MRI at 7 Tesla and above: demonstrated and potential capabilities.

CME JOURNAL OF MAGNETIC RESONANCE IMAGING 41:13–33 (2015)

Review Article

MRI at 7 Tesla and Above: Demonstrated and Potential Capabilities Oliver Kraff, PhD,1* Anja Fischer, PhD,2 Armin M. Nagel, PhD,3 €nninghoff, PhD,2 and Mark E. Ladd, PhD1,3 Christoph Mo sites to investigate new technologies for MR applications. Despite all this development, the pivotal currency in MR remains signal-to-noise ratio (SNR), which must be sufficiently available to trade against reducing the voxel size or acquisition time while maintaining acceptable image quality. Improvements in MR hardware, such as radiofrequency (RF) coils, can increase the available currency, but only to a limited amount as the ultimate intrinsic SNR remains determined by body noise (1). Of course, an obvious step is to increase the spin polarization with higher static magnetic field strength B0, as the two are linearly related to one another. While the very first commercially available MR systems operated at field strengths between 0.3 and 0.6 Tesla (T) using permanent magnets, cryogenically cooled, superconducting 1.5T systems were introduced in rapid succession in 1985 and subsequently dominated the market as the standard for clinical imaging. In fact, to the current day, 1.5T magnets are still the clinical workhorses and have the highest market share. Toward the end of the 1990s, vendors of MR systems decided to double the field strength of clinical systems from 1.5T to 3T, which theoretically doubled the available SNR. Reasons for the selection of this field strength were many. A major determinant, however, was that expected problems related to radiofrequency (RF), such as inhomogeneities of the transmit (B1) field and higher power deposition in human tissue, were expected to be manageable. Additionally, actively shielded magnets were available which reduced risks regarding siting issues in hospital environments. Although the first 3T devices, which had large magnets with less homogeneity and nonoptimized hardware (RF and gradient coil technology and pulse sequences were largely copied and adapted from 1.5T systems) offered only few advantages over 1.5T systems (2), 3T imaging is now increasingly used in clinical practice, and, along with constant technical advancements over the past 10 years, has demonstrated improved imaging quality and speed, as well as concomitant improvement in diagnostic accuracy for a variety of applications (3,4). A final point is that within the regulatory framework of the International Electrotechnical Commission (IEC) (5), the normal operating mode of a MR system comprises a magnetic

With more than 40 installed MR systems worldwide operating at 7 Tesla or higher, ultra-high-field (UHF) imaging has been established as a platform for clinically oriented research in recent years. Along with technical developments that, in part, have also been successfully transferred to lower field strengths, MR imaging and spectroscopy at UHF have demonstrated capabilities and potentials for clinical diagnostics in a variety of studies. In terms of applications, this overview article focuses on already achieved advantages for in vivo imaging, i.e., in imaging the brain and joints of the musculoskeletal system, but also considers developments in body imaging, which is particularly challenging. Furthermore, new applications for clinical diagnostics such as X-nuclei imaging and spectroscopy, which only really become feasible at ultra-high magnetic fields, will be presented. Key Words: ultra-high-field imaging; technical demands; neuro applications; whole-body; x-nuclei applications; clinical J. Magn. Reson. Imaging 2015;41:13–33. C 2014 Wiley Periodicals, Inc. V

SINCE ITS INTRODUCTION into clinical settings in the mid-1980s, magnetic resonance imaging (MRI) has developed into one of the most flexible tools in diagnostic imaging as well as into a highly active field of medical and methodological research. Multiparametric MR, including high-resolution structural imaging as well as a variety of functional techniques, along with technical improvements allowing fast and ultrafast imaging have continuously led to clear diagnostic benefits and thereby inspired vendors and research

1 Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Essen, Germany. 2 Department of Diagnostic and Interventional Radiology and Neuroradiology, University Duisburg-Essen, University Hospital, Essen, Germany. 3 Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. *Address reprint requests to: O.K., Erwin L. Hahn Institute for Magnetic Resonance Imaging, University Duisburg-Essen, Arendahls Wiese 199, 45141 Essen, Germany. E-mail: [email protected] Received October 25, 2013; Accepted January 3, 2014. DOI 10.1002/jmri.24573 View this article online at wileyonlinelibrary.com. C 2014 Wiley Periodicals, Inc. V

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Table 1 Overview of Dedicated Benefits and/or Key Solutions as Well as Limitations of Clinical MRI/MRS at UHF Regarding Installation and Operational Issues* Application area

Benefits / key solutions

Limitations

Technical demands

Shorter and actively shielded magnets with zero helium boil-off have recently become available.

Neuro

Improved depiction of microanatomy, especially of iron-containing brain structures such as the dentate nucleus and basal ganglia, as well as improved visualization of pathophysiology in vivo (e.g. demyelination in MS).

Whole-body

Improvements in image quality and homogeneity have been achieved by dynamically applying static RF shimming solutions along with improved RF coils.

X-nuclei

For 23Na MRI and 31P MRS, the acquisition of reasonable voxel resolutions becomes achievable within clinically reasonable measurement times. Feasibility studies with largely unexplored nuclei (e.g. 35Cl, 39K) have been performed.

Still limited number of RF coils available, and strong support from MR physicists needed for operation of UHF systems. Longer T1 relaxation times at UHF and SAR restrictions, along with much larger acquired matrices, have led to longer acquisition times in clinical examination protocols compared with 1.5 T or 3 T. Gradient echo image quality is impaired due to increased geometric distortions near air-filled cavities, and spin echo image quality is impaired due to imperfections in RF flip angles. Available peak RF power at UHF of typically only 8 or 16 kW on the one hand and SAR restrictions on the other hand limit the penetration depth in large cross sections, most prominently seen in spin echo imaging. SAR limitations often restrict optimal pulse sequence parameters. The optimal magnetic field strength for MRI of many X-nuclei might lie even higher than 7 T or 9.4 T.

*These are categorized for each imaging application area mentioned in the text.

field strength of equal to or less than 3T, so that all current clinical systems can operate in this mode. Inspired by the great success of 3T MRI, even higher magnetic fields up to 9.4T have been explored under appropriate ethical permission for neuroscientific and clinical research since the late 1990s (6–8). Projects in the near future will even target 10.5T (e.g., Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN) and 11.7T magnets (e.g., Neurospin CEA, Saclay, France; National Institute of Health, Bethesda, MD) (9). Currently, most of the approximately 40 installed ultra-high field (UHF) systems operate at 7T. During the past years, the number of finalized or planned installations has increased rapidly indicating the growing interest brought about by initial results demonstrating diagnostic benefits especially in brain imaging (10). On the other hand, technical issues when moving from 3T to UHF systems are much more prominent than what was known from the step between 1.5T and 3T. As in the early years of 3T MRI, 7T systems have started their journey with hardware and software from lower field strengths not optimized for the needs and circumstances of UHF imaging. Time must be granted to achieve the dedicated developments necessary to fully exploit these higher field strengths, and these developments may in turn also positively affect developments for lower field strengths. In the end, the question whether 7T (or above) will emerge as the next benchmark in MR imaging will be answered partly by cost efficiency, but mainly by demonstrated diagnostic benefits and clinical applicability. From a regulatory point of view, all UHF systems are currently considered to be investigational devices. Although the level of nonsignificant risk was raised to 8T in 2003 by the U.S. Food and Drug Administration (FDA) (11), no vendor of UHF systems has yet applied for approval to allow diagnostics. It is expected that

the IEC will change its recommended limits accordingly in an upcoming revision of the current standard within the next 1 or 2 years. So far, approval by institutional review boards is needed for in vivo use, and over the past years the number of clinical research studies has increased rapidly at UHF. Hence, the aim of the current review is to provide an overview of the benefits that have been demonstrated thus far and to discuss potential applications (q.v. Table 1).

