Paroxysmal hemicrania and hemicrania continua are primary headache syndromes characterized by exquisite response to indometacin. Migrainous features such as phonophobia and photophobia occur in hemicrania continua and the differential diagnosis with unilateral chronic migraine can be challenging. This thesis explores the phenotypical aspects of paroxysmal hemicrania, hemicrania continua and unilateral chronic migraine, revisits the current criteria for the identification of paroxysmal hemicrania and hemicrania continua, and identifies clinical markers that can be used to differentiate hemicrania continua from unilateral chronic migraine. The study of thirty-one patients with paroxysmal hemicrania shows the pain is in a wider area of the head and face and a full range of cranial autonomic features occurs with the attacks. The study of thirty-nine patients with hemicrania continua shows 92% of patients have side-locked pain. Ninety-five per cent of patients have at least one autonomic feature and a wider range of autonomic features occurs with severe pain. The study comparing twenty-seven patients with hemicrania continua and twenty-seven patients with indometacin negative unilateral chronic migraine shows that both syndromes share several clinical characteristics. However, cranial autonomic features and phonophobia and photophobia tend to be lateralized to the same side of the pain in hemicrania continua. The thesis concludes that the International Headache Society criteria for paroxysmal hemicrania and hemicrania continua should be revised. The results suggest to remove specification of attack site, and to include the full range of autonomic features in paroxysmal hemicrania; to allow side-swift of the pain, to include a more extensive range of autonomic features, and to consider the occurrence of autonomic features as an important but not an essential criterion in hemicrania continua. In addition, unilateral cranial autonomic features and phonophobia and photophobia may be helpful during the differential diagnosis between hemicrania continua and chronic migraine.

This primary focus of this study is measure development, in which a new measure of knowledge of dementia for residential home care staff is presented. In order to set a contextual frame for the main study, the first part of this paper provides a systematic review of all published knowledge of dementia measures within research literature. The strengths and limitations of the tools are presented by critically reviewing their development procedures and psychometric properties, taking into account their performance and use within research studies. Five measures are analysed in terms of their reliability and validity and conclusions direct the reader towards the most appropriate measure to use within given situations and contexts. Providing a review of the literature demonstrates a need for a new knowledge of dementia measure for use with non-professional care staff, a traditionally underrepresented group in terms of research. Part 2 of the study describes the conceptual development and validation study of the new measure: the DK-20. The strengths and limitations and implications for practice of the new tool are discussed, along with recommendations for further research. Finally, Part 3 offers a critical review of the study. Reasons for choosing the project along with thoughts and reflections on the process, in particular around recruitment and measure development are presented. This study forms part of a joint project focusing on developing questionnaires for dementia care staff. Certain aspects of the project were undertaken in collaboration with a fellow Trainee Clinical Psychologist, Astrid Schepers. The specific areas of joint work and individual work are outlined in Part 2.

Tourette’s syndrome (TS) is a neurodevelopmental disorder often associated with social difficulties and inappropriate behaviours (e.g. Kurlan et al., 1996). These behavioural difficulties may indicate impairment on aspects of social-emotional processing, but may also be related to impairments in executive functions which have been reported in TS, particularly for aspects of inhibition. This thesis aims to examine different aspects of social-emotional processing and executive functions in TS, and to assess the possible contribution of executive processes. A series of experimental studies was conducted to compare those with TS to healthy matched control participants. With respect to social-emotional processing, ability to decode social-emotional cues, to regulate emotional experience, and to regulate social behaviour according to context, and possible executive contributions to these processes were examined. Further studies extended previous research by examining inhibitory functions not previously assessed in TS, and explored the contribution of task complexity to inhibitory performance. The findings of the experimental studies are considered in the context of recent models of social-emotional processing (Ochsner, 2008), executive functions (Miyake et al., 2000) and inhibition (Nigg, 2000). Several alternative explanations of the findings of this thesis were identified: selective inhibitory impairment, level of executive task demands, or multiple deficits in executive and social-emotional processing. The applicability of these different explanations to the findings is discussed, and the implications of the findings are reviewed.

