Orientation Dependence of R2' in White Matter: Digital Characterization, Modelling and Implications for Studying Brain Physiology

Introduction R2* is the transverse relaxation rate of tissue, influenced by local magnetic field inhomogeneities arising from susceptibility differences. It decomposes into R2 and R2', where R2' is the reversible component most sensitive to blood oxygenation and forms the basis of the BOLD fMRI signal. Although orientation dependence of R2 and R2* in white matter (WM) has been attributed primarily to myelin, the vascular contribution to R2' has not been systematically characterized. This study investigated the orientation dependence of WM R2', assessed existing models, and developed an improved model incorporating both myelin and vascular effects. Methods Monte Carlo simulations were performed using BOLDswimsuite with 2D WM voxels generated from 5,000 fibres. Spin-echo (TE = 70 ms) and gradient-echo (TE = 35 ms) signals were simulated across 30 fibre orientations (0{degrees}-90{degrees}), and R2' was calculated as R2* - R2. Oxygenation, cerebral blood volume (CBV), vessel size, and vessel geometry were systematically varied. Four published models and a novel Myelin-Blood model were fitted to simulated R2' data and compared using R2 and RMSE. Results Strong orientation dependence was observed for R2 and R2*. Parallel and mixed vessel geometries produced greater R2' amplitude and orientation dependence than random geometries. Decreasing oxygenation and increasing CBV amplified orientation effects; vessel size altered peak locations. Existing vascular models performed poorly, and the empirical myelin model showed substantial errors near the magic angle. The Myelin-Blood model provided near-perfect fits (mean R2 = 0.999, RMSE = 0.007 Hz), reducing RMSE by approximately 74%. Discussion WM R2' cannot be adequately described by vascular or myelin effects alone. Myelin is the primary determinant of orientation dependence, but systematic vascular contributions were observed, particularly near the magic angle and under low oxygenation. The Myelin-Blood model improves characterisation of WM R2' and may reduce orientation-dependent bias in qBOLD OEF estimation while improving interpretation of WM BOLD fMRI signals.