During the last decade, diffusion tensor imaging (DTI) has been used extensively to investigate microstructural properties of white matter fiber pathways. In many of these DTI-based studies, fiber tractography has been used to infer relationships between bundle-specific mean DTI metrics and measures-of-interest (e.g., when studying diffusion changes related to age, cognitive performance, etc.) or to assess potential differences between populations (e.g., comparing males vs. females, healthy vs. diseased subjects, etc.). As partial volume effects (PVEs) are known to affect tractography and, subsequently, the estimated DTI measures sampled along these reconstructed tracts in an adverse way, it is important to gain insight into potential confounding factors that may modulate this PVE. For instance, for thicker fiber bundles, the contribution of PVE-contaminated voxels to the mean metric for the entire fiber bundle will be smaller, and vice-versa - which means that the extent of PVE-contamination will vary from bundle to bundle. With the growing popularity of tractography-based methods in both fundamental research and clinical applications, it is of paramount importance to examine the presence of PVE-related covariates, such as thickness, orientation, curvature, and shape of a fiber bundle, and to investigate the extent to which these hidden confounds affect diffusion measures. To test the hypothesis that these PVE-related covariates modulate DTI metrics depending on the shape of a bundle, we performed simulations with synthetic diffusion phantoms and analyzed bundle-specific DTI measures of the cingulum and the corpus callosum in 55 healthy subjects. Our results indicate that the estimated bundle-specific mean values of diffusion metrics, including the frequently used fractional anisotropy and mean diffusivity, were indeed modulated by fiber bundle thickness, orientation, and curvature. Correlation analyses between gender and diffusion measures yield different results when volume is included as a covariate. This indicates that incorporating these PVE-related factors in DTI analyses is imperative to disentangle changes in "true microstructural" tissue properties from these hidden covariates.
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