Multinuclear MRI at Ultrahigh Fields.7

REVIEW ARTICLE
Multinuclear MRI at Ultrahigh Fields

Sebastian C. Niesporek, Armin M. Nagel, yz and Tanja Platt
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human brain tumors,4 –6 stroke,7– 9 multiple sclerosis,10–13 or muscle

Abstract: In this article, an overview of the current developments and
ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 04/28/2023
diseases.14,15 Another application is the utilization of 17O MRI for

research applications for non-proton magnetic resonance imaging (MRI) at
the quantitative evaluation of the cerebral metabolic rate of oxygen
ultrahigh magnetic fields (UHFs) is given. Due to technical and methodical
consumption (CMRO2),16– 18 which may be useful to gain further
advances, efficient MRI of physiologically relevant nuclei, such as 23Na, 35Cl,
37 insights into tumor pathophysiology.19 A spatially resolved distribu-
Cl, 39K, 17O, or 31P has become feasible and is of interest to obtain spatially
tion of 31P, 35/37Cl, 39K, 25Mg, 7Li, 19F, or 2H can also provide
and temporally resolved information that can be used for biomedical and
important additional functional information depending on the par-
diagnostic applications. Sodium (23Na) MRI is the most widespread multi-
ticular biomedical question of interest. If different metabolites or
nuclear imaging method with applications ranging over all regions of the
chemical groups of a metabolite exhibit differing resonance frequen-
human body. 23Na MRI yields the second largest in vivo NMR signal after the
cies, in some cases, spectroscopic methods are preferred, for exam-
clinically used proton signal (1H). However, other nuclei such as 17O and 31P
ple, chemical shift imaging. The discussion of spectroscopic methods
(energy metabolism) or 35/37Cl and 39K (cell viability) are used in an
in multinuclear magnetic resonance is not part of this review article,
increasing number of MRI studies at UHF. One major advancement has been
which focuses on multinuclear MRI.
the increased availability of whole-body MR scanners with UHFs (B0 7T)
In addition to the overall low in vivo signal levels of X-nuclei
expanding the range of detectable nuclei. Nevertheless, efforts in terms of
and therefore related increased voxel sizes, MRI of nuclei with
pulse sequence and post-processing developments as well as hardware designs
nuclear spin I >1/2 experience short transverse relaxation times in
must be made to obtain valuable information in clinically feasible measure-
the order of milliseconds requiring specially adapted pulse sequen-
ment times. This review summarizes the available methods in the field of non-
ces. For accurate signal quantification, the relaxation effects, inho-
proton UHF MRI, especially for 23Na MRI, as well as introduces potential
mogeneity of B1- and B0-fields, the effects associated with low
applications in clinical research.
spatial resolution (partial volume effects, PVEs) and tissue motion
Key Words: 2H, 7Li, 17O, 19F, 23Na, 25Mg, 31P, 35Cl, 37Cl, 39K, chloride, (respiratory or heart motion) must be considered. Dedicated recon-
deuterium, fluorine, lithium, magnesium, multinuclear MRI, non-proton, struction techniques can additionally be used to reduce image noise
oxygen, phosphorus, potassium, sodium, UHF, ultrahigh field, X-nuclei and artifacts, for example, in undersampled MR data. In addition,
multinuclear MRI requires special hardware such as radiofrequency
(Top Magn Reson Imaging 2019;28:173–188)
(RF) coils that are tuned to the desired Larmor frequency and
dedicated RF amplifiers that provide the appropriate RF. The
I n recent years, the advancement of ultrahigh field systems with
field strengths (B0) of 7T and beyond has let to numerous
improvements and developments in proton and non-proton
nuclei-specific RF coils used so far are generally custom-made
products or built in-house.
The aim of this review article is to give an overview of the
MR imaging (MRI). In particular, MRI data of nuclei such as current status of applications of non-proton MRI at ultrahigh fields,
23
Na, 35/37Cl, 17O, or 31P bear information of metabolic and func- emphasizing the opportunities and challenges in this area of medical
tional origin. Imaging of these rare nuclei is also called non-proton, imaging. First, the article focuses on the technical characteristics,
X-nuclei, or multinuclear MRI. Starting with the first human in vivo briefly introducing special pulse sequences, post-processing techni-
23
Na MRI data in the 1980s,1 the field of multinuclear MRI has ques, and hardware developments directly related to multinuclear
advanced in a very versatile manner in the areas of pulse sequences, imaging. Then, examples for applications in biomedical research
hardware design, as well as post-processing techniques. are provided.
For multinuclear MRI, the challenges that must be overcome are
mainly related to the physical properties of the nucleus of interest.
The overall in vivo signal of 23Na is roughly 103 to 104 times lower TECHNICAL ASPECTS AND BIOMEDICAL
than the signal of protons and even less for other nuclei (35/37Cl: MOTIVATION
105, 17O: 105, 39K: 107).2 23Na MRI as the most prominent Nuclear magnetic resonance (NMR) signal detection
example provides a useful tool for many biomedical applications.3 requires the presence of a non-vanishing nuclear spin (nuclear spin
An altered sodium ion (23Naþ) concentration has been observed in quantum number I6¼0). Therefore, the number of MR visible and
physiologically relevant nuclei, which provide sufficient MR signal
(naturally or after administration), is limited. This forms the group
From the Division of Medical Physics in Radiology, German Cancer Research of so-called non-proton or X-nuclei in the field of biomedical
Center (DKFZ), Heidelberg, Germany; yInstitute of Radiology, University
Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg imaging.
(FAU), Erlangen, Germany; and zInstitute of Medical Physics, Friedrich-
Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Challenges and Possibilities
Received for publication February 19, 2019; accepted March 6, 2019. Basically, two groups of NMR-sensitive non-proton nuclei can
Address correspondence to Dr. Tanja Platt, German Cancer Research Center
(DKFZ), Division of Medical Physics in Radiology, Im Neuenheimer Feld be distinguished: (1) nuclei with spin I ¼ 1/2 and (2) quadrupolar
280, 69120 Heidelberg, Germany (e-mail: t.platt@dkfz.de). nuclei (spin I >1/2).
Armin M. Nagel is currently receiving research support from Siemens Healthineers The first challenge that arises is the intrinsically reduced NMR
and received research support from Nukem Isotopes Imaging GmbH. sensitivity of X-nuclei compared with 1H sensitivity leading gener-
The authors report no conflicts of interest
Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. ally to a lower signal-to-noise-ratio (SNR) and a worse spatial
DOI: 10.1097/RMR.0000000000000201 resolution. The available signal S is related to the concentration
Topics in Magnetic Resonance Imaging Volume 28, Number 3, June 2019 www.topicsinmri.com | 173
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Niesporek et al Topics in Magnetic Resonance Imaging Volume 28, Number 3, June 2019
TABLE 1. Overview of Physical Properties (Nuclear Spin Quantum Number I, Natural Abundance NA) and Relevant MR
Quantities (Gyromagnetic Ratio g/2p, Resonance Frequency n) for Relevant Nuclei
Nucleus Spin I NA [%] g/2p [MHz/T] n (B0 ¼ 7T) [MHz] Relative Signal
1 1/2
H 100 42.58 297 1
2
H 1 0.015 6.53 45 106
23
Na 3/2 100 11.25 79 104 –105
31
P 1/2 100 17.25 121 106
17
O 5/2 0.037 5.77 40 105
35
Cl 3/2 75.78 4.18 29 105
37 3/2 106
Cl 24.22 3.46 24
19
F 1/2 100 40.08 280 105
7
Li 3/2 92.4 16.55 116 105 –107
39
K 3/2 93 1.99 13 105
25
Mg 5/2 10 2.61 18 107
Properties of 1H are also listed for direct comparison. For all nuclei, the resonance frequency at B0 ¼ 7T as well as the relative signal magnitude in vivo
compared with 1H are listed. Information is taken from Harris et al., Solid State Nucl Magn Reson 2002; 22:458–483.
(c), the nuclear spin quantum number (I), and the gyromagnetic ratio quadrupolar nuclei particularly benefits from pulse sequences that
(g) via the following relationship: enable ultra-short echo times (UTEs). These pulse sequences usually
employ non-Cartesian center-out readout trajectories. Both rapid
S / c I ðI þ 1Þg 3 : (1) transverse relaxation and non-Cartesian readout broaden the FWHM
of the PSF21,22 and reduce the effective spatial resolution.
A listing of these physical properties and MR quantities, which In addition, low intrinsic SNR impose challenges for quantita-
are explained in more detail below, can be found in Table 1.20 All tive multinuclear imaging. In the following sections, approaches are
physiologically relevant nuclei possess a highly reduced in vivo summarized that were developed to overcome these limitations.
sensitivity compared with 1H (Table 1) due to a lower natural
abundance and/or concentration and a lower gyromagnetic ratio, Benefit of Ultrahigh Field Systems
which are not fully compensated by higher spin quantum numbers. A comprehensive discourse on the technical aspects of multi-
Here, the signal level of X-nuclei is reduced by a factor of 103 nuclear imaging has been given in several review articles (e.g., Ladd
(23Na) to 107 (25Mg) compared with the available in vivo NMR et al.,2 Madelin et al.,23 Wiggins et al.24); and thus, only a brief
signal of 1H. To achieve sufficient SNR for imaging, large voxel summary is given here, presenting the benefits of ultrahigh magnetic
volumes have to be used. This implies low nominal spatial reso- fields (UHFs) for X-nuclei applications.
lutions ranging from (Dx)3 ¼ (2 mm)3 to (10 mm)3 that often result in A quantitative and commonly used measure of image quality for
PVEs. A descriptive measure of the imaging system is the full width MR applications is SNR. Combining the assumption regarding
at half maximum (FWHM) of the point-spread function (PSF) that sample-dominated noise25 and NMR theory, the general relationship
depends on the utilized imaging trajectory, the physical properties of between the main magnetic field (B0) and SNR shows at least a linear
the observed nucleus, and the applied reconstruction technique. increase26,27 (c.f. Fig. 1):
X-nuclei with I >1/2 experience very rapid transverse relaxation
properties due to their quadrupolar properties (e.g., 2H, 17O, 23Na), SNR / B01 to 1:75 : (2)
whereas X-nuclei with I ¼ 1/2 (e.g., 31P, 19F) exhibit longer, more This direct gain in SNR by increased field strength is often the
proton-like relaxation properties. Therefore, signal acquisition of leading argument for the installation of UHF systems and enables for
FIGURE 1. Sodium (23Na) MR imaging at 1.5T (A), 3T (B), and 7T (C). A 3D density-adapted projection reconstruction sequence was used to acquire
3D data sets with a nominal isotropic resolution of (4 mm3). The SNR increases linearly with magnetic field strength. Parameters: TE (1.5T and
3T) ¼ 0.2 ms, TE (7T) ¼ 0.5 ms, TR ¼ 50 ms, flip angle a ¼ 778, 13,000 projections, acquisition time: 10 minutes 50 seconds. Copyright 2014 Wiley
Periodicals, Inc.; Figure and caption taken with permission of John Wiley and Sons from Kraff et al., J Magn Reson Imaging 2015; 41:13–33.
174 | www.topicsinmri.com ß 2019 Wolters Kluwer Health, Inc. All rights reserved.

