Background: Central Nervous System (CNS) inflammatory syndromes represent a spectrum of diseases caused by infiltration of inflammatory cells into the tissue of the brain and spinal cord. They comprise a group of diseases that can be acute or chronic, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO) and its spectrum disorders (NMOSD), clinically isolated syndrome (CIS) and multiple sclerosis (MS). MS is the most common one while NMO/NMOSD is relatively rare although the exact population-based epidemiological parameters are lacking. The distinction of MS and NMO/NMOSD in adult patients and of MS and ADEM in paediatric patients is important for considerations of prognosis and treatment. This thesis aims to differentiate NMO/NMOSD from MS using epidemiology analyses and quantitative magnetic resonance imaging at 7 Tesla. The hypothesis of the thesis is that NMO/NMOSD can be differentiated from MS by disease incidence, prevalence, severity, and the quantitative characteristics of the lesion and non-lesion white matter of the brain. Methods: The thesis firstly employed a comparative epidemiological study to estimate incidence and prevalence of MS and NMO/NMOSD, and to estimate risks for associated comorbidities and mortality between NMO/NMOSD and MS. The thesis then applied two quantitative techniques to compare the white matter lesions and non-lesion white matter (so-called normal-appearing white matter [NAWM]) of both NMO/NMOSD and MS. Results: The results are presented in seven chapters. Chapter 1 provides a general review of CNS inflammatory syndromes. Chapter 2 shows the estimated incidence and prevalence of CNS inflammatory diseases in 2012 using the Clinical Practice Research Datalink (CPRD). MS is estimated to be the most prevalent and the NMO/NMOSD the rarest. Chapter 3 shows the case-controlled analytic results on the impact of the burden of comorbidity in MS. The burden is cumulative after MS diagnosis and impacts on patient survival compared to non-MS patients. With an interest of new-onset epilepsy in the course of MS compared to non-MS controls, chapter 4 shows that MS patients have a higher risk of having the first medical recorded epilepsy at and after MS diagnosis. Chapter 5 shows the comorbidity burden in NMO/NMOSD, and estimates the risk for mortality between NMO/NMOSD and age- and gender-matched MS populations. Chapter 6 compares in vivo white matter lesions and NAWM of the brain between adult patients with NMO/NMOSD or MS and healthy subjects using quantitative T1 relaxation time and magnetisation transfer ratio (MTR) magnetic resonance imaging at 7 Tesla. The results show that myelin content of white matter lesions is relatively better-preserved in NMO/NMOSD than that in MS; and they also show some changes in the NAWM of NMO/NMOSD, despite the fact that the metrics of the histogram of both sequences are not different to those in MS. Conclusions: In the UK, NMO/NMOSD is rare with a higher disease severity compared to MS, which is the most prevalent inflammatory disease. In vivo, using T1 relaxation time and MTR imaging at 7 Tesla, the white matter lesions of the brain have more preserved myelin in patients with NMO/NMOSD than in those with MS. There is at least a small proportion of intracranial NAWM having subtle changes in patients with NMO/NMOSD that is detectable, but the changes could not be differentiated from MS in the current study. This thesis helps to better understand the epidemiology of NMO/NMOSD and MS, and MRI detectable changes of lesions and NAWM in NMO/NMOSD.

No description available.

The enteric nervous system (ENS) is commonly referred to as the ‘second brain’ due to its complex networks of neuronal cells. The abnormality of these neurons and/or their absence has been shown to play a fundamental role in diseases of both the ENS and the central nervous system. Accordingly, electrophysiological studies of the ENS and general understanding of how enteric neurons behave in the gastrointestinal tract are critical in the characterization of the pathophysiology of enteric and neurodevelopmental diseases. To date, studies on these aspects have been limited by the difficulty of culturing enteric neurons in-vitro, as well as by their poor adhesion properties. The primary objectives of this thesis are to develop strategies to investigate electrodynamics processes of enteric neurons and close in on their interactions with polymeric substrates, aiming at optimizing conventional experimental approaches and expanding the current knowledge and critical understanding of this elusive cell type. By capitalizing on a rapid and efficient culturing method developed by our group, different polymers were tested in order to assess their ability to promote adhesion of enteric neurons, as confirmed by immunofluorescence analysis. The most effective polymer resulting from this initial screening was then applied as a coating onto the glass surface of multichannel electrode arrays (MEAs) allowing for the analysis of neuron dynamics. While Matrigel® was the most effective at promoting both neuron adhesion and neurite outgrowth, it acted as an insulating material which prevented the MEA electrodes from picking up electrical signals. Therefore, we opted instead for laminin protein and poly-d-lysine immobilized on glass by polydopamine, to study the electrophysiology of the neurons. Of note, polydopamine was found to be critical in enhancing the stability of the protein coating and ensuring cellular viability. The same protein coating was also used to functionalize the surface of blends of poly(styrene) and poly(methyl methacrylate), which segregate when mixed to give rise to varying topographical features. These surfaces aimed at elucidating fundamental processes that dictate how neurons interact with surfaces when compared to smooth rigid surfaces (i.e. glass). Finally, the most effective surface for neuron adhesion was applied to study how chemotaxis influences neurite elongation and directionality. Enteric neurons were cultured onto both a linear concentration gradient of protein created using a microfluidic system and a uniform concentration profile to compare their response to chemical signals. In general, their motion was random and lacked directionality on the uniform protein surface. The neuronal response to the chemical gradient could not be evaluated to completion; however, this analysis still provided meaningful insight as a starting point for future studies. The results presented in this thesis serve as a significant stepping-stone for the improvement of the in-vitro study of the ENS and will be used to gain a deeper understanding of enteric diseases, ultimately contributing to the development of novel polymeric scaffolds for tissue-engineering applications.

