Longitudinal quantitative streamline tractography: robust estimation of white matter connectivity differences

Abstract Longitudinal probing of structural connectivity via diffusion magnetic resonance imaging (dMRI) is experiencing uptake. However, the detection of biological effects is significantly hampered by the limitations of cross-sectional streamline tractography, where even small changes in the dMRI signal can produce drastically different trajectories and therefore quantitative parameterisation; if not properly dealt with, such effects will manifest as spurious longitudinal change, which can obscure subtle biological differences. To overcome this challenge, we here introduce a novel quantitative streamline tractography framework tailored for longitudinal analysis, wherein an individual’s streamline trajectories remain fixed throughout the analysis, allowing only their ascribed density weights to vary between sessions. We present two strategies by which these quantitative streamline weights can be determined, both extensions of the widely adopted SIFT2 method. The performance of this framework is benchmarked against cross-sectional reconstruction with and without SIFT2 optimisation, in both in silico dMRI phantoms with known ground truths and three distinct human in vivo cohorts with clear a priori expectations of biological effects. We demonstrate that the proposed framework drastically reduces methodological imprecisions in synthetic dMRI phantoms and enhances statistical sensitivity and specificity to biological effects in human cohorts, enabling robust longitudinal quantification of structural connectivity. Competing Interest Statement The authors have declared no competing interest. Footnotes Author contacts Philip Pruckner: philip.pruckner{at}florey.edu.au, Remika Mito: remika.mito{at}unimelb.edu.au, David Vaughan: david.vaughan{at}florey.edu.au, Kurt Schilling: kurt.g.schilling.1{at}vumc.org, Victoria Morgan: victoria.morgan{at}vumc.org, Dario Englot: dario.englot{at}vumc.org, Robert Smith: robert.smith{at}florey.edu.au Re-upload of the unchanged manuscript PDF to correct formatting issues that appeared after upload to biorxiv, where figures were appended to the end of the document during processing causing scaling issues. Abbreviations - ACT - Anatomically Constrained Tractography - dMRI - diffusion Magnetic Resonance Imaging - FBC - Fibre Bundle Capacity - FDC - Fibre Density and Cross-section - FOD - Fibre Orientation Distribution - FWE - Family-Wise Error - HCP - Human Connectome Project - IQR - Interquartile Range - ODF - Orientation Distribution Function - SIFT - Spherical-deconvolution Informed Filtering of Tractograms - TFNBS - Threshold-Free Network-Based Statistics - TP - imepoint - absolute error in structural connectivity - absolute error in longitudinal structural connectivity difference