Studies comparing individuals with autism spectrum disorder (ASD) to typically developing (TD) individuals have yielded inconsistent results. These inconsistencies reflect, in part, atypical trajectories of development in children and young adults with ASD compared to TD peers. These different trajectories alter group differences between children with and without ASD as they age. This paper first summarizes the disparate trajectories evident in our studies and, upon further investigation, laboratories using the same recruiting source. These studies indicated that cognition improves into adulthood typically, and is associated with the maturation of striatal, frontal, and temporal lobes, but these age-related improvements did not emerge in the young adults with ASD. This pattern - of improvement into adulthood in the TD group but not in the group with ASD - occurred in both social and non-social tasks. However, the difference between TD and ASD trajectories was most robust on a social task, face recognition. While tempting to ascribe this uneven deficit to the social differences in ASD, it may also reflect the prolonged typical development of social cognitive tasks such as face recognition into adulthood. This paper then reviews the evidence on age-related and developmental changes from other studies on ASD. The broader literature also suggests that individuals with ASD do not exhibit the typical improvements during adolescence on skills important for navigating the transition to adulthood. These skills include execution function, social cognition and communication, and emotional recognition and self-awareness. Relatedly, neuroimaging studies indicate arrested or atypical brain maturation in striatal, frontal, and temporal regions during adolescence in ASD. This review not only highlights the importance of a developmental framework and explicit consideration of age and/or stage when studying ASD, but also the potential importance of adolescence on outcomes in ASD.

Autism spectrum disorder (ASD) is associated with atypical visual processing and deficits in working memory (WM). Visual WM performance typically improves between childhood and adulthood, but such improvement may be atypical in ASD. To better understand how visual WM develops, we used a well-established change detection task across multiple visual features. We examined visual WM for color, shape, and pattern in children, adolescents, and adults with and without ASD. VWM capacity and performance for all visual features improved across age similarly for both the TD and ASD groups. While performance was better on set size 4 trials than set size 8 trials for color, shape, and no change trials, such an effect was not evident for pattern change trials. Overall, the present findings suggest that VWM for different visual features may be intact across development in ASD. The ability to hold multiple objects in mind (WM) improves across typical development, but it remains unclear whether such improvement occurs in ASD. We found that developmental improvements in WM for different types of object details (e.g., color, shape, and pattern) is generally similar for both ASD and typical development. LAY SUMMARY: The ability to hold multiple objects in mind (working memory [WM]) improves across typical development, but it remains unclear whether such improvement occurs in autism spectrum disorder (ASD). We found that developmental improvements in WM for different types of object details (e.g., color, shape, pattern) is generally similar for both ASD and typical development.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

IMPORTANCE:Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE:To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS:Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES:Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS:A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. CONCLUSIONS AND RELEVANCE:In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’s d = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

Visual working memory (VWM) typically improves across childhood and adolescence. Yet, it remains unclear whether such improvement occurs in autism (ASD). We measured color, shape, and pattern VWM performance in children (N=49; Mage=11y; 41 males), adolescents (N=46; Mage=15y; 38 males), and adults (N=51; Mage=24y; 47 males) with and without ASD (91% White, 6% Black or multiracial). By adulthood, color VWM accuracy among 4 items was better in the TD group relative to ASD (p2=.039). In childhood, shape VWM RT among 8 items was faster in the TD group relative to ASD (p2=.063). While VWM capacity was intact in ASD, VWM performance differences between ASD and TD may depend on age and visual feature.

