Individualised quantitative susceptibility mapping reveals abnormal hippocampal iron markers in acute mild traumatic brain injury

Quantitative susceptibility mapping (QSM) is an advanced post-processing technique of magnetic resonance imaging data that can be leveraged as a surrogate marker of iron accumulation in the brain following mild traumatic brain injury (mTBI). However, subtle tissue content changes characteristic of this complex injury may be lost to group-wise averaging when standard statistical models are employed. To provide more clinically- and individually-relevant information, z-tests can be used to build personalised profiles of positive susceptibility as a marker of abnormal iron homeostasis. Here, we mapped subject-specific deviations in iron-related positive susceptibility across 10 bilateral segmentations of the hippocampal subfields and 15 basal nuclei. The healthy normal susceptibility distribution for each region-of-interest (ROI) was derived from the aggregate data of 25 age-matched male controls (M = 21.10 years [range: 16-32], SD = 4.35) using z-tests. Region-wise z-scores for each of the 35 males aged between 16 and 33 years (M = 21.60, SD = 4.98) with acute (< 14 days) sports-related mTBI (sr-mTBI) were compared against the healthy reference range. Of the sr-mTBI participants, 43% exhibited abnormal iron markers in at least one ROI, which involved the hippocampal subfields in a majority (87%) of cases. Across all ROIs, particularly dense concentrations were observed in the parasubiculum and mammillary nucleus. Injury severity scores were not significantly different between sr-mTBI participants with abnormal iron markers (M = 41.7, SD = 34.5) and those without (M = 35.6, SD = 30.8), p = 0.5, however, abnormal iron markers in certain hippocampal subfields and the mammillary nucleus were observationally linked to clinical symptom phenotype. Taken together, these data allude to a region-of-risk model in which areas of the anteromedial hippocampal head, which is proximal to the sphenoid ridge, and midline structures are vulnerable to iron-mediated pathology. These findings underscore the importance of subject-specific analyses and how these sensitive methods can be used to map regional iron dyshomeostasis against cranial-dural morphology and established injury biomechanics.