Transient Anomalous Diffusion MRI in Excised Mouse Spinal Cord: Comparison Among Different Diffusion Metrics and Validation With Histology

Abstract

Neural tissue is a hierarchical multiscale system with intracellular and extracellular diffusion compartments at different length scales. The normal diffusion of bulk water in tissues is not able to detect the specific features of a complex system, providing nonlocal, diffusion measurement averaged on a 10-20 μm length scale. Being able to probe tissues with sub-micrometric diffusion length and quantify new local parameters, transient anomalous diffusion (tAD) would dramatically increase the diagnostic potential of diffusion MRI (DMRI) in detecting collective and sub-micro architectural changes of human tissues due to pathological damage. In DMRI, the use of tAD parameters quantified using specific DMRI acquisition protocols and their interpretation has often aroused skepticism. Although the derived formulas may accurately fit experimental diffusion-weighted data, the relationships between the postulated dynamical feature and the underlying geometrical structure remains elusive, or at most only suggestive. This work aimed to elucidate and validate the image contrast and information that can be obtained using the tAD model in white matter (WM) through a direct comparison between different diffusion metrics and histology. Towards this goal, we compared tAD metrics extracted from pure subdiffusion (α-imaging) and super-pseudodiffusion (γ-imaging) in excised mouse spinal cord WM, together with T2 and T2* relaxometry, conventional (normal diffusion-based) diffusion tensor imaging (DTI) and q-space imaging (QSI), with morphologic measures obtained by optical microscopy, to determine which structural and topological characteristics of myelinated axons influenced tAD contrast. Axon diameter (AxDiam), the standard deviation of diameters (SDax.diam), axonal density (AxDens) and effective local density (ELD) were extracted from optical images in several WM tracts. Among all the diffusion parameters obtained at 9.4 T, γ-metrics confirmed a strong dependence on magnetic in-homogeneities quantified by R2* = 1/T2* and showed the strongest associations with AxDiam and ELD. On the other hand, α-metrics showed strong associations with SDax.diam and was significantly related to AxDens, suggesting its ability to quantify local heterogeneity degree in neural tissue. These results elucidate the biophysical mechanism underpinning tAD parameters and show the clinical potential of tAD-imaging, considering that both physiologic and pathologic neurodegeneration translate into alterations of WM morphometry and topology.

Anomalous diffusion, aging, and nonergodicity of scaled Brownian motion with fractional Gaussian noise: overview of related experimental observations and models

“…168,169,171,172 The detailed features of possible transient anomalous diffusion of water in neural tissues were discussed in ref. 177. For some earlier studies of time-dependent diffusion-with the diffusivities D(t) often decreasing with time-in barrier-or obstacle-containing, compartmentalized, and labyrinthine tissue environments we refer to ref.…”

Acquisition Parameters Influence Diffusion Metrics Effectiveness in Probing Prostate Tumor and Age-Related Microstructure

“…Another substantial difference between normal and neoplastic cells is the presence of prominent nucleoli (with a diameter > 1 µm) in the latter [ 25 ]. However, to make water displacements sensitive to such a difference, it would be necessary to increase considerably the b-value (up to b = 5000 s/mm 2 ), adopting non-Gaussian diffusion models [ 39 , 58 ] or anomalous diffusion models [ 59 , 60 , 61 , 62 , 63 ]. Other strategies to improve the discriminative power of diffusion parameters consider the exploitation of both the diffusion and relaxation properties of tissue compartments, such as in a recently developed biophysical model, called rVERDICT, which allows to obtain MRI parameters with enhanced sensitivity and specificity with respect to the cancer-related tissue modifications [ 64 ].…”