This thesis describes and explores the nature of self-reference and self-conscious emotional processes in men who have survived a traumatic brain injury (TBI). Semi-structured interviews were conducted with nine male survivors of TB I (aged 22 to 59 years), which encouraged them to talk freely of their experience of surviving a TB!. Transcriptions of these accounts were then analysed, using thematic analysis, to identify dominant themes related to their described emotional experience of self in the social world. A detailed description of the analytical approach adopted is discussed in relation to methodological rigour in terms of transparency and coherence of the process, commitment in engagement with the topic and in the resulting completeness of the data collection and analysis process. The findings generated themes of 'abnormality', 'hidden', 'old-me, new me' and 'others treat me differently', which were related to the men's emotional experience and themes of responses to experiences such as 'self-criticism', 'need to be as others want me to be' and 'withdrawal'. These themes were supplemented by some of the men's identified alternative narratives of 'positive growth' through acceptance from others and themselves following injury. The findings are discussed "' in relation to current understanding on the emotional processes and sources of emotional distress for men following TB I, with consideration of the study's context and potential gender and cultural influences on said narratives. The preliminary nature of these findings is highlighted, while recommendations for future research and the consideration of clinical implications for neuropsychological rehabilitation are explored.

Background: Survivors of traumatic brain injury (TBI) may have to contend with changes in their abilities, yet some may be unaware of specific emotional, cognitive and behavioural consequences of the injury. Unawareness of memory difficulties may impact on functional outcome and participation in rehabilitation following TBI. Objectives: This study aimed to examine whether people are aware of their everyday memory ability after TBI. Design: A between-subjects design was used to compare a group with TBI and a healthy comparison group. A within-subjects design compared informant and self memory ratings. Method: Twenty-six healthy people and 26 people with TBI participated. People with TBI were recruited from statutory and voluntary community services available to people with TBI. Awareness was measured by calculating the difference between performance on the Rivermead Behavioural Memory Test - Extended version and the Memory Awareness Rating Scale. Results: The discrepancies between memory test score and pre-test self-ratings were not significantly different between the TBI and comparison group. However, the discrepancy was significantly smaller for the comparison group on post-test ratings. This indicates that the TBI and comparison groups were similar in pre-test rating of their memory compared to memory test performance. However, healthy people were better able to adjust estimates based on performance. Informants' ratings were more strongly correlated to memory performance for part of the rating scale, though neither self nor informant-ratings were significantly correlated to memory performance in the TBI group. Conclusions: Neither people with TBI nor healthy people make accurate estimates of their memory ability. Developing measurement of awareness of memory for research and clinical practice is discussed. Clinicians should endeavour to thoroughly assess awareness, being mindful that healthy people also make relatively poor estimates of memory ability.

Problems with executive functioning may have catastrophic consequences following brain injury. Assessment of these complex functions is critical in planning necessary interventions, yet they present a challenge to traditional methodologies. The review considered the issues that comprise this challenge, and the increasingly important role ecologically valid measures play in neuropsychological assessment is highlighted. Shallice and Burgess (1991) described the Multiple Errands Test (MET), which successfully reflected executive impairments manifest in the context of everyday functioning. Surprisingly, the methodology has been relatively under exploited for use in clinical settings. In the present study, the utility of a simplified MET designed for use on a hospital ward was explored. The measure was designed to be appropriate for patients who are unable to undergo assessment in public settings, and suitable for use with patients who are in the early stages of recovery. Twenty four healthy participants and 21 people with acquired brain injury took part. The main findings were as follows: 1) the test discriminated well between neurological patients and controls, and the groups effects remained when the difference in current general cognitive function and familiarity with the environment were considered; 2) test performance was found to be strongly associated with performance on an established ecologically valid measure of executive function; and 3) preliminary findings indicated that two patterns of error making style were associated with different dysexecutive symptoms in everyday life. The results demonstrated the clinical utility of the ward version of the MET-with the advantage to clinicians in its brevity and sensitivity, whilst capturing aspects of everyday executive difficulties that are not readily accessible from many psychometric measures.

Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI, and although a single concussion rarely results in long-term neurological dysfunction, repeated mild traumatic brain injury (r-mTBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure. Animal models provide a means to examine the factors and mechanisms involved in TBI in experiments that cannot be conducted using human participants. The purpose of this thesis was to develop and fully characterize a reproducible, non-invasive mTBI model that will facilitate the study of repetitive brain injury. In the present study, male wild type mice received a midline concussive blow via an electromagnetic impactor, tuned to produce an injury without fracturing the skull. The injured mice were used to examine the chronic neurobehavioral, neuropathological and biochemical outcomes following single and rmTBI up to 18 months following injury. Importantly, our findings recapitulate many aspects of human long term TBI sequelae, in particular persistent neuroinflammation, white matter injury, and axonal pathology in the corpus callosum. Our results provide the first evidence that, whilst a single concussion produces transient neurobehavioral changes and pathology which remains static in the period following injury, r-mTBI produces behavioral and pathological changes which continue to evolve many months post injury. There have been a number of clinical studies implicating tau in TBI pathology. As such, we investigated the relationship between tau pathologies after trauma in a transgenic mouse model expressing all 6 isoforms of human tau protein on a null murine background (hTau). Our results revealed that that single and r-mTBI induced a modest cortical increase in the soluble fraction of three different p-tau epitopes at 24 h post last injury. Moreover, this increase was not associated with worse behavioral performance when compared to wild type animals. Therefore, tau hyperphosphorylation appears to have a contributory, but not primary, role in the acute phase post-injury. Additional prospective studies in both humans and animal models are required to characterize the contribution of tau to TBI sequelae. The experimental data presented here suggest that inflammation and axonal injury (as seen in both wild-type and hTau models) appear to play a role in the events following single or repetitive mTBI and strongly correlates with the behavioral changes post-injury. The relationship between a history of mTBI and neuroinflammation are likely to be complex and warrant further work to elucidate their association with neurodegenerative disease. This work represents the development of a novel model, and the demonstration of its relevance to human TBJ. This model can now be used for further exploration of TBI-related effects and for evaluation of potential therapeutic and diagnostic approaches, as is discussed throughout the thesis.

This research was undertaken to improve the assessment and treatment of balance disorder after Traumatic Brain Injury (TBI). It had three aims: to identify factors that have shaped healthcare practice concerning balance disorder and describe barriers to improved practice; to develop understanding of the nature of TBI balance disorder; to establish proposals for an improved healthcare response for those with balance disorder following TBI. TBI is a significant cause of disability in the young adult population and problems with balance are consistently reported. A mixed methods approach was employed to address the aims within a common framework. This comprised a series of subject reviews, an observational study and a systematic analysis of emergent findings. Topics for the subject reviews were chosen for their relevance to TBI physiotherapy practice. The observational study involved 27 participants in the recovery and rehabilitation phase after TBI and was structured using a new comprehensive assessment protocol developed from first principles. Findings were explored using frequency analysis and thematic analysis generated from the development of individual participant narratives. Emergent topics were then considered with reference to the literature, existing theories and concepts of postural control. Different conceptualisations of balance were identified, influenced by discipline tradition, their evidence base, the evolution of ideas, and past and current purpose. Practice development was constrained by the lack of a comprehensive conceptualisation of human balance, inconsistent and fragmented service response and limited knowledge concerning the nature and prevalence of impairments affecting balance function after TBI. Balance disorder was found to be highly prevalent and multifactorial in nature. New sensorimotor characteristics of TBI balance disorder were identified, including observations of importance to the contentious debate concerning symptomatic minor TBI. Issues of key importance in the structure and process of assessment were also identified. Balance disorder is prevalent in the rehabilitation and recovery phase following TBI and is multifactorial in nature. Assessment and treatment of suspected balance disorder could be enhanced by the adoption of a single comprehensive conceptualisation of human balance, a systematic approach to assessment and formulation of causal hypotheses and a service process focused on the functional requirements of individuals. Research for the enhanced development of assessment and intervention strategies should also be pursued in the same context.

