Fatigue is a common and major symptom in multiple sclerosis (MS). A number of potential mechanisms exist as to the cause of MS-fatigue. These include that it is an immune-mediated symptom or that it is due to neuroendocrine or autonomic dysfunction. Studies have shown reduced activity in cortical and deep grey matter regions and disruption of cortico-subcortical circuits has been theorised. This may lead to difficulty in the planning or pre-movement stage of activity with compensatory overactivity contributing to fatigue. Finally, dysfunction of the hypocretin system, deficiency of which occurs in narcolepsy, has also been suggested. A number of deep grey matter structures, including the basal ganglia, thalamus and hypothalamus, are implicated in these mechanisms and the work presented in this thesis explores their role. Conventional magnetic resonance imaging (MRI) techniques whilst crucial in diagnosis and monitoring disease activity are generally felt to correlate poorly with disability and symptomatology. Quantitative MRI techniques have been shown to provide a more comprehensive evaluation of the extent of MS pathology and correlate better with clinical deficit. Tl relaxation time measurement is one such quantitative MRI technique and has been shown to demonstrate abnormalities in small structures such as the pyramidal tracts and correlate with disability. Firstly, we measured the T1 relaxation times of the thalamus and basal ganglia in a cohort of MS patients and assessed for any relationship with fatigue severity. Secondly, in view of its key role in the autonomic, neuroendocrine and hypocretin pathways, we performed the same measurement in the hypothalamus of a cohort of patients and again assessed for any relationship to fatigue. Subsequently, to further evaluate any possible contribution from the hypocretin system we measured cerebrospinal fluid (CSF) hypocretin-1 levels in patients with a number of neurological diseases including a cohort of MS patients and evaluated for any relationship with severity of self-reported fatigue and hypersomnolence. Studies in MS-fatigue, including those undertaken by our group, traditionally rely on self-reported measures of fatigue severity. These questionnaire-based measures are subject to a number of drawbacks including rater bias and lack of definition of fatigue. In the final study, we assessed the effectiveness of the wakefulness-promoting drug, modafinil, in MS patients with and without fatigue by assessing its effect on objective measures of alertness and vigilance, including neurophysiological and laboratory-based measures. In addition, in this study we evaluated any potential role of the autonomic system in MS-fatigue. We found significantly higher T1 relaxation times in a number of deep grey matter structures including the thalamus, putamen and latterly the hypothalamus in MS patients as compared to controls. The T1 relaxation time of the thalamus was higher in fatigued patients as compared to non-fatigued patients and it correlated with fatigue severity. We found lower CSF hypocretin-1 levels in patients with MS and inflammatory disorders as compared to non-inflammatory conditions and this was significant in the inflammatory cohort. However, we found no relationship with fatigue or hypersomnolence severity. We did, however, detect a significant difference on a sympathetic cardiovascular reflex test between fatigued and non-fatigued patients. Finally we noted a significant improvement with modafinil, as compared to placebo, in a number of objective measures of alertness in patients with MS-fatigue and notably this was not a class-effect. To this extent, the findings from this thesis provide evidence for the potential involvement of pathology in the thalamus in the mechanism of MS-fatigue, possibly through disruption of cortico-subcortical circuits. In addition, in a separate cohort of patients there was evidence of a relationship between autonomic disturbance and fatigue. We have however found no evidence of a relationship between the hypocretin system and fatigue in MS. Finally we have demonstrated supportive evidence for a role for modafinil in the treatment of fatigue, a symptom for which, despite its frequency and severity, there is often a paucity of treatment options available for MS specialists.

