Magnetic Resonance Spectroscopy and its Clinical Applications: A Review

Journal of Medical Imaging and Radiation Sciences

Journal of Medical Imaging and Radiation Sciences xx (2017) 1-21

Journal de l’imagerie médicale et des sciences de la radiation

www.elsevier.com/locate/jmir

Clinical Perspective

Magnetic Resonance Spectroscopy and its Clinical Applications: A Review Reza Faghihi, PhDab, Banafsheh Zeinali-Rafsanjani, PhDac*, Mohammad-Amin Mosleh-Shirazi, PhDcd, Mahdi Saeedi-Moghadam, PhDc, Mehrzad Lotfi, MDc, Reza Jalli, MDc and Vida Iravani, BSce a

Medical Radiation Department, School of Mechanical Engineering, Shiraz University, Shiraz, Iran b Radiation Research Center, School of Mechanical Engineering, Shiraz University, Shiraz, Iran c Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran d Department of Radiotherapy and Oncology, Shiraz University of Medical Sciences, Shiraz, Iran e Department of Radiology, Chamran Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

ABSTRACT In vivo NMR spectroscopy is known as magnetic resonance spectroscopy (MRS). MRS has been applied as both a research and a clinical tool in order to detect visible or nonvisible abnormalities. The adaptability of MRS allows a technique that can probe a wide variety of metabolic uses across different tissues. Although MRS is mostly applied for brain tissue, it can be used for detection, localization, staging, tumour aggressiveness evaluation, and tumour response assessment of breast, prostate, hepatic, and other cancers. In this study, the medical applications of MRS in the brain, including tumours, neural and psychiatric disorder studies, breast, prostate, hepatic, gastrointestinal, and genitourinary investigations have been reviewed.



RESUM E En 1946, Purcell, Pound et Torrey de l’Universit
e Harvard avec et leurs collegues Bloch, Hansen et Packard de l’Universit
e Stanford ont invent
e la r
esonance magn
etique nucl
eaire (RMN). Par la suite, les
etudes en RMN ont men
e a six prix Nobel dans ce domaine. La spectroscopie RMN in vivo est appel
ee spectroscopie par r
esonance magn
etique (SRM) en clinique. La SRM a
et
e utilis
ee autant comme outil de recherche que comme outil clinique pour la d
etection des anomalies visibles ou non. L’adaptabilit
e de la SRM en fait une technique qui peut examiner une grande vari
et
e d’utilisations m
etaboliques dans diff
erents tissus. Bien que la SRM soit principalement utilis
ee pour les tissus c
er
ebraux, elle peut ^etre utilis
ee pour la d
etection, la localisation, la d
etermination du stade, l’
evaluation du caractere agressif d’une tumeur et l’
evaluation de la r
eponse tumorale dans le cancer du sein, de la prostate, du foie et d’autres organes. Cette
etude, apres un bref examen des fondements de la SRM, passe en revue les applications m
edicales de la SRM dans le cerveau, incluant les tumeurs, les applications m
edicales de la SRM, incluant les cancers et l’
etude des troubles neurologiques et psychiatriques, ainsi que les examens du sein, de la prostate, du foie et des systemes gastro-intestinal et g
enito-urinaire.

Keywords: Magnetic resonance spectroscopy; Medical applications; Review

Introduction In 1946, Purcell, Pound, and Torrey from Harvard University, with their colleagues Bloch, Hansen, and Packard from Stanford University, invented nuclear magnetic resonance (NMR). This idea was sparked in 1921 when researchers found that * Corresponding author: Banafsheh Zeinali-Rafsanjani, PhD, Medical Radiation Department, School of Mechanical Engineering, Shiraz University, Shiraz, Iran. E-mail address: [email protected] (B. Zeinali-Rafsanjani).

magnetic nuclei, such as 1H and 31P in a magnetic field with specific power, obtains the ability to absorb radio frequency energy. Immediately after absorption, the nuclei begin to resonate; in this process, different atoms that exist in a molecule resonate at different frequencies. Having the opportunity to observe this event, researchers started to analyse the molecule structures precisely. Since then, NMR has been used for all kinds of materials such as solids, liquids, and gases for kinetic and structural studies. It is worth noting that NMR investigations led to six Nobel prizes in this field [1–9].

1939-8654/$ - see front matter Ó 2017 Canadian Association of Medical Radiation Technologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jmir.2017.06.004

NMR spectroscopy is an instrument that recognizes molecules and is able to specify biophysical features. The principal use of NMR in health centres is to obtain anatomic images of the body using magnetic resonance imaging (MRI). MRI in conjunction with NMR spectroscopy has numerous applications in the clinic and in biomedicine. NMR spectroscopy in the clinic is known as magnetic resonance spectroscopy (MRS). Like its application in chemistry, spectroscopy permits the discovery of tiny molecules in intracellular and extracellular spaces. The achieved spectra provide detailed evidence about metabolic track and its alterations; as a result, MRS can be used to supervise metabolic variations due to disorders and also to assess effectiveness of treatment [10–13]. Initially, MRS was not a routine clinical option for medical imaging, principally because it was not sensitive enough. But, with the arrival of high strength magnetic field scanners, for instance 3 Tesla (T) clinical magnetic resonance (MR) scanners, evolved coils, and enhanced radio frequency pulse designs, sensitivity has been greatly improved. Therefore, in vivo MRS has become a technique that is increasingly applied in the clinic [14]. MR spectra can be procured from several nuclei in the body, such as 1-Hydrogen, 31-Phosphorus, 19-Fluorine, etc. These nuclei can provide precious metabolic and physiologic data. Typically, 1H-MRS is the matter of choice because of the high sensitivity to this nucleus, proper accessibility, and the plentiful existence of hydrogen in a large number of metabolites. The routine clinical magnetic field strengths of MR systems are between the range of 0.2 and 3 T [15, 16]. Unlike MRI, MRS does not commonly produce powerful signals of water and fat, which are ordinarily of interest. In MRS applications, smaller signals stemming from metabolites are more important. Since the signal is too weak, accordingly, a magnetic field with adequate strength is needed. Hence, numerous MRS measurements are accomplished by 1.5 or 3 T MR systems. The field strength of 3 T has some clinical advantages, such as signalto-noise ratio (SNR) increase and an increase in the ability to provide the spectra from smaller voxels [17, 18]. In this article, we present a review of MRS clinical applications following a brief description of MRS terminology. MRS Terminology Considering MRS has its own terminology, which readers should be familiar with before starting the review, some of the special terms have been described below. Several terms may not have been used in the text, but these words may be encountered in the literature. Absorption Spectrum This is the positive-definite or real part of the complex spectrum [19, 20]. Apodization Multiplying the obtained free induction decay (FID) in a slightly varying function, such as exponentially decaying function or Gaussian. Apodization can help to diminish the noisier end of the FID. This procedure may cause peak broadening [19, 20]. 2