Traumatic brain injury (TBI) involves both an initial primary insult to the brain and a delayed secondary injury in the hours and days thereafter. The delayed nature of secondary brain injury leaves open the possibility for a window of therapeutic intervention to prevent neurodegeneration. As there are currently no approved drugs for the treatment and prevention of secondary injury after TBI, my approach has been to first identify molecular pathways associated with a differential outcome from injury, followed by validation of these pathways by targeting them with a variety of therapeutic strategies ranging from genetic manipulation to novel drug compounds, and dietary supplementation. The Apolipoprotein E (APOE) gene has three major alleles, APOE2, APOE3 and APOE4, the latter of which confers risk for poor outcome following TBI. Using quantitative Liquid Chromatography-Mass Spectrometry, large proteomic datasets can be generated, and the difference in protein expression in response to TBI between transgenic mice expressing APOE3 or APOE4 can reveal changes that reflect a "better" or "worse" outcome, respectively. Analyzing such datasets from APOE3 and APOE4 transgenic mice at a wide range of time points, we examined the differential response to TBI and identified several protein pathways of interest, including: CD40 signaling, NF-kB signaling, and APP related proteins. Optimizing several behavioral I testing paradigms (Rotarod, Morris Water Maze, and Barnes Maze), we characterized spatial memory and motor function deficits resulting from TBI in order to quantify a "good" or "poor" response. Using a variety of targeted intervention strategies (CD40L knockout, administration of (-)-Nllvadipine, or anatabine) to modulate the protein pathways of interest, we showed improvement in response to TBI. Overall, these experiments provide demonstrate the effectiveness of using a systems biology approach to find potential targets for therapeutic intervention.

Neuroimaging studies have provided considerable evidence for frontal lobe involvement in memory processing. Memory impairments arc also frequently reported in patients with frontal lobe lesions. However detailed anatomical localisation is rare, making integration of lesion and imaging findings difficult. An investigation of the functional and anatomical contributions of the frontal lobes to memory was conducted in 42 patients with frontal lobe lesions, examining memory processes identified in previous imaging and neuropsychological research. The results revealed frontal impairments in recall and recognition memory, increased false recognition and intrusions, and confabulation. To investigate specific lesion-behaviour relationships, patients were grouped according to the presence of damage in Right Lateral, Left Lateral, Medial and Orbital frontal regions. The Medial group had impairments in recognition and recall on several tasks, which were due at least in part to deficits at encoding. This group may have a pure memory deficit arising from disruption of cholinergic projections from the basal forebrain to the medial temporal lobe system. The Right Lateral group on the other hand had a strategic retrieval deficit which was aided by cueing at recall. Marked intrusion and confabulation effects were found in the Orbital and Medial groups, providing strong support for an inferior medial localisation for confabulation. In addition an investigation of Schnider and colleagues' theory of confabulation was conducted in three confabulating patients. Strong support was found for a characteristic pattern of performance on their continuous recognition task, with confabulators showing a constant hit rate accompanied by an increasing false positive rate. However the suggestion that the critical impairment is an inability to suppress currently irrelevant memories that intrude into the present was not supported. Instead these patients had a complete inability to place remembered information in its correct temporal context. There was also evidence of a tendency to misidentify imagined experiences as real. It is argued that retrieval process theories incorporating these factors are best able to account for the features of confabulation.

It is now widely accepted that cognitive functions depend on the integrated operation of large-scale distributed brain networks. Recent methodological advances allow both structural and functional connectivity within these networks to be studied non-invasively in vivo. These approaches hold the promise of dramatically extending our understanding of the impact of traumatic brain injury (TBI) on cognition, which should help determine strategic targets for the rehabilitation of individuals with TBI. In this thesis, I present three studies that combine structural and functional magnetic resonance imaging to test the general hypothesis that cognitive deficits after TBI arise from structural disconnection within brain networks that mediate cognitive functions. In the first study, I demonstrate that sustained attention deficits in TBI patients are related to a failure to regulate activity within a ‘default-mode’ network (DMN) thought to be involved, among others, in internally directed processes such as self-referential thought. In addition, these deficits can be predicted by the functional and structural connectivity within the DMN. Next, I present a study investigating the neural basis for inhibitory control in healthy subjects using a modified version of the Stop Signal Task (SST). This study allows a clear distinction between attentional and response inhibition processes, and paves the way for my last study, which investigates inhibitory deficits after TBI. In this study, I demonstrate that a failure of DMN deactivation during response inhibition is associated with impaired inhibitory performance in TBI patients. The ability to efficiently regulate the DMN can be predicted by the structural integrity within a remote brain network previously proposed to be involved in switching between internally and externally directed attention. This work identifies DMN dysfunction as underlying various cognitive deficits after TBI, and confirms the relevance of white matter damage in the development of brain dysfunctions after TBI.

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