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Multi-tissue constrained spherical deconvolution (MT-CSD) leverages the characteristic b-value dependency of each tissue type to estimate both the apparent tissue densities and the white matter fiber orientation distribution function from diffusion MRI data. In this work, we generalize MT-CSD to tensor-valued diffusion encoding with arbitrary b-tensor shapes. This enables the use of data encoded with mixed b-tensors, rather than being limited to the subset of linear (conventional) b-tensors. Using the complete set of data, including all b-tensor shapes, provides a categorical improvement in the estimation of apparent tissue densities, fiber ODF, and resulting tractography. Furthermore, we demonstrate that including multiple b-tensor shapes in the analysis provides improved contrast between tissue types, in particular between gray matter and white matter. We also show that our approach provides high-quality apparent tissue density maps and high-quality fiber tracking from data, even with sparse sampling across b-tensors that yield whole-brain coverage at 2 mm isotropic resolution in approximately 5:15 min.

•Different signal models for estimating µFA were compared using imaging experiments and simulations of time-dependent diffusion.•The gamma-distributed diffusivities assumption consistently resulted in the highest µFA values, 0.1 greater than the second order cumulant expansion when averaged over the whole brain.•The simulations suggest that the bias in µFA caused by time-dependent diffusion is less than 0.1 in human white matter. Microscopic diffusion anisotropy imaging using diffusion-weighted MRI and multidimensional diffusion encoding is a promising method for quantifying clinically and scientifically relevant microstructural properties of neural tissue. Several methods for estimating microscopic fractional anisotropy (µFA), a normalized measure of microscopic diffusion anisotropy, have been introduced but the differences between the methods have received little attention thus far. In this study, the accuracy and precision of µFA estimation using q-space trajectory encoding and different signal models were assessed using imaging experiments and simulations. Three healthy volunteers and a microfibre phantom were imaged with five non-zero b-values and gradient waveforms encoding linear and spherical b-tensors. Since the ground-truth µFA was unknown in the imaging experiments, Monte Carlo random walk simulations were performed using axon-mimicking fibres for which the ground truth was known. Furthermore, parameter bias due to time-dependent diffusion was quantified by repeating the simulations with tuned waveforms, which have similar power spectra, and with triple diffusion encoding, which, unlike q-space trajectory encoding, is not based on the assumption of time-independent diffusion. The truncated cumulant expansion of the powder-averaged signal, gamma-distributed diffusivities assumption, and q-space trajectory imaging, a generalization of the truncated cumulant expansion to individual signals, were used to estimate µFA. The gamma-distributed diffusivities assumption consistently resulted in greater µFA values than the second order cumulant expansion, 0.1 greater when averaged over the whole brain. In the simulations, the generalized cumulant expansion provided the most accurate estimates. Importantly, although time-dependent diffusion caused significant overestimation of µFA using all the studied methods, the simulations suggest that the resulting bias in µFA is less than 0.1 in human white matter.

T1 relaxation and water mobility generate eloquent MRI tissue contrasts with great diagnostic value in many neuroradiological applications. However, conventional methods do not adequately quantify the microscopic heterogeneity of these important biophysical properties within a voxel, and therefore have limited biological specificity. We describe a new correlation spectroscopic (CS) MRI method for measuring how T1 and mean diffusivity (MD) co-vary in microscopic tissue environments. We develop a clinical pulse sequence that combines inversion recovery (IR) with single-shot isotropic diffusion encoding (IDE) to efficiently acquire whole-brain MRIs with a wide range of joint T1-MD weightings. Unlike conventional diffusion encoding, the IDE preparation ensures that all subvoxel water pools are weighted by their MDs regardless of the sizes, shapes, and orientations of their corresponding microscopic diffusion tensors. Accordingly, IR-IDE measurements are well-suited for model-free, quantitative spectroscopic analysis of microscopic water pools. Using numerical simulations, phantom experiments, and data from healthy volunteers we demonstrate how IR-IDE MRIs can be processed to reconstruct maps of two-dimensional joint probability density functions, i.e., correlation spectra, of subvoxel T1-MD values. In vivo T1-MD spectra show distinct cerebrospinal fluid and parenchymal tissue components specific to white matter, cortical gray matter, basal ganglia, and myelinated fiber pathways, suggesting the potential for improved biological specificity. The one-dimensional marginal distributions derived from the T1-MD correlation spectra agree well with results from other relaxation spectroscopic and quantitative MRI studies, validating the T1-MD contrast encoding and the spectral reconstruction. Mapping subvoxel T1-diffusion correlations in patient populations may provide a more nuanced, comprehensive, sensitive, and specific neuroradiological assessment of the non-specific changes seen on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted MRIs (DWIs) in cancer, ischemic stroke, or brain injury.

Magnetic resonance imaging (MRI) is the primary method for noninvasive investigations of the human brain in health, disease, and development but yields data that are difficult to interpret whenever the millimeter-scale voxels contain multiple microscopic tissue environments with different chemical and structural properties. We propose a novel MRI framework to quantify the microscopic heterogeneity of the living human brain as spatially resolved five-dimensional relaxation–diffusion distributions by augmenting a conventional diffusion-weighted imaging sequence with signal encoding principles from multidimensional solid-state nuclear magnetic resonance (NMR) spectroscopy, relaxation–diffusion correlation methods from Laplace NMR of porous media, and Monte Carlo data inversion. The high dimensionality of the distribution space allows resolution of multiple microscopic environments within each heterogeneous voxel as well as their individual characterization with novel statistical measures that combine the chemical sensitivity of the relaxation rates with the link between microstructure and the anisotropic diffusivity of tissue water. The proposed framework is demonstrated on a healthy volunteer using both exhaustive and clinically viable acquisition protocols.