TECHNICAL DEMANDS ON UHF IMAGING While general advantages and challenges for imaging at ultra-high field strength have been expertly described in many previous reviews (2,8–10,12,13), including increases in the level of imaging artifacts with magnetic field strength (14), we focus on the technical demands, and, in particular, how they have been addressed over the past years to bring 7T closer to a clinically applicable field strength. Magnet Issues Magnets of UHF systems are usually passively shielded by a cost-intensive steel casing of the examination room. The 7T MR systems of the first generation needed around 250–450 tons of steel to confine the stray magnetic field. In 2010, a second generation of 7T magnets became available, which are far more compatible with most hospital infrastructures and are a key development for accelerating the use of UHF in clinical settings. The new magnets are not only shorter by approximately 45 cm but, furthermore, actively shielded (15), so that the steel casing can be reduced to only 10% of the previous amount. Additionally, the new systems are now equipped with zero boil-off technology and improved gradient coils for

Capabilities of MRI at 7T and Above

less eddy currents on the cryostat to reduce the overall helium consumption (15). The latter is actually becoming of vital importance, as helium shortages are continuing to challenge the MRI community and especially the UHF sector. The first generation 7T magnets had a helium boil-off of typically 200–250 liters per month with a refill schedule of every 2 months on average (16). Especially during summer months, when natural gas fields are usually in maintenance, shortages have a noticeable impact on the available delivery quantity. However, of paramount importance for new installations of UHF systems and in particular for introducing higher magnetic field strengths beyond 7T is the amount of cryogen needed during installation of a UHF magnet. While around 13,000 liters liquid helium and 13,000 liters liquid nitrogen are needed to cool down a 7T magnet (17), more than 30,000 liters liquid helium and 10,000 liters liquid nitrogen are needed to cool down an 11.7T magnet (18). Unfortunately, only 40 to 50% can be recovered, while the remaining gas is released into the atmosphere during the filling process. RF Characteristics While problems associated with the increase in RF frequency from 64 MHz to 128 MHz for 1H imaging were expected to be manageable at 3T, they could certainly not be ignored at 7T with 300 MHz. At higher field strengths, the wavelength l ¼ c/f0 becomes proportionally shorter with field strength or Larmor frequency f0. Additionally, the distribution of different human tissue types (fat, muscle, fluids) and their frequency-dependent dielectric properties (permeability, permittivity, and conductivity) must be taken into account. These considerations are the roots for the two key challenges of UHF imaging: B1 inhomogeneities in large cross-sections and RF power deposition in tissue. Nonuniform excitation of human tissue leads to patterns of destructive and constructive B1 interference as the Larmor wavelength approaches the dimensions of the human head and larger organs (19). For body imaging, these shading artifacts are already prominent at 3T, and contrary to expectations, they are not always severest in large, adipose patients (14), but often much more so in well-trained muscular subjects. Relative to fat, muscle has a relatively high dielectric constant and also higher conductivity, so that this lossy medium yields stronger interactions with incidental RF waves (20). Not only does this influence flip angle and contrast over the imaging slice, but also the penetration depth. Hence, without adapting the imaging set-up, image quality in body applications at UHF can vary significantly depending on the physique of the subject and the underlying tissue types and distributions. Furthermore, higher and much more spatially varying RF power deposition forces compromises in imaging protocols and RF coil design. The amount of RF power deposition in tissue, expressed by the specific absorption rate (SAR) in units W/kg, scales approximately quadratically with B0 (21). More accurate calculations (22) and experimental verification (7,23) show

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an increase which is not quite as steep as expected at frequencies above 200 MHz, but SAR still represents a significant restriction for many pulse sequences, particularly those relying on large flip angles. Furthermore, local SAR (e.g., the value in any 10 g of tissue) is often the most critical aspect, and field distribution and polarization are especially nonuniform in heterogeneous tissue demanding improved techniques for the assessment of RF safety of transmit coils used at 7T and above (24). Unfortunately, so far no standardized assessment protocol has been formulated. Likewise, as the number of clinically oriented MRI studies at 7T has increased dramatically over the past years, the examination of patients with implants has become relevant at UHF research facilities. Because most implants have only been studied for use in a MRI environment up to 3T, a detailed safety compliance test at 7T, especially with regard to RF induced heating, is a prerequisite to examination. So far, only a few implants have been studied using different compliance protocols (25–28). To minimize limitations from B1 inhomogeneities, pulse sequences have been adjusted mostly by replacing simple rectangular or sinc RF pulses with new classes of RF pulse shapes. Adiabatic pulses (e.g., BIR (29,30) and the hyperbolic secant (31,32)) as well as composite pulses (33) provide nearly constant flip angles independent of B1. However, this advantage comes at the cost of SAR, a problem especially for multislice spin echo imaging, which is considered the workhorse in clinical imaging protocols. Usually, this problem becomes apparent in limited spatial coverage and prolonged acquisition times. And such pulses are only effective for a range of B1, so that signal voids can result in large cross-sections despite their use. To improve workflow for clinical spin echo imaging at UHF, RF pulses are often prolonged to reduce peak RF power and hence SAR (34,35). Recently, slice multiplexing has been successfully demonstrated for wholebrain imaging at 7T; this approach creates a periodic slice profile for which the SAR is independent of the number of slices (36). Another approach to increase image quality in regions of low RF transmit efficiency has been shown with high dielectric permittivity bags placed between the RF coil and a region of low B1, e.g., the cerebellum in the case of a head coil (37,38). A further major challenge for UHF systems, especially for body imaging, is the available peak RF power, which is typically limited to only 8 kW or 16 kW. After taking into account up to 50% attenuation losses over the cable length between the RF power amplifiers in the equipment room and RF coil interface at the patient table, there is an immense difference between UHF systems and state-of-the-art clinical 3T system with typically 32 kW available peak RF power, nowadays placed directly next to the magnet to minimize attenuation losses. Along with SAR constraints, this difference in RF power is one of the key challenges for multislice spin echo imaging in large cross-sections. Transmit Strategies for UHF Parallel transmission with multiple, independent RF coil elements has the most promising capability to

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influence the B1 distribution to achieve noticeable improvements in excitation and coverage in wholebody imaging. It has been shown in numerical simulations and by experimental verification that it is possible at UHF to achieve a much more uniform field distribution in vivo if the amplitude and phase of the RF pulse can be varied independently for each port of a multichannel transmit coil (19,39). Additionally, this approach (called static RF shimming) can be used to reduce SAR (40). For body applications in which a large volume is of interest and using the typical number of currently available RF ports of 8 or 16, however, it comes with the sacrifice that signal nulls can only be shifted locally away from a region of interest, i.e., the liver, and does not enable a homogeneous image over the entire abdominal cross section to be acquired (41). A simple and inexpensive extension of the static RF shimming approach has been formulated by the acquisition of two or more timeinterleaved images acquired with different excitation modes, termed TIAMO (42). Here, the complementary RF patterns of the different modes have successfully been exploited to improve overall signal homogeneity along with correct image contrast for measurements with long TR (PD-, T2-, and T2*-weighted sequences) using an eight-channel transmit system from head to toe at 7T. For T1-weighted imaging, the RF shims for TIAMO should be chosen in such a way that the desired contrast is achieved over a certain organ or within a region of interest; the tissue distribution outside will still be visible without dropouts, albeit possibly with incorrect contrast (43). In analogy to parallel reception, the concept of static RF shimming can be extended further by driving several transmit coil elements with independent RF wave forms, referred to as parallel transmission or Transmit SENSE (44,45). Parallel transmission offers the ability to shorten the duration of multidimensional RF pulses needed for correcting B1 inhomogeneities (46) and spatially selective excitations in general (47), or to modify the SAR characteristics of a given excitation (48). However, one major obstacle in parallel transmission is the question how to manage both global and local SAR, as in contrast to the case of singlechannel excitations, multiple independent excitations will now superimpose inside the human body, depending on the RF coil and individual excitation pattern of the RF pulses. Extremely conservative local SAR estimations based on simple superposition of the maximum electric field components lead to very low permitted RF power levels, making in vivo applications nearly impractical. To overcome the computational demands of numerical simulations for a given excitation and to allow a real-time estimation of the SAR before scanning, two concepts have recently been introduced. Both, the so-called Q-matrices (49) and virtual observation points (VOP) (50) are based on precalculated magnetic and electric fields obtained from numerical simulations of generic human body models. A compressed parameterization then allows consideration of local SAR constraints within reasonable computation times without losing generality with respect to possible RF pulses. Also other studies are currently

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paving the way for safe parallel transmission in UHF MRI. Quantitative MRI methods for generating individualized body models for patient-individual local SAR determination (51,52), or methods to obtain patientspecific conductivity and permittivity maps have been proposed (53–56), along with new models for temperature simulations (57,58) that will not only improve the prediction of but also our general understanding of local SAR and tissue heating.

