Abstract

Neural tissue microstructure plays an important role in developmental, physiological and pathophysiological processes. Diffusion tensor distribution (DTD) MRI helps probe heterogeneity at the mesoscopic length scale, orders of magnitude smaller than the nominal MRI voxel size, by describing water diffusion within a voxel using an ensemble of non-exchanging compartments characterized by a probability density function of diffusion tensors. In this study, we provide a new framework for acquiring tensor encoded diffusion weighted images (DWIs) and estimating DTD from them for in-vivo human brain imaging. We interfused pulsed field gradients (iPFG) in a single spin echo to generate arbitrary b-tensors of rank one, two, or three without introducing concomitant gradient artifacts. Employing well-defined gradient pulse duration and mixing/diffusion times in our diffusion preparation, we show that iPFG retains salient features of traditional multiple-PFG (mPFG) sequence while overcoming some of its implementation issues thereby extending its applications beyond DTD MRI. We assume DTD is a maximum entropy tensor-variate normal distribution whose tensor random variables are constrained to be positive definite (CNTVD) to ensure their physicality. In each voxel, the second-order mean and fourth-order covariance tensors of the DTD are estimated using a Monte Carlo method that synthesizes micro-diffusion tensors with corresponding size, shape and orientation distributions to best fit the measured DWIs. From these tensors we obtain the mean diffusivity (MD) spectrum, spectrum of diffusion tensor shapes, microscopic orientation distribution function ({micro}ODF), and microscopic fractional anisotropy ({micro}FA) which disentangle the underlying heterogeneity within a voxel. Using DTD derived {micro}ODF, we introduce a new method to perform fiber tractography capable of resolving complex fiber configurations. The results obtained in the live human brain showed microscopic anisotropy in various gray and white matter regions and skewed MD distribution in cerebellar gray matter not observed previously. DTD MRI tractography captured complex white matter fiber organization consistent with known anatomy. DTD MRI also resolved some degeneracies associated with diffusion tensor imaging (DTI) and identified the source of microscopic anisotropy which may help improve the diagnosis of various neurological diseases and disorders.