Topics in Magnetic Resonance Imaging Volume 28, Number 3, June 2019 Multinuclear MRI at Ultrahigh Fields
some X-nuclei the ability to move from proof-of-concept studies to on multiple-quantum-filters.30,44 For spin-3/2-nuclei such as 23Na,
actual feasible clinical applications. The change in relaxation prop- double- or triple-quantum coherences can be generated if the sodium
erties with increasing B0 (e.g., T1, T2) can influence image quality nuclei are located in restricted mobility environments. Double-
and available SNR. For example, in proton imaging at UHF, quantum filters with magic angle excitation can be applied to
increased T1 and decreased T2 can be observed. Additional relaxation selectively image sodium or potassium in anisotropic environments
paths such as the chemical shift anisotropy (e.g., for 31P)28 or (e.g., ordered structures in skeletal muscle tissue).45,46 However,
quadrupole interaction (e.g., 23Na, 17O) can lead to a changed multi-quantum filter techniques suffer from reduced signal intensity
behavior of relaxation.29,30 And the T2 properties, which influence of about one order of magnitude lower than the signal intensity
the local signal behavior, can be dependent on the chosen voxel size obtained in conventional 23Na MRI. To increase SNR, biexponential-
and surrounding due to a sample-induced variation of B0. It was seen weighted imaging can be employed. In isotropic environments, the
that for quadrupolar X-nuclei, this effect strongly depends on the resulting image mainly contains triple-quantum-filtered signals.47 A
gyromagnetic ratio of the imaged nucleus22 and is only pronounced combination of single- and triple-quantum filtered imaging can be
in areas of strong B0 variation. employed to estimate the intracellular sodium concentration in
Thus, for UHF X-nuclei applications, the data acquisition and human brain tissue.48 Inversion recovery sequences may also be
processing have to be adapted to the particular setting and problem to the basis for the calculation of intracellular sodium concentrations.49
achieve highest possible image quality and quantitative accuracy. In addition, a multipulse sequence that exploits differences in T1 and
T2 relaxation of different sodium compartments has been applied to
estimate intracellular sodium concentrations.50 A limitation of these
METHODS AND DEVELOPMENTS FOR
techniques is that the required intra- and extracellular relaxation
MULTINUCLEAR MRI APPLICATIONS times cannot be measured directly in humans and, thus, are not
To acquire datasets with smallest possible voxel size and exactly known. This might introduce a bias and reduce the quantita-
adequate SNR in a time-efficient manner, specialized techniques tive accuracy. Therefore, sometimes, the terms ‘‘pseudo’’-intracel-
have to be applied. In the following sections, an overview of pulse lular and ‘‘pseudo’’-extracellular sodium have been preferred for
sequences, post-processing techniques, and RF hardware designs for such an analysis.51
multinuclear imaging is presented. In addition, X-nuclei MRI benefits from advanced image
reconstruction techniques. If multichannel array coils are used for
Pulse Sequences and Image Reconstruction in signal reception, the combination of signals from different coil
Multinuclear Imaging elements has to be performed. However, in the low-SNR regime
This section focuses on imaging of quadrupolar nuclei (I > 1/2). that is typical for multinuclear MRI, a simple sum-of-squares (SOS)
For spin-1/2-nuclei such as 31P or 19F, similar imaging techniques as reconstruction leads to noise amplification. Adaptive combination
in 1H MRI are often applied. In contrast, MRI of quadrupolar nuclei (ADC)52,53 or sensitivity encoding (SENSE)54 incorporate the sen-
usually requires UTE pulse sequences,31 due to aforementioned short sitivity profiles of all coil elements to improve SNR and perform
transverse relaxation times of quadrupolar nuclei. Conventional 3D superior compared with a SOS reconstruction. Image reconstruction
radial sampling of k-space is often used to achieve UTEs.32 However, algorithms that are based on compressed sensing can further improve
advanced UTE techniques such as density-adapted projection recon- image quality.55–58
struction result in higher SNR and reduced image blurring. In
addition, twisted projection imaging (TPI),33 3D CONES,34 acquisi- Data Processing and Correction Techniques
tion-weighted stack of spirals (AWSOS),35 or Fermat-looped projec- As mentioned earlier, the aim of multinuclear MRI is to quantify
tion imaging (FLORET)36 can be applied to improve k-space and display the spatially resolved distribution of the respective
coverage, and are favorable if a given field-of-view shall be sampled nucleus or ion concentration in various regions of the body.
within short acquisition times. These techniques are the basis for MRI of quadrupolar nuclei can be used to fully quantify
quantitative MRI of quadrupolar nuclei. An example of the utiliza- concentrations in the imaged field-of-view (FOV). Generally for
tion of one of these techniques for high-resolution sodium data is this purpose, UTE sequences are typically applied, as described in
given in Fig. 2 with a nominal resolution of (Dx)3 ¼ (1 1 5 mm3) the previous section. In order to estimate the absolute concentration
acquired at B0 ¼ 9.4T.37 in vivo, various influences have to be considered and corrected, for
Besides a quantitative determination of the total concentration example, transverse and longitudinal relaxation, field inhomogeneity
of a specific nucleus, often a separation between different compart- (B0, B1), PVEs, and, if present, motion. Then, external or internal
ments (e.g., intra- and extracellular pool) is of interest. Paramagnetic (e.g., cerebrospinal fluid (CSF)) references of known concentrations
shift reagents that do not penetrate the cell membrane can be used to are used to calibrate the previously corrected signal intensities. These
selectively shift the resonance frequency of sodium in the extracel- corrections are described hereafter.
lular space and, thus can provide a clear separation between intra-
and extracellular sodium.38,39 However, there is no approved human Correction of Field Inhomogeneity and Relaxation
use for these contrast agents. For 23Na MRI, non-invasive approaches Effects
— that are usually based on differences in relaxation times40–42 — In quantitative MRI of quadrupolar nuclei, the signal is deter-
have been used to provide at least a partial separation between mined by the FLASH equation,59 whereby the quantities r (spin
different 23Na compartments. For example, inversion recovery prep- density), a (flip angle), B1 (receive sensitivity), T2 (effective
aration can be applied to suppress signal from a sodium pool with a transversal relaxation time), and T1 (longitudinal relaxation time)
distinct T1 relaxation time and can be employed to achieve a are spatially dependent (voxel position x):
weighting toward the intracellular space. Soft inversion recovery
pulses can be utilized to reduce the specific absorption rate (SAR) T TE
and to increase SNR in non-suppressed tissue with short relaxation SðxÞ / rðxÞ sinðaðxÞÞ B1 ðxÞ e 2 ðxÞ
times.43 1e
T TRðxÞ
1
Another non-invasive approach to exploit information about the T TRðxÞ
(3)
molecular environment in which the sodium ions are located is based 1e 1 cosðaðxÞÞ
ß 2019 Wolters Kluwer Health, Inc. All rights reserved. www.topicsinmri.com | 175