Dispersion Spectrum This is the imaginary part of the complex spectrum [19, 20]. Eddy Currents Field gradient pulses can produce currents in the magnetic structure, which can create extra magnetic fields that add to the static field B0. Zero-order eddy currents can produce phase shifts that are frequency dependent, while first-order eddy currents can cause spin dephasing leading to SNR reduction. Just like magnetic inhomogeneities, these currents may cause peak shape distortion and make the interpretation of spectral quantities more difficult [21, 22]. J-Coupling The magnetic field of one nucleus can affect the external magnetic field that is sensed by the adjacent nucleus. This fact stems from binding electrons that are shared between the two coupled nuclei. This causes the spectrum containing the resonance of the coupled nucleus to split into two lines; in the same manner, a doublet of two peaks can be seen (eg, the lactate [Lac] doublet). The coupling constant explains the difference in frequency between the two peaks [23, 24]. Phasing Whenever the initial phase of FID is not zero, the real and imaginary parts of the complex spectrum contain mixtures of absorption and dispersion mode spectra [25, 26]. Phasing is the process by which the spectrum is sorted into the real and imaginary spectra, such that: Absorption ðuÞ ¼ Real ðuÞ cos ðqÞ þ Imaginary ðuÞ sin ðqÞ Dispersion ðuÞ ¼ Imaginary ðuÞ cos ðqÞ þ Real ðuÞ sin ðqÞ

Shimming Shimming is regulating the resolution of the signal by improving the magnetic field homogeneity. The peaks in MRS spectra are very narrow in the way that the full width at half maximum can be just 1 Hz or even less. In order to obtain spectrums with this resolution, the magnetic field should be very homogeneous. Users have to surround the object with a set of shim coils. These coils produce a small magnetic field with a specific spatial profile that can be applied to cancel out the inhomogeneities in the main magnetic field [27, 28]. MRS Basics Routinely, an MRS procedure begins with the acquisition of MR images in order to use them as a guide to indicate the region of tissue where the user needs to assess the spectrum. In single voxel spectroscopy (SVS), a single voxel (volume of tissue) is located in the tumour or in a certain area where the metabolism may be damaged as a result of patient disease. Another technique of MR spectroscopy is magnetic resonance spectroscopic imaging (MRSI), also known as chemical shift imaging [29]. In this

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Figure 1. A, Localization gradients and SVS localization technique; B, STEAM sequence; C, PRESS sequence [38]. PRESS, point-resolved spectroscopy; RF, radio frequency; STEAM, stimulated echo acquisition mode; SVS, single voxel spectroscopy; TE, echo time; TM, mixing time.

method, a large volume divided into several smaller voxels is selected to provide this ability to produce all voxel’s spectrum simultaneously. This technique is a matter of choice in determining the metabolite’s spatial distributions. Since the water signal is much larger than the metabolite’s signal due to its greater abundance, techniques such as chemical shift-selective water suppression [30] or water suppression enhanced through T1 effects [31] are routinely applied to suppress the water signal. Also, a spectrum without water suppression should be acquired because it may be helpful for quantification or corrections, such as lineshape corrections [32–34]. The routine SVS techniques most commonly applied for 1H-MRS are known as point-resolved spectroscopy (PRESS) [35, 36] and stimulated echo acquisition mode (STEAM) [37]. The principle difference between these two pulse sequences is shown in Figure 1 [10]. In both sequences, each pulse is accompanied with an X, Y, or Z gradient, which is used to select a certain slice. Altering the time intervals between the pulses can change the echo time (TE). Longer TE results in decreasing the signal as a result of T2 relaxation, which leads to altering the phase of multiplet signals because of J-coupling (Figure 2) [40]. For quantitative measurements, both short TE and a long repetition time are commonly performed in order to provide echos with less signal loss stems from T2 and T1 weighting. The measurements with longer TE are applied to achieve a spectrum with a small number of resonances (often singlet), which is easily interpretable. TE of 135-144 ms is typically used, as this leads to the production of a spectrum in which the doublet signal of Lac with a J-coupling constant of nearly 7 Hz is entirely reversed arrangement of a short TE and a long repetition time (TR) [41]. In MRSI, phase-encoding gradients can be applied in all three dimensions to sample k-space in order to select a volume that resembles methods such as in MRI [42]. Typically, these phase-encoding gradients are executed after a radio frequency excitation pulse in conjunction with a slice selection gradient. In MRSI, the spectra of entire volumes are obtained altogether, and the map of spatial distributions of different metabolites can be provided in a single procedure [43]. It is also possible to have a sequence to provide multiple echoes, which is known as turbo spectroscopic imaging [44]. Other fast MRSI techniques for spatial encoding use varying gradient strengths during the data acquisition [45] or are executed in advanced parallel spectroscopic imaging techniques [46]. These fast techniques are very useful for 3D MRSI.

