This dissertation for the Doctorate of Clinical Psychology at the University of Liverpool focuses on the experiences of receiving dialectical behaviour therapy (DBT) in the community by adults diagnosed with borderline personality disorder (BPD). It comprises three distinct chapters, namely a literature review, an article detailing an empirical study, and an extended discussion. Chapter one presents the findings from a literature review that systematically searched the qualitative literature for studies that explored the experiences of receiving community-based DBT by adults diagnosed with BPD. The chapter begins by briefly describing the history, diagnostic criteria, prevalence, and symptoms of BPD, before describing the components of DBT, a psychological treatment that has received strong empirical support for the treatment of BPD. Findings from the systematic search of the qualitative literature reveal five articles that fit the review’s inclusion criteria; this paucity of qualitative research investigating clients’ accounts of DBT in actual clinical settings is surprising considering that DBT has received growing support for its efficacy since the publication of its treatment manual in 1993. When considering the findings from the five qualitative articles, the picture of clients’ experiences of DBT is unclear, as the studies vary fundamentally in their research design. For example, the qualitative studies differ in their research design, including the use of structured interviews, semi-structured interviews, and focus groups, and vary in the methodological approaches deployed to analyse the data. Also, the DBT programmes from which participants were recruited in the qualitative studies differ in their fidelity to the DBT model. With the systematic search of the qualitative literature revealing so few studies exploring the experience of receiving community-based DBT by adults diagnosed with BPD, together with their methodological and analytical differences contributing to an unclear account of the experience, chapter two of this dissertation presents an empirical study aiming to augment the qualitative literature that explores the experience of receiving community-based DBT by adults diagnosed with BPD. This empirical study is vital as not only does it consolidate the existing qualitative research, but, remarkably, is believed to be only the second study of its kind to be conducted in the National Health Service (NHS), with the first being conducted over 6 years ago. The aims of the empirical research are to capture participants’ expectations and experiences of the DBT programme, the impact and experience of the multi-modal components of the programme, determine the meaning of a ‘life worth living’ to someone diagnosed with BPD, and gauge whether DBT contributes to a ‘life worth living’, which is DBT’s overarching aim. Six participants are interviewed, all of whom are diagnosed with BPD and have experience of a community-based DBT programme delivered by the NHS. Six themes are found from analysing the qualitative data derived from the interview transcripts. As the intention is to publish both the literature review and empirical paper in academic journals, and academic journals invariably set a limit regarding the maximum number of words or pages for research articles, the third chapter of this dissertation elaborates on the points made in the discussion section of the empirical article in chapter two. The elaborations extend the implications of the findings to the wider research. Links are made to the wider research literature that focuses on group therapies, and the literature suggesting that those diagnosed with BPD struggle to foster therapeutic alliances with therapists. Links are also made to clinical practice, especially in light of fundamental changes to the landscape of the NHS, such as the Coalition Government’s target to make £20 billion of efficiency savings within the NHS by 2014, and the NHS now facing competition from ‘Any Willing Provider’ offering healthcare provisions. Overall, the participants’ experiences of DBT found by the empirical study presented here is encouraging, and it is hoped that such positive views from users of the NHS may go some way to balance the criticism the NHS has received over the years regarding the quality of care it provides to the public. Chapter three also includes a different version of the empirical article, written for employees and clients of the Trust in which the research was conducted. Chapter three concludes with a section detailing how the empirical research presented in this study could be usefully extended.

