Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies

Abstract

Convection enhanced delivery (CED) is a promising novel technology to treat neural diseases, as it can transport macromolecular therapeutic agents greater distances through tissue by direct infusion. To minimize off-target delivery, our group has developed 3D computational transport models to predict infusion flow fields and tracer distributions based on magnetic resonance (MR) diffusion tensor imaging data sets. To improve the accuracy of our voxelized models, generalized anisotropy (GA), a scalar measure of a higher order diffusion tensor obtained from high angular resolution diffusion imaging (HARDI) was used to improve tissue segmentation within complex tissue regions of the hippocampus by capturing small feature fissures. Simulations were conducted to reveal the effect of these fissures and cerebrospinal fluid (CSF) boundaries on CED tracer diversion and mistargeting. Sensitivity analysis was also conducted to determine the effect of dorsal and ventral hippocampal infusion sites and tissue transport properties on drug delivery. Predicted CED tissue concentrations from this model are then compared with experimentally measured MR concentration profiles. This allowed for more quantitative comparison between model predictions and MR measurement. Simulations were able to capture infusate diversion into fissures and other CSF spaces which is a major source of CED mistargeting. Such knowledge is important for proper surgical planning.

Pulsatile flow drivers in brain parenchyma and perivascular spaces: a resistance network model study

“…Other drivers of net flow may include fluid exudation through the blood brain barrier at the capillary level [ 3 , 12 ] and global pressure gradients responsible for CSF circulation. Capillary fluid production has been included as a global fluid source in previous convection enhanced drug delivery models [ 39 , 40 ]. Net fluid movement could be established in an unverified, continuous arterial PVS to peri-capillary space to venous PVS path [ 2 , 9 ], or an arterial PVS to parenchyma to venous PVS path [ 4 ].…”

Integrating Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging to Improve the Predictive Capabilities of CED Models

“…In this study, we have adopted a rigid approach (whereby the solid part of the tissue is considered undeformed throughout the simulations), that was used also by other authors, 9,19,20,41 because we expect negligible tissue deformations to arise during the procedure identified for the comparison performed in this work. This assumption is supported by the findings of Garcı`a et al 14 that, in a numerical study with comparable tissue properties, catheter dimension and flow rate, computed an average deformation about 0.02 in the immediate proximity of the catheter tip and below 0.009 in the vast majority of the remaining area.…”

“…The proposed methodology, where the permeability tensor eigenvalues are expressed as a function of the VF ECS , was compared with a state-of-the-art DTI approach 9,19,20 which assumes that k k and k ? can be considered constant across all the WM areas.…”

“…A critical point of the latter approach is that, as underlined by many studies, 12,35,41 permeability is still a very controversial parameter with a wide range of values available in the literature. For brevity, we name our model the DTI-NODDI model and we will refer to the more conventional models, such as those developed by Kim et al 19,20 and Dai et al, 9 as the DTI model. FIGURE 1.…”

“…The parallel and perpendicular permeability returned by Eqs (9). and (10) after fitting the numerical results are plotted vs. the VF ECS .…”