ABSTRACT/SUMMARY The dynamics of human connectome reorganization following blood-brain barrier (BBB) disruption during traumatic brain injury (TBI) remains poorly understood. In magnetic resonance imaging (MRI) of the human brain, susceptibility-weighted imaging (SWI) has become the sequence of choice for the clinical identification of micro- hemorrhages, which are indicators of BBB disruption. Partly because blood vessel walls may be more mechanically elastic than axonal membranes, the presence of (micro-) hemorrhages is strongly correlated with that of traumatic axonal injury (TAI) as revealed by diffusion tensor imaging (DTI). To this day, few studies have quantified in systematic detail (A) how white matter (WM) connectivity is affected by BBB disruption and by TAI, and (B) how SWI-resolved micro-hemorrhages (presumably located in regions strongly affected by TAI) lead to changes in the structural and functional organization of the connectome. Without understanding these phenomena at the scale of the entire brain (rather than on a strictly regional or lobar level) it may be very challenging to assess their true impact upon patients' long-term well-being. The goal of this proposed research project is to (A) assess the sequelae of (micro-) hemorrhages in mild TBI and to (B) quantify the short- and long- term effects of hemorrhagic lesions and mechanical shearing upon neurological and neuropsychological function in patients with mild TBI. This work may provide novel insights into how BBB disruption and mechanical shearing of axons during TAI lead to neural and cognitive dysfunction. We propose to use novel quantitative methods for neuroimage analysis to answer fundamental questions pertaining to the role of BBB disruption and TAI in the reorganization of the human connectome. Specifically, we seek to (1) quantify the longitudinal evolution of WM connectivity in (peri-) lesional regions affected by BBB disruption as reflected by the presence of SWI-resolvable (micro-) hemorrhages, (2) resolve the spatio-temporal relationship between the presence of (micro-) hemorrhages, and TAI-related changes in the human connectome which occur within the first 12 months post- injury, and (3) quantify how the interplay between (micro-) hemorrhage-related BBB disruption, TAI and WM atrophy modulates the deterioration and/or recovery of neuropsychological function within the first 12 months after TBI. Improved understanding of these correlations between (micro-) bleed occurrence and functional sequelae could allow the true severity of concussions and other forms of traumatic injuries to be assessed at an early stage. In turn, this could allow clinicians to gain novel insights pertaining to the potential consequences of SWI-resolved (micro-) hemorrhages upon neurological and neuropsychological function.