Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive

The external part of the globus pallidus (GPe) is a core nucleus of the basal ganglia (BG) whose activity is disrupted under conditions of low dopamine release, as in Parkinson's disease. Current models assume decreased dopamine release in the dorsal striatum results in deactivation of dorsal GPe, which in turn affects motor expression via a regulatory effect on other nuclei of the BG. However, recent studies in healthy and pathological animal models have reported neural dynamics that do not match with this view of the GPe as a relay in the BG circuit. Thus, the computational role of the GPe in the BG is still to be determined. We previously proposed a neural model that revisits the functions of the nuclei of the BG, and this model predicts that GPe encodes values which are amplified under a condition of low striatal dopaminergic drive. To test this prediction, we used an fMRI paradigm involving a within-subject placebo-controlled design, using the dopamine antagonist risperidone, wherein healthy volunteers performed a motor selection and maintenance task under low and high reward conditions. ROI-based fMRI analysis revealed an interaction between reward and dopamine drive manipulations, with increased BOLD activity in GPe in a high compared to low reward condition, and under risperidone compared to placebo. These results confirm the core prediction of our computational model, and provide a new perspective on neural dynamics in the BG and their effects on motor selection and cognitive disorders

Adaptive integration of habits into depth-limited planning defines a habitual-goal–directed spectrum

Behavioral and neural evidence reveal a prospective goal-directed decision process that relies on mental simulation of the environment, and a retrospective habitual process that caches returns previously garnered from available choices. Artificial systems combine the two by simulating the environment up to some depth and then exploiting habitual values as proxies for consequences that may arise in the further future. Using a three-step task, we provide evidence that human subjects use such a normative plan-until-habit strategy, implying a spectrum of approaches that interpolates between habitual and goal-directed responding. We found that increasing time pressure led to shallower goal-directed planning, suggesting that a speed-accuracy tradeoff controls the depth of planning with deeper search leading to more accurate evaluation, at the cost of slower decision-making. We conclude that subjects integrate habit-based cached values directly into goal-directed evaluations in a normative manner

Action control in uncertain environments

A long-standing dichotomy in neuroscience pits automatic or reflexive drivers of behaviour against deliberate or reflective processes. In this thesis I explore how this concept applies to two stages of action control: decision-making and response inhibition. The first part of this thesis examines the decision-making process itself during which actions need to be selected that maximise rewards. Decisions arise through influences from model-free stimulus-response associations as well as model-based, goal-directed thought. Using a task that quantifies their respective contributions, I describe three studies that manipulate the balance of control between these two systems. I find that a pharmacological manipulation with levodopa increases model-based control without affecting model-free function; disruption of dorsolateral prefrontal cortex via magnetic stimulation disrupts model-based control; and direct current stimulation to the same prefrontal region has no effect on decision-making. I then examine how the intricate anatomy of frontostriatal circuits subserves reinforcement learning using functional, structural and diffusion magnetic resonance imaging (MRI). A second stage of action control discussed in this thesis is post-decision monitoring and adjustment of action. Specifically, I develop a response inhibition task that dissociates reactive, bottom-up inhibitory control from proactive, top-down forms of inhibition. Using functional MRI I show that, unlike the strong neural segregation in decision-making systems, neural mechanisms of reactive and proactive response inhibition overlap to a great extent in their frontostriatal circuitry. This leads to the hypothesis that neural decline, for 4 example in the context of ageing, might affect reactive and proactive control similarly. I test this in a large population study administered through a smartphone app. This shows that, against my prediction, reactive control reliably declines with age but proactive control shows no such decline. Furthermore, in line with data on gender differences in age-related neural degradation, reactive control in men declines faster with age than that of women

Retrospective model-based inference guides model-free credit assignment

An extensive reinforcement learning literature shows that organisms assign credit efficiently, even under conditions of state uncertainty. However, little is known about credit-assignment when state uncertainty is subsequently resolved. Here, we address this problem within the framework of an interaction between model-free (MF) and model-based (MB) control systems. We present and support experimentally a theory of MB retrospective-inference. Within this framework, a MB system resolves uncertainty that prevailed when actions were taken thus guiding an MF credit-assignment. Using a task in which there was initial uncertainty about the lotteries that were chosen, we found that when participants’ momentary uncertainty about which lottery had generated an outcome was resolved by provision of subsequent information, participants preferentially assigned credit within a MF system to the lottery they retrospectively inferred was responsible for this outcome. These findings extend our knowledge about the range of MB functions and the scope of system interactions

