People with multiple sclerosis (MS) undergo changes to their identity and this might have an effect on mood. The subjective experience of this identity change is currently not well understood. Past research highlights that social groups, established prior to diagnosis, might protect against the harmful effects of identity change. No studies have specifically investigated this and the implications this may have for psychological interventions for mood in people with MS. This thesis first presents a systematic review of the efficacy of group based psychological interventions for low mood in people with MS compared to individual based interventions. Group based interventions were found to be more effective as treatments for depression in people with MS and this may be due to the peer support available. Previous research has highlighted that people may be more willing to accept peer support from people with whom they share a social identity. People undergo changes to identity due to MS, this thesis focuses on identity change following diagnosis. The family is seen as an important source of social support. A meta-synthesis of the role of the family in acting as a secure base for identity reconstruction was undertaken. The family may provide a secure base for identity reconstruction, as long as the coping strategies used by the person with MS and the family are aligned. Sixteen interviews were conducted with people with MS to examine changes to identity over time and what factors might have influenced this. Social support was important for incorporating the MS identity into overall sense of self. A survey study (n = 203) was then conducted to examine whether family identity may have an effect on mood through social support and connectedness to others, as hypothesized on the basis of the Social Identity Model of Identity Change. Family identity was directly negatively correlated to mood; however, it had an increased effect on mood through the mediators of social support and connectedness to others. This research in this thesis found that, if coping strategies are aligned, the family provides a secure base for identity reconstruction through social support, which can lead to self reflected appraisals in the person with MS. Identifying with the family group can have a positive effect on mood and can lead to increased interaction with other people with MS following adjustment. The implications of this research are that people do experience changes to their identity following a diagnosis of MS and that social support can help a person to incorporate this into their sense of self. The family can provide a secure base for identity reconstruction. Identifying with the family group can have a direct positive effect on a person’s mood, in line with the SIMIC. Family identity can also have an indirect effect on a person’s mood through the parallel mediators of family social support and willingness to join new social groups. Group psychological interventions have a greater effect on depression and anxiety in people with MS compared to individual interventions. People may be more willing to engage in-group interventions after an initial period of adjustment. Further research should investigate the SIMIC in people with other chronic conditions. The increased inclusion of the family in support for the person with MS could facilitate the adjustment process.

Objectives: Memory problems are reported in 40-60% of people with multiple sclerosis (MS), they can affect independence in activities of daily living and may limit their ability to benefit from rehabilitation. There was some evidence to support the use of NeuroPage, a memory aid service, in people with neurological conditions, but there were methodological limitations. The aim of this study was to evaluate the effectiveness of the NeuroPage service for people with MS who have memory problems. Systematic Review: A systematic review on external memory aids for people with MS was performed. Eight studies were included; one study reported a treatment effect on subjective memory functioning; one on mood. No effect was demonstrated on objective memory functioning or quality of life. It was concluded that the evidence was insufficient, and high quality trials were needed. Methods: A multicentre, single-blind randomised controlled crossover trial design was employed. People with MS and self-reported memory problems were recruited into the trial, following referral from MS services. The intervention was ‘NeuroText’, a service that sends reminder messages to people’s mobile phones at pre-arranged times via the existing NeuroPage system. In the control condition participants received non-memory texts, containing items of interest, such as news headlines. Outcome measures were completed using postal questionnaires. t-tests were employed to compare intervention and control conditions. Semi-structured feedback interviews were performed with 25 participants. Results: Of the 106 people referred 38 took part. They were aged 28 to 72 (mean=48, S.D.=11) and 10 were men. No significant differences between NeuroText and control were detected on the Everyday Memory Questionnaire (t =0.84, p=0.41). The number of daily diary items forgotten in the NeuroText condition was significantly less than in the control (9% vs. 31%; t=-2.8, p=0.01). Reported psychological distress in the NeuroText condition was also less than control (t=-3.83, p=0.001). Seven themes were identified from participant feedback. Conclusions: NeuroText appears to be help people with MS to achieve their everyday tasks and improve mood, however these improvements were not reflected on the questionnaire measure of the frequency of memory problems in everyday life.

