In this thesis, the haemodynamic, functional and structural changes in Alzheimer's Disease, Huntington's Disease and Multiple Sclerosis are assessed at 7T. Across all chapters, there is a focus on the use of Arterial Spin Labelling (ASL) to provide haemodynamic measures of perfusion (or cerebral blood flow) and transit time (TT) to provide a useful marker of disease. Arterial Spin Labelling (ASL) has the advantage that it is a non-invasive method to measure perfusion using magnetic resonance imaging (MRI). Clinically, perfusion is assessed using contrast-enhanced techniques which requires the intravenous administration of an exogenous gadolinium-based contrast agent, such as Prohance-TM and Gadovist-TM. Contrast-enhanced techniques typically provide higher SNR than ASL methods, however the non-invasive nature of ASL makes it a safe method suited for repeated measures in any subjects, including those with poor renal clearance. Additionally, gadolinium contrast agents have been shown to accumulate in neuronal tissue, and until the clinical significance of this is determined, contrast-enhanced scans should be performed with caution. In Chapter 5, arterial spin labelling is used to assess cerebral perfusion in a patient group with Alzheimer's Disease (AD) and compared with an age-matched healthy control group (HC). Functional MRI (fMRI) is used to assess functional connectivity within the default mode network (DMN) and measures compared between the AD and HC group. In addition, high resolution structural data is acquired to assess the effects of atrophy in AD. Results demonstrate a significant decrease in grey matter perfusion and a significant increase in grey matter transit time in the AD group compared the HC group. A trend showing a decrease in functional connectivity in the DMN was found in the AD group as compared to the HC group. As expected, significant grey matter loss and cortical thinning were observed in the AD group compared to the HC group. Secondly, haemodynamic and vascular changes in a Huntington's Disease (HD) patient group are assessed and compared with healthy age matched controls (HC). Phase contrast angiography is used to assess vessel density and vessel radius distributions between the two groups. Structural data was also acquired to assess grey matter volume and cortical thickness differences between the two groups. A significant reduction in perfusion was found in grey matter, putamen and the caudate in the HD group compared to the HC group. The ASL transit time was found to be significantly increased in the caudate and putamen in the HD group compared to the HC group. Phase contrast angiography data showed an increase in the frequency of smaller vessels (0.15-0.35mm) in the HD group compared to the HC group, whereas larger vessels appeared more frequently in the HC group. A significant reduction in grey matter volume was also observed in the HD group compared to the HC group, which manifested as thinning of the cortical ribbon. In the final study of this thesis, high spatial resolution arterial spin labelling is used to assess perfusion inside cortical lesions and compare with perfusion in surrounding normal appearing grey matter in a Multiple Sclerosis (MS) patient group. Grey matter perfusion as a function of distance from the cortical lesions was also assessed. It was found that cortical lesions have reduced perfusion compared to surrounding normal appearing grey matter. Perfusion increased and stabilised immediately outside of the cortical lesion itself, suggesting that the perfusion deficit observed is highly spatially localised.

Image segmentation of organs in medical images using model-based approaches requires a priori information which is often given by manually tagging landmarks on a training set of shapes. This is a tedious, time-consuming, and error prone task. To overcome some of these drawbacks, several automatic methods were devised. Identification of the same homologous set of points in a training set of object shapes is the most crucial step in Active Shape Modelling, which has encountered several challenges. The most crucial among these are: (C1) defining and characterizing landmarks; (C2) obtaining landmarks at the desired level of detail; (C3) ensuring homology; (C4) generalizing to n>2 dimensions; (C5) achieving practical computations. This thesis proposes several novel modelling techniques attempting to meet C1-C5. In this process, this thesis makes the following key contributions: the concept of local scale for shapes; the idea of allowing level of detail for selecting landmarks; the concept of equalization of shape variance for selecting landmarks; the idea of recursively subdividing shapes and letting the sub-shapes guide landmark selection, which is a very general n-dimensional strategy; the idea of virtual landmarks, which may be situated anywhere relative to, not necessarily on, the shape boundary; a new compactness measure that considers both the number of landmarks and the number of modes selected as independent variables. The first of three methods uses the c-scale shape descriptor, based on the new concept of curvature-scale, to automatically locate mathematical landmarks on the mean of the training shapes. The landmarks are propagated to the training shapes to establish correspondence among shapes. Since all shapes of the same family do not necessarily present exactly the same shape features, another novel method was devised that takes into account the real shape variability existing in the training set and that is guided by the strategy of equalization of the variance observed in the training set for selecting landmarks. By incorporating the above basic concepts into modelling, a third family of methods with numerous possibilities was developed, taking into account shape features, and the variability among shapes, while being easily generalized to the 3D space. Its output is multi-resolutional allowing landmark selection at any lower resolution trivially as a subset of those found at a higher resolution. The best strategy to use within the family will have to be determined according to the clinical application at hand. All methods were evaluated in terms of compactness on two data sets - 40 CT images of the liver and 40 MR images of the talus bone of the foot. Further, numerous artificial shapes with known salient points were also used for testing the accuracy of the proposed methods. The results show that, for the same number of landmarks, the proposed methods are more compact than manual and equally spaced annotations. Besides, the accuracy (in terms of false positives and negatives and the location of landmarks) of the proposed shape descriptor on artificial shapes is considerably superior to a state-of-the-art scale space approach to finding salient points on shapes.

