Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury

Heather C. Bouchard, Delin Sun, Emily L. Dennis, Mary R. Newsome, Seth G. Disner, Jeremy Elman, Annelise Silva, Carmen Velez, Andrei Irimia, Nicholas D. Davenport, Scott R. Sponheim, Carol E. Franz, William S. Kremen, Michael J. Coleman, M. Wright Williams, Elbert Geuze, Inga K. Koerte, Martha E. Shenton, Maheen M. Adamson, Raul CoimbraGerald Grant, Lori Shutter, Mark S. George, Ross D. Zafonte, Thomas W. McAllister, Murray B. Stein, Paul M. Thompson, Elisabeth A. Wilde, David F. Tate, Aristeidis Sotiras, Rajendra A. Morey

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Original languageEnglish (US)
Pages (from-to)2653-2667
Number of pages15
JournalHuman Brain Mapping
Issue number8
StatePublished - Jun 1 2022

Bibliographical note

Funding Information:
The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Navy, or Air Force, Department of Defense, or U.S. Government. This study was supported in part by the National Institutes of Health (R01NS086885 to R.A.M., R01AG067103 to A.S., U54 EB020403 to P.M.T., R01NS100973 to A.I.), the Department of Veterans Affairs (I01CX002293 to R.A.M., I21RX001608 to M.R.N., IK2RX002922‐01A1 to S.G.D., I01RX002174 to E.A.W., I01CX001820 to R.S.S.), the Department of Defense (W81XWH08‐2‐0159 to M.B.S., W81XWH‐18‐1‐0413 to A.I.), U.S. Army Medical Research and Materiel Command (W81XWH‐13‐2‐0025 to D.F.T.), the Chronic Effects of Neurotrauma Consortium (PT108802‐SC104835 to D.F.T.), Hanson‐Thorell Research Scholarship from the University of Southern California to A.I., Defense and Veterans Brain Injury Centers to D.F.T., and the Dutch Ministry of Defence to E.G.

Publisher Copyright:
© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.


  • diffusion MRI
  • mTBI
  • military
  • nonnegative matrix factorization
  • traumatic brain injury

PubMed: MeSH publication types

  • Journal Article
  • Meta-Analysis
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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