Background: In April 2009, the NHS Institute for Innovation and Improvement released four Better Care Better Value (BCBV) prescribing indicators. One indicator targeted renin–angiotensin–aldosterone system (RAAS) drugs, i.e., angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), to improve their prescribing efficiency. The indicator affects the proportion of items written for ACEIs as a percentage of the total number of prescriptions for RAAS drugs. A proportion of 80% ACEIs has been proposed and considered as an achievable target based on the small proportion (2–10%) of patients who cannot tolerate the ACEIs-related side effects, mostly dry cough. However, neither the impact of the BCBV indicator on the utilisation of ACEIs/ARBs nor its cost-saving implication is yet known. The BCBV indicator involves switching established ARBs users to ACEIs, where appropriate. However, no previous studies have specifically investigated the clinical and economic impact of the switch of ARBs and hence it is unclear whether the switch from ARBs to ACEIs, promoted by the BCBV indicator, would be associated with any clinical or economic issues. Without any financial incentives or legislation enforcement, uptake of the BCBV policy is predicted to be low, especially as evidence suggests that single measures are ineffective in altering GPs’ prescribing behaviour. However, the uptake and implementation of the BCBV indicator has not yet been explored. Aims: This thesis aimed to evaluate the impact of the BCBV indicator for ACEIs/ARBs on the utilisation of ACEIs/ARBs in treating hypertension (HT) and any associated cost savings. The effects of switching patients from ARBs to ACEIs on clinical outcomes (adherence, blood pressure [BP] level and HT-related complications), healthcare resources and costs were also investigated. Prior to this, patients’ adherence and persistence patterns (discontinuation and switching), and potential associated factors were studied. Finally, the uptake and implementation of the BCBV indicator in real practice was explored. Methods:This research used an explanatory sequential mixed-method approach. Firstly, an interrupted time series analysis was used on data extracted from the Clinical Practice Research Datalink (CPRD), from April 2006 to March 2012, to examine the impact of the BCBV indicator on the repeated cross-sectional monthly ACEIs/ARBs prescriptions and costs in patients with primary hypertension, which was validated using national dispensing datasets. Secondly, a retrospective cohort study was conducted using prescription records extracted from CPRD for patients with primary hypertension who were prescribed antihypertensive drugs from April 2006 to March 2013. Patients’ adherence and persistence patterns (including switching) to antihypertensive drug classes were quantified and their association with patients’ characteristics tested, using Generalised Linear Models and survival analysis. Thirdly, a retrospective cohort study was conducted on patients who switched their index drug class from ARBs to ACEIs to evaluate the clinical outcomes and resources used associated with ARBs switching, using data from CPRD in linkage with Hospital Episode Statistics, and applying multilevel regression for data analysis. Finally, semi-structured interviews were conducted with 16 general practitioners, to explore their views about ACEIs/ARBs prescribing and the BCBV policy to understand the reasons underpinning the effectiveness/ineffectiveness of the BCBV indicator. The interviews were recorded, transcribed verbatim and analysed using a thematic approach. Results: Impact of the BCBV indicator on ACEIs/ARBs utilisation and cost saving. The ACEIs prescription proportion declined from 71.2% in April 2006 to 70.7% in March 2012. The policy initially resulted in a sudden reduction of 0.3% (95%CI: –0.44, –0.16) in the level of ACEIs prescription proportion; however, it was thereafter associated with a sustained, significant increase of 0.013% (95%CI: 0.0007, 0.02). The failure to achieve the 80% target by the end of the study period resulted in missing a potential cost saving of 23.9% of the total ACEIs/ARBs cost. In June 2014, a potential cost saving of ~£1 million was predicted, had the 80% target been achieved; this substantial saving was several years after the availability of several low-cost generic ARBs. Adherence and persistence to antihypertensive drug classes: Among the 176,835 patients with primary hypertension included in this analysis, 38.4% and 20% were non-adherent (proportion of days covered [PDC]<80%) to their antihypertensive drug class and therapy, respectively. The discontinuation rate of antihypertensive drug class (56.1%) and therapy (35.5%) was relatively high by the end of six-year follow-up period. Using ARBs as the index drug class, prevalent hypertensive patients, prevalent antihypertensive drug users and increasing age were associated with higher PDC to antihypertensive drug class and therapy but a lower risk of drug discontinuation; whereas a higher deprivation level, comorbidity score and switching of antihypertensive drug class were associated with lower PDC to antihypertensive drug therapy but a higher risk of discontinuation. Overall, 26% of the included patients switched their antihypertensive drug class. Using ARBs, higher deprivation, higher comorbidity and prevalent antihypertensive drug users were protective factors against switching; whereas female gender, prevalent hypertensive patients, higher BP level and increasing age were associated with a higher risk of switching. Clinical and economic implications of switching patients from ARBs to ACEIs: Of the 46,193 patients who switched their antihypertensive drug therapy, only 470 patients switched from ARBs to ACEIs – they were included in this study. Based on whether the patient combined ACEIs with other antihypertensive drug classes in the post-switching period, 369 patients were classified into ACEIs-combined group and 101 patients into ACEIs-monotherapy group. Compared with the pre-switching period, the proportion of non-adherent patients (PDC<80%) in the post-switching period increased significantly (17% vs. 27%); however, this significant increase was observed only in the ACEIs-combined group (17.3% vs. 29%). The switching of ARBs was associated with a significant reduction in both systolic and diastolic BP (144.2 vs. 141.9 mmHg, p<0.001) and (84.6 vs. 82.6 mmHg, p<0.001), respectively; however, this effect was found only in the ACEIs-combined group. The incidence of all HT-related complications was comparable in both pre- and post-switching periods, except for the incidence of MI, which reduced significantly only in the ACEIs-combined group (OR=0.1, 95%CI: 0.04, 0.6). Importantly, the switching of ARBs to ACEIs was associated with a significant reduction in the total medical costs (mean cost difference: –£329.2, 95%CI: –534.6, –205.7). Uptake and implementation of the BCBV indicator: Potential barriers suggested for the poor uptake of the BCBV policy, included a lack of GP awareness of the policy, GPs’ negative attitudes toward the policy and a lack of financial incentives. Among other reasons, the current high proportion of ARBs users appeared to be related to an over-switching of ACEIs to ARBs in anticipation of an ACEIs-related dry cough. Suggested measures for increasing the policy uptake included effective dissemination strategies, linking the policy to financial incentives and providing guidance on performing the switching. Furthermore, strategies to address the over-switching of ACEIs to ARBs were considered essential for the BCBV policy to achieve its 80% ACEIs target. Conclusions:The BCBV indicator was ineffective and failed to achieve the 80% ACEIs target. The association of achieving the 80% target with a remarkable cost-saving opportunity and the lack of any negative clinical consequences following the switching of ARBs to ACEIs indicate the ongoing necessity to reconsider and reinforce this policy through multiple initiatives to increase its future effectiveness, building on the study’s identified barriers and suggested solutions. This thesis represents a case study of a failed and an ineffective prescribing policy, attributed primarily to inappropriate policy implementation. It provides key lessons for policy makers and healthcare authorities on the importance of effective implementation strategies as an integral component to any successful policy.

