Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas.

Strain specific mouse brain magnetic resonance imaging (MRI) atlases provide coordinate space linked anatomical registration. This allows longitudinal quantitative analyses of neuroanatomical volumes and imaging metrics for assessing the role played by aging and disease to the central nervous system. As NOD/scid-IL-2Rγ(c)(null) (NSG) mice allow human cell transplantation to study human disease, these animals are used to assess brain morphology. Manganese enhanced MRI (MEMRI) improves contrasts amongst brain components and as such can greatly help identifying a broad number of structures on MRI. To this end, NSG adult mouse brains were imaged in vivo on a 7.0 Tesla MR scanner at an isotropic resolution of 100 µm. A population averaged brain of 19 mice was generated using an iterative alignment algorithm. MEMRI provided sufficient contrast permitting 41 brain structures to be manually labeled. Volumes of 7 humanized mice brain structures were measured by atlas-based segmentation and compared against non-humanized controls. The humanized NSG mice brain volumes were smaller than controls (p < 0.001). Many brain structures of humanized mice were significantly smaller than controls. We posit that the irradiation and cell grafting involved in the creation of humanized mice were responsible for the morphological differences. Six NSG mice without MnCl2 administration were scanned with high resolution T2-weighted MRI and segmented to test broad utility of the atlas.

Landmark optimization using local curvature for point-based nonlinear rodent brain image registration.

Purpose. To develop a technique to automate landmark selection for point-based interpolating transformations for nonlinear medical image registration. Materials and Methods. Interpolating transformations were calculated from homologous point landmarks on the source (image to be transformed) and target (reference image). Point landmarks are placed at regular intervals on contours of anatomical features, and their positions are optimized along the contour surface by a function composed of curvature similarity and displacements of the homologous landmarks. The method was evaluated in two cases (n = 5 each). In one, MRI was registered to histological sections; in the second, geometric distortions in EPI MRI were corrected. Normalized mutual information and target registration error were calculated to compare the registration accuracy of the automatically and manually generated landmarks. Results. Statistical analyses demonstrated significant improvement (P < 0.05) in registration accuracy by landmark optimization in most data sets and trends towards improvement (P < 0.1) in others as compared to manual landmark selection.

A semi-automatic image segmentation method for extraction of brain volume from in vivo mouse head magnetic resonance imaging using Constraint Level Sets.

In vivo magnetic resonance imaging (MRI) of mouse brain has been widely used to non-invasively monitor disease progression and/or therapeutic effects in murine models of human neurodegenerative disease. Segmentation of MRI to differentiate brain from non-brain tissue (usually referred to as brain extraction) is required for many MRI data processing and analysis methods, including coregistration, statistical parametric analysis, and mapping to brain atlas and histology. This paper presents a semi-automatic brain extraction technique based on a level set method with the incorporation of user-defined constraints. The constraints are derived from the prior knowledge of brain anatomy by defining brain boundary on orthogonal planes of the MRI. Constraints are incorporated in the level set method by spatially varying the weighting factors of the internal and external forces and modifying the image gradient (edge) map. Both two-dimensional multislice and three-dimensional versions of the brain extraction technique were developed and applied to MRI data with minimal brain/non-brain contrast T(1)-weighted (T(1)-wt) FLASH and maximized contrast T(2)-weighted (T(2)-wt) RARE. Results were evaluated by calculating the overlap measure (OM) between the automatically segmented and manually traced brain volumes. Results demonstrate that this technique accurately extracts the brain volume (mean OM=94%) and consistently outperformed the region growing method applied to the T(2)-wt RARE MRI (mean OM=81%). This method not only successfully extracts the mouse brain in low and high contrast MRI, but can also be used to segment other organs and tissues.

Effects of transcranial ultrasound and intravenous microbubbles on blood brain barrier permeability in a large animal model.

We sought to determine whether transtemporal-applied 1-MHz ultrasound-induced microbubble destruction may be a safe method of transiently altering blood brain barrier (BBB) permeability for drug delivery in a large animal model. Endothelial cells are an integral component of the BBB but also prevent passage of potentially therapeutic drugs. Ultrasound-mediated destruction (UMD) of microbubbles has been shown to disrupt this barrier in small animals when ultrasound is delivered through bone windows. However, the effects of temporal bone attenuation and scattering in a large animal may limit the clinical application of such a technique. Twenty-four pigs were studied. One-MHz pulsed-wave ultrasound at 2.0 W/cm(2) (20% duty cycle) across the temporal bone was applied for 30 min after intravenous injections of either albumin-coated perfluorocarbon microbubble (PESDA, 8 pigs), lipid-encapsulated perfluorocarbon microbubbles (LEMB, 8 pigs) or ultrasound alone (8 pigs). BBB leak was quantified at 30 and 120 min after insonation using Evans blue. Serial magnetic resonance imaging (MRI) was performed in nine of the pigs (3 for each group) to quantify Gadolinium leak within the parenchyma. Peak negative pressures decreased ten-fold when ultrasound was transmitted across the pig temporal bone. Despite this, spectrophotometric analysis showed that both IV LEMB and PESDA combined with transtemporal ultrasound resulted in a significant increase in Evans blue extravasation across BBB of the treated side at 30 min after insonation (p < 0.001; compared with ultrasound alone) but not at 120 min. There was significant retention of Gadolinium within the insonified parenchyma at 60 and 90 min after insonation, but not at 120 min. Oxygen saturation and arterial pressures were not changed after any microbubble injection. Intravenous microbubbles, combined with transtemporal ultrasound, can transiently increase BBB permeability in a large animal. This induced opening of BBB is reversible and may be a safe noninvasive method of achieving drug or gene delivery across the BBB.

Ingress of blood-borne macrophages across the blood-brain barrier in murine HIV-1 encephalitis.

Blood-borne macrophage ingress into brain in HIV-1 associated neurocognitive disorders governs the tempo of disease. We used superparamagnetic iron-oxide particles loaded into murine bone marrow-derived macrophages (BMM) injected intravenously into HIV-1 encephalitis mice to quantitatively assess BMM entry into diseased brain regions. Magnetic resonance imaging tests were validated by histological coregistration and enhanced image processing. The demonstration of robust BMM migration into areas of focal encephalitis provide 'proof of concept' for the use of MRI to monitor macrophage ingress into brain.