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Research Papers

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

[+] Author and Article Information
Wei Dai

Department of Mechanical and
Aerospace Engineering,
University of Florida,
Gainesville, FL 32611
e-mail: weidai@ufl.edu

Garrett W. Astary

J. Crayton Pruitt Family
Department of Biomedical Engineering,
University of Florida,
Gainesville, FL 32611
e-mail: gwastary@gmail.com

Aditya K. Kasinadhuni

J. Crayton Pruitt Family
Department of Biomedical Engineering,
University of Florida,
Gainesville, FL 32611
e-mail: adityakumar.bme@gmail.com

Paul R. Carney

Department of Neuroscience,
Department of Pediatrics,
Division of Pediatric Neurology,
J. Crayton Pruitt Family
Department of Biomedical Engineering,
Wilder Center of Excellence
for Epilepsy Research,
University of Florida,
Gainesville, FL 32611
e-mail: carnepr@peds.ufl.edu

Thomas H. Mareci

Department of Biochemistry
and Molecular Biology,
University of Florida,
Gainesville, FL 32611
e-mail: thmareci@ufl.edu

Malisa Sarntinoranont

Department of Mechanical
and Aerospace Engineering,
University of Florida,
MAE A 212,
Gainesville, FL 32611
e-mail: msarnt@ufl.edu

1Correcponding author.

Manuscript received February 2, 2015; final manuscript received January 9, 2016; published online March 30, 2016. Assoc. Editor: Ram Devireddy.

J Biomech Eng 138(5), 051007 (Mar 30, 2016) (13 pages) Paper No: BIO-15-1047; doi: 10.1115/1.4032626 History: Received February 02, 2015; Revised January 09, 2016

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.

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Figures

Grahic Jump Location
Fig. 1

MR images of rat brain. (a) AD map of a coronal brain slice (background was set to be black). (b) FA map of a coronal brain slice. (c) GA map of the same slice, with improved contrast between CSF and WM. Squares indicate the location of lacunosum-moleculare layer and circles indicate the location of molecular layer.

Grahic Jump Location
Fig. 2

Segmented brain volume: (a) voxelized brain model (impermeable regions, GM, WM, and CSF spaces); (b) segmentation of dorsal and ventral hippocampi slices without hippocampal fissures (NHF) and with fissures (HF). Atlas figures show location of fissures and CSF in thick lines. Labels indicate the location of the CA1, CA3, corpus callosum (CC), cerebral peduncle (CP), dorsal 3rd ventricle (D3V), dentate gyrus (DG), fimbria (FI), granule cell layer (GC), hippocampal fissure (HF), lateral ventricle (LV), midbrain cistern (MBC), subiculum (S), and velum interpositum (VI).

Grahic Jump Location
Fig. 3

Three-dimensional structure of the fluid-filled lateral ventricles. The fluid-filled space was shown as the bulge part along the sagittal tissue slice. Fissures connected to ventricles and other CSF spaces are also shown.

Grahic Jump Location
Fig. 8

Comparison of experimentally measured DCE-MRI distributions with predicted CED into the ventral hippocampus. (Top) DCE-MRI measured distribution (column 1) and measured concentration profiles (column 2) with simulated tracer distributions of HF model (column 3) and NHF model (column 4) through concentration contour for infusions into ventral hippocampus form anterior to posterior in rows. CED of 7.35 μl of albumin (and Gd-albumin) tracer was infused at 0.3 μl/min. (Bottom) Comparison of tracer distribution area calculated in consecutive MR imaging slices. Area spread is based on a 5% normalized concentration (C/ϕC0) threshold. Filled triangles and circles show an adjusted distribution range that accounts for tissue shrinkage in the model geometry (+7.64%).

Grahic Jump Location
Fig. 7

Comparison of experimentally measured DCE-MRI distributions with predicted CED into the dorsal hippocampus. (Top) DCE-MRI measured distribution (column 1) and measured concentration profiles (column 2) with simulated tracer distributions from the HF model (column 3) and the NHF model (column 4). Different rows show concentration contours from anterior to posterior regions. Albumin of 7.35 μl (and Gd-albumin) tracer was infused at 0.3 μl/min. (Bottom) Comparison of tracer distribution area calculated in consecutive MR imaging slices. Area spread is based on a 5% normalized concentration (C/ϕC0) threshold. Filled triangles and circles show an adjusted distribution range that accounts for tissue shrinkage in the model geometry (+7.64%).

Grahic Jump Location
Fig. 6

Simulated infusate distribution volume in different tissue regions for CED in dorsal and ventral hippocampus. (Left) Volume percentage of tracer in WM, GM, and CSF in HF model. (Right) Volume percentage of tracer in WM, GM, and CSF in NHF model. (Top) In dorsal hippocampus and (bottom) in ventral hippocampus. The infusion rate was 0.3 μl/min.

Grahic Jump Location
Fig. 5

Albumin tracer distribution volumes in the brain (tissue and CSF) after CED. Tracer distribution volume in (left) dorsal and (right) ventral hippocampus for an infusion rate of 0.3 μl/min for fissures (HF) and no fissures (NHF).

Grahic Jump Location
Fig. 4

Albumin tracer distribution volumes in CSF after CED. (Left) Simulations with hippocampal fissures and (right) no fissures for varying infusion volumes in (top) dorsal and (bottom) ventral hippocampus. The hydraulic conductivity of CSF ranged as KCSF/KWMǁ from 10 to 105.

Grahic Jump Location
Fig. 9

CED distribution of albumin tracer in dorsal hippocampus with increasing infusion volume. (Top) DCE-MRI measured distribution (column 1) and measured concentration profiles (column 2) with simulated tracer distributions of HF model (column 3) and NHF model (column 4) for varying infusion volumes: (row 1) Vi = 1.05 μl, (row 2) Vi = 3.15 μl, (row 3) Vi = 5.25 μl, and (row 4) Vi = 7.35 μl. Infusions were at 0.3 μl/min. (Bottom) Comparison of tracer distribution area calculated in the infusion slice of the dorsal hippocampus. Area spread is based on a 5% normalized concentration (C/ϕC0) threshold. Filled triangles and circles show an adjusted distribution range that accounts for tissue shrinkage in the model geometry (+7.64%).

Grahic Jump Location
Fig. 10

CED spread of albumin tracer into the ventral hippocampus with increasing infusion volume. (Top) DCE-MRI measured distribution (column 1) and measured concentration profiles (column 2) with simulated tracer distributions of HF model (column 3) and NHF model (column 4) for varying infusion volumes: (row 1) Vi = 1.05 μl, (row 2) Vi = 3.15 μl, (row 3) Vi = 5.25 μl, and (row 4) Vi = 7.35 μl. Infusions were at 0.3 μl/min. (Bottom) Comparison of tracer distribution area calculated in the infusion slice of the ventral hippocampus. Area spread is based on a 5% normalized concentration (C/ϕC0) threshold. Filled triangles and circles show an adjusted distribution range that accounts for tissue shrinkage in the model geometry (+7.64%).

Grahic Jump Location
Fig. 11

Comparison of calculated distribution volumes in a region after the end of CED into the dorsal (left) and ventral (right) hippocampus. Results from HF and NHF models are long bars. Adjusted distribution volumes are short bars stacked on top (+11.7%).

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