Not sure I understand the terminologic difference (pathway vs connection) but mainly the offer of FBA for this study case what is confusing me.
Well, I kind of made up that terminology on the spot, so the lack of understanding is not terribly surprising.
Imagine two grey matter regions of interest, which are connected through a white matter “pipe”. However, there are also a bunch of other grey matter regions on either side of the pipe, for which the connections between them pass through the same pipe. If one were to assess the “pathway” (i.e. the pipe), using e.g. FBA, then the data you would observe would be a combination of both the connection you are interested in and a bunch of other connections. If the effect of interest is genuinely specifically just the “connection” between those two grey matter regions, then having a quantitative metric reflecting just that connection would be preferable.
This is however predicated on the combination of tracking & SIFT being able to reflect that underlying specific difference within the reconstruction; which may unfortunately be too much to ask in many circumstances. So while e.g. SIFT2 sum of weights is physically and logically the correct way to assess the hypothesis of an altered “connection”, it’s not yet clear whether this specificity is outweighed by the data variance introduced by the necessity to perform individual subject tractography.
In contrast, FBA is method of choice when there is not pathway-specific hypothesis and one wants to test whole-brain fixel-wise.
Typically yes; but “FBA” shouldn’t necessarily be equated with “whole-brain”, and indeed
fixelcfestats now has a -mask option to specifically not do whole-brain analysis. What I was trying to comment on here was not so much the difference of targeted hypothesis v.s. whole-brain analysis, but more the underlying quantities being tested: intra-cellular volumes within fixels v.s. intra-cellular cross-sectional areas ascribed to streamlines connecting grey matter targets. They are very strongly related, but that relationship is achieved through the use of individual subject tractography, which comes with its own set of limitations.
Do you think that one could gain a better sensitivity using FBA (with restriction of the fixel mask to the pathway of interest) when assessing a less identifiable pathway by avoiding the individual subject-wise noisy tracking?
It’s possible. It would certainly be an interesting experiment to see through. However my point was that the hypothesis is not quite equivalent: The test would be of the fibre density values within fixels in which the pathway is thought to reside (and hence other fibres within the same fixels contribute to the result), versus quantifying the strength of the connection itself (which incurs the limitations of quantifying both the pathway via tracking and the strength via SIFT2).