NEURO APPLICATIONS From a neuroradiologist’s point of view, the increase in SNR and enhanced sensitivity to susceptibility differences are key advantages for UHF imaging compared with lower field strengths. The following presents an overview of how UHF MRI has already demonstrated benefits for neuroradiological diagnostics. Primary and Secondary Brain Tumors In clinical brain tumor imaging, the above-mentioned characteristics have allowed a much more detailed depiction of microvascularity in the tumor bed as well as of bleeding-related hemosiderin deposition in primary tumors and metastases at 7T (59,60). In glioma tumors, there is an increase of irregular and welldifferentiated vessels with grade of malignancy. Therefore, angiogenesis is known as the basis for growth and transition of tumors from a benign state to a malignant one, and is used as a marker for the aggressiveness of astrocytomas, especially for glioblastoma multiforme. At UHF, gradient echo sequences can delineate vessels and anatomic structures as small as 100 mm in size, facilitating the depiction of microvascularity (Fig. 1) (61,62). Because primary and secondary brain tumors can be well diagnosed at clinical field strengths in gadolinium-enhanced imaging, an additional value of UHF imaging could be an improved localization of well-differentiated tumor areas in preparation for stereotactic biopsy and surgical planning in general. Furthermore, 7T has demonstrated potential in revealing therapy-induced changes in brain parenchyma, such as microhemorrhages after chemical radiotherapy of gliomas, with susceptibility-weighted imaging (SWI) (63). On the other hand, an increase in magnetic field strength does not necessarily mean a better diagnosis, as shown in a pilot study on the detection rate of brain metastases in patients with bronchial carcinoma. With respect to enhancing regions after contrast administration, T1-weighted imaging yielded no difference in the number of metastases found in 7T images compared with 1.5T. However, in 7T SWI images, 20% more microhemorrhages were found in brain metastases (64) (Fig. 1). Cerebrovascular Diseases With increasing field strength, the T1 relaxation times of the tissues are prolonged, which has been used


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Figure 1. Top row shows comparison of T2*-weighted images at 1.5T and 7T of a patient with glioblastoma. Enlarged transmedullary vessels are clearly depicted at 7T (black arrow), presumably representing draining veins from the tumor bed connecting to cortical veins. Additionally, necrosis could be revealed at 7T as hyperintense regions (white arrow) not visible at 1.5T. Bottom row shows enhanced spatial resolution and sensitivity for hemorrhages in brain metastases with SWI at 7T compared with 1.5T in a patient with bronchial carcinoma (60).

advantageously and with great impact for MR angiography, demonstrating improved background suppression and superb delineation of brain arteries in timeof-flight (TOF) images (65,66). Because of its considerably enhanced potential to depict especially the smaller peripheral vessels up to third-order branches, for example the lenticulostriate arteries and perforating arteries originating from the posterior communicating artery, TOF MRA at 7T may become an important tool in future neuroradiology research and clinical care (66–68). In hypertensive patients, a rarefaction of lenticulostriate arteries could be demonstrated compared with healthy controls (69). The increase in spatial resolution (e.g., 0.5 mm isotropic) at 7T is of further importance for the depiction of intracranial aneurysms, especially for those smaller than 3 mm in size for which the sensitivity at lower field strengths is rather low (70). SAR limitations, which restrict the use of additional RF pulses commonly used at lower field strengths to further improve TOF contrast by saturating venous or subcutaneous fat signal or improving background suppression by

magnetization transfer, have been solved by applying variable-rate selective excitation (VERSE) and sparse pulses (71,72). Furthermore, UHF MRI allows the depiction of hyperintense vessels in nonenhanced T1weighted sequences such as MPRAGE, which enables the simultaneous visualization of both the vessels and brain parenchyma with good diagnostic quality (73,74). Whole-brain imaging at 7T yields valuable additional information about cerebral microvascularity, degeneration of vessel walls, and incidence of ischemic attacks, all needed for the improvement of stroke diagnostics (75). Intracerebral cavernomas are typically detected on thin T2-weighted slices by their venous vessel architecture, and by characteristic fringes of hemosiderin deposition on T2* and SWI images. Due to the increased sensitivity for susceptibility changes and higher spatial resolution at 7T, not only an improved detection rate of cavernomas could be demonstrated compared with lower field strengths, but moreover, 7T enables the depiction of various cavernoma drainages for the first time in vivo (76).

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Figure 2. T2*-weighted images of two patients with multiple sclerosis (MS). In (a), the multilayer structure reveals inhomogeneity within the MS plaques (empty arrow). Also, larger lesions show a hypointense rim at 7T (filled arrow), implicating iron accumulation. In (b), deep white matter MS lesions show a perivascular migration at 7T (arrows) that was not visible at 1.5T. Hence, 7T may be beneficial for monitoring disease severity and for furthering the understanding of inflammatorydemyelinating processes in vivo (80). Images courtesy of Kiriaki Kollia (University Hospital Essen, Germany).

Cerebral Microanatomy and Neurodegenerative Diseases The possibility to acquire 0.5 mm or even smaller isotropic voxels at 7T allows the micro-anatomical depiction of cortical structures such as the hippocampus (77), cranial nerves (78), and deep brain nuclei (79), for example. For patients with temporal lobe epilepsy or hippocampal sclerosis, a deficit of digitations of the Ammon’s horn or a malrotation can be visualized directly at UHF. Inflammatory Diseases of the Central Nervous System MRI plays a central role in the diagnosis and therapy monitoring of multiple sclerosis (MS). Comparative studies at field strengths of 1.5, 3, and 7T have dem-

onstrated a better detection rate of cortical and juxtacortical foci of demyelination with increasing field strength (80,81), and especially 7T outperformed 3T in terms of detecting cortical foci relevant for prognoses (82). With the appearance of the first MS symptoms, most patients exhibit a single or only a few inflammatory foci. Unfortunately, in a study by Wattjes et al in 2008 comparing 3T with 1.5T, 3T imaging did not demonstrate capabilities for earlier diagnosis (83) nor has UHF yet allowed improved insights regarding prognosis, severity, and progression of the disease in comparison to 3T (10). However, the increase in spatial resolution is expected to facilitate the gain of further insight into the pathophysiology of MS. UHF imaging has already uncovered in vivo the microstructure of foci of demyelination and their close proximity to trans-medullar venules (Fig. 2) (80,84,85). On the other hand, the density of


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Figure 3. 7T images of the human cervical spine. In the transverse T2*-weighted images, hyperintense signal (top row, empty arrows) suggests dorsal-column Wallerian degeneration, whereas hypointense signal indicates hemosiderin (bottom row, filled arrow). On the right-hand side, a sagittal overview is given showing the good coverage and penetration depth of the custombuilt cervical spine RF coil. Images courtesy of Julien Cohen-Adad (Ecole Polytechnique de Montreal, Canada).

cerebral venules seems to decrease with increasing number of lesions (86). Direct visualization of perivascular MS plaques with a hypointense rim in T2 imaging at 7T has shown improvements in distinguishing MS from Susac syndrome, where microinfarction is the underlying pathophysiological mechanism rather than demyelination (87). In a pilot study on diffusion tensor spectroscopy, it was shown that 7T may be capable of distinguishing axonal disruption in MS from other processes such as inflammation, edema, demyelination, and gliosis (88). Spine While the availability of suitable RF coil technology accelerated the progress of imaging the neurocranium, there are only a few feasibility studies regarding the depiction of the spine in the current literature (89–94). So far, there is only a four-channel cervical spine array available commercially (91), while various other approaches for UHF spine imaging have been demonstrated by research sites. Some proposed solutions achieve full spine coverage (cervical, thoracic; lumbar) with large multichannel arrays; however, penetration depth, especially in the lumbar spine with spin echo imaging, remains limited (92). Recent studies have resolved gray and white matter parenchyma in cervical spine imaging at 7T, which is rarely visualized at lower field. A high spatial resolution of 0.35 mm in-plane at 7T enabled visualization of abnormalities previously unseen on clinical scans, such as localized hemosiderin and Wallerian degeneration (Fig. 3) (93,94). 1

