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Calibrated funclional magnetic resonance (MRl) has received growing interest in recent years, becoming recognized as a viable technique for quantitatively examining both the cerebral blood flow (CBF) and oxygen metabolism (CMRO2) changes associated with neural activation. It offers a relatively novel approach for examining the physiological effects of ageing and disease in the brain, which if measured by the blood oxygen level dependent (BOLD) signal alone, may be difficult to interpret, Traditionally, a hypercania calibration technique involving the inhalation of a carbon dioxide gas mkture during arterial spin labellmg (ASL) MRI scanning has seentlie method of choice. However, other techniques such as breath-hold induced hypercapnia, and the comparatively new hyperoxia calibration technique involving the inhalation of high concentration oxygen gas, have also been explored as viable alternatives.

Background: In recent years, structural magnetic resonance imaging (MRI) studies have shown dramatic age-associated changes in grey matter volume, density and cortical thickness. Calibrated functional magnetic resonance (fMRI) has become a recognized technique for quantifying both the cerebral blood flow (CBF) and oxygen metabolism (CMR02) changes associated with neural activation. It has been used as an advanced approach for examining the physiological effects of age-related changes in the brain, which may be difficult to interpret if measured by the blood oxygen level dependent (BOLD) signal alone. fMRI studies of aging have revealed increased BOLD response to tasks of executive' function with advancing age, which is generally interpreted as increased neural activity. However, changes in the cerebrovascular system with age can alter the BOLD/signal, complicating this interpretation. Arterial spin labeling (ASL) allows simultaneous acquisition of BOLD and CBF information and can be used to quantify the component parts of the BOLD signal. Aims: Hyperoxia calibration was applied during fMRI to study neurovascular alterations and correlations with age. We aimed: (1) address if age-related differences in the BOLD signal develop from age-related neural plasticity or age-related cerebrovascular changes during a cognitive Stroop task. (2) Understand the underlying physiology of the BOLD signal change that is seen with aging. (3) Determine regional variation in physiological changes with age. (4) Determine regional changes in grey matter density and cortical thickness with increasing age. (5) Assess the impact of this structural change on physiological change. Methods: We used calibrated fMRI approach in 55 healthy participants over an age range of 18-71 years to determine the relative vascular and neuronal contributions to the age-related BOLD changes in response to a Stroop task. We analysed the structural data with the new VBM-DARTEL technique. The cortical thicknesses were analysed using the FreeSurfer tools. Results: The BOLD response increased significantly with increasing age but the CBF response did not alter, such that the BOLD increase is attributed to a significant reduction in CMRO2 response with increasing age. Hence, in this study, the BOLD increase with age should be interpreted as a reduction in neural activity, which would be consistent with neurodegeneration. The greatest BOLD increases with age were found in left and right medial frontal gyri and primary motor cortex and were again linked to a reduction in CMRO2• Age-related decline in grey matter density and cortical thickness were widespread, but the frontal regions, in general, exhibit greater thickness changes than parietal, temporal and occipital. The strongest correlations between age and (BOLD activations, grey matter density, cortical thickness) were found mainly in the frontal cortices. The cortical structure-function relationships are different for each sex. Finally, better performance had been observed to be associated with larger frontal grey matter density and thicker cortex on some executive tasks, and increased frontal CMRO2 response. Conclusions: This study demonstrates the relationship between structure, function, and cognition, as well as the need to take into account alterations in vascular-metabolic coupling and resting blood volume when interpreting changes in the BOLD response with aging. It also highlights the added benefit that calibrated fMRI offers in terms of interpreting the underlying physiological changes that give rise to the measured BOLD response.

The representation of stimuli within the human brain is a core, unresolved issue in Neuroscience. Invasive methods of investigation are not generally suitable for. use on healthy human subjects and so the main methods of investigation have been those using non-invasive imaging techniques including Magnetoencephalography (MEG). This thesis examines the analysis of MEG data using a spatial filtering approach known as beamforming.

Influential models highlight that insular cortex integrates cognitive, affective, sensorimotor and autonomic signals to create unified perceptual experiences or "feeling states". One challenge in developing a satisfactory neuropsychological model of insula function is to account for its involvement across these different domains which require access across multiple functional circuits. This thesis combines behavioural, psychophysiological, functional neuroimaging and lesion methods to inform and extend current models of integration in the insula. In the first two experimental chapters, the integration of cognitive and emotional signals in risky decision making and autonomic regulation and feedback are investigated. In the final two experimental chapters the role of the insula in combining sensory information in the creation of perceptual illusions is explored. I find that the insula mediates urgent decision making, that damage to the insula can disrupt integrative processes in the context of multisensory integration and that the affective elements of synaesthetic illusions are associated with insula engagement. Together these findings shape our understanding of how the insula acts to integrate signals across different contexts and make an important and novel contribution in the development of a potentially unitary account of insula function.

Medium Spiny projection neurons, the sole output neurons of the striatum, are connected by GABAergic synapses. Such connections are classically assumed to be inhibitory, thus it has been suggested that one of the main functions of the striatum is to detect and classify cortical representations of sensory events to trigger appropriate motor responses through a winner-take-all network dynamic.

