Stewart H. Mostofsky

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.

Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder

BACKGROUND Anatomic magnetic resonance imaging (MRI) studies of attention-deficit/hyperactivity disorder (ADHD) have been limited by use of callosal rather than sulcal/gyral landmarks in defining cerebral lobes and functionally relevant sublobar regions (e.g., prefrontal cortex). We present an investigation of cerebral volumes in ADHD using a Talairach-based approach that uses cortical landmarks to define functionally relevant regions. METHODS Volumes were compared between groups of 12 boys with ADHD and 12 age- and gender-matched control subjects, using a series of multiple analyses of variance. RESULTS Boys with ADHD had (on average) 8.3% smaller total cerebral volumes. Significant reductions in lobar volumes were seen only for the frontal lobes. Within the frontal lobes, a reduction was seen in both gray and white matter volumes, with some evidence suggesting lateralization of these findings: reduction in frontal white matter volume was specific to the left hemisphere; there was a bilateral reduction in frontal gray matter volume but more so in the right hemisphere. Subparcellation of the frontal lobe revealed smaller prefrontal, premotor, and deep white matter volumes. CONCLUSIONS Findings suggest that ADHD is associated with decreased frontal lobe gray and white matter volumes. More than one subdivision of the frontal lobes appears to be reduced in volume, suggesting that the clinical picture of ADHD encompasses dysfunctions attributable to anomalous development of both premotor and prefrontal cortices.

Response inhibition and response selection: Two sides of the same coin

Response inhibition refers to the suppression of actions that are inappropriate in a given context and that interfere with goal-driven behavior. Studies using a range of methodological approaches have implicated executive control processes mediated by frontal-subcortical circuits as being critical to response inhibition; however, localization within the frontal lobe has been inconsistent. In this review, we present evidence from behavioral, lesion, neuroimaging, electrophysiology, and neurological population studies. The findings lay the foundation for a construct in which response inhibition is akin to response selection, such that pre-SMA circuits are critical to selection of appropriate behavior, including both selecting to engage appropriate motor responses and selecting to withhold (inhibit) inappropriate motor responses. Recruitment of additional prefrontal and posterior cortical circuits, necessary to guide response selection, varies depending on the cognitive and behavioral demands of the task.

Family income, parental education and brain structure in children and adolescents

Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.

Evaluation of Cerebellar Size in Attention-Deficit Hyperactivity Disorder

Evidence from animal and human research suggests that the cerebellum may play a role in cognition. This includes domains of executive function that are normally attributed to the prefrontal cortex and are typically deficient in individuals with attention-deficit hyperactivity disorder (ADHD). To investigate cerebellar structure in ADHD, magnetic resonance imaging morphometry was used to measure the area of the cerebellar vermis in 12 males with ADHD and 23 male controls matched for age and Wechsler Full-Scale IQ. Analyses were conducted to evaluate group differences, as well as differences between matched pairs of subjects with ADHD and those without ADHD. All measurements were corrected for overall brain size. Both analyses revealed that the size of the posterior vermis was significantly decreased in males with ADHD (P < .05 in both analyses), and that within the posterior vermis, the inferior posterior lobe (lobules VIII-X) was involved in this reduction (P < .05 for group analysis, P < .005 for matched pair analysis), while the superior posterior lobe (lobules VI/VII) was not involved in the reduction. The finding of abnormal inferior posterior vermal size suggests that dysfunction within this region of the cerebellum may underlie clinical deficits seen in individuals with ADHD. (J Child Neurol 1998; 13:434-439).

Decreased connectivity and cerebellar activity in autism during motor task performance

Although motor deficits are common in autism, the neural correlates underlying the disruption of even basic motor execution are unknown. Motor deficits may be some of the earliest identifiable signs of abnormal development and increased understanding of their neural underpinnings may provide insight into autism-associated differences in parallel systems critical for control of more complex behaviour necessary for social and communicative development. Functional magnetic resonance imaging was used to examine neural activation and connectivity during sequential, appositional finger tapping in 13 children, ages 8-12 years, with high-functioning autism (HFA) and 13 typically developing (TD), age- and sex-matched peers. Both groups showed expected primary activations in cortical and subcortical regions associated with motor execution [contralateral primary sensorimotor cortex, contralateral thalamus, ipsilateral cerebellum, supplementary motor area (SMA)]; however, the TD group showed greater activation in the ipsilateral anterior cerebellum, while the HFA group showed greater activation in the SMA. Although activation differences were limited to a subset of regions, children with HFA demonstrated diffusely decreased connectivity across the motor execution network relative to control children. The between-group dissociation of cerebral and cerebellar motor activation represents the first neuroimaging data of motor dysfunction in children with autism, providing insight into potentially abnormal circuits impacting development. Decreased cerebellar activation in the HFA group may reflect difficulty shifting motor execution from cortical regions associated with effortful control to regions associated with habitual execution. Additionally, diffusely decreased connectivity may reflect poor coordination within the circuit necessary for automating patterned motor behaviour. The findings might explain impairments in motor development in autism, as well as abnormal and delayed acquisition of gestures important for socialization and communication.

