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. MRI has been extremely successful at diagnosing soft tissue disease since its discovery in 1972 (1). However, MRI is not as sensitive in comparison with other biomedical imaging techniques, such as CT, positron-emission tomography, or single-photon emission computed tomography. This is a consequence of a very small signal from a small population difference between nuclear energy states. For a spin-1/2 system, the "nuclear spin polarization", P N , is defined as:where N ϩ and N Ϫ denote populations with magnetic spin quantum numbers ϩ1/2 and Ϫ1/2, respectively. Typically, the thermal energy of the sample at temperature T exceeds the energy difference between the nuclear spin states in a magnetic field B 0 by several orders of magnitude ("hightemperature approximation") and the equilibrium polarization can be written as:where ␥ is the magnetogyric ratio, ប is Planck's constant divided by 2 , and k B is Boltzmann's constant. As an example, P N,0 Ϸ 5 ppm is predicted with Eq.[2] for protons ( 1 H) at body temperature (T ϭ 37°C) and B 0 ϭ 1.5T. In view of the inherent sensitivity problem, increasing the signalto-noise ratio (SNR) has been a field of continuous research since the discovery of NMR. Recently, the use of optically polarized noble gas isotopes 3 He and 129 Xe has attracted increasing interest for use in a variety of promising MR applications. These systems exhibit polarizations exceeding the thermal levels by several orders of magnitude. While the use of such "hyperpolarized" (HP) gases for MRI is a recent development, it is based on a solid foundation of work in atomic physics. The groundwork was laid by Kastler (2) more than 50 years ago by demonstrating transfer of angular momentum from circularly polarized light to the electron and nuclear spins of atoms, a process called "optical pumping" (OP). Since 1991, exploitation of OP as a means of enhancing signal initiated the development of a novel field in NMR (3,4). Research involving HP noble gases has been exceptionally fruitful in biomedical MRI as well as providing applications for investigation of materials (5-8).In the context of proton MRI, the lung is a particularly challenging area to study (9). Even at end expiration, the overall density is ...

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Magnetic resonance images of the lungs of a guinea pig have been produced using hyperpolarized helium as the source of the MR signal. The resulting images are not yet sufficiently optimized to reveal fine structural detail within the lung, but the spectacular signal from this normally signal-deficient organ system offers great promise for eventual in vivo imaging experiments. Fast 2D and 3D GRASS sequences with very small flip angles were employed to conserve the norenewable longitudinal magnetization. We discuss various unique features associated with performing MRI with hyperpolarized gases, such as the selection of the noble gas species, polarization technique, and constraints on the MR pulse sequence.

We describe an atlas of the C57BL/6 mouse brain based on MRI and conventional Nissl histology. Magnetic resonance microscopy was performed on a total of 14 specimens that were actively stained to enhance tissue contrast. Images were acquired with three different MR protocols yielding contrast dependent on spin lattice relaxation (T1), spin spin relaxation (T2), and magnetic susceptibility (T2*). Spatial resolution was 21.5 microns (isotropic). Conventional histology (Nissl) was performed on a limited set of these same specimens and the Nissl images were registered (3D-to-3D) to the MR data. Probabilistic atlases for 37 structures are provided, along with average atlases. The availability of three different MR protocols, the Nissl data, and the labels provides a rich set of options for registration of other atlases to the same coordinate system, thus facilitating data-sharing. All the data is available for download via the web.

The multilayered myelin sheath wrapping around nerve axons is essential for proper functioning of the central nervous system. Abnormal myelination leads to a wide range of neurological diseases and developmental disorders. Non-invasive imaging of myelin content is of great clinical importance. The present work demonstrated that loss of myelin in the central nervous system of the shiverer mouse results in a dramatic reduction of magnetic susceptibility in white matter axons. The reduction resulted in a near extinction of susceptibility contrast between gray and white matter. Quantitative magnetic susceptibility imaging and diffusion tensor imaging were conducted on a group of control and shiverer mice at 9.4 T. We measured the resonance frequency distribution of the whole brain for each mouse. Magnetic susceptibility maps were computed and compared between the two groups. It was shown that the susceptibility contrast between gray and white matter was reduced by 96% in the shiverer compared to the controls. Diffusion measurements further confirmed intact fiber pathways in the shiverer mice, ruling out the possibility of axonal injury and its potential contribution to the altered susceptibility. As an autosomal recessive mutation, shiverer is characterized by an almost total lack of central nervous system myelin. Our data provides new evidences indicating that myelin is the predominant source of susceptibility differences between deep gray and white matter observed in magnetic resonance imaging. More importantly, the present study suggests that quantitative magnetic susceptibility is a potential endogenous biomarker for myelination.

Effective pulmonary gas exchange relies on the free diffusion of gases across the thin tissue barrier separating airspace from the capillary red blood cells (RBCs). Pulmonary pathologies, such as inflammation, fibrosis, and edema, which cause an increased blood-gas barrier thickness, impair the efficiency of this exchange. However, definitive assessment of such gas-exchange abnormalities is challenging, because no methods currently exist to directly image the gas transfer process. Here we exploit the solubility and chemical shift of 129 Xe, the magnetic resonance signal of which has been enhanced by 10 5 with hyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchange regions of the lung. Based on a simple diffusion model, we estimate that this MR imaging method for measuring 129 Xe alveolar-capillary transfer is sensitive to changes in blood-gas barrier thickness of Ϸ5 m. We validate the successful separation of tissue barrier and RBC images and show the utility of this method in a rat model of pulmonary fibrosis where 129 Xe replenishment of the RBCs is severely impaired in regions of lung injury.diffusing capacity ͉ fibrosis ͉ gas exchange ͉ blood-gas barrier

Septation of the mammalian heart into four chambers requires the orchestration of multiple tissue progenitors. Abnormalities in this process can result in potentially fatal atrioventricular septation defects (AVSD). The contribution of extracardiac cells to atrial septation has recently been recognized. Here, we use a genetic marker and novel magnetic resonance microscopy techniques to demonstrate the origins of the dorsal mesenchymal protrusion in the dorsal mesocardium, and its substantial contribution to atrioventricular septation. We explore the functional significance of this tissue to atrioventricular septation through study of the previously uncharacterized AVSD phenotype of Shh -/-mutant mouse embryos. We demonstrate that Shh signaling is required within the dorsal mesocardium for its contribution to the atria. Failure of this addition results in severe AVSD. These studies demonstrate that AVSD can result from a primary defect in dorsal mesocardium, providing a new paradigm for the understanding of human AVSD.

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 review in vivo X-ray based small animal imaging, with a focus on in vivo micro-computed tomography (micro-CT) and digital subtraction angiography (DSA). We present the principles, technologies, image quality parameters and types of applications. We show that both methods can be used not only to provide morphological, but also functional information, such as cardiac function estimation or perfusion. Compared to other modalities, x-ray based imaging is usually regarded as being able to provide higher throughput at lower cost and adequate resolution. The limitations are usually associated with the relatively poor contrast mechanisms and potential radiation damage due to ionizing radiation, although the use of contrast agents and careful design of studies can address these limitations. We hope that the information will effectively address how x-ray based imaging can be exploited for successful in vivo preclinical imaging.