The Need for Ultra High Field Magnetic Resonance Imaging
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The Need for Ultra High Field Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) is a noninvasive imaging technology that is known for its superior soft tissue contrast and ability to provide morphological, microstructural, functional, and metabolic information. For this, however, sufficient sensitivity is necessary, and its inherently low sensitivity remains one of MRI’s major challenges. This lack of sensitivity manifests itself in limited spatial resolutions, relatively long measurement times, low Contrast-to-Noise-Ratios (CNR), and/or low Signal-to-Noise-Ratios (SNR)[1].


Currently, the majority of clinical MRI systems operate at moderate field strengths of 1.5 Tesla and 3 Tesla. For small animal imaging, resolutions need to be significantly increased in order to visualize similar structures as in humans. Since the sensitivity increases with the field strength, field strengths of 7 Tesla and 9.4 Tesla are therefore standard in the preclinical field. Beyond this, preclinical UHF systems ranging from 11.7 Tesla to 21 Tesla address specific applications, which demand the highest sensitivity[2].

Ultra High Field (UHF) MRI directly addresses the sensitivity issue of lower magnetic fields since the sensitivity increases with the magnetic field strength[3,4]. In preclinical MRI, cryogenically-cooled MRI CryoProbes[5], provide an additional sensitivity boost[1] and have found widespread use. Combined with UHF MRI, the additional gain is significant and enables highest quality images in reasonable measurement times[6]. Thus, for example, ultra high resolution in vivo mouse brain data can be easily acquired on a preclinical 15.2 Tesla equipped with a MRI CryoProbe.

Ultra high resolution, high contrast T2 weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe

Ultra high resolution, high contrast T2 weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe. Method: RARE, Resolution: (29 x 29) µm2, Slice Thickness: 203 µm, Slices: 12, Measurement time: 26 min.

The advantages of UHF MRI go beyond the sensitivity gain itself. UHF MRI facilitates a range of imaging methods and applications. Increased chemical shift, increased Blood Oxygenation Level Dependent (BOLD) contrast and increased susceptibility effects make it predestinated for applications such as MR Spectroscopy (MRS), BOLD Functional MRI (fMRI), Chemical Exchange Saturation Transfer (CEST), Susceptibility weighted Imaging (SWI), and Quantitative Susceptibility Mapping (QSM).
Taken together UHF MRI can open up completely new avenues in the understanding biological processes.

Features and Applications of Ultrahigh field MRI

1. Advantages of the higher sensitivity:

Applications at Ultra High Field (UHF) directly benefit from the high sensitivity. For clinical systems, it was recently shown that for receive-only arrays the Signal-to-Noise-Ratios (SNR) even increases super-linearly with the magnetic field strength[3]. These results underline the impressive SNR gain when moving to UHF systems. The gained SNR performance can, for example, be invested into higher resolutions and/or shorter scan times, or can be taken advantage of in X-nuclei imaging.

a. Ultra-high resolution MRI

To avoid partial volume effects and thus improve data quality and data analysis, highest resolution is desired. However, if the signal in the individual voxels of the investigated subject is not large enough, the resulting low SNR prohibits analysis of the images. The greater SNR obtainable with UHF instruments, therefore can be directly carried over into higher resolution. This enables researchers to push the resolution in the direction of “in vivo MRI histology” as well as to benefit from the increased data quality in a range of disease models[6,7].

Ultra high resolution T2* weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe

Ultra high resolution T2* weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe. Method: FLASH, Resolution: (20 x 20) µm², Slice Thickness: 150 µm, Slices: 7, Measurement time: 21 min. A/C) Magnitude images, two different slices. B/D) Corresponding phase images.

b. Higher Throughput 
Limited available time of the MRI system, large numbers of needed animals, or instable models, often make shorter measurement times necessary. 
Longer measurements times are often needed to achieve sufficient SNR when using lower field strengths. Using UHF, measurement times can be significantly shortened, since, for example, an increase in sensitivity by a factor of two allows to acquire images with the same resolution and similar quality in a quarter of the time. Therefore, the number of data averages can be reduced, and the time saved can be invested into additional subjects or further studies.

