Figure 2.

Overview of the image processing pipeline. The main analysis steps are outlined, on the left for the tissue‐state segmentation, on the right for the quantification of microstructural damage. Tissue segmentation in patients: Lesion segmentation was performed by two independent operators in order to assess reliability of the lesion segmentation. T1‐weighted images were lesion‐filled and FAST‐segmented in order to obtain a white matter mask. To restrict white matter to lesion‐susceptible regions, a lesion probability map from all patients' individual lesion maps was created and registered to each patient's native space, creating a restricted white matter mask. NAWM was defined as restricted white matter, at least 5 mm away from lesions in order to avoid tissue damage around lesions. White matter lesions were further segmented into T1L and T2L, based on the intensity in the (bias field corrected) T1‐weighted image. The distribution of the intensities on the T1‐weighted image in NAWM voxels is shown in green, while the distribution of the intensities on the T1‐weighted image in lesional voxels is shown in red and in blue. From the distribution of NAWM voxels, a cut‐off was calculated (1.5 IQR below the lower quartile, shown as black line) that was applied to all voxels in the lesion map. Lesional voxels with an intensity below the cut‐off were classified as T1L (red distribution), the rest as T2L (blue distribution). Microstructural damage quantification: For each patient, we derived a parameter map for each FA, RD, MTR, and MWF. We scaled these maps to the distribution (mean and SD) of healthy controls through z‐standardisation, yielding maps of FA(z), RD(z), MTR(z), and MWF(z), respectively. From these, global estimates of damage were obtained from the three segmented tissue‐states. Additionally, voxel‐wise values were considered within each patient's white matter mask in order to (a) look at within‐patient voxel‐wise correlations, (b) combine the four measures through a principal component analysis, and (c) assess sensitivity of each measure to lesional tissue, using a receiver operating characteristic (ROC) analysis. WM: white matter; NAWM: normal appearing white matter; T2L: T2‐hyperintense only lesional tissue; T1L: T2‐hyperintense lesional tissue that appears also T1‐hypointense. FA: fractional anisotropy; RD: radial diffusivity; MTR: magnetisation transfer ratio; MWF: myelin water fraction [Color figure can be viewed at http://wileyonlinelibrary.com]