Longitudinal white-matter abnormalities in sports-related concussion: A diffusion MRI study

Abstract

Objective: To study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC.

Methods: Collegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non-contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time.

Results: In the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non-contact-sport controls.

Conclusions: Changes in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

Figure 1. Longitudinal changes in clinical assessments

(A) Standard Assessment of Concussion (SAC) scores for the concussed athletes (red), contact-sport controls (green), and non–contact-sport controls (blue) across the 4 time points. Higher SAC scores indicate better performance in the test of cognitive function. (B) Symptom scores in the Sports Concussion Assessment Tool (SCAT) across time points. (C) Symptom severity scores in SCAT. (D) Posture stability scores in the Balance Error Scoring System (BESS). (E) Total psychological distress score in the Brief Symptom Inventory (BSI). (F) BSI subcategory to measure somatization (BSI-soma). (G) BSI subcategory to measure anxiety (BSI-anxiety). (H) BSI subcategory to measure depression (BSI-depression). For SCAT, BESS, and BSI, higher scores indicate worse symptoms. Means and 95% confidence intervals of the means were plotted for the primary clinical measures (subplots A–E). Mean proportions estimated by the generalized linear mixed model and their respective 95% confidence intervals were plotted for the BSI subcategories (subplots F–H) because for more than half of the participants, these measures were close to the floor (i.e., zero) at some of the time points. *Significant differences (p < 0.05) between the concussed athletes and contact-sport controls at the situated time point. †Significant differences (p < 0.05) between the concussed athletes and non–contact-sport controls at the situated time point. There were no significant differences detected between the 2 control groups.

Figure 2. Results of group differences in the DTI metrics between the concussed athletes and contact-sport controls

(A) Maps of white-matter voxels (yellow) in which the concussed athletes had significantly elevated mean diffusivity (MD) compared to the contact-sport controls. Tract-based spatial statistics (TBSS) were used with a general linear model; p < 0.05 adjusted for multiple comparisons with the family-wise error rate was deemed significant. Green voxels denote the white-matter skeleton, where the statistical test was performed. Dark red is background enhancement for illustration purposes. (B) Voxels counts of significant TBSS voxels that had significant group differences (e.g., yellow voxels in A) for DTI metrics, including MD, radial diffusivity (RD), axial diffusivity (AD), and fractional anisotropy (FA). NS = not significant.

Figure 3. Longitudinal changes of the DTI metrics in the persistently affected white matter

(A) Maps of the persistently affected white matter. Yellow voxels were selected by intersecting the significant voxels across time points in figure 2A. Dark red voxels are background enhancement for illustration purposes. (B) Longitudinal changes of mean diffusivity (MD) in the persistent white matter for the concussed athletes (red), contact-sport controls (green), and non–contact-sport controls (blue) across the 4 time points. (C) Longitudinal changes in radial diffusivity (RD). (D) Longitudinal changes in axial diffusivity (AD). (E) Longitudinal changes in fractional anisotropy (FA). Means (circle markers) and 95% confidence intervals (error bars) of the means were plotted. *Significant differences (p < 0.05) in the diffusion tensor imaging (DTI) metrics between the time points within a group.

Figure 4. Regression analyses between the DTI metrics and clinical outcome measures within concussed athletes

Each red dot denotes 1 individual's clinical assessment scores and means of diffusion tensor imaging (DTI) measurements in the persistently affected white matter (figure 3A). The r² denotes the coefficient of determination, and p denotes the significance of the regression coefficients. Only significant associations (p < 0.05) are presented. (A) Brief Symptom Inventory (BSI) total score vs mean diffusivity (MD). BSI total score was logarithmically transformed to eliminate left skewness in the original distribution. (B) Subcategory BSI-somatization vs MD. (C) Symptom severity score in the Sports Concussion Assessment Tool (SCAT) vs MD. (D) BSI total vs radial diffusivity (RD). (E) BSI-somatization vs RD. (F) SCAT symptom severity vs RD.

Figure 5. Dependence of recovery time on MD

(A) Effect of mean diffusivity (MD) on the survival curves for time to asymptomatic state. (B) Effect of MD on Kaplan-Meier curves for time to unrestricted return to play. Line colors denote different levels of MD with a unit of 10⁻⁶ mm²/s. Survival curves to estimate the time to event were modeled with a Cox proportional hazards model with MD as a risk factor.