Aluminum powder metallurgy (PM) parts have found applications in automotive, aerospace and transportation. Sintered aluminum parts have been developed and compete with traditionally fabricated ingot metallurgy (IM) products for specific applications. To extend the range of application of (PM) alloys which offer the advantage of net and near net shape production, processing parameters and corrosion behaviour of the aluminum alloys need to be improved. In this research, processing parameters and corrosion behaviour of a commercial Al-Mg-Si aluminum alloy (Alumix 321) were investigated. This alloy is the PM equivalent of wrought AA6061. Four sintering temperatures (610 °C, 620 °C, 630 °C, 640 °C) and two pressing pressures (200 MPa, 400 MPa) were used and the optimum pressing and sintering procedure was selected. In addition to different processing routes of aluminum powder metallurgy alloys, a series of electrochemical experiments on both (IM) and (PM) aluminum alloy was performed with the aim of correlating corrosion behaviour with production techniques. As a modification step, post sintering treatments and surface alteration techniques were applied. Hot rolling, hot swaging, repressing, resin impregnation and shot peening were performed and their effect on corrosion behaviour was investigated; their effect on density, hardness, and microstructure was also studied. Hardness after hot swaging and hot rolling increases and near full density was achieved (? 99%), while for resin impregnation and shot peening surface nature and roughness were affected, respectively. Electrochemical techniques such as open circuit potential (OCP), Tafel extrapolation (TE), cyclic polarization (CP) and stair step polarization (SP) were performed on the ingot, wrought, and post sintered alloys immersed in a 3.5 wt% NaCl solution. Electrochemical experiments show that corrosion current decreases as a result of post sintering treatments. The electrochemical experiments also show different corrosion mechanisms that were later confirmed by the metallographic analysis. The corrosion product and corroded surfaces of the alloys were characterized by optical microscopy, scanning microscopy (SEM), energy dispersive spectroscopy (EDS), wavelength dispersive spectroscopy (WDS), and X-ray diffraction (XRD). Results show that pitting is the main corrosion mechanism of the wrought alloy. However, powder metallurgy alloys show pitting, crevice, and intergranular corrosion. / Effect of processing parameters on corrosion behaviour of Alumix 321 PM alloy

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.