About a third of stroke survivors have some degree of depression. Depression has a significant impact on recovery after stroke, and identification is important so it can be treated. A common symptom of stroke is aphasia, where comprehension or expression of language is significantly impaired. Communication problems following stroke have been shown to be a major predictor of depression after stroke, yet these problems often make assessment of mood using conventional, language-based measures difficult or impossible. Though some non-verbal, self report mood measures exist, their utility is limited and evidence base lacking. The aim of this study was to design, create and validate a non-verbal mood assessment instrument suitable both as a general outcome measure and as a screening measure for depression in stroke patients with aphasia. A series of four judgement experiments were conducted based on 22 photographic sittings, and a series of scales were developed. The resulting prototype instrument Dynamic Visual Analogue Mood Scales (D-VAMS) is a tablet/computer-based instrument consisting of seven bipolar scales comprising images of human faces whose expressions are modulated by sliders. The instrument was then validated in a sample of 46 stroke survivors recruited from online, from stroke clubs and via NHS rehabilitation services. Good construct validity was demonstrated by high correlations between word and face versions of the seven D-VAMS scales (r=.73 to r=.79), however discriminant validity was poor, with substantial cross-correlations between scores for all of the face scales (r=.58 to r=.88). Internal consistency of D-VAMS was very high, with a Cronbach’s α of 0.95. A Principal Components Analysis revealed one factor accounting for 80% of the variance, corresponding to pleasantness or unpleasantness of mood. Excellent criterion validity was evidenced by strong correlations between D-VAMS and Hospital Anxiety and Depression Scale (HADS) depression subscale (HADS-D) scores (r=.73). Excellent test-retest reliability (r=.89), and high sensitivity and specificity against HADS-D cut-offs of 4–7 were also found. The findings suggest that the D-VAMS is a valid, brief measure of pleasantness of mood in a range of 0–100 which is suitable for use as a general outcome measure for stroke survivors with aphasia, and which may serve as an indirect, simplified measure of depression. Though D-VAMS may also be useful as a screening measure for depression following stroke, further validation is needed to examine how it performs in people during the acute stage after stroke. Some supervision may be required for people unfamiliar with using a tablet or PC interface.

The study of spontaneous brain activity using functional Magnetic Resonance Imaging (fMRI) is a relatively young and rapidly developing field born in the mid-nineties. So far, sufficiently solid foundations have been established, mainly in validating the neuronal origin of a significant component of observed low-frequency fluctuations in the 'resting state' fMRI signal. Nevertheless, the field is still facing several major challenges. This thesis first reviews the current state of knowledge and subsequently proceeds to present original research results that are directed towards overcoming these challenges. The first challenge stems from the indirect nature of the fMRI recordings, obscuring the interpretation in terms of the underlying neuronal activity. Two investigations related to this are presented. First, I show that increased head-movement, epiphenomenal to altered states of consciousness, can lead to spurious increases in low-frequency fluctuations in fMRI signal. This may adversely affect inferences on the underlying neurophysiological processes. Second, I demonstrate a direct electrophysiological correlate of increased synchronisation of fMRI activity in areas of the much studied default-mode network. By directly studying electrophysiological correlates of fMRI-based functional connectivity, this study took a pioneering approach to confirming the biological validity of the fMRI functional connectivity concept. Another widely debated question within the field is the optimal method for extracting relevant information from the extreme volumes of neuroimaging data. I present an investigation providing insights and practical recommendations for this question, based on assessing the interdependence information neglected by the commonly used linear correlation for fMRI functional connectivity studies. The results suggest that in typical resting state data, the nonlinear contributions to instantaneous connectivity are negligible. The third major challenge of the field is the integration of the experimental evidence into theoretical models of spontaneous brain activity. In the last part of this thesis, such models are discussed in detail, focusing on the two crucial features of observed spontaneous brain activity: functional connectivity and low-frequency fluctuations. Two specific mechanisms for emergence of the latter are proposed, depending either on the local synchronisation dynamics or the regulatory action of particular neuromodulators. The thesis concludes with discussion of the questions arising from the presented results in the context of the most recent development in the wider field.

