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White matter (WM) characterization is challenging due to its anisotropic and inhomogeneous microstructure that necessitates multiscale and multi-modality measurements. Shear elastography is one such modality that requires the accurate interpretation of 3D shear strain measurements, which hinge on developing appropriate constitutive tissue models. Finite element methods enable the development of such models by simulating the shear response of representative elemental volumes (REV). We have developed triphasic (axon, myelin, glia), 2D REVs to simulate the influence of the intrinsic viscoelastic property and volume fraction of each phase. This work constitutes the extension of 2D- to 3D-REVs, focusing on the effect of the intrinsic material properties and their 3D representation on the viscoelastic response of the tissue. By lumping the axon and myelin phases, a flexible 3D REV generation and analysis routine is then developed to allow for shear homogenization in both the axial and transverse directions. The 2D and 3D models agree on stress distribution and total deformation when 2D cross-sectional snapshots are compared. We also conclude that the ratio of transverse to axial transverse modulus is larger than one when axon fibers are stiffer than the glial phase.

 

Material properties of brain white matter (BWM) show high anisotropy due to the complicated internal three-dimensional microstructure and variant interaction between heterogeneous brain-tissue (axon, myelin, and glia). From our previous study, finite element methods were used to merge micro-scale Representative Volume Elements (RVE) with orthotropic frequency domain viscoelasticity to an integral macro-scale BWM. Quantification of the micro-scale RVE with anisotropic frequency domain viscoelasticity is the core challenge in this study.

The RVE behavior is expressed by a viscoelastic constitutive material model, in which the frequency-related viscoelastic properties are imparted as storage modulus and loss modulus for the composite comprised of axonal fibers and extracellular glia. Using finite elements to build RVEs with anisotropic frequency domain viscoelastic material properties is computationally very consuming and resource-draining. Additionally, it is very challenging to build every single RVE using finite elements since the architecture of each RVE is arbitrary in an infinite data set. The architecture information encoded in the voxelized location is employed as input data and is consequently incorporated into a deep 3D convolution neural network (CNN) model that cross-references the RVEs’ material properties (output data). The output data (RVEs’ material properties) is calculated in parallel using an in-house developed finite element method, which models RVE samples of axon-myelin-glia composites. This novel combination of the CNN-RVE method achieved a dramatic reduction in the computation time compared with directly using finite element methods currently present in the literature. 

Motivated by the need to interpret the results from a combined use ofin vivobrain Magnetic Resonance Elastography (MRE) and Diffusion Tensor Imaging (DTI), we developed a computational framework to study the sensitivity of single-frequency MRE and DTI metrics to white matter microstructure and cell-level mechanical and diffusional properties. White matter was modeled as a triphasic unidirectional composite, consisting of parallel cylindrical inclusions (axons) surrounded by sheaths (myelin), and embedded in a matrix (glial cells plus extracellular matrix). Only 2D mechanics and diffusion in the transverse plane (perpendicular to the axon direction) was considered, and homogenized (effective) properties were derived for a periodic domain containing a single axon. The numerical solutions of the MRE problem were performed with ABAQUS and by employing a sophisticated boundary-conforming grid generation scheme. Based on the linear viscoelastic response to harmonic shear excitation and steady-state diffusion in the transverse plane, a systematic sensitivity analysis of MRE metrics (effective transverse shear storage and loss moduli) and DTI metric (effective radial diffusivity) was performed for a wide range of microstructural and intrinsic (phase-based) physical properties. The microstructural properties considered were fiber volume fraction, and the myelin sheath/axon diameter ratio. The MRE and DTI metrics are very sensitive to the fiber volume fraction, and the intrinsic viscoelastic moduli of the glial phase. The MRE metrics are nonlinear functions of the fiber volume fraction, but the effective diffusion coefficient varies linearly with it. Finally, the transverse metrics of both MRE and DTI are insensitive to the axon diameter in steady state. Our results are consistent with the limited anisotropic MRE and co-registered DTI measurements, mainly in thecorpus callosum, available in the literature. We conclude that isotropic MRE and DTI constitutive models are good approximations for myelinated white matter in the transverse plane. The unidirectional composite model presented here is used for the first time to model harmonic shear stress under MRE-relevant frequency on the cell level. This model can be extended to 3D in order to inform the solution of the inverse problem in MRE, establish the biological basis of MRE metrics, and integrate MRE/DTI with other modalities towards increasing the specificity of neuroimaging.

 

Finite element analysis is used to study brain axonal injury and develop Brain White Matter (BWM) models while accounting for both the strain magnitude and the strain rate. These models are becoming more sophisticated and complicated due to the complex nature of the BMW composite structure with different material properties for each constituent phase. State-of-the-art studies focus on employing techniques that combine information about the local axonal directionality in different areas of the brain with diagnostic tools such as Diffusion-Weighted Magnetic Resonance Imaging (Diffusion-MRI). The diffusion-MRI data offers localization and orientation information of axonal tracks which are analyzed in finite element models to simulate virtual loading scenarios. Here, a BMW biphasic material model comprised of axons and neuroglia is considered. The model’s architectural anisotropy represented by a multitude of axonal orientations, that depend on specific brain regions, adds to its complexity. During this effort, we develop a finite element method to merge micro-scale Representative Volume Elements (RVEs) with orthotropic frequency domain viscoelasticity to an integrated macro-scale BWM finite element model, which incorporates local axonal orientation. Previous studies of this group focused on building RVEs that combined different volume fractions of axons and neuroglia and simulating their anisotropic viscoelastic properties. Via the proposed model, we can assign material properties and local architecture on each element based on the information from the orientation of the axonal traces. Consecutively, a BWM finite element model is derived with fully defined both material properties and material orientation. The frequency-domain dynamic response of the BMW model is analyzed to simulate larger scale diagnostic modalities such as MRI and MRE.