Mumuni, Abdul Nashirudeen (2013) Investigation of brain tissue water NMR response by optimised quantitative single-voxel proton magnetic resonance spectroscopy. PhD thesis. http://theses.gla.ac.uk/4717/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Investigation of Brain Tissue Water NMR Response by Optimised Quantitative Single-voxel Proton Magnetic Resonance Spectroscopy Abdul Nashirudeen Mumuni B.Sc, M.Sc A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy Department of Clinical Physics College of Medical, Veterinary and Life Sciences University of Glasgow June 2013 © Abdul Nashirudeen Mumuni, 2013 2 Abstract Nuclear Magnetic Resonance (NMR) is a phenomenon in which certain nuclei in the presence of a magnetic field and radiofrequency (RF) radiation emit a certain amount of signal at a frequency equal to that of the RF radiation. Proton Magnetic Resonance Spectroscopy (1H-MRS) is an NMR technique capable of measuring the chemical composition, often referred to as metabolites, of the human body non-invasively and in vivo. It is commonly used as a research tool in the investigation of neurological disorders such as multiple sclerosis, brain tumors, stroke, clinical depression, and schizophrenia. Accurate quantification of the metabolites of interest requires a reference standard of known and fixed concentration. Brain tissue water has been previously reported to have a fairly constant and known concentration, and so has been suggested to be a suitable reference concentration in absolute quantitative 1H-MRS of the human brain. In practice, however, it is challenging to measure the actual tissue water concentration; hence, some studies choose to use estimates of tissue water concentration from the literature. These literature values are usually averages from a healthy study group. There are however indications that brain tissue water content could vary widely in certain disease conditions such as in brain tumors and inflammation. In such situations, absolute metabolite quantification using the literature estimates of tissue water content will be inaccurate while the measurement of cerebral water content using the available techniques will be impractical for the patients due to scanning time considerations. It is therefore necessary to develop a technique that can be used to quantify both the reference water and metabolite concentrations, simultaneously without subject tolerance issues. The main objective of this thesis was to investigate the response of water NMR signal from human brain tissue under various measurement conditions using the single-voxel 1H-MRS technique. As part of the investigation, the thesis also focused on the development of methods for the absolute quantification of cerebral water and metabolite concentrations. 3 A standard 1H-MRS water-suppressed acquisition on the General Electric (GE) MR scanner acquires some unsuppressed-water spectra at the beginning of the PRESS pulse sequence. Using the Spectroscopy Analysis by GE (SAGE) software package (version 7), this thesis developed methods to optimise the unsuppressed-water and suppressed-water signals from which, respectively, cerebral water and metabolite concentrations were estimated. The unsuppressed-water signal response characteristics were investigated in experiments at 3 T that involved: 1) variation of the MRS voxel position over a three-dimensional RF field within an eight-channel head coil; 2) measurement of the relaxation times of brain tissue water using standard saturation recovery and multi spin-echo MRS techniques; 3) measurement of brain tissue water content in peripheral inflammation; and 4) estimation of the BOLD effect on the water spectral peak. The stability of the MR scanner used for all the investigations was assessed. Over the project period, the worst precision measurements of the scanner (for both water and metabolite signals) were observed to be about 12 % and 26 % in serial phantom and human studies, respectively. The MRI/MRS scanner was therefore found to measure water and metabolite signals with good precision, both in vivo and in vitro. By recording the water NMR signal responses at various locations within the phased-array head coil, RF sensitivity profile (voxel position-dependent) equations of the head coil were obtained. The coordinates of any in vivo voxel could be substituted into an appropriate profile equation to estimate an unsuppressed-water signal area that could be used as a reference signal to quantify brain tissue water content. This novel technique of quantifying cerebral water content is superior to the previous techniques of performing multi-echo unsuppressed-water signal acquisitions. The method does not require extra unsuppressed-water acquisitions, or corrections for variations in the sensitivity of the eight-channel head coil as both the in vivo and reference signals are acquired from the same voxel position. 4 Brain tissue water content was subsequently quantified accurately using the newly developed method of referencing. In frontal brain voxels, the average water content, WC of grey matter, GM was found to be higher than that of white matter, WM (GM/WM WC ± SE = 46.37 ± 2.58/42.86 ± 2.46 mol/kg; p = 0.02); parietal voxels also showed a similar comparison (GM/WM WC ± SE = 37.23 ± 1.70/34.14 ± 2.02 mol/kg; p = 0.03). These findings were consistent with previous reports of cerebral water content. For regions of mixed proportions of grey and white matter tissues, the average water contents of each tissue type considered separately (by voxel segmentation) and together were found to compare with literature estimates. Using data from five voxel positions, average brain tissue water content was observed to be uniformly distributed across the human brain by one-way ANOVA (p = 0.60), and did not vary significantly with gender (p > 0.05) and age (p > 0.05). For the first time, cerebral water content was observed in this thesis to remain fairly constant in psoriatic arthritis, a peripheral inflammatory condition (one- way ANOVA, p = 0.63). Among five brain metabolites quantified in the psoriasis patients, only the mean concentration of creatine, Cr was found to be significantly lower in the frontal grey matter voxels of the patients, PsA compared to healthy controls, HC at baseline (PsA/HC ± SE = 6.34 ± 0.38/7.78 ± 0.38 mM/kg; p = 0.01) and post-TNF-a blockade medication (PsA/HC ± SE = 6.69 ± 0.25/7.78 ± 0.38 mM/kg; p = 0.03). None of the metabolite concentrations, including Cr (p = 0.27), changed significantly with medication. The condition of PsA was not observed to affect the mood of the patients, as indicated by their BDI scores. The significant