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With a fixed time to acquire a magnetic resonance (MR) image, time can be spent to acquire better spatial resolution with decrease in signal-to-noise ratio (SNR) or decreased resolution with increase in SNR. This resolution/SNR tradeoff at fixed time has been investigated by a visual rater study using images of ex vivo mouse brains. Simulated images with a tradeoff between SNR and resolution were produced from high-quality, 3D isotropic mouse brain images to emulate shorter constant acquisition times. The tradeoff images spanned a range of SNRs (63-6) and isotropic resolutions (32-81 microm). Fourteen readers identified the image which best displayed neuroanatomy. Additional experiments tested for (i) intra-observer consistency, (ii) the effect of emulated scan time, and (iii) specifically biased questions pertaining to the perception of neuroanatomy. Optimal anatomical viewing depended primarily on the SNR of the images. Specifically, for fixed imaging time, preference lay in the SNR range of approximately 30-35 with strong consistency and there was minimal effect from overall imaging time.

Impaired cognitive, memory, or motor performance is a distinguishing characteristic of neu- rological diseases. Although these symptoms are frequently the most evident in human patients, addi- tional markers of disease are critical for proper diagnosis and staging. Noninvasive neuroimaging methods have become essential in this capacity and provide means of evaluating disease and tracking progression. These imaging methods are also becoming available to scientists in the research laboratory for assessment of animal models of neurological disease. Imaging in mouse models of neurological dis- ease is of particular interest, owing to the availability of inbred strains and genetic manipulation tools that permit detailed investigation of the roles of various genes and gene products in disease pathogene- sis. However, the relative prevalence of neuroimaging abnormalities in mice exhibiting neurological symptoms has not been reported. This prevalence has both theoretical and practical value because it is influenced by both the sensitivity of macroscopic anatomical measures to underlying genetic and dis- ease processes and by the efficiency of neuroimaging in detecting and characterizing these effects. In this paper, we describe a meta-analysis of studies involving behavioral mouse mutants at our labora- tory. In summary, we have evaluated 15 different mutant genotypes, of which 13 showed abnormal neuroimaging findings. This indicates a surprisingly high prevalence of neuroimaging abnormalities (87%) and suggests that disease processes affecting behavior generally alter neuroanatomy as well. As a consequence, neuroimaging provides a highly sensitive marker of neurological disease in mice exhib- iting abnormal behavior. Hum Brain Mapp 28:567-575, 2007. V C 2007 Wiley-Liss, Inc.

Dominant mutations in the T-box transcription factor gene TBX5 cause Holt–Oram syndrome (HOS), an inherited human disease characterized by upper limb malformations and congenital heart defects (CHDs) of variable severity. We hypothesize that minor alterations in the dosage of Tbx5 directly influences severity of CHDs. Using a mouse allelic series, we show a sensitive inverse correlation between Tbx5 dosage and abnormal cardiac morphogenesis and gene expression. The CHDs found in mice harbouring a hypomorphic allele of Tbx5 ( Tbx5 lox /+ mice) are less pronounced than those found in Tbx5 haploinsufficient mice ( Tbx5 del /+ ), and homozygous hypomorphic ( Tbx5 lox /lox ) embryos have noticeably more advanced cardiac development than Tbx5 null ( Tbx5 del/del ) embryos. Examination of target gene expression across the allelic series uncovers very fine sensitivity across the range of Tbx5 dosages, in which some genes respond dramatically differently to only 15% differences in Tbx5 mRNA levels. This analysis was expanded to a genome-wide level, which uncovered a Tbx5 dosage-sensitive genetic program involving a network of cardiac transcription factors, developmentally important cell–cell signaling molecules, and ion channel proteins. These results indicate an exquisite sensitivity of the developing heart to Tbx5 dosage and provide significant insight into the transcriptional and cellular mechanisms that are disrupted in CHDs.

The use of mice to study models of human disease has resulted in a surge of interest in developing mouse MRI. The ability to take 3D, high-resolution images of live mice allows significant insight into anatomy and function. However, with imaging times on the order of hours, high throughput of specimens has been problematic. To facilitate high throughput, concurrent imaging of multiple mice has been developed; however, this poses further complexities regarding the ease and rapidity of loading several animals. In this study, custom-built equipment was developed to streamline the preparation process and to safely maintain seven mice during a multiple-mouse imaging session. Total preparation time for seven mice was ∼24 min. ECG and temperature were monitored throughout the scan and maintained by regulating anesthetic and heating. Proof of principle was demonstrated in a 3-h imaging session of seven mice. Magn Reson Med 52:709–715, 2004. © 2004 Wiley-Liss, Inc.

