Due to its unique sensitivity to tissue microstructure, diffusion-weighted magnetic resonance imaging (MRI) has found many applications in clinical and fundamental science. With few exceptions, a more precise correspondence between physiological or biophysical properties and the obtained diffusion parameters remain uncertain due to lack of specificity. In this work, we address this problem by comparing diffusion parameters of a recently introduced model for water diffusion in brain matter to light microscopy and quantitative electron microscopy. Specifically, we compare diffusion model predictions of neurite density in rats to optical myelin staining intensity and stereological estimation of neurite volume fraction using electron microscopy. We find that the diffusion model describes data better and that its parameters show stronger correlation with optical and electron microscopy, and thus reflect myelinated neurite density better than the more frequently used diffusion tensor imaging (DTI) and cumulant expansion methods. Furthermore, the estimated neurite orientations capture dendritic architecture more faithfully than DTI diffusion ellipsoids.

The framework offers a robust and rapid method for estimating MK, with a protocol easily adapted on commercial scanners, as it requires only minimal modification of standard diffusion-weighting protocols. These properties make the method feasible in practically any clinical setting.

Biophysical modelling of diffusion MRI is necessary to provide specific microstructural tissue properties. However, estimating model parameters from data with limited diffusion gradient strength, such as clinical scanners, has proven unreliable due to a shallow optimization landscape. On the other hand, estimation of diffusion kurtosis (DKI) parameters is more robust, and its parameters may be connected to microstructural parameters, given an appropriate biophysical model. However, it was previously shown that this procedure still does not provide sufficient information to uniquely determine all model parameters. In particular, a parameter degeneracy related to the relative magnitude of intra-axonal and extra-axonal diffusivities remains. Here we develop a model of diffusion in white matter including axonal dispersion and demonstrate stable estimation of all model parameters from DKI in fixed pig spinal cord. By employing the recently developed fast axisymmetric DKI, we use stimulated echo acquisition mode to collect data over a two orders of magnitude diffusion time range with very narrow diffusion gradient pulses, enabling finely resolved measurements of diffusion time dependence of both net diffusion and kurtosis metrics, as well as model intra- and extra-axonal diffusivities, and axonal dispersion. Our results demonstrate substantial time dependence of all parameters except volume fractions, and the additional time dimension provides support for intra-axonal diffusivity to be larger than extra-axonal diffusivity in spinal cord white matter, although not unambiguously. We compare our findings for the time-dependent compartmental diffusivities to predictions from effective medium theory with reasonable agreement.

Purpose The clinical use of kurtosis imaging is impeded by long acquisitions and post-processing. Recently, estimation of mean kurtosis tensor W̅ and mean diffusivity (D̅) was made possible from 13 distinct DWI acquisitions (the 1-3-9 protocol) with simple post-processing. Here, we analyze the effects of noise and nonideal diffusion encoding, and propose a new correction strategy. We also present a 1-9-9 protocol with increased robustness to experimental imperfections and minimal additional scan time. This refinement does not affect computation time and also provides a fast estimate of fractional anisotropy (FA). Methods 1-3-9/1-9-9 data are acquired in rat and human brains, and estimates of D̅, FA, W̅ from human brains are compared to traditional estimates from an extensive DKI data set. Simulations are used to evaluate the influence of noise and diffusion encodings deviating from the scheme, and the performance of the correction strategy. Optimal b-values are determined from simulations and data. Results Accuracy and precision in D̅ and W̅ are comparable to nonlinear least squares estimation, and is improved with the 1-9-9 protocol. The compensation strategy vastly improves parameter estimation in non-ideal data. Conclusion The framework offers a robust and compact method for estimating several diffusion metrics. The protocol is easily implemented.

Diffusion kurtosis imaging (DKI) is being increasingly reported to provide sensitive biomarkers of subtle changes in tissue microstructure. However, DKI also imposes larger data requirements than diffusion tensor imaging (DTI), hence, the widespread adaptation and exploration of DKI would benefit from more efficient acquisition and computational methods. To meet this demand, we recently developed a method capable of estimating mean kurtosis with only 13 diffusion weighted images. This approach was later shown to provide very accurate mean kurtosis estimates and to be more efficient in terms of contrast to noise per unit time. However, insofar, the computation of two other critical DKI parameters, radial and axial kurtosis, has required the estimation of all 22 variables parameterizing the full DKI signal expression. Here, we present two strategies for estimating all of DKI’s principal parameters – mean kurtosis, radial kurtosis, and axial kurtosis – using only 19 diffusion weighted images, compared to the current state-of-the-art acquisitions typically requiring about 60 images. The first approach is based on axially symmetric diffusion and kurtosis tensors, presented here for the first time, and referred to as axially symmetric DKI. The second approach is applicable in tissues with a priori known principal diffusion direction, and does not require fitting of any kind. The approaches are evaluated in human brain in vivo as well as in fixed rat spinal cord, and are demonstrated to provide metrics in good agreement with their full DKI counterparts estimated with nonlinear least squares. For small data sets and in white matter, axially symmetric DKI provides more accurate and robust estimates than unconstrained DKI. The significant acceleration achieved further paves the way to routine application of the technique.