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Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings \n, where the deviation from the expected \n scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three\u2010dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next\u2010generation Connectome 2.0 human MRI scanner (\n 500\u2009mT\/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse\u2010grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.<\/jats:p>","DOI":"10.1002\/nbm.5087","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T01:26:35Z","timestamp":1704245195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The effects of axonal beading and undulation on axonal diameter estimation from diffusion MRI: Insights from simulations in human axons segmented from three\u2010dimensional electron microscopy"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-6559","authenticated-orcid":false,"given":"Hong\u2010Hsi","family":"Lee","sequence":"first","affiliation":[{"name":"Athinoula A. 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