Differences in brain networks and underlying white matter abnormalities have been suggested to underlie symptoms of autism spectrum disorder (ASD). However, robustly characterizing microstructural white matter differences has been challenging. In the present study, we applied an analytic technique that calculates structural metrics specific to differently-oriented fiber bundles within a voxel, termed “fixels”. Fixel-based analyses were used to compare diffusion-weighted magnetic resonance imaging data from 25 individuals with ASD (mean age = 16.8 years) and 27 typically developing age-matched controls (mean age = 16.9 years). Group comparisons of fiber density (FD) and bundle morphology were run on a fixel-wise, tract-wise, and global white matter (GWM) basis. We found that individuals with ASD had reduced FD, suggestive of decreased axonal count, in several major white matter tracts, including the corpus callosum (CC), bilateral inferior frontal-occipital fasciculus, right arcuate fasciculus, and right uncinate fasciculus, as well as a GWM reduction. Secondary analyses assessed associations with social impairment in participants with ASD, and showed that lower FD in the splenium of the CC was associated with greater social impairment. Our findings suggest that reduced FD could be the primary microstructural white matter abnormality in ASD.

Early childhood is a period of profound neural development and remodeling during which attention skills undergo rapid maturation. Attention networks have been extensively studied in the adult brain, yet relatively little is known about changes in early childhood, and their relation to cognitive development. We investigated the association between age and functional connectivity (FC) within the dorsal attention network (DAN) and the association between FC and attention skills in early childhood. Functional magnetic resonance imaging data was collected during passive viewing in 44 typically developing female children between 4 and 7 years whose sustained, selective, and executive attention skills were assessed. FC of the intraparietal sulcus (IPS) and the frontal eye fields (FEF) was computed across the entire brain and regressed against age. Age was positively associated with FC between core nodes of the DAN, the IPS and the FEF, and negatively associated with FC between the DAN and regions of the default-mode network. Further, controlling for age, FC between the IPS and FEF was significantly associated with selective attention. These findings add to our understanding of early childhood development of attention networks and suggest that greater FC within the DAN is associated with better selective attention skills.

Children acquire attention skills rapidly during early childhood as their brains undergo vast neural development. Attention is well studied in the adult brain, yet due to the challenges associated with scanning young children, investigations in early childhood are sparse. Here, we examined the relationship between age, attention and functional connectivity (FC) during passive viewing in multiple intrinsic connectivity networks (ICNs) in 60 typically developing girls between 4 and 7 years whose sustained, selective and executive attention skills were assessed. Visual, auditory, sensorimotor, default mode (DMN), dorsal attention (DAN), ventral attention (VAN), salience, and frontoparietal ICNs were identified via Independent Component Analysis and subjected to a dual regression. Individual spatial maps were regressed against age and attention skills, controlling for age. All ICNs except the VAN showed regions of increasing FC with age. Attention skills were associated with FC in distinct networks after controlling for age: selective attention positively related to FC in the DAN; sustained attention positively related to FC in visual and auditory ICNs; and executive attention positively related to FC in the DMN and visual ICN. These findings suggest distributed network integration across this age range and highlight how multiple ICNs contribute to attention skills in early childhood.

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 2016 Wiley Periodicals, Inc.

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Early childhood is an important period for cognitive and brain development, though white matter changes specific to this period remain understudied. Here we utilize a novel analytic approach to quantify and track developmental changes in white matter micro-and macro-structure, calculated from individually oriented fiber-bundle populations, termed "fixels". Fixel-based analysis and mixed-effects models were used to assess tract-wise changes in fiber density and bundle morphology in 73 girls scanned at baseline (ages 4.09-7.02, mean=5.47, SD=0.81), 6-month (N=7), and one-year follow-up (N=42). For comparison, we also assessed changes in commonly utilized diffusion tensor metrics: fractional anisotropy (FA), and mean, radial and axial diffusivity (MD, RD, AD). Maturational increases in fixel-metrics were seen in most major white matter tracts, with the most rapid increases in the corticospinal tract and slowest or non-significant increases in the genu of the corpus callosum and uncinate fasciculi. As expected, we observed developmental increases in FA and decreases in MD, RD and AD, though percentage changes were smaller relative to fixel-metrics. The majority of tracts showed more substantial morphological than microstructural changes. These findings highlight early childhood as a period of dynamic white matter maturation, characterized by large increases in macroscopic fiber bundle size, mild changes in axonal density, and parallel, albeit less substantial, changes in diffusion tensor metrics.

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Early childhood is an important period of sensory, motor, cognitive and socio-emotional maturation, yet relatively little is known about the brain changes specific to this period. Voxel-based morphometry (VBM) is a technique to estimate regional brain volumes from magnetic resonance (MR) images. The default VBM processing pipeline can be customized to increase accuracy of segmentation and normalization, yet the impact of customizations on analyses in young children are not clear. Here, we assessed the impact of different preprocessing steps on T1-weighted MR images from typically developing children in two separate cohorts. Data were processed with the Computational Anatomy Toolbox (CAT12), using seven different VBM pipelines with distinct combinations of tissue probability maps (TPMs) and DARTEL templates created using the Template-O-Matic, and CerebroMatic. The first cohort comprised female children aged 3.9–7.9 years (N = 62) and the second included boys and girls aged 2.7–8 years (N = 74). We found that pipelines differed significantly in their tendency to classify voxels as grey or white matter and the conclusions about some age effects were pipeline-dependent. Our study helps to both understand age-associations in grey and white matter volume across early childhood and elucidate the impact of VBM customization on brain volumes in this age range.