Resolution limit of cylinder diameter estimation by diffusion MRI: The impact of gradient waveform and orientation dispersion.

Diffusion MRI has been proposed as a non-invasive technique for axonal diameter mapping. However, accurate estimation of small diameters requires strong gradients, which is a challenge for the transition of the technique from preclinical to clinical MRI scanners, since these have weaker gradients. In this work, we develop a framework to estimate the lower bound for accurate diameter estimation, which we refer to as the resolution limit. We analyse only the contribution from the intra-axonal space and assume that axons can be represented by impermeable cylinders. To address the growing interest in using techniques for diffusion encoding that go beyond the conventional single diffusion encoding (SDE) sequence, we present a generalised analysis capable of predicting the resolution limit regardless of the gradient waveform. Using this framework, waveforms were optimised to minimise the resolution limit. The results show that, for parallel cylinders, the SDE experiment is optimal in terms of yielding the lowest possible resolution limit. In the presence of orientation dispersion, diffusion encoding sequences with square-wave oscillating gradients were optimal. The resolution limit for standard clinical MRI scanners (maximum gradient strength 60-80 mT/m) was found to be between 4 and 8 μm, depending on the noise levels and the level of orientation dispersion. For scanners with a maximum gradient strength of 300 mT/m, the limit was reduced to between 2 and 5 μm.