Toward a Multimodal, Multiscale Understanding of White Matter Abnormalities in Autism Spectrum Disorder

Abstract

Convergent evidence suggests that autism spectrum disorder (ASD) is manifest in anatomic changes to the brain during development that affect neural connectivity. Autism as a disconnection syndrome has been discussed for some time (1), and recent effort has focused on measuring and characterizing aberrant structural and functional connectivity in the disorder. For practical reasons, most of these studies were conducted in older children or adults. However, gross measures, such as head circumference and brain volume, suggest a change in the phenotypic profile from early childhood, when children with ASD have increased brain size relative to control subjects, to older childhood and adulthood, when the effect is not seen (2). Thus, there is strong motivation to expand the study of ASD characteristics in very young cohorts to better understand the developmental trajectory of the disease. Moreover, the rapid increase in ASD incidence, estimated to affect 1 in 68 8-year-old American children (3), suggests an urgent need for improved understanding of the pathologic features and especially the early developmental pathophysiology to assist early diagnosis, identify high-risk individuals, and inform therapeutic options. In this issue of Biological Psychiatry, Solso et al. (4) provide convincing evidence for irregular developmental trajectories in frontal fiber tracts in young children 1–4 years old with autism. This investigation included what may be the largest toddler ASD cohort in a diffusion imaging study to date (N 5 61), a subset of whom (n 5 14) was scanned twice approximately 1 year apart. With data from this population, the researchers have an exceptional opportunity to capture early alterations in brain development that may pinpoint root causes of ASD behaviors and provide a basis for assisting early diagnosis. The fundamental result of this work showed that average fractional anisotropy (FA) values within several fiber tracts that innervate the frontal lobes (forceps minor, inferior frontal– superior frontal tract, uncinate tract, and arcuate fasciculus) were significantly higher in children with ASD than in control subjects among the youngest study participants, with three of these pathways also showing increased tract volume. Furthermore, for the older children with ASD—even within this very young sample—the increased FA and volume values disappeared or showed signs of reversal, reflecting distinct trajectories of white matter (WM) development for children with ASD and control subjects. Fiber bundles interconnecting the posterior cortices did not show the same pattern of altered FA, suggesting the critical importance of frontal lobe development during the time period in which ASD symptoms and diagnoses stabilize. The measures from frontal fiber tracts in the youngest participants (12–28 months old), particularly from the