We derive the Iterative Confidence Enhancement of Tractography (ICE-T) framework to address the problem of path-length dependency (PLD), the streamline dispersivity confound inherent to probabilistic tractography methods. We show that PLD can arise as a non-linear effect, compounded by tissue complexity, and therefore cannot be handled using linear correction methods. ICE-T is an easy-to-implement framework that acts as a wrapper around most probabilistic streamline tractography methods, iteratively growing the tractography seed regions. Tract networks segmented with ICE-T can subsequently be delineated with a global threshold, even from a single-voxel seed. We investigated ICE-T performance using ex vivo pig-brain datasets where true positives were known via in vivo tracers, and applied the derived ICE-T parameters to a human in vivo dataset. We examined the parameter space of ICE-T: the number of streamlines emitted per voxel, and a threshold applied at each iteration. As few as 20 streamlines per seed-voxel, and a robust range of ICE-T thresholds, were shown to sufficiently segment the desired tract network. Outside this range, the tract network either approximated the complete white-matter compartment (too low threshold) or failed to propagate through complex regions (too high threshold). The parameters were shown to be generalizable across seed regions. With ICE-T, the degree of both near-seed flare due to false positives, and of distal false negatives, are decreased when compared with thresholded probabilistic tractography without ICE-T. Since ICE-T only addresses PLD, the degree of remaining false-positives and false-negatives will consequently be mainly attributable to the particular tractography method employed. Given the benefits offered by ICE-T, we would suggest that future studies consider this or a similar approach when using tractography to provide tract segmentations for tract based analysis, or for brain network analysis.
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