The nuclear spin polarization of the noble gas isotopes (3)He and (129)Xe can be increased using optical pumping methods by four to five orders of magnitude. This extraordinary gain in polarization translates directly into a gain in signal strength for MRI. The new technology of hyperpolarized (HP) gas MRI holds enormous potential for enhancing sensitivity and contrast in pulmonary imaging. This review outlines the physics underlying the optical pumping process, imaging strategies coping with the nonequilibrium polarization, and effects of the alveolar microstructure on relaxation and diffusion of the noble gases. It presents recent progress in HP gas MRI and applications ranging from MR microscopy of airspaces to imaging pulmonary function in patients and suggests potential directions for future developments.

Emphysema is a pulmonary disease characterized by alveolar wall destruction, resulting in enlargement of gas exchange spaces without fibrosis. This condition is a part of chronic obstructive pulmonary disease (COPD), which causes 3.5% of deaths worldwide [Anonymous (1990) World Health Stat. Q. Special , 1–51] and contributes greatly to the global burden of disease [Murray, C. J. & Lopez, A. D. (1996) Science 274, 740–743]. Alveolar regeneration has been shown in animal models and could have potential for clinical treatment of early-stage emphysema. However, current techniques for detection of emphysema are not sensitive at the initial stages. Early-stage human panacinar emphysema is modeled in elastase-treated animals. Here, we provide an in vivo imaging method for differentiating normal and emphysematous rat lungs by measuring the apparent diffusion coefficient (ADC) of hyperpolarized 3 He by using magnetic resonance imaging. These data show that the ADC is significantly larger in elastase-treated rats, indicating alveolar expansion. Whereas these rats were clinically asymptomatic, conventional histology confirmed presence of injury. Our results indicate that measurement of the hyperpolarized 3 He ADC can be a valuable research tool and has potential application in the clinical setting.

Hyperpolarized (HP) 3He can be encapsulated within biologically compatible microspheres while retaining sufficient polarization to be used as a signal source for MRI. Two microsphere sizes were used, with mean diameters of 5.3 ± 1.3 μm and 10.9 ± 3.0 μm. These suspensions ranged in concentration from 0.9–7.0% gas by volume. Spectroscopic measurements in phantoms at 2 T yielded 3He relaxation times that varied with gas concentration. At the highest 3He concentration, the spin-lattice relaxation time, T1, was 63.8 ± 9.4 sec, while the transverse magnetization decayed with a time constant of T*2 = 11.0 ± 0.4 msec. In vivo MR images of the pelvic veins in a rat were acquired during intravenous injection of 3He microspheres (SNR ≈ 15). Advantages such as intravascular confinement, lack of background signal, and limited recirculation indicate quantitative perfusion measurements may be improved using this novel signal source. Magn Reson Med 43:440–445, 2000. © 2000 Wiley-Liss, Inc.

The magnetization in hyperpolarized gas (HP) MRI is generated by laser polarization that is independent of the magnet and imaging process. As a consequence, there is no equilibrium magnetization during the image acquisition. The competing processes of gas inflow and depolarization of the spins lead to large changes in signal as one samples k-space. A model is developed of dynamic changes in polarization of hyperpolarized 3He during infusion and in vivo imaging of the lung and verified experimentally in a live guinea pig. Projection encoding is used to measure the view-to-view variation with temporal resolution

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. Image results can provide important comparisons of human conditions with mouse disease models, evaluations of treatment, development or disease progression, as well as direction for histological or other investigations. Effective mouse MRI studies require attention to many aspects of experiment design. In this chapter, we provide details and discussion of important practical considerations: hardware requirements, mouse handling for in vivo imaging, specimen preparation for ex vivo imaging, sequence and contrast agent selection, study size, and quantitative image analysis. We focus particularly on anatomical phenotyping, an important and accessible application that has shown a high potential for impact in many mouse models at our imaging center.

