Abstract
Traumatic brain injury is a major cause of long-term cognitive impairment, yet the mechanisms underlying recovery remain poorly understood. Neuroimaging methods such as diffusion MRI, functional MRI, and positron emission tomography (PET) provide insight into micro- and macro-scale changes post-TBI, but the relationships between regional cellular and functional alterations remain unclear. In this study, we conducted a longitudinal, multimodal neuroimaging analysis quantifying TBI-related pathologies in four biomarkers, namely flumazenil PET derived binding potential, dMRI-derived structural connectivity, and resting-state fMRI-derived functional connectivity and fractional amplitude of low-frequency fluctuations in individuals with mild-to-severe brain injury at the subacute (4-6 months post-injury) and chronic (1-year postinjury) stages. Brain injury related regional pathologies, and their changes over time, were correlated across the four biomarkers. Our results reveal complex, dynamic changes over time. We found that flumazenil-PET binding potential was significantly reduced in frontal and thalamic regions in brain injured subjects, consistent with neuronal loss, with partial recovery over time. Functional hyperconnectivity was observed in brain injured subjects initially but declined while remaining elevated compared to non-injured controls, whereas cortical structural hypoconnectivity persisted. Importantly, we observed that brain injury related alterations across MRI modalities became more strongly correlated with flumazenil-PET at the chronic stage. Regions with chronic reductions in flumazenil-PET binding also showed weaker structural node strength and lower amplitude of low frequency fluctuations, a relationship that was not found at the subacute stage. This observation could suggest a progressive convergence of structural and functional disruptions with neuronal loss over time. Additionally, regions with declining structural node strength also exhibited decreases in functional node strength, while these same regions showed increased amplitude of low frequency fluctuations over time. This pattern suggests that heightened intrinsic regional activity may serve as a compensatory mechanism in regions increasingly disconnected due to progressive axonal degradation. Altogether, these findings advance our understanding of how multimodal neuroimaging captures the evolving interplay between neuronal integrity, structural connectivity, and functional dynamics after brain injury. Clarifying these interrelationships could inform prognostic models and enhance knowledge of degenerative, compensatory, and recovery mechanisms in traumatic brain injury.