Small animal magnetic resonance microscopy (MRM) has evolved significantly from testing the boundaries of imaging physics to its expanding use today as a tool in noninvasive biomedical investigations. MRM now increasingly provides functional information about living animals, with images of the beating heart, breathing lung, and functioning brain. Unlike clinical MRI, where the focus is on diagnosis, MRM is used to reveal fundamental biology or to noninvasively measure subtle changes in the structure or function of organs during disease progression or in response to experimental therapies. High-resolution anatomical imaging reveals increasingly exquisite detail in healthy animals and subtle architectural aberrations that occur in genetically altered models. Resolution of 100 mum in all dimensions is now routinely attained in living animals, and (10 mum)(3) is feasible in fixed specimens. Such images almost rival conventional histology while allowing the object to be viewed interactively in any plane. In this review we describe the state of the art in MRM for scientists who may be unfamiliar with this modality but who want to apply its capabilities to their research. We include a brief review of MR concepts and methods of animal handling and support, before covering a range of MRM applications-including the heart, lung, and brain-and the emerging field of MR histology. The ability of MRM to provide a detailed functional and anatomical picture in rats and mice, and to track this picture over time, makes it a promising platform with broad applications in biomedical research.

Magnetic resonance microscopy (MRM) has become an important tool for small animal cardiac imaging. In relation to competing technologies (microCT and ultrasound), MR is limited by spatial resolution, temporal resolution, and acquisition time. All three of these limitations have been addressed by developing a four-dimensional (4D) (3D plus time) radial acquisition (RA) sequence. The signal-to-noise ratio (SNR) has been optimized by minimizing the echo time (TE) (300 us). The temporal resolution and throughput have been improved by center-out trajectories resulting in repetition time (TR) <2.5 ms. The contrast has been enhanced through the use of a liposomal blood pool agent that reduces the T 1 of the blood to <400 ms. We have developed protocols for three specific applications: 1) high-throughput with spatial resolution of 87 ؋ 87 ؋ 352 um 3 (voxel volume ‫؍‬ 2. Magnetic resonance microscopy (MRM) has become a standard tool for investigating cardiac structure and function in the mouse. The majority of MR work on mice has been performed with two-dimensional (2D) acquisition methods with limited resolution along the third axis (1-4). 3D studies have shown promise in the clinical arena as they increase the signal-to-noise ratio (SNR) per unit time and allow for higher in-plane resolution, ultimately allowing more sensitive calculation of cardiac function. But 3D applications in small animal imaging thus far have been limited. While 3D studies have been performed in the rat (5), those studies had limited temporal resolution (systole and diastole). Feintuch et al. (6) have shown 4D (3D spatial ϩ time) data in the mouse at limited spatial resolution (8 nL), limited temporal resolution (12 ms), and with long scan times of 1-2 h. Recent work in the clinical arena has extended methods for cardiac functional assessment with 4D acquisitions that can be divided into two categories: 4D human studies that use contrast (7,8); and 4D studies that use inherent MR contrast (black blood, steady-state imaging techniques) (9,10). In both cases, the increased resolution along the Z-axis provides reduction in volume averaging and increased precision in measurement of end systolic and diastolic volume (ESV, EDV), and ejection fraction (EF). The utility of a routine method for highthroughput assessment of cardiac function in the mouse is clear. But extension of clinical techniques to the mouse is not straightforward. The 25-g mouse is nearly 3000 times smaller than a human. To view the mouse anatomy at anatomic resolution comparable to that achieved in the clinical domain (voxel volumes of 48 mm 3 at 0.96 s/frame) (10) will require voxels on the order of 16 nL (Ͻ275 um in every dimension). Because of the higher heart rate in the mouse (450 -550 beats per min), achieving a frame rate similar to humans will require a temporal resolution of 12 ms. We describe a method for functional 4D cardiac assessment of the mouse using radial encoding of a free induction decay (FID) (11). The method is relatively fast (16 -32 min/study), with spatial r...

Small animal imaging has a critical role in phenotyping, drug discovery, and in providing a basic understanding of mechanisms of disease. Translating imaging methods from humans to small animals is not an easy task. The purpose of this work is to compare two cardiac imaging modalities, i.e., magnetic resonance microscopy (MRM) and microcomputed tomography (CT) for preclinical studies on rodents. We present the two technologies, the parameters that they can measure, the types of alterations that they can detect, and show how these imaging methods compare to techniques available in clinical medicine. While this paper does not refer per se to the cardiac risk assessment for drug or chemical development, we hope that the information will effectively address how MRM and micro-CT might be exploited to measure biomarkers critical for safety assessment.

Two-dimensional intersecting k-space trajectories have previously been demonstrated to allow fast multispectral imaging. Repeated sampling of k-space points leads to destructive interference of the signal coming from the off-resonance spectral peaks; on-resonance data reconstruction yields images of the on-resonance peak, with some of the off-resonance energy being spread as noise in the image. A shift of the k-space data by a given off-resonance frequency brings a second frequency of interest on resonance, allowing the reconstruction of a second spectral peak from the same k-space data. Given the higher signal-to-noise per unit time characteristic of a 3D acquisition, we extended the concept of intersecting trajectories to three dimensions. A 3D, rosette-like pulse sequence was designed and implemented on a clinical 1.5T scanner. An iterative density compensation function was developed to weight the 3D intersecting trajectories before Fourier transformation. Three volunteers were scanned using this sequence and separate fat and water images were reconstructed from the same imaging dataset. MRI is exquisitely sensitive in identifying anatomical changes associated with pathological conditions. It is becoming increasingly obvious, however, that early detection of disease, prior to anatomical transformations, is paramount for the treatment of disease. Changes in tissue biochemistry usually precede changes in anatomy and have been identified and visualized through MR spectroscopic imaging (MRSI) (1,2). Given the low concentration of endogenous compounds, MRSI exams generally require a long scan time and produce images with a low signal-tonoise ratio (SNR) and low spatial resolution.The recent development of hyperpolarization techniques promises to fundamentally expand the capabilities of MRI, increasing SNR of MRSI exams and allowing realtime, in vivo imaging of metabolism (3-5). To follow rapidly evolving changes in metabolite concentrations, as cell metabolism transforms an injected compound into its downstream metabolites the use of fast, multispectral MR data acquisition techniques is required. Chemical shift imaging (CSI) techniques have been used to encode spectral and spatial information in MRSI exams (6,7). These techniques, however, have not been optimized for acquisition of hyperpolarized signals, and need to be improved to fully exploit the benefits offered by the large, slowly decaying, nonrenewable hyperpolarized signals.Intersecting trajectories in k-space are a promising alternative for fast multispectral imaging and have been previously demonstrated in 2D (8,9). These two previously presented techniques are both a variation of chemical shift imaging, in which the spectral information is acquired through multiple crossings of the same points in k-space. In the first approach (8), random intersecting trajectories were used to reconstruct on-and off-resonant frequency information. The random stochastic trajectories proposed (8) were taxing on the gradient system and the quality of the reconstructed imag...