Cerebral contusions that result from brain trauma have the propensity to enlarge over the days following injury, including extension of the haemorrhage core and swelling of the surrounding peri-contusional brain. This secondary injury increases the likelihood of death and severe disabil- ity, and interventions to prevent or limit contusion progression may improve clinical outcomes. In preclinical studies a number of pathophysiological process have been identified that contribute to brain oedema including blood brain barrier (BBB) disruption, neuroinflammation, and cerebral metabolic dysfunction. This work has set out to measure and quantify contusion progression in TBI patients, characterise BBB permeability with computed tomography imaging, and identify key mediators of this process using intracerebral microdialysis.

• Study I: A robust and effective stereological method for measuring the volume of brain lesions was validated and applied to a cohort of TBI patients to examine the temporal course of contusion progression. Intracranial pressure and brain lactate/pyruvate ratio were found to be associated with the magnitude of contusion expansion.

• Study II: Dynamic contrast enhanced computed tomography (DCE-CT) was applied in pa- tients with brain contusions to quantify BBB permeability. The imaging showed profound reduction in cerebral blood flow associated with contusions but did not show evidence of contrast extravasation or BBB permeability.

• Study III: Paired microdialysis catheters, one inserted in proximity to a contusion and an- other in non-injured brain, were used to characterise the peri-contusional inflammatory response with a multiplex assay of 42 cytokines, chemokines, and growth factors. Peri- contusional tissue was found to exhibit an early pro-inflammatory signature.

• Study IV: A paired microdialysis study of pericontusional expression of matrix metalloproteinases (MMP). Specific increase in the expression of MMP-9 was identified in pericontusional brain.

• Study V: Nitric oxide (NOx) concentrations were assayed in pericontusional and uninjured brain with paired microdialysis. NOx levels were lower in pericontusional brain and exhibited significant correlations with brain glucose, pyruvate, and lactate.

• Study VI: Microdialysis data from 619 TBI patients with collated to explore the physiological correlates of deranged metabolism and elevated LPR. Cerebral glucose was found to a key determinant of LPR.

The implications of these findings in the context of existing knowledge of BBB permeability, in- flammation, and cerebral metabolism in TBI are discussed. Future investigations to clarify the mechanisms highlighted, and potential therapeutic studies directed at reducing contusion pro- gression and brain oedema are suggested.