H Brain Spectroscopy

MR spectroscopy (MRS) at UHF has demonstrated improvements for the differential diagnosis of brain tumors, metastases, and inflammatory and metabolic diseases of the central nervous system (59). While single voxel spectroscopy (SVS) allows the measurement of the concentration of metabolites in a volume of pathologic tissue in comparison to a volume of

healthy brain parenchyma, chemical shift imaging (CSI) is used for mapping the concentration voxelwise over the complete imaging region. Both the spatial and spectral resolution of proton spectroscopy is improved due to the increased SNR and improved spectral dispersion at UHF compared with clinical field strength. For brain spectroscopy, 7T has successfully demonstrated benefits in reliably measuring major metabolites, such as N-acetyl-asparate (NAA), total creatine (Cr), and choline compounds (Cho), but it has also demonstrated improved specificity for other important metabolites for which only rather limited quantification can be obtained at lower field strengths, i.e., lactate (Lac), glutamine (Gln), and glutamate (Glu) (95,96). In a recent study, excellent reproducibility of 12 metabolites, including GABA, substantiated the potential of UHF MRS (97). WHOLE-BODY IMAGING Whole-body imaging at ultra-high field strength is known to be impaired by RF inhomogeneities due to the short wavelength and enhanced absorption, leading to strong flip angle variations and limited penetration depth, especially in large cross sections. Although the progress in demonstrating the capabilities of UHF imaging for body imaging has not advanced as fast as for neuroimaging, at least initial hints at its clinical potential have been revealed. Abdominal Imaging Dynamic MRI of the liver is one of the most powerful imaging techniques for the evaluation of focal liver lesions or diffuse liver disease, or to assess liver vessel pathologies. As the largest parenchymatous organ in the upper abdomen, 7T imaging covering the entire liver is particularly challenging. In a recent feasibility trial, in vivo dynamic MRI of the liver was investigated (41). Imaging at 7T provided good overall image quality and a very good delineation of nonenhanced liver vessels in gradient echo sequences, with 2D spoiled gradient echo (FLASH) imaging showing superiority

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Figure 4. Transverse T2-weighted TSE images of a 65-year-old patient with prostate cancer at 3T (upper row) and 7T (lower row). Prolonged radiofrequency pulses and B1þ shimming with an external eight-channel transceiver array coil provided nearly full signal refocusing in the echo train resulting in excellent TSE image quality at 7T. The tumor lesion is indicated by white arrows and was confirmed as cancer (Gleason 5) with an MR-guided biopsy. Note that at 7T the endorectal coil (31P) was not used for signal reception, whereas at 3T an endorectal 1H receive coil was used for signal reception. Images courtesy of Tom Scheenen (University Medical Center Nijmegen, The Netherlands).

compared with lower field strengths. The application of Gd-based contrast media for the acquisition of dynamic series revealed a homogeneous contrast enhancement of liver parenchyma and surrounding structures as well as an increase in vessel delineation (41). In recent years, MR cholangiography (MRC) has gained an important role as a noninvasive imaging tool for the depiction of the intra- and extrahepatic biliary tract. MRC is usually performed at 1.5T or 3T based on heavily T2-weighted sequences using the contrast provided by the long T2 relaxation time of stationary or slowly moving fluid. However, T2weighted spin echo imaging in large organs at 7T remains challenging. SAR restrictions on the one hand and the limited available RF peak power available for achieving the large flip angles needed for spin echo imaging on the other hand are unsolved challenges (19). In recent years, hepatocytic-specific contrast media were introduced and used for T1-weighted contrast-enhanced MRC as an alternative to conventional T2-weighted techniques for the evaluation of the biliary tract. In a current 7T study, Gadoxetic acid (Gd-EOB-DTPA) was administered in healthy volunteers and provided a high biliary signal at T1weighted imaging with maximum contrast at 20 min after injection in healthy subjects (98). Compared with the clinically applied T2-weighted MRC at 3T, 7T VIBE and FLASH with inversion recovery (IR) sequences revealed a slight superiority in the depiction of the intrahepatic bile ducts, while 3T MRC was superior in the delineation of the extrahepatic biliary tract (98). In vivo imaging of the kidneys was one of the first body applications to be pursued at 7T. After investigation of T1-weighted gradient echo MRI, which provided high anatomical detail and excellent conspicuity of the nonenhanced vasculature (99), dynamic imaging was shown to obtain a homogeneous enhancement of the renal parenchyma and a good

corticomedullar discrimination as well as accurate interorgan differentiation and depiction of small anatomic structures such as the adrenal glands or corticomedullar kidney vessels (100). Clinical anatomical imaging of the human prostate predominantly relies on T2 contrast. A recent publication by Maas et al demonstrated high quality T2weighted TSE imaging of the prostate at 7T using an external eight-channel transceiver body array (34). Examinations were performed in healthy volunteers and in patients with prostate cancer. A dedicated T2weighted TSE sequence protocol was defined by measuring T1 and T2 relaxation times and using prolonged excitation and refocusing pulses to reduce SAR. For improved image quality, B0 and RF shimming as well as localized flip angle calibration were performed. With this technique, high quality T2-weighted TSE imaging could be achieved in less than 2 min, providing full prostate coverage with 3 mm slices. In this study, tumors of patients with gold standard tumor localization (MR-guided biopsy or prostatectomy) were well visualized on 7T images (34) (Fig. 4). MR Angiography Very early on, MR angiography at UHF was able to demonstrate benefits in assessing cerebrovascular diseases as described before, and studies regarding whole-body MR angiography applications have been recently performed. The feasibility of non-contrastenhanced renal MRA was first demonstrated by Metzger et al using a respiratory-gated turbo-FLASH sequence consisting of a slab-selective inversion and chemical shift selective fat suppression followed by signal readout. By using more amplitude-efficient B1þ shimming solutions for the inversion preparation and more homogeneous solutions for the excitation, high quality images of the renal arteries were obtained without venous and background signal artifacts (101).


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Figure 5. 7T TOF MRA demonstrated high quality delineation of liver vessel segments due to a hyperintensive vessel signal and an effective suppression of background signal. The left image was obtained in a 24-year-old female (60 kg, 1.75 m) showing the main portal vein (MPV), common hepatic artery (CHA), aorta, inferior vena cava (IVC), bifurcation of right portal vein (RPV), and right hepatic artery (RHA). Additionally, in the right image (29y f, 60 kg, 1.65 m) the proper hepatic artery (PHA) and coeliac trunk are shown. Images courtesy of Lale Umutlu (University Hospital Essen, Germany).

Recently, nonenhanced imaging of the renal arteries was investigated with FLASH and TOF sequences, and all sequence variants could provide a robust to excellent delineation of the renal arteries (102). In direct comparison, TOF imaging showed superiority regarding qualitative and quantitative evaluation of intraparenchymal vessel branches up to peripheral renal arteries at the corticomedullar junction. However, TOF imaging showed slight impairment due to venous overlay. The application of additional saturation pulses was prevented by SAR limitations associated with the higher magnetic field strength. TOF imaging seems to be a robust sequence option not only for nonenhanced renal MRA but also for imaging of the hepatic vessels, providing sharply defined and homogeneously hyperintense signal of the hepatic arteries, veins, and portal veins as well as an effective suppression of background signal (Fig. 5) (Fischer et al, submitted). A further promising application of 7T nonenhanced MRA is imaging of the peripheral arteries. Initial results of 7T MRA of the lower extremity arteries have been published demonstrating the feasibility of this emerging technique in healthy volunteers (103). Examinations were performed with a custom-built 16channel transceiver coil, whereby the subjects were placed in the feet-first supine position on a rolling, hand-positionable AngioSURF table that enabled multistation MRA. Here, the TIAMO (42) concept for acquiring complementary RF patterns was essential to reduce B1 artifacts and to obtain homogeneous images of the arteries. The T1-weighted FLASH sequence with venous saturation pulse used in this study provided a hyperintense arterial signal in all leg artery segments without application of contrast agent. The large arteries of the pelvis and lower extremity as well as small pedal and intramuscular vessels could

be delineated with overall moderate to good image quality (103). Considerable image quality improvement and a reduction of artifacts was achieved after sequence optimization and the integration of cardiac gating using a phonocardiogram trigger (104). This nonenhanced technique at 7T enabled good to excellent arterial delineation in healthy subjects (Fig. 6) as well as promising results regarding the evaluation of stenosis or occlusions in patients with peripheral arterial occlusive disease (PAOD) compared with the clinical contrast-enhanced standard at 1.5T (104), but further studies will be required to verify this potential. As a nonenhanced MRA technique, 7T imaging of the abdominal and leg arteries might be an important development as there is a high prevalence of chronic renal impairment in patients with PAOD (105) and gadolinium-enhanced MRA can only be used in specific cases because these patients are at risk of nephrogenic systemic fibrosis (106). Cardiac Imaging Cardiovascular MRI has evolved as a powerful diagnostic imaging tool to achieve an accurate morphologic and functional assessment in clinical routine. The ambition to move to ultra-high magnetic field strength and ongoing scientific work have in recent years provided manifold technical solutions and practical advances of cardiac MRI at 7T. In 2009, the feasibility of cardiac imaging at 7T was investigated in healthy volunteers using an eight-channel transmission line array and local B1 shimming (107). At clinical field strengths of 1.5 or 3T, the most important technique is SSFP-based cine imaging for evaluation of myocardial function. SSFP imaging at 7T remains limited due to RF power deposition constraints and increased banding artifacts. As a valuable alternative,

