White Matter Abnormalities Between Youth with Autism and Unaffected Siblings: A Pilot Study Using Tract-Based Spatial Statistics

Background: Numerous studies have been published using diffusion tensor imaging (DTI) to demonstrate white matter abnormalities in autism spectrum disorders (ASD).  However, only one study to date has used DTI to assess whether white matter abnormalities exist in unaffected siblings (US) of those with ASD, reporting similar aberrations in a group of children with ASD and their US.  More specifically, the ASD and US groups did not differ significantly in white matter structure; however, both groups differed significantly from controls.  While these results support the presence of an intermediate brain phenotype in US, they also suggest that this is skewed more towards the ASD phenotype.

Objectives: The present study was conducted to confirm that an intermediate neuroendophenotype exists in US.  Given that US participants show no autistic symptomatology (absence of the broad autism phenotype), it is hypothesized that this intermediate brain phenotype is not skewed towards to that of ASD participants.

Methods: Participants included 15 boys with ASD (mean age = 10.9 ±3.7 years), 13 US (mean age = 10.4 ±2.9 years), and eight gender- and age-matched controls (mean age = 11.5 ±2.6 years).  T1-weighted and diffusion-weighted MRI (directions = 30 and b0 = 5) were acquired using a 3-Tesla scanner.  FMRIB Software Library (FSL) was used to process and analyze diffusion-weighted data.  Fractional anisotropy (FA) was chosen as the primary measure of the structural integrity of fiber tracts.  Voxel-wise analysis of multi-subject diffusion data was conducted using FSL’s Tract Based Spatial Statistics (TBSS).  Three comparisons were made: ASD versus control, ASD versus US, and US versus control.  Areas of significant difference were computed using Threshold-Free Cluster Enhancement and displayed as p-value images, where p < 0.0167 corrected for multiple comparisons.  Post-hoc correlation analyses were performed between FA of each affected fiber tract and scores on the Social Responsiveness Scale.

Results: When compared to controls, the ASD group had significant bilateral reductions in FA involving association, commissural, and projection tracts.  Affected association tracts included the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum.  Commissural fibers included the forceps minor, and projection fibers included the anterior thalamic radiation.  The tract with the greatest number of affected voxels was the forceps minor.  There were no areas of increased FA in the ASD group.  There were no significant group differences in FA for the ASD versus US and US versus control comparisons.  There were no significant group differences in age and intracranial volume.  All post-hoc correlation analyses became non-significant after controlling for multiple comparisons.

Conclusions: This study supports the presence of an intermediate neuroendophenotype in US.  The presence of significant differences only in the ASD and control comparison suggests that this intermediate brain phenotype is neither skewed towards that of ASD participants nor controls.  Lack of significant differences in the US and control comparison does not preclude that aberrant white matter structure could represent a marker for increased risk for ASD.