functioning-particularly the gap between cognitive and adaptive functioning. We addressed our research questions separately for a school-age (N = 101 ages 7-12) cohort and a preschool (N = 48 ages 2 and 4) cohort of autistic children without cognitive delays. Both cohorts of parents reported on their children's adaptive and executive functioning skills. The difference between adaptive and cognitive skills was computed for each participant. For each cohort, we evaluated whether adaptive skills decline with age. Next, we measured, in each cohort, whether children's executive function corresponded with this gap between their adaptive and cognitive skills. Adaptive functioning did not decline relative to cognitive ability in the younger cohort, but the gap was present in the school-age cohort. Yet, reduced executive function consistently corresponded with a greater cognitive-adaptive gap in socialization domains for both preschool and school-age children. Targeting EF, specifically emotional control, during preschool years may support both adaptive functioning and social connectedness for autistic children without cognitive delays.

Irritability as a Transdiagnostic Risk Factor for Functional Impairment in Autistic and Non-autistic Toddlers and Preschoolers.

Trait irritability in toddlerhood is a powerful risk factor for later internalizing and externalizing challenges in non-autistic children, but the predictive clinical utility of irritability is unknown in autism. Irritability is a trait-level emotional response (i.e., frustration) to a blocked goal and is one source of disruptive behavior. Irritability has two facets: Frustration is the degree to which emotion is elevated after a blocked goal, while soothability is the rate of recovery from peak distress. We aimed to: (1) compare and describe the two facets of irritability in non-autistic and young autistic children, and (2) assess whether children's reward sensitivity and executive function moderate the relation between irritability and clinical symptoms. Participants were 90 autistic (n=43) and non-autistic (n = 47) 2- and 4-year-olds. Autistic children did not have different levels of frustration but were more difficult to soothe compared to non-autistic children, according to parents. Further, frustration and soothability were less strongly correlated for autistic compared to non-autistic children. For all children, executive function (specifically, inhibition) moderated, or ameliorated the strength of, the relation between irritability (both soothability and frustration) and externalizing challenges. This study provides evidence for irritability as a transdiagnostic risk factor for clinically significant emotion regulation challenges. Further, the effect of trait irritability may be ameliorated by children's executive function in a transdiagnostic manner. Future work should examine the unique aspects of soothability to how irritability presents within autism, as well as evaluate and modify emotion regulation interventions for autistic toddlers and preschoolers.

Perceptions of Individuals with Autism Spectrum Disorder on How Health Care Providers Address Sexual Health.

OBJECTIVE: Medical providers report barriers that prevent them from discussing sexual health with patients with autism spectrum disorder (ASD). No investigations have examined the perspectives of adults with ASD about their sexual health care experiences. METHODS: Twenty-five verbal young adults diagnosed with ASD and 40 young adults without ASD participated. An 8-item self-report survey assessed frequency of health care visits, age when sexual health was first discussed, and frequency/content of discussions with providers. RESULTS: The likelihood of discussing sexual health topics did not differ by group, χ2s < 3.25; ps > 0.07, except sexual victimization, which the ASD group reported having discussed less than the non-ASD group (32 vs 9%), χ2 (1, N = 57) = 4.36, p = 0.04. Groups did not differ in their reported comfort level discussing sex/sexual health, having a primary care provider, or frequency of visits. The non-ASD group was significantly more likely to have received sexual health counseling (81%) than ASD group (52%), χ2 (1, N = 58) = 5.33, p = 0.02. Participants in both groups reported having received sexual health information from similar sources except the ASD group was more likely to receive information from parents than the non-ASD group (68% vs 30%), χ2 (1, N = 65) = 8.99, p = 0.003. CONCLUSION: Participants in the ASD and non-ASD groups reported similar comfort levels with sexual health discussions and access to health providers. Yet, the ASD group received less counseling related to sexual health-particularly sexual victimization screening-suggesting that critical information may be missing. Future studies should determine how to help providers overcome barriers to providing young adults with ASD sexual health aligned with their needs.

Parsing evoked and induced gamma response differences in Autism: A visual evoked potential study.