finding of Cr concentration alteration in psoriatic arthritis thus suggests that Cr may not be a reliable denominator in studies of psoriasis that express the metabolite levels as ratios. The T and T relaxation times of water and the metabolites were measured in 1 2 the prefrontal grey matter (T /T ± SE = 1574 ± 61/147 ± 6 ms) and bilateral 1 2 Hippocampi (T /T ± SE; left = 1475 ± 68/178 ± 83 ms, right = 1389 ± 58/273 ± 1 2 98 ms). The relaxation time estimates for the metabolites were in agreement with literature values; relaxation times for water however were measured for the first time in those regions and at 3 T. The measured relaxation times were used to correct the water and metabolite signals for relaxation effects during 5 their absolute quantification, and could as well serve the same purpose in future studies. There is increasing interest in the BOLD response of cerebral metabolites and water during tasks. This thesis thus also assessed changes in brain tissue metabolite and water contents while a subject experienced a visual stimulus. In the presence of the visual stimulus, the BOLD effects on the metabolite and water spectral peaks were found to be comparable, as has been observed in previous studies. For the first time, this thesis further investigated the impact of temporal resolution (determined by NEX) on the amount of the BOLD signal acquired from cerebral water and metabolites. In a single visual activation paradigm, the BOLD effect resulted in increased water peak area which differed significantly between NEX values of 2 and 8 (p < 0.01); this observation also was true for NAA and Glu. The findings thus suggest that temporal resolution of the MRS data could result in significant differences in the results of functional MRS studies. In conclusion, by its detailed investigations of the water signal characteristics and newly developed methods for the absolute quantification of cerebral water and metabolite concentrations, this thesis has corroborated the suitability of the brain tissue water signal as a reference and has also improved on the accuracy of quantitative MRS using the endogenous water signal as a reference standard. The techniques presented in this thesis can thus be applied in future 1H-MRS brain studies where the endogenous unsuppressed-water signal is required. 6 Table of Contents Abstract ............................................................................................................ 2 Table of Contents ............................................................................................. 6 List of Tables .................................................................................................. 15 List of Figures ................................................................................................. 18 Acknowledgements ........................................................................................ 23 Author’s Declaration ....................................................................................... 25 List of Abbreviations/Definitions ...................................................................... 27 Chapter 1: Introduction ................................................................................... 32 1.1 Overview of MR Spectroscopy as Applied in this Thesis ...................... 32 1.1.1 Advances in MR Spectroscopy ....................................................... 32 1.1.2 MR Spectroscopy in Practice ......................................................... 34 1.1.3 Overview and Objective of this Thesis ............................................ 35 1.2 The Role of Water in Neurophysiology .................................................. 38 1.3 The Relevance of Tissue Water in MRI ................................................. 41 1.3.1 Proton Density ................................................................................ 41 1.3.2 Proton Relaxation ........................................................................... 42 1.3.3 Tissue-bound Protons .................................................................... 42 1.3.4 BOLD Contrast ............................................................................... 45 1.4 The Relevance of Tissue Water in MRS ............................................... 46 1.4.1 Reference Standard ....................................................................... 46 1.4.2 MRS Thermometry ......................................................................... 48 1.4.3 Eddy current correction .................................................................. 49 1.4.4 Signal Weighting in Phased-Array Coil Data Combination ............. 51 1.5 Structure and Outline of this Thesis ...................................................... 52 Chapter 2: Background ................................................................................... 54 2.1 Principles of Nuclear Magnetic Resonance ........................................... 54 2.1.1 Origin of the NMR Signal ................................................................ 55 2.1.1.1 Alignment of Magnetic Spins in B ........................................... 55 0 2.1.1.2 Irradiation of the B -aligned Spins with an RF Pulse ................ 57 0 7 2.1.1.3 Generation of the NMR Signal ................................................. 59 2.1.2 Relaxation of the NMR Signal ........................................................ 60 2.1.2.1 T Relaxation ........................................................................... 61 1 2.1.2.2 T Relaxation ........................................................................... 62 2 2.1.2.3 T * Relaxation .......................................................................... 63 2 2.1.3 Methods of Measuring Relaxation .................................................. 64 2.1.3.1 Measurement of T Relaxation Time ........................................ 64 1 2.1.3.2 Measurement of T Relaxation Time ........................................ 67 2 2.2 Principles of MR Spectroscopy ............................................................. 69 2.2.1. Chemical Shift ............................................................................... 69 2.2.2 Spin-Spin Coupling ......................................................................... 71 2.2.3 Water Suppression and MRS Pulse Sequences ............................ 71 2.2.3.1 CHEmical Shift Selective (CHESS) Preparation ...................... 72 2.2.3.2 Point-RESolved Spectroscopy (PRESS) ................................. 73 2.2.3.3 STimulated Echo Acquisition Mode (STEAM) .......................... 