FIGURE 2. Human 23Na MRI data (TSC map) with a nominal resolution of (Dx)3 ¼ (1 x 1 x 5 mm3), acquired at B0 ¼ 9.4T.37 Calibration was
performed with a silicone-caoutchouc and contained 6 compartments filled with agarose gels. Note that no correction for relaxation effects has been
performed for the TSC values. The transverse slices (A) exhibit a higher spatial resolution than the coronal (B) and sagittal (C) ones because of the
asymmetric voxel size used for the acquisition. Copyright 2014 Wiley Periodicals, Inc.; Figure and caption with permission of John Wiley and Sons
taken from Mirkes et al., Magn Reson Med 2015; 73:342–351.
Different methods for flip angle mapping in sodium MRI are If a true flip angle map is obtained, the signal distribution can be
well compared in simulations, phantoms, and tissue by Allen et al.60 corrected for inhomogeneity in the RF fields as follows:
(breast tissue) and Lommen et al.61 (brain). In these organs, where no
large-scale motion is present, the phase-sensitive (PS) method62 SðxÞ
rðxÞ / (4)
yielded the most accurate maps. In contrast to the established and sinðaðxÞÞ B1 ðxÞ
straightforward double-angle (DA) method,63 the PS method offers a
slightly higher SNR. However, for the PS method, typically a 1808
and a 908 pulse are applied. As short pulse durations should be If separate transmit and receive coils are used (e.g., coil array),

employed due to the very fast signal decay, the maximum permissible the receive sensitivity distribution B1;array ðxÞ of the receive coils has
pulse voltage or the maximum permissible SAR can be a limiting to be determined. By obtaining one image acquired with the transmit

factor. In these cases, it can be advantageous to use the DA method coil and one with the receive coils, B1;array ðxÞ of the receive coils can
where lower flip angles can be applied.64 be determined by dividing the corresponding signals S(x) from the
If wavelength effects can be neglected, distributions of transmit FLASH equation.
field B1þ ðxÞ ðB1þ ðxÞ / aðxÞÞ and receive sensitivity B1 ðxÞ of the B0 field maps can be calculated from the phase differences of
same coil can be assumed to have the same distribution: two acquired MR images at TE1 and TE2.67 The quantitative MRI
B1 ðxÞ / B1þ ðxÞ.65 However, due to a much shorter wavelength, acquisition is then corrected with the frequency offsets resulting from
differences in the relative distributions of B1þ ðxÞ and B1 ðxÞ can the B0 map.
occur, for example, for 1H or 19F excitation at about 300 MHz (B0 ¼ The influence of relaxation on quantification can be reduced by
7T) or higher.66 applying a short echo time (TE << T2) and a long repetition time