Background: The Ministry of Health in Saudi Arabia estimates that there are at least 20,000 strokes per year across the country (126/100,000) and approximately half of those with stroke may develop cognitive dysfunction or mood disorders. However, a review of the literature revealed that research in the area of post-stroke cognitive dysfunction and mood disorders in the Kingdom of Saudi Arabia (KSA) is severely lacking. Accordingly, these studies aimed to bridge the knowledge gap with an emphasis on three central aspects. The first aim was to assess the prevalence of post-stroke cognitive dysfunctions in the KSA population using neuropsychological tests. The second aim was to assess the prevalence of post-stroke mood disorders in the KSA using self-report scales. The third aim was to evaluate the relationship between cognitive dysfunctions and mood disorders. Method: Observational methods were used to collect descriptive information about the prevalence of cognitive dysfunctions and mood disorders in the Saudi population. Participants were recruited from three medical centres in the KSA: King Abdulaziz Medical City, King Fahad Medical City, and Sultan Bin Abdulaziz Humanitarian City. The target sample was age 18 years and above who were diagnosed by neurologists with ischemic or haemorrhagic stroke according to CT-scan results, and who were at least one month post first-ever stroke, and either attending out-patient clinics or admitted to medical centre. Participants were excluded from the study sample if they satisfied any the following conditions: severe dementia; sever aphasia; chronic psychiatric or other concurrent neurological disorders; a known history of alcohol or drug abuse; blindness or deafness; participant non Saudi citizen; an inability to speak or understand Arabic; or medically unstable. Results: For the empirical investigation, 76 men and 24 women were recruited (mean age 60.53 ± 11.26 years). Of these, 52% had deficits of orientation/attention, 55% of memory, 36% of fluency, 46% of language, 26% of visuospatial ability, 35.7% of visual neglect, 58.4% of visual-motor skills, 69% of executive function, and 52% had overall cognitive impairment, 36% had anxiety and 44% had depression after stroke. The results confirmed a strong relationship between cognitive dysfunctions and mood disorders. However, from the regression model, it was found that ‘literacy’ (literate vs. illiterate), ‘time since stroke’ (≤ 6 vs. ≥ 7 months), ‘fluency impairment’ and ‘memory impairment’ were significant predictors of the severity of anxiety disorder after stroke. Similarly, ‘literacy’ (literate vs. illiterate), ‘time since stroke’ (≤ 6 vs. ≥ 7 months), ‘fluency impairment’, ‘memory impairment’, ‘visuospatial ability impairment’ and ‘visual neglect’ were significant predictors of the severity of depression after stroke. Conclusion: Based on the sample of Saudi patients (n= 100), it can be concluded that cognitive dysfunctions have an effect on the stroke patient’s mood. The severity of cognitive dysfunction is significantly related with mood disorders, in particular depression disorder.

Introduction: Improving confidence following stroke has been cited as a research priority (Pollock et al 2012). It is difficult to measure a change in confidence levels without valid and reliable measures. This research aims to develop and conduct a psychometric evaluation of a self-reported, confidence after stroke measure [CaSM]. Methods: Items were generated from themes highlighted in the literature review, and from a qualitative interview study, exploring the meaning of confidence. The CaSM was piloted with expert groups to establish face and content validity. The CaSM was administered to a sample of stroke and healthy elderly people recruited from the community. Completed postal questionnaires were analysed for reliability (internal consistency and test-retest), construct validity (factor analysis) and convergent validity. A visual analogue scale, to correlate therapists opinion with CaSM scores was used to assess concurrent validity. Sensitivity to change was assessed by comparing change scores at three time points after a confidence intervention. Case vignettes were used with stroke clinical experts to detect a minimal clinically meaningful change score. Results: Stroke (n=101) and healthy elderly participants (n=101) were recruited. Using item reduction techniques, a 53 item scale was reduced to 27 items. Factor Analysis was used to derive a three factor solution, Self-Confidence, Positive Attitude and Social Confidence, which explained 52% of variance. There was good evidence for internal consistency (α=0.94) and good temporal stability (rs=0.85 p=0.001). There was a small positive correlation between the two variables when assessing concurrent validity (rs=0.18, n=31, p<0.34), and did not demonstrate statistical significance. Four points on the CaSM was recommended by clinical experts as being a clinically important change score. Conclusion: The 27 item CaSM [Appendix 1] was shown to be a valid and reliable measure. The CaSM was designed to be used to identify people with low confidence after stroke in order to facilitate appropriate treatment. The CaSM could be used in research, as a patient reported outcome measure to evaluate strategies to improve confidence after a stroke. Assessment of the CaSM’s ability to detect sensitivity to change needs further assessment.