This thesis explores what a range of people know and understand about cognitive impairment. The research presented here also explores the language and terminology that people use when discussing cognitive impairment. In order to do so, a mixed methods design was employed, involving three related studies; a systematic review of the literature about knowledge and understanding of mild cognitive impairment (MCI), a questionnaire study exploring respondents’ knowledge and understanding of cognitive impairment, and an interview study building on the results of the questionnaire and exploring perceptions of cognitive impairment in-depth. The systematic review included 30 studies; 20 qualitative articles and 10 survey studies. The questionnaire study received 417 responses predominantly from England, but including some international responses. Questionnaire respondents were drawn from six population groups: people living with cognitive impairment, care partners, younger adults, older adults, healthcare professionals, and dementia specialists. Twenty-one semi-structured interviews were conducted with representatives from each of these six participant groups. The findings from these studies suggest that most participants were able to offer a definition of cognitive impairment, highlighting similar symptoms (focusing on memory problems) and causes (such as brain damage and ageing). Participants discussed cognitive impairment in the context of dementia and were uncertain as to whether the two were synonymous or different. Where participants felt that cognitive impairment and dementia were different, they were unable to articulate these differences suggesting that the boundaries between cognitive impairment and dementia are not clear to the wider population. Participants offered causation accounts and narratives which suggested both controllable and uncontrollable factors may play a role in cognitive health, but participants generally claimed that cognitive impairment was beyond an individual’s personal sphere of control. Participants identified that professionals and the lay population used different language and labels when discussing cognitive impairment and most felt that MCI was not an acceptable or appropriate label. The use of the word memory in diagnostic services for cognitive impairment and dementia (such as memory clinic, memory assessment service) is challenged as this may contribute to the perception that cognitive impairment and dementia are conditions which are solely or primarily characterised by a memory impairment. The results of the studies inform the development of an illness representation model of cognitive impairment, providing a framework on which to base future information resources, media messages and public health and awareness campaigns. This thesis has begun to address a key gap in the literature, considering the views of a range of populations about cognitive impairment. However, future research is needed to explore factors which influence perspectives about cognitive impairment and to consider whether these perspectives change over time and can be influenced by educational campaigns and information.