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Figure 6. MR angiograms of the lower extremities of an 82year-old male patient with multiple stenoses of the superficial femoral artery (arrows) and popliteal artery (dashed arrows): contrast-enhanced MRA at 1.5T (left) compared with non– contrast-enhanced MRA at 7T (right). Multistation imaging at 7T was performed using a manually positionable AngioSURF table and a 16-channel transceiver body coil (103,104).

cine imaging based on spoiled gradient echo sequences (FLASH) at 7T provides comparable results regarding cardiac chamber quantification in terms of left and right ventricular volume parameters and ejection fraction compared with SSFP at 1.5T (108). In clinical MR practice, cardiac motion is commonly monitored using electrocardiographic (ECG) gating to synchronize data acquisition with the cardiac cycle. At higher field strength, the ECG signal is often impaired

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by magneto-hydrodynamic effects, as elevation of the T-wave results in trigger artifacts and impaired image quality. Thus, a noninvasive cardiac gating device which uses acoustic signals induced by cardiac activity has been proposed (109), enabling cardiac gating free of interferences with electromagnetic fields. As a further emerging application of UHF cardiac MRI, the application of temporally-resolved and high spatial resolution myocardial T2* mapping was recently demonstrated (110). Due to the linear relationship between magnetic field strength and susceptibility effects, cardiac T2* mapping at 7T might be valuable for myocardial tissue characterization for the assessment of myocardial iron deposition or myocardial perfusion deficits, for instance, but this clinical backdrop will have to be addressed in future studies. Finally, initial results in 7T coronary MR angiography using a quadrature transceiver coil and gradient echo imaging have been shown (111). In this pilot study, artery sharpness at 7T was found to be improved compared with that at 3T. Further hardware developments such as a recently published modular 32-channel transceiver array compatible with multichannel transmission (112) will provide a robust technical basis for high quality and high spatial resolution cardiac MRI at 7T (Fig. 7). First application of twospoke RF pulses to cardiac imaging with a 16-channel pTx system at 7T has just been published by Schmitter et al, demonstrating the practical feasibility and improved excitation fidelity (Fig. 8) (113). Breast Imaging A recently published work by Brown et al demonstrated high-quality breast MRI at 7T with the usage of a dual solenoid coil enabling bilateral imaging with high B1 uniformity. Soft tissue structures could be delineated at high spatial resolution (0.6 mm isotropic), and adiabatic inversion-based fat suppression obtained good fibroglandular/fat contrast in healthy females. A similar or better image quality was shown at 7T compared with 3T for T1-weighted gradient echo imaging (114). As T2-weighted and diffusion-weighted sequences are required in a clinical breast MR imaging protocol, the known challenges associated with SAR and T2/T2* blurring are being addressed in

Figure 7. Cardiac imaging at 7T. a: A modular 32-channel transceiver coil array (MRI.TOOLS GmbH, Berlin, Germany) tailored for cardiac MR was used for excitation and reception (106). The array comprises 4 moderately concave anterior and 4 planar posterior building blocks, each equipped with four elements. Two-chamber (b), four-chamber (c), and short-axis (d) views of the heart derived from 2D cine spoiled gradient echo (FLASH) imaging with a spatial resolution of 1.0 1.0 2.5 mm3. An acoustic triggering system was applied for cardiac gating (112). Images courtesy of Thoralf Niendorf, Berlin Ultrahigh Field Facility, Berlin, Germany.


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Musculoskeletal

Figure 8. Short-axis view (a) and pseudo four-chamber view (b) obtained from cardiac cine images acquired with twospoke parallel transmit excitation. The corresponding estimated flip angle maps were obtained from Bloch simulations, and the black ROI indicates the optimization area. The acquired images were not corrected for receive profile variations (113). Images courtesy of Sebastian Schmitter (CMRR, University of Minnesota, Minneapolis, MN).

current research to provide a wide variety of tissue contrasts. A considerable benefit at 7T compared with 3T was shown in a recent study by Korteweg et al regarding the increase in SNR for breast imaging (115). A 5.7-fold higher SNR was measured and more anatomic details could be depicted at 7T in a small group of breast cancer patients, which reflects the advantages of a higher field strength coupled with the usage of optimized RF coils (115). In summary, the admittedly limited initial experience indicates that high-resolution 7T breast imaging can be expected to improve both the detection of pathological masses and lesion classification.

Musculoskeletal imaging at UHF has already demonstrated clinical benefits in enhancing diagnostic confidence in morphological imaging, especially in cartilage and trabecular bone imaging (116). Compared with 3T, it has not only been shown in multiple joints, such as the knee, wrist and ankle, that resolution at 7T can be increased or that acquisition time can be reduced without compromising superior quantitative and comparable qualitative results (117), but UHF has also started to enrich diagnostic potential with compositional MRI. Besides water, major components of cartilage are collagen fibers and proteoglycans along with their side chains glycosaminoglycans (GAG). With improved spatial resolution at 7T, mapping the T2 relaxation time constant has been successfully applied as a parameter for zonal variations in water and collagen content and allowed the assessment of stratification between deep and superficial cartilage layers at 7T, which was not significant at 3T (118). However, before any of these changes occur, the very first sign of cartilage degeneration is loss of GAG. The labile solute amide and hydroxyl protons of GAG have high exchange rates with bulk water protons, making GAG content accessible in vivo through chemical exchange saturation transfer (CEST) measurements (119). Due to the small frequency offset between hydroxyl protons and bulk water of 1 and 1.5–2 ppm, selective saturation transfer pulses at 3T also attenuate the bulk water signal, which impairs the quantification of the CEST effect at this field strength. The greater absolute frequency offset at higher magnetic field strength, however, and in combination with longer T1 relaxation times, is certainly favorable for CEST measurements. In a recent 7T study, GAG was reliably detected in the knee cartilage of patients after cartilage repair surgery (120). Larger joints (hip (121–123), c.f. Figure 9, and shoulder (124,125)), on the other hand, have only recently become accessible at 7T through new RF coil technology and RF shimming techniques.

X-NUCLEI APPLICATIONS Theoretically, all atomic nuclei that possess a nuclear magnetic moment (i.e. nuclei with an odd number of protons or an odd number of neutrons or both) can be used for MRI or MRS (Table 2). In the context of magnetic resonance, these nuclei are often referred to as Xnuclei. UHF systems enable X-nuclei MRI with sufficient SNR and spatial resolution for clinical research (Fig. 10). However, all of the nuclei listed in Table 2 possess either lower NMR sensitivity or much lower in vivo abundance than protons. Thus, only a few nuclei have been used for in vivo examinations in humans. Whereas 23Na and 31 P MR studies are performed frequently in clinical research applications, other nuclei (e.g., 17O, 7Li, 19F, 35 Cl, and 39K) have only rarely been investigated. In the past 30 years, there has been tremendous technological progress in the field of MRI, and Xnuclei MRI benefits both from optimized acquisition techniques and the increasing availability of UHF MRI

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Figure 9. Bilateral hip imaging in a 49-year-old male patient suffering from avascular necrosis incompletely treated by advanced core decompression. T1w images with identical resolution and contrast settings of both hips in coronal orientation at 7T (a) and 3T (b) show high anatomical detail and pathological/postoperative changes in the femoral head and along the femoral neck (bone graft substitute inside the drill hole, black arrow) after advanced core decompression; slightly higher resolution at 7T but more homogenous excitation over the complete FOV at 3T. At 7T T1w (a) and STIR (c) images show prominent B1 inhomogeneities shifted medially (*). Sufficient suppression of bone marrow signal can be achieved in STIR imaging to depict residual necrosis of the femoral head (strongly hyperintense, arrowhead) and moderate hyperintensities along the drill hole. High resolution 7T DESS (d) of the left femoral head and its magnification (e) provide details of the ostochondral junction and a subtle cartilage defect (arrowheads). With kind permission from Springer Science and Business Media. Reproduced from Theysohn JM et al., Skeletal Radiol 2013;42:1555–1563 (122).

