A computational approach to motivated behaviour and apathy

The loss of motivation and goal-directed behaviour is characteristic of apathy. Across a wide range of neuropsychiatric disorders, including Huntington’s disease (HD), apathy is poorly understood, associated with significant morbidity, and is hard to treat. One of the challenges in understanding the neural basis of apathy is moving from phenomenology and behavioural dysfunction to neural circuits in a principled manner. The computational framework offers one such approach. I adopt this framework to better understand motivated behaviour and apathy in four complementary projects. At the heart of many apathy formulations is impaired self-initiation of goal-directed behaviour. An influential computational theory proposes that “opportunity cost”, the amount of reward we stand to lose by not taking actions per unit time, is a key variable in governing the timing of self-initiated behaviour. Using a novel task, I found that free-operant behaviour in healthy participants both in laboratory conditions and in online testing, conforms to predictions of this computational model. Furthermore, in both studies I found that in younger adults sensitivity to opportunity cost predicted behavioural apathy scores. Similar pilot results were found in a cohort of patients with HD. These data suggest that opportunity cost may be an important computational variable relevant for understanding a core feature of apathy – the timing of self-initiated behaviour. In my second project, I used a reinforcement learning paradigm to probe for early dysfunction in a cohort of HD gene carriers approximately 25 years from clinical onset. Based on empirical data and computational models of basal ganglia function I predicted that asymmetry in learning from gains and losses may be an early feature of carrying the HD gene. As predicted, in this task fMRI study, HD gene carriers demonstrated an exaggerated neural response to gains as compared to losses. Gene carriers also differed in the neural response to expected value suggesting that carrying the HD gene is associated with altered processing of valence and value decades from onset. Finally, based on neurocomputational models of basal ganglia pathway function, I tested the hypothesis that apathy in HD would be associated with the involvement of the direct pathway. Support for this hypothesis was found in two related projects. Firstly, using data from a large international HD cohort study, I found that apathy was associated with motor features of the disease thought to represent direct pathway involvement. Secondly, I tested this hypothesis in vivo using resting state fMRI data and a model of basal ganglia connectivity in a large peri-manifest HD cohort. In keeping with my predictions, whilst emerging motor signs were associated with changes in the indirect pathway, apathy scores were associated with connectivity changes in the direct pathway connectivity within my model. For patients with apathy across neuropsychiatry there is an urgent need to understand the neural basis of motivated behaviour in order to develop novel therapies. In this thesis, I have used a computational framework to develop and test a range of hypotheses to advance this understanding. In particular, I have focussed on the computational factors which drive us to self-initiate, their potential neural underpinnings and the relevance of these models for apathy in patients with HD. The data I present supports the hypothesis that opportunity cost and basal ganglia pathway connectivity may be two important components necessary to generate motivated behaviour and contribute to the development of apathy in HD

Neuroimaging biomarkers associated with clinical dysfunction in Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder in the world, directly affecting 2-3% of the population over the age of 65. People diagnosed with the disorder can experience motor, autonomic, cognitive, sensory and neuropsychiatric symptoms that can significantly impact quality of life. Uncertainty still exists about the pathophysiological mechanisms that underlie a range of clinical features of the disorder, linked to structural as well as functional brain changes. This thesis thus aimed to uncover neuroimaging biomarkers associated with clinical dysfunction in PD. A 'hubs-and-spokes' neural circuit-based approach can contribute to this aim, by analysing the component elements and also the interconnections of important brain networks. This thesis focusses on structures within basal ganglia-thalamocortical neuronal circuits that are linked to a range functions impacted in the disorder, and that are vulnerable to the consequences of PD pathology. This thesis investigated neuronal 'hubs' by studying the morphology of the caudate nucleus, putamen, thalamus and neocortex. The caudate nucleus, putamen and thalamus are all vital subcortical 'hubs' that play important roles in a number of functional domains that are compromised in PD. The neocortex, on the other hand, has a range of 'hubs' spread across it, regions of the brain that are crucial for neuronal signalling and communication. The interconnections, or 'spokes', between these hubs and other brain regions were investigated using seed-based resting-state functional connectivity analyses. Finally, a morphological analysis was used to investigate possible structural changes to the corpus callosum, the major inter-hemispheric white matter tract of the brain, crucial to effective higher-order brain processes. This thesis demonstrates that the caudate nucleus, putamen, thalamus, corpus callosum and neocortex are all atrophied in PD participants with dementia. PD participants also demonstrated a significant correlation between volumes of the caudate nuclei and general cognitive functioning and speed, while putamina volumes were correlated with general motor function. Cognitively unimpaired PD participants demonstrated minimal morphological alterations compared to control participants, however they demonstrated significant increases in functional connectivity of the caudate nucleus, putamen and thalamus with areas across the frontal lobe, and decreases in functional connectivity with parietal and cerebellar regions. PD participants with mild cognitive impairment and dementia show decreased functional connectivity of the thalamus with paracingulate and posterior cingulate cortices, respectively. This thesis contributes a deeper understanding of the relationship between structures of basal ganglia-thalamocortical neuronal circuits, corpus callosal and neocortical morphology, and the clinical dysfunction associated with PD. This thesis suggests that functional connectivity changes are more common in early stages of the disorder, while morphological alterations are more pronounced in advanced disease stages

Characterising the structural brain changes in Huntington’s disease using translational neuroimaging