Background: Paediatric ependymomas are the second most common malignant brain tumours in children. Tumour recurrence, chemoresistance and invasion of surrounding critical structures are the hallmarks of ependymomas. These features are consistent with the cancer stem cell (CSC) hypothesis which states that tumours harbour a sub-population of stem-like cells which underlie therapeutic resistance. This study investigates the role of the radial glial stem cell marker BLBP, the multidrug transporter ABCB1, and the DNA repair enzyme MGMT in therapy failure in ependymomas with particular emphasis on the role of CSCs. Material and Methods: Database analyses were performed to assess the expression of the aforementioned markers in patients from 3 publicly available gene expression datasets. Furthermore, samples from 2 European paediatric ependymoma trial cohorts were screened for ABCB1, BLBP and MGMT expression by immunohistochemistry to elucidate their prognostic value. The expression of these markers was also determined in a panel of 5 ependymoma derived cell lines by QRT-PCR or western blotting analysis. Roles in chemoresistance (clonogenic & cytotoxicity assays) and tumour invasion (wound healing & 3D invasion assay) were then investigated. Results: Poor survival in the chemotherapy-led paediatric ependymoma CNS9204 trial was significantly associated with ABCB1 (P=0.007) and BLBP (P=0.03) expression whilst MGMT (P<0.001) and BLBP (P=0.002) expression predicted poor survival in the radiotherapy-led CNS9904 trial cohort. ABCB1 and BLBP expression was consistent with the CSC hypothesis whilst MGMT was expressed in both CSCs as well as the tumour bulk. Inhibition of ABCB1 and BLBP, with the phosphodiesterase-5 inhibitor vardenafil and PPAR-ϒ antagonist GW9662 respectively, potentiated response to chemotherapy and also inhibited the ability of ependymoma cell lines to migrate and invade. Finally, whilst each of the tested cell lines were resistant to the alkylating agent temozolomide, they were sensitive to the novel N3-propargyl analogue of temozolomide. Conclusion: ABCB1, BLBP and MGMT were not only markers of robust prognostic value but they also contributed functionally to the aggressive behaviour of ependymoma. Inhibition of ABCB1 and BLBP by vardenafil and GW9662 may represent effective approaches to overcome chemoresistance and invasion in ependymoma patients. The N3-propargyl analogue of temozolomide could also represent a novel treatment option for MGMT expressing ependymoma patients.

Individuals living with Complex Regional Pain Syndrome (CRPS) often experience difficulties taking part in social and recreational activities, which can leave them with a greatly reduced social network and limited opportunities for obtaining social support. Online support communities may provide individuals with an alternative way of obtaining social support, but few studies have examined these communities in the context of CRPS. Furthermore, most online support community research has focussed on established communities, and little is known about how new communities become established. This thesis examines a bespoke CRPS online support community with two broad aims: to examine the development of online support processes in relation to the launch of a new online support community, and to investigate the provision of social support for CRPS within an online support community. The dataset comprised 221 messages posted by 23 participants. Study 1 used the full dataset to examine engagement with the online support community, focussing on the number of individuals who used the forum (membership growth), how they used it (header analysis) and how they introduced themselves (introductory messages). Study 2 used the full dataset to investigate how support processes became established, the support content of messages, and how this contributed to the CRPS ‘four pillars of intervention’. Study 3 used four longitudinal case studies from the dataset to conduct a linguistic analysis of messages, focussing on support providing behaviour and the number of replies received. The results indicate that support processes start almost immediately when a new online support community is launched, and membership growth is closely linked to promotional strategies. Online support may play an important role in CRPS self-management by contributing to the ‘four pillars of intervention’, and there is a possibility that diffusion of responsibility may occur in forums. The longitudinal case study approach may produce important new insights and suggests that the use of health words is unrelated to the number of replies received, the use of self and other-oriented messages may be linked to health status and support providing activities, and that the ratio of positive-to-negative words could potentially be used to identify individuals who might benefit from additional support.

Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system and the formation of protein inclusions in surviving neurones. The mechanisms underlying neurodegeneration and neuroprotection in the nervous system remain elusive. Ubiquitin is one of the hallmarks of neuropathological inclusions in the majority of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Therefore, dysfunction of the ubiquitin proteasome system has been implicated in disease cause and/or progression. This thesis investigates a unique conditional genetic mouse model of neurodegeneration caused by conditional genetic 26S proteasomal depletion in mouse forebrain neurones. We have identified potential proteins targeted for ubiquitination in brain using bio-affinity chromatography of zinc finger protein ZNF216 coupled with mass spectrometry. This lead to the identification of several potential ubiquitinated proteins involved in gene expression and regulation. We have also investigated the global brain proteome in response to 26S proteasomal depletion in neurones using two-dimensional fluorescence difference in-gel electrophoresis coupled to mass spectrometry for protein identification. Several differentially expressed proteins were identified in the 26S proteasome-depleted cortex. Astrocytic intermediate filament proteins glial acid fibrillary protein and vimentin, as well as the antioxidant peroxiredxoin-6, were upregulated. Mitochondrial fumarate hydratase and stathmin-1, involved in the tricarboxylic acid cycle and cytoskeletal microtubule dynamics respectively, were downregulated. These proteins have been validated by biochemical and immunohistochemical approaches. Further analysis of oxidative stress revealed increased lipid and protein oxidation that may be involved in the neurodegeneration associated with 26S proteasomal depletion. However, we also show increased phospholipase A2 activity associated with peroxiredoxin-6 expression that may have additional roles in neurodegenerative and/or neuroprotective functions. Interestingly, the levels of reactive oxygen species were inversely correlated with the upregulation of peroxiredoxin-6. We suggest that peroxiredoxin-6 may play an important role in the brain in the protection against oxidative stress and our studies may improve our physiological and pathological understanding of neurodegenerative disease.

Background: Microglial cells can be regarded as the macrophages of the central nervous system. Their activation has protective functions in the destruction of pathogens, removal of debris and release of neurotrophic factors, but excessive activation can exacerbate the effects of inflammation contributing to neurodegenerative conditions such as Alzheimers disease. The cannabinoids have a variety of anti-inflammatory properties and the main aim of this project is to determine the role of cannabinoids in modulation of microglial cell function using in vitro approaches, and to investigate the molecular mechanisms underlying such modulation. Methods: BV-2 murine microglial and primary murine microglial cells were activated using bacterial lipopolysaccharide (LPS). Nitric oxide (NO) was determined with a Griess assay. Western blotting was used to measure the expression of NFκB p65, Ikβα, inducible nitric oxide synthase (iNOS), COX-2, and total and phosphorylated forms of the MAP kinases, p38, JNK1/2 and ERK1/2; blots were analysed with an Odyssey imaging system (Li-Cor Bioscience), Expression of GPR55 mRNA was determined by RT-PCR. Phagocytosis was assessed in BV-2, HAPI and primary murine microglial cells and in RAW 264.7 monocyte/macrophages using fluorescent latex beads and the cells viewed by confocal microscopy. Fluorescent bead accumulation was quantified on consecutive image and rate phagocytic was calculated by normalizing the number of beads to the number of cells in each field. Western blotting was used to measure the expression of the receptor channels TRPV2 and TRPV1 and AKT. Immunocytochemistry was used to investigate the translocation of TRPV2, and the involvement of MLC11, PLCγ2, PKCα, ε in phagocytosis. Fura-2-based Ca2+ imaging of