Synopsis

This work explored the hypothesis that the activation of N-methyl-D-aspartate (NMDA)-receptors in the thalamus results in persistent calcium deposits after a sports-related concussion that can be visualized clinically with Quantitative Susceptibility Mapping at 3 Tesla. The study involved 22 retired professional contact-sports athletes and 45 controls. We found a significantly higher incidence of thalamic micro-calcifications in contact-sports athletes compared to controls, in particular in ice hockey players.

Introduction

Intracellular calcium influx is a key event in the pathophysiology of concussion¹. Animal experiments have demonstrated a continuing, delayed influx of Ca²⁺ into the thalamus for 48 hours and longer after the injury². Preliminary data using the fluid percussion injury model of traumatic brain injury [submitted to this conference] suggest that the strong diamagnetism of calcium phosphates^3-5 allows in vivo visualizing elevated thalamic calcium concentrations with the novel phase-based technique Quantitative Susceptibility Mapping (QSM)^6-9.

In the present work, we explored the hypothesis that sports-related concussion results in persistent thalamic calcium deposits that can be visualized clinically with QSM at 3 Tesla.

Methods

Subjects: This IRB-approved study included 68 subjects (no females); 22 retired professional contact-sports athletes (15 ice hockey and 7 American football players; 55.5±11.2 years), 20 professional athlete controls (retired non-contact sports athletes: cycling, running, skiing, swimming, triathlete; 57.2±9.8 years), and 25 normal controls (non-professional, never played contact sports, self-reported; 55.1±9.9 years). All three groups were age- and sex-matched.

Data acquisition and image reconstruction: Participants were imaged at 3T (GE Signa Excite HD 12.0) with an eight-channel head-and-neck coil using a 3D gradient-echo (GRE) sequence (matrix 512x192x64, 256x192x128mm³, TE/TR=22ms/40ms, BW=13.9kHz, tip=12°). We reconstructed magnetic susceptibility maps from k-space using scalar-phase-matching^10,11, gradient unwarping¹², best-path unwrapping¹³, V-SHARP^14-16, and HEIDI¹⁷. Also, we reconstructed Susceptibility Weighted Images (SWI) and filtered phase images^18,19.

Analysis: A trained image analyst outlined thalamic calcifications based on the following definition: Focal, hyperintense region in the thalamus on susceptibility maps, associated with a co-localized intensity variation on phase images (to avoid over-interpretation of QSM-related artifacts). For every identified lesion we determined the lesion’s volume and average magnetic susceptibility. If a calcification was identified, the analyst inspected both GRE magnitude and SWI for intensity variations at the location of the lesion. Differences in the incidence of thalamic calcifications between groups were tested using Pearson Chi-Square test. A p-value below 0.05 was considered as statistically significant.

Results

We found thalamic micro-calcifications in 23% (N=5; -48.5±23.5ppb; 22.5±10.6mm³) of contact-sports athletes, 10% of athlete controls (N=2; -50.6±6.9ppb; 18.5±7.0mm³), and none in the normal controls. The incidence of micro-calcification was significantly different between groups (p=0.039). All contact-sports athletes with calcifications were ice hockey players (100%); none of the football players showed calcifications. Athlete controls with lesions were runners/triathletes.

All lesions were found in the medial nuclear group of the thalamus; one athlete control had lesions in the anteroventral and reticular nuclei. All lesions appeared hypointense on both high-pass filtered and SHARP phase images but were substantially better defined on QSM. None of the lesions could be identified on either magnitude images or SWI. Lesions in contact-sports athletes were found bilaterally (2) or only in the left (2) and right (1) thalami, respectively. Lesions in athlete controls were found bilaterally. Figure 1 shows images of an exemplary subject with thalamic calcification.

Discussion

QSM revealed pathology that was not discernible on conventional magnitude-based images, despite the use of a clinical pulse sequence that had not been optimized for QSM. The lack of magnitude lesion contrast indicates a diffuse microscopic distribution of the calcium (potentially intracellular), compared to agglomeration in a solid calcium core. The presence of thalamic calcification years after acute concussions indicates that calcium deposits are persistent over time.

Calcium deposition may be related to the activation of N-methyl-D-aspartate (NMDA)-receptors in the thalamus following concussion¹, which results in abnormally high levels of intracellular Ca²⁺.²⁰ Mitochondria buffer large amounts of calcium and may undergo a Ca²⁺-induced permeability transition. The free calcium is sequestered in CaHPO₄ and practically insoluble Ca₃(PO₄)₂,²¹ which may be persistent. Ice hockey players may be more affected by concussion-related pathology than football players because collision speeds are higher in hockey and they commonly play more games per season with longer average activity times per game.

Conclusion

Acknowledgements

References

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