Mild traumatic brain injury increases cortical iron: evidence from individual susceptibility mapping

Quantitative susceptibility mapping has been applied to map brain iron distribution after mild traumatic brain injury to understand properties of neural tissue which may be related to cellular dyshomeostasis. However, this 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 alterations at the individual level can be obscured by averages and confounded by within-group variability. More precise and individualized approaches are needed to characterize mild traumatic brain injury better and elucidate potential cellular mechanisms to improve intervention and rehabilitation. To address this issue, we use quantitative MRI to build individualized profiles of regional positive (iron-related) magnetic susceptibility across 34 bilateral cortical ROIs following mild traumatic brain injury. Healthy population templates were constructed for each cortical area using standardized Z-scores derived from 25 age-matched male controls aged between 16 and 32 years (M = 21.10, SD = 4.35), serving as a reference against which Z-scores of 35 males with acute (<14 days) sports-related mild traumatic brain injury were compared [M = 21.60 years (range: 16-33), SD = 4.98]. 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. Primary analyses indicated that approximately one-third (11/35; 31%) of injured participants exhibited elevated positive susceptibility indicative of abnormal iron profiles relative to the healthy population, a finding that was mainly concentrated in regions within the temporal lobe. Injury severity was significantly higher (P = 0.02) for these participants than their iron-normal counterparts, suggesting a link between injury severity, symptom burden, and elevated cortical iron. Secondary exploratory analyses of cortical depth and curvature profiles revealed abnormal iron accumulation in 83% (29/35) of mild traumatic brain injury participants, enabling better localization of injury-related changes in iron content to specific loci within each region and identifying effects that may be more subtle and lost in region-wise averaging. Our findings suggest that individualized approaches can further elucidate the clinical relevance of iron in mild head injury. Differences in injury severity between iron-normal and iron-abnormal mild traumatic brain injury participants identified in our primary analysis 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 pathology after mild traumatic brain injury.