microglia was undertaken and migration was assessed using a novel “Compass” device. Result: BV-2 cells did not express CB1 or CB2 receptor mRNA; however, the cannabinoid receptor agonist CP55-940, the CB1 antagonist AM251and the non-psychoactive cannabinoid cannabidiol (CBD) all at 10μM produced significant inhibitions of lipopolysaccharide (LPS; 100ng/ml)-stimulated nitric oxide (NO) formation. The putative GPR55 receptor agonists VSN16R and O1916 (were without effect, as was the endogenous GPR55 agonist lysophosphatidylinositol (LPI). A number of other cannabinoid receptor agonists and antagonists and the phytocannabinoids (CBG, CBDV, THCV, CBDA and CBGA (Pertwee, 2008) (all 10 µM) were without. Cannabidiol inhibited LPS-enhancement of both iNOS and COX-2 expression. LPS significantly induced phosphorylation of the MAP kinases ERK 1/2, p38 and JNK and CBD inhibited both LPS-induced p38 and JNK phosphorylation but was without effect on phosphorylation of ERK1/2. The p38 inhibitor SB203580 (10 µM) also significantly reduced iNOS expression after 24 hours of LPS stimulation. LPS increased NF-KB p65 expression and this was significantly attenuated by CBD. LPS also stimulated NF-KB p65 translocation to the nucleus whereas CBD inhibited the effect. CBD-induced phagocytosis of BSA latex beads was similarly induced in HAPI, RAW264.7 and primary murine microglial cells. Inhibitors of Rho kinase (Y27632) and PI (3)kinase (wortmannin) inhibited basal but not CBD-enhanced phagocytosis. CBD increased intracellular calcium in BV-2 cells and the TRP channel blocker ruthenium red reversed CBD-induced phagocytosis. CBD increased expression of TRPV2 protein and mRNA and caused a translocation to the cell membrane. This was abolished in presence of cycloheximide and PI3K inhibitor. Other cannabinoids and phytocannabinoids (CBG, CBDV, THCV, CBDA and CBGA) were without effect. CBD also increased BV-2 cell migration. Conclusion: The data presented demonstrate that CBD, despite inhibiting NO formation, mediated by reduction of NF-kβ P38 MAPK, JNK and ROS activity, enhances microglial migration and phagocytosis. The mechanism of action appears to involve TRPV2 channel activation accompanied by increased protein synthesis and translocation to the cell membrane. Therefore, CBD might be developed as a useful treatment for neurodegenerative disease.

This study was designed to identify the processes which underlie pain in symptomatic diverticular disease (SDD). Our hypothesis was that a spectrum of both peripheral and central pathologies were involved, with those that had a more peripheral problem having abdominal symptoms only while those with multiple symptoms throughout the body, having an altered central pain processing. The first study examining the brain response to cutaneous pain using functional magnetic resonance imaging (fMRI) has supported this hypothesis. Although a statistically significant difference in sensory pain threshold was not demonstrated between the groups, fMRI imaging has shown greater emotional processing during pain and reduced anticipatory inhibitory responses in the high somatising symptomatic diverticular disease (HSDD) groups. However this is not as clear cut as we had anticipated which may be due to subject selection and demonstrate a spectrum of mixed peripheral and central changes as well as those with only peripheral or central components. In the second part we performed a randomized placebo controlled study of mesalazine 3gm versus placebo. Mesalazine significantly reduced expression of many genes associated with inflammation in SDD patients. A reduction in the median number of hours of pain per week was seen. The study was not designed to allow intention to treat analysis but has shown promising results which will need to be consolidated with future large scale studies. Both these studies support a tailored approach to SDD patient treatment based on the underlying pain process which can be both central and peripheral. The Patient health questionnaire 12(PHQ12) may be one simple measure of doing this, but again needs to be confirmed with further larger studies.