systems. A decisive advantage for X-nuclei MRI (except for 19F MRI) is that the wavelength for most nuclei is more than a factor of two longer than the wavelength of 1H. Thus, for currently available UHF systems, B1 inhomogeneity effects due to short RF wavelength do not limit X-nuclei MRI. In the following, the demonstrated and putative capabilities of X-nuclei MRI/MRS in humans at ultrahigh magnetic field strengths are reviewed. 31

P MRI / MRS

Phosphorous compounds play a key role in metabolism, because phosphocreatine (PCr) and adenosine triphos-

phate (ATP) represent the energy-carrying molecules in cells. Therefore, 31P MRI and MRS can provide insight into the in vivo energy metabolism of cells, and 31P MRS is often used to study the energy metabolism of skeletal muscle (126) and brain (127,128). The chemical shift of inorganic phosphate (Pi) can be used to determine intracellular pH values (129). Additionally, the phospholipid metabolism is altered in many cancer tissues (130); thus, 31P MRI/ MRS are valuable tools to study metabolic processes in healthy and diseased tissue. However, in vivo concentrations of phosphorous metabolites are in the millimolar range, and the NMR sensitivity of 31P is only approximately 6.6% of the sensitivity of protons. Furthermore, 31P exhibits long T1

Table 2 Atomic Nuclei That Can Be Used for MRI or MRS* Nucleus (spin) 1

H (1/2) Li (3/2) 13 C (1/2) 17 O (5/2) 19 F (1/2) 23 Na (3/2) 31 P (1/2) 35 Cl (3/2) 39 K (3/2) 7

Natural abundance [%]

MR Larmor frequency [MHz @ 7 T]

Sensitivity [%]

Composition of the human body [atomic %]

in vivo sensitivity [%]

99.99 92.41 1.07 0.038 100 100 100 75.78 93.26

300 117 75 41 282 79 121 29 14

100 27.1 0.017 0.0011 83.4 9.26 6.63 0.356 0.0473

63 0 0.1 0.01 0.001* 0.03 0.1 0.02 0.06

100 0 2.5 103 4.6 104 1.3 103 4.4 103 1.1 102 1.5 104 4.8 105

Their Larmor frequencies are given for a magnetic field strength of 7T. Values for natural abundances are adapted from reference (158). The relative MR sensitivity is normalized to the sensitivity of 1H MRI. The “in vivo sensitivity” considers also the relative composition of the human body. Note that the relative SNR can be higher compared to the in vivo sensitivity because image noise also increases with frequency. *Fluorine is only located in bones and teeth.


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Figure 10. Sodium (23Na) MR imaging at 1.5 (a), 3 (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 mm)3. The SNR increases linearly with magnetic field strength. Parameters: TE (1.5 and 3T) ¼ 0.2 ms, TE(7T) ¼ 0.5 ms, TR ¼ 50 ms, flip angle a ¼ 77 , 13,000 projections, acquisition time: 10 min 50 s.

relaxation times in the range of seconds that hinder fast signal averaging; consequently, 31P MRS/MRI suffer from low SNR and require large voxel sizes as well as long repetition times. Because of the increased SNR at high magnetic field strengths ( 7T), localized in vivo 31P spectra can be acquired with excellent spectral resolution and sensitivity (9). Qiao et al obtained 56% higher SNR at 7T compared with 3T (131). Also, the line-width of the PCr resonance showed a less than linear increase with increasing magnetic field strength, which leads to a significant improvement in the spectral resolution of 31P MRS (131). Due to the increasing influence of chemical shift anisotropy (CSA) with field strength, the transverse and longitudinal relaxation times are significantly shorter for most of the 31P metabolites in muscle tissue at 7T compared with 3T (132). The reduced longitudinal relaxation time enables shorter repetition times and thus faster signal averaging, which leads to an additional SNR gain with increasing field strength. In contrast, in brain tissue, an increase of the longitudinal relaxation times with magnetic field strength has been reported (133). The chemical shift between different phosphorous metabolites increases proportional to the main magnetic field. This can lead to larger chemical shift displacement errors. Therefore, Chmelik et al developed a fully adiabatic 2D CSI (chemical shift imaging) sequence with improved slice selection and performed 2D CSI at 7T in calf muscle as well as liver and brain tissue (134). These in vivo experiments could be performed within clinically feasible measurement times (< 10 min) and with nominal voxel volumes of 5.65– 10 mL depending on the type of tissue (134). Recently, a new acquisition strategy was proposed that acquires the multiple spectral peaks of different 31P metabolites using flexible twisted projection imaging readout trajectories (135). Because the longitudinal relaxation times are in the range of several seconds, long repetition times are required for 31P MRI, which can be exploited to excite and acquire only single resonances of the spectrum in an interleaved manner. Using this type of sequence, the PCr/ATP ratio of the human brain can be mapped with a nominal isotropic spatial resolution of 1.5 cm within 33 min at 9.4T (135).

Phospholipids play a decisive role in cancer tissues. In vitro results suggest that the levels of the major phospholipid compounds can be used to distinguish between prostate cancer and benign prostatic hyperplasia (136). Kobus et al developed a setup for combined 1H MRI and 31P MRS of the human prostate at a 7T whole-body MRI system. An eight-channel bodyarray 1H coil enabled anatomic imaging. Using a 31P transceiver endorectal coil, 3D CSI of the entire healthy prostate could be performed with an effective voxel volume of 4 cm3 in an acquisition time of 18 min (137). Klomp et al investigated patients with breast tumors and found altered levels of phosphoethanolamine (PE), phosphocholine (PC), and glycerol phosphocholine (GPC) in the 31P MR spectrum compared with the spectrum of a healthy control (Fig. 11) (138). In contrast, 1H MRS measures only the total pool of choline-containing compounds. It is expected that the PC to GPC ratio is more specific than the total choline level. The feasibility of quantitative 31P MRS of the human breast was also demonstrated in an additional study (139). To conclude, 31P MRS at UHF enables the separation of resonance peaks from different phosphorus metabolites that overlap at lower field strength. The increased SNR due to the higher magnetization and CSA-induced shortening of the T1 relaxation time in muscle tissue can be used to improve the spatial resolution of 31P MRS. Also, 3D MRI or CSI becomes feasible with clinically acceptable voxel dimensions and measurement times.

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Na MRI

In healthy tissue, there is a high concentration gradient between intra- and extracellular sodium ([Na]intra ¼ 10–15 mmol/L, [Na]extra 145 mmol/L) (140). A breakdown of this concentration gradient or an increase of the intracellular sodium content can be used as an early marker in many disease processes. Madelin and Regatte recently published an up-to-date overview of potential biomedical applications of 23Na MRI (141). Although most of the cited work was performed at lower field strengths (B0 4.7T), they cited

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Figure 11. Localized in vivo 31P spectra from a patient with breast cancer (a) and from a healthy control (c) at 7T. Corresponding transverse proton MR images are shown in (b) and (d). The spectrum of the tumor patient (a) was detected in the region of the dotted circle (b). The tumor tissue shows altered levels of phosphoethanolamine (PE), phosphocholine (PC), and glycerol phosphocholine (GPC) compared with the healthy control (c). Additionally, the chemical shift of the inorganic phosphate resonance (Pi) can be used to calculate the pH value (pH: 7.5). In tumor tissue a second Pi resonance (Pi2) is visible that corresponds to a pH value of 6.9. Images courtesy of Dennis W. J. Klomp (University Medical Center Utrecht, the Netherlands).