75 2.2.4 Types of MRS Localisation ............................................................. 77 2.2.5 Echo Times .................................................................................... 78 2.2.6 Neurohistology, Brain Tissue Water and Metabolites ..................... 80 2.2.6.1 Water ....................................................................................... 81 2.2.6.2 myo-Inositol.............................................................................. 82 2.2.6.3 Choline-Containing Compounds .............................................. 83 2.2.6.4 Creatine ................................................................................... 84 2.2.6.5 Glutamate and Glutamine ........................................................ 85 2.2.6.6 N-Acetyl Aspartate ................................................................... 86 2.2.6.7 Lactate ..................................................................................... 87 2.2.6.8 Lipids and Macromolecules...................................................... 88 2.2.7 Challenges of in vivo MRS ............................................................. 88 2.2.7.1 Static Field Inhomogeneity ....................................................... 88 8 2.2.7.2 Detection Sensitivity ................................................................. 89 2.2.7.3 Solvent Signal .......................................................................... 89 2.2.7.4 Eddy Currents .......................................................................... 90 2.2.7.5 Phase Detection ....................................................................... 91 2.2.7.6 Motion ...................................................................................... 91 2.3 Materials and Methods .......................................................................... 92 2.3.1 Overview of Spectral Analysis ........................................................ 92 2.3.1.1 Spectral Fitting in LC Model ..................................................... 95 2.3.1.2 Spectral Fitting in SAGE .......................................................... 96 2.3.1.3 Quantification of Water-suppressed and Unsuppressed-water Spectra ................................................................................................ 98 2.3.2 Spectral Fitting Software used in this Thesis ................................ 100 2.3.3 The MRI Scanner, Head Coil and MRS Phantom......................... 100 2.3.4 Statistics in this Thesis ................................................................. 101 2.3.5 Ethical Approval of Human Studies .............................................. 103 Chapter 3: Reproducibility Measurements of Water and Metabolites ........... 105 3.1 Introduction and Objectives ................................................................. 105 3.2 Methods .............................................................................................. 107 3.2.1 PRESS versus STEAM ................................................................ 107 3.2.2 Reproducibility Studies ................................................................. 108 3.2.2.1 Phantom Studies .................................................................... 108 3.2.2.2 Human Studies ...................................................................... 109 3.2.3 Spectral Analyses in Reproducibility Studies ................................ 110 3.2.4 Assessment of Reproducibility ..................................................... 111 3.3 Results and Discussion ....................................................................... 111 3.3.1 PRESS versus STEAM SNRs Compared .................................... 111 3.3.2 Reproducibility Results ................................................................. 113 3.3.2.1 In vitro Measurements ........................................................... 113 3.3.2.2 Temperature Effect on in vitro Measurements ....................... 116 9 3.3.2.3 In vivo Measurements ............................................................ 117 3.4 Summary and Conclusions ................................................................. 122 Chapter 4: RF Field Mapping Using the Unsuppressed-Water Signal .......... 124 4.1 Overview and Objectives .................................................................... 124 4.1.1 Absolute versus Relative Quantitative MRS ................................. 125 4.1.2 Internal versus External Referencing ............................................ 126 4.1.3 Spatial Sensitivity of the RF Coil................................................... 128 4.2 Methods .............................................................................................. 129 4.2.1 Sensitivity mapping along the RL axis .......................................... 130 4.2.2 Sensitivity mapping along the AP axis .......................................... 131 4.2.3 Sensitivity mapping along the SI axis ........................................... 132 4.2.4 Sensitivity mapping in the RL-AP plane along the SI axis ............ 132 4.2.5 Data Analysis ............................................................................... 134 4.2.6 Derivation of Sensitivity Maps ...................................................... 135 4.3 Results and Discussion ....................................................................... 135 4.3.1 RF Field Maps along the Principal Axes of the RF Coil ................ 135 4.3.2 Inter-slice RF Field Maps along the SI Axis of the RF Coil ........... 137 4.4 Use of RF Field Maps in Cerebral Water Quantification ...................... 143 4.5 Summary and Conclusions ................................................................. 143 Chapter 5: Corrections for Relaxation and Partial Volume Effects ............... 145 5.1 Overview and Objectives .................................................................... 145 5.1.1 NMR Relaxation Effects ............................................................... 146 5.1.2 Partial Recovery of Longitudinal Magnetisation of Water ............. 147 5.1.3 Partial Volume Effect .................................................................... 149 5.1.4 Objectives ..................................................................................... 151 5.2 Methods .............................................................................................. 152 5.2.1 Measurement of NMR Relaxation Times in the Brain ................... 152 5.2.1.1 Subjects ................................................................................. 152 5.2.1.2 MR Imaging............................................................................ 152