Nuclear magnetic resonance (NMR) of small samples and nuclei with a low gyromagnetic ratio is intrinsically insensitive due to the received signal dependence on Boltzmann's statistics. This insensitivity can be partially overcome through the application of hyper polarisation techniques such as Dissolution Dynamic Nuclear Polarisation (D-DNP). It is hoped that the hyper polarised 13C signal received from labelled small molecules could facilitate imaging of metabolic and transporter processes in biological systems. In order to realise this, appropriate molecules and experimental hardware must be used. A detailed description of the experimental set-up used for carrying out DDNP is given and the system is characterised. the advantageous use of a dual iso-centre magnet system is elucidated with optimisation of acquisition of fast relaxing molecules. such a system allows for interrogation of processes with short relaxation times, not possible with traditional, stand-alone polarisers. To acquire the maximum amount of hyper-polarised 13C signal in an imaging experiment, parallel acquisition techniques have been implemented and the hardware designed with such goals in mind. Multiple coils have been used to allow accelerated image acquisition. As such this work has validated the SENSE algorithm for artefact free, image reconstruction on the micro-scale. These techniques require an array of coils which add to the complexity of the design of the probehead. Decoupling methods and array coil construction must be considered the methods used to ensure well isolated coils, such as geometric decoupling, are presented. The novel fabrication and implementation of micro-coils for imaging and spectroscopy of nL scale samples is presented this will help facilitate the acquisition of images showing metabolic processes in active transport in cells. By placing the coils close to the sample it is possible to gain sensitivity relative to the mass of the sample in question. To achieve signal detection on the order of nL a novel, exible micro-coil array has been fabricated and the results of NMR experiments carried out on both protons and 13C are shown. This is the final stage before integrating the coils with the D-DNP system. The acquisition of 13C signal with the micro-coils displays optimal electronic characteristics when compared with other detectors presented in the literature. The final goal of the work is to produce a system that is capable of micro imaging in small biological samples such as the Xenopus Oocyte with a view to monitoring metabolic processes and transportation without the need for the use of the large fluorescing proteins (GFP's) that have been used in previous work (1). The need for GFP's attached to metabolites results in the measured data being non-physical as the fluorescing protein is often much larger than the molecule being transported. It is hoped that the use of hyperpolarised small molecules (such as pyruvic acid) may be able to remove this need for GFP's in the study of metabolite transportation.

Although NMR is a versatile technique, the low values associated with nuclear spin polarization provide inherently weak signals. A novel system to perform temperature-jump dynamic nuclear polarization (DNP) has been designed and developed at the University of Nottingham, with the aim to enhance this signal and improve the sensitivity of the NMR experiment. This system utilizes a bespoke helium flow cryostat, located within the bore of a superconducting magnet, to achieve temperatures down to 1.75 K for high levels of polarization to build up on an electron spin population. This high level of polarization can then be transferred to a nuclear species of interest using microwave irradiation, while remaining at low temperature, allowing the weak signals associated with NMR to become enhanced. Following ample nuclear polarization build-up, a powerful mid-IR laser is used to rapidly bring the sample to 300 K, ensuring the spectra benefit from the line narrowing associated with liquid-state NMR. An Er:YAG laser with a wavelength of 2.94 μm has been chosen for this as it couples energy directly into the vibrational modes of hydroxyl groups present within the sample. The rapid heating mechanism underpins the success of this experiment twofold. Firstly, performing the temperature-jump in a shorter time period preserves a greater signal enhancement. This needs to be done carefully as too much heating will obliterate the sample, destroying the signal. Secondly, a temperature-jump without dilution of the sample, as occurs in dissolution DNP, allows sample recycling to take place. This opens the technique up for otherwise unavailable applications, such as multidimensional correlation spectroscopy with repetitive excitations. Development of the cryo-system, heating mechanism and NMR probe, alongside preliminary experiments and calculations, suggest that this technique should greatly improve the sensitivity of the liquid state NMR experiment.

Inaug.-Diss.--Cologne. / Vita. Bibliography: leaves iv-viii.