Introduction: This thesis explored Chronic Neuropathic Pain (CNP) patients' experiences of the treatment journey of Spinal Cord Stimulation (SCS) surgery, considering life prior to, and after the surgery. Previous SCS literature has predominantly focused on technology, SCS efficacy, and the role of psychological factors in SCS patient selection and outcomes. Whilst research highlights SCS as an effective treatment for various CNP conditions, it predominantly employs quantitative outcome measures, thereby reducing the depth of information yielded about the experience of SCS surgery and patient satisfaction. There is a dearth of in-depth understanding of the lived experience of the SCS surgery treatment journey. Objectives: The aim of this thesis was to explore participant experiences of the SCS surgery treatment journey considering life prior to and after the surgery. Methods: Ethical and NHS trust approval were obtained. A purposive sample of seven CNP patients who had undergone SCS surgery 2-8 months previously were recruited. Each participant took part in a face-to-face semi-structured interview which was audio recorded. Interviews were transcribed verbatim and analysed using Interpretative Phenomenological Analysis (IPA). Results: Three super-ordinate themes were generated: Diminished control and coping, identity transitions and SCS conflict. The themes were interpreted as being interconnected with each other. To demonstrate the treatment journey, all themes were included in the journal paper and further details of convergences and divergences between participants were included in the extended paper. Discussion: In line with previous research, patients’ expectations of SCS surgery were significant in patient satisfaction with the outcomes, reinforcing the importance of identifying and addressing expectations in pre-surgery preparation. Given SCS is often the last treatment option; the current study found post-SCS participants were going through a process of acceptance of lost identities and of current pain relief and capabilities. Simultaneously, participants were adjusting to living with the stimulator, indicating the significance of offering psychological treatments adjunct to SCS treatment to support participants through these processes. Difficulties in acceptance of identity changes and adjustment to SCS could negatively impact on mood and sense of control which can have adverse effects on pain perception.

Stroke is a major contributor to the global burden of disease. It is the third main cause of death and the largest cause of adult disability in the UK. Stroke is reported to be the second most common cause of disability after dementia in the UK care home population with an estimated 25% of residents living with the consequences of stroke. The aim of this PhD programme of research was to explore the current research evidence for the provision of occupational therapy to stroke survivors living in care homes; investigate current routine occupational therapy practice for this specific stroke population in UK care homes; and to contribute original new knowledge on the health outcomes of sub groups of the care home population with stroke. This study was divided into four distinct projects that were completed alongside a National Institute for Health Research funded phase III multi-centre cluster randomised controlled trial of occupational therapy for care home residents with stroke known as the ‘OTCH study’. The OTCH study evaluated the efficacy of delivering occupational therapy interventions targeted towards increasing and maintaining independent performance of personal self-care activities of daily living and mobility. The PhD student was a member of the OTCH study team with responsibility for delivering the intervention at the Nottingham site. A PhD studentship from the University of Nottingham enabled the development of this complimentary and integrated programme of research. Stage one (reported in chapter two) involved the completion of a Cochrane systematic review and meta-analysis as a means of systematically appraising published randomised controlled trials of occupational therapy interventions for care home residents with stroke to the highest gold standard. Systematic searching identified 1,436 unduplicated records however only 1 study met the inclusion criteria, with another trial ongoing. There was insufficient evidence from the reviewed randomised controlled trial to determine that occupational therapy improves outcomes for care home residents with stroke and therefore further high quality research in this area is needed. Stage two (reported in chapter three) involved a national online survey study to provide contextual demographic data, along with data on the aims, content, funding and provision of occupational therapy services currently being delivered to stroke survivors residing in UK care homes. Out of a total of 138 completed questionnaires, data were analysed from 114 respondents who met the eligibility criteria of providing assessment and treatment to residents in a care home setting. The survey findings confirmed that occupational therapy is being delivered in some care homes; however, interventions for residents with stroke are not routinely delivered by stroke specialist occupational therapists and are not routinely delivered using a systematic, evidence-based approach. Stage three (reported in chapter four) utilised the raw data from the 1,042 participants recruited to the OTCH study to perform subgroup analysis and predictive modelling (including regression modelling and generalised estimating equation (GEE) modelling) with the aim of further investigating the effect of occupational therapy on various subgroups of the participant sample. Subgroup analysis determined that age, time since stroke onset, cognitive status, mood and pain made no difference to the effect of a three month occupational therapy intervention aimed at improving or maintaining independence in basic ADLs (as measured by the Barthel Index (BI)). Predictive modelling found type of care home (residential or nursing) and cognitive status (dementia or normal cognition) to be a far greater predictor of ADL performance and mobility outcome than whether or not the resident had received the occupational therapy intervention. Stage four (reported in chapter five) involved analysis of the content of occupational therapy intervention delivered to the OTCH study participants and their performance in self-care ADLs to account for possible reasons why the trial produced neutral results by (1) exploring the content of the treatment that the intervention arm participants received from the study occupational therapists; and (2) investigating the performance of those participants who had received the allocated occupational therapy intervention, whilst accounting for possible predictor covariates. Binary logistic regression was used to model the relationship between the dependent outcome variable and the explanatory predictor variables. Results of the analyses demonstrated that the therapists did not allocate their time according to those with greater levels of disability and higher levels of need. Residents with dementia received less therapy input than those with mild cognitive impairment or normal cognition. Cognitive status was the strongest predictor of functional outcome. The thesis concludes by highlighting the implications of this new body of research evidence for occupational therapy clinical practice, policy, and future research.

