title: Mapping axonal density and average diameter using non-monotonic time-dependent gradient-echo MRI.
abstract: White Matter (WM) microstructures, such as axonal density and average diameter, are crucial to the normal function of the Central Nervous System (CNS) as they are closely related with axonal conduction velocities. Conversely, disruptions of these microstructural features may result in severe neurological deficits, suggesting that their noninvasive mapping could be an important step towards diagnosing and following pathophysiology. Whereas diffusion based MRI methods have been proposed to map these features, they typically entail the application of powerful gradients, which are rarely available in the clinic, or extremely long acquisition schemes to extract information from parameter-intensive models. In this study, we suggest that simple and time-efficient multi-gradient-echo (MGE) MRI can be used to extract the axon density from susceptibility-driven non-monotonic decay in the time-dependent signal. We show, both theoretically and with simulations, that a non-monotonic signal decay will occur for multi-compartmental microstructures - such as axons and extra-axonal spaces, which were here used as a simple model for the microstructure - and that, for axons parallel to the main magnetic field, the axonal density can be extracted. We then experimentally demonstrate in ex-vivo rat spinal cords that its different tracts - characterized by different microstructures - can be clearly contrasted using the MGE-derived maps. When the quantitative results are compared against ground-truth histology, they reflect the axonal fraction (though with a bias, as evident from Bland-Altman analysis). As well, the extra-axonal fraction can be estimated. The results suggest that our model is oversimplified, yet at the same time evidencing a potential and usefulness of the approach to map underlying microstructures using a simple and time-efficient MRI sequence. We further show that a simple general-linear-model can predict the average axonal diameters from the four model parameters, and map these average axonal diameters in the spinal cords. While clearly further modelling and theoretical developments are necessary, we conclude that salient WM microstructural features can be extracted from simple, SNR-efficient multi-gradient echo MRI, and that this paves the way towards easier estimation of WM microstructure in vivo.
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Av. Brasilia 1400-038, Lisbon, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nunes
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Av. Brasilia 1400-038, Lisbon, Portugal.
authors.forename: Tomás L
authors.initials: TL
authors.lastname: Cruz
authors.affiliation: Center of Functionally Integrative Neuroscience (CFIN) and MINDLab, Clinical Institute, Aarhus University, Aarhus, Denmark; Department of Physics and Astronomy, Aarhus University, Aarhus, Denmark.
authors.forename: Sune N
authors.initials: SN
authors.lastname: Jespersen
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Av. Brasilia 1400-038, Lisbon, Portugal. Electronic address: noam.shemesh@neuro.fchampalimaud.org.
authors.forename: Noam
authors.initials: N
authors.lastname: Shemesh
mesh_terms: D000465:Algorithms; D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D001931:Brain Mapping; D003198:Computer Simulation; D017352:Echo-Planar Imaging / Q000379:methods*; D004574:Electromagnetic Fields; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D018613:Microscopy, Confocal; D051381:Rats; D020318:Rats, Long-Evans; D059629:Signal-To-Noise Ratio; D013116:Spinal Cord / Q000166:cytology / Q000000981:diagnostic imaging; D066127:White Matter / Q000166:cytology / Q000000981:diagnostic imaging
keywords: Axon density; Axon diameter; Gradient echo; Magnetic resonance imaging (MRI); Multi-gradient echo; Susceptibility; T2(∗); Ultrahigh field MRI