In this thesis, new acquisition and analysis methods are described for multinuclear magnetic resonance spectroscopy (MRS) for the quantification of brain metabolites at ultra high magnetic field strengths (7T). An analytical model was derived for the optimisation of the stimulated echo acquisition mode (STEAM) sequence timing parameters for lactate detection. The effects of the chemical shift displacement artefact on the J-modulated signal for a weakly-coupled spin system were considered in the three applied directions of field gradients and the product operator formalism was used to obtain expressions for the signal modulation in each compartment of the excited volume. The validity of this model was demonstrated experimentally in a phantom and acquisitions with optimised parameters were performed on a healthy volunteer. The spectra acquired with an echo time (TE) of 144 ms and with an optimised mixing time and TE of 288 ms showed easily detectable lactate peaks in the normal human brain. Additionally, the acquisition with the longer TE resulted in a spectrum with less lipid/macromolecular (MM) contamination. The simulations demonstrated that the proposed analytical model is suitable for correctly predicting the resulting lactate signal. With the optimised parameters, it was possible to use a simple sequence with sufficient signal-to-noise ratio (SNR) to reliably distinguish lactate from overlapping resonances in a healthy brain at ultra high-field. Estimation of metabolic changes during neuronal activation represents a challenge for in vivo MRS, especially for metabolites with low concentration and signal overlap, such as lactate. This thesis also includes work focused on the reliable quantification of lactate during a paradigm with 15 minutes of visual stimulation. The lipid and MM signals were significantly reduced by using a long TE (144 ms) sequence and the remaining MM signals in the vicinity of the lactate peak were individually fitted with simulated Lorentzian peaks, to ensure a good fit of the inverted lactate doublet. Statistically significant changes in lactate (~10%) and glutamate (~3%) levels during stimulation were detected in the visual cortex and agree with previous measurements. Furthermore, the use of a prolonged stimulation period unveiled a distinctive metabolic response pattern, which can provide further insight into brain activation mechanisms. 13C MRS combined with the infusion of labelled substrates is able to provide unique information on the relationship between neuroenergetics and brain function. However, the lack of sensitivity associated with the general complexity of 13C experiments has hampered its widespread use for research into human brain disease. In this study, a new methodology for acquisition and analysis of 13C signal is presented for the study of neuroenergetics and neurotransmission in a deep brain structure - anterior cingulate cortex - that is thought to play a major role in the processing of sensory information and can be impaired in patients with schizophrenia. In vitro testing was performed to evaluate the performance of the implemented sequence for signal localisation and polarisation transfer, both proving adequate for the intended purpose. In vivo data were acquired in four subjects, one diagnosed with early schizophrenia, with a protocol which involved 60 minutes of infusion of [1-13C]glucose. Turnover curves for the labelled products were generated from the dynamic 13C spectra with a temporal resolution of 10 minutes and were in agreement with the ones obtained from rodent experiments. Therefore, the feasibility of 13C experiments for the study of psychosis was here demonstrated, taking advantage of the increase in SNR at ultra high-field for determination of metabolic fluxes.

The regulation of atomic energy has had a long and unique history in the United States and it is the effectiveness of that regulation which poses the problem analyzed here. Government documents and secondary sources are used to provide data and critical opinion about atomic energy regulation. The first chapter deals with the history of the earliest attempts to deal vith atomic energy while the second chapter is concerned with the political nature of the Atomic Energy Commission (AEC). Questions o secrecy and potential environmental danger from the nuclear enterprise are topics for the third and fourth chapters respectively. A concluding chapter indicates the future direction the regulation of nuclear power may take under the newly established Nuclear Regulatory Commission and the Energy Research and Development Administration.