There is a call to elucidate the poorly understood link between perivascular adipose tissue (PVAT) and nervous systems controlling the vasculature. The principle aims of this study were to investigate the expression of sympathetic and sensory nerves in PVAT of rat mesenteric arteries, to characterize their role(s) in vascular tone and to investigate the interaction between these nervous systems and PVAT-derived vasoactive compounds. Immunofluorescence staining was employed to investigate the localisation of sympathetic and sensory nerves in mesenteric arteries. Rat mesenteric arterial beds (MABs; with and without PVAT, removed by careful dissection) were perfused with Krebs’-Henseleit buffer and changes in pressure recorded, or different sized rat mesenteric arteries (MA), rat abdominal aortas, porcine splenic arteries (PSA) and porcine coronary arteries (PCA) (with and without PVAT, removed by careful dissection) were isolated and set up for isometric recording. Responses to electrical field stimulation (EFS) were obtained under basal and raised tone conditions induced by methoxamine, an α1-adrenoceptor agonist,‎ in the presence and absence of agonists/antagonists. Enzyme immunoassay (EIA) was conducted to quantify capsaicin-evoked calcitonin gene-related peptide (CGRP) release of different mesenteric arterial segments and the dissected PVAT. A multiplex assay was carried out to investigate the link between sympathetic and sensory nerves and PVAT-derived vasoactive compounds. Immunofluorescence showed the presence of both tyrosine hydroxylase (TH; the rate-limiting enzyme of catecholamine biosynthesis)-immunoreactive and CGRP (the principal neurotransmitter for sensory nerves)-immunoreactive nerves at the adventitia and within PVAT. EFS elicited frequency-dependent vasoconstriction of the mesenteric beds. These responses were abolished by guanethidine, a sympathetic nerve blocker, indicating an involvement of sympathetic nerves. In the absence of PVAT, neurogenic contractile responses were markedly attenuated. There was no significant difference in concentration-dependent contractions to methoxamine in preparations with and without PVAT, thus suggesting that vascular smooth muscle remains intact in PVAT-denuded preparations. Contractile responses to EFS were significantly decreased after Krebs’-Henseleit solution containing PVAT was transferred to preparation without PVAT, indicating PVAT contains transferrable factor/s. Incubation with candesartan, but not losartan, angiotensin II receptor inhibitors, in the presence of PVAT significantly attenuated EFS-evoked contraction, indicating a potential involvement of PVAT-derived angiotensin II in PVAT-enhanced neurogenic contractile response. In PSA, removal of PVAT significantly attenuated EFS-evoked contractile responses. Exogenous methyl palmitate had no effect on sympathetic neurogenic contractions while exogenous apelin-13 reduced sympathetic responses in both PVAT-intact and PVAT-denuded PSAs. EFS of PVAT-intact MABs in the presence of guanethidine and methoxamine elicited frequency-dependent vasodilatation due to stimulation of sensory nerves. Neurogenic vasodilatation was abolished in preparations with PVAT removed. In contrast, dose-dependent vasodilator responses to capsaicin, an agonist at vanilloid receptor subtype 1 (TRPV1), and exogenous CGRP, were comparable between PVAT-intact and PVAT-denuded preparations. This suggests that the PVAT removal procedures did not damage vascular smooth muscle relaxation in PVAT-denuded preparations. Myography experiments revealed that EFS-evoked vasodilator responses were greater in PVAT-intact preparations than in PVAT-denuded preparations in both MA and second order MA (2OMA) segments. EIA indicated that CGRP release was greater in dissected PVAT with capsaicin compared to dissected PVAT without capsaicin in 2OMA preparations, which further supports the concept of the presence of sensory nerves in PVAT of MABs. Sodium sulfide (Na2S), a hydrogen sulphide (H2S) donor, caused concentration-dependent vasodilation and this effect was attenuated by incubation with HC030031, a TRPA1 antagonist, and pre-treatment with capsaicin. The vasodilator response was greatly attenuated in the second response curve, indicating the involvement of desensitization mechanism. EFS elicited frequency-dependent vasodilatation due to stimulation of sensory nerves but these responses were attenuated in the presence of Na2S. Incubation with H2S-synthesizing enzyme inhibitors, DL-propargylglycine, aminooxyacetic-acid and aspartate, had no significant effect on EFS-evoked neurogenic vasodilatation. The presence of PVAT enhanced leptin release under normal oxygenation (95 % O2 and 5 % CO2), while gassing with 95 % N2 and 5 % CO2 enhanced interleukin-6. Leptin release was enhanced during EFS of sympathetic nerves under low oxygen level and EFS of sensory nerves under normal oxygen level in the presence of PVAT. In conclusion, the present study provides clear evidence for the expression of sympathetic and sensory nerves within PVAT of mesenteric arteries and shows these nerves contribute to the regulation of vascular tone. H2S causes vasodilatation of MABs by activating sensory nerves through the TRPA1 signalling pathway, and subsequently impairs sensory nerve function, demonstrating a capsaicin-like action. H2S-producing enzymes and endogenous H2S are not involved in EFS-evoked neurogenic vasodilator responses under the conditions of the present study. Activation of sympathetic and sensory nerves in PVAT can modify PVAT-derived mediator(s) release. Collectively, these data show that sympathetic and sensory nerves are expressed in PVAT and have functional roles in modulation of vascular contractility and PVAT-derived mediator release.