Visual working memory (VWM) typically improves across childhood and adolescence. Yet, it remains unclear whether such improvement occurs in autism (ASD). We measured color, shape, and pattern VWM performance in children (N=49; Mage=11y; 41 males), adolescents (N=46; Mage=15y; 38 males), and adults (N=51; Mage=24y; 47 males) with and without ASD (91% White, 6% Black or multiracial). By adulthood, color VWM accuracy among 4 items was better in the TD group relative to ASD (p2=.039). In childhood, shape VWM RT among 8 items was faster in the TD group relative to ASD (p2=.063). While VWM capacity was intact in ASD, VWM performance differences between ASD and TD may depend on age and visual feature.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

BACKGROUND:Autism Spectrum Disorder (ASD) is associated with atypical activation in the ventral stream during face processing. The current study further characterizes the development of face processing in ASD using a multivoxel pattern analysis, which assesses the similarity in the representation of exemplars from the same category.METHODS:Ninety-two children, adolescents and adults - with and without ASD - performed the Cambridge Face Memory Test, the Australian Face Memory Test, and a matched car memory test. Regions of interest during these tasks included Fusiform Face Area (FFA), based on the literature, and additional, structurally-defined regions in the ventral stream. Group differences in the patterns of activity within these ROIs when memorizing exemplars were examined using a representational similarity analysis (RSA).RESULTS:The RSA revealed significant interactions between age group and diagnostic group in R FFA, with increasing similarity within a category (faces, cars) into adulthood typically but not in those with ASD. This pattern was also evident in structurally defined ventral stream regions, namely L inferior frontal gyrus (IFG), bilateral temporoparietal junction (TPJ), L inferior temporal lobule, and the R fusiform gyrus.CONCLUSIONS:The specialization of face and object processing from adolescence to adulthood evident in typical development may be impaired in ASD, undermining the ability to reach adult-level visual processing in those with ASD.

Background Left-right asymmetry is an important organizing feature of the healthy brain. Various studies have reported altered structural brain asymmetry in autism spectrum disorder (ASD). However, findings have been inconsistent, likely due to limited sample sizes and low statistical power. Methods We investigated 1,774 subjects with ASD and 1,809 controls, from 54 datasets, for differences in the asymmetry of thickness and surface area of 34 cerebral cortical regions. We also examined global hemispheric measures of cortical thickness and area asymmetry, and volumetric asymmetries of subcortical structures. Data were obtained via the ASD Working Group of the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. Results ASD was significantly associated with reduced leftward asymmetry of total hemispheric average cortical thickness, compared to controls. Eight regional thickness asymmetries, distributed over the cortex, also showed significant associations with diagnosis after correction for multiple comparisons, for which asymmetry was again generally lower in ASD versus controls. In addition, the medial orbitofrontal surface area was less rightward asymmetric in ASD than controls, and the putamen volume was more leftward asymmetric in ASD than controls. The largest effect size had Cohen’s d = 0.15. Most effects did not depend on age, sex, IQ, or disorder severity. Conclusion Altered lateralized neurodevelopment is suggested in ASD, affecting widespread cortical regions with diverse functions. Large-scale analysis was necessary to reliably detect, and accurately describe, subtle alterations of structural brain asymmetry in this disorder.

OBJECTIVE:Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group.METHOD:The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach.RESULTS:The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions.CONCLUSIONS:The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

Difficulties with face recognition increase from adolescence to adulthood in autism, reflecting a lack of typical late development. We examined whether this reflects differences in the development of patterns of fixation to eyes and mouths during face recognition. Children, adolescents, and adults (aged 7–30) with and without autism completed the Cambridge Face Memory Test while gaze was recorded. Average duration and number of fixations were calculated for eyes and mouth regions of interest, defined individually for each face image in the task. All groups and age groups made more and longer fixations to eyes than mouths. However, during face memorization, typically developing children and adults, but not adolescents, made more fixations to eyes than did their peers with autism. During face recognition, typically developing children and adults made shorter fixations on mouths than did their peers with autism; this pattern was reversed in adolescence, with adolescents with autism making more fixations to mouths than typically developing adolescents. Results suggest that group differences in patterns of fixations to faces change with age. Furthermore, different relationships between patterns of fixations and face recognition performance in typical development and autism suggest that these differences contribute, at least in part, to difficulties in autism.