OBJECTIVE: Electroencephalography (EEG) measures of visual evoked potentials (VEPs) provide a targeted approach for investigating neural circuit dynamics. This study separately analyses phase-locked (evoked) and non-phase-locked (induced) gamma responses within the VEP to comprehensively investigate circuit differences in autism. METHODS: We analyzed VEP data from 237 autistic and 114 typically developing (TD) children aged 6-11, collected through the Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Evoked and induced gamma (30-90 Hz) responses were separately quantified using a wavelet-based time-frequency analysis, and group differences were evaluated using a permutation-based clustering procedure. RESULTS: Autistic children exhibited reduced evoked gamma power but increased induced gamma power compared to TD peers. Group differences in induced responses showed the most prominent effect size and remained statistically significant after excluding outliers. CONCLUSIONS: Our study corroborates recent research indicating diminished evoked gamma responses in children with autism. Additionally, we observed a pronounced increase in induced power. Building upon existing ABC-CT findings, these results highlight the potential to detect variations in gamma-related neural activity, despite the absence of significant group differences in time-domain VEP components. SIGNIFICANCE: The contrasting patterns of decreased evoked and increased induced gamma activity in autistic children suggest that a combination of different EEG metrics may provide a clearer characterization of autism-related circuitry than individual markers alone.

Short report: Recommendations for education, clinical practice, research, and policy on promoting well-being in autistic youth and adults through a positive focus on sexuality and gender diversity.

LAY ABSTRACT: In this article, we propose recommendations on what we can do to promote that autistic people can enjoy their sexuality and gender identity, because that contributes to overall well-being.First, we briefly summarize the existing research on sexuality and gender diversity in autistic individuals.Next, we propose recommendations for how to promote sexual and gender diversity-related health and well-being. Based on what is known about sexuality, gender diversity, and relationships in autistic adolescents and adults, we convened an international group of autistic and non-autistic researchers, advocates, parents, and professionals to develop recommendations to promote sexual and gender health in autistic people.The resulting recommendations were checked through an online survey distributed to autistic people across the world. The online participants endorsed the importance of eight final recommendations related to:1. Providing education and information on sexuality, relationships, and gender diversity to autistic individuals and their families;2. Improving expertise in and accessibility to healthcare for sexuality, relationships, and gender-related questions, with specific attention to prevention of and support after sexual victimization; and3. Meaningfully including the autism community in future research that addresses well-being relating to sexuality, relationships, and gender diversity.These community-driven recommendations aim to promote sexual health and well-being in autistic individuals internationally.

Here's the Story: Narrative Ability and Executive Function in Autism Spectrum Disorder.

Background: Difficulties with narrative have been reported in individuals diagnosed with autism spectrum disorder (ASD), but the role of executive function on narrative ability has not been examined in ASD. In this study, we aimed to (1) examine whether narrative abilities of ASD children differed from neurotypical (NT) children who did not differ in age, sex, and IQ; and (2) investigate relations between executive function and narrative ability in ASD children. Method: Narratives were elicited from 64 ASD children and 26 NT children using a wordless picture book and coded to derive several aspects of narrative ability such as propositions, evaluative devices, and self-repairs. Executive functions (specifically, inhibition and working memory) were measured using both experimenter-administered assessment and parent-report measures. Results: Compared to NT children, ASD children produced fewer propositions but did not differ in their use of evaluative devices and self-repairs during narrative production. Greater inhibitory challenges related to more self-repairs involving repetition of story elements, whereas working memory did not relate to any of the measures of narrative ability among ASD children. Conclusions: This study revealed that narratives by verbally fluent ASD children were shorter and less complex than those by NT children but did not differ in the specific features of narratives. Furthermore, although ASD children did not make more self-repairs than NT children, difficulty with inhibition was related to more self-repairs, indicating more dysfluent narrative production in ASD children, which has implications for intervention.

Sexual Knowledge, Experiences, and Pragmatic Language in Adults With and Without Autism: Implications for Sex Education.

Autistic adults have similar levels of desire for sexual and romantic relationships as their non-autistic peers. However, autistic adults are less likely to be in relationships and have less dating experience. We compared sexual knowledge, experiences, and pragmatic language ability in a community sample of young adults with (n = 27, mean age = 22.11) and without autism (n = 122, mean age = 19.47). Receipt of sex education and sexual knowledge did not differ between groups. However, autistic adults had significantly fewer partnered experiences and impaired pragmatic language. Within both groups, pragmatic skill predicted accurate sexual knowledge above and beyond general communication abilities. Findings suggest that sex education for autistic adults must address the social communication component of healthy romantic and sexual relationships.

Reduced Visual Evoked Potential Amplitude in Autistic Children with Co-Occurring Features of Attention-Deficit/Hyperactivity Disorder.