Title: The language of acute pain assessment: a corpus-based Critical Discourse Analysis approach Aim: Through use of real time interactions between healthcare workers and patients in an acute hospital setting this study sets out to investigate how health care workers help or hinder patients to express their pain during the pain assessment process. Background: Pain has long been an issue for investigation and there are a multitude of assessment options available. However, despite using an assessment framework, the ability of patients to use language to express pain has been shown to be more problematic than might be first considered. This study sets out to investigate how both patients and healthcare workers use language in this assessment process. Method: Real time data was recorded in an acute hospital in-patient setting. The use of corpus based critical discourse analysis enabled specific instances of word use and phrases related to pain experience to be identified and analysed. Findings: Two key areas were identified in the analysis of these interactions. The first area related to the traditional aspects of pain assessment relating to terminology used, location and function of pain. The second more important area related to how healthcare professionals presented a certain ‘mentality’ about the assessment process in how they appeared to be patient centred but through the use of brevity of interaction and trivialisation of the issues actually presented an opposite view. Conclusion: The primary conclusion is that although healthcare workers apply pain assessment processes, their use of language can show that they are both patient-centred and have their own motivations and agendas.

The work in this thesis is focused on the study of neuroinflammation with molecular magnetic resonance imaging (MRI) methods. Neuroinflammation is a response of the central nervous system to pathological insult and it is present in many neurological disorders, such as Alzheimer’s disease. Being able to image neuroinflammation non-invasively with MRI techniques would have an important clinical value for diagnosis and assessment of therapy effectiveness. The aim of this work is to develop and validate an MR biomarker of neuroinflammation using MR Spectroscopy (MRS) and chemical exchange saturation transfer imaging (CEST). First, intravenous administration of lipopolysaccharide (LPS) is used as a mild inflammatory stimulus in wild type mice and in a mouse model of Alzheimer’s disease (AD). Elevated levels of the osmolyte myo-inositol, measured with MRS and microglia activation are found in AD mice after LPS administration. Due to the inherent low spatial resolution of MRS, a CEST MRI method is developed next. A myo-inositol CEST protocol is optimised, using Matlab simulations based on the Bloch-McConnell equations for a three pool model, in order to maximize the contrast and to estimate the amount of signal that can be expected in vivo. In vitro and in vivo tests are presented and a fast CEST sequence is developed, while the experimental difficulties and limitations of the technique are discussed. A CEST protocol is finally applied to evaluate the metabolite response to an LPS inflammatory challenge using MRS and histology as validation. A correlation is described between CEST and MRS myo-inositol levels, as well as between CEST and microglia concentration (Iba1 immunostaining), which highlight the potential of CEST as a non-invasive in vivo neuroinflammatory biomarker.

No description available.