This thesis examined the macro-structural and micro-structural changes in Huntington’s disease (HD) in order to improve understanding of the temporal and spatial patterns of neurodegeneration, and the functional relevance of these changes. Translational techniques were employed using genetic mouse models of HD in combination with a patient cohort to examine grey and white matter changes with a particular focus on white matter microstructure. In the patient cohort, the cognitive profile was examined using a cognitive battery not before applied in HD. Specific deficits were found in set-shifting and flexibility, verbal reasoning, working memory and paired associate learning, along with subtle differences in response inhibition that were sensitive to disease burden. A composite cognitive score was produced to examine the relationship between cognitive function and brain structure. A multi-modal examination of white matter tract-specific microstructural measurements revealed abnormalities in the corpus callosum and cingulum bundle that were sensitive to disease burden (chapter 4). In chapter 5, multiple analysis techniques converged to reveal tissue macrostructure abnormalities that were also sensitive to disease burden in HD. Cortical changes were less consistent, and unlike the microstructure findings, white matter macrostructural abnormalities were not related to disease burden. In chapters 6 and 7, genetic mouse models of HD were used to examine changes across the disease course, and to pilot an interventional design. In vivo diffusion MRI and T2-weighted MRI sequences were acquired at 2 different time points in the HdhQ150 knock-in model of HD and imaging data is presented alongside behavioural results and immunohistochemistry. In chapter 7, an environmental modification regime was tested in the YAC128 mouse model using in vivo MRI. Environmental intervention reduced the degree of disease-related atrophy, altered tissue microstructure and improve motor but not cognitive performance in YAC128 mice

MRI and cognitive changes in Huntington's disease.

This thesis focused on cognitive and MRI measures of early change and progression in Huntington's disease (HD). HD is clinically heterogeneous and previous findings about the location of brain atrophy in the early stages, and its relation to cognition, are equivocal. A pilot study assessed the practicality of using serial volumetric MRI in early HD and the usefulness of cognitive tasks in longitudinal assessment. A larger study investigated cross-sectional and longitudinal aspects of these domains in premanifest and early HD. Global and regional cerebral volumes were investigated using manual volumetry and voxel-based morphometry (VBM). The work describes the application of the Brain Boundary Shift Integral (BBSI) to measure of whole-brain atrophy rate. Preparatory technical work included choice of templates for optimum scan alignment and segmentation in VBM, and adjustment of BBSI parameters to obtain maximum agreement between it and manual measures. Cognitive ability was assessed using a wide-ranging battery of tests, some standard and some novel. Atrophy in early HD was found to be more extensive than previously reported, involving widespread extra-striatal loss, and not all functional deficits could be attributed to striatal damage. Emotion recognition deficits were broad and associated with striatal and extra-striatal brain regions. Executive function and memory tasks demonstrated decline over one year. Whole-brain atrophy rates were increased in early HD and associated with decline in cognition and CAG repeat length. This work elucidates the extent of, and associations of, atrophy and cognitive impairment in HD, and adds weight to the suggestion that variability in progression rates is partly explained by genetic factors. The suggestion that motor learning might be impaired even in very far-from-onset gene carriers, and that tasks other than those tapping executive function were sensitive to decline, should motivate further work aimed at detecting the very earliest signs of change in this disease

Exploring the beneficial effects of cardiorespiratory fitness and exercise on cerebrovascular health in Huntington’s Disease: a cross-species approach

This thesis explores the benefits of physical activity on cerebrovascular health in healthy subjects and in Huntington’s Disease (HD), where cerebrovascular health is thought to be jeopardised. A cross-species approach was employed, to inform the relevance of MRI findings in humans, using histology and pre-clinical imaging. In Chapter 2, measurement of cerebrovascular markers using arterial spin labelling (ASL) MRI showed that arterial compliance and resting cerebral blood flow was lower in subjects with higher cardiorespiratory fitness, whilst differences in cerebrovascular reactivity (CVR) to a breath-hold task were not statistically significant. Measurements of vessel density in Chapter 3 showed that running mice had greater vessel density than non-running mice following a 6-week voluntary wheel running intervention, which may be attributed to a process of angiogenesis. Methods developed in healthy subjects were subsequently applied to investigate the cerebrovascular benefits of exercise in HD. In Chapter 4, pre-/early- symptomatic patients with HD were assessed for subtle differences in cerebrovascular health and whether this varied with cardiorespiratory fitness. Disease-related differences were observed in cognition, and ASL measures including resting CBF and CVR, but no clear relationship with fitness was observed. Preclinical imaging was used in Chapter 5 to measure longitudinal changes in resting CBF and CVR in a transgenic Q175 mouse model of HD, prior to behavioural deficits (preHD). Neither CBF or vessel density differed between preHD animals and controls, and did not appear altered by voluntary running

Addictions

Addiction, increasingly perceived as a heterogeneous brain disorder, is one of the most peculiar psychiatric pathologies in that its management involves various, often non-overlapping, resources from the biological, psychological, medical, economical, social, and legal realms. Despite extensive efforts from the players of these various fields, to date there are no reliably effective treatments of addiction. This may stem from a lack of understanding of the etiology and pathophysiology of this disorder as well as from the lack of interest into the potential differences among patients in the way they interact compulsively with their drug. This book offers an overview of the psychobiology of addiction and its current management strategies from pharmacological, social, behavioural, and psychiatric points of view