(TR > 5T1). If these conditions are not fulfilled, the influences of blurring. However, in most multinuclear studies in the human torso,
relaxation must be corrected. This requires the distributions of the influence of motion on the determined concentration was
relaxation times T1(x) and T2(x) to be known, measured, or esti- neglected. To minimize respiratory motion influences during 23Na
mated. The signal is adjusted via MRI, Pabst et al.80 proposed that subjects are positioned in the prone
position and James et al.81 told their volunteers to breathe in a short,
SðxÞ shallow pattern. Up to now, only a few X-nuclei studies considered
rðxÞ / (5)
TE
1e
TR
T 1 ðxÞ heart motion by triggered acquisition80,82 or retrospective sorting of
e T 2 ðxÞ acquired data.64,83– 85 Recently, respiratory motion has also been
TR
1e T 1 ðxÞ cosðaðxÞÞ
taken into account in 23Na torso MRI by retrospective respiratory
sorting based on an intrinsic respiratory signal.64,86
Calibration for Concentration Mapping Hardware

As mentioned before, in MRI of quadrupolar nuclei, absolute As the Larmor frequency is a nucleus-specific quantity, which
concentration values can be ascertained by scaling to one or more depends on the field strength (yL ¼ 2p 1
g x B0 ), there is an individual
internal or external references of known concentrations. External resonance frequency for each combination of nucleus X and field
references can be vials with calibration solutions with known con- strength (c.f. Table 1). Standard MR systems only support the
centrations of the nuclei of interest — optionally mixed with, for frequency of hydrogen. For MRI of other nuclei, the MR scanner
example, agarose to adjust the T2 relaxation properties for a better hardware has to be extended,87,88 for example, by an additional
tissue model.68 Falsifying influences of relaxation in the vials must narrowband power amplifier dedicated to the desired frequency or by
be evaluated and, if necessary, corrected. Signal intensities of the a broadband amplifier that allows handling of more than one
reference vials are then plotted against their known concentrations, additional frequency.
and a calibration curve is determined by linear fitting.69 Furthermore, dedicated RF coils for spin excitation and MR
signal detection are required, which are tuned and matched to the
Partial Volume Correction respective resonance frequency of the nucleus of interest. Most RF
A limiting factor for accurate quantification in small coils used so far are custom-made products or home-built. In general,
volumes is the comparatively low spatial resolution achievable these RF coils must enable the transmission and reception of RF
that is additionally degraded by broadening of the PSF. For multi- signals. In the transmission field for 1H or 19F spin excitation at about
nuclear imaging, the non-Cartesian acquisition schemes, rapid 300 MHz (B0 ¼ 7T) or higher, strong inhomogeneities can occur due
transverse relaxation as well as reconstruction filters enlarge the to wavelength effects, which can lead to cancellations in the B1þ field
FWHM compared with conventional cartesian imaging of protons. and to regional peaks in the distribution of the SAR.2 For frequencies
Typical voxel sizes range from (Dx)3 ¼ (2.0 mm)3 to (10.0 mm)3 lower than 130 MHz (approx. 1H at B0 ¼ 3T or 31P at B0 ¼ 7T), these
with an additional PSF enlargement by a factor of FWHM ¼ 1.59 effects were expected to be manageable.89 In contrast to excitation at
to 2.25.22 300 MHz and higher, which may require special RF coil designs90
Initially developed for positron emission tomography (PET) and imaging techniques (e.g., parallel transmit pTx),91–93 for exci-
quantification, some partial volume correction (PVC) algorithms can tation below 130 MHz, standard RF coil designs can be used. Here,
be adapted and applied to multinuclear MRI data. A comprehensive surface coils94 provide high transmit and receive efficiency close to
overview of available algorithms is given in the works of Erlandsson the coil but inhomogeneous field distributions whereas birdcage
et al.70 or Soret et al.71 For MRI applications, PVC methods that coils95,96 enable homogeneous field distributions in a large FOV
correct in the imaging domain are most favorable to exclude bias in with the drawback of a lower sensitivity. In general, an additional
signal regions of similar physical properties. An example for a receive coil array can be used in order to improve the receive
region-based correction approach is the geometric transfer matrix properties.
(GTM) method72 that was successfully applied in several X-nuclei Furthermore, double-tuned or multi-tuned RF coils are often
studies18,22,73,74 for improved concentration quantification. In the used. By supporting 1H imaging, standard phase shimming as well as
work of Stobbe and Beaulieu,75 the potential error in small objects anatomical localization and coregistration can be performed. A
was thoroughly investigated and could be used for more precise combination of two or more X-nuclei (e.g., 23Na/35Cl) can provide
investigation of, for example, small lesions. a wide range of additional physiological information.
The main limitation of the GTM-method is the volume-wise Up to now, there have been several studies dealing with
correction, impeding an individual evaluation after correction. Fur- multinuclear imaging of the head and calf muscle, mostly using
ther inaccuracy mainly during registration, segmentation, and simu- birdcage coils for transmission and reception. However, there are
lation of the PSF due to not fully known transverse relaxation also more sophisticated designs with receive arrays that, for example,
properties lead to an incomplete solution of the PVE problem22,76 provide 27 receive channels or 30 receive channels.52,97 An exem-
and not fully recovered intensities. plary complex RF coil design with a 27-channel 23Na receive
An alternative approach that was presented recently estimates array for 9.4T head imaging is shown in Fig. 3A,B. For more details
dynamic signal-time curves directly in the frequency domain, based on X-nuclei RF coils, these interesting review articles are referred to:
on parcellation of a coregistered 1H MR image and k-space acquisi- Wiggins et al.24 and Bangerter et al.98
tion.77 Pixel-wise correction utilizes iterative deconvolution techni- For MRI of the human torso, several RF coils are used: Coils
ques where edge information is put in.78,79 A possible MRI with small or medium FOV, for example, in breast,99,100 abdomi-
implementation would be desirable for a more flexible utilization nal,101 –105 spine,106 or prostate MRI107 and coils with a large
of data. FOV,81,86,108,109 for example, in lung, heart,64,110 or even whole-
body MRI.111 Two exemplary 7T coil designs that provide a large
Consideration of Motion in the Torso FOV for 23Na imaging inside the human torso are presented in
If respiratory and/or heart motion are present in the region of Fig. 3C to F. As there is no built-in commercial 1H body coil in a UHF
interest (ROI, e.g., tissue, reference vials), the determination of MR scanner, a body coil can be installed at this location enabling
spatially resolved concentrations can be impaired by motion MRI of another nucleus at UHF112 such as 31P.