The ability to track moving objects is a crucial skill for performance in everyday spatial tasks. The tracking mechanism depends on representation of moving items as coherent entities, which follow the spatiotemporal constraints of objects in the world. In the present experiment, participants tracked 1 to 4 targets in a display of 8 identical objects. Objects moved randomly and independently (moving condition), passed behind an invisible bar (occluded condition), or momentarily disappeared by shrinking (implosion condition). Scholl and Pylyshyn (1999) found that adults can track entities under the moving and occluded conditions, but not under implosion. This finding suggests that the tracking mechanism is constrained by the spatiotemporal properties of physical objects as they move in the world. In the present study, we adapt these conditions to investigate whether this constraint holds for people with severe spatial impairments associated with Williams syndrome (WS). In Experiment 1, we compare the performance of individuals with WS and typically developing (TD) adults. TD adults replicated Scholl and Pylyshyn's findings; performance was no different between the moving and occluded conditions but was worse under implosion. People with WS had reduced tracking capacity but demonstrated the same pattern across conditions. In Experiment 2, we tested TD 4-, 5-, and 7-year-olds. People with WS performed at a level that fell between TD 4- and 5-year-olds. These results suggest that the multiple object tracking system in WS operates under the same object-based constraints that hold in typical development.

This study disentangled the influences of language and social processing on communication in autism spectrum disorder (ASD) by examining whether gesture and speech production differs as a function of social context. The results indicate that, unlike other adolescents, adolescents with ASD did not increase their coherency and engagement in the presence of a visible listener, and that greater coherency and engagement were related to lesser social and communicative impairments. Additionally, the results indicated that adolescents with ASD produced sparser speech and fewer gestures conveying supplementary information, and that both of these effects increased in the presence of a visible listener. Together, these findings suggest that interpersonal communication deficits in ASD are driven more strongly by social processing than language processing.

Face recognition abilities improve between adolescence and adulthood over typical development (TD), but plateau in autism, leading to increasing face recognition deficits in autism later in life. Developmental differences between autism and TD may reflect changes between neural systems involved in the development of face encoding and recognition. Here, we focused on whole-brain connectivity with the fusiform face area (FFA), a well-established face-preferential brain region. Older children, adolescents, and adults with and without autism completed the Cambridge Face Memory Test, and a matched car memory test, during fMRI scanning. We then examined task-based functional connectivity between the FFA and the rest of the brain, comparing autism and TD groups during encoding and recognition of face and car stimuli. The autism group exhibited underconnectivity, relative to the TD group, between the FFA and frontal and primary visual cortices, independent of age. Underconnectivity with the medial and rostral lateral prefrontal cortex was face-specific during encoding and recognition, respectively. Conversely, underconnectivity with the L orbitofrontal cortex was evident for both face and car encoding. Atypical age-related changes in connectivity emerged between the FFA and the R temporoparietal junction, and R dorsal striatum for face stimuli only. Similar differences in age-related changes in autism emerged for FFA connectivity with the amygdala across both face and car recognition. Thus, underconnectivity and atypical development of functional connectivity may lead to a less optimal face-processing network in the context of increasing general and social cognitive deficits in autism.

Previous work indicates that adults with autism display a decreased capacity when rapidly enumerating small sets of elements (i.e., subitizing), compared to typically developing (TD) individuals. This ability is crucial for fundamental visual functions such as object individuation and parallel processing. Thus, the deficit in autism suggests limits in these skills. To examine the neural basis of this limitation, adults with and without high functioning autism rapidly enumerated 1 to 8 randomly located squares during a neuroimaging study. Typically, adults are thought to use parallel visual processes to quantify up to three or four elements, and serial processes to enumerate more (5+) elements. We hypothesized that parietal lobe regions associated with counting would be recruited with smaller sets of elements in adults with autism, compared to TD adults. Consistent with this hypothesis, activation in parietal regions increased with smaller set sizes in adults with autism compared to TD adults. Increased activation for three elements was evident in several regions, including those thought to underlie subitizing. In addition, regions specific to the counting range in TD adults were often equally active for set sizes in the subitizing range in the adults with autism. Finally, significant deactivation was evident in TD adults, presumably reflecting relative suppression of regions specialized for competing processes, but was not apparent in adults with autism. These differences in brain function in adults with autism on a simple enumeration task suggest atypical brain organization and function that is likely to impact most visual tasks, especially those with multiple elements. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.