Comparative Evaluation of Microstructural Diffusion Methods in Characterizing Multiple Sclerosis Lesions: The Importance of multi-b shells acquisition

BackgroundDiffusion MRI (dMRI) is widely used to assess microstructural abnormalities in multiple sclerosis (MS), yet conventional diffusion tensor imaging (DTI) is limited by single b-shell acquisitions and reduced pathological specificity. Higher-order diffusion models enabled by multi-b-shell data may provide complementary information, but their relative performance across tissue classes remains unclear. PurposeTo evaluate lesion-resolved microstructural alterations across MS tissue classes using multiple diffusion models and to assess the impact of diffusion acquisition strategy on discriminative performance. MethodsMulti-shell dMRI was acquired in 57 treatment-naive patients with early MS and 17 healthy controls. Five diffusion models were evaluated (DTI, DKI, NODDI, SMT, and SMI). 3602 manually delineated ROIs, including chronic black holes, T2 lesions, lesion-matched normal-appearing white matter (NAWM), and normal white matter (NWM), were analyzed. Microstructural differences were assessed using linear mixed-effects models, and discriminative performance was evaluated using ROC analysis across single-shell, multi-shell, and joint modeling strategies. Feature selection was performed using LASSO regression. ResultsAcross all models, lesions exhibited coherent microstructural abnormalities relative to normal white matter, while NAWM showed concordant but more subtle alterations. Lesion-normal tissue contrasts demonstrated strong discriminative performance, whereas classification of NAWM versus NWM and lesion subtypes remained limited, reflecting substantial biological overlap. Two b-shell and joint modeling approaches consistently outperformed single-shell analyses, yielding the highest AUCs. LASSO identified a small set of biologically meaningful diffusion features driving tissue discrimination. ConclusionMulti-b-shell diffusion MRI enables more robust and informative characterization of MS-related white matter pathology than single-shell acquisitions alone, supporting multi-model, multi-b-shell strategies for lesion-resolved assessment in MS.