Investigation of brain tissue water NMR response by optimised quantitative single-voxel proton magnetic resonance spectroscopy

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. 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. 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). 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-alpha 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 T1 and T2 relaxation times of water and the metabolites were measured in the prefrontal grey matter (T1/T2 ± SE = 1574 ± 61/147 ± 6 ms) and bilateral Hippocampi (T1/T2 ± SE; left = 1475 ± 68/178 ± 83 ms, right = 1389 ± 58/273 ± 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 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.