Dyspraxia in Autism: Association with Motor, Social, and Communicative Deficits.

Impaired performance of skilled gestures, referred to as dyspraxia, is consistently reported in children with autism; however, its neurological basis is not well understood. Basic motor skill deficits are also observed in children with autism and it is unclear whether dyspraxia observed in children with autism can be accounted for by problems with motor skills. Forty‐seven high‐functioning children with an autism spectrum disorder (ASD), autism, or Asperger syndrome (43 males, four females; mean age 10y 7m [SD 1y 10m], mean Full‐scale IQ (FSIQ) 99.4 [SD 15.9]), and 47 typically developing (TD) controls (41 males, six females; mean age 10y 6m [SD 1y 5m], mean FSIQ 113.8 [SD 12.3], age range 8–4y) completed: (1) the Physical and Neurological Assessment of Subtle Signs, an examination of basic motor skills standardized for children, and (2) a praxis examination that included gestures to command, to imitation, and with tool‐use. Hierarchical regression was used to examine the association between basic motor skill performance (i.e. times to complete repetitive limb movements) and praxis performance (total praxis errors). After controlling for age and IQ, basic motor skill was a significant predictor of performance on praxis examination. Nevertheless, the ASD group continued to show significantly poorer praxis than controls after accounting for basic motor skill. Furthermore, praxis performance was a strong predictor of the defining features of autism, measured using the Autism Diagnostic Observation Schedule, and this correlation remained significant after accounting for basic motor skill. Results indicate that dyspraxia in autism cannot be entirely accounted for by impairments in basic motor skills, suggesting the presence of additional contributory factors. Furthermore, praxis in children with autism is strongly correlated with the social, communicative, and behavioral impairments that define the disorder, suggesting that dyspraxia may be a core feature of autism or a marker of the neurological abnormalities underlying the disorder.

Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data

In recent years, there has been growing enthusiasm that functional magnetic resonance imaging (MRI) could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement-related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to (1) examine the impact of emerging techniques for controlling for “micro-movements,” and (2) provide novel insights into the neural correlates of ADHD subtypes. Using support vector machine (SVM)-based multivariate pattern analysis (MVPA) we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C) and Inattentive (ADHD-I) subtypes demonstrated some overlapping (particularly sensorimotor systems), but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that resting-state functional connectivity MRI (rs-fcMRI) data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD.

Developmental dyspraxia is not limited to imitation in children with autism spectrum disorders

Impaired imitation of skilled gestures is commonly reported in autism. Questions, however, remain as to whether impaired imitation is associated with a more generalized deficit in performance of gestures consistent with a dyspraxia and whether the pattern of errors differs from that observed in typically developing children. To address these questions, praxis in 21 high-functioning children with autism spectrum disorders (ASD) was compared with 24 typically developing controls using a traditional approach in which performance was evaluated through detailed examination of error types. Children with ASD produced significantly fewer correct responses not only during Gesture to Imitation, but also during Gesture to Command and with Tool Use. The pattern of errors in ASD was similar to that of controls with spatial errors being most common in both groups; however, body-part-for-tool errors were more common in children with ASD, suggesting dyspraxia is not entirely attributable to motor deficits. The findings suggest that autism is associated with a generalized praxis deficit, rather than a deficit specific to imitation. In a developmental disorder such as autism, the findings may reflect abnormalities in frontal/parietal-subcortical circuits important for acquisition (i.e., learning) of sensory representations of movement and/or the motor sequence programs necessary to execute them.

Decreased cerebellar posterior vermis size in fragile X syndrome: Correlation with neurocognitive performance

We examined whether posterior vermis size is smaller in individuals with fragile X syndrome (fra X) than in control subjects and whether this decreased size is associated with cognitive performance. Cognitive and behavioral dysfunctions have been identified in fra X; however, underlying neuropathogenic mechanisms remain unclear. MRI was used to investigate the posterior fossa in 32 males with fra X, 28 males with other causes of cognitive disability (CD), and 38 males with normal development (ND) as well as and in 37 females with fra X and 53 female control subjects. Among females with fra X, neurocognitive correlates of posterior vermis size were examined. Posterior vermis size (cross-sectional area) in males with fra X was significantly smaller compared with CD and ND groups, particularly when corrected for intracranial area. Posterior vermis size corrected for intracranial area was significantly smaller in females with fra X compared with control subjects. Compared with males with fra X and non-fra X control subjects, posterior vermis size in females with fra X was intermediate. After statistically removing the effect of mean parental IQ, posterior vermis size predicted a significant proportion of the variance (10 to 23%) of performance on full-scale, verbal, and performance IQ; block design; categories achieved on the Wisconsin Card Sorting Test; and the Rey inventory score. The size of the posterior vermis is significantly decreased in fra X, more so in males than in females. In females with fra X, posterior vermis size predicts performance on selected cognitive measures.