There is growing evidence that suggests Traumatic brain injury (TBI) may initiate long-term neurodegenerative processes. Exposure to a single moderate or severe TBI, or to repetitive TBI, reveals a complex of pathologies including abnormalities of tau, amyloid-β and TDP-43; neuronal loss; neuroinflammation; and white matter degradation. The mechanisms driving these late post-TBI neurodegenerative pathologies remain elusive. Firstly, a potential association between blood-brain barrier (BBB) disruption and TBI was investigated. Results showed that increased and widespread BBB disruption was observed in material from patients dying in the acute phase following a single, moderate to severe TBI and persisted in a high proportion of patients surviving years following injury. Furthermore, there was preferential distribution to the deep layers of the cortex and to the crests of the gyri rather than the depths of the sulci. This post-TBI BBB disruption was investigated further within a paediatric TBI cohort. BBB disruption was noted in both paediatric and adult TBI in a similar pattern and distribution, however, interestingly, in sharp contrast to adult TBI cases, BBB disruption in paediatric cases appears preferentially distributed to capillary sized vessels. This vulnerability of the small vessels was rarely observed in adult material. In addition to the post-TBI vascular change observed, the cellular response was investigated, which interestingly, demonstrated regional differences. Specifically, in the grey matter, reactive astrogliosis was observed subpially, around cortical vessels, at the grey and white matter boundaries and subependymally. This astrogliosis was evident in a proportion of acute and continued into the late phase following TBI. In contrast, microglial activation was observed as a delayed response and localised to the white matter tracts. In addition, this delayed microglial response expressed an M2-like phenotype. Furthermore, there was an increased population of inactivated perivascular microglia beyond the perivascular space in the grey matter regions, observed in the acute phase and persisted in a proportion of patients surviving years following injury. Collectively these findings are interesting and indicate TBI induces both a vascular and cellular responses which may contribute to the long-term post-TBI neurodegenerative processes.

The work carried out in this thesis is focused on the proposal, comparison and assessment of survival analysis models for epilepsy data. Although the Cox proportional hazards model provides a popular approach to medical recurrent events modelling, other accelerated life alternatives seem more appropriate when compared under goodness of t tests. In our research we apply the Cox proportional hazards model and two models consisting of a Poisson-Gamma mixture model that could assume the existence of a cure fraction , and which have been developed and proposed by B. Cowling[11] and J. Rogers[39] respectively. We applied these methods to the Multicentre study of early Epilepsy and Single Seizures (MESS) data set. In this epilepsy study, patients with different types of seizures were randomized to either immediate or delayed treatment, which consisted in being administered one of seven types of drugs. The aim of the study consisted in producing a prognosis with which the clinicians and patients could take an informed decision on whether or not it was preferable to take an anti-epileptic drug. We investigated the behaviour of the survival function for the Cox proportional hazards model, the joint model and the joint with cure fraction model under the epilepsy data set, under the framework of residual analysis studies, as well as empirical vs theoretical survival functions. As a final contribution of our work, we proposed modification of the accelerated life models. Since a patient cannot be diagnosed with epilepsy unless he or she presents at least two un-provoked seizures, we proposed a zero-truncated joint model, which considers the pre-randomization counts to be strictly positive. This model has been extended to consider a cure fraction of the population, but is still under development, since the corresponding parameter estimations become considerably more complicated.

This thesis is concerned with the factors that determine the performance of everyday action. Six empirical chapters are subsequently presented. First, I sought to investigate the effects of the presence of distractors and of task load on the performance of everyday life tasks, comparing a patient with ADS and controls operating with a task load (Chapter 2). The data indicate that controls and patients with ADS may suffer different demands. The role of the task schema on ADL was examined in Chapter 3. The results showed that there is a problem in using task schema to drive action under the on-line constraints of performing the action. Relation between object recognition and action was tested in Chapters 4 and 5. I showed that 'object use' effect was maintained even when the patients showed impaired semantic access for the objects. The final empirical study (Chapter 7), investigated the role of eye movements on performing an everyday. There were proportionately more unrelated fixations and more fixations concerned with locating objects in the ADS patient than in controls. In addition, eye movements away from objects being used were made earlier in the ADS patient, and toying errors were linked to multiple, brief fixations being made to the object involved. In the final chapter (8), I review the evidence from across the thesis and discuss the implications of the work for understanding both normal and disordered everyday actions. The results not only point to the complexity of processes supporting such actions, but also to the critical interactions between action and attention in such tasks.

