Structural Abnormalities in Corpus Callosum Fibers during Early Autism Development

Background: It has been hypothesized that abnormalities in the development of the corpus callosum (CC) may be a common characteristic of many individuals with autism. This hypothesis, however, has rarely been tested during early stages of autism development, in infants and toddlers. Furthermore, previous diffusion tensor imaging (DTI) studies have subdivided the CC roughly into two or three segments without determining the cortical projections of the fibers in each segment. A more detailed examination of CC development, which takes into account the projection of CC fibers into specific cortical areas, is critical for determining which inter-hemispheric connections develop abnormally in autism and for revealing the nature and timing of abnormalities in each fiber group.

Objectives: To determine the nature and developmental timing of potential abnormalities in specific inter-hemispheric CC tracts of 1-4 year old toddlers with autism.

Methods: We examined DTI scans from 68 toddlers with autism and 29 toddlers with typical development. All toddlers were 1-4 years old during the MRI scan and underwent thorough behavioral assessments including ADOS, ADI, Mullen, and Vineland tests. The DTI protocol was a single-shot, echo-planar diffusion-weighted sequence that was applied along 51 diffusion directions in fifty 2.5mm thick axial slices (±10, depending on head size) with in-plane resolution of 1.875 x 1.875 mm and b-value of 1000 sec/mm². Toddlers who were under the age of 2.5 years old returned for a second visit to establish a final diagnosis and assess potential changes in symptom severity. DTI analyses were performed using the Automated Fiber Quantification toolbox, which utilizes a deterministic tractography algorithm to identify seven CC fiber tracts according to their cortical projections in the native space of each subject. The different diffusion properties were then compared across groups in each of the tracts.

Results: Younger (<2.5 years old), but not older (> 2.5 years old) toddlers with autism exhibited abnormally high fractional anisotropy and low mean, radial, and axial diffusivity values in the CC tracts connecting occipital, temporal, mid-frontal, and anterior-frontal areas (t-test, p<0.05 in all cases, FDR corrected). Furthermore, early diffusion measures in the temporal CC tract of the young toddlers were correlated with outcome measures of autism severity at later ages.

Conclusions: We suggest that abnormally low diffusivity values, which indicate that water diffusion is more restricted in the CC of young toddlers with autism, may be due to an overabundance of small caliber axons as predicted by the early overgrowth and excess neuron theories of autism. These findings reveal critical details regarding the nature, timing, and location of CC abnormalities in early autism development and add to accumulating evidence which suggests that poor inter-hemispheric connectivity in the first years of life is a hallmark of the disorder.