Allergic responses are mainly mediated by immunoglobulin E (IgE) and mast cells or basophils expressing the high-affinity IgE receptor FcεRI. Cross-linking of FcεRI and IgE complexes with allergen induces basophil degranulation and release of inflammatory chemical mediators, leading to clinical symptoms. Common allergy diagnostic tests such as ImmunoCAP, focused on the measurement of specific IgE in patients, commonly lead to misdiagnosis. The allergen-specific IgE in patients’ sera might not always lead to FcεRI cross-linking on mast cells or basophils, resulting in no related clinical symptoms, as observed in some food allergies. In order to mimic the allergic response and generate an in vitro diagnostic device to address these issues, a basophil-microarray platform that couples the diversity of a protein array with the biological output of basophilic cells is being developed. This platform allows testing of up to five thousand allergens using a drop of patient’s blood. In this study, the optimisation steps and preliminary results are presented. The platform in development relies upon the use of a humanised rat basophilic leukaemia (RBL) cell line RBL-703/21 and different methods to measure the levels of basophil activation. ß-hexosaminidase assay showed that the human FcεRI expressing RBL-703/21 cell line was able to bind human IgE in the presence of anti-IgE/allergens and led to degranulation. Fibronectin has shown to greatly avoid cell losses during experiments, calcium ionophore A23187 is an unsuitable positive control due to a fast down regulation of VLA-4 and subsequent detachment of cells. The commercial Ca2+ probe (fluo-4, AM) was shown to efficiently measure the intracellular calcium flux upon activation in the micro-well plate, but due to the lack of a detection system, it can not to be used in the microarray. Two reporter plasmids encoding GFP or DsRed with an NFAT promoter region were transfected into RBL-703/21s and optimised. Both reporter systems were able to detect the presence of functional allergen-specific IgE in the sera of patients, and showed the expected bell–shaped dose response curves. Results correlated with those measured by clinical diagnostic methods. The fluorescence system developed using reporter genes does not need further processing, making it an ideal system for the future development of basophil microarray platforms.

Reports of inter-ethnic differences in metabolism for phenytoin and carbamazepineh have raised questions concerning the importance of monitoring serum levels to the standardised population therapeutic concentrations. Although the pharmacokinetics of phenytoin, carbamazepine, valproic acid and phenobarbitone displayed both intra and inter-individual variations, the influence of ethnicity is still unclear. This thesis has thus set its objectives of investigating the impact of ethnicity on the efficacy of these therapeutic ranges and pharmacokinetics of these drugs. A total 1554 serum concentrations were randomly selected by a set of criteria from 470 Malays, 423 Chinese and 322 Indian of adult and paediatric patients. The Mantel-Haenzel method was used to estimate for inter-ethnic differences in response to the defined therapeutic ranges. The influence of ethnicity on pharmacokinetics was examined by the test of heterogeneity of the slopes estimates in the linear relationship of either serum concentration or clearance to dose. Coefficient of variation on the ratios of the above relationships was used to measure for inter individual variation. The results showed a highly variable response to treatment within the defined therapeutic ranges. Therapeutic response is not dependent on ethnicity and age although the latter was determined on carbamazepine and valproic acid treated patients only. The pharmacokinetics of carbamazepine, valproic acid and phenobarbitone showed high inter-individual variations and were unaffected by weight, age or ethnicity. Similar high inter-individual variation for phenytoin pharmacokinetic parameters (Km and Vmax) were observed. However, Km and Vmax(mg/day) of adult Chinese patients were significantly lower than Malay or Indian patients. The relationship between Km and Vmax and age or weight were insignificant. These findings demonstrate that Malaysian patients only differed in handling phenytoin therapy and support the use of ethnic specific phenytoin pharmacokinetic parameters during therapy.