This thesis describes the development and application of novel techniques to reduce the EEG artefacts at source during the simultaneous acquisition of EEG and fMRI data. The work described in this thesis was carried out by the author in the Sir Peter Mansfield Magnetic Resonance Centre, School of Physics & Astronomy at the University of Nottingham, between October 2010 and January 2013. Large artefacts compromise EEG data quality during simultaneous fMRI. These artefact voltages pose heavy demands on the bandwidth and dynamic range of EEG amplifiers and mean that even small fractional variations in the artefact voltages give rise to significant residual artefacts after correction, which can easily swamp signals from brain activity. Therefore any intrinsic reduction in the magnitude of the artefacts would be highly advantageous, allowing data with a higher bandwidth to be acquired without amplifier saturation, and facilitating improved detection of brain activity. This thesis firstly explores a new method for reducing the gradient artefact (GA), which is induced in EEG data recorded during concurrent MRI, by investigating the effects of the cable configuration on the characteristics of the GA. This work showed that the GA amplitude and its sensitivity to movement of the cabling is reduced by minimising wire loop areas in the cabling between the EEG cap and amplifier. Another novel approach for reducing the magnitude and variability of the artefacts is the use of an EEG cap that incorporates electrodes embedded in a reference layer, which has a similar conductivity to tissue and is electrically isolated from the scalp. With this arrangement, the artefact voltages produced on the reference layer leads are theoretically similar to those induced in the scalp leads, but neuronal signals are not detected in the reference layer. Therefore taking the difference of the voltages in the reference and scalp channels should reduce the artefacts, without affecting sensitivity to neuronal signals. The theoretical efficacy of artefact correction that can be achieved by using this new reference layer artefact subtraction (RLAS) method was investigated. This was done through separate electromagnetic simulations of the artefacts induced in a hemispherical reference layer and a spherical volume conductor in a time-varying magnetic field and the results showed that similar artefacts are induced on the surface of both conductors. Simulations are also performed to find the optimal design for an RLAS system, by varying the geometry of the system. A simple experimental realisation of the RLAS system was implemented to investigate the degree of artefact attenuation that can be achieved via RLAS. Through a series of experiments on phantoms and human subjects, it is shown here that RLAS significantly reduces the GA, pulse (PA) and motion (MA) artefacts, while allowing accurate recording of neuronal signals. The results indicate that RLAS generally outperforms the standard artefact correction method, average artefact subtraction (AAS), in the removal of the GA and PA when motion is present, while the combination of RLAS and AAS always produces higher artefact attenuation than AAS alone. Additionally, this work demonstrates that RLAS greatly attenuates the unpredictable and highly variable MA that are very hard to remove using post-processing methods.

Hyperpolarisation encompasses a multitude of methods to increase the species' spin polarisation for nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) applications. Hyperpolarised 129Xe is produced via spin-exchange optical-pumping (SEOP). Firstly, electronic spins of alkali metal vapour are polarised via absorption of circularly polarised light. Alkali metal polarisation is subsequently transferred to noble gas nuclei via collisions. Within this thesis, the SEOP process is examined by probing the kinetics of the 129Xe polarisation build up. A combination of diagnostic techniques are used including low field NMR to measure 129Xe polarisation (PXe) at different spatial positions, near-IR optical absorption to give a global estimate of the alkali metal polarisation, and in situ Raman spectroscopy to spatially monitor the energy transport processes by detecting the internal gas temperatures (TN2). TN2 values were found to be dramatically elevated above oven thermocouple readings, with observations of up to 1000 K for an oven heated to only 400 K. Internal gas temperatures are presented for the first time along the length of the optical cell, showing spatial temperature and PXe variations during steady state and rubidium runaway conditions. Two contrasting methods of Raman spectroscopy are examined: a conventional orthogonal arrangement of detection and excitation optics, where intrinsic spatial filtering of the probe laser is utilised; and a newly designed inline module with all components in the same optical plane. Optical filtering is used to reduce the Rayleigh scattering and the probe laser line. This new inline device is presented herein and has a 23 fold improvement in signal to noise enabling increased accuracy and precision of `real-time' temperature monitoring. Rubidium, caesium and a rubidium/caesium hybrid are compared as the alkali metal of choice in the SEOP process. Caesium has a higher spin-exchange cross-section with 129Xe, thus a system is envisaged where current Rb D1 lasers in many polarisers can be utilised with a Rb/Cs hybrid to gain improvements in polarisation rates or levels. Xenon polarisations are shown up to 50% for a hybrid cell. Finally, preparatory experiments crucial to the imminent lung imaging study are presented, including measurements of PXe at low and high magnetic fields. In addition, polariser technology is examined including the current Nottingham device and an open-source consortium polariser.

This thesis is intended to contribute to a quantitative understanding of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in order to increase its clinical potential. Here, the vascular, neuronal and physical processes which combine to give a resulting BOLD signal are investigated using respiratory challenges. The effect of isocapnic hyperoxia on vascular responses is investigated at 7 Tesla. No significant change was found in resting-state cerebral blood flow (CBF), resting-state cerebral blood volume (CBV) and task-evoked CBF. This challenges a previously held idea that hyperoxia is vasoconstrictive. The effect of isocapnic hyperoxia on neuronal oscillations was assessed with magnetoencephalography (MEG). Whilst a significant reduction in oscillatory power is reported in the occipital lobe, the change is significantly smaller than the global reduction previously measured with hypercapnia. These findings suggest that hyperoxia is an ideal tool for calibrated BOLD fMRI. The relationship between the change in blood oxygenation and change in transverse relaxation plays a key role in calibrated BOLD fMRI. However, previous measurements have been confounded by a change in CBV. Here, the relationship was found to be sub-linear across 1.5, 3 and 7 Tesla. Previous results which suggest a supralinear relationship at 1.5/3 Tesla and a linear relationship at 7 Tesla, are attributed to the relative contribution of intravascular/extravascular signals and their dependence on field strength, blood oxygenation and echo time. Finally, a comparison of single and multiphase ASL is made at 7 Tesla, with a modified Look-locker EPI sequence presented which allows simultaneous measurement of CBF and transit time, whilst increasing the available BOLD signal. This could have important implications for hypercapnia calibrated BOLD fMRI, where choice of ASL sequence may affect the estimated change in CMRO2. Furthermore, it provides a framework for future cerebral haemodynamic studies where simultaneous measurements are required.

