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.

Perceptual decision-making describes the process of choosing one of at least two response alternatives based on sensory evidence. This sensorimotor process underlies a range of human behaviours and has been studied extensively by both psychologists and neuroscientists. There is now a consensus, that perceptual decision-making can be explained by sequential sampling models, which assume that we make decisions by accumulating sensory evidence over time until a decision threshold is reached and the response is executed. Although these models are designed to explain behavioural data, the accumulation-to-bound processes they predict have recently been shown to occur in the brain. In this project, we set out to explore these neural correlates of decision-making in the human brain by combining mathematical modelling with neuroimaging. We fitted sequential sampling models to human decision-making data collected in a number of paradigms and directly compared the associated accumulation profiles with neural signals, which were generated either by using electroencephalographic (EEG) recordings or through transcranial magnetic stimulation (TMS). We found that decision-related accumulation profiles can be observed using a parietal EEG signal, namely the event-related potential centroparietal positivity (CPP). Additionally, we showed that accumulation is fed forward to the motor system, where it can be measured using TMS-induced motor evoked potentials. We demonstrated that, under a number of manipulations, namely difficulty, response speed instructions, non-stationary evidence, decision biases, and number of alternatives, these signals display profiles similar to those predicted by sequential sampling models. Our findings support the notion that sequential sampling occurs in the human brain and demonstrate that a model-based approach in which sequential sampling models and neuroimaging are combined and inform each other, can shed light on the underlying mechanisms of human perceptual decision-making.

Affordances play a part in how we prepare to handle objects. Tools and other manipulable objects are said to automatically “afford” various actions depending upon the motor repertoire of the actor. Evidence obtained through behavioural experiments, fMRI, EEG and TMS has proven that this is the case but, as yet, the temporal evolution of affordances has not been fully investigated. Determining the critical time-scale may have significance to patients with brain damage or motor disorders when attempting object manipulation. There are many other factors involved in therapy but it is worth considering that there could be an optimum period of time to view an object before the benefit of an automatic affordance is no longer available. In a series of experiments using the novel approach of positioning the participant’s dominant hand closer to or further from the object being viewed, together with use of three dimensional stimuli, and through application of behavioural assays, TMS pulses and EEG recordings, this research examined temporal properties of affordances in young healthy control subjects. Verification of this motoric activity by EEG led to investigating chronic phase stroke survivors with remaining upper limb deficits and comparing their brain activity with age-matched control participants. As EEG and TMS both have good temporal properties, they are ideal converging methodologies for this kind of investigation. By mapping how affordances develop and dissipate, this work has yielded pure scientific advances in the field of motor decision making. Further, it has resulted in suggestions for future research relating to a possible method to improve rehabilitation interventions for patients who are neurologically impaired by stroke.

The world’s biggest forced migration is currently taking place. This population now makes up a considerable proportion of those accessing trauma services in the UK. Narrative exposure therapy (NET) is increasingly used with this population in services across the NHS. However, there are no studies reporting on its acceptability or how this group experiences this narrative and exposure-informed approach. Although the evidence base for the use of NET is promising, it remains symptom-reduction focused. This study sought to capture the accounts of seven forced migrants who had had NET for their PTSD through Interpretative Phenomenological Analysis. Six super-ordinate themes emerged from the data: (1) The struggle with therapy, fear, ambivalence and exposure; (2) Living with loss, pain, grief and uncertainty; (3) Trusting someone else to be your voice; (4) A life more than just trauma – ‘remembering the good and the bad’; (5) From trauma and despair to understanding the big things in life – ‘something to navigate from’; and (6) Reconstructing a sense of self, identity and attachment. The latter three themes reflect new findings in relation to the existing trauma-focused literature for this population, unique to NET. A sub-theme that emerged unanimously from the accounts was NET as ‘shaking up symptoms’. The tangible and experiential aspects of the therapy contributed to participants being able to ‘see the bigger picture’ at a flashback and gestalt level, seeing the ‘self’ as a survivor and as having ‘a life more than just trauma’. Developing a future orientation, reinvesting in the ‘self’, developing a balanced perspective of life and of a ‘self’ that endured more than just trauma, were some of the outcomes. The findings represent real-world subjective outcomes that existing studies on NET for this population have not been able to capture. Implications, limitations, and suggestions for future research are discussed.

