No disease-modifying compounds are available to halt disease progression in Alzheimer’s disease (AD). Immunotherapy offers promising possibilities for the manipulation of Aβ levels which the amyloid cascade hypothesis proposes as the causative factor in AD. However, antiAβ antibodies have caused inflammation in vivo. An alternative antibody (2B3) which targets the β-secretase cleavage site of the amyloid precursor protein (APP) from which Aβ is cleaved has been shown to downregulate Aβ in human cell lines. The approach is thought unlikely to cause inflammation as the immune system is not relied upon for Aβ clearance. It was hypothesised that the administration of 2B3 to aged transgenic APP mutation mice would lower Aβ levels through the inhibition of Aβ production, with an associated lowering of cognitive deficits. Two murine APP mutation models [London APP(V717I) and Indiana PDAPP(V717F)] were characterised in order to identify cognitive deficits against which the ability of 2B3 to reduce deficits could be assessed. APP(V717I) mice were assessed in the marble burying task, the elevated plus maze and a foraging task assessing spatial working memory at 3, 6 and 19 months of age. The radial arm water maze was carried out at 10 months, before the T-maze non-matching to position task was administered at 11 months. Object recognition memory was assessed at 18 months. Similarly, PDAPP mice were assessed using the marble burying and elevated plus maze (9.5months), the T-maze (9-10 months), the foraging task (11 and 14 months) and the object recognition task (12 months). Whilst aged transgenic PDAPP mice displayed disrupted spatial working memory, no evidence of agerelated cognitive decline was observed in APP(V717I) transgenic mice despite increases in Aβ pathology with age. 2B3 did not alter Aβ levels or spatial working memory in PDAPP(V717F) mice in a pilot study, whilst the in vitro downregulation of Aβ was successfully replicated in primary murine neurons. The findings indicate that transgenic models of neurodegenerative disease require thorough characterisation to optimise their use in pre-clinical research. Furthermore, the use of alternative immunotherapy in the treatment of AD remains a promising, but early stage avenue of study.

Introduction: Values have a strong tradition in social psychology, but until recently they have been largely neglected in mental health literature. More recently, the importance of values has been recognised by some psychological therapies (e.g. Acceptance and Commitment Therapy); however, the relative importance of values in mental health problems has not been empirically tested. Aims: The current research aimed to investigate the value priorities of people with anxiety and eating disorders, and to assess the relationship between value discrepancies and distress, and in doing so to draw upon Schwartz’s (1992) model of values and Higgins’s (1987) self-discrepancy theory. More specifically, it investigated whether people with anxiety and eating disorders differ from people without mental health problems in the values that they hold, and the level of value discrepancies in these values, and additionally whether these discrepancies were associated with anxiety and depression. Methods: A cross-sectional questionnaire-based design was employed, with data being collected from 122 participants (an anxiety disorder group, n=30; eating disorder group, n=31; and reference group n=61). Multivariate statistics, paired sample t-tests and Pearson’s correlations were used to test the hypotheses. All participants completed a measure assessing values and discrepancies in values (adapted PVQ), and the mental health groups also completed a measure assessing psychological distress (HADS). Results: The reference group rated particular values (e.g. self-direction, stimulation, hedonism) as more important than did the mental health groups, apart from the achievement value, which the eating disorders group rated as more important. The mental health groups had higher value discrepancies than the reference group. Actual-Ideal and Actual-Ought value discrepancies were found to be related to anxiety and depression. However, unexpectedly, depression was found not to be specifically associated with Actual-Ideal discrepancies and anxiety was found not to be specifically associated with Actual-Ought discrepancies. Conclusions: This study provides empirical support and evidence for considering the values that people with mental health problems hold and the role that values has in relation to the psychological distress experienced by people. The results are discussed with reference to existing literature and the strength and limitations of the research were outlined. In addition, the clinical limitations were discussed and ideas for future research were outlined.

Work towards the development of a new computer-assisted methodology for psychological study and intervention is described. This is referred to as the Personal Knowledge Methodology since it focuses on the elicitation and presentation of personal knowledge. Personal knowledge includes the knowledge individuals have of their life history, their behaviours, their moods, their relationships, their ambitions, and so on. Principles and techniques used in Knowledge Engineering form the basis of the design of the Personal Knowledge Methodology. At the heart of the methodology is the use of a suite of knowledge acquisition and modelling techniques. These are referred to as Personal Knowledge Techniques. Based on a review of a wide-range of literature, eight techniques were selected to be assessed for their possible use as Personal Knowledge Techniques. These included interview-based techniques, repertory grid techniques and diagram-based techniques. Two in-depth studies took place involving 18 participants and a total of 100 knowledge acquisition sessions. The results revealed that each of the eight techniques showed promise at efficiently capturing and structuring aspects of an individual’s personal knowledge. In addition, the techniques showed potential for providing help in allowing reflection and revealing insights. In particular, a technique based on the construction and use of a state transition network was found to be the most highly rated by the participants. A content analysis of the knowledge acquired formed the basis of an ontology of personal knowledge that would underpin many uses of the Personal Knowledge Methodology. The empirical work and analysis led to a number of ideas for future developments of the methodology and uses for the Personal Knowledge Techniques.

