Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

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.

Visual working memory performance is intact across development in autism spectrum disorder.

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.

Age differences and brain maturation provide insight into heterogeneous results in autism spectrum disorder.

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.

Representational similarity analysis reveals atypical age-related changes in brain regions supporting face and car recognition in autism.

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.

Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets.

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.

Patterns of fixation during face recognition: Differences in autism across age.

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.

Functional connectivity differences in autism during face and car recognition: underconnectivity and atypical age-related changes.

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.

Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group.

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.

Enhancing studies of the connectome in autism using the autism brain imaging data exchange II.

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.

Altered Gesture and Speech Production in ASD Detract from In-Person Communicative Quality.

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.

Abnormalities in brain systems supporting individuation and enumeration 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.

Developmental changes in brain function underlying inhibitory control in autism spectrum disorders.

The development of inhibitory control-the ability to suppress inappropriate actions in order to make goal-directed responses-is often impaired in autism spectrum disorders (ASD). In the present study, we examined whether the impairments in inhibitory control evident in ASD reflect-in part-differences in the development of the neural substrates of inhibitory control from adolescence into adulthood. We conducted a functional magnetic resonance imaging (fMRI) study on the anti-saccade task, a probe of inhibitory control, in high-functioning adolescents and adults with ASD compared to a matched group of typically developing (TD) individuals. The ASD group did not show the age-related improvements in behavioral performance from adolescence to adulthood evident in the typical group, consistent with previous behavioral work. The fMRI results indicated that much of the circuitry recruited by the ASD group was similar to the TD group. However, the ASD group demonstrated some unique patterns, including: (a) a failure to recruit the frontal eye field during response preparation in adolescence but comparable recruitment in adulthood; (b) greater recruitment of putamen in adolescence and precuneus in adolescence and adulthood than the TD group; and (c) decreased recruitment in the inferior parietal lobule relative to TD groups. Taken together, these results suggest that brain circuitry underlying inhibitory control develops differently from adolescence to adulthood in ASD. Specifically, there may be relative underdevelopment of brain processes underlying inhibitory control in ASD, which may lead to engagement of subcortical compensatory processes.

Developmental plateau in visual object processing from adolescence to adulthood in autism.

A lack of typical age-related improvement from adolescence to adulthood contributes to face recognition deficits in adults with autism on the Cambridge Face Memory Test (CFMT). The current studies examine if this atypical developmental trajectory generalizes to other tasks and objects, including parts of the face. The CFMT tests recognition of whole faces, often with a substantial delay. The current studies used the immediate memory (IM) task and the parts-whole face task from the Let's Face It! battery, which examines whole faces, face parts, and cars, without a delay between memorization and test trials. In the IM task, participants memorize a face or car. Immediately after the target disappears, participants identify the target from two similar distractors. In the part-whole task, participants memorize a whole face. Immediately after the face disappears, participants identify the target from a distractor with different eyes or mouth, either as a face part or a whole face. Results indicate that recognition deficits in autism become more robust by adulthood, consistent with previous work, and also become more general, including cars. In the IM task, deficits in autism were specific to faces in childhood, but included cars by adulthood. In the part-whole task, deficits in autism became more robust by adulthood, including both eyes and mouths as parts and in whole faces. Across tasks, the deficit in autism increased between adolescence and adulthood, reflecting a lack of typical improvement, leading to deficits with non-face stimuli and on a task without a memory delay. These results suggest that brain maturation continues to be affected into adulthood in autism, and that the transition from adolescence to adulthood is a vulnerable stage for those with autism.

Age related changes in striatal resting state functional connectivity in autism.

Characterizing the nature of developmental change is critical to understanding the mechanisms that are impaired in complex neurodevelopment disorders such as autism spectrum disorder (ASD) and, pragmatically, may allow us to pinpoint periods of plasticity when interventions are particularly useful. Although aberrant brain development has long been theorized as a characteristic feature of ASD, the neural substrates have been difficult to characterize, in part due to a lack of developmental data and to performance confounds. To address these issues, we examined the development of intrinsic functional connectivity, with resting state fMRI from late childhood to early adulthood (8-36 years), using a seed based functional connectivity method with the striatal regions. Overall, we found that both groups show decreases in cortico-striatal circuits over age. However, when controlling for age, ASD participants showed increased connectivity with parietal cortex and decreased connectivity with prefrontal cortex relative to typically developed (TD) participants. In addition, ASD participants showed aberrant age-related connectivity with anterior aspects of cerebellum, and posterior temporal regions (e.g., fusiform gyrus, inferior and superior temporal gyri). In sum, we found prominent differences in the development of striatal connectivity in ASD, most notably, atypical development of connectivity in striatal networks that may underlie cognitive and social reward processing. Our findings highlight the need to identify the biological mechanisms of perturbations in brain reorganization over development, which may also help clarify discrepant findings in the literature.

The development of individuation in autism.

