<p>The accurate diagnosis of disorders of consciousness presents substantial difficulty because of the reliance on behaviour-based assessment tools. A patient may be covertly aware but unable to indicate their state due to physical impairments. Neuroimaging researchers have begun to seek alternate methods of assessment that rely on brain responses rather than behavioural ones. To this end, mental imagery has been employed as a voluntary cognitive activity that can be measured with fMRI or EEG to indicate awareness. In this dissertation I examine the advantages and limitations of these two imaging techniques and argue that EEG is more suitable for this patient population. I expand upon existing mental imagery research by exploring additional tasks that have not been applied to this problem, in order to address three previously unanswered questions that are central to the development of imagery-based diagnostic tools. First, do individuals differ on which imagery tasks produce the most reliable activation? Second, can the robustness of brain activation during imagery be predicted from familiarity with the imagined activity? Third, do fMRI and EEG provide converging evidence about individual imagery performance? In order to answer these questions, 6 mental imagery tasks were examined using simultaneous EEG and fMRI recordings, in combination with participant ratings. The findings revealed that, of the mental imagery tasks studied, mental arithmetic consistently produced the most robust activation at the single subject level. Additionally, there was no relationship between participants’ familiarity with an activity and the level of brain activation during performance. The key finding demonstrated that EEG and fMRI were in agreement on both of these questions, lending support to the increasing use of EEG over fMRI in disorders of consciousness.</p> / Doctor of Philosophy (PhD)

<p>This thesis examines how ERP responses to music provide an index of emotion in control, alexithymic, depressed and depressed alexithymic individuals using a musical affective priming task, with the objective being its clinical application to assess emotion in brain injured patients. Participants listened to pairs of music primes and music targets (music-music paradigm) and word targets (music-word paradigm) to mentally decide if they matched or not according to emotional valence (happy, sad). Responses manifested in the N300 (emotional categorization), P300 (emotional recognition) and N400 (emotional meaning) ERP components, with larger and more differentiated responses for the music-word paradigm indicating a less automatic nature than the music-music paradigm. Alexithymic individuals showed disrupted responses for all components for sad word targets, indicating a sequence of disconnects producing their decreased awareness of and difficulty with regulating emotion. Depressed participants displayed an emotional negativity bias for sad word targets in the P300 and N400, attributable to difficulty disengaging (cognitive rumination), reflecting how emotional deficits affect awareness. Disrupted P300 and N400 responses in the depressed alexithymic individuals were isolated to alexithymia rather than the emotional negativity bias. Specific processing deficits of happy music targets found only in depressed alexithymic individuals demonstrate how alexithymia increases the severity of depression. Although depression effects are more pervasive, alexithymia modifies depressive effects in emotional regulation. The P300 was most reliably seen in depression, and alexithymia to a lesser extent. Therefore, ERP responses to music can effectively and covertly measure emotion and different levels of automaticity, alexithymia and depression. This thesis is the first to demonstrate: 1) how music conveys emotion in a pure musical context (music-music); 2) musical emotion perception in alexithymia, depression and depressed alexithymia; 3) an effective non-verbal measure of emotion for assessing emotional states in brain injured populations.</p> / Doctor of Philosophy (PhD)