Multiple Sclerosis is a major cause of neurological disability in the population of the UK with an incidence of 2,500 new cases diagnosed each year. The estimated number of people affected with MS in the UK is currently believed to be 85,000. (MS Trust 2006). The disease affects those in the prime of their lives as well as those more advanced in years. The reality of living with a progressive neurological condition requires self-management strategies as well as professional involvement. One method of encouraging self-management is the use of exercise to ameliorate some of the problems presented by MS and thus to encourage independence. This study was developed to compare the effects of a home-based physiotherapy exercise programme against readily accessible self-selected exercise opportunities. It was conducted entirely in the community with a convenience sample of 40 subjects recruited from the caseload of the Rehabilitation Medicine Service in Lincolnshire, 39 people eventually completed the study. The participants were of mixed MS presentations but were capable of fulfilling the exercise requirements of the study. The study was in two parts, a pre-exercise phase and an exercise phase. Assessments were carried out at three stages during the study at week 1, week 12 and week 36. A baseline assessment taken at study onset, focused on physical function using the Amended Motor Club Assessment, (AMCA), as the primary outcome variable. The Health Assessment Questionnaire, (HAQ) and Timed Walk were also used to assess function. Muscle tone and muscle strength, were assessed using the Modified Ashworth Scale, (MAS), and the Medical Research Council, (MRC), strength scale. Psychological state was gauged using the MSQOL 54 and a Numerical Rating Scale. Symptom presentation was assessed using the Guys Neurological Disability Scale, (GNDS). The participants were given a journal at week 1 and this remained with the participant until week 36. It was returned to the researcher after the final assessment. Indications of psychological state and exercise experiences were extracted from the journals where unfettered comments regarding the regimes and any other MS or personal issues were recorded. The first and second assessments were carried out by the investigator. The third assessment was completed by one of the two independent physiotherapy assessors. Phase one of the study, the pre-exercise phase, extended over 12 weeks during which time educational material plus the MS Trust booklet “Tips to Living With MS” was distributed. This time also provided a washout period negating the effects of previous exercise involvement. In phase two the participants joined their respective exercise groups. Group 1 participants received the home physiotherapy programme consisting of a three-part exercise regime administered over eight weeks. The regimes included exercises in lying, sitting, standing with a strengthening element using red, medium strength theraband. The group 2 participants selected their own activity regime providing it was compatible with their exercise capabilities. The activities selected included progressive walking, gym attendances, swimming, Pilates, yoga and motorcise, a motorised cycling routine. The exercise phase lasted for 24 weeks. Total study involvement lasted for 36 weeks. The results from the pre exercise phase indicated that there were no improvements in physical or psychological function except a perceived improvement in symptom presentation as shown by a significant improvement in the GNDS score. This could be attributable to the nature of the information offered and the previous extensive knowledge already in the possession of the participants. Exercise positively influenced the AMCA, the primary outcome variable in both groups but the benefit of one approach over the other was not conclusively demonstrated. Physiotherapy appeared to produce significantly better results than self-selection in the HAQ, the NRS, lower limb tone, and lower limb strength. The Timed Walk did not improve in either group. Neither group showed improvement after exercise on the GNDS. The MSQOL 54 was affected but significant differences were only seen in one domain in each of the two groups. Supporting evidence from analysis of the participants’ journals indicated the desire for exercise and showed subjectively how those in the study benefited from it. These results did not offer definitive proof as to the most beneficial regime but they provided compelling evidence to support the relevance of exercise to those with MS to maintain physical and psychological wellbeing. A follow-up questionnaire was issued to each participant 26 weeks after the study completion to assess whether they had continued to exercise. Of the 39 people who completed the study, 34 responded to the follow-up questionnaire. Of these 34 people, 33 were still engaging in some type of exercise indicating that the changes necessary to embed the new behaviour had been successfully achieved.

