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.

The hypothesis that high heart rate and low perceived skill would be associated with greater return of fear than low heart rate and high perceived skill was investigated in a group of anxious musical performers (N=63) in response to an anxiety-reduction training program. Musicians were taught progressive muscle relaxation and attention-focusing skills over the course of four weekly meetings. Return of subjective fear was assessed between training program sessions and at a three-month followup assessment. The three major fear response systems were measured at pre, post and followup assessments and throughout the three training program sessions that included behavioural rehearsal. Subjects (pianists, violinists and vocalists) performed a short piece before an audience (at assessments) or before their fellow group members. Performance quality ratings by independent musicians served as the behavioural measure, anticipatory heart rate as the physiological measure, and subjective units of distress scales as the subjective measure. In addition, subjects completed memory questionnaires, designed to assess their recall of the setting and their response to previous performances, and thought questionnaires, to provide data pertinent to processes hypothesised to underlie return of fear. Four classification groups (high heart rate, low perceived skill; high heart rate, high perceived skill; low heart rate, low perceived skill; and low heart rate, high perceived skill) were formed on the basis of median splits of heart rate and perceived skill pre-assessment levels. At post-assessment, each group demonstrated fear reduction, heart rate reduced in high-heart-rate subjects, and performance quality improved overall. Followup return of fear was evident in high-heart-rate subjects regardless of initial perceived skill status, and was not dependent on initial fear levels. Perceived skill was not associated with return of fear. High-heart-rate subjects also overestimated their level of fear for previous performances, and reported more anxious thoughts and thought resensitization between performances. High non-performance heart rate was associated with greater return of fear only in extreme group analyses. Post-hoc analyses compared subjects who did (n=24) and did not (n=25) display followup return of fear. Return-of-fear subjects, in general, had higher heart rates and lower perceived skill than no-return-of-fear subjects, and tended to report thought resensitization between post and followup assessment. In addition, return-of-fear subjects were generally less skilled and performed on fewer occasions over the followup interval. The assessment of between-session return of fear was limited by design faults. The results were consistent with a dishabituation model of return of fear. They also lent support to Wagner's consolidation model in which an alteration of stimulus representations between exposures is believed to producedishabituation. The findings did not support the hypothesis that lack of consolidation may also arise from failure to attend to contextual cues, and hence, impaired retrieval of stimulus representations. Similarities of the data to Bower's description of mood-dependent cognitions were noted. It was suggested that salient internal autonomic cues during mood-congruent states facilitated overestimation of previous fear, expectation of distress and return of fear. Finally, research possibilities and treatment implications were considered. / Arts, Faculty of / Psychology, Department of / Graduate

Somatostatin is a neuropeptide found throughout the brain. Several studies have established its anatomical distribution as being quite heterogenous with relatively high concentrations appearing in the limbic and striatal systems. Presently, very little is known about the functions of somatostatin systems in the brain and how they interact with other transmitter systems. The following report is a summary of experiments undertaken to assess the functional and chemical interactions of somatostatin with other neurotransmitter systems. Previous studies have established that the dopaminergic inputs to the basal ganglia are important for locomotor activity and reward. These systems have also been implicated in several mental and neural diseases such as schizophrenia, depression, and Parkinson’s disease. In the first experiment, interactions between dopamine and somatostatin systems were examined using paradigms involving behavioural responses to dopamine agonists. Depletion of somatostatin levels by the drug cysteamine was found to attenuate amphetamine- and apomorphine-mediated motor behaviours but not the reinforcing aspects of amphetamine. The second experiment attempted to further characterize the nature of the dopamine-somatostatin interaction by examining the effects of haloperidol, a dopamine antagonist, on central somatostatin levels. Short term treatment with haloperidol decreased striatal somatostatin levels. Long term treatment (8 months) with haloperidol failed to alter somatostatin levels in the caudate-putamen. Since somatostatin levels appear to be normal in Parkinsonian brains, the effects of MPTP poisoning in mice on central somatostatin levels was also studied to examine the accuracy of this animal model of Parkinson's disease and examine the effects of dopaminergic lesions on somatostatin levels. The results of this experiment indicate that MPTP causes a dose dependent increase in nigral somatostatin levels without altering striatal or cortical levels. These results are in partial disagreement with results obtained from both post-mortem Parkinsonian brains and primates given MPTP, thereby questioning the accuracy of this mouse model of Parkinson's disease. The final experiment examined the effects of the anticonvulsant-antidepressant carbamazepine on central somatostatin levels in the rat. Although the chemical mechanisms responsible for the therapeutic effects of carbamazepine are unknown, previous studies have suggested that its efficacy in the treatment of both manic-depression and epilepsy may be associated with the ability of this drug to reduce the abnormal somatostatin levels observed in these diseases. In this experiment, neither acute, chronic, nor withdrawal from chronic treatment with carbamazepine were found to alter the levels of somatostatin in rats. The lack of effects of carbamazepine on basal somatostatin levels may indicate somatostatin cells are susceptible to carbamazepine only under pathological situations. Together, these results are discussed in the context of recent observations of abnormal somatostatin levels in several diseases of the central nervous system and provide some insight into the interactions and functions of somatostatin systems in the normal and abnormal brain. / Medicine, Faculty of / Graduate