Spinal cord injury (SCI) is a neurodegenerative disease with research centered on axon regeneration and preservation to cure paralysis. Mice and rats are widely studied and experienced models used to imitate SCI due to differences in vascular disruption, blood vessel loss and cavitation at SCI epicenters. This study investigates sub-acute SCI responses, documenting angiogenic/inflammatory factors and matrix deposition in both species. Although cavitation was absent in mice, the lesion site in rats was larger at 8 and 15 days post lesion (dpl). Absence of cavitation in mice correlated with increased levels of pro-angiogenic/wound healing factors within the wound compared to rats at 8 dpl, coinciding with microarray analysis along with increased axonal sparing at T7 and T9 spinal segments. Despite similar deficits in thermal sensitivity 2 hours after injury, by 7 days the responses were comparable to controls in both species. Furthermore, inducing inflammation directly after injury using zymosan resulted in inflammatory-induced angiogenic responses between both species at 8 dpl, contributing to tissue damage and micro-cavities in the CNS. In conclusion angiogenic responses in mice attenuates wound cavitation, reducing secondary axon damage and thus induces axon sprouting/regeneration. These results suggest potential therapeutic utility of manipulating angiogenic/inflammatory responses after human SCI.

Magnetic Resonance Spectroscopic Imaging (MRSI), a functional MR imaging technique, has proven via the identification of metabolite biomarkers to be useful in the diagnosis and prognosis of numerous diseases, for example brain tumours. However, a number of factors impede its routine clinical use: i) long acquisition times mean its use is limited to low resolution 2-dimensional slabs, ii) large quantity of data produced means its interpretation can be time consuming and iii) data quality can be variable and therefore interpretation can be difficult for a non-expert. Further developments in MRSI are designed to reduce the impact of these issues. The focus of this work is to address some of the above issues; developing acquisition protocols and optimising analysis methods in order to increase the clinical feasibility of MRSI. Within this study a fast-MRSI protocol has been developed for absolute metabolite quantitation and has demonstrated its feasibility for clinical use, accurately reproducing data in a shorter clinically feasible acquisition time. An experimentally derived fitting model has been developed which increases metabolite measurement accuracy. Finally, a 3D MRSI protocol has been successfully optimized allowing robust metabolite information to be mapped throughout the brain.

Unlike the peripheral nervous system, the spinal cord which forms part of the central nervous system (CNS) is unable to regenerate. Intrinsic and extrinsic environment changes following spinal cord injury are the main factors contributed to inhibit neuronal survival and axonal growth. However, manipulating the growth-relative genes in the CNS after injury can induce limited axon regeneration. In this study we demonstrate by manipulating expression of three protein molecules AMIGO3 (an amphoterin-induced gene open reading frame), RTN3 (Reticulon 3) and astrocyte elevated gene-1 (AEG-1/ also known as MTDH/LYRIC1)), where axon regeneration in the CNS is possible. Data from a microarray screen in regenerating and non-regenerating spinal cord injury models showed that low levels of AMIGO3 expression correlated with regenerating sciatic nerve (SN) and preconditioning SN+DC lesion models. Conversely, high levels of RTN3 and AEG-1 were found to be correlated with regeneration injury models. \(In\) \(vitro\) knockdown of AMIGO3 combined with neurotrophin 3 (NT3) has been shown to promote dorsal root ganglion neuron (DRGN) neurite outgrowth, and in vivo delivery of non-viral mediated shRNA/AMIGO3 plasmid to suppress AMIGO3 expression demonstrated significant DC axon regeneration. In addition, in vitro knockdown of both RTN3 and AEG-1 suppressed DRGN neurite outgrowth, demonstrating that they are required for axonal growth. The mechanisms by which AMIGO3, RTN3 and AEG-1 suppress or promote axonal regeneration is not yet known but we conclude that they play a major role in axonal regeneration and could be harnessed to promote regeneration of the CNS.

