Edited by: Liying Zhang, Wayne State University, USA
Reviewed by: Vassilis E. Koliatsos, Johns Hopkins University School of Medicine, USA; Steven Robicsek, University of Florida, USA
Specialty section: This article was submitted to Neurotrauma, a section of the journal Frontiers in Neurology
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Traumatic brain injury (TBI) is among the most common neurological disorders. Hemorrhagic lesions and white matter hyperintensities (WMH) are radiological features associated with moderate and severe TBI. Brain volume reductions have also been observed during the months following injury. In concussion, no signs of injury are observed on conventional magnetic resonance imaging (MRI), which may be a true feature of concussion or merely due to the limited sensitivity of imaging techniques used so far. Moreover, it is not known whether volume reductions are due to the resolution of trauma-related edema or a true volume loss. Forty-five collegiate-level ice hockey players (20 females) and 15 controls (9 females), 40 players underwent 3-T MRI for hemorrhages [multi-echo susceptibility-weighted imaging (SWI)], WMH (three-dimensional fluid-attenuated inversion recovery), and brain volume at the beginning and the end of the hockey season. Concussed athletes underwent additional imaging and neuropsychological testing at 3 days, 2 weeks, and 2 months after injury. At the end of the hockey season, brain volume was reduced compared to controls by 0.32% (
Traumatic brain injury (TBI) is one of the most common neurological disorders, with incidence rates >650/100,000/year (
Twenty female and 25 male players (mean age = 21.2 ± 3.1 years) from two Canadian Interuniversity Sports ice hockey teams participated in this study. Players received baseline MRI and Sport Concussion Assessment Tool 2 (SCAT2) tests in September before the beginning of the ice hockey season (
Concussed players were referred to MRI and neuropsychological testing at 72 h, 2 weeks, and 2 months after concussion. Athletes were imaged after the end of the hockey season in March. Four non-concussed players completed only one time point and were excluded. Fifteen subjects (six males, nine females, age = 22.9 ± 2.3 years) from the same university were enrolled as controls for WMH and microhemorrhages and were scanned once. Inclusion criteria for controls were university students with matching age, not engaged in contact sports, and without a history of concussion or neurological condition. Five additional subjects who did not engage in contact sports were scanned four times over 6 months as healthy controls for the volume measurements. In addition, a phantom designed for quality control of the volumetric measurements in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study was scanned once a month (
Magnetic resonance imaging data were acquired on a Philips Achieva 3T scanner equipped with an eight-channel SENSE head coil, including the following scans: (a) sagittal three-dimensional T1-weighted scan (TR = 8.1 ms, TE = 3.7 ms, flip angle = 6°, acquisition matrix = 256 × 256 × 160, field of view = 256 mm × 256 mm × 160 mm, voxel size = 1 mm × 1 mm × 1 mm, and SENSE factor of 2 along the left–right direction); (b) sagittal three-dimensional FLAIR (TR = 8000 ms, TI = 2400 ms, TE = 337 ms, flip angle = 6°, acquisition matrix = 256 × 256 × 160, field of view = 256 mm × 256 mm × 160 mm, voxel size = 1 mm × 1 mm × 1 mm, and SENSE factor of 2 along the left–right direction and 2.5 along the anterior–posterior direction); and (c) multi-echo SWI using an axial 3D gradient echo scan (TR = 36 ms, TE = 6/12/18/24/30 ms, flip angle = 17°, acquisition matrix = 440 × 222 × 64, field of view = 220 mm × 166 mm × 128 mm, acquired voxel size = 0.5 mm × 0.5 mm × 2 mm, reconstructed voxel size = 0.5 mm × 0.5 mm × 1 mm, and SENSE factor of 1.2 along the left–right direction) (