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, motivated by the need for improved tools for characterizing and evaluating mouse models of human disease. Image results can provide important comparisons of human conditions with mouse disease models, evaluations of treatment, development or disease progression, as well as direction for histological or other investigations. Effective mouse MRI studies require attention to many aspects of experiment design. In this chapter, we provide details and discussion of important practical considerations: hardware requirements, mouse handling for in vivo imaging, specimen preparation for ex vivo imaging, sequence and contrast agent selection, study size, and quantitative image analysis. We focus particularly on anatomical phenotyping, an important and accessible application that has shown a high potential for impact in many mouse models at our imaging center.

Image registration serves many applications in medical imaging, including longitudinal studies, treatment verification, and more recently, morphometry. Registration processing is regularly applied in magnetic resonance (MR) images, where imaging is highly adaptable in capturing soft tissue contrast. To obtain the greatest registration accuracy in MR imaging, the inherent imaging tradeoff between SNR and resolution at a given scan time should be optimized for computational accuracy, rather than human viewing. We investigated this SNR-resolution tradeoff to optimize registration for digital morphometry. Tradeoff images were simulated from acquired gold standard MR images to emulate a shorter, constant acquisition time, but at the expense of SNR, resolution, or both. The group of images from each tradeoff was nonlinearly registered toward an average atlas producing deformation fields, useful for identifying differences in morphology. The gold standard data were also registered. The deformation fields were used to evaluate registration performance of each tradeoff relative to the gold standard. For fixed scan times, the optimal SNR for registration with MR imaging was found to be ∼20. Image resolution should be adjusted to produce this target voxel SNR when registration is a central processing task. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc.

Mouse models are crucial for the study of genetic factors and processes that influence human disease. In addition to tools for measuring genetic expression and establishing genotype, tools to accurately and comparatively assess mouse phenotype are essential in order to characterize pathology and make comparisons with human disease. MRI provides a powerful means of evaluating various anatomical and functional changes and hence is growing in popularity as a phenotypic readout for biomedical research studies. To accommodate the large numbers of mice needed in most biological studies, mouse MRI must offer high-throughput image acquisition and efficient image analysis. This article reviews the technology of multiple-mouse MRI, a method that images multiple mice or specimens simultaneously as a means of enabling high-throughput studies. Aspects of image acquisition and computational analysis in multiple-mouse studies are also described. Copyright © 2007 John Wiley & Sons, Ltd.

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, with both MRI physicists and biologists starting to use MRI to identify mouse models of human disease. The purpose of this chapter is to provide details of the animal handling necessary for routine and robust in vivo imaging with particular emphasis on multiple-mouse imaging. In addition, techniques for perfusion-fixation for postmortem imaging of specimens and whole mice are given.

The field of mouse phenotyping with magnetic resonance imaging (MRI) is rapidly growing, with both MRI physicists and biologists starting to use MRI to identify mouse models of human disease. The purpose of this chapter is to provide details of the animal handling necessary for routine and robust in vivo imaging with particular emphasis on multiple-mouse imaging. In addition, techniques for perfusion-fixation for postmortem imaging of specimens and whole mice are given.

With the enormous and growing number of experimental and genetic mouse models of human disease, there is a need for efficient means of characterizing abnormalities in mouse anatomy and physiology. Adaptation of magnetic resonance imaging (MRI) to the scale of the mouse promises to address this challenge and make major contributions to biomedical research by non-invasive assessment in the mouse. MRI is already emerging as an enabling technology providing informative and meaningful measures in a range of mouse models. In this review, recent progress in both in vivo and post mortem imaging is reported. Challenges unique to mouse MRI are also identified. In particular, the needs for high-throughput imaging and comparative anatomical analyses in large biological studies are described and current efforts at handling these issues are presented.

High-resolution magnetic resonance imaging is emerging as a powerful tool for phenotyping mice in biologic studies of genetic expression, development, and disease progression. In several applications, notably random mutagenesis trials, large cohorts of mice must be examined for abnormalities that may occur in any part of the body. In the aim of establishing a protocol for imaging multiple mice simultaneously in a standardized high-throughput fashion, this study investigates variations of a three-dimensional fast spin-echo sequence that implements driven equilibrium, modified refocusing, and partial excitation pulses. Sequence variations are compared by simulated and experimental measurements in phantoms and mice. Results indicate that when using a short repetition time (TR

The search for new mouse models of human disease requires a sensitive metric to make three-dimensional (3D) anatomical comparisons in a rapid and quantifiable manner. This is especially true in the brain, where changes in complex shapes such as the hippocampus and ventricles are difficult to assess with 2D histology. Here, we report that the 3D neuroanatomy of three strains of mice (129S1/SvImJ, C57/Bl6, and CD1) is significantly different from one another. Using image co-registration, we 'morphed' together nine brains of each strain scanned by magnetic resonance imaging at (60 microm)3 resolution to synthesize an average image. We applied three methods of comparison. First, we used visual inspection and graphically examined the standard deviation of the variability in each strain. Second, we annotated 42 neural structures and compared their volumes across the strains. Third, we assessed significant local deviations in volume and displacement between the two inbred strains, independent of prior anatomical knowledge.

