7.6 VA Reading - Smith 2006 NeuroImage (cont.)

Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TEJ (2006). Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage; 31: 1487-505.

Limitations and dangers
A serious limitation of VBM-style approaches is the need for spatial smoothing, and the problem of arbitrarily choosing the spatial smoothing extent. When tract width is smaller than original voxel size, it is very difficult to determine whether a reduction in FA is really due to within-tract FA change or a change in tract thickness. Hard to solve this problem; partly for that reason, the mean FA skeleton is thresholded (typically 0.2), rather than being allowed to fall all the way to zero.
A similar possible confounding effect is within-scan head motion. One could potentially estimate head motion using image entropy measures and/or motion estimates from the eddy-current/head motion preprocessing and feed this into final statistical analyses as a confound regressor, but this would not be guaranteed to remove all related problems, and could remove the effect of interest.
Another area requiring careful interpretation is crossing tracts or tract junctions, which is difficult to be estimated by voxelwise statistics. Practically, a more sophisticated data projection approach is needed. An apparent reduction in FA at junctions can in fact be due to an increase in one of the tracts feeding into the junction, if it is a "weaker" tract than others feeding into the junction (what is a weaker tract?).

• (7.7) http://www.pnas.org/content/102/34/12212.long
  In both WM and thalamus, physiological factors other than myelin that could influence the correlation include intravoxel fiber crossing or axon diameter. In anatomic regions containing intravoxel fiber crossing, increased FA of an individual fiber population can result in a decrease in the overall FA. e.g. between optic radiation and posterior forceps.

Pathology could reduce FA too strongly, leading to exclusion of potential areas from analysis (e.g. due to the thresholding of the mean FA values). This may be a subtle effects due to the nature of most of the pathologies. But in case it happens, an appropriate approach would be to use a target FA image for registration, and mean FA skeleton, derived from a relevant control group.