This thesis focuses on non-motor symptoms (NMS) of Parkinson’s disease (PD), particularly the neuropsychiatric symptoms of visual hallucinations, apathy and impulse control disorders. A clinical cohort study and pathology study were performed. PD patients (N=94) were recruited and each underwent neurological examination for motor aspects of the disease, detailed multi-domain cognitive assessment including executive and visuoperceptive function, and a battery of validated non-motor assessments for symptoms including mood, apathy, sleep, fatigue, psychosis, autonomic function, disability and health-related quality of life (QOL). A subgroup (N=50) also had detailed ophthalmological examination. In the autopsy study, the presence of ante-mortem visual hallucinations (VH) in PD donors was correlated with Lewy body (LB) density and distribution at different cortical locations. The clinical study examined the impact of NMS on QOL and found that NMS, particularly depression, had stronger association with QOL than motor scores, but despite this NMS were often under-reported by their treating neurologist. A significant proportion of pathologically confirmed PD patients presented exclusively with NMS and this led to misdiagnosis and, in some cases, inappropriate investigations and treatment. An aetiological model of VH was proposed and examined; factors investigated included dopaminergic medication, higher cortical function, sleep and ophthalmic pathology. Clinical associations of VH were rapid eye movement sleep behaviour disorder, autonomic function, and executive and visuoperceptive cortical function. There was however no clear association with co-existing ophthalmic pathology. In the post-mortem analysis, LB involvement at corresponding cortical areas was confirmed, including frontal (executive) and temporal and trans-entorhinal (visuoperception) cortices. A meta-analysis of studies reporting pathological gambling was performed and an association with dopaminergic medication, particularly dopamine agonist therapy, and co-existing psychopathology was confirmed.

Our experience with the auditory world can shape and modify perceptual, cognitive and neural processes with respect to audition. Such experience can occur over multiple timescales, and can vary in its specificity and intensity. In order to understand how auditory perceptual, cognitive and neural processes develop, it is important to explore the different means through which experience can influence audition. This thesis aims to address these issues. Using an expertise framework, we explore how the auditory environment and ontogenetic factors can shape and guide perceptual, cognitive and neural processes through long- and short-term profiles of experience. In early chapters, we use expertly-trained musicians as a model for long-term experience accrued under specific auditory constraints. We find that expertise on a particular instrument (violin versus piano) yields training-specific auditory perceptual advantages in a musical context, as well as improvements to ‘low-level’ auditory acuity (versus non-musicians); yet we find limited generalisation of expertise to cognitive tasks that require some of the skills that musicians hone. In a subsequent chapter, we find that expert violinists (versus non-musicians) show subtle increases in quantitative MR proxies for cortical myelin at left auditory core. In latter chapters, we explore short-term sound learning. We ask whether listeners can learn combinations of auditory cues within an active visuo-spatial task, and whether development can mediate learning of auditory cue combinations or costs due to cue contingency violations. We show that auditory cue combinations can be learned within periods of minutes. However, we find wide variation in cue learning success across all experiments, with no differences in overall cue combination learning between children and adults. These experiments help to further understanding of auditory expertise, learning, development and plasticity, within an experience-based framework.