The aim of this thesis was to identify both patient and carer factors relating to caregiver strain in spouses of stroke patients. The secondary aim was also to assess the effectiveness of an intervention in reducing levels of strain, involving the provision of cognitive assessment information to both patients and spouses. Previous research has not investigated specific cognitive impairment after stroke in relation to strain and reports of the relationship between patient disability and strain are not consistent. Assessment of physical function and detailed neuropsychological examination was carried out with stroke patients in Nottingham, Derby and Mansfield as part of a prospective, multicentre, single-blind randomised controlled trial. The assessment battery included measures of general mental state, language, perception, memory, executive function and praxis. Individualised information about cognitive function was provided in verbal and written form to each patient and carer. Carer strain was assessed in 57 spouses three and six months later. Around a third of spouses experienced significant strain. Results confirmed the importance of patient physical function with disability becoming an important factor with time. Basic self-care skills (Barthel Index) measured at three and six months, were significantly associated with carer strain at six months. Impairment of the patient's general mental state on the Mini-Mental State Examination (MMSE) and communication difficulties on the Sheffield Screening Test for Aphasia (SST) were related to carer strain and were also associated with emotional rather than physical strains. Carer strain was not significantly associated with other cognitive deficits, including impairments of perception, memory, executive function and praxis. Previous research has not assessed specific carer characteristics in relation to strain. In order to identify these, 222 spouses of stroke patients were sent questionnaire measures of strain, stress, mood, handicap, adjustment, social support, life satisfaction and personality and their perceptions of the patient's mood and independence in activities of daily living. Univariate analysis suggested that strain was associated with increased carer handicap, high stress, poor mood, 'chance' health locus of control, expression of depressed mood, low optimism, low positive affectivity, high negative affectivity and low self-esteem. Strain was also related to poor adjustment, low satisfaction with life, less emotional and practical support and a greater discrepancy between actual and ideal levels of support and increased help from professional services. Strained carers also perceived poor mood and increased disability in the stroke patient. Multivariate analysis indicated that the most important factors were low carer mood on the General Health Questionnaire-12 (GHQ-12), poor perceived patient independence in activities of daily living on the Extended Activities of Daily Living Scale (EADL) and high negative affectivity on the Positive and Negative Affect Schedule (PANAS). The relationship between these factors and strain needed to be tested prospectively. In a multicentre study of 116 spouses in Nottingham and Leicester, carers were sent the CSI, GHQ-12, EADL and PANAS at three and six months after the stroke. Again, over a third of carers experienced significant strain. Results confirmed those of the previous study and mood, perceived disability and negative affectivity at three months were found to predict high levels of carer strain six months after stroke. The most important caregiver factors were therefore the spouse's appraisal of their partner's disability, together with two emotional components of subjective well-being, one transient and one stable. The results also highlighted the role of other factors, including incontinence, disturbed sleep, communication difficulties and the amount of time spent caregiving in carer strain. Early identification of carers who may be at risk of strain later on will enable services to be targeted at prevention rather than cure. There was a non-significant trend towards reduced strain in carers who had received information about cognitive deficits after stroke. Spouses may benefit from individualised information about their partner's stroke. Strain is emotionally laden and services might focus on teaching effective coping strategies to reduce depression and provide emotional support. More research is needed to identify services that are effective in alleviating or indeed preventing strain. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.

Only 5% of excitatory input to primary visual cortical (V1) neurons corresponds to feedforward input from the retina, and only 20% of responses by these neurons can be explained by retinal input (Carandini, 2005; Muckli and Petro, 2013). Neuronal responses are therefore highly influenced by non-feedforward interactions, allowing the brain to combine external input from the retina with context and knowledge. This is accomplished by integrating feedforward input with signals from neurons processing higher-level or associative information. The signals transmitted from higher cortical areas to V1 are known as cortical feedback. The neuroscientific community is in agreement that cortical feedback is an important aspect of brain processing. However, the information transmitted by feedback and what factors give rise to contextual