Multiple sclerosis (MS) is the most common demyelinating disease. It is characterised by a great variety of neurological deficits, which most commonly present initially in a relapsing remitting fashion and then take on a gradually progressive course. MS is incurable, since present medications do not counteract progression of the disease. Therefore, an additional strategy aims to focus on prevention of the neuronal loss in an attempt to stop or slow down the progression of the disease. In this thesis the neuroprotective potential of modafinil is tested in MS in a retrospective study. The ability of modafinil to reduce neurological dysfunction in the MS animal model is also investigated. In retrospective study the expanded disability status scale (EDSS) progression of thirty patients with MS who received modafinil for the treatment of MS-related fatigue for an uninterrupted period of 3 years or more was compared with ninety matched patients not treated with modafinil, followed up for a matching period of time. We found that the EDSS increase in patients not treated with modafinil was greater than in those treated with modafinil in both relapsing/remitting and progressive MS. In another experiment, we evaluated the effect of two treatment doses (low dose and high dose) of modafinil on the level of disability in experimental autoimmune encephalomyelitis (EAE) in a placebo controlled study. Modafinil decreased the severity of EAE at both treatment doses and the effect was greater in high dose. The study in chapter 4 was aimed to explore the anti-fatigue and alerting effects of modafinil in MS in an attempt to link these with the potential neuroprotective effects of modafinil. This was a detailed reanalysis of a prospective placebo controlled study (based on prospectively collected data), in which we examined whether there is any difference between MS patients with fatigue, MS patients without fatigue, and healthy controls on measures of alertness and autonomic function. We found that MS patients with fatigue, compared with healthy controls, had reduced level of alertness on all the tests used, MS patients with fatigue had a reduced level of autonomic function compared to the other two groups. Furthermore, we found that Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects. In Chapter 5, we assessed a problem relevant to the progression of MS. We take advantage of the methods and data used in the chapter 2 to apply the same retrospective study methodology and statistical retrospective modeling of EDSS progression using the linear regression model to look at the role of oligoclonal band (OCB) positivity or negativity in EDSS progression. Unlike previous studies in smaller cohorts, we did not find that OCB negative patients have a more benign course of disease. The meta-analysis study in chapter 6 was designed to generate some knowledge regarding the central mechanism of fatigue in general and fatigue related to MS, using a novel functional magnetic resonance imaging (fMRI) meta-analysis method developed by CR Tench in our group. The study has also aimed to explore the brain areas which could be activated by modafinil treatment. The conclusion of this study was that the thalamus and striate are central and relevant nodes for the pathogenesis of fatigue in MS. The study has not detected the specific brain area to be activated by modafinil and showed multiple brain activations. With regard to the promising findings in our previous experiments, the protocol of a prospective phase II clinical trial was designed and detailed in appendix 10 using radiological primary and clinical secondary outcome measures. In conclusion, modafinil may slow down the progression of disability in patients with MS and decrease disease severity in EAE. Modafinil can display alerting and sympathomimetic effects in MS patients as well as in healthy subjects. The thalamus and striate are central and relevant nodes for the pathogenesis of fatigue in MS. These are also areas affected by the MS gray matter pathology and may be targets for neuroprotection by modafinil in MS. Finally, we have not reported a significant difference in disease progression measured by EDSS and MSSS between OCB negative and OCB positive in our patients with MS. This seemingly heterogeneous group of experiments, primarily centred on modafinil’s potential as mechanistic therapy in MS, bring, I hope, new knowledge of aspects of disease progression and pharmacological neuroprotection in a stage of the disease where therapeutic options are currently limited and the need for new treatments is great.

