Periventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder

Abstract

Malformations of cortical development are found at higher rates in autism spectrum disorder (ASD) than in healthy controls on postmortem neuropathological evaluation but are more variably observed on visual review of in-vivo MRI brain scans. This may be due to the visually elusive nature of many malformations on MRI. Here, we utilize a quantitative approach to determine whether a volumetric measure of heterotopic gray matter in the white matter is elevated in people with ASD, relative to typically developing controls (TDC). Data from a primary sample of 48 children/young adults with ASD and 48 age-, and gender-matched TDCs, selected from the Autism Brain Imaging Data Exchange (ABIDE) open-access database, were analyzed to compare groups on (1) blinded review of high-resolution T1-weighted research sequences; and (2) quantitative measurement of white matter hypointensity (WMH) volume calculated from the same T1-weighted scans. Groupwise WMH volume comparisons were repeated in an independent, multi-site sample (80 ASD/80 TDC), also selected from ABIDE. Visual review resulted in equivalent proportions of imaging abnormalities in the ASD and TDC group. However, quantitative analysis revealed elevated periventricular and deep subcortical WMH volumes in ASD. This finding was replicated in the independent, multi-site sample. Periventricular WMH volume was not associated with age but was associated with greater restricted repetitive behaviors on both parent-reported and clinician-rated assessment inventories. Thus, findings demonstrate that periventricular WMH volume is elevated in ASD and associated with a higher degree of repetitive behaviors and restricted interests. Although the etiology of focal WMH clusters is unknown, the absence of age effects suggests that they may reflect a static anomaly.

Keywords: Autism spectrum disorder; Magnetic resonance imaging; Malformations of cortical development; Periventricular heterotopia; Restricted repetitive behaviors; White matter hypointensities.

Fig. 1

Calculation of WMH volume from periventricular region and gray–white matter junction. (A) The white matter hypointensity (WMH) mask (green clusters) from a single subject is overlaid on (B) the dilated ventricle masks (red = right lateral and inferior ventricle; blue = left lateral and inferior ventricle) to calculate the total number of WMH voxels that fall within the periventricular region. The WMH mask is overlaid on (C) the dilated white matter surface mask (pink = right hemisphere; yellow = left hemisphere) to calculate the total number of WMH voxels that fall within the gray–white matter junction (GWJ).

Fig. 2

Location of WMH-labeled clusters. Images depict T1-weighted scans of individual ASD participants. The subcortical segmentation overlay is depicted on the left-sided images for A–C. WMH clusters are purple (circled). (A) WMH cluster in the perivascular region; (B–C) WMH clusters in the periventricular region.

Fig. 3

White matter hypointensity volumes (WMHV) are elevated in ASD. Bar graph depicting group differences in total average WMHV and WMHV-corrected (WMHV-corr) volumes. WMHV-corr volumes include only the periventricular and deep subcortical white matter clusters. Blue bars depict the autism spectrum disorder (ASD) group and red bars depict the typically developing control (TDC) group. Sample 1 refers to the primary single-scanner NYU sample (48 ASD/48 TDC). Sample 2 refers to the secondary multi-site sample (80 ASD/80 TDC). Error bars depict standard error.

Fig. 4

Scatterplots depicting linear relationship between WMH-corrected volumes (i.e., periventricular and deep subcortical WMH volume) and A.) Autism Diagnostic Observation Schedule Stereotyped Behaviors and Repetitive Interests; and B.) Autism Diagnostic Inventory—Revised Restrictive, Repetitive Behaviors.