Traumatic brain injury (TBI) is a global health crisis, with incidence rates growing rapidly. Further, TBI is the leading cause of injury-related death and disability, with lifelong impacts on the individual and their families. Of increasing concern is mild TBI (mTBI), which is overexpressed in the population yet lacks adequate attention in current clinical practice. Despite many experiencing long-term consequences of so-called ‘mild’ TBI, the relative paucity of clinical understanding and care of these patients has created a disconnect between injury and outcome. Thus, we are currently unable to explain the neurological underpinnings of poor outcome after mTBI, predict who might experience long-term effects, or sufficiently treat these patients. In this thesis, I aim to re-frame ‘mild’ TBI as a non-trivial and long-term disease, using multiple neuroimaging methods to better understand and prognosticate the outcomes of these individuals.

Using data from collaborative multi-centre project CENTER-TBI, Chapters 2-5 explore the acute and enduring neurological effects after even the ‘mildest’ TBI. Expressly, those individuals within hospital settings who do not present existing markers of poor outcome such as damage on computerised tomography (CT) or pre-injury neuropsychiatric conditions. Even with such ‘mild’ injury, Chapter 2 finds that this does not necessitate mild outcome, as 47% of our mTBI group show incomplete functional and/or symptomatic recovery at 6 months post-injury. This chapter further identifies that common structural neuroimaging methods or blood-based biomarkers are not associated with poor outcome in this cohort, necessitating the need for novel markers of chronic outcome. Chapter 3 establishes mTBI as a global functional disorder, using resting-state functional magnetic resonance imaging. Explicitly, all resting-state networks intrinsic to healthy brain function show vast alterations in functional connectivity. Additionally, these networks show injury-induced changes in how they are spatially distributed across the brain using a novel measure of component distribution complexity. Both measures show preliminary associations between disrupted network functional connectivity and poor outcome, but require further acute biomarkers to successfully differentiate chronic outcome.

Chapter 4 begins to focus investigations on a globally connected subcortical structure, previously ignored in TBI; the thalamus. In the same cohort of mTBI, I find acute thalamic hyperconnectivity, with specific vulnerabilities of individual thalamic nuclei. These acute fMRI markers differentiate those with versus without chronic post-concussive symptoms, additionally with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, chronic emotional and cognitive symptoms are associated with acute changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. This begins to bridge the gap between macrostructural and microstructural investigation; translating findings from acute imaging into treatment-relevant targets and aiming for each field to mutually influence the other for therapeutic development. Chapter 5 additionally finds that thalamocortical connectivity is exacerbated in the special interest group of repeat mTBI. These results further establish thalamic pathophysiology as a marker of acute injury and outcome, and has important implications for both public and professional sports players.

In the final experimental Chapter 6, I further explore the evolving and potentially lifelong thalamic neuronal consequences of TBI, across all severities. Using rarely-collected 11C-flumazenil positron emission tomography (PET), the thalamus shows unique markers of selective neuronal loss extending many years post-injury, which additionally mirror regions of cortical damage. These thalamic markers are related to multiple adverse outcomes, thereby substantiating that the thalamus can link the injury event with the long-term disease of TBI.

Overall, this thesis establishes functional neuroimaging as an invaluable tool for better understanding and prognosticating mTBI. Moreover, I propose the thalamus is a common source of injury, outcome, and long-term disease following TBI. It thus demands greater recognition and investigation in the TBI community, which is beginning to take flight. So-called ‘mild’ TBI is neither trivial nor temporary, and has traditionally been dismissed in public and clinical settings. For the many individuals experiencing long-term symptoms, multidisciplinary teams must work together to form new therapeutic pathways, towards a precision medicine approach. Only then will future research and healthcare professionals be able to sufficiently care for this growing population.