Acute White-Matter Abnormalities in Sports-Related Concussion: A Diffusion Tensor Imaging Study from the NCAA-DoD CARE Consortium

Abstract

Sports-related concussion (SRC) is an important public health issue. Although standardized assessment tools are useful in the clinical management of acute concussion, the underlying pathophysiology of SRC and the time course of physiological recovery after injury remain unclear. In this study, we used diffusion tensor imaging (DTI) to detect white matter alterations in football players within 48 h after SRC. As part of the NCAA-DoD CARE Consortium study of SRC, 30 American football players diagnosed with acute concussion and 28 matched controls received clinical assessments and underwent advanced magnetic resonance imaging scans. To avoid selection bias and partial volume effects, whole-brain skeletonized white matter was examined by tract-based spatial statistics to investigate between-group differences in DTI metrics and their associations with clinical outcome measures. Mean diffusivity was significantly higher in brain white matter of concussed athletes, particularly in frontal and subfrontal long white matter tracts. In the concussed group, axial diffusivity was significantly correlated with the Brief Symptom Inventory and there was a similar trend with the symptom severity score of the Sport Concussion Assessment Tool. In addition, concussed athletes with higher fractional anisotropy performed better on the cognitive component of the Standardized Assessment of Concussion. Overall, the results of this study are consistent with the hypothesis that SRC is associated with changes in white matter tracts shortly after injury, and these differences are correlated clinically with acute symptoms and functional impairments.

Keywords: CARE; acute; diffusion tensor imaging; sports-related concussion; tract-based spatial statistics; white matters.

FIG. 1.

Averaged maps of the DTI metrics for the 58 subjects in MNI standard space. The DTI metrics include fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). The gray scale is 0–3*10⁻⁶ mm²/s for diffusivities and is 0–1 for FA. DTI, diffusion tensor imaging; MNI, Montreal Neurological Institute.

FIG. 2.

Results of between-group differences in MD. (A) Significant maps of tract-based spatial statistics (TBSS) using a general linear model. Green voxels denote the white-matter skeleton where the statistical test was performed. Yellow color denotes voxels having significant differences in MD between the concussed and contact-sport athlete control group at p < 0.05 adjusted for multiple comparisons using family-wise error rate (FWER). Dark red is background enhancement for illustration purposes. Three separated significant clusters can be appreciated on the maps. (B) Bar plots of the post-hoc ROI analyses on the means of MD in the three clusters. Black dots denote the mean MD for each subject. Consistently across the three clusters, the concussed group demonstrated significantly higher MD. (C) The table lists the size, minimum p value (as in P_min), and anatomical distribution of the three clusters. The anatomical labeling was performed by superimposing the clusters with the skeletonized JHU white-matter atlas in Supplementary Figure S3A (see online supplementary material at http://www.liebertpub.com). MD, mean diffusivity; JHU, Johns Hopkins University; ROI, region of interest.

FIG. 3.

Significant correlation maps of the TBSS analysis on AD and BSI of the concussed athletes. Green voxels denote the white-matter skeleton where the statistical test was performed. Yellow color denotes voxels having significant positive correlations between AD and the BSI total score at p < 0.05 adjusted for multiple comparisons using family-wise error rate (FWER). Dark red is background enhancement for illustration purposes. Maps are defined in MNI standard space and the X, Y, and Z are the MNI space coordinates. The anatomical interpretation of the significant white-matter voxels is summarized in Figure 7A, top row. AD = axial diffusivity; BSI = Brief Symptom Inventory; MNI, Montreal Neurological Institute; TBSS, tract-based spatial statistics.

FIG. 4.

Significant correlation maps of the TBSS analysis on MD and BSI of the concussed athletes. Green voxels denote the white-matter skeleton where the statistical test was performed. Yellow color denotes voxels having significant positive correlations between MD and the BSI total score at p < 0.05 adjusted for multiple comparisons using family-wise error rate (FWER). Dark red is background enhancement for illustration purposes. Maps are defined in MNI standard space and the X, Y, and Z are the MNI space coordinates. The anatomical interpretation of the significant white-matter voxels is summarized in Figure 7A, middle row. BSI = Brief Symptom Inventory; MD, mean diffusivity; MNI, Montreal Neurological Institute; TBSS, tract-based spatial statistics.

FIG. 5.

Significant correlation maps of the TBSS analysis on FA and SAC of the concussed athletes. Green voxels denote the white-matter skeleton where the statistical test was performed. Yellow color denotes voxels having significant positive correlations between FA and the SAC total score at p < 0.05 adjusted for multiple comparisons using family-wise error rate (FWER). Dark red is background enhancement for illustration purposes. Maps are defined in MNI standard space and the X, Y, and Z are the MNI space coordinates. The anatomical interpretation of the significant white-matter voxels is summarized in Figure 7A, bottom row. FA, fractional anisotropy; MNI, Montreal Neurological Institute; SAC, Standard Assessment of Concussion; TBSS, tract-based spatial statistics.

FIG. 6.

Results of post-hoc regression analyses between DTI metrics and clinical outcome measures for concussed athletes. Each black dot denotes one individual's clinical assessment scores and means of DTI measurements over the significant voxels in the TBSS analysis (see Figs. 3–5). ρ denotes correlation coefficient. (A) Brief Symptom Inventory (BSI) total score versus axial diffusivity (AD). BSI total score was logarithmically transformed to eliminate left skewness in the original distribution. (B) BSI total score versus mean diffusivity (MD). (C) Standardized Assessment of Concussion (SAC) versus fractional anisotropy (FA). (D) BSI-Soma (somatization) versus AD. Similarly, BSI-soma score was logarithmically transformed to eliminate left skewness in the original distribution. (E) BSI-Soma versus MD. AU, arbitrary units; DTI, diffusion tensor imaging; MNI, Montreal Neurological Institute.

FIG. 7.

Occupancy matrices summarizing anatomical distributions of the significant correlations between the DTI metrics and clinical outcomes within the concussed group. The vertical axis denotes the DTI-outcome pairs that had significant results in the TBSS analyses. The horizontal axis denotes the JHU white-matter labels with the length of the interval reflecting its three-dimensional size (in cubic root) in the atlas. Warm colors denote the percentage (%) of voxels in the labeled white-mater tract having significant positive correlations. (A) The occupancy matrix for AD-BSI, MD-BSI, and FA-SAC pairs. AD denotes axial diffusivity, MD denotes mean diffusivity, FA denotes fractional anisotropy, BSI denotes Brief Symptom Inventory (total score), and SAC denotes Standardized Assessment of Concussion. The acronyms of the white-matter labels are listed in Table 3 or Supplementary Figure S3 (see online supplementary material at http://www.liebertpub.com). (B) The occupancy matrix for AD versus BSI-soma and MD versus BSI-soma. BSI-soma is one of the three subcategories of the BSI test and assesses the somatic symptoms (i.e., somatization) after concussion. DTI, diffusion tensor imaging; TBSS, tract-based spatial statistics.