The principle drawback of MRSI is the occurrence of voxel bleed. This term is used when the spectrum of a certain volume is contaminated with the signal of adjacent volumes. Adjacent signals with positive or negative intensities result from the point spread function shape, which in turn is a consequence of limited matrix size that is defined in MRSI [47]. The impact of the signals originates from neighbour volumes and can be decreased using some special filters prior to Fourier transformation (FT) in the spatial domain, but this may increase the size of voxels. Commonly, SVS is the preferred choice, while accurate quantification is required, and MRSI is used to provide a vision of spatial distributions [10, 42]. There should be some postprocessing of SVS spectra to obtain interpretable results. The typical postprocessing technique includes FT, baseline correction, zero filling, and phasing. This processing mostly resembles the postprocessing of NMR data. There are some artefacts that should be avoided using these postprocessing techniques. For instance, the gradient switching may lead to time- and space-dependent artefacts that are known as eddy current artefacts. Such artefacts can be diminished with a reference water signal that can be produced without water suppression by means of the same sequence and from the same volume of interest. This correction, known as eddy current correction (ECC), is the first postprocessing method which leads to line-shape corrections. However, eddy currents are reduced in current MR scanners, which results in decreasing the importance of line-shape correction (Figure 3). In MRSI, the application of filters (Hamming, Hanning) is performed first, and then the FT is applied in the spatial domain. Afterwards, the timedomain SVS information corresponding to each voxel is analysed to create MR spectra, the spatial distribution of metabolites can be shown in a spectral map [10, 48, 50–52]. MRS in Medicine Approximation of the number of existing metabolites in the body suggests a number between 2,000 and 20,000 [10]. In patients with metabolic congenital problems, the number of these metabolites is remarkably different from normal people. This issue results from a congenital fault in enzymatic function. MRS is the best tool to noninvasively and quantitatively show alterations in metabolite levels; therefore, this method is proper in the diagnosis of metabolic disturbance [53–55]. It should be noticed that only tiny metabolites with adequate concentration can be detected by

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Figure 3. A single voxel water signal without ECC (1.5 T, TE 35 ms) (blue line), water signal with ECC (red line) [49]. ECC, eddy current correction; TE, echo time.

produce an MRS signal. The peaks of each metabolite arise from several compositions (Table 1) [56–58]. Cr and its derivatives contribute to energy metabolism, and their intensity is considerably fixed. Hence, they are applied in the computing of metabolite ratios. Although local variation exists, some pathologies like cancer lessen the Cr concentration. In contrast, some situations such as gliosis in white matter may increase its concentration slightly. The complete lack of Cr signal implies a deficiency in Cr production, as in guanidinoacetate methyltransferase imperfection [59–62] or in L-arginine glycine amidinotransferase shortcoming [63], or to a Cr transporter failure [64]. With short TE, some other signals can be observed. For instance, another notable signal is observable at 3.6 ppm that chiefly stems from myoinositol (Ins, 3.61 ppm) and also has a contribution in the peak of glycine (Gly, 3.55 ppm). Especially in spectra produced at low magnetic field strengths, the pseudo-singlet of Ins and the singlet of Gly are hardly distinguished, but in spectra provided by higher magnetic field strength, the pattern of Ins is altered and dissociation is more obvious, even at short TE. Ins is a kind of sugar that is mainly incorporated into glial cells; hence, it is assumed as a glial marker. The amount of Ins enhances with multiplication of glial cells or the enlargement of these cells, which happens in inflammation. Furthermore, Ins may affect the myelination. Increased level of Ins occurs Figure 2. Brain MRS spectra in three different echo times [39]. (A) 3 T, TE ¼ 30 msec and TR ¼ 2000 msec. (B) 1.5 T, TE ¼ 144 msec and TR ¼ 1500 msec. (C) 1.5 T, TE ¼ 288 msec and TR ¼ 1500 msec. MRS, magnetic resonance spectroscopy; TE, echo time; TR, repetition time.

MRS. Moreover, trend of alterations in the MR spectrum can be an index of a general pathology not a special metabolic disorder. The changes of metabolite concentration trends in conjunction with other test results can be helpful in determining the problem. Brain MRS N-acetyl aspartate (NAA), creatine (Cr), and choline (Cho) are the most important metabolites of brain that 4

Table 1 The ppm of the Peaks of NAA, Cr, and Cho Metabolites and the Compositions They Arise from Component

ppm

Metabolite

N-acetyl aspartate N-acetylaspartyl glutamate Methyl protons Methylene protons Methyl groups of free choline Glycerophosphoryl choline Phosphocholine Myoinositol Glycine Methyl group of lactate

2.01 2.04 3.03 3.91 3.19 3.21 3.21 3.61 3.55 1.31

NAA

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Cr Cho

m-ins Gly Lac

in gliosis, astrocytosis, and in diseases such as Alzheimer, and its growth is not very peculiar. The Gly has a longer T2, and its signal can be observed at approximately the same position. Because of the T2 relaxation time, its signal exists in MR spectra provided at longer TE. The significant growth of glycine concentration can be the index of nonketotic hyperglycinemia that stems from a deficiency in the glycine division system [65]. The Lac signal that can be seen around 1.31 ppm has a low concentration of almost 0.5 mM, so that it is not difficult to observe in brain MRS. Alanine (Ala) is another methabolite that is located around 1.47 ppm [66–68]. The signals of several other metabolites are not so high. These small peaks are produced as a result of breaking the signals into multiplets. In healthy brain MR spectra, multiplet signals of glutamate (Glu) and glutamine (Gln) are visible in 2–2.4 ppm and 3.6–3.8 ppm regions. In particular, at 1.5 T, the resonances of these metabolites are hardly recognizable, so that the integral of them is called glutamine-glutamate-GABA complex (Glx). Glu is a neurotransmitter, and Gln has another duty, like responding to disease [69, 70]. Brain tumours commonly cause an increase in Cho concentration (Figure 4). Cho level corresponds to the ability to proliferate and existence of malignancy [72]. Hence, an increased Cho signal is a marker of the presence of brain tumour. It should be noted that a Cho increase is not a specific sign of brain cancer because a Cho increase can also be seen in other pathologies as well. Some of the disorders that lead to increased Cho signal are swelling, multiple sclerosis (MS), stroke, radiation-induced necrosis, etc. Moreover, the relation of existence of malignancy and the intensity of the Cho signal is not easy to interpret; for instance, in glioblastoma, which is an inhomogeneous texture, the relation between the Cho signal and brain cancer is not so straightforward [73, 74]. Contrary to Cho, the signal of NAA, which is a neuronal marker, typically diminishes in brain tumours (Figure 4). This signal reduction is because a large number of brain tumours do not have a neuronal basis. Besides, it should be noted that reduced NAA does not exclusively belong to brain tumours and it can happen in other pathologies as well. Some of the

Figure 4. The spectrum of glioblastoma multiform and normal contralateral region spectrum [71]. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate.