Carpal tunnel syndrome (CTS) presentation is usually classic but cold-related Raynaud's phenomenon (RP)-like symptoms were described in CTS and more commonly in the injured hand (HI). The work presented in this thesis is divided into two domains; the first aims to extend understanding of the response of the hand to cold in CTS and HI using two processes. [1] The modified cold provocation test (CPT) validated in a group of controls and both primary and secondary (vibration induced) RP subjects. Both hands were immersed in a 12°C water bath and the digital temperature recorded every 6 seconds using thermocouples until the digital temperature dropped to 15°C. The hands were then removed and allowed to passively re-warm. Baseline temperature (difference between the ambient temperature and the digital temperature), T30sec (temperature gain in the first 30 seconds post-cooling) and T5°C (time required to gain 5°C) were assessed. [2] Laser Doppler Imaging (LDI), a well-established method for investigating skin microcirculation with an endothelial challenge (facilitated by iontophoresis delivery Sodium Nitroprusside and Acetylcholine). The second domain centred on the management of CTS and in particular outcome assessment of conservative versus surgical treatment in registrar and nurse practitioner CTS clinics in a community hospital. Data on 86 controls, 31 primary RP and 59 secondary RP were collected. In the control group the baseline temperature was >6°C, which was higher than the primary and secondary RP groups (p-value <0.05, sensitivity 79%, 78%, specificity 43%, 45%, inter-class correlation 53%, 49%); T30sec in secondary RP was >1.8°C, which was higher than controls and the primary RP groups (p value <0.001, sensitivity 70%, 71%, specificity 76%, 79%, inter-class correlation 3%, 40%); and T5°C in primary RP was >300 seconds, which was longer than that of the controls and secondary RP groups (p-value <0.001, sensitivity 64%, 61%, specificity 70%, 64%, inter-class correlation 70%, 70%); data given for left and right hands respectively. CPT and LDI studies were undertaken on 60 controls and 60 CTS patients pre-operatively and repeated on 40 subjects 5-7 months post-decompression. Post-operatively, the baseline temperature increased by 1.5°C (p-value <0.05) in both hands and 2.5°C (p-value <0.001) in the median nerve supplied digits, T5oC was reduced in the hands (pre- versus post-operative from 474 to 348 seconds) (p-value 0.06) and from 468 to 273 seconds in the median nerve supplied digits (p-value 0.01). Endothelial dependent and independent control at mean and maximum pre- and post-cooling perfusion was significantly depressed (p value 0.05) post-cold exposure in the control group. LDI limited to the dorsum of the hand identified no significant difference pre- and post-operatively (p-value >0.05). HI subject recruitment was challenging: the absence of a financial incentive and the possible income loss during working days for a young working cohort might have contributed to the poor recruitment. Of the 60 subject targets only 14 recruited and the injury severity varied widely between the recruits; the data gathered through CPT and LDI in this group did not show a significant difference from that collected in controls. CTS management audits on 74 subjects in a nurse-led clinic and 173 subjects in a registrar-led clinic identified a high failure rate of the conservative management (60%) at 6 months follow up in both clinics with unclear success predictors suggesting an extra burden on clinics providing decompression surgery.

Germ cell tumour (GCT) is the collective term for several subtypes of tumour. GCTs most commonly occur in the testis or ovary around puberty, but they also occur at several non-gonadal locations in the human body. These so-called “extra-gonadal” GCTs have the same histology and protein markers as those that arise at gonadal locations. This observation prompted several hypotheses to explain where these tumours come from. Extragonadal locations include the base of the spine (sacrococcygeal region), the abdomen (retroperitoneum), the chest cavity (mediastinum), and the brain (intracranial). The origin of central nervous system (CNS) GCTs is the main focus of this thesis. The most widely accepted hypothesis for extragonadal GCTs was originally proposed by Gunnar Teilum in 1965. Teilum proposed that all GCTs that arise in the human body have a common cell of origin. Teilum’s experiments showed that a germ cell progenitor could give rise to a GCT. This was one piece of evidence that led him to suggest that since GCTs in the testis and ovary arise from a germ cell progenitor, perhaps GCTs in other locations also arise from these progenitors. For extra-gonadal GCTs, these progenitors are thought to mismigrate and become trapped at several locations around the body. The regions where GCTs occur are suggested to be those regions where these progenitors have become trapped, such as the brain. However, research into pluripotency has revealed a mechanism of generating a GCT from an endogenous population of cells isolated from the brain, neural stem cells, using the upregulation of only a single gene, Oct4. In this thesis I test the hypothesis that CNS GCTs may arise from a neural progenitor, and not just from a germ-cell progenitor. I will use several strategies to test this hypothesis with different methodologies. Published literature is first used to review and re-analyse the case for a neural cell of origin for CNS GCTs. This hypothesis is then experimentally tested in subsequent chapters, culminating in a unifying hypothesis for how CNS GCTs may arise.

