The objective of the proposed research is to investigate theoretical and practical problems associated with magnetic resonance microscopy and to develop new methods and probes capable of achieving significant improvements in spatial resolution of human tissue and cell preparations. When spatial resolution becomes on the order of the molecular diffusion distance over the acquisition time a new imaging regime is entered not usually considered in clinical MRI. The dimensions of special interest to us are less than approximately 10 microns. Building on the early work by Mansfield, Lauterbur, Hoult, and Callaghan and their colleagues, our group as well as others are now able to obtain spatial resolution of approximately 5-10 microns for H(1) in biological systems which borders on this new regime. Progress to date has utilized relatively routine methods, including improved filling factor, large gradients, and multiple signal averages. AH the basic experimental results to date can be understood in the framework of the several existing models. To attempt to extend the limits of magnetic resonance resolution to the truly subcellular realm we have taken a somewhat different, more microscopic point of view and realized that, in fact, the problem in the microimaging regime is quite different than clinical MRI because the micron size voxels are considerably smaller than the path travelled by the spins as they diffuse during the acquisition period and that different, more rapid methods of spatial encoding are needed and different methods for analyzing contrast and resolution. The goal of practical realization of subcellular NMR microscopy is not necessarily any more achievable with a microscopic view, however, the explanation will at least be complete - and perhaps provide some surprises. We have developed a model based on fundamental energetic and kinetic phenomena that accurately predicts the present 5-10 mm limit (for H(1)) and, more importantly, provides a means of demonstrating that alternative methods of detection and spatial encoding can lead to improvements in spatial resolution by several orders of magnitude over current methods. The proposed research will: (1) continue to push the limits of resolution, utilizing optimized conventional methods; (2) investigate alternative methods, including i) signal detection using cooled superconducting probe systems, ii) rotating frame r.f. gradient zeugmatography imaging methods, and ultra-fast pulsed gradients; (3) utilize the improved spatial resolution and understanding of basic processes in two practical applications: i) to study human subarticular histopathology in joint disease and ii) to image the two and three dimensional structure of chemical wave analogs of cardiac tissue.
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