Figure 1 illustrates the impact of the directionality bias on a subsequent analysis: the full brain atrophy estimation. In this example, two -weighted MRIs from the same subject and acquired with a 1-year interval are spatially normalized to a midspace based on an affine transformation. This step ensures that no resampling bias affects the brain atrophy estimation. Three registration approaches are used to estimate the affine parametrization: (i) an asymmetric registration where the baseline scan is considered as the reference and the follow-up scan as the floating, , (ii) an asymmetric registration where the follow-up scan is considered as the reference and the baseline scan as the floating, , and (iii) a symmetric registration scheme, . After the resampling of the input images to a midspace, they are corrected for differential bias fields and the atrophy is estimated using the boundary shift integral method as described by Leung et al.2 The obtained full brain volume changes over one year are 14.49, 20.55, and 16.51 mm using the forward, backward, and symmetric registration schemes, respectively. It can be noted that using the asymmetric registration approaches, the obtained atrophy measurements are different even though the composition of the obtained matrices for this specific case is close to identity, hence close to being inverse consistent Display Formulawhere denotes the composition operator.