Measurement of brain temperature using magnetic resonance spectroscopic imaging

The study of brain temperature is important for a number of clinical conditions such as stroke, traumatic brain injury, schizophrenia and birth asphyxia (for neonates). A direct method to estimate brain temperature non-invasively will allow assessment of brain thermoregulation and its variation in clinical conditions. Magnetic resonance imaging is a powerful technique widely used for diagnosis of a range of neurological conditions. All magnetic resonance procedures involve manipulation of the hydrogen nuclei in the water molecules of the human body. The resonance frequency of the water molecules is temperature dependent, thus MR thermometry is a powerful tool for non-invasive temperature measurement. Using internal reference MR spectroscopic imaging (MRSI), absolute brain temperature maps can be estimated. However a number of temperature independent factors influence MRSI data acquisition, thus a thorough validation is necessary and is the focus of this PhD study. In this PhD study using phantom (test object) studies it was shown that optimization of the MRSI pulse sequence is necessary to reduce systematic error in temperature maps and extensive in-vitro validation of MRSI temperature mapping was performed. A custom made temperature-controlled phantom was designed for this purpose and is presented in this thesis. MRSI data acquired from healthy (young and elderly) volunteers was employed to assess regional brain temperature variations and repeatability. Finally, the feasibility of employing fast echo planar spectroscopic imaging for volumetric MRSI temperature mapping will be presented in this thesis

A 4D-flow cardiovascular magnetic resonance study of flow asymmetry and haemodynamic quantity correlations in the pulmonary artery

Objective: In this paper we elucidate the asymmetric flow pattern and the haemodynamic quantity distributions and correlations in the pulmonary artery (PA) vasculature in healthy adults having structurally normal hearts, to provide reference on the flow characteristics in the PA and the right ventricle. Approach: Velocity data are acquired non-invasively from 18 healthy volunteers by 4D-Flow magnetic resonance imaging, resolved to 20 phases with spatial resolution 3 × 3 × 3 mm3. Interpolation is applied to improve the accuracy in quantifying haemodynamic quantities including kinetic energy, rotational energy, helicity and energy dissipation rate. These quantities are volumetrically normalised to remove size dependency, representing densities or local intensity. Main results: Flow asymmetry in the PA is quantified in terms of all the flow dynamic quantities and their correlations. The right PA has larger diameter and higher peak stroke velocity than the left PA. It also has the highest rotational energy intensity. Counter-rotating helical streams in the main PA appear to be associated with the unidirectional helical flow noticed in the left and the right PA near the peak systole. Significance: This study provides a fundamental basis of normal flow in the PA. It implies the validity to use these flow pattern-related quantitative measures to aid with the identification of abnormal PA flow non-invasively, specifically for detecting abnormalities in the pulmonary circulation and response to therapy, where haemodynamic flow is commonly characterised by increased vortical and helical formations

The role of flow rotation in the adult right atrium: a 4D flow cardiovascular magnetic resonance study

Objective: In healthy adults, the right atrium (RA) serves as a reservoir for the systemic flow return from the superior vena cava (SVC) and inferior vena cava (IVC), preparing the two flows to be transferred to the right ventricle (RV) and pulmonary circulation. This study aims to quantify the haemodynamics of the RA and the associated SVC and IVC inflows, which have not been fully understood to date. Approach: Eighteen adults with structurally normal hearts underwent 4D flow magnetic resonance imaging. The cardiac cycle was resolved to 20 temporal phases with a spatial resolution of 3x3x3mm3. Analysis included objective visualisation of the flow structures in the RA identified by three different vortex identification criteria, kinetic energy (KE), enstrophy and dissipation. KE and helicity flux were also assessed in both caval veins. Main results: Vortex identification methods confirmed that in the majority of subjects the blood flow from the caval veins filling the RA during ventricular systole is not chaotic, but rather forms an organised pattern of a single coherent forward turning vortex structure. Thirteen subjects displayed a single vortex flow structure, four showed multiple vortices and one had a helical flow pattern without a clear vortex structure. A strong positive correlation exists between the flow KE and enstrophy density. Significance: This suggests that flow energy in the RA is mainly rotational, part of which is convected by the highly helical SVC and IVC inflows. Multiple vortices tend to be associated with higher dissipation rates in the central RA region due to turbulence. The rotational nature of the flow in the RA maintains KE better than non-rotational flow. RA flow characteristics are highly related to the helicity content in the caval veins, as well as the KE flux intensity. Lower caval helicity or IVC KE flux dominance tends to favour single vortex formation while the opposite tends to lead to multiple vortices or the rare helical flow patterns. Atria lacking single vortex flow are inclined to have a larger energy input from atrial contraction

