Kirsten O'Hearn

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)—a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7–64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Neurodevelopment and executive function in autism

Autism is a neurodevelopmental disorder characterized by social and communication deficits, and repetitive behavior. Studies investigating the integrity of brain systems in autism suggest a wide range of gray and white matter abnormalities that are present early in life and change with development. These abnormalities predominantly affect association areas and undermine functional integration. Executive function, which has a protracted development into adolescence and reflects the integration of complex widely distributed brain function, is also affected in autism. Evidence from studies probing response inhibition and working memory indicate impairments in these core components of executive function, as well as compensatory mechanisms that permit normative function in autism. Studies also demonstrate age-related improvements in executive function from childhood to adolescence in autism, indicating the presence of plasticity and suggesting a prolonged window for effective treatment. Despite developmental gains, mature executive functioning is limited in autism, reflecting abnormalities in wide-spread brain networks that may lead to impaired processing of complex information across all domains.

Magnetic Resonance Imaging of Children Without Sedation: Preparation With Simulation

OBJECTIVE It was hypothesized that a scanner simulator that replicates the magnetic resonance imaging (MRI) environment could be used to prepare pediatric subjects for successful completion of a diagnostic-quality MRI examination without pharmacological sedation. METHOD Sixteen healthy children, 6 to 17 years of age, were matched for age and sex with 16 psychotropic medication-naive children with obsessive-compulsive disorder. Distress was measured throughout simulation and scanning procedures using heart rate and a self-report distress scale. Ten healthy children, 6 to 17 years of age, also underwent the same actual MRI scanning procedure but did not undergo the simulation scanning procedure. RESULTS Significant decreases in heart rate and self-reported distress level were observed in all subjects during the simulator session that were maintained to the end of the actual scanner experience. All subjects successfully completed MRI examinations without chemical restraint. Subjects who were not trained in the simulator had higher heart rates and self-reported distress levels in the actual scanner than did simulation-trained subjects. CONCLUSIONS Simulation without pharmacological sedation successfully prepared pediatric subjects in this pilot study for high-quality MRI studies. Subject preparation may be an alternative procedure to sedation for routine MRI examination in healthy and anxious children 6 years of age and older.

Multiple Object Tracking in People With Williams Syndrome and in Normally Developing Children

Multiple object tracking is hypothesized to utilize visual indexes, which may provide rapid, parallel access to a limited number of visual objects, thereby supporting a variety of spatial tasks. We examined whether faulty indexing might play a role in the severe visuospatial deficits found in Williams syndrome. We asked observers to track from one to four targets in a display of eight identical objects. Objects remained stationary (static condition) or moved randomly and independently (moving condition) for 6 s, after which observers pointed to the objects they thought were targets. People with Williams syndrome were impaired in the moving condition, but not the static condition, compared with mental-age-matched control participants. Normal children who were younger than the mental-age-matched control children did not show the same profile as individuals with Williams syndrome, which suggests that the difference between the tasks in Williams syndrome did not reflect simple developmental immaturity. Error analysis revealed that all groups had “slippery” indexes, falsely identifying target neighbors, and further suggested that people with Williams syndrome deploy fewer indexes than do people without this disorder.

Lack of developmental improvement on a face memory task during adolescence in autism

Autism Spectrum Disorders (ASD) are associated with abnormalities in face memory, which evidence suggests has a protracted development through adolescence. The development of face memory in people with and without ASD, from 9 to 29 years old, was examined using the Cambridge Face Memory Test (CFMT). Results indicate that the developmental improvement evident from adolescence to adulthood typically was not apparent in individuals with ASD. While children and adolescents with ASD performed similarly to typically developing individuals comparable in age and IQ, adults with ASD displayed limitations on the CFMT. The pattern of performance was constant across conditions despite differences in the timing of the presentation and delay. This atypical development in ASD is consistent with the view that the processing of complex visual stimuli continues to develop through adolescence, along with the function and structure of the temporal lobes, but that this process is disrupted in ASD. This result underscores the importance of characterizing adolescent development for understanding ASD, and suggests additional opportunities for intervention.

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.

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.

Developmental Profiles for Multiple Object Tracking and Spatial Memory: Typically Developing Preschoolers and People with Williams Syndrome.

The ability to track moving objects, a crucial skill for mature performance on everyday spatial tasks, has been hypothesized to require a specialized mechanism that may be available in infancy (i.e. indexes). Consistent with the idea of specialization, our previous work showed that object tracking was more impaired than a matched spatial memory task in individuals with Williams syndrome (WS), a genetic disorder characterized by severe visuo-spatial impairment. We now ask whether this unusual pattern of performance is a reflection of general immaturity or of true abnormality, possibly reflecting the atypical brain development in WS. To examine these two possibilities, we tested typically developing 3- and 4-year-olds and people with WS on multiple object tracking (MOT) and memory for static spatial location. The maximum number of objects that could be correctly tracked or remembered (estimated from the k-statistic) showed similar developmental profiles in typically developing 3- and 4-year-old children, but the WS profile differed from either age group. People with WS could track more objects than 3-year-olds, and the same number as 4-year-olds, but they could remember the locations of more static objects than both 3- and 4-year-olds. Combining these data with those from our previous studies, we found that typically developing children show increases in the number of objects they can track or remember between the ages of 3 and 6, and these increases grow in parallel across the two tasks. In contrast, object tracking in older children and adults with WS remains at the level of 4-year-olds, whereas the ability to remember multiple locations of static objects develops further. As a whole, the evidence suggests that MOT and memory for static location develop in tandem typically, but not in WS. Atypical development of the parietal lobe in people with WS could play a causal role in the abnormal, uneven pattern of performance in WS. This interpretation is consistent with the idea that multiple object tracking engages different mechanisms from those involved in memory for static object location, and that the former can be particularly disrupted by atypical development.

Mathematical skill in individuals with Williams syndrome: Evidence from a standardized mathematics battery

Williams syndrome (WS) is a developmental disorder associated with relatively spared verbal skills and severe visuospatial deficits. It has also been reported that individuals with WS are impaired at mathematics. We examined mathematical skills in persons with WS using the second edition of the Test of Early Mathematical Ability (TEMA-2), which measures a wide range of skills. We administered the TEMA-2 to 14 individuals with WS and 14 children matched individually for mental-age on the matrices subtest of the Kaufman Brief Intelligence Test. There were no differences between groups on the overall scores on the TEMA-2. However, an item-by-item analysis revealed group differences. Participants with WS performed more poorly than controls when reporting which of two numbers was closest to a target number, a task thought to utilize a mental number line subserved by the parietal lobe, consistent with previous evidence showing parietal abnormalities in people with WS. In contrast, people with WS performed better than the control group at reading numbers, suggesting that verbal math skills may be comparatively strong in WS. These findings add to evidence that components of mathematical knowledge may be differentially damaged in developmental disorders.

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.