nine research articles with work performed on UHF systems (B0 7T). Image quality of 23Na MRI can be markedly improved at UHF (c.f., Fig. 10), and 7T MRI enables the analysis of the tissue sodium content in small brain lesions such as in multiple sclerosis (142) and brain tumors (Fig. 12) (143). Nominal in-plane resolutions down to 0.86 mm (slice thickness 4 mm) have already been achieved in 23Na brain imaging at 7T (144). Small tissue structures such as articular cartilage (145) and the Achilles tendon (146) can also be examined with sufficient SNR and spatial resolution. As already mentioned, changes of the intracellular sodium concentration are of interest in many (patho-) physiological processes such as neoplasia, ischemia (147), multiple sclerosis (148), and muscular diseases (149). Different approaches have been proposed to selectively detect intracellular sodium or to partially suppress signal from the extracellular compartment. For applications in humans, inversion recovery (IR) imaging or triple-quantum filtration (TQF) are often applied. IR imaging is usually used with an appropriate inversion time (TI) to suppress signal from sodium pools with T1 relaxation times such as in cerebrospinal (143,150) and synovial fluids (151). In muscular diseases it could be demonstrated that this approach

enables a weighting toward intracellular sodium (152). 23Na MRI in patients with different brain tumor grades has showed that IR imaging enables further differentiation between different lesions by suppressing signal from sodium ions with long T1 relaxation times (c.f., Fig. 12e) (143). IR and TQF pulse sequences lead to markedly reduced SNR compared with conventional 23Na MRI. UHF MRI helps to achieve sufficient SNR in IR and TQF MRI, but also leads to SAR restrictions, because these techniques require multiple excitation pulses or an additional inversion pulse. Thus, Stobbe and Beaulieu proposed a concept for the optimization of the SNR under SAR constraints (153). Benkhedah et al introduced a sequence for biexponentially weighted sodium imaging that requires only two instead of three 90 excitation pulses and thereby reduces SAR and enables shorter repetition times (154). 7

Li MRI

Lithium is not naturally present in the human organism. However, medication with lithium salts is a common treatment in bipolar disorders (BPD) (155). BPDs are mental disorders with relatively high lifetime prevalence that affect 4.4% of the population of the


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Figure 12. The 3T 1H MRI (a–c) and 7T 23Na MRI (d–f) of a cerebral metastasis (bronchial carcinoma) in the left parietal convexity. The tumor exhibited inhomogeneous signal intensities on native T1-weighted (a) and T2-weighted images, rim enhancement upon application of contrast medium (b), and a hypo- and hyperintense perifocal signal on T1-weighted and T2-weighted images, respectively, compatible with brain edema (c). d: The total 23Na signal (23NaT) showed high intensities in the central tumor portion and perifocal edema. A nominal spatial resolution of 4 mm isotropic was achieved in an acquisition time of 10 min. e: 23Na IR imaging (23NaRIR) revealed hyperintensities of the central tumor and hypointensities of the perifocal edema. A nominal spatial resolution of 5.5 mm isotropic was achieved in an acquisition time of 10 min. f: A similar image contrast can be achieved based upon 23Na multiecho imaging and calculating a weighted subtraction image. Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Investigative Radiology (152), copyright 2011.

United States (156). Medication with lithium can also have severe side effects such as neurotoxicity (157) due to lithium accumulation in the brain. For this reason, brain lithium concentrations would be a better diagnostic indicator for treatment response than the commonly used serum lithium concentration. Lithium exhibits two stable MR sensitive isotopes: 6 Li and 7Li with natural abundances of 7.59% and 92.41%, respectively (158). Therefore, 7Li is usually used for MRS or MRI, which is a spin 3/2 nucleus with a resonance frequency of 117 MHz at 7T. Due to low NMR sensitivity and low therapeutic concentrations of lithium (< 1 mmol/L), SNR at lower magnetic field strengths is not sufficient for imaging. At 7T, Boada et al recently demonstrated the feasibility of 3D 7Li MRI of the human brain (159). 17

O MRI

Alterations in the metabolic rate of oxygen consumption have been found in many diseases such as Alz-

heimer’s (160) and brain tumors (161), and 17O MRI can noninvasively determine the cerebral metabolic rate of oxygen consumption (CMRO2) (162). 17O is the only stable and NMR sensitive isotope of oxygen (158). It has a low natural abundance of 0.038% which leads to low SNR, but the low natural abundance enables studies with enriched 17O2 gas. Because of the high costs of enriched 17O2 gas, only a limited amount of gas can be applied in an inhalation experiment (usually less than 5 L). The combination of an efficient 17 O2 delivery system (163) and UHF are thus desirable for efficient signal detection. Atkinson and Thulborn proposed a three-phase metabolic model to calculate CMRO2 (164). They performed an 17O inhalation experiment on a 9.4T system. A healthy volunteer inhaled 4.8 L of 53% enriched 17O2 gas for approximately 15 min from a rebreathing circuit. Additionally, 23Na MRI data were acquired to correct for the tissue mass. Using their three-phase model, they calculated CMRO2 maps with a nominal isotropic spatial resolution of 8 mm

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body 7T system if an efficient rebreathing system is used (163). In Figure 13, signal time curves of this 17 O inhalation experiment are shown. During the inhalation of enriched 17O2 gas, gray matter exhibits a faster signal increase compared with white matter, which corresponds to higher CMRO2 values in gray matter (Fig. 13). Recently, the same group performed the first 17O inhalation experiment in a tumor patient (166). Reduced CMRO2 values were found in all tumor compartments. In the future, the quantitative measurement of CMRO2 by UHF 17O MRI might provide valuable insights into the metabolic status of pathologic tissue. Figure 13. Time courses of ROIs placed in the periphery of the brain attributed to gray matter and in the center of each hemisphere attributed to white matter. The dark blue bar marks 17O2 administration by means of a demand oxygen delivery system for the first 5 min. The light blue bar marks the period of breathing in a closed rebreathing circuit. Reproduced from Hoffmann et al., Magn Reson Med 2011;66:1109–1115 (163).

(additionally, a Gaussian filter with a FWHM of 14 mm was used to smooth the images). CMRO2 values of 1.42 6 0.05 mmol/g brain/min and 0.75 6 0.11 mmol/g brain/min were determined for gray and white matter, respectively (164). These values are in agreement with data obtained by 15O positron emission tomography (PET) (165), which is still the gold standard for CMRO2 determination. However, quantification of CMRO2 by 15 O PET requires multiple 15O PET measurements, an on-site cyclotron due to the short half-life (2.1 min) of the 15O isotope (165), and exposes the patient to ionizing radiation. These obstacles hinder a broader clinical application of 15O PET studies. Hoffmann et al demonstrated that CMRO2 can also be determined with a comparably small amount of 70% enriched oxygen 17O gas (2.2 6 0.1 L) on a whole-

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Cl MRI

Chlorine (Cl) is the most abundant anion in the human body. It is involved in many physiological processes, such as the regulation of the ionic composition of cells and the regulation of cell volume (167). In skeletal muscle tissue, the resting potential of muscle cells can be calculated from the intra- and extracellular Cl concentration by means of the Nernst equation. This membrane potential is altered in many muscular channelopathies (168). Cl exhibits two NMR sensitive isotopes, 35Cl and 37 Cl, with natural abundances of 75.8% and 24.2%, respectively (158). The in vivo NMR sensitivity of 35Cl is approximately 30-fold smaller than the in vivo sensitivity of 23Na. Nevertheless, the feasibility of 35Cl MRI of the human brain and muscle has been demonstrated on a 7T whole-body system (169). 39

K MRI

Potassium ions (Kþ) play an important role in cellular processes. Healthy cells exhibit a high intracellular Kþ concentration (140 mmol/L) and very low extracellular concentrations (2.5–3.5 mmol/L) (140).

Figure 14. 1H (left), 23Na (middle), and 39K (right) MR images of the right healthy thigh muscle in a 26-year-old female volunteer. 23Na and 39K MR imaging were performed with a nominal spatial resolution of 3.75 3.75 10.14 mm3 and 8 8 16 mm3, respectively. The acquisition times were approximately 30 minutes. Reference tubes containing 4% agarose gel with 20 mmol/L NaCl and 103 mmol/L KCl solutions are marked in the 1H image by the numbers 1 and 2, respectively. The femur is clearly visible on 23Na and 39K MR images as areas of reduced signal intensity. The territory of the femoral artery and vein (arrow) exhibits high signal intensity in the 23Na MR image but reduced signal intensity in the 39K MR image. The fatty tissue that surrounds the ischiadic nerve (circles) exhibits low 39K signal intensity, while the subcutaneous fat shows no 39K MR signal. The mean estimated Naþ and Kþ concentrations of muscle tissue (white region of interest) are [Naþ] ¼ 18 mmol/L 6 1 and [Kþ] ¼ 116 mmol/L 6 4. Color bars show measured Naþ and Kþ concentrations (in millimoles per liter) in 39 Na and 39K MR images. Reproduced from Umathum, R€ osler and Nagel, Radiology 2013 (172). Figure and modified caption reproduced by permission of the Radiological Society of North America (RSNA).