Functional magnetic resonance imaging (fMRI) is an important tool for understanding neural mechanisms underlying human brain function. Understanding how the human brain responds to stimuli and how different cortical regions represent the information, and if these representational spaces are shared across brains and critical for our understanding of how the brain works. Recently, multivariate pattern analysis (MVPA) has a growing importance to predict mental states from fMRI data and to detect the coarse and fine scale neural responses. However, a major limitation of MVPA is the difficulty of aligning features across brains due to high variability in subjects’ responses and hence MVPA has been generally used as a subject specific analysis. Hyperalignment, solved this problem of feature alignment across brains by mapping neural responses into a common model to facilitate between subject classifications. Another technique of growing importance in understanding brain function is real-time fMRI Neurofeedback, which can be used to enable individuals to alter their brain activity. It facilitates people’s ability to learn control of their cognitive processes like motor control and pain by learning to modulate their brain activation in targeted regions. The aim of this PhD research is to decode and to align the motor representations of multi-joint arm actions based on different modalities of motor simulation, for instance Motor Imagery (MI) and Action Observation (AO) using functional Magnetic Resonance Imaging (fMRI) and to explore the feasibility of using a real-time fMRI neurofeedback to alter these action representations. The first experimental study of this thesis was performed on able-bodied participants to align the neural representation of multi-joint arm actions (lift, knock and throw) during MI tasks in the motor cortex using hyperalignment. Results showed that hyperalignment affords a statistically higher between-subject classification (BSC) performance compared to anatomical alignment. Also, hyperalignment is sensitive to the order in which subjects entered the hyperalignment algorithm to create the common model space. These results demonstrate the effectiveness of hyperalignment to align neural responses in motor cortex across subjects to enable BSC of motor imagery. The second study extended the use of hyperalignment to align fronto-parietal motor regions by addressing the problems of localization and cortical parcellation using cortex based alignment. Also, representational similarity analysis (RSA) was applied to investigate the shared neural code between AO+MI and MI of different actions. Results of MVPA revealed that these actions as well as their modalities can be decoded using the subject’s native or the hyperaligned neural responses. Furthermore, the RSA showed that AO+MI and MI representations formed separate clusters but that the representational organization of action types within these clusters was identical. These findings suggest that the neural representations of AO+MI and MI are neither the same nor totally distinct but exhibit a similar structural geometry with respect to different types of action. Results also showed that MI dominates in the AO+MI condition. The third study was performed on phantom limb pain (PLP) patients to explore the feasibility of using real-time fMRI neurofeedback to down-regulate the activity of premotor (PM) and anterior cingulate (ACC) cortices and whether the successful modulation will reduce the pain intensity. Results demonstrated that PLP patients were able to gain control and decrease the ACC and PM activation. Those patients reported decrease in the ongoing level of pain after training, but it was not statistically significant. The fourth study was conducted on healthy participants to study the effectiveness of fMRI neurofeedback on improving motor function by targeting Supplementary Motor Cortex (SMA). Results showed that participants learnt to up-regulate their SMA activation using MI of complex body actions as a mental strategy. In addition, behavioural changes, i.e. shortening of motor reaction time was found in those participants. These results suggest that fMRI neurofeedback can assist participants to develop greater control over motor regions involved in motor-skill learning and it can be translated into an improvement in motor function. In summary, this PhD thesis extends and validates the usefulness of hyperalignment to align the fronto-parietal motor regions and explores its ability to generalise across different levels of motor representation. Furthermore, it sheds light on the dominant role of MI in the AO+MI condition by examining the neural representational similarity of AO+MI and MI tasks. In addition, the fMRI neurofeedback studies in this thesis provide proof-of-principle of using this technology to reduce pain in clinical applications and to enhance motor functions in a healthy population, with the potential for translation into the clinical environment.