Foetal MRI represents a non-invasive imaging technique that allows detailed visualisation of foetus in utero and the maternal structure. This thesis outlines the quantitative imaging techniques used to investigate the effect of maternal diabetes and maternal smoking on foetal development at 1.5 Tesla. The effect of maternal diabetes on placental blood flow and foetal growth was studied. The placental images were acquired using Echo Planar Imaging and blood flow was measured using Intra Voxel Incoherent Motion. The results indicate that peak blood flow in the basal plate and chorionic plate increases across gestation in both normal and diabetic pregnancies. Conversely, diffusion in the whole placenta decreases across gestation, with a more pronounced decrease in diabetic placentae. Following this, a method was developed to use a Tl weighted fat suppressed MRI scan to quantify foetal fat images in-utero. In addition, HAlf Fourier Single-shot Turbo spin Echo (HASTE) and balanced Fast Field Echo (bFFE) were used to acquire images encompassing the whole foetus in three orthogonal planes. These scans were used to measure foetal volume, foetal length and shoulder width. The data shows that foetal fat volume and intra-abdominal fat were increased in foetuses of diabetic mothers at third trimester. The HASTE and bFFE sequences were also used to study the effect of maternal smoking on foetal development. Here, foetal organ volumes, foetal and placental volume, shoulder width and foetal length were measured using a semiautomatic approach based on the concept of edge detection and a stereological method, the Cavalieri technique. The data shows that maternal smoking has significant negative effect on foetal organ growth and foetal growth, predominantly foetal kidney and foetal volume. The work described here certainly has a great potential in non-invasive assessment of abnormal placental function and can be used to study foetal development.

The inflationary paradigm of standard big bang cosmology provides a mechanism to generate primordial curvature perturbations and explain the large scale homogeneity and isotropy of the observable universe. This is achieved through requiring a period of accelerated expansion during the early universe and requires a deep understanding of particle physics for its correct formulation. With the emergence of string theory as a potential description of a fundamental laws of nature provides a the natural framework in which we can construct realistic models of inflation seems plausible. A common feature of string theories is the requirement of extra dimensions and, in the absence of a complete formulation of the theory, it is necessary to dimensionally reduce the theories to give a 4d effective theory. String compactifications provide a promising approach through which this can be done. However compactifications lead to the generation of a large number of massless scalar fields (moduli) which would mediate unobserved 'fifth forces'. Methods of stabilising these fields give rise to exponentially flat potentials which provide the means of obtaining inflation quite naturally. In the introductory chapters a review of Type IIb flux compactifications gives methods to stabilise the complex structure moduli and dilaton through the use of fluxes. In order to stabilise the Kähler moduli additional non perturbative corrections to the superpotential are required. We introduce the well know class of meta stable de Sitter string vacua obtained when such corrections are included. An additional class vacua at large volume are discussed, these are found when leading order perturbative corrections to the Kähler potential are also considered. The large volume vacua are then shown to give rise to a model of inflaton using a Kähler modulus as an inflaton field. We show that there exists a large class of inflationary solutions corresponding to a constant volume V of the compactification manifold. In a second chapter on this inflationary model the existence of a basin of attraction for inflation with a constant volume is described. We also find a larger class of inflationary solutions when we evolve the axionic components of the Kähler moduli and the phenomenological aspects are discussed. We finally review the standard slow roll analysis and discuss its use in multiple field inflationary models. We introduce two multiple field extensions to the standard single field slow roll approach. We proceed with an investigation into the suitability of the multiple field slow roll approaches in predicting the slow roll footprint of Supergravity models of inflation. This is achieved through comparing the results with single field results and numerical simulation data when more complex models are considered.