Catechol-O-methyltransferase (COMT) metabolizes catechols, notably dopamine. The COMT Val158Met polymorphism influences its enzyme activity, and multiple neural correlates of this genotype on dopaminergic phenotypes have been reported, particularly with regards to working memory. COMT activity can also be regulated pharmacologically by COMT inhibitors. The ‘inverted-U’ relationship between dopamine signalling and cognitive performance predicts that the effects of COMT inhibition will differ according to COMT genotype. The goal of this thesis was to better understand COMT’s impact on brain function and behaviour. Here, 33 subjects homozygous for COMT Val158 (‘Val homozygotes’) and 34 homozygous for COMT Met158 (‘Met homozygotes’) were randomly assigned, double-blind, to a single dose of the brain-penetrant COMT inhibitor tolcapone (200mg) or placebo. They completed the N-back task of working memory, an emotional face processing task, and a gambling task, in a magnetoencephalography (MEG) scanner, allowing both behavioural performance and neural activity to be investigated. The data presented in this thesis confirm that COMT activity influences performance on, and neural activity during, the N-back task, in a way consistent with the inverted-U model of dopamine function. The effect on risky decision making is novel, and indicates that COMT plays roles in domains beyond working memory, and that such domains may also follow an inverted-U. Neural activity during the faces task and the gambling task also show COMT-modulated differences. The behavioural results show that the direction of effect of a drug can be influenced by sequence variation in its target gene. They are of translational relevance, since COMT inhibitors are used in the adjunctive treatment of Parkinson’s disease and are under evaluation in schizophrenia and other disorders. The MEG data show that for the three tasks, there are effects of Val158Met genotype, of tolcapone, and their interaction, on neural activity (for example, the P300 during N-back), revealing a complex temporal and spatial pattern which sheds some light on the neural processing underlying these tasks and their previously reported fMRI correlates.

This study examined the role of specific pattern coloring, such as coloring books for adults, on conceptual, behavioral and physiological measures of anxiety. Undergraduate female students (n = 8) had ECG electrodes and a respiration belt attached and completed the State Trait Anxiety Inventory (STAI) at five time points; at baseline, after an initial autobiographical anxiety induction, following a passive relaxation condition, after a repeat induction and then after a coloring condition. The participants were randomly split into a control and experimental group; the control group free colored while the experimental group colored in a mandala pattern. Participants had the option of coloring before bed to test the effect of coloring on sleep onset latency. The electrodes and respiration belt measured heart rate and respiratory sinus arrhythmia (RSA) data and MATLAB transformed the raw data to produce heart rate variability (HRV) values. The self-report data indicated that the manipulation did not induce anxiety and that there was no reduction in anxiety after the coloring conditions. Physiological data indicated that the manipulation successfully induced anxiety, however, there was no significant reduction in anxiety. Although the results of this study were not significant, they suggest that with a larger sample size, it would be possible to see an effect of specific pattern coloring on the reduction of anxiety.

published_or_final_version / abstract / Humanities / Master / Master of Philosophy

I argue that conscious visual experience consists in a direct and noninferential grasp of the way one’s current perceptual contact with the environment poises one to pursue various intentional plans, goals and projects. I show that such a view of visual consciousness is supported by current work in cognitive neuroscience, affords a compelling account of colour perception, and suggests a way to bridge the ‘explanatory gap’ between consciousness and the language of the natural sciences. In chapter 1, I examine the reasoning that leads to the appearance of an explanatory gap between the phenomenal and the physical in more detail, and set out the constraints on a solution that our discussion of the problem has imposed. I then sketch the two rival takes on the relationship between perception and action mentioned above – adjudicating between these two theories (and finding in favour of the action-space view) is the task of the next two chapters, and is a recurring theme throughout. Chapter 2 moves on to discuss some recent work in the neuropsychology of vision and what it might suggest about the functional role of conscious vision, and the first half of chapter 3 considers two puzzle cases concerning colour perception. Each of these discussions turns out to constitute a source of support for the actionspace view that visual perception consists in a grasp of the practical consequences of sensation, and the second half of chapter 3 sets out this view and responds to an initial range of questions and objections it might face. Chapter 4 illustrates our view via a discussion of colour perception, and chapter 5 discusses the type of grasp of practical consequences that is necessary for perceptual sensitivity to issue in conscious experience. By chapter 6, we are in a position to see how the action-space approach can help close the explanatory gap for phenomenal consciousness, and our final chapter sets out how I think this should be done. I conclude with a brief discussion of further questions and prospects for the action-space approach.

