Characterising Microstructural Grey Matter Pathology in Acute Mild Traumatic Brain Injury: A Quantitative Susceptibility Mapping Approach

Abstract

Mild traumatic brain injury (mTBI) is a heterogeneous injury characterised by complex pathophysiological cascades. Brain iron dyshomeostasis is increasingly recognised as a driver of secondary injury including cytotoxicity and inflammation following mTBI, and alterations to myelin integrity, calcification, and proteinopathy have been implicated in post-injury pathology. However, standard radiographic methods are often insensitive to these microscopic alterations to brain tissue. This limitation necessitates the use of advanced magnetic resonance imaging (MRI) techniques to detect the subtle structural changes associated with this condition.

This thesis applied quantitative susceptibility mapping (QSM), an advanced MRI post‐processing method, to elucidate differences in the distribution and concentration of magnetisable tissue constituents between male sports athletes (aged 16-33) with acute (<14 days) mTBI and age‑matched male controls. QSM data were first thresholded to generate separate maps of positive (iron-related) and negative (protein-, calcium-, and myelin-related) voxel-wise susceptibility to enable targeted analyses of cerebral grey matter. Extensive segmentations of the basal ganglia and hippocampal formation were used to investigate deep grey matter, while column-based analyses sensitive to cortical depth and curvature were leveraged to approximate the location of tissue dyshomeostasis within the cortical laminae and account for the effect of gyrification. Variables such as injury severity, time since injury, and age were also used in statistical models to elucidate the influence of these factors on tissue pathology.

Bilateral, between-group analyses were first conducted across all regions of interest (ROIs) to identify signatures of tissue dyshomeostasis that may represent common features of mTBI. However, traditional group-wise statistical approaches may obscure subtle, yet clinically relevant, inter-individual variability. To address this limitation, subsequent studies constructed healthy population templates for each ROI using standardised z-scores, against which the z-scores of mTBI participants were analysed.

Group-wise analyses revealed significantly decreased negative susceptibility in the cornu ammonis 4 region of the hippocampus among mTBI participants, suggesting the presence of injury-related effects on myelin content or cell loss. Cortical analyses indicated a trauma-induced increase in positive susceptibility, a marker of iron deposition, localised to the superficial depths of the parahippocampal sulcal bank and fundus. Decreased negative susceptibility values in distinct voxel populations within the same region suggested a dual pathology of neural substrates.

Individualised analyses of deep grey matter identified significantly elevated z-scores indicative of abnormal iron profiles relative to the healthy population, primarily in regions proximal to the hippocampal head and in the mammillary nucleus. Individual-level cortical analyses revealed abnormal iron markers predominantly localised to the temporal lobe. mTBI participants with abnormal cortical iron markers exhibited significantly higher injury severity scores than their iron-normal counterparts, suggesting a link between potential iron deposition and symptom burden.

The findings of this thesis converge to underscore the vulnerability of the temporal lobe region to tissue dyshomeostasis following mTBI. This highlights the need for enhanced anatomical specificity in QSM-based investigations and suggests that the current emphasis on major basal ganglia substructures and an over-reliance on group-wise analysis is limiting. Collectively, the works contained within this thesis not only advance the current understanding of grey matter micropathology in mTBI and its clinical relevance, but provides both a compelling rationale for refining future QSM methodologies and a framework by which this can be achieved.