The focus of this study is on guided fantasy; a technique which is increasingly used in educational and psychotherapeutic situations. The potential coherence of guided fantasy is examined by establishing the degree to which the elements of various guided fantasy experiences are perceived as being similar. Two forms of guided faintasy are examined: (a) A situation in which an individual subject is relaxed, with closed eyes and he is given a theme to begin the fantasy journey. The subject describes the fantasy aloud and the experimenter acts as a guide, using a non-directive mode of intervention. (b) A group form of guided fantasy in which the subjects are relaxed, with closed eyes, and a script of the fantasy journey, with long pauses, is read to the group. The elements of fantasy were evaluated using the subjects' personal constructs, except in the case of one group study where Cattell's sixteen personality factors were used. All of the individual subjects, the two group analyses and the individuals within the groups produced significant organizations of fantasy experience. This provides a basis for discussion of guided fantasy in terms of its meaningful structure. This is relevant to the consideration of interpretation, the possibility of sub-personalities and the ideas of overdetermination and condensation. NB. This ethesis has been created by scanning the typescript original and contains some inaccuracies. In case of difficulty, please refer to the original text.

The work undertaken involves the use of functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) as separate but complementary non-invasive functional brain imaging modalities. The aim in combining fMRI and MEG is centred around exploitation of the high temporal resolution available in MEG, and the high spatial resolution available in fMRI. However, whilst MEG represents a direct measure of neuronal activity, BOLD fMRI is an indirect measure and this makes the two modalities truly complementary. In both cases, the imaging signals measured are relatively poorly understood and so the fundamental question asked here is: How are the neuromagnetic effects detectable using MEG related to the metabolic effects reflected in the fMRI BOLD response? Initially, a novel technique is introduced for the detection and spatial localisation of neuromagnetic effects in MEG. This technique, based on a beamforming approach to the MEG inverse problem, is shown to yield accurate results both in simulation and using experimental data. The technique introduced is applied to MEG data from a simple experiment involving stimulation of the visual cortex. A number of heterogeneous neuromagnetic effects are shown to be detectable, and furthermore, these effects are shown to be spatially and temporally correlated with the fMRI BOLD response. The limitations to comparing only two measures of brain activity are discussed, and the use of arterial spin labelling (ASL) to make quantitative measurements of physiological parameters supplementing these two initial metrics is introduced. Finally, a novel technique for accurate quantification of arterial cerebral blood volume using ASL is described and shown to produce accurate results. A concluding chapter then speculates on how these aCBV measurements might be combined with those from MEG in order to better understand the fMRI BOLD response.

It was hypothesized that the deficits underlying reading impairment may arise from supra-modal deficits in temporal and spatial attention, disrupting, on the one hand, the ability to segment the temporally ordered phonemes of language and thus the acquisition of decoding skills, and, on the other, the ability to integrate spatially and temporally ordered orthographic information acquired from the fluent visual scanning of written text. Temporal and spatial attentional deficits in dyslexia were investigated using a lateralized visual temporal order judgment (TOJ) paradigm that allowed both sensitivity to temporal order and spatial attentional bias to be measured. Dyslexic and non-dyslexic participants were required to report the temporal order of two simple visual stimuli presented in either the same or different lateral hemifields. Findings indicated that dyslexic participants showed markedly impaired sensitivity to temporal order, and that the degree of impairment was correlated with the severity of their dyslexia. Furthermore, the findings suggested that at least three partially dissociated deficits may underlie both impaired TOJ task performance and reading disorder. One is a deficit associated with difficulty in reporting the temporal order of two visual stimuli, particularly when the first is presented in right hemifield; with slow word recognition and non-word reading; and with deficits in spelling and phonological skill. This constellation of deficits was interpreted as reflecting deficits in networks in left cerebral hemisphere implicated in phoneme-grapheme mapping and visual orienting. The second is a deficit that is associated with a rightward attentional bias; with inaccurate non-word reading that is worse than predicted by phonological skill or by word recognition; and with poor sustained attention. This constellation of impairments was interpreted as evidence of a deficit in right-lateralised networks implicated in the modulation of arousal, and possibly reflecting a “developmental left-neglect” syndrome. A third deficit was associated with impaired temporal order sensitivity, regardless of hemifield presentation; with symptoms of Attentional Deficit and Hyperactivity Disorder (ADHD); and with increased interference from distractor stimuli. This constellation of deficits suggests that the impaired network is implicated in executive control of attention, including conflict resolution and working memory. The results of the investigation as a whole suggests that the reading impairments of dyslexia may arise from attentional deficits that have with substantial overlap with those of ADHD, and include deficits in attentional networks implicated in orienting attention to temporally presented stimuli.