Whole exome sequencing (WES) – the targeted sequencing of the subset of the human genome that is protein coding – is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits, some of which have proved to be intractable to conventional gene-discovery strategies. My PhD thesis focuses on the use of whole exome sequencing to dissect the genetic aetiologies of families with Mendelian forms of Parkinson’s disease and Dystonia. First I present a project where next generation sequencing played an important role in the identification of a novel Parkinson’s disease gene (VPS35). I then describe the use of WES in i) an autosomal dominant PD kindred, where a novel DCTN1 mutation was identified; and show a number of examples of successes and failures of WES in ii) autosomal recessive Parkinson’s disease and iii) autosomal recessive generalised dystonia.

This project was undertaken jointly with fellow trainee Niamh Shanahan. It focuses on the field of dementia care research and consists of three parts. Firstly, the literature review aimed to evaluate measures assessing subjective psychological factors in dementia care staff. A systematic search identified 28 dementia care staff measures fulfilling a set of inclusion criteria. The measures covered seven domains: Attitudes, Coping, Job-satisfaction, Job Strain, Perception of Care Recipient's Behaviour and Needs, Sense of Competence, and Views about Falling. Using a methodical evaluation framework the review highlighted measures with the best research potential in each domain. Finally, new challenges and opportunities for future research in the field of staff factors in dementia care were discussed. Secondly, the empirical paper, based on the conclusions of the literature review, developed a new measure to assess the sense of competence in dementia care staff. Development of the measure was guided by a framework derived from a review and critique of existing measures. The construct of sense of competence was defined and a questionnaire developed with the help of care staff and experts. A pilot study and a large-scale reliability and validity study were undertaken to refine the instrument and evaluate psychometric properties. The final measure, the Sense of Competence in Dementia Care Questionnaire for Staff (SOCID-S), is a 17-item instrument with promising quality characteristics. Opportunities for future research, improvement and application of the measure were explored. Finally, a critical appraisal was used as to reflect on the challenges of developing a new measure and to explore alternatives to the decisions taken to overcome those difficulties.

Part 1, the systematic literature review, examines the empirical literature on symbolic and non-symbolic number representation in humans. A diverse range of experimental methodologies were explored, including 19 studies which comprised computational modelling, neuroimaging, behavioural and clinical evidence, and 15 review articles which focused on the acquisition of number competence and the underlying form of number representation. The review revealed a lack of evidence on the qualitative differences between representations of symbolic and non-symbolic numbers, and hardly any clinical evidence of the underlying pathways. Part 2, the empirical paper, reports a study adapted from Roggeman, Verguts and Fias (2007), which used healthy participants, by using patients with lesions to the parietal lobe, an area commonly associated with numbers. We aimed to determine whether there were differences between symbolic and non-symbolic notations from which differences in underlying representations and areas engaged in the processing of these notations could be inferred. The priming task provided a measurable indicator of any differences between notations and the impact of these lesions on the ability to identify numbers presented as digits and dots. There were no significant differences in digit and dot notations between the patient and control groups. However, two case studies revealed normal digit and dot number representation following a left lesion, whereas normal digit and abnormal dot number representation was observed following a right lesion, thereby supporting a notation-dependent view. Part 3, the critical appraisal, provides a reflective discussion of the project from start to finish, addressing methodological choices, the clinical and research duality and wider conceptual issues.

It has been shown that brain activity before an item can predict whether this item will later be remembered. However, the cognitive mechanisms underlying this so-called prestimulus brain activity are poorly understood. The studies in this PhD thesis addressed the role of prestimulus neural activity in long-term memory encoding and whether this activity is under voluntary control. To allow better dissociation between brain activity before and after an item, electroencephalography (EEG) was used due to its high temporal resolution. In a series of studies EEG data were analyzed in terms of Event-Related Potentials (ERPs) and oscillatory power in the theta frequency band (4-8 Hz) that plays a crucial role in memory processes. The findings demonstrate that brain activity preceding a stimulus is indeed under a person‟s control. In one experiment, ERP and frontal theta prestimulus activity before an item was only evident when participants were highly motivated to encode an upcoming item. In another experiment, ERP prestimulus activity only emerged when participants prioritized encoding over a concurrent task. These studies suggest that, at least, some prestimulus activities reflect preparatory processes that depend on the available cognitive resources. Two further experiments demonstrated that frontal prestimulus encoding-related theta power is specific to semantic encoding conditions. Finally, a series of behavioural experiments showed that memory performance does not differ depending on the opportunity to prepare during encoding. The findings of my PhD thesis suggest that (i) some prestimulus signals (i.e. frontal theta) reflect a preparatory process ahead of semantic encoding, (ii) and, most importantly, prestimulus signals (i.e. ERPs and frontal theta) reflect active preparatory processes for long-term memory formation. The results of this thesis could lead to the development of new strategies of how to improve memory, especially in clinical settings.