Background: Self-injury is reported to be common in autism spectrum disorder (ASD). However, there are limited robust data detailing the prevalence, persistence, associated person characteristics and operant function of self-injury in ASD. Method: Three large scale survey studies were employed to establish the prevalence, persistence and risk markers for self-injury in ASD compared to contrast groups. Experimental functional analyses were conducted, including a fine grained temporal analysis of behaviours associated with self-injury. Results: Self-injury was displayed by 50% of the ASD sample and was persistent over three years in 77.8% of the group. Self-injury was associated with higher levels of autistic behaviour in individuals without idiopathic autism. Self-injury was associated with higher levels of impulsivity, hyperactivity, painful health conditions, repetitive behaviours and lower levels of adaptive behaviour. ‘ASD weighted’ operant functions for self-injury were identified for the majority of children with ASD. Conclusions: Self-injury is prevalent and persistent in ASD. The presence of ASD phenomenology is a risk marker for self-injury. There is a role for repetitive behaviours, pain and impaired behavioural inhibition in the development and persistence of self-injury. Self-injury is likely to be maintained by operant reinforcement in many individuals with ASD, through ‘ASD weighted’ reinforcement contingencies.

This thesis has evaluated the roles of dorsal and ventral processing streams in recognition and use of objects. Four main empirical studies are presented. First, to investigate how the cortical brain processes semantic and action knowledge in different object-related tasks, I examined structural data from stroke patients (Chapter 2) and functional data from healthy individuals (Chapter 3) using a voxel-wise statistical analysis method. Using data of different modalities (structural CT, fMRI) from different sources (patients’ lesions; healthy subjects’ functional activity) handled with a systematic analysis approach, I attempted to find convergent evidence to support the dissociation of semantic and action processing. Second, I also looked into the potential differentiation within the mechanisms underlying object-related action (Chapter 4) and object naming (Chapter 5) separately. Overall, comparable findings were provided from the voxel-based morphometric analysis of patients’ lesion data and the fMRI study with healthy participants: an association was observed between ventral brain structures and the retrieval of semantic knowledge/object recognition while a dorsal fronto-parietal-occipital network was found to support the processing of action knowledge/object-oriented action. Specific dissociations were also observed within the representations for object-oriented actions as well as the mechanisms underlying naming of objects.

The Drosophila Toll receptor is crucial for dorsoventral patterning in embryos, and for innate immunity. Toll also functions during central nervous system development, promoting neuronal survival and targeting. There are nine Toll paralogues in Drosophila, and it is unknown whether any of these also function in the CNS. Toll’s ligand, Spz, has an NGF domain. NGF is a vertebrate neurotrophin - a growth factor that regulates the development and function of the nervous system. Drosophila Neurotrophin 1 (DNT1), identified by homology to the vertebrate neurotrophin BDNF, and DNT2 are paralogues of spz. The three DNTs – DNT1, DNT2 and spz – are structural and functional homologues of vertebrate neurotrophins, and they promote neuronal survival, targeting and synaptogenesis in Drosophila. However, the receptors for DNT1 and DNT2 are unknown. Here, using a combination of in situ hybridisations and reporters that drive GFP expression, I investigate the expression of Toll paralogues in the Drosophila nervous system. By generating null mutant flies and gain-of-function transgenic flies, I examine genetic interactions between Tolls and DNTs. I also investigate the rolls of these receptors in adult locomotion, axon targeting and cell survival. Finally, in cell culture, I test whether DNTs can signal through Tolls to activate NFκB.