feedback remain largely unknown. Feedback connections provide V1 neurons with information about their far surround receptive fields (Angelucci and Bressloff, 2006), and stimulation in the surround provides contextual information about the scene to non-stimulated portions of V1 (Smith and Muckli, 2010; Muckli et al., 2015). Occluded V1 activity patterns recorded using fMRI have been used to decode different scenes, but again, little is known regarding the nature and content of the contextual information that feedback transmits. This thesis aims to examine the information in contextual feedback to early visual cortex, with a particular focus on V1. To investigate this topic we used an occlusion paradigm derived from that of Smith and Muckli (2010) and Muckli et al. (2015). During normal vision, both feedforward and feedback signals are present. As such, a useful approach to study feedback is to isolate it from feedforward input. We occluded one quadrant of the visual field during stimulus presentation in order to remove meaningful feedforward input about scenes in a portion of retinotopic visual cortex. We used fMRI to assess brain activity in early visual cortex, allowing us to detect dendritic signaling associated with cortical feedback due to its sensitivity to cortical energy consumption (Logothetis, 2007, 2008; Petro et al., 2014). In Chapter 2, we investigated potential high-level information in cortical feedback to V1 and V2. We presented subjects with an expanded version of the occlusion paradigm from Smith and Muckli (2010) and Muckli et al. (2015). We included twenty-four partially occluded scenes from six categories and spatial depths. These two high-level scene characteristics were chosen because they have previously been shown to modulate early visual cortical responses (Walther et al., 2009; Kravitz et al., 2011). We were therefore interested in whether these characteristics also modulate feedback to V1 and V2. We found that response patterns in these subregions contain high-level category information, but we did not find that visual depth information generalized across exemplars. Additionally, we found that retinotopic responses in Occluded V1 and V2 differed from each other, suggesting that feedback to these two areas has different information content, and matching the known anatomical connections from mid- and higher-level visual areas in the ventral stream (Rockland et al., 1994; Rockland and Ojima, 2003). In Chapter 3, we probed the information content of Occluded V1 and V2 responses at multiple levels of complexity using Representational Similarity Analysis (RSA) and encoding models. By analyzing data from Chapter 2 in these frameworks, we were able to compare both local (voxelwise) and distributed (multi-voxel) Occluded responses to three biologically-inspired computational models (the contrast energy-based Weibull model, the orientation-based Gist model, and the mid-level vision H-Max model), and the high-level scene characteristics explored in Chapter 2. Using RSA, we also compared scene representations from Occluded and Non-Occluded areas. We found that in Non-Occluded areas, V1 and V2 represent scenes similarly, while Occluded V1 and V2 do not. We also found that scene representations in Occluded V1 and V2 were correlated with high-level Category and H-Max models. Individual voxel encoding models showed that Occluded V1 voxels within 5◦ visual angle of fixation encode low-level information about the occluded scene, while voxels outside of 5◦ encode higher-level information. These results highlight a potential visual field bias in the type of information transmitted to V1 through feedback, with foveal voxels receiving more precise, low-level scene information, and peripheral voxels receiving more invariant or global scene features. In Chapter 4, we examined the laminar profile of Occluded V1 using high-resolution (0.8mm3) 7T fMRI. We again expanded our stimulus set, now with 192 Occluded scenes and 192 Non-Occluded scenes. This large stimulus set allowed us to map scene information onto voxel responses in greater detail, and the use of both Occluded and Non-Occluded scenes allowed us to compare voxel responses when receiving only feedback with responses when receiving feedforward, lateral and feedback information. We found that V1 responses exhibit predictive and high-level response properties in addition to feedforward orientation and spatial frequency properties typically associated with V1 responses. These predictive and high-level responses were primarily associated with superficial layers of cortex. We also found that voxel tuning toward feedforward and feedback signals was different between cortical layers of V1. Our findings suggest that feedback connections terminating in superficial layers provide V1 neurons with contextual and associative information not available via localized feedforward input. The neuroscientific results presented in this thesis extend our knowledge about the information content of cortical feedback to early visual cortex. These results add support to the notion that V1 can be considered to speak two languages (Muckli and Petro, 2013). Not only does it play a role as an early stage of processing of sensory visual input, where it deals with processing low-level features, but it also receives messages from diverse areas of cortex and these messages supplement local processing by providing contextual information.

