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

Neurobiological mechanisms of hallucinations in schizophrenia

All perception is a construct of the brain. Yet occasionally, sensory constructions emerge without origin in the physical world and are experienced as hallucinations. Hallucinations occur transdiagnostically, cross-culturally, and in all sensory modalities. They are common in people with schizophrenia, presenting in 60-80% of patients. Despite over 20 years of active neuroimaging research on hallucinations, the neural systems supporting these anomalous perceptual experiences remain disputed. This dissertation investigates the neurobiology of hallucinations, integrating research across structural and functional magnetic resonance imaging (MRI) to elucidate how hallucinations, chiefly in the context of schizophrenia, are supported by the brain, drawing on MRI indices of neurodevelopment. I introduce the phenomenon of hallucinations and motivate the utility of MRI for studying hallucinations. Considering their prevalence in other medical conditions, I conduct a meta-analysis and systematic review of the structural brain basis of hallucinations across diagnoses, primarily schizophrenia spectrum disorders and Parkinson’s disease. This illustrated distinct neuroanatomical organizations of grey matter associated with hallucinations that occur in neurodevelopmental compared to neurodegenerative disorders, which I hypothesise constitute at least two distinct mechanisms. Focussing on the neurodevelopmental mechanism characterized by fronto-temporal and insular grey matter reductions, I turn to the contribution of cortical sulcation, a product of second and third trimester neurodevelopmental processes, which has been robustly implicated in schizophrenia pathology, and, more recently, in hallucinations. Sulcal patterns derived from structural MRI provide a proxy in adulthood for early brain development. I studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MRI from the United Kingdom and Shanghai, China, stratified into those with and without hallucinations, and healthy controls from Shanghai. I first replicate the finding that left hemisphere paracingulate sulcus (PCS) length is reduced in patients who experience hallucinations, then demonstrate similar associations for superior temporal sulcus depth. Length and depth alterations occurred with focal deviations in sulcal geometry. The interindividual and interhemispheric variability of the PCS necessitated the development of semi-automated methods to characterize its morphology and validation to a manual protocol. I used structural covariance networks of the local gyrification index to investigate how specific sulcal deviations relate to global neurodevelopmental coordination, demonstrating that hallucinations correspond to increased covariance within and between salience and auditory networks. Hypothesizing structure-function relationships, I analyse resting-state functional MRI data from the same datasets described, finding significant interactions between PCS length and hallucinations status, but no main effects. There were no effects of hallucination status on salience and auditory network connectivity or in graph theoretical measures of connectivity, suggesting that resting-state connectivity is not a trait marker for hallucinations. Together, the discovery of neurodevelopmental alterations contributing to hallucinations provides mechanistic insight into the pathological consequences of prenatal origins. The interaction of sulcal alterations and hallucination status are associated with connectivity, which may have a role in the pathophysiology of hallucinations. I provide clear predictions and recommendations for future research.Gates Cambridge Scholarshi

Neuroanatomy of the bipolar brain: from brain structure to treatment

In this thesis, I summarized results from researches done during my PhD course, organizing them in a brief introduction and five chapters. Specifically, the first chapter of this work is dedicated to the progress made during the past years in neuroimaging technologies and techniques, with a focus on structural Magnetic Resonance Imaging techniques and their employment into the neuropsychiatric research. The following three chapters are dedicated to the three studies, all developed though a specific research topic and directed to the understanding of the neural basis of Bipolar Disorder and its clinical implications

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

Clinical and neuroimaging prognostic markers in Alzheimer's Disease and Lewy Body Dementia: The role of muscle status and nutrition