Provided the significant overlap in features of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), there is a critical need to identify transdiagnostic markers that could meaningfully stratify subgroups. The objective of this study was to compare the visual evoked potential (VEP) between 30 autistic children, 17 autistic children with co-occurring ADHD presentation (ASD + ADHD), and 21 neurotypical children (NTC). Electroencephalography was recorded while children passively viewed a pattern-reversal stimulus. Mean amplitude of the P1 event-related potential was extracted from a midline occipital channel and compared between groups. P1 mean amplitude was reduced in the ASD + ADHD group compared to the ASD and NTC groups, indicating a distinct pattern of brain activity in autistic children with co-occurring ADHD features.

A functional model for studying common trends across trial time in eye tracking experiments.

Eye tracking (ET) experiments commonly record the continuous trajectory of a subject's gaze on a two-dimensional screen throughout repeated presentations of stimuli (referred to as trials). Even though the continuous path of gaze is recorded during each trial, commonly derived outcomes for analysis collapse the data into simple summaries, such as looking times in regions of interest, latency to looking at stimuli, number of stimuli viewed, number of fixations or fixation length. In order to retain information in trial time, we utilize functional data analysis (FDA) for the first time in literature in the analysis of ET data. More specifically, novel functional outcomes for ET data, referred to as viewing profiles, are introduced that capture the common gazing trends across trial time which are lost in traditional data summaries. Mean and variation of the proposed functional outcomes across subjects are then modeled using functional principal components analysis. Applications to data from a visual exploration paradigm conducted by the Autism Biomarkers Consortium for Clinical Trials showcase the novel insights gained from the proposed FDA approach, including significant group differences between children diagnosed with autism and their typically developing peers in their consistency of looking at faces early on in trial time.

Attention Allocation During Exploration of Visual Arrays in ASD: Results from the ABC-CT Feasibility Study.

Visual exploration paradigms involving object arrays have been used to examine salience of social stimuli such as faces in ASD. Recent work suggests performance on these paradigms may associate with clinical features of ASD. We evaluate metrics from a visual exploration paradigm in 4-to-11-year-old children with ASD (n = 23; 18 males) and typical development (TD; n = 23; 13 males). Presented with arrays containing faces and nonsocial stimuli, children with ASD looked less at (p = 0.002) and showed fewer fixations to (p = 0.022) faces than TD children, and spent less time looking at each object on average (p = 0.004). Attention to the screen and faces correlated positively with social and cognitive skills in the ASD group (ps < .05). This work furthers our understanding of objective measures of visual exploration in ASD and its potential for quantifying features of ASD.

Concomitant medication use in children with autism spectrum disorder: Data from the Autism Biomarkers Consortium for Clinical Trials.

LAY ABSTRACT: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

The Autism Biomarkers Consortium for Clinical Trials: Initial Evaluation of a Battery of Candidate EEG Biomarkers.

OBJECTIVE: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials. METHODS: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations. RESULTS: Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170. CONCLUSIONS: In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.

Evaluation of clinical assessments of social abilities for use in autism clinical trials by the autism biomarkers consortium for clinical trials.

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials.

The Selective Social Attention task in children with autism spectrum disorder: Results from the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) feasibility study.

The Selective Social Attention (SSA) task is a brief eye-tracking task involving experimental conditions varying along socio-communicative axes. Traditionally the SSA has been used to probe socially-specific attentional patterns in infants and toddlers who develop autism spectrum disorder (ASD). This current work extends these findings to preschool and school-age children. Children 4- to 12-years-old with ASD (N = 23) and a typically-developing comparison group (TD; N = 25) completed the SSA task as well as standardized clinical assessments. Linear mixed models examined group and condition effects on two outcome variables: percent of time spent looking at the scene relative to scene presentation time (%Valid), and percent of time looking at the face relative to time spent looking at the scene (%Face). Age and IQ were included as covariates. Outcome variables' relationships to clinical data were assessed via correlation analysis. The ASD group, compared to the TD group, looked less at the scene and focused less on the actress' face during the most socially-engaging experimental conditions. Additionally, within the ASD group, %Face negatively correlated with SRS total T-scores with a particularly strong negative correlation with the Autistic Mannerism subscale T-score. These results highlight the extensibility of the SSA to older children with ASD, including replication of between-group differences previously seen in infants and toddlers, as well as its ability to capture meaningful clinical variation within the autism spectrum across a wide developmental span inclusive of preschool and school-aged children. The properties suggest that the SSA may have broad potential as a biomarker for ASD.