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

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.