The experiments in this thesis investigated the mechanisms controlling input and output gating of working memory. In chapter 3, accuracy and reaction time data from a precision/capacity working memory task with prospective and retrospective cues were analysed. The results suggest that retrocues boost performance by facilitating output gating from working memory. In chapter 4, the role of perceptual cortex in mediating the cue benefits in this task was investigated with magnetoencephalography (MEG). The pattern of alpha (8-12Hz) power in visual cortex was modulated by cue direction following both precues and retrocues, but whilst this modulation was sustained following a precue (until presentation of the memory array) it was transient following a retrocue, suggesting that a memory representation was briefly retrieved or refreshed, but that there was not a sustained biasing of top-down input to visual cortex following retrocues. This argues against the standard model of working memory as sustained attention to internal representations, and in favour of a more dynamic view in which perceptual cortex is recruited transiently, and otherwise freed up for on-going processing. In chapter 5, the role of frontal networks in precueing and retrocueing was investigated. An fMRI meta-analysis identified control networks involved in preparatory and mnemonic selection: whilst the fronto-parietal network is recruited in both cases, the cingulo-opercular network is recruited only by retrocues. This spatial pattern was replicated with a source-space ROI analysis of MEG induced-responses. These data also characterised the time-course of control network activation shedding light on their functional roles. The fronto-parietal network was activated immediately following both precues and retrocues, consistent with a direct role in top-down influence over perceptual cortex. By contrast, the cingulo-opercular network was activated following retrocues only after the perceptual refreshing event was complete, suggesting a downstream role, perhaps in selecting representations to guide action. Chapter 6 investigated the role of reward associations in controlling access to working memory, testing behavioural predictions of two theories implicating the dopamine system and basal ganglia in control of working memory. The results supported a temporal gating account in which encountering reward associated items triggers a brief (<300ms) window in which there is a boost of encoding for WM. Chapter 7 discusses the implications of the current work and suggests some future directions.

Bipolar disorder and borderline personality disorder are common psychiatric diagnoses. One is a mood disorder with a strong genetic basis while the other is a disorder of personality commonly related to abusive experiences in childhood. Despite contrasting aetiologies they can be difficult to differentiate because of overlapping clinical presentations and symptoms. Diagnostic accuracy is important because of their polarised treatment approaches: long term treatment with mood stabilizers for bipolar disorder and psychotherapy for borderline personality disorder. A qualitative study of psychiatrists revealed comprehensive knowledge of the diagnostic criteria however, many expressed the view that diagnostic criteria did not assist diagnostic differentiation. These findings were validated in a large electronic survey of UK psychiatrists. A detailed study of actual diagnostic processes revealed that this scepticism appeared to influence actual practice. Clinicians largely ignored diagnostic criteria but continued to give diagnoses. Age and IQ matched women with bipolar disorder, borderline personality disorder and a healthy control group were compared in a series of cognitive tasks. Borderline personality disorder was associated with a failure to establish and maintain reciprocal cooperation in a game theoretic measure of social exchange. This behavioural change was not seen in euthymic bipolar disorder. Borderline personality disorder was also associated with an insensitivity to reward and losses in a risky decision-making task. Using a simple two-choice reaction task post error slowing was significantly amplified in the borderline group despite overall reaction times and error rates being similar in all three groups. Clinical diagnostic practice as revealed in this study is not adequate to reliably differentiate between bipolar disorder and borderline personality disorder. Laboratory measures of social exchange, decision making and post-error slowing highlight fundamental difficulties in borderline personality disorder not seen in euthymic bipolar disorder. These findings support the differentiation of bipolar disorder from borderline personality disorder and offer translational models for developing and evaluating new treatments for borderline personality disorder.

