Probing Tissue Structures Using Short Diffusion Times

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I propose to develop and optimize an important new method for distinguishing the size of very small (~ 1 µm) tissue structures, such as small axon diameters, using diffusion magnetic resonance imaging (MRI). The method relies on probing the shortest possible diffusion time scales so that the transition from restricted to hindered diffusion within the smallest structures can be detected. Current state-of-the-art methods cannot distinguish these small structures because current methods use pulse sequences which limit the ability to probe the shortest diffusion times. My method circumvents those limitations by using oscillating gradients in place of pulsed gradients. I am a world expert in the use of oscillating gradients for diffusion measurements. The new method will have important biological and neuroscience applications. I will extend the measurements made with OGSE from studying the variation of ADC with diffusion time or frequency to creating a method which uses this variation to infer restriction sizes using the shortest possible diffusion times. This method overcomes problems with high gradient strengths necessary in current MR diffusion methods (PGSE and q-space) and allows smaller restriction sizes to be distinguished. I will develop this method to push the ability of MRI to distinguish the smallest possible sizes. Once the method has been demonstrated on axon diameter distribution measurements, a new era of MRI with sensitivity of micron scale structures will begin. The method will then be adapted to other systems, biological or otherwise. The OGSE and PGSE methods can be used together to distinguish a large range of restriction sizes from very small (OGSE) to fairly large (PGSE). Combining the two methods will allow for a more complete understanding of the geometry of the sample.