Mapping complex cell morphology in the grey matter with double diffusion encoding MR: A simulation study

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter. To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (microA), a promising contrast derived from DDE measurements. The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived microA, for both water and metabolites. Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI.