Migraine is a frequent debilitating neurological disorder that is considered to be genetically complex with a multifactorial mode of inheritance. It has a high prevalence with approximately 18% of women and 6% of men suffering from the disorder. Migraine is characterized by severe head pain with associated nausea, emesis, photophobia, phonophobia, and neurological disturbances. The International Headache Society (IHS) has classified various types of migraine according to their clinical features. The two main subtypes of migraine are migraine without aura (MO), occurring in ~70-75% of migraineurs, and migraine with aura (MA) which occurs in ~25% of migraineurs. Some people experience both types of attack in their lives. While the precise pathogenesis of migraine is unknown, it is widely accepted that short-term alterations in neuronal activity occur in relation to the attack, along with temporary changes in the cerebral vasculature. Trigeminal nerve activation is also considered pivotal to progression of a migraine attack. Neurotransmitters, especially serotonin (5-hydroxytryptamine, 5-HT), platelet activation and sympathetic hyperactivity all appear to play a part, whether as part of the primary triggering event, or as a response mechanism. Migraine imparts a significant burden on society, both socially and financially. The World Health Organization has identified migraine among the world's top 20 leading causes of disability, with an impact that extends far beyond individual suffering. There is significant evidence from family and twin studies to indicate a strong genetic component to migraine. The current understanding of migraine is that it is a polygenic multifactorial disorder. It has been postulated that genetic factors set the individual migraine threshold, with environmental influences playing a modulating role. It is likely that many genes may provide an important although moderate contribution to an individual’s migraine susceptibility. The identification of migraine susceptibility genes has been the focus of substantial research to date and could eventually lead to improved treatments and greater understanding of the disorder. Several loci have shown promise, although these need to be followed up by both replication and functional studies to determine a definitive causative role. This research investigated the role of both hormonal and vascular related genes as candidate genes that may play a role in migraine susceptibility due to the well-known role of hormones and vascular changes in some migraineurs. The estrogen receptor (ESR) and progesterone receptor (PGR) genes are potential migraine candidates due to the recognized hormonal influence on migraine susceptibility. Migraines in women frequently occur during the childbearing years and are often influenced by significant hormonal milestones. The fluctuating hormone levels of the menstrual cycle have been implicated in migraine but a definitive role is yet to be established. It has been suggested that factors additional to circulating hormone levels may be at play. This research considered that variation in the ESR 1 and PGR genes may confer an increased migraine risk. To investigate the potential role of these genes in migraine, association studies investigating variants in ESR 1 and PGR were undertaken in two independent casecontrol cohorts. This was followed up by mutation screening and gene expression analysis in an effort to elucidate a functional role for these genes in the pathogenesis of migraine. Vascular genes also represent likely migraine candidates as alterations in both vascular function and cerebral blood flow are well known in migraine. Furthermore, cortical spreading depression (CSD), a depolarization wave that propagates across the brain cortex and has been speculated to cause the neurological symptoms that present in MA, has also been linked to vascular dysfunction. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTRR) genes both play a role in vascular functioning and were thus considered potential migraine candidates for this study. Both are involved in the pathway of homocysteine metabolism. Impaired activity of these enzymes can lead to mild hyperhomocysteinemia which is believed to lead to oxidative arterial damage. This may in turn impact on migraine susceptibility, possibly through the activation of trigeminal fibres. The MTHFR 677T allele results in an amino acid change in the catalytic domain of the enzyme leading to mild hyperhomocysteinemia. This particular variant has been implicated in migraine in four separate studies. One of these studies also suggested a role for the MTHFR 1298C allele in migraine. This allele also results in an amino acid change and reduced enzyme activity. Similarly, the MTRR 66G allele results in an amino acid change and has been associated with reduced activity of MTRR and increased plasma homocysteine concentration. To investigate the role of the ESR 1, PGR, MTHFR and MTRR genes in migraine, samples from two large independent case control cohorts were investigated. Cohort 1 was comprised of 275 migraineur samples and 275 age, sex and ethnicity matched controls while cohort 2 comprised 300 cases and 300 matched controls. All individuals were collected at the Genomics Research Centre with migraine diagnosis undertaken by HIS criteria and migraine affected individuals designated as MO or MA. Results of analysis of ESR 1 indicated a positive association with migraine in the two large independent cohorts for the exon 8 G594A polymorphism (P = 0.003; P = 8x10-6). Similarly, the PGR analysis showed a positive association with migraine for the PROGINS allele (P = 0.02; P = 0.003). Results also showed that individuals with both ESR 1 and PGR susceptibility alleles were 3.2 times more likely to suffer migraine those those with no susceptibility alleles. As the ESR 1 variant is synonymous, a mutation analysis was undertaken in a small sub-sample of individuals carrying the susceptibility allele, but no mutations were detected in these particular samples. Detailed mutation analysis of ESR 1 in a larger study group may be warranted. An ESR 1 and PGR expression analysis by RT-PCR was undertaken to examine if there were any notable expression level changes in migraineurs versus controls and additionally whether the susceptibility genotypes influenced gene expression. Altered expression levels may point to a functional change in the gene. Although results did not show any significant difference in expression levels in the case/control group, nor any influence in gene expression conferred by the specific susceptibility genotypes, ESR 1 expression did appear to be down-regulated in the migraine group and more specifically in the migraine susceptibility genotype subgroup. A larger study group may therefore be warranted to detect any potential genuine changes in gene expression. Overall, these results suggested that these hormonal genes appear to play a role in migraine susceptibility, although further studies are needed to define this. Results of the MTHFR 677 analysis showed that the TT genotype was significantly associated with the MA subgroup in a joint analysis of the two independent cohorts (P = 0.004). Results of analysis of MTHFR 1298, which is tightly linked to the 677 locus, showed a significant association in female migraineurs (P = 0.009). Similarly, results of the MTRR analysis also showed a significant difference between the female case and control groups with the G allele over-represented in female migraineurs (P = 0.022) These results may indicate that a significant gender effect appears in this locus as well as the MTHFR 1298 locus although results may also be due to a larger number of female migraineurs conferring increased statistical power to the gender subgroup. Interaction analysis of the MTHFR 1298 locus and the MTRR locus showed that females who carried both variants under a recessive model were 5 times more likely to suffer migraine those those with no susceptibility genotypes. Overall these results indicated that these vascular genes appear to play a role in migraine susceptibility. The final study focused on 6 genetic variants that had shown a positive association with migraine and/or MA in the same large association population analysed in this research. The aim of this study was to provide preliminary data on the potential role of genetic profiling in migraine. Using the genotypic data to create vascular and hormonal risk profiles based on positive association and interaction of MTHFR 677 T and ACE D alleles, and MTHFR 1298 AA and MTRR GG genotypes as vascular variants; and positive association and interaction of ESR 1 594 A and PGR PROGINS as hormonal variants, this study was able to demonstrate the relevance of genetic risk profiling to migraine. Results showed a significantly higher proportion of individuals with at least one genetic risk profile in the migraine group compared to those in the control group (P = 6 x 10-6). Individuals who possessed either the vascular and/or hormonal genetic risk profile were 8.6 times more likely to suffer from migraine than those who possessed a ‘no risk’ profile. This indicated a greater effect than the individual effect of each of these variants. Furthermore individuals who possessed a vascular or both risk profiles were more likely to suffer nausea, emesis, phonophobia and photophobia, and have a mother who also suffered migraine. Overall, the genetic profiling approach provided interesting preliminary data on migraine susceptibility and indicated that such an approach may prove very useful for migraine diagnosis, particularly when all migraine genes have been identified. In conclusion this study provided the first indication that hormone receptor genes play a role in migraine susceptibility. Hormones have long been considered to play a role in the disorder but this study has provided the first molecular evidence to support this premise. In addition, this study showed that vascular related genes also play a role in migraine susceptibility. Finally, this study has clearly shown that migraine is a complex disorder involving multiple genes. Although a number of studies have implicated neurotransmitter related genes in the disorder, the present study is the first to show that both vascular and hormonal genes also play a role in migraine susceptibility. Thus there now appear to be three classes of genes that affect migraine susceptibility and although this study has implicated new variants, the preliminary genetic profiling study has shown that not all predisposing variants involved in the disorder have been defined.

The purposes of this study were to identify and analyze characteristics of patients who fall, the types and circumstances of their falls, and analyze risk factors for fall-related injuries. In this retrospective study of 137 patients who fell between July 1, 2002 and December 31, 2005 at the neurological unit of a medical center located in the south of Taiwan. Data on patient characteristics, fall circumstances, and injuries were collected by reviewing of adverse event reports. Analyses were performed by use of SPSS statistical software. The result of this study found that the average age of patient who fell was 59.6 years. The majority of sex of the patient falls is male (61.3%). Many patients who fell had caregivers taking constant care (84%), and occurred in the patient room (68.6%). The most frequent diseases related to falls were cerebrovascular disease (47.5%). They usually falls happened during 12AM to 8AM (50.4%). Most falls (81%) did not result in severe injury, or disturbances of gait (78.8%). The most common activity performed at time of fall was during ambulation (39.4%), and getting out of bed (29.9%).The study found that significant risk factors for dizziness were correlated with fall injury (P<0.05); location and activity at time of fall were related to fall injury (P<0.05). The logistic regression model revealed that the significant risk factors for fall-related injuries were activity at time of fall sit and trying to pick up something (OR=18.15 with 95% CI of 1.15 to 285.92). The identified factors associated with injury may provide the information on reducing falling injuries for neurological patients, and development of fall intervention programs. The preventive strategies can ensure patient safety, improve health care quality and reduce resource utilization.

Conventional methods such as serology and microscopy are unreliable for diagnosis of encephalitozoonosis in domestic rabbits. Previous studies have reported PCR to be insensitive but it is unclear whether this is because of inherent limitations or the lack of assay optimization and validation. The studies described in this thesis assess DNA quality and quantity for combinations of six DNA extractions kits and four spore disruption methods. The resulting DNA underwent PCR using a published primer set. The optimal method had a detection threshold of 100 spores/ml in saline. However, when repeated in urine, the detection threshold was much higher (10,000 spores/ml) and non-target DNA amplification was present. Various methods were used to improve analytical sensitivity and eliminate non-target amplification. One method involving PEG 8000 treatment produced a detection threshold of 1,000 spores/ml and decreased non-target DNA amplification. Ultimately, new primers were designed and when the optimized method was tested with these primers, a detection threshold of 100 spores/ml with no non-target DNA amplification was achieved. The optimal method and new primers were tested using clinical samples of rabbit urine and 32.4% were found to be positive for E. cuniculi. The final assay was shown to be both analytically sensitive and specific; however further clinical investigation is warranted to determine clinical utility. / OVC Pet Trust

This thesis explores the use of familiar pre-composed music and unfamiliar improvised music in clinical music therapy with adults with acquired non- traumatic neurological illness. A detailed examination was made of six participants whose individual music therapy sessions spanned approximately six months. Clinical techniques used both songs and improvisation to explore issues pertinent to their lives. Primary data was collected in the form of focused interviews during and after music therapy sessions. Secondary sources of data included musical, behavioural and verbal material from the clinical sessions. Interview data was analysed using a modified form of Grounded Theory (Strauss and Corbin, 1990) to reveal emergent themes central to the participants' experiences of music therapy. Drawing from a neurobehavioural framework, analyses of the clinical material were made incorporating psychodynamic reflection through clinical supervision. This offered an alternative viewpoint and served as triangulation, in addition to checks with the multidisciplinary team. Open coding of the data established three major categories pertaining to the experience of the music, the experience of illness, and the emotional strategies to cope with illness. Three detailed case studies explored the relationships between these major categories using axial coding. The findings demonstrate that individuals living with chronic degenerative neurological illness find emotional meaning through the temporal relationship held with songs throughout their lives. Through songs which hold personal meaning, individuals are able to explore and express a wider range of emotional states than through words. Improvisation, on the other hand, possesses enhanced interactive properties pertaining specifically to the therapeutic relationship. Through playing and singing, individuals may monitor their physical selves. In this way, the therapist validates the individual's developing sense of 'self' through mutual music making, thereby shifting concepts of `self' from less able and damaged identities to identities which involved feelings of greater independence and ability.

Dystonia is a little known neurological disease of the central nervous system and consists of a group of related movement disorders, characterised by involuntary and prolonged spasms of muscle contraction. Although it is nearly 90 years since this neurological disorder was first named, relatively little research had been undertaken into dystonia, for the first 65 years and it was not until the mid 1970's that researchers started to look at the disorder. This particular programme of research has taken place exactly over a six year period, starting in May 1993, and relates to a large number of different areas of study. This research has proven that dystonia is far more prevalent than previously thought, it is next to Parkinson's Disease in degree of prevalence and is far more common than other better known neurological conditions, such as Motor Neurone Disease, and yet it remains largely unknown to most members of the medical profession and the general public at large. Dystonia has been historically extremely difficult to diagnosis and this meant it has been previously very difficult to obtain sufficient numbers for study, which in turn has created a number of significant social and economic consequencesw, hich has mainly meant that most cases of people with dystonia have remained undiagnosed or misdiagnosed for many years. This research was designed to measure the severity and prevalence of dystonia in the northern part of the UK, the implication the disease has had on the working life and environment of each patient and how that person is coping with the various personal, social and family relationships caused by the onset and potential gradual deterioration of the disorder, as well as measuring the quality of life of each patient during a number of different therapies. Although there has been research into other neurological disabilities, very little is known about the implications that dystonia can have on the affected person and their families. This is the first time that all types of dystonia have been studied and that certain related subjects have been specifically included. This research has been enormously helped by the tremendous expansion in the use of Botulinurn Toxin therapy and although an enormous amount of work has been completed and accomplished during this research programme, it should never be forgotten that the subjects of this thesis are real people and that the implications and results of this research have had, and will have, a tremendous impact on their lives and that of their families.

Cerebrovascular accidents are a leading cause of morbidity and mortality in the United States. Many conditions exist which may mimic this disease process including seizures, migraines, metabolic derangements, infections, space-occupying lesions, neurodegenerative disorders, peripheral neuropathy, cervical myelopathy, syncope, other vascular disorders, and functional neurologic disorder. Timely diagnosis and treatment are important in order to preserve functional status in these patients. A 48-year-old male presented to the emergency department with a 28-hour history of worsening left sided numbness, tingling, weakness, and feeling off balance. The patient stated that for the past several months he had noticed these symptoms, but they suddenly became worse the day prior. He also described shooting pains down the left arm with certain movements of his neck. The patient denied any difficulty with speaking, understanding words, performing mental tasks, bowel or bladder incontinence, or right sided symptoms. Physical exam showed intact cranial nerves II-XII, 5/5 strength of upper and lower extremities on the right side, 4/5 strength of upper and lower extremities on the left side. Romberg test was normal, heel to shin and finger to nose were intact bilaterally. Foot drop was noted on the left side and placement of the foot on the ground was noted to be clumsy. Initial head CT in the emergency department showed a frontal lobe hypodensity and was without intracranial hemorrhage. Computed tomography angiography of the head and neck showed no large vessel thrombosis or stenosis. Echocardiography revealed normal chamber sizes, normal left ventricular ejection fraction, no patent foramen ovale, and no left atrial or left ventricular thrombus. Telemetry monitoring throughout the stay remained sinus rhythm. Magnetic resonance imaging of brain and cervical spine was performed showing multifocal acute infarcts of the right and left frontal lobes and severe cervical spondylosis at C4-C6 with spinal cord edema in T2 sequences slightly below that level. The patient subsequently underwent a cervical spine decompression for the spinal cord compression during the hospital stay. Due to the multifocal lesions noted on the brain MRI, a vasculitis workup was performed which returned negative for any abnormal test findings. The patient was also diagnosed with diabetes mellitus type 2 during the stay as he was found to have a glycosylated hemoglobin A1C of >12. He was initially hypertensive during hospitalization, but this resolved on its own after day three of the hospitalization so anti-hypertensives were not required. The patient was discharged home on high intensity statin therapy, dual oral hypoglycemic therapy for his diabetes mellitus, home physical therapy, and he was scheduled to start dual antiplatelet therapy seven days after cervical spine surgery. This dual antiplatelet therapy with clopidogrel and aspirin was to be continued for three weeks after which continuation with low dose aspirin was advised. As seen in this case, patients that present with a cerebrovascular accident should always be evaluated for other etiology behind his or her symptoms and having a low threshold for pursing other additional diagnoses is reasonable.

Necrosis is considered to be an unregulated and chaotic cell death. However, recent advances in cell death strategies support necroptosis as a form of regulated programmed necrotic cell death. In response to TNF-a or Fas ligands, necroptosis can be induced by cell death receptors in multiple cell lines in the presence of a caspase inhibitor z-VAD; necroptotic cell death has been found to play an important role in normal development, immunity, inflammation, cancer, and human diseases. In this chapter, the molecular mechanisms governing necroptosis, recent findings about the upstream and downstream schema of necroptosis, and potential therapeutic targets in neurological disorders are discussed. After being activated by TNF-a (or Fas ligands) and death receptors, receptor-interacting proteins 1 and 3 (RIP1 and RIP3) form a complex, which play a central role in the induction of necroptosis. RIP3 phosphorylates and activates mitochondrial proteins mixed lineage kinase domain-like protein (MLKL) and PGAM5, resulting in the execution of necroptosis by dynamin-related protein 1, the GTPase that controls mitochondrial fission. Some small molecules such as necrostain-1 and necrosulfonamide target different steps of necroptosis and impede the progress of necroptosis. FADD, caspase-8, CLIP, and CYLD positively or negatively regulate RIP1-/RIP3-dependent necroptosis by different mechanisms. Recent studies demonstrate the involvement of necroptosis in many neurological disorders including stroke, trauma, neonatal hypoxic-ischemic encephalopathy, and Huntington's disease. As a potential therapeutic target, the understanding of necroptotic mechanisms will provide new insights to develop more potent neuroprotectants and specific therapeutic strategies for clinical treatments of neurological disorders.

Title: Hypersensitive and circadian effects of acebutolol administration in Scn1b-/- mice. Rationale: Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by homozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrhythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Methods: Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). In the day group, ECG was recorded daily from P13 until animal death. Starting at P15 mice were recorded both pre- and post- injection to analyze the long-term and acute effects of treatment. Results: A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. To investigate the timing of drug delivery, a subset of mice was given injections at night. In this group there was actually a decrease in lifespan, with an earlier onset of death compared to saline treated mice. On a daily basis from P13, the heart rate (HR) of KO mice was significantly lower than WT but remained steady until the day prior to animal death. HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). Analysis of acute recordings following ACE administration showed that KO mice had a significantly larger reduction in heart rate compared to WT (38% vs. 11%). Further analysis of heart rate variability in these recordings demonstrated that RMSSD (a measure of vagal control of the heart) was reduced in KO mice, with differences in both baseline and following ACE administration. Conclusions: Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modestly increased lifespan. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Finally, these results suggest that there is a possible hypersensitivity to beta-adrenergic blockade in Scn1b-/- mice. Funding: This work was supported by a grant from the Research Development Committee at East Tennessee State University and NIH grant R21NS116647 to C.R.F.