Susceptibility-weighted imaging data were reconstructed offline, and the SWI of the individual echoes were averaged with weights to optimize contrast between hemorrhages and surrounding tissue, assuming R2* relaxation rates of 20 ms−1 for white matter and 60 ms−1 for hemorrhage, which leads to weighting coefficients of 0.12, 0.19, 0.22, 0.24, and 0.24 (
Two time point global brain volume changes were estimated based on the three-dimensional T1-weighted scans, using FSL’s SIENA (
Statistical tests on the full season data were performed using MATLAB (2011a, The MathWorks, Inc., Natick, MA, USA). Volume changes compared to baseline were evaluated for the following groups: (1) concussed players for all post-concussion time points, (2) all concussed players postseason, (3) all non-concussed players postseason, (4) all subjects postseason with two or more WMH (observed at baseline), and (5) all subjects postseason with a maximum of one WMH at baseline. Comparison of subject and control WMH count at baseline were performed using the Wilcoxon rank-sum test. Repeated measures of the brain volume change for concussed subjects were analyzed using a mixed effect model in R (R Foundation for Statistical Computing, Vienna, Austria) (
Over the season, 11 players were diagnosed with a concussion. Their age, gender, and number of brain lesions scores are listed in Table
Player | Age | Gender | # of lesions at BL | # of lesions at 72 h | # of lesions at 2 weeks | # of lesions at 2 months | # of lesions at EOS |
---|---|---|---|---|---|---|---|
1 | 22 | m | 2 | 1 | 2 | 0 | 0 |
2 | 21 | m | 0 | 0 | 0 | 0 | 1 |
3 | 21 | f | 1 | 1 | 1 | 2 | 2 |
4 | 19 | f | 0 | X | 0 | 0 | X |
5 | 22 | f | 1 | 1 | 1 | 1 | 0 |
6 | 21 | f | 0 | 0 | 0 | 0 | 0 |
7 | 22 | m | 1 | 1 | 1 | 0 | 0 |
8 | 24 | m | 6 (+1 bleed) | X | 6 (+1 bleed) | X | X |
9 | 19 | f | 4 | X | 4 | 4 | 4 |
10 | 19 | f | 0 | 0 | 0 | 0 | 0 |
11 | 23 | m | 5 | 6 | 6 | X | X |
Subject | Concussed (Y/N) | Sex | Age | Preseason MWHI | Postseason MWHI |
---|---|---|---|---|---|
1 | Y | M | 22 | 2 | 0 |
2 | Y | M | 21 | 0 | 1 |
3 | Y | F | 21 | 1 | 2 |
4 | Y | F | 19 | 0 | X |
5 | Y | F | 22 | 1 | 0 |
6 | Y | F | 21 | 0 | 0 |
7 | Y | M | 22 | 1 | 0 |
8 | Y | M | 24 | 7 | X |
9 | Y | F | 19 | 4 | 4 |
10 | Y | F | 19 | 0 | 0 |
11 | Y | M | 23 | 5 | X |
12 | N | F | 23 | 3 | 3 |
13 | N | M | 21 | 0 | 0 |
14 | N | F | 18 | 5 | 5 |
15 | N | F | 20 | 10 | 11 |
16 | N | F | 18 | 0 | 0 |
17 | N | F | 18 | 5 | 3 |
18 | N | M | 21 | 3 | 3 |
19 | N | M | 24 | 2 | 3 |
20 | N | F | 21 | 1 | 1 |
21 | N | M | 22 | 2 | 5 |
22 | N | M | 25 | 2 | 2 |
23 | N | M | 22 | 8 | 9 |
24 | N | M | 21 | 1 | 1 |
25 | N | F | 19 | 0 | 1 |
26 | N | F | 18 | 1 | 1 |
27 | N | M | 22 | 32 | 29 |
28 | N | M | 20 | 14 | 13 |
29 | N | M | 21 | 0 | 0 |
30 | N | M | 21 | 3 | 4 |
31 | N | F | 20 | 2 | 2 |
32 | N | M | 22 | 6 | 5 |
33 | N | F | 18 | 3 | 0 |
34 | N | M | 23 | 1 | 1 |
35 | N | F | 17 | 0 | 0 |
36 | N | M | 20 | 1 | 1 |
37 | N | F | 19 | 3 | 2 |
38 | N | F | 17 | 0 | 1 |
39 | N | M | 21 | 2 | 2 |
40 | N | M | 23 | 6 | 6 |
41 | N | F | 36 | 6 | 7 |
An example of punctuate WMH in non-concussed ice hockey player is shown in Figure
In the control subjects, PBVC changes between baseline and subsequent time points were positive but not significant [+0.07% (
Based on the mixed effect model, the only factor found significantly related to PBVC of concussed subjects was time after injury (
The main findings of this prospective neuroimaging study on mild TBI were (1) that no volume changes were observed at 3 days and 2 weeks post injury, but both concussed and non-concussed athletes exhibited reduction in brain volume over the course of one season; (2) that neither concussion nor playing a season of ice hockey led to detectable microbleeds; and (3) that in athletes, WMH were more numerous and significantly closer to the GM–WM interface compared to controls.