Evidence suggests that people with autism rely less on holistic visual information than typical adults. The current studies examine this by investigating core visual processes that contribute to holistic processing--namely, individuation and element grouping--and how they develop in participants with autism and typically developing (TD) participants matched for age, IQ, and gender. Individuation refers to the ability to "see" approximately four elements simultaneously; grouping elements can modify how many elements can be individuated. We examined these processes using two well-established paradigms, rapid enumeration and multiple object tracking (MOT). In both tasks, a performance limit of four elements in typical adults is thought to reflect individuation capacity. Participants with autism displayed a smaller individuation capacity than TD controls, regardless of whether they were enumerating static elements or tracking moving ones. To manipulate the holistic information available via element grouping, elements were arranged into a design in rapid enumeration, or moved together in MOT. Performance in participants with autism was affected to a similar degree as TD participants by element grouping, whether the manipulation helped or hurt performance, consistent with evidence that some types of gestalt/grouping information are processed typically in autism. There was substantial development from childhood to adolescence in the speed of individuation in those with autism, but not from adolescence to adulthood, a pattern distinct from TD participants. These results reveal how core visual processes function in autism, and provide insight into the architecture of vision (i.e., individuation appears distinct from visual strengths in autism, such as visual search).

Quantitative analysis of gray and white matter in Williams syndrome.

Williams syndrome is a developmental disorder with a genetic basis, which results in an uneven cognitive profile with relatively strong language skills and severely impaired visuospatial abilities. To better understand the brain structure underlying this profile, we compared individuals with Williams syndrome with controls using multimodal neuroimaging data and new analytic methods (diffeomorphic mapping and atlas-based analysis). People with Williams syndrome had basal ganglia atrophy, while the fusiform, the medium temporal gyri, and the cerebellar cortex were relatively preserved. The right superior longitudinal fasciculus, the left frontooccipital fasciculus, the caudate, and the cingulum demonstrated increased fractional anisotropy, whereas the corticospinal tract revealed decreased values. These findings may be linked to the uneven cognitive profile evident in Williams syndrome.

Object recognition in Williams syndrome: uneven ventral stream activation.

Williams syndrome (WS) is a genetic disorder associated with severe visuospatial deficits, relatively strong language skills, heightened social interest, and increased attention to faces. On the basis of the visuospatial deficits, this disorder has been characterized primarily as a deficit of the dorsal stream, the occipitoparietal brain regions that subserve visuospatial processing. However, some evidence indicates that this disorder may also affect the development of the ventral stream, the occipitotemporal cortical regions that subserve face and object recognition. The present studies examined ventral stream function in WS, with the hypothesis that faces would produce a relatively more mature pattern of ventral occipitotemporal activation, relative to other objects that are also represented across these visual areas. Using functional magnetic imaging, we compared activation patterns during viewing of human faces, cat faces, houses and shoes in individuals with WS (age 14-27), typically developing 6-9-year-olds (matched approximately on mental age), and typically developing 14-26-year-olds (matched on chronological age). Typically developing individuals exhibited changes in the pattern of activation over age, consistent with previous reports. The ventral stream topography of individuals with WS differed from both control groups, however, reflecting the same level of activation to face stimuli as chronological age matches, but less activation to house stimuli than either mental age or chronological age matches. We discuss the possible causes of this unusual topography and implications for understanding the behavioral profile of people with WS.

Small Subitizing Range in People with Williams syndrome.

Recent evidence suggests that the rapid apprehension of small numbers of objects-- often called subitizing-- engages a system which allows representation of up to 4 objects but is distinct from other aspects of numerical processing. We examined subitizing by studying people with Williams syndrome (WS), a genetic deficit characterized by severe visuospatial impairments, and normally developing children (4-6.5 years old). In Experiment 1, participants first explicitly counted displays of 1 to 8 squares that appeared for 5 s and reported "how many". They then reported "how many" for the same displays shown for 250 ms, a duration too brief to allow explicit counting, but sufficient for subitizing. All groups were highly accurate up to 8 objects when they explicitly counted. With the brief duration, people with WS showed almost perfect accuracy up to a limit of 3 objects, comparable to 4 year-olds but fewer than either 5 or 6.5 year-old children. In Experiment 2, participants were asked to report "how many" for displays that were presented for an unlimited duration, as rapidly as they could while remaining accurate. Individuals with WS responded as rapidly as 6.5 year-olds, and more rapidly than 4 year-olds. However, their accuracy was as in Experiment 1, comparable to 4 year-olds, and lower than older children. These results are consistent with previous results indicating that people with WS can simultaneously represent multiple objects, but that they have a smaller capacity than older children, on par with 4 year-olds. This pattern is discussed in the context of normal and abnormal development of visuospatial skills, in particular those linked to the representation of numerosity.

Deficits in adults with autism spectrum disorders when processing multiple objects in dynamic scenes.

People with autism spectrum disorders (ASD) process visual information in a manner that is distinct from typically developing individuals. They may be less sensitive to people's goals and, more generally, focus on visual details instead of the entire scene. To examine these differences, people with and without ASD were asked to detect changes in dynamic scenes with multiple elements. Participants viewed a brief video of a person or an inanimate object (the "figure") moving from one object to another; after a delay, they reported whether a second video was the same or different. Possible changes included the figure, the object the figure was moving from, or the object the figure was moving toward (the "goal"). We hypothesized that individuals with ASD would be less sensitive to changes in scenes with people, particularly elements that might be the person's goal. Alternately, people with ASD might attend to fewer elements regardless of whether the scene included a person. Our results indicate that, like controls, people with ASD noticed a change in the "goal" object at the end of a person's movement more often than the object at the start. However, the group with ASD did not undergo the developmental improvement that was evident typically when detecting changes in both the start and end objects. This atypical development led to deficits in adults with ASD that were not specific to scenes with people or to "goals." Improvements in visual processing that underlie mature representation of scenes may not occur in ASD, suggesting that late developing brain processes are affected.