High frequency activity (HFA) is oscillatory brain activity faster than ~100 Hz. It is subdivided into physiological ripples (~100-250 Hz) and pathological fast ripples (~250-500 Hz). Ripples in the hippocampus are paced by recurrent inhibition from interneurons. The mechanism for pathological HFA is unknown, but may be the same as for ripples and could provide new insight into the pathological nature of epileptic tissue. HFA was induced using the high potassium (\({in vitro}\)) and tetanus neurotoxin (\({ex vivo}\)) models of epilepsy. Field HFA was recorded simultaneously with action potentials from visually targeted interneurons, made possible using VGAT-Venus A rats and a membrane chamber. The phase relationship between HFA and interneuron firing was examined. In both models, HFA frequency was normally distributed between 100-300 Hz. Interneurons increased their firing rate during epileptiform bursts and were subdivided into four groups based on their firing patterns. The most pertinent group fired at >100 Hz throughout epileptiform bursts and were candidates to pace HFA. Of this group, significant phase relationships were seen in four interneurons using high potassium and one interneuron with tetanus neurotoxin. These interneurons were compatible with the hypothesis that they pace HFA, but blockade of GABAergic signalling using bicuculline did not abolish HFA, suggesting a modulatory rather than causative role for interneurons.

This thesis combines two research papers. The first paper is a systematic literature review investigating risk factors associated with suicidality in Huntington’s disease. The review discusses the importance of clinicians using the identified factors as ‘red flags’ when screening for suicide ideation so that either preventative measures can be put in place or psychological interventions provided to ameliorate any distress. The second paper is an empirical study which explores the concept of ‘rational suicide’ in Multiple Sclerosis (MS). It also investigates whether depression forms an important link between disability and suicide ideation, compares types of Progressive MS and examines whether there are differences in levels of suicide ideation for different disability types. The findings are discussed in terms of current literature, future research recommendations and clinical implications.

Two types of electrolytic growth processes have been investigated as possible means of controlling impedances in adaptive systems. One of these entails the growth of conductors by metallic deposition and the other the growth of insulation by anodic oxidation. The way in which the growth of a metallic dendrite changes the impedance of a cell has been determined, and it has been found that this depends very much on the shape of the cell. By restricting growth to narrow channels it has been found possible to reliably control the impedance of cells. The properties of devices employing this principle are described. The growth of insulating films on aluminium has been found to be another satisfactory method of reproducibly adjusting the impedance of a cell. The properties of these films and the impedance changes which take place during their 'formation' and 'erosion' are discussed. These films have special properties which make them suitable for use in the fabrication of devices containing many variable impedances in a single unit. The construction and properties of these devices are described. An adaptive system employing the growth of dendrites has been constructed, and trained to distinguish between four simple patterns. The design of this machine and the training procedure employed are given. Suggestions are made for future work and for other applications or electrolytic growth processes.

A form of apparent visual movement which occurs when spatio-temporally random visual noise is confined in an annular channel has been investigated. The phenomenon, known as the Omega Effeot, does not seem to be related to the phi-phenomenon, although there are formal similarities with observations sometimes made in certain stroboscopically illuminated fields. The period of omega movement was found to be independent of most of the statistics of the visual noise used to evoke it. Over 100 subjects were tested with a variety of stimulus-annuli. Although large individual differences occurred, the mean period and variance of most Ss did not generally vary, although there was some dependence on performance in the recent past. Significant sex differences were found in estimates of the mean period. The more of observation had little effect that could be measured. Simple, circular annuli evoked the clearest and most consistent reports of apparent movement. The two parameters which conditioned the mean period p were found to be the annulus diameter D and the channel thickness T. For large enough groups of' Ss , it was shown that p = K1 D log T + K2 log T + K3 D + K4 fitted the experimental data very closely. It was demonstrated that both changes in distance and changes in angle of regard affected the mean period, there existing a negative and a positive correlation, respectively. The former finding was in agreement with prediction, but the latter was not. It was postulated that the effect depends to at least some extent on the presence of long-range interactions which possibly exceed the limits normally found in the retina. Some suggestions are made for possible future work.