We describe a novel technique to perform whole-body perfusion fixation in mice with specific relevance to micro-imaging. With the guidance of high-frequency ultrasound imaging, we were able to perfuse fixative and contrast agents via a catheter inserted into the left ventricle, and therefore preserved the integrity of the chest and abdominal cavity. In this preliminary study, our success rate over 15 animals was 73%. We demonstrate applications of this technique for magnetic resonance imaging and micro-CT, but we expect that this method can be generally applied to whole-body perfusions of other small animals in which the intact body is necessary.

The nuclear spin polarization of the noble gas isotopes (3)He and (129)Xe can be increased using optical pumping methods by four to five orders of magnitude. This extraordinary gain in polarization translates directly into a gain in signal strength for MRI. The new technology of hyperpolarized (HP) gas MRI holds enormous potential for enhancing sensitivity and contrast in pulmonary imaging. This review outlines the physics underlying the optical pumping process, imaging strategies coping with the nonequilibrium polarization, and effects of the alveolar microstructure on relaxation and diffusion of the noble gases. It presents recent progress in HP gas MRI and applications ranging from MR microscopy of airspaces to imaging pulmonary function in patients and suggests potential directions for future developments.

The nonequilibrium bulk magnetic moment of hyperpolarized (HP) noble gases generated by optical pumping has unique characteristics. Based on the Bloch equations, a model was developed describing the signal dynamics of HP gases used in magnetic resonance imaging (MRI) of the lung with special consideration to the breathing cycle. Experimental verification included extensive investigations with HP 3 He and 129 Xe during both inspiration and held breath in live guinea pigs. Radial acquisition was used to investigate the view variations with a temporal resolution of 5 ms. Agreement between theoretical predictions and in vivo results was excellent. Additionally, information about effects from noble gas diffusion and spin–lattice relaxation was obtained. In vivo results for T 1 were 28.8 ± 1.8 s for 3 He and 31.3 ± 1.8 s for 129 Xe. Comparison with in vitro data indicated that relaxation in the pulmonary gas space is dominated by dipolar coupling with molecular oxygen. The results provide a quantitative basis for optimizing pulse sequence design in HP gas MRI of the lung.

A technique using hyperpolarized (HP) 3He to image the small airways of the lung by using moderate flip angles and a short scanning period during early inspiration is demonstrated. Flip angles (alpha) ranging from 10-90 degrees were used in guinea pig experiments with scanning during the entire inspiration period. A second series acquired data throughout a short window of the ventilatory cycle with alpha = 45 degrees. The success of the animal studies has motivated implementation of similar imaging techniques in the clinical arena. Human studies involved imaging over the total inspiration period with alpha approximately 10 degrees. The first series of guinea pig experiments demonstrated that larger flip angles (50-90 degrees) destroy the magnetization before it reaches the smaller airways. At moderate flip angles (20-40 degrees), airway branching down to the fourth generation was apparent. Fifth-order branchings were seen in the images of the second series. The trachea down to fourth generation pulmonary airway branching, along with some distal air spaces, was seen in the human lung images.

Laser-polarized gases ( 3 He and 129 Xe) are currently being used in magnetic resonance imaging as strong signal sources that can be safely introduced into the lung. Recently, researchers have been investigating other tissues using 129 Xe. These studies use xenon dissolved in a carrier such as lipid vesicles or blood. Since helium is much less soluble than xenon in these materials, 3 He has been used exclusively for imaging air spaces. However, considering that the signal of 3 He is more than 10 times greater than that of 129 Xe for presently attainable polarization levels, this work has focused on generating a method to introduce 3 He into the vascular system. We addressed the low solubility issue by producing suspensions of 3 He microbubbles. Here, we provide the first vascular images obtained with laser-polarized 3 He. The potential increase in signal and absence of background should allow this technique to produce high-resolution angiographic images. In addition, quantitative measurements of blood flow velocity and tissue perfusion will be feasible.