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Longitudinal White-Matter Abnormalities in Sports-Related Concussion: A Study of Diffusion Magnetic Resonance Imaging from the NCAA-DoD CARE Consortium
Yu-Chien Wu1, Sourajit M Mustafi1, Jaroslaw Harezlak2, Nahla M Elsaid1, Zikai Lin3, Larry M Riggen4, Kevin Koch5, Andrew Nencka5, Timothy Meier5, Yang Wang5, Christopher Giza6, John DiFiori6, Kevin Guskiewicz7, Jason Mihalik7, Stephen LaConte8, Stefan Duma8, Steven Broglio9, Michael McCrea5, Andrew Saykin1, and Thomas McAllister3

1Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States, 2Indiana University School of Public Health, Bloomington, IN, United States, 3Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States, 4Biostatistics, Indiana University School of Medicine, Indianapoilis, IN, United States, 5Medical College of Wisconsin, Milwaukee, WI, United States, 6University of California Los Angeles, Los Angeles, CA, United States, 7University of North Carolina, Chapel Hill, NC, United States, 8Virginia Tech University, Roanoke, VA, United States, 9University of Michigan, Ann Arbor, MI, United States

Synopsis

In this study, we investigated the longitudinal recovery trajectories of white-matter microstructures in collegiate athletes who sustained sports-related concussion (SRC). We use diffusion tensor imaging (DTI) to detect white-matter alterations in collegiate athletes longitudinally at four timepoints: 24-48 hours postinjury, the point at which asymptomatic (cleared for return-to-play), seven days following return-to-play, and six months postinjury. We are interested in the extent of white-matter abnormalities over time and whether the white-matter changes persist beyond the point when athletes are considered clinical recovered (i.e., with normal clinical assessments).

Purpose

Sport-related concussion (SRC) is an important public health issue. While standardized assessment tools are useful in the clinical management of SRC,1 the underlying pathophysiology of SRC and the time course of pathophysiological recovery after injury remain unclear.2,3 We have previously shown that diffusion tensor imaging (DTI) is sensitive to acute changes in brain microstructures 24 to 48 hours post-SRC.4 In this study, we investigated the longitudinal recovery trajectories of white-matter microstructures in collegiate athletes who sustained SRC. Particularly, we are interested in the extent of white-matter abnormalities over time and whether the white-matter changes persist beyond the point when athletes are considered clinical recovered.

Methods

Participants: As part of the Concussion Assessment, Research and Education (CARE) consortium study on SRC, 68 collegiate athletes diagnosed with concussion, 64 matched contact-sport controls, and 63 matched non-contact-sport controls underwent clinical assessments and advanced MRI scans (Table 1). Clinical assessments followed the protocol of the CARE Consortium study and included a comprehensive SRC-specific battery of clinical outcome measures.5 The tests were performed on concussed athletes at four timepoints: 24-48 hours postinjury, the point at which asymptomatic (cleared for return-to-play), seven days following return-to-play, and six months postinjury. The two matched control groups, with matched sports type, number of prior concussions, and intellectual score (WTAR), received the same clinical assessments at similar timelines. All the participants underwent advanced MRI scans6 on the same day as clinical assessments. DTI scans and parameters: DTI scans were performed in Siemens TimTrio and Prisma scanners across three sites with an SS-SE-EPI sequence. The diffusion encoding scheme consisted 30 directions at b-value= 1000s/mm2 and 4 b0 volumes (b-value= 0s/mm2). One of the b0 volumes was acquired with a reversed phase-encoding direction. Other parameters included TE/TR= 98/7900ms, FOV= 243mm, matrix size= 90x90, whole brain coverage of 60 slices with a slice thickness of 2.7mm, and isotropic voxel at 2.7mm. Image processing: The diffusion-weighted images were de-noised using local PCA denoiser7 followed by motion, eddy, and fieldmap corrections using FSL EDDY_OPENMP8. DTI metrics computed by FSL DITFIT were non-linearly transformed to standard MNI space using ANTs registration9. Data Analysis: A common whole-brain while-matter skeleton map was extracted using FSL Tract-based spatial statistics (TBSS)10. TBSS was also used for voxelwise statistical analysis within the white-matter skeleton testing for group differences in diffusion metrics at each timepoint. Post-hoc ROI studies of TBSS significant voxels were used to demonstrate the longitudinal recovery of SRC, within-group correlation between DTI metrics with clinical assessment scores, and group-time interactions. Generalized-least-square models (GLS) adjusted for age, sites, and scanners was used for TBSS and ROI studies.