FIGURE 3. RF coil designs (A, C, E) and implementations (B, D, F) for 23Na MRI applications. The 9.4T head coil (A, B) and the 7T cardiac coil (C, D)
are double-resonant RF coils (1H, 23Na) and the 7T torso coil (E, F) is a single-resonant 23Na RF coil. A, B, Three-layered RF coil for 23Na MRI of the
human brain at 9.4T. Innermost layer shown in (A): 27-channel 23Na receive helmet, intermediate layer: 4-channel 23Na transceiver array, outer
layer: 4-channel 1H dipole array. Copyright 2015 Wiley Periodicals, Inc., Reprinted with permission of John Wiley and Sons from Shajan et al., Magn
Reson Med 2016; 75:906–916. C, D, RF coil array tailored for cardiac 23Na MRI at 7T consisting of two sections: anterior section (coil elements #1 and
#2 as well as 1H dipole element), posterior section (coil elements #3 and #4). Copyright 2015 John Wiley & Sons, Ltd., Adapted with permission of
John Wiley and Sons from Graessl et al., NMR Biomed 2015; 28:967–975. E, F, 23Na transceive oval-shaped body resonator with 12 rungs and 4 feed
ports for 23Na MRI of various regions of the human torso at 7T. The coil can be separated into two halves for comfortable positioning of the subject.
Copyright 2018 International Society for Magnetic Resonance in Medicine, Reprinted with permission of John Wiley and Sons from Platt et al., Magn
Reson Med 2018; 80:1005–1019.
A uniform B1þ field distribution in the ROI can be advantageous covered by several review articles.113,114 In normal brain tissue,
in multinuclear MRI, because high SAR-demanding adiabatic RF sodium concentrations close to 50 and 40 mmol/L have been mea-
pulses, which limit the SNR,112 can be avoided (e.g., in 31P MRSI) sured for grey and white matter, respectively.74 This reflects a
and a correction of B1 inhomogeneity effects is less prone to errors due volume-weighted average of the intra- and extracellular sodium
to its homogeneous distribution86 (e.g., in quantitative 23Na MRI). compartment. Due to the large concentration gradient between intra-
and extracellular sodium, the tissue sodium concentration (TSC) is
BIOMEDICAL APPLICATIONS FOR X-NUCLEI particularly sensitive to changes in the intracellular volume-fraction
Areas of possible X-nuclei application are widespread and the (e.g., caused by cell death) and to increases of the intracellular
information targeted strongly depend on the nucleus of interest. sodium concentration (e.g., caused by energy failure). It has been
The following passage is structured by the imaged nucleus, starting estimated that approximately half of the brain’s oxygen consumption
with 23Na, but also treating 17O, 31P, 39K, 25Mg, and other exotic is used to pump sodium ions out of the cells and potassium ions into
imaging nuclei. the cells. Thus, the sodium ion gradient plays an important role for
normal functioning of the brain. Alterations of this cellular ion
23
Na — Functional Information of the Cell gradient — usually indicated by an increased TSC — can be an
Sodium (23Na) plays a crucial role in a multitude of physiologi- early marker in many pathologies.
cal processes. 23Na MRI represents a direct method for quantifying In multiple sclerosis, studies indicate that pathologic intracel-
the 23Na concentration in tissue and therefore offers the possibility to lular sodium accumulation may play a pivotal role in inflammatory
directly investigate tissue viability. The potential of quantitative 23Na as well as neurodegenerative process.12 Inglese et al.10 and Zaaraoui
MRI has been demonstrated in preclinical and clinical studies, et al.11 showed that TSC in areas of normal-appearing white matter
particularly in brain and muscle applications. can be significantly increased compared with those in corresponding
white matter regions in healthy controls. In addition, studies in
Brain ischemic stroke,115 brain tumors,4,6,116– 119 Alzheimer diseases,120
Most 23Na MRI studies that have been performed so far have Huntington disease,121 and traumatic brain injury122 have been
been focused on healthy or diseased brain. The topic has been performed. For example in stroke, 23Na MRI may add information

FIGURE 4. Glioblastoma multiforme of the right temporal lobe and the corpus callosum. First column: Contrast-enhanced 1H T1-weighted
(1H T1 CE) and 1H T2-weighted fluid-attenuated inversion recovery (IR) (1H T2 FLAIR) show visualization of contrast-enhancing parts and perifocal
edema. Second column: Concentration-weighted 23Na MR imaging (23Na MRI) reveals elevated signal intensity in all parts of the tumor, whereas
23
Na IR MRI showed parts with reduced and others with increased signal intensities. Third column: Slightly increased signal intensities are also visible
in concentration-weighted 35Cl MR imaging. In contrast to 23Na IR MR imaging, 35Cl IR MR imaging reveals a strong signal increase in the affected
brain region. 1H images were acquired at 3T, 23Na and 35Cl images at 7T. Each 23Na and 35Cl examination required approximately a measurement
time of 10 min. Figure and figure caption adapted with permission of the Radiological Society of North America (RSNA) from Nagel et al. Radiology
2014; 271:585–595/Ladd et al., Prog Nucl Magn Reson Spect 2018; 109:1–50. Copyright RSNA.
about the preservation of the tissue ion homeostasis and thus may In summary for dedicated TSC studies,22 TSC values for
permit identification of patients with viable tissue, despite an normal gray matter (NGM) were TSCNGM ¼ 30 to 62 mmol/L; for
unknown symptom onset time.123 normal white matter (NWM): TSCNWM ¼ 19 to 72 mmol/L. Studies
An application example in a glioblastoma patient is given in with external calibration obtained TSCCSF ¼ 125 to 155 mmol/L.
Fig. 4 showing elevated signal intensity in concentration-weighted Exact knowledge of relaxation properties improves the correction
23
Na MRI in all parts of the tumor, whereas 23Na IR MRI shows a capability.22
heterogeneous distribution of signal intensities.
In many use-cases, an absolute quantification of TSC is Fields of Application in other Body Regions
desired. Several approaches with decreasing voxel volumes The review by Bangerter et al.128 provides a very interesting
without specific PVC6,10,69,124,125 were presented over the years. summary on quantitative 23Na MRI of the musculoskeletal system,
Mirkes et al.37 presented the so far highest spatial resolution including cartilage, muscle, and tendon. 23Na MRI can be used to
(1.0 1.0 5.0 mm3) for 23Na MRI of human brain (c.f. Fig. 2). estimate the glycosaminoglycan (GAG) content of cartilage, which
The total acquisition time was 30 minutes at B0 ¼ 9.4T. For in vivo performs a crucial role in cartilage homeostasis.129 Studies demon-
23
Na MRI of the human eye, even a nominal spatial resolution of strated its feasibility in healthy and osteoarthritic cartilage as well as
1.0 mm isotropic could be achieved using a dedicated RF receiver in cartilage repair tissue, which is restored in surgery. Staroswiecki
array.126 et al.26 showed 2.3-fold higher sodium SNR in the cartilage at 7T
In general, lower than expected TSC values of CSF compared with 3T and thus confirmed the linear relationship between
(healthy person 135 to 155 mmol/L127) in many studies are SNR and field strength. An axial image from a knee MRI scan in a
indicating an uncorrected bias in the process of quantification. healthy volunteer at 7T is illustrated in Fig. 5A showing high signal
The necessity and feasibility of adequate PVC for TSC in cartilage.
quantification was shown in a small volunteer study76 applying 23
Na MRI of small tissue structures such as cartilage and skin
the GTM-algorithm for the first time to multinuclear MRI data of is particularly challenging due to large voxel sizes required and
healthy volunteers. associated PVEs. Skin sodium was investigated at 7T to explore

