Voxelized Computational Model for Convection-Enhanced Delivery in the Rat Ventral Hippocampus: Comparison with In Vivo MR Experimental Studies

Abstract

Convection-enhanced delivery (CED) is a promising local delivery technique for overcoming the blood–brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, therapeutics are infused directly into brain tissue and the drug agent is spread through the extracellular space, considered to be highly tortuous porous media. In this study, 3D computational models developed using magnetic resonance (MR) diffusion tensor imaging data sets were used to predict CED transport in the rat ventral hippocampus using a voxelized modeling previously developed by our group. Predicted albumin tracer distributions were compared with MR-measured distributions from in vivo CED in the ventral hippocampus up to 10 μL of Gd-DTPA albumin tracer infusion. Predicted and measured tissue distribution volumes and distribution patterns after 5 and 10 μL infusions were found to be comparable. Tracers were found to occupy the underlying landmark structures with preferential transport found in regions with less fluid resistance such as the molecular layer of the dentate gyrus. Also, tracer spread was bounded by high fluid resistance layers such as the granular cell layer and pyramidal cell layer of dentate gyrus. Leakage of tracers into adjacent CSF spaces was observed towards the end of infusions.

Convection-enhanced delivery to the central nervous system

“…Further, groups have used computational analyses based on diffusion tensor imaging (an MRI technique that measures the restricted diffusion of water in nervous system tissues and measures axonal alignment) that account for preferential fluid flow and diffusion transport directions, which can vary in the extracellular spaces within complex nervous system anatomical structures. 39,40,55,89,101 …”

“…The ability to accurately predict optimal cannula placement and the capability to precisely anticipate infusate distribution based on preinfusion CT and MRI planning will be important for clinical trial development. 40,55,56,89,102 references…”

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

“…Many neurological disorders like temporal lobe epilepsy, Alzheimer's disease, and schizophrenia have been confirmed to be related with hippocampal abnormality [25][26][27][28]. Previously in our group, corresponding computational models developed from these segmentation maps have been developed for CED into the corpus callosum and hippocampus [13,22]. However, these models did not include the hippocampal fissure.…”

“…Data gathered from DWI allows the use of diffusion tensor imaging [21] to determine the preferential transport direction in WM or other tissues [9,10,12,13,[22][23][24]. In previous studies by our group and others [10,13,22,23], brain tissue segmentation was based on diffusion tensor measures, specifically, values of fraction anisotropy (FA) and average diffusivity (AD). The hippocampus, which is a rolled structure consisting of densely packed layers of neurons, projecting axons and a hippocampal fissure, is an intricate and heterogeneous region.…”

“…Tissue segmentation is often based on diffusion weighted imaging (DWI) which is a magnetic resonance imaging (MRI) technology that measures the effective diffusivity of water in various tissue structures [19] and has been used for brain fiber track reconstruction [20]. Data gathered from DWI allows the use of diffusion tensor imaging [21] to determine the preferential transport direction in WM or other tissues [9,10,12,13,[22][23][24]. In previous studies by our group and others [10,13,22,23], brain tissue segmentation was based on diffusion tensor measures, specifically, values of fraction anisotropy (FA) and average diffusivity (AD).…”