The sympathetic nervous system is important in maintaining cardiovascular homeostasis. Elevated cardiovascular-related sympathetic activity can lead to neurogenic hypertension and a host of other serious cardiac-related abnormalities. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in sympathetic cardiovascular regulation. Neurons from the PVN project to the rostral ventrolateral medulla (RVLM), which is the main brain stem sympathetic cardiovascular control center. While RVLM-projecting PVN neurons have been well characterized, the topographical organization within the PVN subnuclei is still not fully known. This neuroanatomical study aimed to map the topographical distribution of RVLM-projecting PVN neurons. Four different carboxylate FluoSphereTM retrograde tracers (blue, 365/415; green, 505/515; red, 565/580; and far-red, 660/680) were injected at different rostro-caudal coordinates within the RVLM. The vast majority of RVLM-projecting PVN neurons were ipsilateral and located in the medial parvocellular subnucleus. Whereas most neurons were ipsilateral, there is a small fraction of neurons that crossed the midline. RVLM-projecting neurons were also identified within the dorsal, ventral, and posterior parvocellular subnuclei of the PVN with no labeling found in the anterior parvocellular or magnocellular subnuclei. Additionally, we observed different efficiencies of the retrograde tracers with blue (365/415) being the least efficient and red (565/580) being the best. These neuroanatomical data will serve as important preliminary data for future research investigating the functional and histochemical properties of these PVN neurons.

Spinal cord stimulation (SCS) applied to the dorsal aspect of the cranial thoracic cord imparts cardioprotection under conditions of neuronally dependent cardiac stress. This study investigated whether neuronally induced atrial arrhythmias can be modulated by SCS. In 16 anesthetized dogs with intact stellate ganglia and in five with bilateral stellectomy, trains of five electrical stimuli were delivered during the atrial refractory period to right- or left-sided mediastinal nerves for up to 20 s before and after SCS (20 min). Recordings were obtained from 191 biatrial epicardial sites. Before SCS (11 animals), mediastinal nerve stimulation initiated bradycardia alone (12 nerve sites), bradycardia followed by tachyarrhythmia/fibrillation (50 sites), as well as tachyarrhythmia/fibrillation without a preceding bradycardia (21 sites). After SCS, the number of responsive sites inducing bradycardia was reduced by 25% (62 to 47 sites), and the cycle length prolongation in residual bradycardias was reduced. The number of responsive sites inducing tachyarrhythmia was reduced by 60% (71 to 29 sites). Once elicited, residual tachyarrhythmias arose from similar epicardial foci, displaying similar dynamics (cycle length) as in control states. In the absence of SCS, bradycardias and tachyarrhythmias induced by repeat nerve stimulation were reproducible (five additional animals). After bilateral stellectomy, SCS no longer influenced neuronal induction of bradycardia and atrial tachyarrhythmias. These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protective effects depend on the integrity of nerves coursing via the subclavian ansae and stellate ganglia.