Investigation of structural brain changes in Charles Bonnet Syndrome

Background and objectives In Charles Bonnet Syndrome (CBS), visual hallucinations (VH) are experienced by people with sight loss due to eye disease or lesional damage to early visual pathways. The aim of this cross-sectional study was to investigate structural brain changes using magnetic resonance imaging (MRI) in CBS. Methods Sixteen CBS patients, 17 with eye disease but no VH, and 19 normally sighted people took part. Participants were imaged on a 3T scanner, with 1 mm resolution T1 weighted structural imaging, and diffusion tensor imaging with 64 diffusion directions. Results The three groups were well matched for age, sex and cognitive scores (MMSE). The two eye disease groups were matched on visual acuity. Compared to the sighted controls, we found reduced grey matter in the occipital cortex in both eye disease groups. We also found reductions of fractional anisotropy and increased diffusivity in widespread areas, including occipital tracts, the corpus callosum, and the anterior thalamic radiation. We did not find any significant differences between the eye disease participants with VH versus without VH, but did observe a negative association between hippocampal volume and VH severity in the CBS group. Discussion Our findings suggest that although there are cortical and subcortical effects associated with sight loss, structural changes do not explain the occurrence of VHs. CBS may relate instead to connectivity or excitability changes in brain networks linked to vision

Metabolic effects of bezafibrate in mitochondrial disease.

Funder: Medical Research Council (MRC): Confidence in Concept award to Newcastle UniversityMitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae

Variance components associated with long-echo-time MR spectroscopic imaging in human brain at 1.5T and 3T

<div><p>Object</p><p>Magnetic resonance spectroscopic imaging (MRSI) is increasingly used in medicine and clinical research. Previous reliability studies have used small samples and focussed on limited aspects of variability; information regarding 1.5T versus 3T performance is lacking. The aim of the present work was to measure the inter-session, intra-session, inter-subject, within-brain and residual variance components using both 1.5T and 3T MR scanners.</p><p>Materials and methods</p><p>Eleven healthy volunteers were invited for MRSI scanning on three occasions at both 1.5T and 3T, with four scans acquired at each visit. We measured variance components, correcting for grey matter and white matter content of voxels, of metabolite peak areas and peak area ratios.</p><p>Results</p><p>Residual variance was in general the largest component at 1.5T (8.6–24.6%), while within-brain variation was the largest component at 3T (12.0–24.7%). Inter-subject variation was around 5%, while inter- and intra-session variance were both generally small.</p><p>Conclusion</p><p>Multiple variance contributions associated with MRSI measurements were quantified and the performance of 1.5T and 3T MRI scanners compared using data from the same group of subjects. Residual error is much lower at 3T, but other variance components remain important.</p></div

Proton spectroscopic imaging of brain metabolites in basal ganglia of healthy older adults