Idiopathic intracranial hypertension (IIH) is common in obese women and can lead to significant visual impairment. The cause of IIH is unknown and management controversial, due to the lack of prospective trials. This thesis provides a comprehensive review of the aetiology and management of IIH. The hypothesis that IIH is associated with a pro-inflammatory cytokine profile, suggested by its established association with female gender and obesity, was tested. Laboratory studies demonstrated the novel finding of elevated leptin in the cerebrospinal fluid from women with IIH, suggesting a role in the pathogenesis of IIH. The first randomised controlled trial in IIH is then reported. Treatment with acetazolamide was examined prospectively in 50 patients, providing seminal information to guide the design of future large-scale trials and data on the natural history of the condition. The observation that management of IIH is guided by a variety of clinical parameters was translated into a simple composite scoring system which was prospectively tested. Visual fields and optic disc appearance are shown to have the greatest influence on clinical outcome. Finally, a systematic study of the evaluation of papilloedema in IIH highlights the major limitations of the widely adopted Frisen staging scheme in the condition.

Individuals with acquired brain injury-related memory impairment learned routes around a complex virtual reality town under various conditions. Errorless learning, a technique used with considerable success in verbal learning tasks after brain injury (e.g. Baddeley & Wilson, 1994), resulted in significantly fewer route errors than trial-and-error (or 'errorful') learning, demonstrating the technique's potential for training practical daily living skills. The combining of explicit, naturalistic route learning strategies of cognitive map creation and landmark memorization with errorless learning did not, within the sample as a whole, further improve its efficacy. However, closer analysis of performance by participants with impaired verbal ability or deficits in executive function indicates that people with such cognitive profiles may derive particular benefit from these additional strategies. Applications and suggestions for further research are discussed.

Background: This study validates the Neuropsychological Assessment Battery Screening Tool (NAB-S) against a battery of established neuropsychological tests, used as a convergent validity test battery (CVTB). Method: Forty-four participants with traumatic brain injury (TBI) were recruited from an outpatient clinic at a UK trauma centre and residential rehabilitation centre. The NAB-S and CVTB were administered to the sample. Results: Strong positive correlations were observed between NAB-S indices and NAB-S TBI index in comparison with indices for distinct cognitive domains from the CVTB, and the convergent validity test battery mean (CVTBM). There was a high collinearity between NAB-S subtest indices, and poor internal consistency for some indices. Semi-partial correlations revealed the unique variance between NAB-S and CVTB indices, which were highly significant for the NAB-S attention and memory indices. An area under the receiver operator characteristic curve (AUROC) revealed that the NAB-S and NAB-S TBI indices are highly predictive of impairment measured by the CVTB. Conclusions: The NAB-S has good predictive validity of overall impairment as measured by the CVTB and is an adequate screen of cognitive impairment following TBI. Some indices had poor internal consistency and high collinearity, suggesting that further assessment with more sophisticated tests would be warranted.

The principal aim of this thesis is to examine how emotion regulation and mindfulness are related to cardiovascular activity and the implications of these relationships for the understanding of aggression. Studies one and two aimed to detail the relationship of mindfulness to psychopathic traits and emotion regulation. Results of these studies collectively imply that mindfulness shares certain features with primary psychopathic traits, including reduced physiological responding to aversive stimuli. Study three aimed to investigate whether slow-paced breathing, associated with an increase in vagal output and thus decrease in heart rate, may exert effects on emotion regulation. Participation in a paced breathing course improved emotion regulation and increased trait mindfulness in a sample of male offenders. Study four aimed to explore how cardiovascular activity and psychopathic traits relate to female perpetrated intimate partner violence. Increased vagal activity, was found to be positively linked to proactive aggression and partner violence. Study five aimed to extend the results of Study four to a sample of male offenders. The results showed that high vagal activity is related to low empathy and good performance on the Stroop task. Collectively, these findings have implications for the use of mindfulness based treatments and the understanding of aggression.