title: White matter microstructure from nonparametric axon diameter distribution mapping.
abstract: We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue. In the current study, this framework was used on an ex vivo ferret spinal cord, while emphasizing the way in which the ADD can be weighted by either the number or the volume of the axons. The different weightings, which result in different spatial contrasts, were considered throughout this work. DDE data were analyzed to derive spatially resolved maps of average axon diameter, ADD variance, and extra-axonal volume fraction, along with a novel sub-micron restricted structures map. The morphological information contained in these maps was then used to segment white matter into distinct domains by using a proposed k-means clustering algorithm with spatial contiguity and left-right symmetry constraints, resulting in identifiable white matter tracks. The method was validated by comparing histological measures to the estimated ADDs using a quantitative similarity metric, resulting in good agreement. With further acquisition acceleration and experimental parameters adjustments, this ADD estimation framework could be first used preclinically, and eventually clinically, enabling a wide range of neuroimaging applications for improved understanding of neurodegenerative pathologies and assessing microstructural changes resulting from trauma.
authors.affiliation: Quantitative Imaging and Tissue Sciences, NICHD, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biomedical Engineering, The Iby and Aladar Fleischman Faculty of Engineering, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: dan.benjamini@nih.gov.
authors.forename: Dan
authors.initials: D
authors.lastname: Benjamini
authors.affiliation: Quantitative Imaging and Tissue Sciences, NICHD, National Institutes of Health, Bethesda, MD 20892, USA; Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Michal E
authors.initials: ME
authors.lastname: Komlosh
authors.affiliation: Microscopy & Imaging Core, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Holtzclaw
authors.affiliation: Department of Biomedical Engineering, The Iby and Aladar Fleischman Faculty of Engineering, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Nevo
authors.affiliation: Quantitative Imaging and Tissue Sciences, NICHD, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Basser
mesh_terms: D000465:Algorithms; D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D003627:Data Interpretation, Statistical; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005289:Ferrets; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D066298:In Vitro Techniques; D008297:Male; D010363:Pattern Recognition, Automated / Q000379:methods; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016008:Statistical Distributions; D066127:White Matter / Q000166:cytology* / Q000000981:diagnostic imaging*
keywords: Average axon diameter; Axon diameter distribution; Double diffusion encoding; Double pulsed field gradient; Empirical; MRI; Nonparametric; Pore size distribution