Difficulties with the ability to appreciate the perspective of others (mentalizing) and saliency-based selection are central to both autism and psychosis spectrum disorders. Both disorders can co-occur in the same individual at both the diagnostic and trait levels. It has been hypothesized that their co-occurrence would lead to greater impairment than would be observed in each of the disorders alone. An alternative theory suggests that these disorders are etiologically and phenotypically diametrical, and thus predicts that these disorders would have opposing effects on these abilities. The current thesis examined these contrasting hypotheses using behavioral, eye-tracking and neuroimaging paradigms, in neurotypical adults in whom both autism tendencies and psychosis proneness were assessed in tandem. The thesis provides converging evidence that autism and psychosis tendencies interactively improve mentalizing abilities as well as target selection in the presence of irrelevant salient distractors. This interactive effect is also discerned at the neuronal level where autism and psychosis tendencies diametrically modulate activity within the attentional and mentalizing subdivisions of the right temporo-parietal junction (rTPJ). These findings suggest that co-occurring autistic and psychotic traits can exert opposing influences on performance, resulting in improvement possibly by way of their diametrical effects on attentional and socio-cognitive abilities.

Recently, observation of pain has been linked to areas of the brain coding the sensory/discriminative aspects of pain (Avenanti et al., 2005; Avenanti et al., 2006). The experiential qualities associated with observing another in pain are poorly understood. In this thesis, we demonstrate that pain generated by observation of others in pain is reported by a significant minority of healthy individuals. The pain reported is mild, transient and occurs in the same location as the observed pain. Ten pain responders were matched with ten non-responders to take part in an fMRI study observing others in pain. Responders activated emotional and sensory brain regions associated with pain while the non-responders activated very little. Reports of pain were more likely to be accompanied by a pain memory. Pain responders are quicker to represent the perspective of others and have a more flexible sense of body ownership but are not more likely to report somatic symptoms during incongruent sensori-motor feedback. These findings provide convincing evidence that some people can readily experience pain during observation of others‘ pain. It is plausible that the mechanism underpinning pain reports evoked by observation of pain is not specific to pain processing per se.

The relationship between the behavioural effects of cocaine and the increase in dopamine caused by its blockade of dopamine re-uptake has been a major focus of research interest. However, little is known regarding the involvement of recently cloned dopamine D2-like receptor subtypes (D2, D3 and D4) in different cocaine induced behaviours. The purpose of the work described in this thesis was to use a series of behavioural tests to assess dopamine receptor subtype involvement in cocaine's effects. In the first series of experiments, we tested the effects of antagonists selective for receptors within the D2-like subfamily on the discriminative stimulus effects of cocaine (10 mg/kg), and compared them with the effects of a Dl-like receptor antagonist. A separate group of rats were trained to discriminate a low dose of cocaine (3 mg/kg). Neither U-99194A (a D3 antagonist) nor L-745,870 (a D4 antagonist) substituted for cocaine, and neither drug shifted the dose-response function for cocaine at the higher training dose. On the other hand, pre-treatment with SCH 39166 (a selective Dl-like antagonist) produced significant dose-related rightward shifts in the cocaine generalisation curve, indicating effective antagonism. Three other centrally-acting D2-like antagonists (L-741,626; haloperidol and raclopride) produced rightward shifts in the dose-response function for cocaine at both training doses. The D2-like antagonists, however, produced dissimilar effects on cocaine-induced hypophagia and hyperactivity in the rat. The D3 and D4 antagonists (which produced minimal effects on feeding and motor behaviours on their own) failed to alter any of the behavioural effects induced by cocaine. The D21D3 antagonist, raclopride, produced only a marginal attenuation of cocaine-induced hyperactivity and rearing, but a marked attenuation of cocaine-induced decreases in grooming. On the other-hand, a Dl-like antagonist potently reversed cocaine-induced hypophagia, hyperactivity and rearing, but failed to affect grooming behaviour. While drug discrimination studies suggests negligible involvement of D3 and D4 receptors in cocaine's effects, an important role for Dl-like and D2 receptors was observed. In contrast, it seems that the Dl-like subfamily may play a more prominent role than the D2-like subfamily in cocaine-induced hypophagia and motor hyperactivity, although cocaine-induced inhibition of grooming appears to be specifically a D2-mediated effect.