Object: We sought to measure brain metabolite levels in healthy older people. Materials and methods: Spectroscopic imaging at the level of the basal ganglia was applied in 40 participants aged 73–74 years. Levels of the metabolites N-acetyl aspartate (NAA), choline, and creatine were determined in "institutional units" (IU) corrected for T1 and T2 relaxation effects. Structural imaging enabled determination of grey matter (GM), white matter (WM), and cerebrospinal fluid content. ANOVA analysis was carried out for voxels satisfying quality criteria. Results: Creatine levels were greater in GM than WM (57 vs. 44 IU, p < 0.001), whereas choline and NAA levels were greater in WM than GM [13 vs. 10 IU (p < 0.001) and 76 versus 70 IU (p = 0.03), respectively]. The ratio of NAA/cre was greater in WM than GM (2.1 vs. 1.4, p = 0.001) as was that of cho/cre (0.32 vs. 0.16, p < 0.001). A low voxel yield was due to brain atrophy and the difficulties of shimming over an extended region of brain. Conclusion: This study addresses the current lack of information on brain metabolite levels in older adults. The normal features of ageing result in a substantial loss of reliable voxels and should be taken into account when planning studies. Improvements in shimming are also required before the methods can be applied more widely

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2–Induced Changes for a Randomized Double-blind Controlled Trial

Background:Depression is a significant health and economic burden. In approximately one third of patients, depression is resistant to first line treatments and therefore it is essential that alternative treatments are found. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the UK and the US in treatment resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness and mechanism of action between standard treatment repetitive TMS (rTMS) targeted at the F3 EEG site, with a newer treatment – a type of TMS called theta-burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines the brain imaging acquisition and analysis for the BRIGhTMIND trial that is used to create personalised TMS targets and answer the proposed mechanistic hypotheses.Objective:The objectives of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and cgiTBS and to identify imaging-based markers predicting response to treatment.Methods:The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of a) TBS or b) standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired per participant at baseline (prior to TMS treatment) with T1-weighted and task-free functional MRI during rest (rsfMRI) utilised to estimate TMS targets. For participants enrolled in the mechanistic substudy additional diffusion-weighted, sequences are acquired at baseline and at post-treatment follow-up 16 weeks after treatment randomisation. Core datasets of T1-weighted and task-free functional MRI during rest (rsfMRI) are acquired for all participants and utilised to estimate TMS targets. Additional sequences of arterial spin labelling, magnetic resonance spectroscopy and diffusion-weighted images are acquired dependent on recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex whilst TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from a level of MRI-guidance but only TBS is provided with precision targeting based on functional brain connectivity.Results:Recruitment began January 2019 and is ongoing. Data collection is expected to continue until January 2023.Conclusions:This trial will determine the impact of precision MRI guidance on rTMS treatment, and furthermore, assess the neural mechanisms underlying this treatment in treatment resistant depressed patients. Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN) 19674644; https://www.isrctn.com/ISRCTN19674644. Registered 2nd October 2018

Left ventricular functional, structural and energetic effects of normal aging: Comparison with hypertension.

Both aging and hypertension are significant risk factors for heart failure in the elderly. The purpose of this study was to determine how aging, with and without hypertension, affects left ventricular function.Cross-sectional study of magnetic resonance imaging and 31P spectroscopy-based measurements of left ventricular structure, global function, strains, pulse wave velocity, high energy phosphate metabolism in 48 normal subjects and 40 treated hypertensive patients (though no other cardiovascular disease or diabetes) stratified into 3 age deciles from 50-79 years.Normal aging was associated with significant increases in systolic blood pressure, vascular stiffness, torsion, and impaired diastolic function (all P<0.05). Age-matched hypertension exacerbated the effects of aging on systolic pressure, and diastolic function. Hypertension alone, and not aging, was associated with increased left ventricular mass index, reduced energetic reserve, reduced longitudinal shortening and increased endocardial circumferential shortening (all P<0.05). Multiple linear regression analysis showed that these unique hypertensive features were significantly related to systolic blood pressure (P<0.05).1) Hypertension adds to the age-related changes in systolic blood pressure and diastolic function; 2) hypertension is uniquely associated with changes in several aspects of left ventricular structure, function, systolic strains, and energetics; and 3) these uniquely hypertensive-associated parameters are related to the level of systolic blood pressure and so are potentially modifiable