Background Less than 50% of people return to work after traumatic brain injury. Despite this, specialist traumatic brain injury (TBI) vocational rehabilitation (VR) in the UK is scarce with outcomes, interventions or costs rarely reported. This study aimed to compare the work outcomes and costs of participants receiving specialist TBI VR (specialist group) to those receiving usual care (usual care group) and to describe the content of the specialist intervention. Method People with TBI requiring hospitalisation ≥48 hours in work or education prior to their injury, were followed up by postal questionnaire at 3, 6 & 12 months post hospital discharge. Primary outcomes were work/education. Secondary outcomes were functional ability, mood and quality of life. Specialist intervention was recorded on a proforma specifically developed for the study. Health resource use was by self-report. Results Fifty-four usual care and 40 specialist participants were recruited. At 12 months, 15% more specialist group participants were in work/education than usual care group participants (27/36, 75% v 27/45, 60%). For those with moderate/severe TBI, the difference was 27% (16/23, 70% v 9/21, 43%). Secondary outcomes showed no significant differences between groups at one year. The proforma showed that the specialist intervention was primarily focussed at preparing participants to return to work. It cost £501.53 more in health and social care costs (UK£2007) to return a specialist group participant to work at one year than a usual care participant. Discussion More specialist group participants were working at one year with an extra cost of only £500 per person. This suggests specialist TBI VR may be cost effective. The ability to describe the intervention aids replication and implementation. Conclusion As returning to work is a cost effective outcome for individuals and society, this study justifies the need for further investigation of this TBI VR intervention.

This thesis presents the design, development and application of a novel overt picture-naming paradigm through a series of exploratory behavioural and imaging experiments. The paradigm is subsequently used in a functional magnetic resonance imaging study of recovery from post-stroke aphasia. The possibility of comparing correct and error naming responses in aphasic patients and unimpaired subjects induced to make errors was investigated and successfully trialled. This research improves on techniques currently favoured in imaging studies to explore the processes involved in functional recovery in a more analytical way. The novel study design provides a new way to interrogate processing involved in the production of aphasic responses. The intentions of this project were to drive the research field of post-stroke aphasia recovery forward by suggesting and applying new methods of using functional imaging to investigate the current pertinent research questions. In addition to this, it was aimed that data collected from participants who have an aphasic deficit, and those with a healthy language system, would be analysed to provide evidence of how a stroke damaged brain may recover functional language. It was hypothesised that results from aphasic patients would show that successful language performance is associated with cortical activation of the patients' normal left hemispheric language areas, around their lesion site. Conversely, the hypotheses state that production of linguistic errors would correlate with an increase in activation in areas of the right hemisphere homologous to the left lateralised fronto-temporal language production network. It was thought that further investigation of successful and unsuccessful language performance in unimpaired speakers would echo this finding. The current debate in this research field centres on the role of the undamaged hemisphere in successful recovery. Five chronic stage aphasics were tested using the developed continuous scanning, event-related paradigm and their correct and error naming trials were compared. Results indicate that recruitment of cortical areas homologous to the stroke lesion can support successful language processing. This is contrary to the theory that disinhibition of non-dominant language areas may contribute to the production of aphasic errors. An investigation of forced errors in unimpaired speakers was also conducted to provide comparisons with the aphasic patient group. Imaging results showed that the naming-to-deadline paradigm used may provide a useful baseline for the normal processes involved in the monitoring and control of task performance.