Variability is an inherent component in movement and provides an insight into control processes involved in producing motor responses. This thesis investigates the interactions between force and timing processes in the production of repetitive actions from an information processing perspective. Force-time interactions are examined in steady state sequences, sequences with step changes, and steady state sequences with a secondary visual search task as an attentional load. The account of control in normal healthy participants is then applied to describe behaviour of patients with cerebrovascular accidents (CVAs) in two case studies. Interaction was found to be present in variability measures and was quantified using cross-correlation analysis. Overall, results demonstrated that one locus of force-time interaction is at a cognitive level where motor responses are organised for execution. Corresponding changes in magnitude of dependence according to availability of attentional resources and task prioritisation supported this observation. Dependence patterns in patients with CVAs reflected loss of control when task difficulty increased. Finally, based on the findings, a conceptual model describing the interaction is proposed towards the development of a formal model for simulation studies.

The aim of this longitudinal, qualitative PhD was to explore the commissioning and implementation of early intervention services for first episode psychosis across a number of sites in England. Methods: After a literature review of policy, implementation, and empirical RCT and cohort studies, 147 semi-structured interviews and six focus groups involving 35 people from different managerial and operational levels of the health service were undertaken between February 2004 and March 2009. May’s Normalization Process Theory was used as the underpinning conceptual framework and data were analysed using the Framework Analytical Approach. Results: the main findings were the importance of partnership working, influenced positively by the role of a facilitator; challenges which arose when commissioning mental health services, alleviated by the involvement of senior managers acting in a mentor role and the ‘work’ undertaken, from the perspective of Normalization Process Theory. A new service model, called the ‘trailblazer’ early intervention service was identified, which is not accounted for within Normalization Process Theory. Conclusion: further work is needed to define the characteristics and qualities of the mentoring role of senior managers and the facilitator and explore how best to adapt and extend Normalization Process Theory to incorporate the new ‘trailblazer’ service model.

The thesis starts with a review of the various branches of schizophrenia research, concluding that there is no evidence that biological differences should take precedence over psychological differences in people with schizophrenia, and that the opposite argument is as compelling. The purpose of the opening section is to critically evaluate and make explicit these key paradigm assumptions, and in doing so lay the framework for the rest of the thesis. The literature on normal adolescent development is then reviewed and a theory about late-adolescent onset schizophrenia put forward. The first empirical study demonstrates that levels of mild psychotic-like `symptoms' in normal teenagers were intimately linked to levels of psychological development. The second study shows that people with a diagnosis of schizophrenia showed on average a level of psychological development much more akin to young teenagers than normal adult controls. From the two studies it is speculated that psychosis sufferers become stuck at that point in development where normal psychotic-like symptoms are most prevalent. Unlike `normal' adolescents, psychosis-sufferers fail to resolve this phase. The second part of the thesis focuses on the psychological mechanisms whereby this may come about and elaborates a theory of selfconstruction, threat and defence, within the context of the established literature on the Self. An empirical study reconstructs key episodes from schizophrenia sufferer's lives. It was found that clients experience a dilemma between self-actualisation goals and affiliative goals, and that the pressure of this dichotomy could explain the development over time of many of the symptoms of schizophrenia. Finally, hypotheses derived from the empirical self-construction chapter are tested in another empirical study, and the thesis as a whole is discussed.