A remarkable feature of the human visual system is that it is possible to extrapolate a large amount of information about the three-dimensional structure of the environment simply from the pattern of light that falls on the retinae. This information is derived from a number of different cues to depth. The mechanisms by which these are encoded in the brain, combined into an overall percept, and subsequently interpreted are reasonably well understood. However, individuals who participate in studies of depth perception tend to have acute sensitivity to certain depth cues, meaning that the consequences of individual differences in depth perception have been largely ignored. In this thesis I investigate how individual differences in the ability to utilise a single cue, binocular disparity, affects overall perception of depth and then go on to explore the wider function significance of such a deficit. I also examine whether an underlying deficit in stereopsis may account for some of the perceptual differences observed in autism spectrum disorder (ASD). The first set of experiments explored the consequences of individual differences in stereopsis upon perception. The initial study of this thesis used a shape constancy paradigm to identify how individual cues to depth are utilised and combined in typical children and adults. I report that while children are more sensitive to certain depth cues compared to adults, they still show some degree of cue combination (though only for higher- level information). In addition, I observed that an inability to use binocular information appears to cause re-weighting to occur in favour of monocular cues, regardless of age. In the second study, I used the same paradigm to explore depth cue sensitivity and combination in typically-developing (TD) and ASD teenagers. The results from this experiment indicated that contextual and binocular information interact when creating an overall percept of depth. A main effect of ASD diagnosis was found, with this group reporting perception that was less biased and closer to the raw sensory input. Although participants with ASD exhibited poorer stereoacuity than their TD counterparts, this did not explain the differences between the groups. I propose this indicates that perceptual differences in autism likely stem from underlying neurological differences specific to the disorder as opposed to a more general stereopsis deficit. The third study assessed the combination of ordinal and metric depth cues in TD and ASD adults. Cue integration did not depend on sensitivity to disparity or autism diagnosis. Unlike previous research, and inconsistent with perceptual theories of autism, I found that individuals with ASD automatically integrated depth cues, even when it was not advantageous to do so. Additionally, I found that the processing of uncrossed disparities was particularly difficult for those with an ASD. The second part of the thesis aimed to characterise the functional significance of impaired stereopsis. For the fourth study, I wanted to establish whether the functional significance of stereopsis followed a developmental trajectory. I was also interested if the motor deficits observed in those with poor stereopsis were limited to hand-eye coordination tasks. Using three tasks derived from a standardised test of motor proficiency – catching a ball, balancing on one leg, and bead-threading – I measured the effect of binocular vision and stereoacuity on motor ability. Stereoacuity affected performance across a range of tasks involving the use of fine and gross motor skill, and – importantly – the effect of stereopsis did not change with age. In the final study, I enquired as to the further-reaching consequences of poor stereopsis. Using a quantitative survey I aimed to establish how stereopsis, motor skills, and social skills related to one another. While motor ability mediated the relationship between stereopsis and social skill, stereopsis also directly contributed to social skill, causing me to suggest that the functional significance of stereopsis is not limited to motor ability. It is concluded that while individual differences in stereoacuity may affect the amount of depth experienced, they do not affect the ability to combine different cues to depth. While those with ASD experience differences in perception, these cannot be attributed to the increased prevalence of stereopsis impairment. It does, however, seem that individual differences in stereoacuity impact upon the development of motor proficiency and social skill, which are typically compromised in those with ASD.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease defined by severe memory loss and the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The experiments presented in this thesis examined cognitive performance in a well-­‐characterised mouse model of AD, the APPswe/PS1dE9 (TG) mouse, at 4-­‐5 months old prior to extensive amyloid plaque deposition. The experiments employed were associative learning tasks, which are not often used to measure cognitive performance in classical neuroscience research into neurodegenerative disease. Chapter 1 looked at appetitive Pavlovian cue and context conditioning and extinction, and found some evidence of impaired contextual discrimination during conditioning. Cue conditioning and extinction was found to be intact in the TG mouse model. Chapter 2 looked at appetitive Pavlovian delay and trace conditioning before examining the ability to time the arrival of the unconditioned stimulus (US). No genotype differences were found during delay or trace conditioning; however, TG mice were impaired (lost precision) in their ability to time the arrival of the US during test trials. Chapter 3 examined recognition memory performance, via the spontaneous novel object recognition (sNOR), relative recency (RR) and context priming (CP) tasks, interpreting the results in terms of Wagner’s SOP model of memory. No genotype differences were found in the sNOR or RR tasks, supporting intact stimulus-­‐generated priming; however, evidence from Bonardi et al. (2016) and non-­‐significant trends in the CP task supported impaired retrieval-generated priming. Chapter 4 looked at the levels of neuro-­‐inflammation (microglia) in the cortex, hippocampus and striatum to assess the possible early contribution of inflammation on the development of AD. This chapter reported greater levels of microglia in the hippocampus and striatum of TG mice compared to wild types. Greater microglia clusters were also seen in the cortex and hippocampus of TG mice compared to wild types. The results from this thesis show evidence of impaired cognitive performance, prior to extensive plaque deposition, in associative learning tasks that are not routinely employed in neuroscience research. Further work is required in these learning tasks to establish whether they could be effectively used to diagnose AD at an early stage.

The British population are increasingly using mobile devices (e.g. smartphones, tablets) to gamble. The empirical work in this thesis looks at how the interaction of gambling’s schedule of reinforcement and mobile device behaviours accelerate the acquisition of learned maladaptive behaviours. The first four chapters report psychometric modelling of gambling prevalence data to understand problem gambling further and identify key indicators relevant to associative processes in gambling behaviour. Chapter 2 reports a taxometric analysis of problem gambling assessment data to test whether these screens measure a dimensional or latent class model, finding stronger support for the latter. However, this only identified a small taxon consisting of around 5% of gamblers endorsing more than one problem gambling symptom. Chapter 3 reports the use of latent class analysis to examine distinct subtypes of responding to different screens, findings a common three-class model that showed signs of a mixed latent structure: the same taxon as Chapter 2 was observed, but the three classes showed little overlap in symptom count. Chapter 4 reports further work modelling the sociodemographic characteristics of these different subgroups. Together the data from these chapters were used help to identify indicators of those most likely to a) be most susceptible to gambling harm and b) common to all problem gamblers. In Chapter 5 a Monte Carlo analysis was conducted to understand the efficacy of taxometric procedures on binary variables, before replicating the taxometric analysis reported in Chapter 2 using dichotomous variables and extending the work to the South Oaks Gambling Screen. The indicators derived from these chapters were then used in laboratory and field studies to study mobile gambling behaviour. The laboratory study in Chapter 6 manipulated two behavioural processes, trial spacing and partial reinforcement, that are relevant to mobile gambling behaviour, showing how a mobile-like schedule is related to increased perseverance and loss-chasing. The same paradigm was used to deliver an experiment on participants’ mobile phones in a field environment in Chapter 7. They further demonstrate that a mobile style schedule of reinforcement is associated with considerable persistence in the face of mounting losses, as participants continued to persevere in the face of losses despite a free choice to cease playing. Finally in the discussion I apply the key themes of the thesis to in-play betting, a form of play that has been heavily promoted alongside mobile gambling, and to an understanding of behavioural addictions.