The volume changes in both the concussed and non-concussed players were small (corresponding to 3 cm3 if a typical brain volume is assumed), yet significant. This reduction is in line with previous studies in mild TBI, where reductions in volume by about 7.6 cm3 within 1 year were measured (
Microhemorrhages have not been reported in concussion; this may be a feature of concussion or simply a result of the limited sensitivity of imaging methods used in concussion so far. The new multi-echo SWI technique used for this study has 40% better signal-to-noise ratio compared to its single echo counterpart (
However, the lack of hemorrhagic injury in this cohort does not mean that contact sports, such as ice hockey, are harmless. Neither microhemorrhages nor WMH are unequivocal signs of recent brain injury. Microbleeds and WMH are associated with various conditions, including TBI, and they may persist for several years (
It was suggested that chronic changes in the brains of some athletes may be a result from multiple hits. A recent postmortem study on the brains of 85 people with histories of repetitive mild TBI, for instance, found that in the subgroup of 35 professional American football players, pathological signs of chronic traumatic encephalopathy (CTE) were present in 34 players (
This study had some limitations. The variability in the counts of WMH seen pre- and postseason, as well as post-concussion may have limited the ability to detect change over time and following injury. Partial volume averaging was minimized by the 3D acquisition with 1 mm isotropic resolution and two radiologists worked by consensus in order to minimize inter- and intra-rater variability. The variability in WMH counts highlights the subjective nature and the difficulty in identifying small punctuate lesions, particularly when the observers were blinded to the chronology of the scans. The high sensitivity of the multi-echo SWI and the 3D FLAIR comes at the expense of limited comparability with studies that use standard clinical MRI protocols, although SWI and 3D FLAIR are now commonly available sequences. The sample size of concussed athletes is relatively small, which precludes an in-depth analysis of the relationship between neuropsychological scores and the number and location of WMH or any differences between male and female players. This also may have been a factor in the lack of change in SCAT2 scores. In contrast, these significant changes seen in a small cohort encourage future prospective studies on mild TBI in high-risk groups. The prospective nature of the study limited the sample size but allowed us to directly compare players before and after playing a season of hockey and before and after injury, greatly reducing the influence of intersubject variability encountered in cross-sectional studies. Finally, not all subjects had all MRI scans or all neuropsychological tests. However, the statistical power is similar at all time points with eight out of 11 concussed subjects scanned at 72 h, all 11 scanned at 2 weeks, and nine out of 11 scanned at 2 months. The time points after concussion were chosen to sample the acute phase after concussion, the phase after which people are normally regarded as recovered (2 weeks), and a follow-up several weeks after full recovery. The 72-h time point was the earliest feasible time point to perform post-injury MRI. In particular, in the early phase after injury, a different choice of time points may have an influence on the results. Our choice of time points after concussion is not unusual, however (
The present study demonstrates that concussions do not cause acute increases in brain volume and that even with advanced MRI at high field strength, no microhemorrhages are detected. The findings also suggest that playing ice hockey may lead to observable volume changes in the athletes’ brains, irrespective of their concussion status, indicating that better monitoring of players and more protective measures may be warranted. However, in this study, the degree of change was small and factors other than repetitive impact from playing ice hockey cannot be ruled out. Future prospective studies should address whether these changes accumulate over consecutive seasons of contact sports and whether they are reversible once athletes stop playing competitively.
AR, JT, and DL designed the study. AR and DL designed the imaging protocol. SD coordinated the study and performed neuropsychological testing. MJ and YZ performed statistical analysis. RT designed the lesion marking workflow, software, and performed quality control and visual inspection of all marked lesions. MJ, EH-T, RT, and ES performed image reconstruction and preprocessing. NM and WP marked lesions. AR and DL supervised imaging and image analysis. AR and MJ conducted literature research. MJ and AR wrote the first draft. All authors contributed to the writing of the paper. All authors read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are very grateful to the ice hockey teams, athletes, and volunteers who participated in this study. We acknowledge the continued research support at the UBC MRI Research Centre by Philips Healthcare. We wish to thank Alexander Wright and Vanessa Wiggermann for helpful discussions. We would like to thank Linda Chandler for her support.
Funding was provided by the London Drugs Award for Research Excellence. AR is supported by a Canadian Institutes for Health Research New Investigator Award. EH-T is supported by a grant from CONACYT.