diseases which result in NAA signal reduction are stroke and MS. Since the level of Cho and NAA signal alters, respectively, in brain tumours, the calculation of this metabolite ratio, which is called Cho-NAA index, can be helpful for interpretation of brain tumour’s MRSI spectra [75–77]. Cr signal is usually reduced in brain tumours due to changes in energy metabolism (Figure 4). This is not a general rule because there are some exceptions. For instance, in gliomatosis cerebri, which is an unusual and rare kind of glioma, the signal of Cr will be increased [78]. The other metabolites that can be helpful in diagnosis of brain tumours are Ins and Glx. The signal of myoinositol in low-grade gliomas is high, and it reduces with increase of tumour grade. The signal intensity of Glx can be applied in differentiation of oligodendroglioma (high Glx) and astrocytoma (lower Glx) [79]. Glx level is enhanced in meningioma as well. The meningioma spectra also contain signals of Ala, in which y belong exclusively to this type of tumour [80]. The Lac signal is produced in anaerobic metabolism. Lac signal usually appears in brain tumour’s spectra. However, it may be assumed that the Lac signals do not have any relevance to tumour malignancy [81, 82]. Finally, fat and macromolecule’s signals are the markers of necrotic regions in high-grade tumours and metastases [80]. It can be concluded that Lac and lipid signal increases over a period of time are warning signs of tumour progression and its conversion from a low-grade tumour to a high-grade one. Brain tumour MRS can be performed as SVS, in which a single voxel is placed in the lesion and the other at a symmetric contralateral position of the brain. This method permits spectral acquisition from abnormal and normal tissues and allows us to compare the spectra. As mentioned above, brain tumours are commonly inhomogeneous so that multivoxel MRSI can be much more valuable for the purpose of spatial distribution evaluation of more aggressive regions of the tumour. Moreover, advanced malignant tumours usually penetrate into adjacent tissues; this function can just be detected using MRSI, a tool which can display abnormal pattern spectra that originate from adjacent area of the lesion in combination with enlarged signal level produced by contrast-enhanced MRI. Hence, MRSI can be applied in order to differentiate high-grade glioma and metastasis. MRSI has this ability because glioma typically demonstrates infiltrations, but a metastasis is spatially limited. Furthermore, the proportion of lipid methylene signal and lipid methyl signal intensities around 1.3 and 0.9 ppm increase more in metastases in comparison to high-grade gliomas [83, 84]. Besides 1H-MRS, the spectroscopy of other elements such as 31P and 13C can be helpful to evaluate brain disorders. 31PMRS is a valuable tool to evaluate pH or the proportionality of phosphodiesters and phosphomonoesters in brain tumours by in vitro and in vivo techniques. Modern evolutions that result in the increase of 31P-MRS sensitivity on the basis of polarization transfer from 1H to 31P [85–87] in combination with the accessibility of more high field MR systems, which leads to further administration of 31P-MRS in order to assess the response of the tumour to the treatment. 13C-MRS has also

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been applied for some in vitro and in vivo examinations on animal models. Moreover, an increase in the generation of dynamic Lac has been observed in a high-grade brain tumour using 13C-MRS in conjunction with polarization transfer [88, 89] in infusion period with glucose molecules labelled with 13C [90, 91]. 13C-MRS is a valuable device in the discovery of hyperpolarized compounds [92–94]. MRS Application in Neural Diseases Systemic Lupus Erythematosus. Systemic lupus erythematosus (SLE) is an inflammatory disease that can affect all parts of the body. Considering the patient’s neurologic or psychotic episodes, this disease can also be evaluated by MRI and MRS following psychiatric and cognitive assessment. Proton SVS in which the voxel is centred on white matter demonstrates a decrease in NAA/Cr ratio in comparison to normal white matter in a healthy brain (Figures 5 and 6). However, it should be considered that this finding does not permit discrimination of SLE from MS. The limitation of diagnosis is because of the resemblance in the chemical materials that are altered in diseases or abnormal metabolic characteristics [96–99]. Multiple Sclerosis. MS is another central nervous system autoimmune disease. In this disease, the axons’s myelin pods are

Figure 5. Typical brain MR spectra [95]. Cho, choline; Cr, creatine; MR, magnetic resonance; NAA, N-acetyl aspartate; PCr, phosphocreatine.

6

Figure 6. Metabolic changes due to SLE [95], in comparison with Figure 5. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate; PCr, phosphocreatine; SLE, systemic lupus erythematosus.

destroyed and cause several symptoms such as inflammation, gliosis and axonal degeneration, demyelination, and neuronal affection. As mentioned above, 1H-MRS can provide some information about MS because it can demonstrate the signs of basic pathologic processes of the disease, such as active inflammatory demyelination and neuronal injury [100]. Demyelinating can cause an increase in the concentration of Cho and Lac metabolites because the phospholipids of membrane are released as a result of active myelin breakdown and the impaired metabolism of the inflammatory cells. The increments of lipids, mI, and Glu concentrations can also be seen in short TE imaging. In acute MS lesions, the signal of Glu enhances, which reflects the direct axonal injury. The increase of mI signal is a consequence of glial proliferation and astrogliosis. This remodelling of the metabolites concentration is in conjunction with reduction of NAA as a result of axonal injury. This reduction is a sign of metabolic or structural changes. The important point which should be considered is that the spectroscopic changes observed in MS plaques resemble metabolic changes due to brain tumours (high Cho, low NAA, increased Lac) (Figures 5 and 7) [102–104]. Lac, Cho, and lipid values return back to the normal state after passing the acute phase. NAA metabolite is the only chemical compound whose concentration does not show partial recovery for several months. Brain Abscesses. Brain abscesses are a kind of infection that starts with a local cerebritis. The organisms that cause these diseases are diverse, and they can be a mixture of different organisms, such as facultative anaerobes in combination with aerobes/anaerobes, or any of these organisms alone [105, 106]. MRS can differentiate brain abscesses from other cystic lesions. This ability allows implementation of proper antimicrobial therapy. Brain abscesses may affect some special metabolites, including succinate, acetate, Ala, valine, pyruvate, leucine, lipids, and Lac (Figure 8). All of these metabolites correspond to untreated bacterial abscesses immediately after commencement of treatment. Lac, acetate, and succinate signal enhancement occurs in brain abscesses, which can be attributed to the enhanced glycolysis and zymosis of the infecting microorganisms. The ultimate outcomes of

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neoplasms, so their presence can strongly differentiate abscesses from malignant tumours [107, 109].

