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In this article, SIENA-XL, a new segmentation-based longitudinal pipeline is introduced, for: (i) increasing the precision of longitudinal volume change estimation for white (WM) and gray (GM) matter separately, compared with cross-sectional segmentation methods such as SIENAX; and (ii) avoiding potential biases in registration-based methods when Jacobians are used, with a smoothing extent larger than spatial scale between tissue-interfaces, which is where atrophy usually occurs. SIENA-XL implements a new brain extraction procedure and a multi-time-point intensity equalization step before performing the final segmentation that also includes separate segmentation of deep GM structures by using FMRIB's Integrated Registration and Segmentation Tool. The detection of GM and WM volume changes with SIENA-XL was evaluated using different healthy control (HC) and multiple sclerosis (MS) MRI datasets and compared with the traditional SIENAX and two Jacobian-based approaches, SPM12 and SIENAX-JI (a version of SIENAX including Jacobian integration - JI). In scan-rescan data from HCs, SIENA-XL showed: (i) a significant decrease in error, of 50-70% when compared with SIENAX; (ii) no significant differences in error when compared with SIENAX-JI and SPM12 in a scan-rescan HC dataset that included repositioning. When tested in a HC dataset with scan-rescan both at baseline and after 1 year of follow-up, SIENA-XL showed: (i) significantly higher precision (P < 0.01) than SIENAX; (ii) no significant differences to SIENAX-JI and SPM12. Finally, in a dataset of 79 MS patients with a 2 years follow-up, SIENA-XL showed a substantial reduction of sample size, by comparison with SIENAX, SIENAX-JI, and SPM12, for detecting treatment effects of 25, 30, and 50%. Hum Brain Mapp 39:1063-1077, 2018. © 2017 Wiley Periodicals, Inc.

Original publication




Journal article


Hum Brain Mapp

Publication Date





1063 - 1077


SIENA, SIENA-XL, brain atrophy, gray matter atrophy, white matter atrophy, Adult, Brain, Follow-Up Studies, Gray Matter, Humans, Image Processing, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Multiple Sclerosis, Organ Size, White Matter