Opposite development of short- and long-range anterior cingulate pathways in autism

Autism has been linked with the changes in brain connectivity that disrupt neural communication, especially involving frontal networks. Pathological changes in white matter are evident in adults with autism, particularly affecting axons below the anterior cingulate cortices (ACC). It is still unknown whether axon pathology appears early or late in development and whether it changes or not from childhood through adulthood. To address these questions, we examined typical and pathological development of about 1 million axons in post-mortem brains of children, adolescents, and adults with and without autism (ages 3–67 years). We used high-resolution microscopy to systematically sample and study quantitatively the fine structure of myelinated axons in the white matter below ACC. We provide novel evidence of changes in the density, size and trajectories of ACC axons in typical postnatal development from childhood through adulthood. Against the normal profile of axon development, our data revealed lower density of myelinated axons that connect ACC with neighboring cortices in children with autism. In the course of development the proportion of thin axons, which form short-range pathways, increased significantly in individuals with autism, but remained flat in controls. In contrast, the relative proportion of thick axons, which form long-range pathways, increased from childhood to adulthood in the control group, but decreased in autism. Our findings provide a timeline for profound changes in axon density and thickness below ACC that affect axon physiology in a direction suggesting bias in short over distant neural communication in autism. Importantly, measures of axon density, myelination, and orientation provide white matter anisotropy/diffusivity estimates at the level of single axons. The structural template established can be used to compare with measures obtained from imaging in living subjects, and guide analysis of functional and structural imaging data from humans for comparison with pathological states. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-018-1904-1) contains supplementary material, which is available to authorized users.