The problem of representing decision making behaviour in discrete event simulation was investigated. Of particular interest was modelling variety in the decisions, where different people might make different decisions even where the same circumstances hold. An initial investigation of existing and alternative approaches for representing decision making was carried out. This led to the suggestion of using a neural network to represent the decision making behaviour in the form of a multi-criteria probability distribution based on data of observed decision making. The feasibility of the stochastic neural network approach was investigated. Models were fitted using artificial data from discrete and continuous distributions that included the shape parameters as inputs, and tested against known results from the distributions. Also a bank simulation was used to collect data from volunteers who controlled the queuing decisions of customers inside the bank. Models of their behaviour were created and implemented in the bank simulation to automate the decision making of customers. The investigation established the feasibility of the approach, although it indicated the need for substantial amounts of data showing examples of decision making. A hybrid model that combined the stochastic neural network approach with a rule-based approach allowed the development of more general models of decision making behaviour.

The present thesis sought to investigate the precise relationship between the cognitive and psychophysiological profiles of developing readers, of established readers and of failed readers. Phonological processing tasks and visuospatial tasks were used to assess relevant auditory and visual cognitive skills; handedness and EEG measures were used to provide indices of cortical organisation and activation. A 21/2 year longitudinal investigation of some 150 pre-readers provided evidence of mutually facilitative relationships between and within specific types of phonological skill and phonological memory. Early significance of visual skills was subsequently superseded by the importance of these phonological skills. The acquisition of early reading skills was associated with a shift towards increased dextrality as measured by hand skill and hand preference; this relationship was not evident in subsequent stages. Cross-sectional studies comparing dyslexic children with chronological- and reading-age matched controls extended these findings. The dyslexic readers displayed impaired phonological processing and phonological memory skills relative to chronological-age matched competent readers; similarities were observed between dyslexics and reading-age matched controls. Visual perceptual skills failed to differentiate between the chronological-age matched competent and impaired readers, although both out-performed younger control readers. ERP measures consistently demonstrated diffuse patterns of bilateral activation in dyslexic readers as opposed to asymmetric activity lateralised to the left hemisphere in control readers. Between group comparisons of inter-hemispheric activity revealed greater levels of right-hemisphere involvement in the dyslexic samples; between group comparisons of intra-hemispheric activity revealed evidence of greater involvement of fronto-central regions in the dyslexic samples. It is proposed that these data provide supportive evidence for the central involvement of phonological processing skills in the development of reading, underpinned by the normal development of asymmetric patterns of cortical lateralisation. Children where this development is delayed or deficient will display the reading difficulties characteristic of developmental dyslexia.

‘Voices’ or auditory hallucinations are a common phenomenon in clinical settings. In recent years, primarily in the United Kingdom, cognitive behavioural researchers have begun to turn their attention to the psychoses in general and voices and delusions in particular. Researchers have sought to develop theoretical models of voices to inform understanding and clinical intervention. Chadwick and Birchwood’s (1994) model, particularly, emphasises the role of delusional beliefs about voices. The present volume explores the role that beliefs about voices may have in understanding people’s reactions to voices and in alleviating the difficulties often associated with this experience. An initial review of the literature focused on the current evidence for a role of delusional beliefs about voices in mediating the emotional and behavioural response to voices. Evidence, from theoretical and outcome studies, was considered in assessing the validity of a cognitive model and areas for future research identified. A particular form of behavioural response to voices i.e. ‘safety behaviours’ was then investigated. Types of safety behaviours used by voice hearers were compared to those reported in persecutory delusions by an inter-rater reliability study of the Safety Behaviour Questionnaire (Freeman, Garety and Kuipers, 2001). These categories were applicable to voice hearers. The role of safety behaviours in maintaining delusional beliefs about voices, threat appraisal and distress was examined. Voice hearers with schizophrenia were compared on structured interview and questionnaire measures. Safety behaviours were implicated in the maintenance of delusional beliefs and distress. Clinical implications and areas for future research were discussed. Finally, ethical, methodological and clinical issues were considered along with personal reflections on the research process in the reflective research review.

Background: Despite its status within internationally agreed psychiatric systems, the extent to which the behavioural symptoms of Conduct Disorder are indicative of mental disorder is debatable. The aim of this thesis is to assess the extent to which the collection of behaviours currently defined as Conduct Disorder might be better understood within a sociological framework. Methods: In-depth semi-structured interviews were carried out to explore young people’s perspectives on behaving badly. Most of the participants interviewed met DSM-IV criteria for Conduct Disorder, which was identified on the basis of Voice-DISC profiles at two earlier phases of the West of Scotland 11-16/16+ study (West, Sweeting, Der et al., 2003). Findings. The findings highlighted that behaving badly was generally perceived as normative, purposive and adaptive, therefore reflecting more sociological interpretations of behaving badly. Two participants appeared to link their behaviour to mental distress, which provided limited support for the view that some forms of antisocial behaviour might be indicative of mental disorder. Since young people often depicted behaving badly as adaptive and purposive, the findings suggested that epidemiological research may be neglecting the positive functions of antisocial behaviour for young people. Implications. An in-depth exploration of young people’s accounts led to the conclusion that the current diagnostic criteria for Conduct Disorder are over-inclusive. Four amendments to the criteria were proposed which might help to distinguish between individuals with disorderly conduct and those with Conduct Disorder before the publication of DSM-V and ICD-11