Abstract

Purpose Double diffusion encoding (DDE) MRI enables the estimation of microscopic diffusion anisotropy, yielding valuable information on tissue microstructure. A recent study proposed that the acquisition of rotationally invariant DDE metrics, typically obtained using a spherical “5‐design,” could be greatly simplified by assuming Gaussian diffusion, facilitating reduced acquisition times that are more compatible with clinical settings. Here, we aim to validate the new minimal acquisition scheme against the standard DDE 5‐design, and to quantify the proposed method's noise robustness to facilitate future clinical use. Theory and Methods DDE MRI experiments were performed on both ex vivo and in vivo rat brains at 9.4 T using the 5‐design and the proposed minimal design and taking into account the difference in the number of acquisitions. The ensuing microscopic fractional anisotropy (μFA) maps were compared over a range of b ‐values up to 5000 s/mm 2 . Noise robustness was studied using analytical calculations and numerical simulations. Results The minimal protocol quantified μFA at an accuracy comparable to the estimates obtained by means of the more theoretically robust DDE 5‐design. μFA's sensitivity to noise was found to strongly depend on compartment anisotropy and tensor magnitude in a nonlinear manner. When μFA < 0.75 or when mean diffusivity is particularly low, very high signal‐to‐noise ratio is required for precise quantification of µFA. Conclusion Our work supports using DDE for quantifying microscopic diffusion anisotropy in clinical settings but raises hitherto overlooked precision issues when measuring μFA with DDE and typical clinical signal‐to‐noise ratio.