Background: Functional magnetic resonance imaging (fMRI) provides maps of haemodynamic activity with uniform resolution across the brain. Simultaneous recording of electroencephalography (EEG) during fMRI (EEG-fMRI) was developed to localize spontaneously occurring epileptiform discharges. In focal epilepsy, it can identify candidate brain regions for surgical removal as a treatment option in medically refractory epilepsy; and in generalized epilepsy syndromes reveals those involved during the EEG changes. In healthy subjects, EEG-fMRI has linked spontaneous ongoing EEG activity with fMRI resting state networks. Methods: After method refinements, patients with medically refractory focal epilepsy and those with generalized epilepsy were studied with EEG-fMRI and group analyses performed to identify typical sets of brain regions involved in the epileptic process. Findings: In individual patients with refractory focal epilepsy, EEG-fMRI can produce activity maps including the seizure onset zone and propagated epileptic activity. Clinically, these can be confirmatory of results from alternative diagnostic techniques, or alternatively serve to generate a hypothesis on the potential epileptic focus, but under certain conditions may also be of negative predictive value with respect to surgical treatment success. At the group level in patients with temporal lobe epilepsy and complex partial seizures as well as in patients with generalized epilepsy and absence seizures, altered resting state network activity during EEG changes were found in default mode brain regions fitting well the ictal semiology, because these are known to reduce their activity during states of reduced consciousness. In (1) lateralized temporal lobe epilepsies, (2) an unselected mix of focal epilepsies, and (3) generalized epilepsies, activity increases occurred in typical brain regions suggesting an associated “hub function”, namely ipsilateral to the presumed cortical focus in the hippocampus; in an area near the frontal piriform cortex; and bilaterally in the thalamus, respectively. These findings argue for a network rather than a zone concept of epilepsy.

This thesis explores the nature of reading impairment in posterior cortical atrophy (PCA), a degenerative syndrome most commonly caused by Alzheimer’s disease (AD) pathology. PCA is characterised by cognitive deficits associated with posterior brain atrophy, including disruption to various visual domains, with relatively spared episodic memory function. Acquired dyslexia is an early and debilitating symptom of PCA; however, there is a lack of group investigations of reading dysfunction. Through a better understanding of dyslexia, including the contribution of visual deficits, the optimal conditions for PCA patients’ reading might be revealed. A series of studies were conducted to characterise reading and other visual deficits in PCA patients, typical AD (tAD) patients and healthy controls, accompanied by a consistent and comprehensive battery of neuropsychological tests. One form of early visual processing deficit that has been proposed to crucially limit reading in normal peripheral vision is crowding. Behavioural and neuroimaging investigations confirmed the qualitative similarity between crowding and deficits in identifying centrally presented flanked stimuli in PCA. Assessments of single word recognition and passage reading were carried out through behavioural, eye movement and neuroimaging analysis. Perceptual and spatial factors primarily determined single word and passage reading ability in PCA, not tAD. One counter-intuitive finding was how PCA patients demonstrated particular difficulty reading text in large font. Results also identified two patients who demonstrate remarkably preserved reading despite showing grave visual impairment; this discrepancy poses problems for general visual accounts of reading deficits. The two patients were followed longitudinally, revealing how the development of enhanced crowding effects coincided with loss of reading ability. Insights from the thesis informed the development of two interventions which intended to provide the optimal conditions for reading in PCA; both interventions resulted not only in consistent gains in reading accuracy, but also in improvements in self-reported reading ease and comprehension.

The rodent hippocampus and associated structures are implicated in spatial memory and navigation. A necessary requirement of these roles is the ability to integrate incoming sensory information with pre-existing knowledge about an environment. With this dichotomy in mind, sensory control over place cell firing in the hippocampus, and grid cell firing in the entorhinal cortex were investigated. In the first experimental chapter a computational model of hippocampal place cell firing is presented. The model, a two layer feed-forwards network, describes place fields as a function of the distance and direction to boundaries surrounding an animal. It is shown that by incorporating the idea of boundaries with distinct sensory qualities, and by allowing synaptic weights to be updated by application of the BCM learning rule, the model is able to capture: (1) Experiential changes in place fields resulting from prolonged exposure to a static environment, and (2) Changes in place field position and firing rate induced by movement of cues and boundaries in a familiar environment. The model is shown to compare favourably with novel electrophysiological data collected for this purpose and with experimental findings published by other authors. The second experimental chapter investigates the affects geometric manipulations of a familiar environment have on the firing of medial entorhinal grid cells. Novel data is presented that shows grid cell firing represents an experience-dependent interaction between sensory input and learnt expectation about the size of an animal's enclosure. It is also shown that this interaction evolves with time to resolve conflict between the two sources of information. Finally it is noted that grids from a single animal are aligned and have fixed relative sizes. The final chapter discusses the data in terms of how the brain perceives and represents the world.