Figure 7. Metabolic changes due to MS [101], in comparison with Figure 5. Cho, choline; Cr, creatine; Lac, lactate; NAA, N-acetyl aspartate.

proteolysis via enzymes secreted from neutrophils are several amino acids, including valine and leucine. In cerebral abscesses, there are no visible peaks of NAA and Cr/phosphocreatine (PCr) because there are no neurons. If NAA or Cr/PCr peaks are detected in abscess spectrum, this can be due to either signal contamination or incorrect explanation of acetate peak as NAA. Also, tCho signal should not be seen in an abscesses spectrum because the necrotic core does not contain membranous structures. Conversely, the abscesses induced by tuberculosis can be recognized by the sharp signal of lipids and enhanced signal of tCho [108–110]. The routine problem of differentiating brain abscess from a brain tumour, especially brain tumours with cystic or necrotic components, is still problematic. However, it can be solved because amino acids do not exist in brain

Figure 8. Metabolic changes due to brain abscesses at long and short echo time [107]. AA, amino acids; Ac, acetate; Ala, alanine; Lac, lactate; Suc, succinate.

Brain Infarction. The most important marker of brain ischaemia in 1H-MRS is the NAA and Lac signal, but some changes can also be detected in the other metabolite signals such as Cho, Cr, Glu, and glutathione. The time changes of these metabolites are one of the contributing factors in diagnosis and prognosis of brain infarction [111, 112]. The prominent Lac peak that occurs due to cell death, together with a broad lipid peak, are signs of acute stroke. Lac signal can also be detected due to some other circumstances such as hypoxic conditions. In this situation, the potentially viable cells that carry on metabolizing glucose can lead to a shift toward anaerobic glycolysis. The Lac signal, but with weaker strength, is observable in the ischemic penumbra that exist around the core [113, 114]. In contrast to Lac, NAA signal gradually decreases during several hours after incidence of ischemia. NAA reduction may occur as a result of NAA degradation via enzymes that exist in injured neurons immediately after infarction, and it can even be due to alterations of other molecules such as Glu, Gln, and gamma-aminobutyric acid (GABA) that superimpose on NAA resonance (Figures 5 and 9) [116]. tCho changes in acute and chronic ischaemia can be either increasing or decreasing, which can be the consequence of gliosis or ischaemic damage to myelin, oedema, necrosis, or cell loss. Initial reduction in Cr/PCr occurs immediately after infarction and can reduce even more up to 10 days after the initiation. mI is the other metabolite whose changes can be useful to perceive the response of brain tissue to ischaemia [116]. Temporal Lobe Epilepsy. Temporal lobe epilepsy (TLE) is a disease that corresponds to the hippocampal sclerosis, and it is also one of the most common types of epilepsy. The metabolite concentrations in the temporal lobe of both hemispheres particularly in the hippocampus and temporal poles, compare with together in order to determine that which hemisphere is the origin of seizures. Important metabolites in evaluation of epilepsy are NAA, GABA, and Glx and to some extent, mI, and Lac. Several studies revealed the reduction of NAA levels and trivial changes or mild increment of tCho signal. A decrease of NAA concentration accompanied with the presence of Lac in the temporal lobe is the marker of the epileptogenic zone (Figures 5 and 10) [118–121]. In epileptic patients, besides the reduction of NAA, an increase of Glu may be observable and also a level of imbalance between Glx and GABA can be seen [122, 123]. Some changes in mI level were observed in studies, but its real contribution in TLE is still controversial [124–126]. Alzheimer’s Dementia. Alzheimer’s dementia (AD) is a general term for memory loss. 1H-MRS has been proved that it has a rational specificity and sensitivity for diagnosis of AD. Again, NAA reduction is the most common incidence, which is detected by 1H-MRS in AD patients. Reductions of NAA/Cr

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Figure 10. Metabolic changes due to TLE [117], in comparison with Figure 5. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate.

There is a distinct chemical compound that is observed in all meningiomas, so it can be another specific marker that can help in recognition of meningioma from high-grade gliomas Figure 9. Metabolic changes due to cerebral infarction [115], in comparison with Figure 5. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate; PCr, phosphocreatine.

ratio in SVS evaluation of AD are a frequent finding, especially in temporal regions, posterior cingulate gyrus, temporoparietal area, and occipital lobes (Figures 5 and 11). Cho level shows inconsistent changes in AD patients. mI has exhibited an increase, especially in temporoparietal region, posterior cingulate gyrus, parietal white matter, and sometimes in the frontal lobes. Some studies reported a decrease in Glx levels in the posterior cingulated gyrus and lateral temporal cortex of AD patients in comparison to healthy people [128–132]. Meningioma. Meningiomas are prevalent tumours that can be readily diagnosed by radiological imaging. Solid mushroom appearance in images is the pattern of meningioma that involves the extracranial area, dura matter conjunction, and sinus. However, this tumour cannot be differentiated from other diseases. For instance, 15% of meningiomas may contain eminent cystic components, haemorrhage, or metaplasia so that they cannot be differentiated from gliomas or cerebral metastatic tumours. 1HMRS is a powerful modality to solve this problem [133, 134]. Short TE 1H-MRS demonstrated low levels of mI and Cr, which are the specific signs of meningiomas compared to grade II astrocytomas, anaplastic astrocytomas, and glioblastomas. In both short and long TE MRS studies, it has been demonstrated that meningiomas can produce the highest Cho/Cr ratio among the other brain tumours. Another characteristic sign of meningiomas is the absence of NAA (Figure 12) [135]. 8

Figure 11. Metabolic changes due to AD [127], in comparison with Figure 5. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate.

