Atypical Relation Between Age and Measures of White Matter Diffusivity in Children with An Autism Spectrum Disorder (ASD)

Background:  Recent research suggests that brain growth follows an abnormal trajectory in children with autism spectrum disorders (ASD), which may specifically affect white matter development and connectivity.

Objectives:  To examine changes in diffusivity with age within defined white matter tracts in a group of typically developing children and a group of children with an ASD, aged 6 to 14 years.

Methods:  Participants were 23 children diagnosed with ASD (4 female, mean age = 11.07 years, range 6-14) and 23 age- and gender-matched typically developing control children (4 female, mean age = 11.13 years, range 6-14). Subjects were scanned on a GE 1.5 T magnetic resonance imaging (MRI) scanner with an 8-channel array head coil. Diffusion tensor images were acquired using a single-shot spin echo planar imaging sequence with 35 non-collinear directions (b-value of 1000 s/mm2), and 3 non diffusion-weighted volumes. Slices were 3 mm thick, oriented parallel to the anterior commissure – posterior commissure (AC-PC) axis of the subject. In-plane resolution was 2.5 mm × 2.5 mm. Image processing was performed using a combination of FSL, AFNI, RESTORE and Camino software packages. All volumes were registered to one of the non-diffusion weighted volumes using an affine transformation (FLIRT) to correct for motion and residual eddy current effects. From the estimated diffusion tensor, fractional anisotropy (FA), mean diffusivity (MD), longitudinal (Dmax = first eigenvalue) and radial diffusivity (Drad = average of second and third eigenvalues) were calculated. To perform a group analysis, all FA maps were aligned to the JHU-ICBM DTI-81 FA template (included in FSL) using non-linear registration (FNIRT). The same warp was applied to MD, Dmax and Drad maps. Data were blurred by a 3 mm full-width half-max Gaussian kernel. In each subject, average values for FA, Dmax, Drad, and MD were computed for major fibre tracts in the brain, as defined in the JHU-ICBM DTI-81 white matter atlas.

Results:  Age by group interactions were observed in frontal, long distant, interhemispheric and posterior tracts, for longitudinal, radial and mean diffusivity but not for fractional anisotropy. In all cases, these three measures of diffusivity decreased with age in the typically developing group, but showed little or no change in the ASD group. It is important to note, that if the data had been analysed without taking into account age, no group differences would have been found.

Conclusions:  These findings support the hypothesis of an abnormal developmental trajectory of white matter in the ASD population, which could have profound effects on the development of neural connectivity, and contribute to atypical cognitive development in these children. The results also underline the critical importance of considering age in the analyses of this neurodevelopmental disorder.