(379f) Discovery of Cerebral Transport and Metabolic Reaction Properties by Problem Inversion

The treatment of certain diseases of the central nervous system (Alzheimer, Huntington disease, etc) require the insertion of therapeutic drug molecules directly into the porous tissue of target areas deep in the brain. The design of invasive drug delivery therapies [Nicholson, 1985] constitutes a challenging transport problem with complex metabolic drug-neural interaction. The efficiency of the treatments depends strongly on the drugs' molecular properties and its metabolic uptake into the brain tissue. Until today it is very difficult to experimentally measure transport and metabolic reaction properties of large drug molecules in the brain tissue with high accuracy. This presentation proposes a novel computational analysis techniques aiming at extracting apparent physical and chemical properties relevant in invasive drug therapy from advanced imaging data such as magnet resonance images (MRI), computer tomographies (CT) or ultrasound.

We will demonstrate a novel computational approach to quantify unknown diffusion and convection phenomena as well as metabolic reaction rates of drug molecules from clinically observed three-dimensional drug distributions within the highly specialized and segmented treatment targets in the brain. The approach involves the inversion of large-scale transport and kinetic inversion problems (TKIP) in generalized curvilinear coordinates and unstructured computational grids. The paper will present solutions to an array of technological challenges in image processing, computational fluid mechanics and mathematical programming. One unique advantage of the novel approach is its ability to acquire unknown transport mechanism consistent with the clinical imaging data.

Novel techniques to discover covert transport and metabolic phenomena in the midbrain will allow physicians and scientists to design and optimize therapeutic approaches in a systematic fashion, thus reducing the need for trial-and-error animal experiments. This technique promises a pathway to a scientific approach to achieve desired therapeutic volumes and drug penetration depth as a function of design parameters such as catheter location, drug-infusate concentration and bulk injection flow rates.

The proposed methodology advances mathematical programming techniques to solve large-scale transport and kinetic inversion problems of distributed systems in complex multi-dimensional geometry and inhomogeneous anisotropic tissue properties of the human brain. The approach infers apparent directional diffusion, convection and metabolic reaction phenomena of drug distribution in the human brain from highly accurate imaging data obtained by MRI, CT and ultrasound. The goal of this research is to systematically design invasive equipment (e.g. catheters, osmotic pumps, etc) for efficient drug delivery of large molecules into the central nervous system. The solution of simultaneous transport and kinetic inversion problem for optimal drug distribution in the human brain is a first to the best of our knowledge.

References:

Hamilton J.F., Morrison P.F., Chen M.Y., Harvey-White J., Pernaute R.S., Phillips H., Oldfield E., Bankiewicz K.S., Heparin Coinfusion during Convection-Enchanced Delivery (CED) Increases the Distribution of the Glial-Derived Neurotrophic Factor (GDNF) Ligand Family in Rat Striatum and Enhances the Pharmocological Activity of Neurturin, Experimental Neurology, 168, 155-161, 2001.

Nicholson, C., Diffusion from an injected volume of a substance in brain tissue with arbitrary volume fraction and tortuosity, Brain Research, 333, 325-329, 1985

Morrison, P.F., Laske, D.W., Bobo, H., Oldfield, E.H., Dedrick, L.R., High-flow microinfusion: tissue penetration and pharmacodynamics, American Journal of Physiology, 266, R292-R305, 1994.