FIGURE 5. 23Na MRI applications in various body regions performed at 7 Tesla. A, Transversal knee MRI in healthy volunteer showing high signal in
cartilage. Copyright 2010 Wiley-Liss, Inc., Reprinted with permission of John Wiley and Sons from Staroswiecki et al., J Magn Reson Imaging 2010;
32:446–451. B, Transversal 1H MRI of calf placed on external references and below 23Na MR image of calf skin. Copyright 2014 John Wiley & Sons,
Ltd.; Modified with permission of John Wiley and Sons from Linz et al., NMR Biomed 2015; 28:54–62. C, Sagittal slice showing chronic Achilles
tendinopathy with 23Na signal increase in the whole tendon. Reproduced, with permission from Springer Nature Customer Service Centre Gmbh:
Springer Nature, Juras et al., Radiology 2012; 262:199–205. Copyright RSNA. D, Transversal MRI of the resting calf of a healthy volunteer with
reference phantoms. Reprinted by permission from Chang et al., Eur Radiol 2010; 20:2039–2046. E, Bilateral transversal MR images of breast tissue
obtained in a healthy woman. Reproduced, with permission, from Zaric et al., Radiology 2016; 280:39–48. Copyright RSNA. F, Transversal cardiac
slice of a healthy volunteer in the diastolic and exhaled state (Courtesy of Johanna Lott, Division of Medical Physics in Radiology, German Cancer
Research Center (DKFZ), Heidelberg, Germany). G, Coronal renal MR images in healthy volunteer. Reprinted by permission from Springer Nature
Customer Service Centre Gmbh: Springer Nature, Haneder et al., Eur Radiol 2013; 24:494–501.
Naþ storage in the skin aiming to provide answers to open questions The feasibility of in vivo sodium MRI of the intervertebral disk
on Naþ balance and storage.130 With the presented setup, a reliable was demonstrated at 4T by Insko et al.141 The 23Na concentration in
quantification could be performed at UHF (c.f. Fig. 5B showing the intervertebral disk was estimated by using CSF as an internal
transversal 1H and 23Na MRI of calf skin). At 3 Tesla, the quantitative standard. The negative fixed charge density (FCD) in the interverte-
accuracy of skin sodium measurements is limited. However, it could bral discs, which was estimated depending on the 23Na concentra-
be shown that skin sodium content is significantly higher in men than tion, corresponds well with the literature values.
in women and correlates with systolic blood pressure.131 23
Na MRI studies have also demonstrated an increased 23Na
Furthermore, the feasibility of 23Na MRI to visualize differ- concentration in malignant tissue breast lesions,99 suggesting that it
ences in 23Na signal intensity between healthy tendons and subjects may serve as an indicator of malignancy. In addition, significant
with Achilles tendinopathy has been demonstrated at 7T132 (c.f. decreases in 23Na concentration were observed in responders to
Fig. 5C). In addition, 23Na MRI was investigated as a potential chemotherapy.142 The clinical feasibility of 23Na breast MRI at
diagnostic imaging modality for muscle diseases that are expected to 7T was demonstrated by Zaric et al.,143 allowing good differentiation
alter the distribution of intracellular and extracellular 23Naþ con- between malignant and benign breast lesions and showing an inverse
centrations.14,133,134 Weber et al.135 demonstrated increased Naþ and correlation with the apparent diffusion coefficient. A bilateral axial
Cl concentrations in periodic paralyses compared with healthy MR image of breast tissue obtained in a healthy woman at 7T is
subjects, which were most pronounced in the severe phenotype. shown in Fig. 5E.
Elevated muscular Naþ concentrations were also observed in Duch- Bottomley144 has thoroughly reviewed sodium MRI in the
enne muscular dystrophy.136 Gerhalter et al.137 showed that these human heart. The feasibility of cardiac 23Na MRI at clinically
changes can be present even in the absence of fatty degenerative acceptable acquisition times110 and of retrospectively-gated CINE
changes and water T2 increases. In addition, elevated muscular cardiac 23Na MRI83 was demonstrated at UHF. Recently, Lott et al.64
sodium content is present in dialysis patient138 and in particular have investigated the influences of various corrections on quantita-
in diabetic dialysis patients.139 Muscle response to exercise was also tive 23Na cardiac MRI (e.g., PVC, cardiac and respiratory sorting).
explored by 23Na MRI.14 The results of Chang et al.140 at 7T suggest Figure 5F demonstrates an axial cardiac image of a healthy volunteer
that the 23Na signal intensity of the skeletal muscle recovers more in the diastolic and exhaled state obtained at 7T.
slowly after exercise in diabetics compared with healthy subjects. An Henzler et al.145 demonstrated preliminary 23Na MR images in
axial image from an MRI scan at 7T of the resting calf of a healthy lung cancer in three patients and suggested that 23Na MRI may provide
volunteer is shown in Fig. 5D as an example. additional information on tumor viability and therapy response.