The focus of this thesis falls upon three different compounds (two related to cellular toxicity and one to cellular protection) and their effects in hippocampal culture.  Aluminium (A1) is controversially associated with neurodegenerative diseases such as Alzheimer’s Disease (AD).  Beta-amyloid (β A), the main constituent of senile plaques characteristic of AD, develops into its most toxic form upon aggregation with A1.  Cannabidiol (CBD), on the other hand, is a non-psychotropic constituent of marijuana implicated as a potential neuroprotectant.  The discovery of the endocannabinoid (e CB) system has dramatically accelerated the field of CB research. Intracellular Ca²⁺ ([Ca²⁺]_i) homeostasis and signalling in cultured hippocampal neurones were monitored using the Ca²⁺-sensitive fluorescent dye Fura-2 AM and microscopic time-lapse imaging techniques.  Cell survival studies were conducted and visualised using cell-death markers with fluorescent and confocal laser scanning microscopy. The potencies of two novel organic Al citrate salts were ascertained and compared to an inorganic A1 (in HC1) solution.  All treatments exerted toxicity in a dose-dependent manner within the concentration range tested, with neurones exhibiting greater sensitivity than glia.  Since Al facilitates βA aggregation, the two were applied in combination, however, they did not demonstrate obviously facilitated responses compared to individual application. CBD induced a clear [Ca²⁺]_I rise that partially required L-type voltage-gated Ca²⁺ channels and release from intracellular stores, possibly via ryanodine receptor-regulated Ca²⁺-induced Ca²⁺ release.  The CBD response was independent of antioxidant, phospholipase C and characteristic CB receptor pathways, however, their blockade facilitated the response, suggesting that an endogenous CB tone exists, to which the CBD mechanism may be negatively coupled.

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Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that have been implicated in a variety of brain functions as well as pathological states. In the Mppocampus, nAChRs appear to modulate both excitatory and inhibitory circuits. The numerous subunits that make up nAChRs result in a great diversity of functional receptors, equipping them with different pharmacological and biophysical properties. It has recently been found that certain forms of epilepsy may arise from mutation in the genes responsible for encoding of nAChR subunits. Moreover, many reports have shown that high doses of nicotine induce seizures in animals, which are blocked by different nAChR antagonists. However, the mechanism underling the role of nAChRs in patterning epileptiform activity is poorly understood. This project aims to establish the role that nAChRs may play in experimental models of epilepsy and to assess whether pharmacological agents acting at these receptors might represent a novel avenue for developing future anticonvulsants. To assess the possible modulatory influence of nAChRs on epileptiform activity, a range of nAChR ligands were applied during experimentally induced epileptiform activity in hippocampal slices prepared from wistar rats (2-6 weeks). Extracellular recordings were obtained in the stratum pyramidale of the area CAS (n=280). Initial experiments investigated the effects of nAChR ligands on 4-aminopyridine (4AP)-induced epileptiform activity. The work presented in the rest of the thesis was focused to establish the mechanisms by which nAChRs mediate their pro-epileptogenic actions. This study demonstrates that nAChRs regulate epileptiform discharges generated by a number of different pharmacological manipulations. The cellular mechanisms generating each pattern of epileptiform activity are quite distinct involving complex interactions between synaptic and non-synaptic elements of different neuronal circuits. Since nAChRs produce a similar phenotype of modulation in each epileptiform model it is possible that nAChRs target a common cellular mechanism that is prevalent in each model and which mediates the increase in burst frequency in these models.

Currently 7-8% of all babies born in the UK are born preterm and the incidence has increased significantly over the past two decades. Improving medical care has led to increased survival in those born prematurely; however, preterm infants carry a profound risk of severe neurological disabilities along with a spectrum of major deficits across several domains including cognition, attention, coordination and behaviour. These wide-ranging and long-term consequences represent a significant burden to health and education services, yet the aetiology of the most prevalent cognitive and behavioural disorders remain unclear. Magnetic resonance imaging provides the means to quantitatively assess cerebral growth and development and is being increasingly employed to study the developing preterm brain. Evidence from neonatal imaging studies has revealed a number of specific cerebral alterations present in the preterm population that appear to predict neurodevelopmental outcome in early childhood and include diffuse microstructural disturbances of the developing white matter and regional volumetric tissue losses. In addition, a number of perinatal risk factors have been identified that are associated with both preterm birth and altered cerebral development. This thesis aims to test the hypothesis that connectivity and growth of developing neural systems are adversely affected by prematurity at birth and additionally influenced by specific perinatal risk factors. This is achieved through the application of multi-subject, multi-modal MRI analysis to quantify tissue microstructure and volume alongside novel methods for defining regional connectivity in the developing preterm brain. Evidence is provided that suggests connected neural structures are disturbed in preterm infants resulting in a complex pattern of regional micro- and macrostructural alteration that is evident at term-equivalent age and potentiated by respiratory morbidity. This is convergent with current theories of the mechanisms underpinning preterm brain injury and provides further insight into the consequences of preterm birth on brain development.