Exemplary high resolution, fast T2 weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe in 1 minute

Exemplary high resolution, fast T2 weighted in vivo mouse brain data acquired at 15.2 Tesla with the MRI CryoProbe in 1 minute. Method: RARE, Resolution: (47 x 49) µm² (a) , Slice Thickness: 400 µm, Slices: 12, Measurement time: 1 min.

c. A boost for X-Nuclei Imaging
An additional benefit of the SNR gain at UHF is that imaging of X-nuclei with low gyromagnetic ratios, quadruple moments, and low abundances can be significantly improved or even made feasible for the first time[4,8,9].
This opens up a multitude of different research applications, such as sodium (²³Na) imaging. Sodium MRI is currently used for a wide range of applications. On clinical systems, for example, sodium concentration measurements are used to study tissue viability[10]. Due to the high sensitivity, the use of UHF greatly facilitates sodium imaging[8]. Furthermore, UHF MRI can potentially lead to a breakthrough for oxygen (17O) imaging which allows direct access to the cellular oxygen metabolism. Cellular oxygen metabolism is altered in several diseases such as Alzheimer’s and Parkinson’s as well as in cancer. Thus, 17O MRI has the potential to visualize local pathology changes in the brain, underling the importance of this imaging approach[9].

2. Capitalizing on higher spectral dispersion:

a. Spectroscopy
Due to the increased sensitivity and high spectral dispersion at Ultra High Field (UHF), a natural UHF application is magnetic resonance spectroscopy (MRS). Commercially available MRS instruments are readily available today with field strengths up to 23.5 Tesla, allowing ultra-high resolution spectroscopy experiments of small samples[11].
Similarly, UHF MRI magnets can exploit the increased chemical shift and sensitivity in vivo. Thus, significant improvements in preclinical in vivo MRS have been reported when using UHF magnets[4,12,13,14]. Notably, it has been shown that certain metabolites could be detected for the first time in vivo due to the high magnetic field strength[13].
Beyond the benefits in sensitivity gain and high chemical shift, it could be further shown that a relaxation enhanced MRS strategy allows to additionally utilize the difference in relaxation times between water and metabolites at UHF to generate “water-free” MRS without the need for common water suppression techniques[12].

Exemplary in vivo mouse spectrum acquired at 15.2 Tesla with the MRI CryoProbe

Exemplary in vivo mouse spectrum acquired at 15.2 Tesla with the MRI CryoProbe. A & B) Anatomical reference with indicated voxel position. C) Corresponding spectrum. Method: STEAM, Echo Time: 1.1 ms, Voxel Size: (2 x 2 x 2) mm³, Resolution enhancement with shifted Gauss filtering, Shift: 7%, Broadening: 7 Hz, Measurement time: 17 min.

b. Chemical Exchange MRI
In addition to spectroscopy, the increased spectral dispersion also benefits magnetization transfer techniques such as Chemical Exchange Saturation Transfer (CEST) imaging, leading to a high selectivity[15]. Further advantages of chemical exchange techniques at UHF include the higher saturation which can be achieved[15] and a reduction of the exchange rate relative to the chemical shift[16]
A recent paper from Chung et al. demonstrated a significantly increased chemical exchange effect for the amine proton signal in rat brain at 15.2 Tesla compared to 9.4 Tesla. An increase of 65% compared to 9.4 Tesla was reported emphasizing the importance of UHF for chemical exchange applications[16.24].
A prominent CEST application which benefits from UHF is GluCEST, which monitors local metabolic defects in neurodegenerative diseases[15,17]. For example, GluCEST was identified in the past to be a potential in vivo biomarker of Huntington’s disease when applied in a knock-in mouse model using UHF[17].