Perceptual decision making involves the classification of sensory information, usually followed by an overt behavioural response. Any decision making, and perceptual decision making in particular, can be understood both theoretically and neurologically as a process of an accumulation of evidence to some threshold, at which point a commitment to a choice is made. This process can be examined in human subjects by analysing EEG data during perceptual decision making and identifying temporal components that are the neural signatures of the accumulation-to-bound decision making (see Philiastides & Sajda, 2006; Philiastides, Ratcliff, & Sajda, 2006a; Philiastides et al., 2006a; Ratcliff, Philiastides, & Sajda, 2009b). It may also be statistically modelled using sequential sampling models (see Ratcliff & Smith, 2004; Ratcliff, Gomez, & McKoon, 2004; Ratcliff & McKoon, 2008; Ratcliff & Van Dongen, 2011). Taken together, these provide us with a experimental and theoretical framework for the study of the neuroscience of human decision making. In this thesis, our aim is to address some open questions with respect to human perceptual decision making using the theoretical framework of sequential sampling models and the experimental paradigm of measuring temporal components in single-trial EEG discriminant analysis. In Chapter 2, we will describe our studies of the role of learning on perceptual decision making. In particular, here we address competing hypotheses about the nature and location of perceptual learning in the brain. We provide evidence that perceptual learning arises from changes in higher level brain areas that are related to decision-making, rather than from perceptually earlier areas that are related to the encoding of sensory stimuli. In Chapter 3, we provide a specific mechanistic account of how learning affects perceptual decision making. This work follows from the work of others who have applied reinforcement learning theories (see Sutton & Barto, 1998) to the study of perceptual learning. In Chapter 4, we will describe our studies of the interaction of prior expectation and learning on decision making. In this study, we particularly aim to address whether prior expectation affects baseline activation or evidence accumulation in the decision making system, and how this changes with training. Here, we obtain evidence showing how the effects of prior expectation are more related to evidence accumulation rather than baseline activation. In Chapter 5, we provide sequential sampling models, particularly drift diffusion models, of the data that we’ve obtained in the main experiments described in Chapter 2 and Chapter 4. The principal results here show how learning and prior expectation primarily have their effect on perceptual decision making by increasing the rate of evidence accumulation. Our general conclusion is that using a combination of the theoretical framework of sequential sampling models and the experimental paradigm of measuring temporal components in single-trial EEG discriminant analysis provides an effective and comprehensive means to address open questions with respect to human perceptual decision making.

There is growing evidence that suggests Traumatic brain injury (TBI) may initiate long-term neurodegenerative processes. Exposure to a single moderate or severe TBI, or to repetitive TBI, reveals a complex of pathologies including abnormalities of tau, amyloid-β and TDP-43; neuronal loss; neuroinflammation; and white matter degradation. The mechanisms driving these late post-TBI neurodegenerative pathologies remain elusive. Firstly, a potential association between blood-brain barrier (BBB) disruption and TBI was investigated. Results showed that increased and widespread BBB disruption was observed in material from patients dying in the acute phase following a single, moderate to severe TBI and persisted in a high proportion of patients surviving years following injury. Furthermore, there was preferential distribution to the deep layers of the cortex and to the crests of the gyri rather than the depths of the sulci. This post-TBI BBB disruption was investigated further within a paediatric TBI cohort. BBB disruption was noted in both paediatric and adult TBI in a similar pattern and distribution, however, interestingly, in sharp contrast to adult TBI cases, BBB disruption in paediatric cases appears preferentially distributed to capillary sized vessels. This vulnerability of the small vessels was rarely observed in adult material. In addition to the post-TBI vascular change observed, the cellular response was investigated, which interestingly, demonstrated regional differences. Specifically, in the grey matter, reactive astrogliosis was observed subpially, around cortical vessels, at the grey and white matter boundaries and subependymally. This astrogliosis was evident in a proportion of acute and continued into the late phase following TBI. In contrast, microglial activation was observed as a delayed response and localised to the white matter tracts. In addition, this delayed microglial response expressed an M2-like phenotype. Furthermore, there was an increased population of inactivated perivascular microglia beyond the perivascular space in the grey matter regions, observed in the acute phase and persisted in a proportion of patients surviving years following injury. Collectively these findings are interesting and indicate TBI induces both a vascular and cellular responses which may contribute to the long-term post-TBI neurodegenerative processes.