Raman spectroscopy for accurately characterizing biomolecular changes in androgen-independent prostate cancer cells

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Metastatic prostate cancer resistant to hormonal manipulation is considered the advanced stage of the disease and leads to most cancer-related mortality. With new research focusing on modulating cancer growth, it is essential to understand the biochemical changes in cells that can then be exploited for drug discovery and for improving responsiveness to treatment. Raman spectroscopy has a high chemical specificity and can be used to detect and quantify molecular changes at the cellular level. Collection of large data sets generated from biological samples can be employed to form discriminatory algorithms for detection of subtle and early changes in cancer cells. The present study describes Raman finger printing of normal and metastatic hormone-resistant prostate cancer cells including analyses with principal component analysis and linear discrimination. Amino acid-specific signals were identified, especially loss of arginine band. Androgen-resistant prostate cancer cells presented a higher content of phenylalanine, tyrosine, DNA and Amide III in comparison to PNT2 cells, which possessed greater amounts of L-arginine and had a B conformation of DNA. The analysis utilized in this study could reliably differentiate the 2 cell lines (sensitivity 95%; specificity 88%)

Keeping Europe in Order Conservative International Political Thought in Victorian Britain, 1854-1880

PhDConservative international thought in Victorian Britain is a prominent landmark in the landscape of international thought which has up to now gone unmapped. In illuminating this body of thought, the thesis addresses weaknesses present in three different historiographies. As the first detailed study of conservative international thought in Victorian Britain, the thesis rectifies a marked bias in Victorian intellectual history towards the study of liberal and radical thought. Furthermore, by analysing the political thought of major representatives of the conservative educated classes, this thesis provides context for the history of conservative high politics, thereby leading us to view these in a different light. Finally, this study, by providing a historically nuanced account of the evolution of major themes of international relations theory in mid-Victorian Britain, functions as a corrective to the self-history of the academic field of International Relations. The thesis makes its argument by analysing conservative contributions in periodicals, pamphlets, and newspapers to British public debates on international affairs, from the Crimean War (1854-56) until the Eastern Question crisis of 1876-80. The general claim of this thesis is that there existed a distinctly conservative perspective on the international sphere. The core elements of this conservative perspective were the primacy of statesmen in setting foreign policy; of interests, military force, and stature in determining the course of international politics; and of order and equilibrium as its normative content. Conservative authors used this constellation of ideas in the major debates of the mid-Victorian era on international affairs, both as a means to make sense of events, and as a counterpoint to liberal narratives – with which Victorian international thought is all too often identified. In recovering the international political thought of Victorian conservatives, this thesis illuminates an important but neglected aspect of how international relations were understood and conceptualised in mid-Victorian Britain.Queen Mary University of London School of Histor

Public awareness and healthcare professional advice for obesity as a risk factor for cancer in the UK:a cross-sectional survey

BACKGROUND: Overweight and obesity is the second biggest preventable cause of cancer after smoking, causing ~3.4 million deaths worldwide. This study provides current UK data on awareness of the link between obesity and cancer by socio-demographic factors, including BMI, and explores to what degree healthcare professionals provide weight management advice to patients. METHODS: Cross-sectional survey of 3293 adults completed an online survey in February/March 2016, weighted to be representative of the UK population aged 18+. RESULTS: Public awareness of the link between obesity and cancer is low (25.4% unprompted and 57.5% prompted). Higher levels of awareness existed for least deprived groups (P < 0.001), compared to more deprived groups. Most respondents had seen a healthcare practitioner in the past 12 months (91.6%) and 17.4% had received advice about their weight, although 48.4% of the sample were overweight/obese. CONCLUSION: Cancer is not at the forefront of people’s minds when considering health conditions associated with overweight or obesity. Socio-economic disparities exist in health knowledge across the UK population, with adults from more affluent groups being most aware. Healthcare professionals are uniquely positioned to provide advice about weight, but opportunities for intervention are currently under-utilized in healthcare settings