3. Profting from higher magnetic susceptibility

a. Functional MRI (fMRI)
An application which greatly benefits from Ultra High Field (UHF) MRI is Blood Oxygenation Level Dependent (BOLD) fMRI. The increased susceptibility effects at UHF translate into a greater observable BOLD signal change and therefore improved fMRI experiments[18]
Functional MRI is used to study functional connectivity to further understand brain function in health and disease[19]. Combined with the high sensitivity provided by UHF, high resolution fMRI preclinical experiments thus become feasible[20]. Notably, initial preclinical experiments in rat brain at 15.2 Tesla showed a significant BOLD signal change increase compared to 9.4 Tesla[21,24], demonstrating the benefits of field strength increase for functional imaging.

Independent component analysis (ICA) identifies sets of bilateral cortical and striatal connectivity networks without á priori hypotheses

Independent component analysis (ICA) identifies sets of bilateral cortical and striatal connectivity networks without á priori hypotheses. Data acquired in in vivo rat brain at 11.7 Tesla[19]. Courtesy: Mathias Hoehn, Max-Planck-Institute for Neurological Research, Cologne, Germany

b. SWI and QSM
In addition to BOLD imaging, further imaging applications which rely on high susceptibility effects combined with a high SNR and therefore benefit from UHF, are Susceptibility Weighted Imaging (SWI) and Quantitative Susceptibility Mapping (QSM)[22]. QSM can for example be applied in vivo to study the microvasculature in animal stroke models[23].

References:

[1] Niendorf T, Pohlmann A, Reimann HM, et al. Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology. Frontiers in Pharmacology. 2015;6:255. doi:10.3389/fphar.2015.00255.
www.ncbi.nlm.nih.gov/pmc/articles/PMC4642111/
[2] Overview BioSpec MRI - Multi Purpose High Field MRI/MRS Research Systems | Bruker: www.bruker.com/products/mr/preclinical-mri/biospec/overview 
[3] Pohmann, R., Speck, O. and Scheffler, K. Signal-to-noise ratio and MR tissue parameters in human brain imaging at 3, 7, and 9.4 tesla using current receive coil arrays. Magn. Reson. Med., 2016; 75: 801-809. doi:10.1002/mrm.25677
www.ncbi.nlm.nih.gov/pubmed/25820458
[4] Öz G, Tkáč I, Uğurbil K. Animal models and high field imaging and spectroscopy. Dialogues in Clinical Neuroscience. 2013;15(3):263-278.
www.ncbi.nlm.nih.gov/pmc/articles/PMC3811099/
[5] MRI CryoProbes | Bruker
www.bruker.com/products/mr/preclinical-mri/mri-cryoprobes.
[6] Petiet A, Aigrot M-S, Stankoff B. Gray and White Matter Demyelination and Remyelination Detected with Multimodal Quantitative MRI Analysis at 11.7T in a Chronic Mouse Model of Multiple Sclerosis. Frontiers in Neuroscience. 2016;10:491. doi:10.3389/fnins.2016.00491.
www.ncbi.nlm.nih.gov/pmc/articles/PMC5081351/
[7] Ong HH, Webb CD, Gruen ML, Hasty AH, Gore JC, Welch EB. Fat-water MRI of a diet-induced obesity mouse model at 15.2T. Journal of Medical Imaging. 2016;3(2):026002. doi:10.1117/1.JMI.3.2.026002.
www.ncbi.nlm.nih.gov/pmc/articles/PMC4877437/
[8] Deutsches Krebsforschungszentrum:
www.dkfz.de/en/medphysrad/projectgroups/t7_x-nuclei/t7_x-nuclei_Na_MRI
[9] Deutsches Krebsforschungszentrum::
www.dkfz.de/en/medphysrad/projectgroups/t7_x-nuclei/t7_x-nuclei_O_MRK
[10] Thulborn KR, Lu A, Atkinson IC, Damen F, Villano J. Quantitative Sodium MR Imaging and Sodium Bioscales for the Management of Brain Tumors. Neuroimaging clinics of North America. 2009;19(4):615-624. doi:10.1016/j.nic.2009.09.001.
www.ncbi.nlm.nih.gov/pmc/articles/PMC3718497/
[11] Overview Aeon 1GHz | Bruker: www.bruker.com/products/mr/nmr/magnets/magnets/aeon-1ghz/overview
[12] Shemesh N, Rosenberg JT, Dumez J-N, Muniz JA, Grant SC, Frydman L. Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields. Nat Commun. 2014; 5: 4958. doi: 10.1038/ncomms5958
www.ncbi.nlm.nih.gov/pubmed/25229942