Results

Table 1 summarizes demographics and clinical assessment scores at the acute timepoint. As expected, the concussed athletes differed significantly from the control groups at the acute timepoint for all the clinical assessments (Table 1 and Figure 1). Also, as expected, the acute changes in clinical outcomes recovered and there were no significant group differences at timepoint 2 (i.e., asymptomatic) and beyond, except for psychiatric distress measured by Brief Symptom Inventory (BSI) and its subcategories. DTI metrics in the brain white matter, however, demonstrated persistent group differences beyond the acute timepoint till 6 months postinjury. Particularly, radial diffusivity (RD) was significantly higher in the concussed athletes compared to the controls at the acute timepoint, and mean diffusivity (MD) was higher for all four timepoints (Figure 2(A)). The extent of white-matter abnormalities decreased over time as fewer voxels were detected significant in TBSS (Figure 2(B)). No differences in diffusion metrics were observed between the two control groups (contact- vs. non-contact-sport controls). White-matter areas with persistent group differences in DTI metrics (Figure 3(A)) were generated by intersecting all the TBSS significant voxels in Figure 2(A). The post-hoc ROI study of 512 persistent white-matte voxels demonstrated longitudinal recovery trajectories. MD and RD decreased significantly from the acute timepoint to a stable level, albeit still higher than controls, that lasted till 6 months postinjury (Figure 3(B,C)). In the persistently affected white matter, MD and RD increased with higher psychiatric distress level (BSI and BSI-soma) and symptom severity (Figure 4) at the acute timepoint.

Discussion and conclusion

Consistent with previous small-scale studies,3,11-14 we found that changes in white-matter measured by DTI were detectable even when clinical assessments returned to normal levels. We further demonstrated that these significant changes, albeit decreasing in volume and intensity, persisted at 6 months postinjury, suggesting lasting effects of SRC. The group differences were mainly detected from concussion effects (concussed athletes vs. contact-sport controls), whereas there were no detectable differences from exposure effects (i.e., between the two control groups).

Acknowledgements

This publication was made possible, in part, with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the National Collegiate Athletic Association (NCAA) and the Department of Defense (DOD). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under Award NO W81XWH-14-2-0151. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense (DHP funds.) Other funding supports include National Institutes of Health grant R21 NS075791 to YCW and TWM, R01 AG053993 to YCW, P30 AG010133 and R01 AG019771 to AJS, and a Project Development Team within the ICTSI NIH/NCRR Grant Number UL1TR001108 to YCW.

The authors would also like to thank Jody Harland, Janetta Matesan (Indiana University); Ashley Rettmann (University of Michigan); Melissa Koschnitzke (Medical College of Wisconsin); Michael Jarrett, Vibeke Brinck and Bianca Byrne (Quesgen); Thomas Dompier, Melissa Niceley Baker, and Sara Dalton (Datalys Center for Sports Injury Research and Prevention); and the research and medical staff at each of the participating sites.

References

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Figures

Table 1. Sample sizes, demographics, and clinical assessment scores at the acute timepoint (24-48 post injury). The 68 concussed athletes were from football (n=43), lacrosse (n=5), and soccer players (n=20). Clinical assessment measures included the Sports Concussion Assessment Tool (SCAT)2 to assess symptom severity, Brief Symptom Inventory (BSI)15 to assess psychological distress, the Standardized Assessment of Concussion (SAC)16 to assess cognition, and the Balance Error Scoring System (BESS)17 to assess postural stability. The BSI instrument can be further divided into three subcategories: BSI-soma for physical symptoms, BSI-anxiety, and BSI-depression to evaluate mood disorders.

Figure 1. Longitudinal changes in clinical assessments. At the acute timepoint (timepoint 1), there were significant differences in all the clinical assessments between concussed athletes and controls, but not between the two control groups as expected (also Table 1). These abnormal clinical assessment scores returned to normal ranges, and the concussed group was not different from the two control groups at the asymptomatic timepoint (timepoint 2) and beyond. Except, Brief Symptom Inventory total score (BSI) and its subcategories (i.e., BSI-soma for somatization and BSI-anxiety for mood distress) had significant group differences at timepoint 2, though the score numbers are all within normal ranges.

Figure 2. TBSS results of group differences in DTI. (A). Significant maps of between-group differences in MD using tract-based spatial statistics (TBSS). Green voxels denote the white-matter skeleton where the statistical test was performed. The yellow color denotes voxels having significant group differences in MD at P < 0.05 adjusted for multiple comparisons using the family-wise error rate (FWER). The dark red is background enhancement for illustration purposes. Results were shown for four timepoints: Acute; Asym denotes asymptomatic; 7 RTP denotes seven days following return-to-play (RTP); and 6 months postinjury. (b) Significant-voxel counts across timepoints and DTI metrics.

Figure 3. Longitudinal recovery trajectories of persistently affected white matter. (A). There were 512 voxels of persistently affected white matter (yellow) generated by intersecting significant maps in Figure 2(A). (B). Changes of MD for the concussed athletes (black), contact-sport controls (red), and non-contact-sport controls (green) across four timepoints. (C)-(E). Longitudinal changes in RD, AD, and FA, respectively. The asterisk (*) denotes significant differences between timepoints using a generalized-least-square model (GLS) with time-group interactions. Only MD and RD demonstrated significant differences between the acute and asymptomatic timepoints at P-value < 0.05 adjusted for multiple comparisons across timepoints using the Tukey method.

Figure 4. Correlations between the clinical assessment scores and the DTI metrics in persistently affected white matter. Only MD ((A)-(C)) and RD ((D)-(F)) demonstrated significant correlations (P-value < 0.05 and R > 0.70) with the Brief Symptom Inventory total score (BSI) for overall psychological distress (A,D), BSI somatization for physical distress (B,E), and the symptom severity score in Sports Concussion Assessment Tool (SCAT) (C,F). Black dots denote the individual concussed athletes. P denotes P-values and R denotes correlation coefficient.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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