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.

Neurons are the targets of injury and disease in many neurological conditions, and achieving neuronal survival/repair is a key goal for regenerative medicine. In this context, genetic engineering of neurons offers a platform for (i) basic research to enhance our understanding of neuronal biology in normal, disease/and injury conditions; and (ii) for regenerative medicine to enhance the functionality of neurons. Although, a wide range of attempts have been made to promote gene delivery to primary neurons, these cells are still difficult to genetically engineer, and current methods rely heavily on viral vectors which pose safety considerations. Magnetic nanoparticles (IONPs) are currently of great interest in regenerative medicine including for non-viral gene delivery by the ̳magnetofection‘ strategy, i.e when used with applied magnetic fields. This project aimed to examine (i) the influence of two novel uniaxial and biaxial oscillating magnetic field devices on primary neuronal transfection efficiency, and (ii) examine the safety of magnetofection using histological and electrophysiological studies. In order to do this, a robust protocol to derive primary cortical neurons was first established. A second issue is that surgical delivery of Neurons results in low survival. Additionally, most basic research has relied on neurons grown on ̳hard‘ substrates such as plastic, which do not mimic the mechanical properties of the in vivo microenvironment. To address these limitations, primary cortical neurons were grown in a 3-dimensional ̳soft‘ collagen hydrogel construct which can serve both as a protective cell delivery system and a ̳neuromimetic‘ substrate. The safety of the established protocol was evaluated by electrophysiological analyses on neurons. The findings demonstrate that the safety of magnetofection is magnetic field dependent, and at optimal conditions, electrophysiological properties of the nano-engineered neurons were normal. Secondly, I have shown that collagen hydrogels can support the 3D growth of neurons and electrophysiological studies can be carried out on the construct neurons; small differences were found between neurons grown on hard and soft materials. Finally, the amenability of genetic engineering of neurons within hydrogels using IONPs has been shown.

This thesis examines the effectiveness of social problem solving programmes and the efficacy of an assessment tool designed for mentally disordered offenders (MDOs) and intellectually disabled (ID) offenders in secure hospital settings. Firstly, a systematic review concluded that all studies reported benefits of the social problem solving programmes with MDOs. Several studies also identified that shorter revised programmes had lower drop-out rates, and were more cost-effective. Methodological limitations were identified and suggested further research is needed. Secondly, Interpretative Phenomenological Analysis (IPA) was utilised to explore the meanings ID offenders in a secure hospital attribute to their experience of the Thinking Skills Offender Programme (TSOP). Five themes emerged and participants’ conveyed a sense of hope in relation to their treatment, discussed challenges they faced, identified the impact the TSOP had on factors contributing to their offending behaviour, and wanted to share their experiences with a wider audience. Further research to develop effective programmes for ID offenders is discussed. Thirdly, an assessment and treatment of an adult male violent offender with ID and Autistic Spectrum Disorder (ASD) who undertook the TSOP in a medium secure unit is examined. The findings highlighted the difficulties in assessing and treating such patients using conventional methods and the need for standardised assessments and interventions for this population is discussed. Finally, the reliability and validity of the Novaco Anger Scale and Provocation Inventory (NAS-PI) is examined with MDOs and ID offenders. Its clinical utility in inpatients settings and limitations are also discussed. This thesis has highlighted the benefits of social problem solving programmes with MDOs and ID offenders, difficulties of conducting research with this population, and the need for further rigorous research into assessments and interventions.

