Mapping White Matter Development in Children and Adolescents with Autism

Background: Imaging studies of white matter (WM) volume (morphometry) and microstructure (predominantly assessed via diffusion tensor (DT)-MRI) throughout infancy, childhood and adolescence have shown consistent differences in regional WM development and architecture.  Temporally coincident with the first reports of autistic symptoms and early micro-structural differences, is the process of myelination.

Objectives: To-date, no direct study of myelin development across childhood or adolescence in ASD has been performed. We sought to fill this knowledge gap, performing a cross-sectional study of myelin content in this age group.

Methods: 47 ASD males (5-17 years; 11.8±3.1), diagnosed according to the International Statistical Classification of Diseases, 10th Revision(ICD-10), confirmed using Autism Diagnostic Interview-Revised (ADI-R), and Autism Diagnostic Observation Schedule (ADOS), and 40 age and IQ-matched typically developing (TD) males (7-17 years;12.3±2.8) of IQ>70 were recruited.  A measure of myelin content, myelin water fraction (MWF), was acquired using the multi-component relaxometry technique mcDESPOT, which derives MWF estimates by fitting a three-pool model to a combination of T1-weighted SPGR and T2/T1-weighted balanced SSFP imaging data, with additional correction for B0 and B1 inhomogeneities. 

After voxel-wise calculation of MWF maps and non-linear co-registration to a common template, mean myelin development trajectories were compared between ASD and TD groups in 12 predetermined WM pathways; as well as voxel-wise comparisons of WM.  Developmental slopes for the 12 pathways were estimated using a wild bootstrap approach with residual re-sampling and then compared using an unpaired two-tailed t-test.

To investigate associations between MWF values and symptom measures in the ASD group, correlation analysis was performed on a voxel-wise level between the MWF values and ADOS and ADI-R sub-scores.  Significance was defined as p<0.05, cluster corrected for multiple comparisons.

Results: The ASD group displayed lower absolute MWF values at 6 years, followed by an accelerated developmental trajectory leading to overall increased MWF by 17 years.  The ‘crossover’ point at which ASD children went from reduced to increased MWF relative to controls was observed consistently between 12-13years across the majority of tracts.

MWF values differed significantly in; the body, genu and splenium of the corpus callosum; fornix; bilateral internal capsule; anterior thalamic radiations; bilateral uncinate and left inferior longitudinal fasciculus.  Voxel-wise comparisons confirmed these results and also implicated the, bilateral corticospinal tracts; forceps; cingulum; inferior fronto-occipital fasciculus; portions of the superior longitudinal fasciculus; and cerebellum. Significant negative correlations were seen between MWF values and ADI-R sub-scores though no significant correlations were identified between myelin content and ADOS measures.

Conclusions: In this first cross-sectional analysis of myelin development through childhood and adolescence, we found that children with ASD had a significantly greater myelin development rate compared with TD children in brain regions previously implicated in ASD.  Our findings argue for more statistically powerful longitudinal studies of myelin development that span development from infancy through to early adulthood to complete the picture of myelin development in typical development and ASD.