Axon morphology is modulated by the local environment and impacts the noninvasive investigation of its structure–function relationship

Significance Axons, the brain’s communication cables, have been described as cylinders since their discovery in 1860. Their structure is linked to how fast they conduct signals and is thus indicative of brain health and function. Here, we demonstrate an interplay between the micromorphology of axons and other extra-axonal structures, showing that axons are noncylindrical and exhibit environment-dependent diameter and trajectory variations. The nonspecificity in diameter, and thus conduction velocity, challenges the current knowledge of how axons communicate signals. Diffusion magnetic resonance imaging can be used to measure axon diameter in the living brain in order to explore the brain network and detect potential biomarkers of disease, but we show here that the observed complex morphologies of axons bias these measurements.