Potassium has two stable NMR sensitive isotopes, K and 41K, with resonance frequencies of 14 MHz and 8 MHz at 7T, respectively. The natural abundances are 93.26% (39K) and 6.73% (41K). Thus, 41K has much lower sensitivity than 39K. Among all nuclei that are presented in this review, 39K exhibits the lowest sensitivity for MRI. Therefore, in vivo 39K MRI was considered to be impractical for many years (170). In 2009, Augath et al presented the first in vivo images of the rat brain using a 9.4T small animal MRI system (171). Imaging of 39K is usually not supported on commercially available whole-body MRI systems. Therefore, Umathum et al developed a frequency conversion scheme that uses the resonance frequency of a supported nucleus (e.g., 7Li, 115 MHz). In this setup, the 7 Li frequency was mixed with an externally provided local oscillator frequency of 101 MHz. In this way, the 39 K frequency (14 MHz) could be generated. In the receive path, the same local oscillator frequency source was used to generate the 7Li frequency. Using this setup, the feasibility of in vivo 39K MRI of the human brain and muscle was recently demonstrated on a 7T MRI system (172), and Umathum et al could quantify the potassium content in thigh muscle tissue (Fig. 14). Atkinson et al have also demonstrated the feasibility of 39 K brain imaging on a 9.4T system (173). 39

DISCUSSION There has been accelerated development for clinical imaging at ultra-high magnetic fields, at 7T in particular, over the past years. Especially for neuroradiological imaging and for assessing degenerative joint diseases of the musculoskeletal system, intriguing capabilities and benefits have already been demonstrated. For neuro applications, the increase in SNR and the enhanced sensitivity to susceptibility have allowed a more detailed depiction of microvascularity and microhemorrhages in tumor and ischemic disease, high-resolution imaging of cerebral vessel pathologies as well as micro-anatomical depiction of cortical structures, aspects which offer potential benefits for patient treatment in terms of diagnostics, surgical planning, and therapy monitoring. For whole-body applications, recent methodological developments regarding transmit strategies and SAR supervision are just now enabling the exploitation of the potential of UHF imaging. Despite the challenges, whole-body imaging at UHF has achieved some advances in recent years such as temporally-resolved and high spatial resolution T2* mapping for myocardial tissue characterization, high-resolution breast cancer imaging, and improved diagnostic confidence in morphological imaging of cartilage or bone. Another application that may benefit dramatically from the increase of the magnetic field strength is MR angiography, particularly nonenhanced MRA techniques for imaging abdominal or peripheral vessel pathologies in patients who cannot undergo gadolinium-based contrast agents. Novel applications for clinical diagnostics may lie in the increased sensitivity for 23Na MRI and 31P MRS/ MRI at UHF, allowing sufficient spatial resolution

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within clinically feasible measurement times, and early indications for possible clinical impact have been shown at 7T in breast and prostate imaging and for assessing degenerative joint diseases. Furthermore, opportunities for imaging nuclei with even lower in vivo sensitivity such as 7Li, 17O, 35Cl, 39K will be investigated with great interest in the coming years. Here, the optimal magnetic field strength for these X-nuclei might lie even higher than 7T or 9.4T. In conclusion, to set a new benchmark for clinical imaging, UHF will need to demonstrate evidence for earlier or more detailed diagnosis and improved treatment control in a variety of diseases. However, it is in our opinion already unquestionable that 7T will emerge as a clinical diagnostic tool, albeit most likely not as a clinical workhorse; it is much more likely that 7T will be more application-specific and less available than 1.5T or 3T systems. REFERENCES 1. Ocali O, Atalar E. Ultimate intrinsic signal-to-noise ratio in MRI. Magn Reson Med 1998;39:462–473. 2. Blamire AM. The technology of MRI–the next 10 years? Br J Radiol 2008;81:601–617. 3. Alvarez-Linera J. 3T MRI: advances in brain imaging. Eur J Radiol 2008;67:415–426. 4. Lee VS, Hecht EM, Taouli B, Chen Q, Prince K, Oesingmann N. Body and cardiovascular MR imaging at 3.0 T. Radiology 2007; 244:692–705. 5. International Electrotechnical Commission. Medical electrical equipment - Part 2–33: particular requirements for the safety of magnetic resonance diagnostic devices. IEC 60601-2-33. 3.0 ed; 2010. 6. Robitaille PM, Abduljalil AM, Kangarlu A. Ultra high resolution imaging of the human head at 8 tesla: 2K x 2K for Y2K. J Comput Assist Tomogr 2000;24:2–8. 7. Vaughan JT, Garwood M, Collins CM, et al. 7T vs. 4T: RF power, homogeneity, and signal-to-noise comparison in head images. Magn Reson Med 2001;46:24–30. 8. Norris DG. High field human imaging. J Magn Reson Imaging 2003;18:519–529. 9. Moser E, Stahlberg F, Ladd ME, Trattnig S. 7-T MR–from research to clinical applications? NMR Biomed 2012;25:695– 716. 10. van der Kolk AG, Hendrikse J, Zwanenburg JJ, Visser F, Luijten PR. Clinical applications of 7 T MRI in the brain. Eur J Radiol 2013;82:708–718. 11. United States Food and Drug Administration. Guidance for industry and FDA staff: criteria for significant risk investigations of magnetic resonance diagnostic devices. 2003. Available at: http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm072688.pdf. Accessed November 26, 2013. 12. Regatte RR, Schweitzer ME. Ultra-high-field MRI of the musculoskeletal system at 7.0T. J Magn Reson Imaging 2007;25:262– 269. 13. Ugurbil K. The road to functional imaging and ultrahigh fields. Neuroimage 2012;62:726–735. 14. Bernstein MA, Huston J III, Ward HA. Imaging artifacts at 3.0T. J Magn Reson Imaging 2006;24:735–746. 15. Siemens AG Healthcare Sector, Magnetic Resonance. MAGNETOM 7T: technical details. Available at: http://www.healthcare. siemens.de/magnetic-resonance-imaging/7t-mri-scanner/magnetom-7t/technical-details. Accessed November 26, 2013. 16. Siemens AG Healthcare Sector, Magnetic Resonance. System owner manual 7T: technical data. 2008. Print No. MR02000.629.02.01.02, p 1–20. 17. Magnex Scientific. Cryostat Data. 2006. p 13. 18. National Institutes of Health. Delivery of liquid helium, liquid nitrogen and helium gas. Volume 2013: Federal Business Opportunities (FedBizzOpps.gov). Available at: https://

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Quantitative techniques for musculoskeletal MRI at 7 Tesla.

MRI of the carotid artery at 7 Tesla: quantitative comparison with 3 Tesla.

High-resolution MRI and diffusion-weighted imaging of the human habenula at 7 tesla.

The Interventional Loopless Antenna at 7 Tesla.

7 Tesla MRI in cerebral small vessel disease.

FLAIR images at 7 Tesla MRI highlight the ependyma and the outer layers of the cerebral cortex.

Radiofrequency configuration to facilitate bilateral breast (31) P MR spectroscopic imaging and high-resolution MRI at 7 Tesla.

Experimental implementation of array-compressed parallel transmission at 7 tesla.

Quantitative oxygen extraction fraction from 7-Tesla MRI phase: reproducibility and application in multiple sclerosis.

Non-enhanced T1-weighted liver vessel imaging at 7 Tesla.

1H spectroscopic imaging of rat brain at 7 tesla.

Hip imaging of avascular necrosis at 7 Tesla compared with 3 Tesla.

In vivo high-resolution 7 Tesla MRI shows early and diffuse cortical alterations in CADASIL.

Local specific absorption rate in brain tumors at 7 tesla.

Feasibility of high-resolution pituitary MRI at 7.0 tesla.

Scanning fast and slow: current limitations of 3 Tesla functional MRI and future potential.

Detection of glutamate, glutamine, and glutathione by radiofrequency suppression and echo time optimization at 7 tesla.

Assessment of MRI issues at 7 T.

Comparison of brain gray and white matter macromolecule resonances at 3 and 7 Tesla.

Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study.

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI.

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.

Cerebral lesions on 7 tesla MRI in patients with sickle cell anemia.

Optimizing the ICE decoupling element distance to improve monopole antenna arrays for 7 Tesla MRI.