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and metastases. The peak of this chemical material is centred at 3.8 ppm, and it can be observed in short TE 1H-MRS [136]. Primary Central Nervous System Lymphoma. Primary central nervous system lymphoma (PCNSL) is a rare, dense brain tumour without a necrotic area and other imaging characteristic of PCNS lymphoma. Sometimes, the distinguishing PCNSLs from highgrade gliomas will be difficult, which in turn makes difficulties in the selection of effective therapy method [137, 138]. 1H-MRS is a valuable tool to diagnose and distinguish these neoplasms. Prominent Cho signal combined with reduced NAA levels is a sign of this disease. Lac changes in different studies were inconsistent in different studies (Figure 13) [140, 141]. Research Applications MRS, with its advanced methodology, has the capability of performing complicated tests of disease pathology in psychiatric disorders. 1H-MRS is a powerful tool to assess psychiatric disorders, such as panic disorder (PD), depression, autism spectrum disorders (ASDs), schizophrenia (SZ), and bipolar disorder (BD) [142–145]. Psychiatrists have tried to clarify the relationship between psychological processes and brain mechanisms [146–148]. The evolution of modern imaging modalities such as MRS turns this into reality. The usage of MRS techniques allows psychiatrists and neuroscientists to examine whether the patient’s behaviour is a normal emotional expression or whether it is abnormal (regarding emotional expression disorders) or if it is psychosis [149]. The ASD is a behavioural syndrome. There is a view that the environmental and genetic factors may affect the normal brain evolution. MRI studies demonstrated that ASD patients had cerebral enlargement in their childhood. Performing MRI combined with 1H-MRSI clearly explains the mechanisms of anatomic changes related to ASD. For example, MRS performance on ASD children revealed that there is a locally increased concentration of NAA, which results in increase the numbers of neurons and creation of more neural interconnections due to perturbation of normal neuronal apoptosis or other processes during the childhood of autism patients [150–158].

Figure 12. Metabolic changes due to meningioma (black line) in comparison to astrocytoma spectra. Ala, alanine; Cho, choline; Cr, creatine.

SZ is a rare psychiatric disease that incapacitates the patient. The results of neuroimaging and anatomic, receptor, and metabolic evaluations on SZ patients revealed that main signs stem from irregular neurobiological routes, which lead to this disorder. MRS and, recently, 31P-MRS studies demonstrated the changes that happen in membrane phospholipid characteristics, pH, and bioenergetic status. Also, 1H-MRS can be applied to map local NAA variations and the treatment effects [159–168]. Wide investigations have been performed on differentiation between anxiety disorders and PD. Studies showed that PD is a respiratory irregularity related to brain metabolic changes. The mechanism of sodium Lac infusion is one of the issues that has been evaluated using 1H-MRS. In this way, the panic induced by Lac could be biologically explained [39, 169–174]. Major depressive disorder and BD are prolonged affective psychiatric disorders. MRS studies could provide valuable evidence of the relationship between metabolic changes and mood state through phospholipid metabolism. 31P-MRS is a proper device to investigate phosphorous compounds. This metabolite leads to an increase in the phosphomonoester concentrations and decreases the amount of phosphocreatine in depressed patients (Figure 14) [176–182]. Breast MRS 1H-MRS research has been concentrated mostly on brain studies. One of the most important reasons for using MRS in brain studies is that it has fewer technical challenges in comparison with other organ sites. Since a large number of researches and developments are in the field of brain MRS, MR systems which are commercially available are optimized for brain imaging rather than breast studies. High-intensity signals from portable lipids are the specific problem of breast tissue spectrum. This problem does not present in brain spectroscopy. The height of the lipid signal is function of tissue heterogeneity. The adipose tissue of normal regions can cause

Figure 13. Metabolic changes due to PCNSL [139]. Cho, choline; Cr, creatine; NAA, N-acetyl aspartate.

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Figure 14. A, Normal brain spectrum; B, Metabolic changes due to BD [175]. BD, bipolar disorder; C, choline; Cr, creatine; G, glutamine; N, N-acetyl aspartate.

Figure 15. The water-suppressed spectrum of a patient with ductal carcinoma [183].

Figure 16. A, Spectrum of cancerous region; B, spectrum healthy tissue [233]. Cho, choline; Cr, creatine.

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Figure 17. MRS spectra of normal liver and NAFLD disease [251]. MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; PME, phospho mono esters.

problems for breast MRS, including lipid tissue in the spectrum voxel, which leads to partial volume effect and reduces the effective volume of spectroscopy (Figure 15) [184]. A usual breast MRS procedure is generally achieved instantly after dynamic contrast-enhanced (DCE) MR imaging. The technologist should be an expert in order to be able to suitably locate the MRS voxel, because it is typically dependent on lesion shape and the uptake characteristics of contrast agent. It should be noted that in SVS, the location of the voxel is relatively significant. The voxel should be positioned in such a way that it contains maximum lesion tissue while excluding other tissues, including normal fibroglandular and adipose tissue [185]. MRS can be applied in conjunction with MRI in order to assess the chemical content of breast lesions. This information can be helpful in monitoring the response of tumour to cancer therapies and improving the accuracy of lesion diagnosis. The preliminary breast MRS studies demonstrated promising results, and several research groups added this technique to their breast MRI protocols [183].

The first breast MRS studies provide the signal from phosphorus atoms (31P). These investigations revealed that alteration can be seen in phospholipid metabolism. This information was applied for cancer detection and checking the tumour response to treatment. Although breast MRS started from phosphorus atoms, today because of the higher sensitivity of 1H-MRS in comparison with 31P-MRS, there is increasing interest in breast cancer research by means of hydrogen 1H-MRS. Several studies have shown that the signal of tCho can be observed in malignant lesions; however, it is not visible in normal tissues or benign tumours [186–190]. Several research groups have revealed that tCho can be a marker of malignancy with clinical 1.5 T scanners. Some groups have also demonstrated that the tCho peak reduces in response to chemotherapy treatment. The results of these studies provide hope that MRS will be a useful tool in diagnosis and management of breast cancer [191–193]. Ex vivo investigations have been used to recognize the diverse Cho composites that superimpose on the tCho signal around 3.2 ppm [194]. Several studies on biopsy tissues revealed that

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Figure 18. A, Spectra of normal tissue; B, spectra of colorectal cancer sample [259].