Existing knowledge identifies the prefrontal cortex (PFC) as the modulatory area for pain. Previous neuroimaging studies suggest the existence of the cortico-cortical pathway, an alternative pain modulatory pathway distinct from the descending modulatory pathway of pain. However, little is known of the extent, mechanism and underlying substrate of the modulation. The objective of this study is therefore to explore the role of the PFC in pain modulation. To examine the extent of PFC involvement in pain, meta-analyses of imaging studies in healthy volunteers and patients with chronic pain were performed. Using Gaussian-process regression (GPR) analysis, brain maps were produced from foci of activation as reported in the studies. Since structure dictates function, our next study was to performprobabilistic tractography on diffusion-weighted brain images to ascertain the connection probability of lateral PFC subdivisions and pain-related brain regions as well as intrinsic PFC connections. Two behavioural studies were conducted to investigate cognitive modulation of pain. The first was a study to assess the subjective and physiological correlates of cognitive stress, as previously used in stress-induced analgesia studies. The second was to investigate the involvement of the endogenous opioid system inthe cognitive modulation of pain through effortful reappraisal and contextual modulation. Meta-analyses in healthy volunteers and chronic pain patients revealed activation mainly in the lateral aspect of the PFC due to pain. Distinct pattern of activation was demonstrated in patients with significant ventrolateral PFC (VLPFC) activation across subtypes of chronic pain. Probabilistic tractography further illustrate the functional significance of lateral PFC subdivisions by demonstrating differential connection probability to pain-related brain regions; dorsolateral PFC (DLPFC) regions displayed higher connection probability with brain regions serving more sensory-discriminative function while VLPFC showed high connection probability with both sensory-discriminative and affective regions. Behavioural study of stress showed that cognitive stress failed to induce significant increases in biomarkers of stress, and was not affected by increased level of difficulty. Lastly, behavioural study on contextual modulation and reappraisal confirmed opioid mediation for contextual modulation while negating its involvement in effortful reappraisal. Findings from this studyillustrate the extent of PFC involvement in pain modulation especially in chronic pain patients and provide further evidence of an alternative pathway distinct from the opioid-mediated descending inhibitory pathway.

The brainstem plays a crucial role in a great number of vital functions such as respiratory regulation, visual reflexes, and the perception of pain. The small size and close proximity of the nuclei requires high-resolution functional magnetic resonance imaging (FMRI). However, brainstem FMRI using conventional gradient-echo echo-planar imaging (GRE-EPI) techniques is challenging due to the increased signal dropout and geometric distortions in the brainstem. The primary aim of the work presented in this thesis was to investigate alternative methods for brainstem FMRI in order to overcome some of the challenges associated with single-shot GRE-EPI techniques. Towards this goal 3D segmented sequences were explored, which have the advantage that the size of the geometric distortions is not proportional to the resolution at which is scanned. In particular, two sequences were investigated: balanced steady-state free-precession (bSSFP) and spoiled gradient echo (SPGR). First, a set of experiments was conducted, in which each experiment aimed to isolate a limited range of sequence properties in order to characterize and assess the potential of the candidate sequences. It was found that bSSFP has better noise characteristics compared to GRE-EPI when applied with a 2D acquisition, but when 3D readouts were used the signal instabilities increased dramatically. Based on these findings, experiments that investigate the influence of multishot acquisitions on signal instabilities caused by physiological noise were performed. The signal instabilities were found to mainly originate from regions of CSF and blood and were highly correlated to the cardiac cycle. Several correction methods were explored and one method was identified to be implemented in vivo. A novel method that allows real-time cardiac synchronization of the k-space acquisition was developed. The developed methods used a custom parallel imaging reconstruction to allow for acquisition with a fixed volume frame rate, which is desirable for FMRI purposes. The method was found to reduce the signal instabilities in 3D SPGR and bSSFP significantly. A comprehensive assessment of two currently available retrospective correction techniques was conducted and their practicalities were compared. Recommendations are made to improve the robustness of the investigated correction methods. A novel optimization method was implemented, which was developed to determine the optimal regressor set for retrospective corrections. The method can be applied to image based as well as k-space based methods.