Multi-parametric analysis reveals metabolic and vascular effects driving differences in BOLD-based cerebrovascular reactivity associated with a history of sport concussion

ABSTRACT

Objective: Identify alterations in cerebrovascular reactivity (CVR) based on the history of sport-related concussion (SRC). Further explore possible mechanisms underlying differences in vascular physiology using hemodynamic parameters modeled using calibrated magnetic resonance imaging (MRI).

Method: End-tidal targeting and dual-echo MRI were combined to probe hypercapnic and hyperoxic challenges in athletes with (n = 32) and without (n = 31) a history of SRC. Concurrent blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL) data were used to compute BOLD-CVR, ASL-CVR, and other physiological parameters including resting oxygen extraction fraction (OEF₀) and cerebral blood volume (CBV₀). Multiple linear and logistic regressions were then used to identify dominant parameters driving group-differences in BOLD-CVR.

Results: Robust evidence for elevated BOLD-CVR were found in athletes with SRC history spreading over parts of the cortical hemispheres. Follow-up analyses showed co-localized differences in ASL-CVR (representing modulation of cerebral blood flow) and hemodynamic factors representing static vascular (i.e., CBV₀) and metabolic (i.e., OEF₀) effects suggesting that group-based differences in BOLD-CVR may be driven by a mixed effect from factors with vascular and metabolic origins.

Conclusion: These results emphasize that while BOLD-CVR offers promises as a surrogate non-specific biomarker for cerebrovascular health following SRC, multiple hemodynamic parameters can affect its relative measurements.

Abbreviations: [dHb]: concentration of deoxyhemoglobin; AFNI: Analysis of Functional NeuroImages (https://afni.nimh.nih.gov); ASL: arterial spin labeling; BIG: position group: defensive and offensive linemen; BIG-SKILL: position group: full backs, linebackers, running backs, tight-ends; BOLD: blood oxygen level dependent; CBF: cerebral blood flow; CMRO2: cerebral metabolic rate of oxygen consumption; CTL: group of control subjects; CVR: cerebrovascular reactivity; fMRI: functional magnetic resonance imaging; FSL: FMRIB software library (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/); HC: hypercapnia; HO: hyperoxia; HX: group with history of concussion; M: maximal theoretical BOLD signal upon complete removal of venous dHb; pCASL: pseudo-continuous arterial spin labeling; P_ETCO₂: end-tidal carbon dioxide; P_ETO₂: end-tidal oxygen; SCAT: sport-concussion assessment tool; SKILL: position group: defensive backs, kickers, quarterbacks, safeties, wide-receivers; SRC: sport-related concussion.

KEYWORDS:

• Cerebrovascular reactivity
• calibrated MRI
• sport-related concussion
• cerebral blood flow
• neuroimaging

Acknowledgments

The authors of this paper would like to thank Mr. Don Brien and Mrs. Janet Mirtle-Stroman for their dedication and willingness to help with data collection. The authors would like to acknowledge Dr. Clarisse I. Mark for her help with collecting parts of the data, along with the Queen’s football program (Kingston, Ontario, Canada), for their generous contributions and participation in this research project. Finally, we would like to thank Dr. J. J. Wang at UCLA for sharing the pCASL sequence used in this study.

Author contribution statement

A.A.C and N.S.C. were responsible were the collection of the data. M.G. helped with the computational framework designed for the data analysis. A.A.C. wrote the manuscript and performed all analyses on the data. D.J.C. supervised the project. All authors discussed the results and contributed to editing the final manuscript.

Disclosure/Conflicts of interest

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the Southeastern Ontario Academic Medical Organization (SEAMO); Southeastern Ontario Academic Medical Organization [6021315].