A comprehensive review article on quantitative sodium MRI of invasive, measurements to determine the cerebral blood flow. The
the kidney is given by Zoellner et al.146 Its feasibility at 7T was validation of this metabolic model allowed the straightforward
shown by Haneder et al.,105 who investigated the corticomedullary application of dynamic 17O MRI in volunteers16–18 and
concentration gradient and the T2 relaxation. Quantitative renal 23Na patients.73,161
MRI (c.f. Fig. 5G) was obtained with an improved resolution For a distinct functional quantification, a gas application system
compared with studies at lower field strength (at 7T: in-plane is required, which is described, for example, in the works of
resolution: 4 mm x 4 mm, slice thickness: 5 mm). Baumgardner et al.,162 Hoffmann et al.,17 and Niesporek et al.18
for a 4-phase and 3-phase experiment, respectively. The elementary
17
O MRI — Imaging of the Energy Metabolism functionality must allow switching between room air (natural abun-
The energy metabolism on the cellular level as an indicator of dance 17O2) and a closed circuit, whereby enriched gas is inhaled
cell viability can directly be measured via dynamic 17O MRI.16 The from a reservoir. A rebreathing approach requires a third breathing
basic process that is mapped is the production of H217O in the process pathway to make use of the exhaled gas. All inhalation systems
of oxidative phosphorylation. Glucose and capillary blood oxygen contain CO2-absorber to allow longer closed-circuit breathing dura-
are metabolized within the cell mitochondria to produce adenosine tions (normally 6 to 10 minutes16,18) and are located close to the
triphosphate (ATP) where H2O is released as a waste product; this subject within the magnet to minimize dead space and breathing
turnover rate is denoted as CMRO2. From the biomedical point of resistance.
view, an alteration of the CMRO2 value is connected to diseases such
as cancer (‘‘Warburg Effect’’),19 Parkinson disease, or Alzheimer CMRO2 Results in Humans
disease.147–149 There are only a handful of examples for human applications of
A quantitative assessment of the H217O concentration via 17O dynamic 17O experiments for UHF16–18,73 and some at lower fields
MRI opens the possibility of directly imaging this metabolic param- (B0 ¼ 3T)77,151 mainly due to the high costs of the rare oxygen
eter, but it requires a change in the inhaled 17O2 gas concentration isotope (2500 USD/L). Studies with one or two individual meas-
above natural abundance and a suitable metabolic model. The first urements16,17 demonstrated the general feasibility and were able to
successful experiments have been performed at B0 ¼ 9.4T,16 state the first CMRO2 values for NGM and NWM. The accuracy of
7T,17,18,73 and 3T76,150– 152 so far. Preceding small animal stud- functional quantification can be seen in a very low CSF value. The
ies153–158 demonstrated the general feasibility. A detailed overview gold standard so far is the quantification via 15O PET,163 which has a
is given in work of Zhu et al.159,160 comparable resolution of (Dx)3 ¼ (5.0 to 10.0 mm)3. A dedicated 17O
MRI reproducibility study18 evaluated the robustness of the sug-
Metabolic Model and Gas Application gested method and applied a PVC algorithm to reduce the bias of low
The metabolic model, which allows direct quantification of the resolution induced PVE bias, stating higher values in the NGM
CMRO2 value from quantified H217O content, requires a change in compartment and comparable CMRO2 in NWM. Still, data avail-
inhaled 17O2 gas concentration. Here, basically two approaches are ability is very limited and more experiments at various sites must be
used: (1) direct inhalation of enriched gas16,18 leading to a 3-phase conducted to further confirm dynamic 17O MRI as a valuable tool for
model (three inhalation phases: natural abundance — enriched — metabolic imaging.
natural abundance) and (2) a 4-phase inhalation where exhaled The first application of 17O MRI in a patient was performed in
oxygen (still enriched) is used in an additional breathing phase. 2014 with a single WHO grade IV (Glioblastoma) patient revealing
The latter optimizes the use of cost-intensive 17O2 gas, but increases the expected strong decrease of CMRO2 in the tumor volume, as seen
the technical challenges for the gas application system and the in Fig. 6. Further measurements in high and low-grade patients
uncertainty in parameter estimation.151 In any case, the model (WHO IV and WHO II)161 supported the character of direct meta-
considers the creation of metabolic water and wash-in/wash-out bolic imaging. In tumor patients, it is now possible to visualize
from the blood pool and does not have the need for additional, often the Warburg effect and perform quantitative analysis of tumor
FIGURE 6. Example of 17O MRI application: Anatomical 1H image (T1w-MP-RAGE) after contrast media administration with typical ring
enhancement (A). Parameter map of the relative 17O signal increase after 17O2 inhalation in the corresponding slice (without PVC) (B). Colored
overlay of the signal increase and the registered 1H data for anatomical reference. The central necrotic region of the tumor coincides well with the
area of the lowest 17O signal increase of <2%. The highest gain in intensity was found in regions with a high gray matter fraction. With permission of
Springer Nature; figure and figure caption adapted from Hoffmann et al., Magn Reson Mater Phy 2014; 27:579–587.

pathophysiology, which may contribute to treatment planning and More Spectroscopic Applications (7Li, 19
F, 31
P, 2H)
follow-up monitoring based on a physiological contrast. Magnetic resonance spectroscopy (MRS) applications of some
X-nuclei are already well established. However, imaging — for
Exotic Nuclei (25Mg, 35/37
CI, 39
K) Imaging example, imaging phosphorus(31P)-containing compounds — has
Some other nuclei with very low NMR sensitivity are also rarely been used so far. Other examples are lithium (7Li), fluorine
detectable and can have potential use for obtaining specific and (19F), or deuterium (2H) MRI. The following section briefly
alternative metabolic information. describes advances in the field of imaging for those nuclei.
Chloride Imaging
Apart from the sodium ion, discussed in previous sections, Lithium Applications
An example of direct imaging of pharmaceuticals in a target
detection and imaging of chloride (Cl), the most abundant anion