The hereditary motor neuropathies (HMN) encompass diseases of motor axons and neurons and range from the progressive, length dependent distal hereditary motor neuropathies (dHMN) to the developmental, non-progressive dominant congenital spinal muscular atrophies (DCSMA). In this Thesis I have investigated the pathomechanisms of HMN and undertaken a natural history study of patients with dHMN. In Chapter 2 I investigated the pathomechanism of dHMN due to homozygous mutations in the heat shock protein HSJ1, using primary motor neurons (MNs) from HSJ1 knockout mice. Using live cell confocal imaging I examined mitochondrial axonal transport and ER calcium levels, but found no evidence of axonal transport deficits or ER stress. In Chapter 3 I examined the pathomechanism of dHMN due to a novel mutation in FBXO38. FBXO38 modulates the transcriptional activity of KLF7; a transcription factor with a role in neuronal development and repair. I therefore examined neurite outgrowth in lentivirus-infected primary MNs and demonstrated a reduction in neurite outgrowth in mutant FBXO38 infected MNs. In Chapter 4, I identified a mutation in a new disease gene, BICD2, in a family with a form of DCSMA termed lower extremity dominant SMA. BICD2 is a dynein adaptor protein and using immunoprecipitation I found that two disease mutations in BICD2 increase dynein binding affinity. In Chapter 5, I performed a genetic study of the HMNs and showed that mutations in HSPB1 are the most common cause of dHMN. I also evaluated plasma neurofilament heavy chain (NFH) as a biomarker of disease activity in the inherited neuropathies but was unable to detect a difference between patients and healthy volunteers. This would suggest that plasma NFH levels are not a suitable biomarker of disease activity in the inherited neuropathies.

Multiple system atrophy is a sporadic neurodegenerative disorder presenting clinically with parkinsonism, ataxia and autonomic dysfunction in variable combinations. It is clinically and pathologically heterogenous but unified by the key pathological finding of alpha-synuclein containing glial cytoplasmic inclusions. Little is known about the pathogenesis of this relatively newly defined sporadic disease. In this PhD I will present an analysis of different genetic risk factors as in many diseases, in particular neurodegenerative disorders, the study of genetics has revealed important knowledge about the biological mechanisms. As a basis for genetic studies the largest cohort of MSA samples with about 1000 MSA samples was collected as part of this PhD. These samples were then used to investigate common genetic risk factors by performing a genome wide association study (GWAS) and several candidate genes - namely MAPT, Pink1, Parkin and EIF4G1 - known to be involved in similar disorders were screened for mutations. I also collected DNA from one of the few described families with proposed autosomal dominant inheritance and performed exome sequencing, thus screening this family genome-wide for coding mutations. I then went on to study clinically or pathologically related disorders. In the genetically very heterogeneous group of hereditary ataxias new genomic technologies were shown to rapidly diagnose two families with SCA14 and SCA20, the latter being the second family of SCA20 described to date. Finally, genetic variants in the SNCA gene known to be involved in PD and MSA were investigated in a cohort of Dementia with Lewy Bodies cases.