Alzheimer's Disease and Lewy body dementia are the two most common neurodegenerative dementias. They have a progressive course with devastating consequences for the people living with these diseases and their families, but there are large individual variations. Finding early markers and markers of progression and prognosis could promote actions to improve the quality of life of the people affected with these diseases. Nutrition and muscle status are closely related and have systemic functions and interactions that affect the brain. This thesis describes the role of nutritional and muscle status biomarkers in the prognosis of people diagnosed with mild Alzheimer's disease, Lewy body dementia, and mild subjective cognitive decline. Methods For the aim of this thesis, I used data from 2 community-based prospective Norwegian multicenter cohort studies: DemVest (The Dementia Study of Western Norway) and DDI (Dementia Disease Initiation). In DemVest, patients with mild dementia, defined as a Mini-Mental Status Examination (MMSE) score; equal or higher to 20 or Clinical Dementia Rating (CDR) global score equal to 1, with different types of dementia, were included. The DDI study was designed to investigate early cognitive impairment and dementia markers. DDI participants included in this thesis were those classified as having Subjective cognitive decline (SCD) according to the SCD-I framework. Comprehensive clinical assessments, including measures of cognition, daily functioning and anthropometric measurement, blood samples, and brain MRI were performed in both studies. Brain morphology was studied using FreeSurfer segmentation and muscle morphology using slice O-Matic software. Results This thesis findings first indicate that nutritional status has an essential role in the 5-year prognosis of people living with dementia in the capacity to perform daily life activities and mortality. Second, the quality of the muscle, here the muscle of the tongue, and its amount of fat infiltration were associated with malnutrition onset in people with dementia. Finally, in patients with SCD, muscle function measured with the timed up and go test (TUG) was associated with cognitive decline. TUG, in addition, was associated with cortical thickness in areas related with cognitive and motor functioning. Conclusion Nutritional and muscular status predict prognosis in people with SCD and with dementia. These findings suggest that interventions focused on these areas may improve outcomes such as cognition, function, and survival in these groups

Small-World Network Analysis of Cortical Connectivity in Chronic Fatigue Syndrome using EEG

The primary aim of this thesis was to explore the relationship between electroencephalography (qEEG) and brain system dysregulation in people with Chronic Fatigue Syndrome (CFS). EEG recordings were taken from an archival dataset of 30 subjects, 15 people with CFS and 15 healthy controls (HCs), evaluated during an eye-closed resting state condition. Exact low resolution electromagnetic tomography (eLORETA) was applied to the qEEG data to estimate cortical sources and perform functional connectivity analysis assessing the strength of time-varying signals between all pairwise cortical regions of interest. To obtain a comprehensive view of local and global processing, eLORETA lagged coherence was computed on 84 regions of interest representing 42 Brodmann areas for the left and right hemispheres of the cortex, for the delta (1-3 Hz) and alpha-1 (8-10 Hz) and alpha-2 (10-12 Hz) frequency bands. Graph theory analysis of eLORETA coherence matrices for each participant was conducted to derive the “small-worldness” index, a measure of the optimal balance between the functional integration (global) and segregation (local) properties known to be present in brain networks. The data were also associated with the cognitive impairment composite score on the DePaul Symptom Questionnaire (DSQ), a patient-reported symptom outcome measure of frequency and severity of cognitive symptoms. Results showed that small-worldness for the delta band was significantly lower for patients with CFS compared to HCs. Small-worldness for delta, alpha-1, and alpha-2 were associated with higher cognitive composite scores on the DSQ. Finally, small-worldness in all 3 frequency bands correctly distinguished those with CFS from HCS with a classification rate of nearly 87 percent. These preliminary findings suggest disease processes in CFS may be functionally disruptive to small-world characteristics, especially in the delta frequency band, resulting in cognitive impairments. In turn, these findings may help to confirm a biological basis for cognitive symptoms, providing clinically relevant diagnostic indicators, and characterizing the neurophysiological status of people with CFS

Oscillatory and structural measures of connectivity in psychosis, psychosis-risk and the healthy population

Magnetoencephalography (MEG) and Diffusion Tensor Imaging (DTI) are important tools for probing functional and structural properties of the brain. The interactions between the brain’s local and long-range circuitry could provide a key to understanding schizophrenia as a disorder of dysconnectivity and related risk factors in the healthy population. The aim in the first chapters of this thesis was to understand how high frequency local visual circuitry and long-range low frequency connectivity can be best estimated from MEG data. It was shown that using a finer sampling grid in source estimation leads to improved measures of high frequency responses. Furthermore, that networks usually measured in the resting-state can be extracted from task data was another key discovery and has positive implications for data quality and participant comfort going forward. The second aim of this thesis was to understand how specific local and global entities interact by investigating the relationships between local visual circuitry and long-range structural and oscillatory connectivity. An important finding was that the magnitude of local connectivity in the superficial layers of the visual cortex, as probed by gamma amplitude, was associated with reduced long-range connectivity beyond primary visual areas. The other novel finding was that the frequency of local visual oscillations was correlated with structural measures, possibly reflecting increased myelination. The third aim of this work was to better understand how psychosis-risk relates to functional and structural connectivity in health and schizophrenia. Schizotypy was robustly correlated with reduced long-range functional connectivity but not structural connectivity. The opposite was true for correlations between polygenic risk and connectivity. However, the aforementioned risk factors were not robustly correlated with local functional connectivity. The last chapter showed novel but non-significant differences in local and global oscillatory connectivity that were related to excitatory-inhibitory copy number burden in patients