in the body is also feasible at UHF.68 Similar to 23Naþ, the Cl- ion is area is the mapping of lithium in the human brain. In most cases,
involved in cellular physiological processes. Examples are the lithium is administered orally as Li2CO3 for treatment of acute mania
inhibition of cells (muscular164/neuronal165), cellular volume regu- or bipolar disorder.178,179 With a natural abundance of 92.4%, 7Li is
lation,166 and cell migration in cancer.167,168 the most abundant lithium isotope and detectable with MR.180 In
The available signal and relaxation constants for in vivo imag- healthy humans, lithium is only present in trace levels and rises
ing made the application at lower field strengths impractical. Fol- during medication and treatment to a concentration 0.5 to 1 mM.
lowing initial small animal 35Cl MRI studies at 9.4T,169,170 some Little is known about the effects of lithium on the cellular level and
investigational 35Cl MRI studies in brain tumors (c.f. Fig. 4) and in its clinical effects. Here, detection and mapping of the lithium
muscle diseases were performed.68,135 Here, voxel sizes of (6 mm to distribution in treated patients might help to understand the underly-
12 mm)3 were used and permitted, visualization of pathophysiologi- ing pathways and treatment approaches. The development
cal change in cancer or muscle cells. In general, chloride quantifica- of 7Li MRS/MRSI studies have been progressing slowly, but
tion with a compartment-wise PVC approach is possible, partially steadily. A comprehensive overview is given in the review articles
balancing strong signal cross-talk.76 of Komoroski.181,182
The chlorine isotope 35Cl has a natural abundance of 76%. Some Fully quantitative imaging applications must cope with unfa-
experimental applications have been performed with 37Cl imaging in vorable relaxation properties (T12 seconds)183 and low SNR.
rats171 and in the human calf.172 The less abundant (24%) chlorine Therefore, for 7Li MRI, suitable pulse sequences have to be chosen.
isotope 37Cl exhibits favorable relaxation properties for a more reliable Recent applications at 3T184 utilized a cartesian-balanced steady-
absolute quantification. Special technical modifications88 and the neces- state free precession (b-SSFP) for 3D datasets and full brain cover-
sity of UHF systems impede a broader application of chloride imaging. age. Investigation of the lithium brain distribution at 7T used a
comparable approach with radial acquisition.185 In both cases, a
Potassium Imaging quantitative evaluation was feasible with an acquisition time of 8 to
For Kþ, the cellular concentration is reversed and even more 30 minutes and a spatial resolution of (Dx)3 ¼ (17–25)mm3. It was
pronounced than the cellular Naþ gradient. Approximately 98% of stated that further work will evaluate the observed heterogeneity to
the body Kþ content is located in the intracellular space. Thus, 39K treatment response and administered serum dose.
MRI mainly detects intracellular Kþ, which is currently not accessi-
ble in a clinical examination. Despite an extensive reduced available Fluorine Applications
signal in vivo (107) compared with 1H, 39K MRI was performed in The fluorine (19F) nucleus represents an interesting imaging
the rat brain173,174 and in a limited number of human subjects.88,175 modality and has the potential to be used as a tracking agent on the
The measured Kþ concentrations of the healthy thigh muscle (112 to molecular or cellular level. The feasibility of 19F MRI was demon-
124 mmol/L) were within the expected physiological range.88 For strated shortly after the development of MRI with protons.186 The
muscle tissue, also, quadrupolar splitting of the 39K resonance could physical properties of 19F (I ¼ 1/2) are comparable to 1H, leading to
be observed, which is compatible with a non-vanishing electrical an intrinsic sensitivity of 83% of 1H (c.f. Table 1). In vivo 19F is only
field gradient interacting with 39K nuclei in the intracellular space of present in an immobilized form in teeth and bones, and absolutely
muscle tissue.45 absent in soft tissue. This enables tracking of labeled substrates with
nearly no background signal (hot spot detection). Due to the structure
25
In Vivo Mg Spectroscopy and Imaging of the outer-electron shell, 19F has a very wide and sensitive
The feasibility of 25Mg in vivo imaging of humans was demon- spectroscopic range, leading to numerous 19F MRS/MRSI applica-
strated176 despite the challenges arising from its low NMR sensitivity tions. A summary of this area of research is given in the review of
and in vivo concentration (see Table 1). As the magnesium ion plays Yu et al.187
an important role in cellular processes, alteration of 25Mg content is Imaging of administered 19F-containing compounds is an inter-
connected to several diseases.177 The first 25Mg imaging experiments esting method for quantitative assessment of the structure, function,
of the human calf muscle were performed at B0 ¼ 7T with a custom- and molecular processes in diseases. Nonetheless, applications so far
built coil, using a density-adapted radial sequence. In addition to in have solely been limited to in vitro or animal experiments.188 The
vivo images obtained with Dx3 ¼ (25 mm)3, MR data were used to transfer to humans or even human patients has not yet happened, as
estimate T2 relaxation times in the soleus and gastrocnemius even in animal experiments at UHF, with fewer restrictions on
muscles. Here, a T2 of (107 36)ms was estimated in the human administered concentration and SAR, the SNR of 19F data is barely
calf. A second peak in the in vivo MR spectrum suggests that, in above the detection threshold.189 One promising approach is the
addition to free 25Mg2þ ions, it is possible to detect 25Mg in a bound investigation of tumor hypoxia by 19F MRI pO2 mapping.190 Another
state. Within this study, it was possible to determine T2, T2, and T1 field of application is the use of perfluorocarbon (PFC) in nanopar-
relaxation constants in model solutions with varying agarose con- ticle form for a wide variety of tracking applications191; a compre-
centration (0% to 5%). Long T1 relaxation times [T1 ¼ (220–111)ms] hensive overview is given in work of Srinivas et al. (focus on cell
combined with short T2 [T2 ¼ (42–12)ms] of these model solutions tracking)189,192 and Chen et al.188 The main challenge arising is the
indicate unfavorable properties for quantitative imaging. detection with an adequate spatial and temporal resolution with a low

compound concentration present. The utilization of UHF systems is Nevertheless, at 7 Tesla — currently the most common field
one major improvement toward a further use for human applications, strength for UHF MRI — imaging of sodium with reasonable voxel
which would permit an interesting molecular imaging approach. volumes is feasible within clinically reasonable acquisition times.
This may foster the translation of sodium MRI from a clinical
Phosphorus Imaging research tool to a diagnostic tool in the near future. For MRI of
In living cells, 31P-containing compounds are involved in most other nuclei with lower sensitivity such as 17O, 35Cl, and 39K,
processes of energy metabolism. The concentration of those metab- potential clinical research applications can be explored for the first
olites allow investigators to draw conclusions about workload in time at ultrahigh fields. An important step can be studies with many
healthy or diseased states in malignant tissue and to monitor tissue subjects or multicenter studies in which findings and the numerous
pH level. Due to a wide frequency spectrum of 31P compounds, MRS approaches can be compared and standardized. In this way,
applications are often preferred.193–196 Direct 31P imaging is favor- the clinical potential of multinuclear imaging at UHF can be
able in terms of spatial resolution and coverage, but faces problems demonstrated.
of available SNR and frequency selectivity. In addition, proton-like
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Multinuclear MRI at Ultrahigh Fields

human brain tumors,4 –6 stroke,7– 9 multiple sclerosis,10–13 or muscle

diseases.14,15 Another application is the utilization of 17O MRI for

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Calibration for Concentration Mapping Hardware

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detection and imaging of chloride (Cl), the most abundant anion

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