Introduction The number of prescriptions dispensed for opioid medicines has increased in the U.K. in the last two decades and studies have shown patients are receiving opioids for longer periods than in the past. There is a lack of evidence as to the effectiveness of these drugs when used long-term, as efficacy evidence is taken from short clinical trials in populations who do not have the comorbidities commonly seen in chronic pain patients. Large observational studies of patients prescribed opioid medicines outside of clinical trials, have identified that some patients taking long-term opioids are reporting they are still in high levels of pain. There is also a concern that patients are receiving high dosages of opioid medicines without effective pain relief. However, no studies in the U.K. have looked at the proportion of patients who continue to receive opioids (for all conditions) in the long-term or at high dosages so we do not know how opioid use develops in the U.K. Research from other countries has also identified that long-term and high dose use is linked to patient characteristics such as patient demographics and psychological and physical comorbidities. For example, a prior history of depression has been found to increase the risk of long-term and high dose use. This is of concern as this may indicate that patients may be potentially medicating the depression with the opioid. This may not be the case in the U.K. due to key factors such as the structure of the health system, so the aim of this thesis was to see if this phenomenon could potentially be occurring in the U.K. Methods This thesis was a retrospective observational cohort study of patients receiving opioid medicines for non-cancer conditions using data from a U.K. derived primary care database, the clinical practice research datalink (CPRD). Patients were included in the study if they received a prescription for opioid medication at any point in the year 2009 and followed, where possible to January 2015 (though data was collected for baseline variables prior to 2009). This thesis consists of a series of longitudinal analyses that attempt to define and describe the probability of long-term use and proportion of patients who receive high dosages in the U.K and seeks to understand how baseline characteristics (such as having a comorbid condition occurring before opioid use starts) affect the probability of long-term and high dose use. Competing risks methods were used to calculate the probability of continuation of opioid medicines (using death as a competing risk) and to determine long-term use. Cox regression models were used to determine whether baseline factors (such as prior antidepressant use) were associated with discontinuation of long-term use. Calculation of odds ratios were used to predict whether baseline characteristics predicted high dose use. Cox regression was also used to predict time to discontinuation of high dose use. Results In the U.K., 10.58% of patients received opioid medicines to treat non-cancer pain in the year 2009. Of the non-cancer patients included in the study, 41.41% were patients who received opioids in the six months prior to 2009 and the remaining were new users of opioid medicines. In the new user opioid group, 5.75% continued to be prescribed opioids for at least one year. When including new and existing users of opioid medicines, one in thirty people in the U.K. population who started opioids for non-cancer pain in 2009 were continuously prescribed opioids for a full year. Patients who were female, received an antidepressant before opioid use started and were in the youngest age category were more likely to continue opioid use past 2 years. The probability of continuing to take opioid medicines is higher in patients who have been receiving opioids for longer and are on higher dosages; in patients who had received over 10mg OMEQ for over two years, over half of patients continued to receive prescriptions for opioid medicines for the five year period study after 2009. In the U.K. population, one in a hundred opioid medicine users were prescribed a high dose (estimated dosage received >120mg oral morphine equivalents per day for at least 91 days) for non-cancer pain in their first 91 days of use in the year 2009. Patients receiving high dosages were likely to be receiving multiple opioid drug types and to receive preparations with multiple release profiles. In new users of opioid medication, the odds of high dose use were increased in patients who were younger (aged 18-49 years), had 3 or more comorbidities or were in receipt of an antidepressant or benzodiazepine and/or anti-anxiety drug before or after opioid use started. In new and existing users of opioid medicines, patients who were receiving high dosages were more likely to be diagnosed or be recorded with symptoms of depression or anxiety and to have been prescribed an antidepressant or benzodiazepine and/or other anti-anxiety drug in the youngest age group compared to the older age groups. Of the patients that were prescribed high dosages of opioid medicines for at least 91 days, 37.64% of patients did not have a second consecutive high dose quarter due to death or stopping high dose use. Almost one in five patients who had a high dose quarter continued to have a high dose for the next three years (22.98%). Older patients, patients prescribed weak opioids and/or tramadol discontinued high dose use at a faster rate than younger patients. Conclusion Both high dose and long-term use were found to be associated with a prior prescribing of antidepressants before opioid use started, suggesting that in the U.K. psychological comorbidities are associated with continued and high dose opioid use. Further work is required to measure outcomes within these groups and to understand the care that these patients have already received. Most patients who start opioid medicines in the U.K. stop taking them in their first year of use. However, of those who continue use past two years, a large proportion continue for the full five year period. Similarly, only a small proportion of patients receive high dosages of opioid medicines but once this use is established, many patients have a high probability of continuation. Further work should be undertaken to facilitate effective review of these patients in practice.

Synaesthesia is a cognitive trait in which stimuli of one sensory modality are automatically and consistently experienced in conjunction with perceptions in a separate modality or processing stream. Investigations of synaesthesia may help determine the neural processing required in the generation of a conscious experience. In order to gain the most complete understanding of synaesthesia, we have applied an integrated neurophenomenological approach. In Chapter 2 we present an extended case study of spatial-form synaesthesia (SFS) phenomenology. This investigation goes significantly beyond the rudimentary accounts of provided elsewhere, and provides novel observations on inducer-concurrent relationships, suggesting that guided introspection techniques can provide neurobehaviourally relevant information. In Chapters 3-5 we investigate neural activity in grapheme-colour synaesthesia (GCS). In Chapter 3 we demonstrate that activation in colour selective areas during synaesthetic colour processing is dependent on individual differences in phenomenology, thereby reconciling previous attempts to replicate this key finding in the GCS literature. In Chapter 4 we find no evidence for trait level differences in context specific functional connectivity in GCS, however, we demonstrate that localisation of the synaesthetic concurrents modulate connectivity between colour and low-level visual areas. In 5 we replicate findings of trait level differences in resting state fronto-parietal networks, suggesting that the RFPN may be a significant network in aspects of the synaesthetic experience common to all participants. We demonstrate that localisation of concurrents also modulates resting state visual networks, whilst automaticity of concurrents modulates parietal networks. Both Chapters 4 and 5 support a model of synaesthesia in which localisation of concurrents is modulated by bottom-up connectivity, between colour and early visual areas. This thesis demonstrates that individual differences in synaesthetic phenomenology significantly impact neural activity. We propose that future investigations place emphasis on the phenomenological experience of the participant in the interpretation of neural effects.