Cortical iron-related markers are elevated in mild Traumatic Brain Injury: An individual-level quantitative susceptibility mapping study

Quantitative susceptibility mapping (QSM) has been applied to map brain iron distribution after mild traumatic brain in-jury (mTBI), to understand properties of neural tissue which may be related to microstructural damage. However, mTBI is a heterogeneous injury associated with microstructural brain changes, and ‘traditional’ group-wise statistical approaches may lead to a loss of clinically relevant information, as subtle individual-level changes can be obscured by averages and confounded by within-group variability. More precise and individualised approaches are needed to characterise mTBI better and elucidate potential cellular mechanisms to improve intervention and rehabilitation. To address this issue, we build individualised profiles of regional positive (iron-related) magnetic susceptibility across 34 bilateral cortical regions of interest (ROIs) following mTBI. Healthy population templates were constructed for each cortical area using standardised z-scores derived from 25 age-matched male controls, serving as a reference against which z-scores of 35 males with acute (< 14 days) sports-related mTBI (sr-mTBI) were compared. Secondary analyses sensitive to cortical depth and curvature were also generated to approximate the location of iron accumulation in the cortical laminae and the effect of gyrification. Our primary analyses indicated that approximately one-third (11/35; 31%) of mTBI participants exhibited elevated positive sus-ceptibility indicative of abnormal iron profiles relative to the healthy control population, a finding that was mainly concentrated in ROIs within the temporal lobe. Injury severity was significantly higher (p < 0.01) for these mTBI participants than their iron-normal counterparts, suggesting a link between injury severity, symptom burden, and elevated cortical iron. Secondary analyses of cortical depth and curvature profiles revealed abnormal iron accumulation in 83% (29/35) of mTBI participants, enabling better localisation of mTBI-related changes in iron content to specific loci within each ROI and identifying effects that may be more subtle and lost in ROI-wise averaging. Our findings suggest that individualised approaches can further elucidate the clinical relevance of iron in mTBI. Differences in injury severity between iron-normal and iron-abnormal mTBI participants highlight not only why precise investigation is required to understand the link between objective changes in the brain and subjective symptomatology, but also identify iron as a candidate biomarker for tissue damage after mTBI.