[13] Mlynárik V, Cudalbu C, Xin L, Gruetter R. 1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: improvements in quantification of the neurochemical profile. J Magn Reson. 2008; 194: 163–168. doi: 10.1016/j.jmr.2008.06.019
www.ncbi.nlm.nih.gov/pubmed/18703364
[14] Shemesh N, Rosenberg JT, Dumez J-N, Grant SC, Frydman L. Metabolic T1 dynamics and longitudinal relaxation enhancement in vivo at ultrahigh magnetic fields on ischemia. Journal of Cerebral Blood Flow & Metabolism. 2014;34(11):1810-1817. doi:10.1038/jcbfm.2014.149.
www.ncbi.nlm.nih.gov/pmc/articles/PMC4269758/
[15] Metabolic Imaging in Neurodegenerative Disease using CEST MRI | Bruker: www.bruker.com/service/education-training/webinars/pci-webinars/metabolic-imaging-in-neurodegenerative-disease-using-cest-mri
[16] Chung JJ, Choi W, Jin T, Lee JH, Kim S-G. Chemical-exchange-sensitive MRI of amide, amine and NOE at 9.4 T versus 15.2 T. NMR in Biomedicine. 2017;30:e3740. doi.org/10.1002/nbm.3740
www.ncbi.nlm.nih.gov/pubmed/28544035
[17] Pépin J, Francelle L, Carrillo-de Sauvage M-A, de Longprez L, Gipchtein P, Cambon K, Valette J, Brouillet E, Flament J. In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's disease. Neuroimage. 2016; 139: 53–64. doi: 10.1016/j.neuroimage.2016.06.023
www.ncbi.nlm.nih.gov/pubmed/27318215
[18] Duyn JH. The future of ultra-high field MRI and fMRI for study of the human brain. Neuroimage. 2012;62(2):1241-1248. doi:10.1016/j.neuroimage.2011.10.065.
www.ncbi.nlm.nih.gov/pmc/articles/PMC3389184/
[19] Kalthoff D, Hoehn H. Functional Connectivity MRI of the Rat Brain. Bruker Application Note 2012
Functional_Connectivity.pdf
[20] Seehafer JU, Hoehn H. Insights in the rat brain by high resolution BOLD functional MRI. Bruker Application Note 2011
BOLD_MRI_AppsNote_T13106.pdf
[21] Han S, Park J, Jeong W, Kim S-G. Spin Echo and Gradient Echo BOLD FMRI at Ultrahigh Magnetic Field of 15.2T. ISMRM 2017; 5254
www.ismrm.org/members-only/past-annual-scientific-meeting-proceedings-and-syllabi/
[22] Duyn J. MR Susceptibility Imaging. Journal of magnetic resonance (San Diego, Calif : 1997). 2013;229:198-207. doi:10.1016/j.jmr.2012.11.013.
www.ncbi.nlm.nih.gov/pmc/articles/PMC3602381/
[23] Hsieh M-C, Tsai C-Y, Liao M-C, Yang J-L, Su C-H, Chen J-H. Quantitative Susceptibility Mapping-Based Microscopy of Magnetic Resonance Venography (QSM-mMRV) for In Vivo Morphologically and Functionally Assessing Cerebromicrovasculature in Rat Stroke Model. Jiang Q, ed. PLoS ONE. 2016;11(3):e0149602. doi:10.1371/journal.pone.0149602.
www.ncbi.nlm.nih.gov/pubmed/26974842
[24] New insights into brain function with molecular and functional MRI of the rodent brain at ultra-high fields | Bruker:
https://www.bruker.com/service/education-training/webinars/pci-webinars/new-insights-into-brain-function-with-molecular-and-functional-mri-of-the-rodent-brain-at-ultra-high-fields.html