Diffusion-weighted (DW) magnetic resonance imaging allows the quantification of water diffusion within tissue. Due to the hindrance of water molecules by the various tissue compartments, probing for the diffusive properties of a region can provide information on the underlying structure. This is particularly useful for the human brain, whose anatomy is complex. Diffusion imaging provides currently the only tool to study the brain connectivity and organization non-invasively and in-vivo, through a group of methods, commonly referred to as tractography methods. This thesis is concerned with brain anatomical connectivity and tractography. The goal is to elucidate problems with existing approaches used to process DW images and propose solutions and methods through new frameworks. These concern data from two popular DW imaging protocols, diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI), or Q-ball imaging in particular. One of the problems tackled is resolving crossing fibre configurations, a major concern in DW imaging, using data that can be routinely acquired in a clinical setting. The physical constraint of spatial continuity of the diffusion environment is imposed throughout the brain volume, using a multi-tensor model and a regularization method. The new approach is shown to improve tractography results through crossing regions. Quantitative tractography algorithms are also proposed that, apart from reconstructing the white matter tracts, assign relative indices of anatomical connectivity to all regions. A fuzzy algorithm is presented for assessing orientational coherence of neuronal tracts, reflecting the fuzzy nature of medical images. As shown for different tracts, where a-priori anatomical knowledge exists, regions that are coherently connected and possibly belong to the same tract can be differentiated from the background. In a different framework, elements of graph theory are used to develop a new tractography algorithm that can utilize information from multiple image modalities to assess brain connectivity. Both algorithms inherently consider crossing fibre information and are shown to solve problems that affect existing methods.

This thesis investigates the normal appearing brain tissue in multiple sclerosis (MS) using high resolution quantitative MRI measures acquired at high magnetic field. The use of magnetisation transfer ratio (MTR) and longitudinal time (T1) were employed to investigate changes in normal appearing white matter (NAWM) for healthy control subjects and patients with clinically isolated syndromes suggestive of MS (CIS) and relapsing-remitting multiple sclerosis (RRMS). The results showed a significant difference in the median peak position, full width at half maximum, the 25th percentile of the MTR histograms and the 75th of the T1 histograms. The magnetic susceptibility mapping technique was used to quantitatively investigate the accumulation of iron in deep grey matter structures in healthy controls, CIS and RRMS patients. The results showed an increase in iron deposition in the caudate nucleus, putamen, globus pallidus structure in CIS and RRMS when compared to those in healthy controls. Combining functional MRI and magnetic susceptibility mapping was used to elucidate the mechanisms underlying the visual activation in lateral geniculate nucleus (LGN) in healthy controls. The results showed an increase in the accuracy of the LGN delineation. This is in turn, highlights the importance of this method in quantifying the visual disturbances associated with MS and CIS patients.

Background: Traditionally, Multiple Sclerosis (MS) has been considered to be a predominantly white matter (WM) disease. More recent studies have revealed considerable grey matter (GM) involvement in the brain. However there is a paucity of literature examining GM pathology in the spinal cord. Objectives and methods: We use human post-mortem material to explore various aspects of spinal cord GM pathology in MS including (i) the extent and pattern of spinal cord demyelination, (ii) the relative contributions of GM and WM volume loss to spinal cord atrophy, (iii) the extent of neuronal pathology within the spinal cord and (iv) the sensitivity of post-mortem MRI for detecting spinal cord GM plaques. Results: Within the spinal cord, GM demyelination is more extensive than WM demyelination with many lesions showing a novel morphological pattern whereby the plaque borders maintain a strict respect for the GM/WM boundary. Demyelination is more extensive in the spinal cord GM than in other brain regions examined. Post-mortem MR imaging at 4.7 Tesla is highly sensitive for detecting the spinal cord GM plaques. We demonstrate substantial neuronal loss in the spinal cord in MS, observing reductions in both interneuron and motoneuron numbers. This neuronal loss occurs predominantly within GM plaques. We also observe reductions in interneuron size, both within plaques and in the myelinated GM. Despite this, we find no evidence of spinal cord GM atrophy. Conclusions: This study represents the first detailed examination of spinal cord GM involvement in MS. We demonstrate substantial GM pathology in the spinal cord, further challenging the concept that MS is a predominantly WM disease. A greater understanding of this pathology may provide important insights into MS pathogenesis and mechanisms of disability in the disease.