Novel targets for the treatment of pain are continually being sought. These new targets may lie within the pain pathway, which facilitates the detection, transmission and perception of pain and include ion channels which control neuronal excitability such as Kv7/M-channels which have been implicated in the control of neuronal excitability in peripheral neurons. The aim of this work was to determine the expression of Kv7/M-channels in the peripheral components of the nociceptive sensory pathway and to investigate aspects of their functional significance. Immunohistochemical techniques to determine the localisation of the channel were completed using antibodies to the Kv7.2 subunit of the channel and to various neuronal makers. Immunoreactivity to Kv7.2 was detected in a variety of DRG sensory neurons and peripheral sensory nerve fibres; including small nociceptive neurons. Immunoreactivity to Kv7.2 was also detected diffusely along unmyelinated fibres within the vagus nerve. Electrophysiological measurement found that these fibres could be hyperpolarised in a XE991 sensitive manner by retigabine. The Kv7/M-channel was also identified in keratinocytes by immunoreactivity for Kv7.2, RT-PCR, electrophysiological recordings and a potentiated induced release of ATP by retigabine was observed, this effect was blocked by XE991. These new neuroanatomical locations for M-channel are helpful in the interpretation of functional studies on the role of M-channels in regulating peripheral nociception. The localisation of the channel in presumably non-nociceptive fibres raises additional possibilities regarding their role in other forms of sensation. The functional studies also expand potential roles for M-channels to the regulation of C-fibre activity and also to aspects of keratinocyte function. These results also raise the question of how far the effects of retigabine (and other M-channel enhancers) observed in other studies are due to peripheral actions.

N-type calcium channels belong to the family of voltage gated calcium channels , which open in response to membrane depolarisation. These channels are responsible for the calcium influx that triggers neurotransmitter release at presynaptic terminals. N - type channels are particularly important in mediating neurotransmitter release at the presynaptic terminals of peripheral sensory neurons and have been implicated i n neuropathic pain. Understanding the regulation of N - type channels is critical to the development of treatments that target these channels. Until now it has been difficult to directly investigate the regulation of their expression at the cell surface due to the inability to selectively visualise channels at the surface. Although N - type channels are thought to consist of a Ca v 2.2, α 2 δ and β subunits, there is uncertainty over whether the pore forming Ca v 2.2 subunit does indeed interact with α 2 δ at the cell surface. The work in this thesis has yielded two tagged functional Ca v 2.2 subunits that can be selectively visualised at th e plasma membrane , and has led to conclusive evidence that Ca v 2.2 and α 2 δ - 1 are closely associated at the cell surface. Furthermore, these tools have allowed the investigation of the mechanism by which α 2 δ - 1 enhances surface expression of Ca v 2.2 and which domains of α 2 δ - 1 are involved. Interestingly, this work implicates two poorly characterised chemosensory - like domains of α 2 δ - 1 as important for the interaction with Ca v 2.2, and also demonstrates that α 2 δ - 1 exerts its effect through increased forward traffi cking rather than increased surface stability. The application of gabapentin, a drug used to treat neuropathic pain, reduces surface expression of Ca v 2.2 through a mechanism that is wholly dependent on binding to α 2 δ - 1. T he tools generated in this work can be used to examine Ca v 2.2 regulation in neurons, val idating their potential for characterising the regulation of Ca v 2.2 in the nervous system.

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