the tCho signal is a combination of a number of echoes. The main components are those with a trimethylamine moiety such as free Cho, phosphocholine, and glycerophosphocholine. There are also some other components such as taurine, glucose, phosphoethanolamine, and myoinositol [195–197]. To summarize breast MRS applications, it should briefly be stated that the most important application is for distinguishing benign from malignant lesions before biopsy. Roebuck et al [198] in 1998 published the first paper on this issue. The tCho can be applied as a sign of malignancy. This study inspired numerous other studies in this issue [191, 195, 199–203]. On the other hand, other studies declare that detection of tCho in breast cancers did not describe diagnostic specificity 12

and sensitivity. Since there is a possibility that even benign pathologies can also create observable levels of tCho, there is some evidence that can be cited [198, 204–209]. For instance, at 1.5 T, an observable tCho signal has been seen in fibroadenomas, tubular adenomas, and lactating subjects. There are also some other studies that tried to assess whether MRS can enhance the specificity of a diagnostic breast MR examination or not. The answer in most studies was positive. MRS is able to increase the sensitivity, specificity, and accuracy of breast MRI [209]. The other breast MRS application is the prediction of tumour response to cancer treatment [210]. Clinical methods which are used to forecast the tumour response are imaging and palpation based on alterations in the size of tumour.

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morphological change. The first paper that used tCho quantitation in order to assess the breast cancer reaction to treatment was published by Jagannathan et al [194], who was the first researcher to find the tCho signal is diminished or suppressed in 89% of cases that underwent chemotherapy [211–216]. Prostate MRS

Figure 19. Spectra of normal and cancerous ovary epithelial noncells. A, Spectra of normal ovarian surface epithelial (OSE) cells, immortalized cell variant of human telomerase reverse transcriptase (hTERT and ovarian carcinoma (OVCAR3) cells. B, Expanded 1H NMR spectral profiles of total choline in normal OSE, hTERT cells, and two ovarian carcinoma cell lines (CABA I and IGROV1) [263]. GPC, glycerophosphocholine; TSP, 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid.

Tumour size changes can be detectable after several weeks. However, breast MRS can recognize intracellular metabolism changes, which would happen prior to any detectable

The ideal imaging technique for prostate should be cost efficient and noninvasive, with the least disparities in interpretation. The test should also provide the ability to predict tumour stage, volume, and location with high specificity and sensitivity. Although the ideal technique does not exist, there are some imaging modalities that are suitable enough for prostate imaging. MRS is one of them [217]. One of the most important applications of prostate MRS is staging the prostate cancer, which is a more accurate technique compared with clinical examinations, computerized tomography (CT) imaging, and transrectal ultrasound (TRUS). MRS also permits simultaneous and precise assessment of pelvic anatomy, prostate, and periprostatic regions. Endorectal magnetic resonance imaging (endoMRI) and MRSI provide an improved visualization of the prostate anatomy and better determination of tumour details such as location, volume, and its stage. A metabolic criterion for identification and localization of prostate cancers is endoMRI/MRSI, in order to improve the accuracy of the examination and restricting interobserver disparities in interpretation [218–220]. Since available radiological techniques cannot accurately delineate prostate cancer in vivo, the only method is prostate biopsy, which is performed for prostate cancer patients. Unfortunately, false-negative rates in biopsy are high [221]. MRSI can be the best option to assess some prostate cancers. For instance, ruling out prostate adenocarcinoma can be done based on three examinations, including digital rectal examination, blood sampling to check prostate-specific antigen (PSA), and TRUS, and is confirmed by TRUS-guided biopsies that were mentioned previously [222–225]. Modern imaging modalities, such as CT, ultrasonography, and MRI, have some limitations in diagnosis of prostate adenocarcinoma [226–229]. MRSI has shown that it has high diagnostic accuracy, and dynamic contrastenhanced magnetic resonance (DCEMR) imaging showed its worth in the management of prostate cancer [230–232]. The benefit of MRSI corresponds to gathering metabolic information of prostatic tissue by calculating the relative concentrations of chemical compounds such as citrate, Cr, and Cho. In practice, prostate adenocarcinoma can be differentiated from healthy adjacent tissue on the basis of the (Cho þ Cr)/citrate ratio. To illustrate, in normal surrounding tissues, (Cho þ Cr)/citrate ratio is less than 0.8, and in the cancerous tissues, the ratio is more that 0.8 (Figure 16) [234–237]. There are some issues with respect to technique which should be considered in practice. First of all, 1.5 T or 3 T MRI systems are used for prostate imaging. The hybrid usage of endorectal and pelvic phased-array coils is suggested in order to increase

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SNR [238–241]. In order to provide optimal spectra, special care should be taken for locating the coils. Hence, it is essential to observe the preliminary images which are called scout images in order to reassure that the sensitive volume of the coil is placed on the prostate without any large tilt (20 ) of the probe and prostate axial plane in relation to each other [242].

MRS can also be used to assess the female pelvic lesions. The overall outcome of these lesions was that the Cho level does not change in malignant or benign pelvic cancers except ovarian cancer in which the Cho level was higher in malignant tumours. Some other scientists suggest that Cho/Cr ratio can be a proper indicator of malignancy (Figure 19) [264–269].

Hepatic, Gastrointestinal, and Genitourinary MRS Hepatic MRS is a developing technique that has the ability to enhance the accuracy of tissue analysis. H1-MRS can be applied in the diagnosis of cirrhosis, hepatitis, and malignancies, and also in treatment monitoring. One of the problems that this technique encounters is the technical difficulties in providing high-quality spectra as a result of respiratory motions. In other words, it can be said that hepatic proton MRS technique is in the primary steps of development. The importance of spectral quality and quality control should be considered in hepatic proton MRS. There is no agreement about the criteria of quality evaluation. The important point is that diagnostic value corresponds to the quality of abdominal MRS, which in turn is affected by proper technical factors, including prescan shimming and efficient water suppression. In short TE spectra, line width is the effectual factor in model fitting since poor resolution results in absurd results. High amplitude water signal can disturb the signal of lower-concentration compounds [243, 244]. Despite of all the problems in providing a proper signal in this technique, hepatic MRS is performed in clinics, specifically to assess and quantify the liver fat. For instance, steatosis is the most common liver disease which can stem from alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) [245–248]. In both cases, a large number of vacuoles comprising fatty content cumulate in the cytoplasm of the hepatocytes. In contrast to ALD, NAFLD disease typically corresponds to metabolic syndrome, fatness, and insulin resistance. Biopsy is the gold standard to evaluate the liver fat content, but it should be considered that this technique is very invasive [249, 250]. MRS is a method which can accurately detect even small concentrations of fat (Figure 17) [252–255]. Despite the fact that hepatic fibrosis is the main cause of chronic liver disease, unfortunately most of the diagnostic tests are not sufficiently sensitive or specific for early diagnosis of these liver injuries. Again, the invasive liver biopsy can determine the extent of fibrosis. There are also some noninvasive methods such as serum marker panels and ultrasound-based transient. MRS, diffusion-weighted MR, and MR elastography are the other noninvasive options as proper tools to detect fibrosis. The advantage of MRS and the other MR techniques over other noninvasive methods is that MR imaging is able to produce functional and biological information about hepatic pathophysiology [256–258]. There are also some studies on evaluation of gastrointestinal tumours using 1H-MRS. The overall results of these studies revealed that cancer lesions can be determined by the increase of Cho peak and Lac doublets (in short TE) and decrease of lipid signal (Figure 18) [260–262]. 14