No description available.

Stroke is the second most common cause of death worldwide and the commonest cause of dependency, creates a huge societal burden and is responsible for billions of pounds in health and social care costs. About 30% of strokes occur in individuals with a previous transient ischaemic attack (TIA) or minor stroke. Effective prevention would minimise the consequences. However, the diagnosis of TIA is difficult, particularly by non-experts. About 50% of patients with a suspected TIA or minor stroke have atypical TIAs or a non-vascular diagnosis (TIA/minor stroke mimics). Although there is some evidence that non-specific Transient Neurological Attacks (TNAs) have an increased risk of acute vascular events, the evidence is still both thin and controversial. The aim of my thesis has been to evaluate the burden of TIA/minor stroke mimics, TNAs and all acute cerebrovascular events among all referrals from the general population to a TIA clinic; to determine the reliability of clinical diagnosis of TIA and non-specific TNA; to improve the classification of non-specific TNAs; and to predict the risk of stroke and other major vascular events after a non-specific TNA and TNA syndromes. I have collected and analysed data from a population-based study, the Oxford Vascular Study (OXVASC). OXVASC is an ongoing prospective, population-based incidence study of all vascular diseases in all territories in Oxfordshire, UK, which started in 2002. The study population comprises approximately 92,728 individuals registered with nine GP practices and uses multiple overlapping methods of "hot" and "cold" pursuit to identify patients with acute vascular events. The research described in this thesis has several clinically relevant findings which can contribute to improving the diagnosis and treatment of patients with suspected TIAs. First, I highlighted that TIA/minor stroke mimics (mimics) were responsible for one quarter of all suspected TIAs, had similar short- and long-term risk of acute cardiac events as did TIAs, and that the majority (70%) of mimics were complex neurological conditions. Second, I showed that TIA/minor ischaemic strokes are each more common than major ischaemic strokes and that TIA/minor ischaemic stroke patients together had two-thirds of all recurrent strokes and two-thirds of all myocardial infarctions and sudden cardiac deaths. Moreover, the 10 years' cumulative risk of stroke in patients with TIA, minor stroke and major stroke was very high and the risk of death among all cerebrovascular events was greater than 50%. Third, I found that the crude incidence rate of TNAs per 1000 people in OXVASC was slightly higher than the crude incidence rate of TIAs (0.73 versus 0.67) and increased with age. In addition, I reported that among TNA syndromes, transient isolated vertigo, unilateral sensory symptoms, migraine-aura like events and transient confusion had high incidence rates, whereas transient total paralysis and transient speech arrest had low incidence rates. Fourth, I showed that about one-third of TIAs seen in the first 10 years of OXVASC did not fulfil the classical criteria (NINDS-negative TIA) and had the same short- and long-term risk of stroke as NINDS-positive TIAs. Fifth, although the 90 days stroke risk after a TNA was lower than after a NINDS-positive TIA, in the post 90 days up to 10 years period the risk of recurrent stroke was not significantly different between the two groups. Sixth, the risks of stroke were higher than expected in the background population in all TNA categories (focal-TNA, non-focal TNA and focal plus non-focal TNA) and all TNA syndromes (isolated brainstem syndrome, migraine-like syndrome, isolated sensory syndromes, isolated visual disturbance, isolated speech disturbance, transient confusion and transient unresponsiveness) except transient amnesia. Moreover, non-focal TNAs and focal plus non-focal TNAs had a six times higher risk of stroke than expected and a similar risk to NINDS-positive TIAs. Finally, transient confusion and transient unresponsiveness had a relative risk of stroke nine times higher than expected and twice the risk of NINDS-positive TIAs.