This thesis examines how the human brain translates decisions between differently valued outcomes into the ensuing motor responses. Our work resides at the interface between two fields of study, value-based decision making and action selection, which have been regarded as one process by some and considered entirely separate by others. But the underlying neuro-anatomical substrates likely depend on the exact type of choice we face. We conduct a series of studies to specifically explore the temporal relationship of value-comparison and motor preparation, the regions at the interface between abstract choice and action, and the integration of both action-related and abstract reward information for computing a choice. In the first study, we exploit the high temporal resolution of transcranial magnetic stimulation (TMS) to show that primary motor cortex (M1) receives continuous updates about a decision process. Critically, this argues against a serial processing of decision and action. The second study uses TMS to probe trial-by-trial variability as a marker of motor preparation in M1. We demonstrate that during choice processing, a decrease in variability prepares M1 to issue a motor response. The third experiment uses functional magnetic resonance imaging (fMRI) to investigate brain regions and functional interactions that mediate the transformation of abstract choice signals into action commands. We propose a role for intraparietal cortex as one of the critical interfaces between value-decisions and actions. In the final two studies, we examine decisions that require integrating reward and physical effort, an action-related cost. We propose a behavioural model for the impact of effort costs on reward valuation and use fMRI to show that the comparison of rewards tied to efforts is mediated by a region in anterior cingulate cortex. Collectively, these studies reveal some of the neuro-anatomical substrates and inter-regional interactions that enable the brain to translate value-decisions into actions.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer’s disease (AD). There exists a paucity of quantifiable, sensitive, and specific biomarkers to detect this disease and track its manifestation and progression. The primary aim of this thesis was to develop and investigate new biomarkers for FTD, and focused on the examination of neuropsychological biomarkers in the behavioural variant of FTD (bvFTD) and their neuroanaotmical correlates. Chapters 4 and 5 explored social cognition in patients with FTD and the neural correlates of this behaviour. bvFTD patients displayed gross dysfunction in the perception of sarcasm and the ability to understand basic social signals, and this mapped onto a larger social cognition neural network that has previously been defined in the literature. These findings delineate a brain network substrate for the social impairment that characterises FTD syndromes. In Chapters 6 and 7, I explored the executive functions of task switching, reaction time, and neural timing in patients with FTD. Results indicated several dissociable executive capacities, which mapped onto discrete neural areas as part of a larger executive function network, suggesting that structures implicated in aspects of executive functioning can be targeted by FTD and may underpin aspects of the bvFTD phenotype. In the final Chapter, I devised a novel battery to examine the bases of psychosis in FTD patients with the C9ORF72 mutation, which demonstrated a specific and unique impairment in the ability to interpret somatosensory proprioceptive information in these patients, which may represent a candidate mechanism for psychosis. The studies described in this thesis contribute to the growing interest in characterising and understanding the neuropsychological phenotypes of bvFTD. Improved understanding of the anatomical associations of neuropsycholgical performance in this patient population could potentially facilitate earlier and more accurate diagnosis and symptom management.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Although most cases of PD are sporadic, 5-­‐10% are genetically inherited. The identification of genes associated with PD has enabled the dissection of molecular pathways implicated in the pathogenesis of the disease. A number of these genes encode mitochondrial proteins or proteins with a function in mitochondrial quality control, responsible for maintaining mitochondrial integrity and cellular homeostasis. Disease-­‐ associated mutations have shown to disrupt their protective function, associating mitochondrial dysfunction to the pathogenesis of the familial and idiopathic forms of the disease. This thesis investigates the function of PD-­‐associated proteins in mitochondrial quality control and how disease-­‐associated mutations contribute to mitochondrial dysfunction. Biochemical and live imaging techniques were used to assess the protective role of HtrA2 in mitochondria. Similar approaches were applied to investigate the effect of other PD-­‐ associated proteins on mitochondrial maintenance, and in particular, the mitochondrial localisation and function of Fbxo7. Results from this study revealed that upon activation of the p38-­‐cell-­‐stress pathway, phosphorylation of HtrA2 by CDK5 mediates a mitochondrial stress-­‐response necessary to maintain mitochondrial function. Fbxo7 was shown to translocate to mitochondria and, together with PINK1 and Parkin, mediate the selective autophagic clearance of depolarised mitochondria. Fbxo7 was shown to play a role in maintaining mitochondrial metabolism, as Fbxo7 deficient cells exhibit complex I deficiency combined with reduced maximal respiratory capacity and ATP content. PARP inhibitor restored respiration driven through complex I, suggesting that metabolic defects in Fbxo7 deficient cells are caused by PARP overactivation. Fibroblasts from PD patients carrying mutations on Vps35 or DJ-­‐1 exhibit increased Mfn1/2 levels, suggesting a possible effect on regulating Mfn expression and/or degradation. These results contribute to our understanding of the mitochondrial role of PD-­‐related proteins and help to explain why defective quality control mechanisms lead to mitochondrial dysfunction in PD.