Conclusion According to the aforementioned applications of 1H-MRS in medicine, MRS has been applied as both a research and a clinical tool in order to detect visible or nonvisible abnormalities. MRI does not have this ability to detect most of the microabnormalities because it can only create a map of the spatial distribution of water and lipid protons, while MRS has the ability to measure the chemical content of MRvisible nuclei, such as the elements corresponding to 1H, 13C, and 31P. Since MRS can measure chemical contents, it is a proper option for evaluating metabolism. This ability stems from the fact that the chemical properties and its surrounding environment determine its location in the MR spectrum. It can be concluded that the peak position on the spectrum corresponds to a specific metabolite and the constituent nuclei of each metabolite. The adaptability of MRS provides a technique that can probe a wide range of metabolic usages across different tissues. Although MRS is mostly applied for brain tissue, it can be used for detection, localization, staging, tumour aggressiveness evaluation, and tumour response assessment of breast, prostate, hepatic, and other cancers. MRS is used for brain studies, in order to provide precise information about the metabolites of different regions of brain tumours. This information can help in tumour grading, differentiation of neoplastic and nonneoplastic legions, prediction of tumour response to the treatment, demonstration of active and invasive parts of tumour and even radiation treatment planning, etc. 31P-MRS is a powerful device to assess the PH and the ratio of phosphodiesters and phosphomonoesters in brain tumours. 13C-MRS is applied for evaluation of Lac level. 1H-MRS techniques have also been employed to detect and evaluate cerebral diseases via monitoring the metabolic changes. Many studies have been done on the evaluation of SLE, MS, brain abscess and infarction, TLE, AD, meningioma, and PCNSL. For example, Lac concentration increases in infarcted regions following a stroke, whereas NAA is reduced. Also, decreases in NAA and GABA have been observed in epileptogenic regions of the brain. In SLE, the ratio of NAA/Cr decrease, which is a similar finding as in AD. In MS disease, the level of NAA decreases, but the amount of Cho and Lac increases. Contrary to most neural disease, there are not visible peaks of NAA and Cr in brain abscess, but the changes can be seen in the amount of Ala and acetate. The capabilities of MRS have also been shown to be a useful tool in research as well. It develops our knowledge about mechanisms underneath metabolic processes and the pathogenesis of

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diseases. It is an especially useful research tool to justify and interpret the generation of psychiatric diseases. It can be hoped that in near future, MRS will play a significant role in the diagnosis and monitoring of psychiatric disease progression and even evaluation of treatment response in mental disorders. There are many studies on the spectrum of metabolites in ASD, SZ, PD, BD, and major depressive disorder that provide valuable information of metabolic changes in these patients. In breast applications, like brain evaluation, several studies have shown that MRS can differentiate between benign and malignant breast lesions. Since the pCho is an important metabolite in breast diseases, the 31P-MRS can also be helpful. In summary, lesions with observable Cho peaks are suspicious for malignancy. MRS can also be helpful in monitoring the tumour response to chemotherapy with a reduction of total Cho. In prostate lesions, MRS has been proven to be a powerful device in diagnosis, position delineation, classification of tumours, evaluation of aggressiveness, and tumour-response assessment. The important issue in prostate MRS is that in this technique, which has a low SNR, the usage of endorectal coil and a higher magnetic field strength (3.0 T) can be useful in order to improve spectral resolution. MRS applications in the hepatic system and gastrointestinal tract are mainly limited because of respiratory motion, which can be improved by using breath-hold acquisition and abdominal compression. Moreover, signal preprocessing or postprocessing such as automatic corrections of phase and frequency can diminish motion-induced distortions. It can be concluded that in vivo MRS is a key technique for investigation of human metabolism in this century. References [1] Derrick, K., & Revathi, S. (2016). NMR: Introduction). [2] Ramsey, N. F. (1999). Early history of magnetic resonance. Phys Perspective 1(2), 123–135. [3] Mansfield, P., & Grannell, P. K. (1973). NMR ’diffraction’ in solids? J Phys C: Solid State Phys 6(22), L422. [4] Weinmann, H.-J., Brasch, R., Press, W., & Wesbey, G. (2005). 6.4 Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. Classic Pap Mod Diagn Radiol 416. [5] W€ uthrich, K. (2001). The way to NMR structures of proteins. Nat Struct Mol Biol 8(11), 923–925. [6] W€ uthrich, K. (2003). NMR studies of structure and function of biological macromolecules (Nobel Lecture). Angew Chem Int Edition 42(29), 3340–3363. [7] Jezzard, P., & Buxton, R. B. (2006). The clinical potential of functional magnetic resonance imaging. J Magn Reson Imaging 23(6), 787–793. [8] Vandenberg, J. I., & Kuchel, P. W. (2003). Nobel Prizes for magnetic resonance imaging and channel proteins. Med J Aust 179(11/12), 611– 613. [9] Bl€ umich, B. (2005). Essential NMR: for Scientists and Engineers. Berlin Heidelberg: Springer-Verlag. [10] van der Graaf, M. (2010). In vivo magnetic resonance spectroscopy: basic methodology and clinical applications. Eur Biophys J 39(4), 527–540. [11] Claridge, T. D. (2008). High-resolution NMR techniques in organic chemistry. Amsterdam, Netherlands: Elsevier.

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