The work carried out in this thesis is focused on the proposal, comparison and assessment of survival analysis models for epilepsy data. Although the Cox proportional hazards model provides a popular approach to medical recurrent events modelling, other accelerated life alternatives seem more appropriate when compared under goodness of t tests. In our research we apply the Cox proportional hazards model and two models consisting of a Poisson-Gamma mixture model that could assume the existence of a cure fraction , and which have been developed and proposed by B. Cowling[11] and J. Rogers[39] respectively. We applied these methods to the Multicentre study of early Epilepsy and Single Seizures (MESS) data set. In this epilepsy study, patients with different types of seizures were randomized to either immediate or delayed treatment, which consisted in being administered one of seven types of drugs. The aim of the study consisted in producing a prognosis with which the clinicians and patients could take an informed decision on whether or not it was preferable to take an anti-epileptic drug. We investigated the behaviour of the survival function for the Cox proportional hazards model, the joint model and the joint with cure fraction model under the epilepsy data set, under the framework of residual analysis studies, as well as empirical vs theoretical survival functions. As a final contribution of our work, we proposed modification of the accelerated life models. Since a patient cannot be diagnosed with epilepsy unless he or she presents at least two un-provoked seizures, we proposed a zero-truncated joint model, which considers the pre-randomization counts to be strictly positive. This model has been extended to consider a cure fraction of the population, but is still under development, since the corresponding parameter estimations become considerably more complicated.

This thesis is concerned with the factors that determine the performance of everyday action. Six empirical chapters are subsequently presented. First, I sought to investigate the effects of the presence of distractors and of task load on the performance of everyday life tasks, comparing a patient with ADS and controls operating with a task load (Chapter 2). The data indicate that controls and patients with ADS may suffer different demands. The role of the task schema on ADL was examined in Chapter 3. The results showed that there is a problem in using task schema to drive action under the on-line constraints of performing the action. Relation between object recognition and action was tested in Chapters 4 and 5. I showed that 'object use' effect was maintained even when the patients showed impaired semantic access for the objects. The final empirical study (Chapter 7), investigated the role of eye movements on performing an everyday. There were proportionately more unrelated fixations and more fixations concerned with locating objects in the ADS patient than in controls. In addition, eye movements away from objects being used were made earlier in the ADS patient, and toying errors were linked to multiple, brief fixations being made to the object involved. In the final chapter (8), I review the evidence from across the thesis and discuss the implications of the work for understanding both normal and disordered everyday actions. The results not only point to the complexity of processes supporting such actions, but also to the critical interactions between action and attention in such tasks.

Spinal cord injury (SCI) is a neurodegenerative disease with research centered on axon regeneration and preservation to cure paralysis. Mice and rats are widely studied and experienced models used to imitate SCI due to differences in vascular disruption, blood vessel loss and cavitation at SCI epicenters. This study investigates sub-acute SCI responses, documenting angiogenic/inflammatory factors and matrix deposition in both species. Although cavitation was absent in mice, the lesion site in rats was larger at 8 and 15 days post lesion (dpl). Absence of cavitation in mice correlated with increased levels of pro-angiogenic/wound healing factors within the wound compared to rats at 8 dpl, coinciding with microarray analysis along with increased axonal sparing at T7 and T9 spinal segments. Despite similar deficits in thermal sensitivity 2 hours after injury, by 7 days the responses were comparable to controls in both species. Furthermore, inducing inflammation directly after injury using zymosan resulted in inflammatory-induced angiogenic responses between both species at 8 dpl, contributing to tissue damage and micro-cavities in the CNS. In conclusion angiogenic responses in mice attenuates wound cavitation, reducing secondary axon damage and thus induces axon sprouting/regeneration. These results suggest potential therapeutic utility of manipulating angiogenic/inflammatory responses after human SCI.