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. 2023 Aug 21;12(16):5415.
doi: 10.3390/jcm12165415.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary

Lara Pankatz  1   2 , Philine Rojczyk  1   2 , Johanna Seitz-Holland  1   3 , Sylvain Bouix  1   4 , Leonard B Jung  1   2 , Tim L T Wiegand  1   2 , Elena M Bonke  1   2   5 , Nico Sollmann  1   2   6   7   8 , Elisabeth Kaufmann  1   2   9 , Holly Carrington  1   10 , Twishi Puri  1 , Yogesh Rathi  1 , Michael J Coleman  1 , Ofer Pasternak  1   11 , Mark S George  12   13 , Thomas W McAllister  14 , Ross Zafonte  15   16 , Murray B Stein  17   18   19 , Christine E Marx  20   21 , Martha E Shenton  1   11 , Inga K Koerte  1   2   3   5
Affiliations

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary

Lara Pankatz et al. J Clin Med. .

Abstract

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Keywords: cognitive impairment; diffusion tensor imaging; fractional anisotropy; magnetic resonance imaging; mild traumatic brain injury; post-concussion symptoms.

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Conflict of interest statement

E. Kaufmann received speaker honoraria and financial compensation for travel expenses from Medtronic, UCB, Livanova, and Eisai and has participated in clinical trials for Medtronic, UCB and Precisis, all unrelated to the submitted work. Her research is supported by the Medical Clinical Scientist Program (MCSP). M. B. Stein has received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Eisai, Clexio, EmpowerPharm, Engrail Therapeutics, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. M. B. Stein holds stock options in Oxeia Biopharmaceuticals and EpiVario. He is compensated for his work as Editor-in-Chief of Depression and Anxiety, Deputy Editor of Biological Psychiatry, and Co-Editor-in-Chief for Psychiatry of UpToDate. I. K. Koerte is a professor at Ludwig-Maximilians-Universität Munich (paid position). She serves as European Editor at the Journal of Neurotrauma (unpaid position) and as Vice President of the European Neurotrauma Organization (unpaid position). She receives research grant funding from the National Institutes of Health, the European Research Council, and the German Ministry for Research and Education. She receives funding for a research study on sport-related concussions from Abbott Inc. The Ludwig-Maximilians-University Hospital received donations for her research from the Schatt Foundation and from Mary Ann Liebert Inc. She receives royalties for book chapters published by Thieme Publishers. Her spouse is an employee at Siemens, and she thus holds stock options at Siemens and Siemens Healthineers. I. K. Koerte’s in-kind contributions: Ph.D. students working under her supervision receive scholarships from the Villigst Foundation, the China Scholarship Council collaboration with Ludwig-Maximilians-University Munich, and Fulbright. The other authors disclose no financial or other biomedical interests or potential conflict of interest.

Figures

Figure 1
Figure 1
Image Processing. Structural MRI sequences were segmented into GM and WM using FreeSurfer 5.3.0, to identify the GM/WM boundary (in blue). Diffusion MRI (dMRI) images were fitted with the free-water (FW) map to create a voxel-wise map of FA corrected for FW. Each participant’s FW-corrected dMRI data were registered onto the respective FreeSurfer segmentation. All images were overlayed with the Destrieux brain atlas to identify and extract FA values along the GM/WM intersection in different regions of the brain. Note. GM, gray matter; WM, white matter; FA, fractional anisotropy Tissue; Images are displayed using Freeview. The FW-corrected FA map is shown in color scheme ‘Heat’ for better visualization.
Figure 2
Figure 2
Group differences between participants with mTBI and participants without mTBI. ANCOVA revealed significantly lower whole-brain GM/WM boundary FA (pFDR = 0.001), and deep WM FA (pFDR = 0.001) in mTBI subjects compared to participants without mTBI. No significant differences were observed between groups in cortical thickness (pFDR = 0.843). The area of the brain where the imaging measure was acquired is displayed beneath for better visualization. Note. mTBI, Mild traumatic brain injury; FA, Fractional Anisotropy; ns = not significant; *** = p < 0.001.
Figure 3
Figure 3
Association between GM/WM boundary diffusion, deep white matter, cortical thickness, and long-term outcomes (symptoms, functional impairment, processing speed, executive functioning), displayed by a heatmap of pFDR-values. Dark red boxes indicate a stronger relationship between imaging and outcome measures, whereas brighter boxes indicate a weak relationship between imaging and outcome measures. Note. FA, Fractional anisotropy.
Figure 4
Figure 4
Associations between GM/WM boundary diffusion, post-concussive symptoms, functional impairments, and cognitive functioning. In all analyses, GM/WM boundary diffusion was negatively correlated with the outcome measure, suggesting an association between lower GM/WM diffusion and poorer long-term outcome. Note. FA, Fractional anisotropy; Post-Concussion Symptoms (RPQ13 Score); Functional Impairment (SDS Score); Processing Speed (TMT-A time in seconds); Executive Functioning (TMT-B time in seconds).
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