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REVIEW ARTICLE

Magnetic Resonance Fingerprinting Part 1:


Potential Uses, Current Challenges,
and Recommendations
Megan E. Poorman, PhD,1,2 Michele N. Martin, PhD,2 Dan Ma, PhD,3
Debra F. McGivney, PhD,3 Vikas Gulani, MD, PhD,3 Mark A. Griswold, PhD,3 and
Kathryn E. Keenan, PhD2*

Magnetic resonance fingerprinting (MRF) is a powerful quantitative MRI technique capable of acquiring multiple property
maps simultaneously in a short timeframe. The MRF framework has been adapted to a wide variety of clinical applications,
but faces challenges in technical development, and to date has only demonstrated repeatability and reproducibility in
small studies. In this review, we discuss the current implementations of MRF and their use in a clinical setting. Based on
this analysis, we highlight areas of need that must be addressed before MRF can be fully adopted into the clinic and make
recommendations to the MRF community on standardization and validation strategies of MRF techniques.
Level of Evidence: 2
Technical Efficacy: Stage 2
J. MAGN. RESON. IMAGING 2020;51:675–692.

and dictionary matching.2,3 In this review we summarize recently


Q UANTITATIVE MAGNETIC RESONANCE IMAG-
ING (MRI) has the potential to impact patient care by
providing functional information about biomarkers, such as
published efforts to advance MRF with a focus on adoption in clini-
cal practice. We highlight efforts to overcome technical challenges,
metabolites and tissue composition, coregistered to the anatomy. such as field inhomogeneities and volume coverage, and point out
However, quantitative MRI has yet to be widely accepted in the technical gaps in the literature that must be addressed. We aim not
clinic, in part due to the long acquisition times required to obtain only to point out challenges that need to be overcome, but also sug-
a full-volume property map. Acquiring more than one property gest recommendations to ensure the continued growth of MRF.
map extends the acquisition time, limiting its practical use. Mag- These recommendations include guidelines for standardized
netic resonance fingerprinting (MRF) has the potential to over- reporting and best-practices to enhance the validation, repeatability,
come this barrier by providing an accelerated acquisition scheme and reproducibility of MRF techniques. This article serves as Part
that quantifies multiple properties at once. This technique can 1 of a pair of reviews, the second of which4 addresses recent technical
deliver multiple, inherently spatially-registered property maps in advances including pulse sequence design, optimization, dictionary
the time it would take to acquire just one map using conventional generation, pattern matching algorithms, and machine learning.
methods, eliminating errors due to motion or temporal delays.
Since it was first introduced by Ma et al,1 advances have Overview of MR Fingerprinting
adapted this technique for use in many clinical applications, as well MRF is an image generation framework that can be used to
as to improve the speed and efficiency of acquisition, reconstruction, acquire multiple quantitative property maps simultaneously.

View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.26836

Received Mar 30, 2019, Accepted for publication May 31, 2019.

*Address reprint requests to: K.E.K., National Institute of Standards and Technology, 325 Broadway, MC 686-08, Boulder, CO 80305.
E-mail: kathryn.keenan@nist.gov
Contract grant sponsor: National Institute of Standards and Technology and University of Colorado.

From the 1Department of Physics, University of Colorado Boulder, Boulder, Colorado, USA; 2Physical Measurement Laboratory, National Institute of Standards
and Technology, Boulder, Colorado, USA; and 3Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA
Additional supporting information may be found in the online version of this article

© 2019 International Society for Magnetic Resonance in Medicine 675


Journal of Magnetic Resonance Imaging

FIGURE 1: An overview of the MRF framework. (a) Through-time signals are acquired with a highly undersampled pulse sequence
where the parameters vary every repetition. This sequence (Ref. 1) varied the FA and TR every repetition according to the displayed
plots. Every voxel generates a unique through-time signal. (b) A dictionary of all possible signals is simulated from combinations of
the properties of interest. In this sequence, the dictionary values were: T1 from 100 to 5000 msec, T2 from 20 to 1900 msec, and B0
from –50 to 50 Hz. (c) The signal acquired using the pulse sequence in (a) is matched to the dictionary from (b). For each voxel, the
dictionary entry that has the highest correlation to the acquired signal is considered the match and used to assign property values to
that voxel. These values are used to generate the property maps.

It is based on the assumption that each tissue or material of (SNR) and sensitivity to the properties of interest. To gener-
interest can generate a unique MRI signal evolution given the ate an MRF pattern, parameters such as the flip angle
appropriate pulse sequence implementation. It consists of (FA) and TR of the prescribed pulse sequence are varied every
three parts: the signal acquisition, dictionary creation, and repetition, yielding a temporally incoherent signal (Fig. 1a).
pattern matching for data visualization. Instead of acquiring The original MRF sequence used a balanced steady-state free
full-resolution images like conventional MRI, MRF relies on precession (bSSFP) sequence.1,5 This sequence can also be
a simulated library of signal evolutions, based on prior knowl- referred to as a TrueFISP, FIESTA, or Balanced-FFE,
edge of how a particular tissue behaves in a magnetic field. depending on the vendor. The spin behavior provided by
Parameters are varied every repetition time (TR), generating a this sequence is well understood and described by the Bloch
unique through-time signal evolution per voxel. This signal equations, making its signal evolution straightforward to
"fingerprint" is matched to a dictionary of known, simulated simulate.6,7 To accelerate the acquisition, a variable density
signals generated over all combinations of the properties of spiral was applied at every readout, yielding a highly under-
interest. From this matching, the underlying properties of the sampled image with undersampling artifacts (Fig. 1a). These
tissue can be inferred and mapped. This matching process is errors are able to be eliminated in the matching process due
tolerant to errors, allowing a highly undersampled pulse to their temporal incoherence with the expected signal.
sequence to be used. An overview of the MRF framework can Other methods have successfully demonstrated MRF with
be seen in Fig. 1. Cartesian,8 echo planar imaging (EPI),9 and radial trajecto-
ries.10 Undersampling in MRF offers a key advantage over
Signal Acquisition conventional methods, a fully sampled, high-resolution
The goal of an MRF pulse sequence is to sensitize the MRI image is not required to generate a usable signal evolution.
magnetization to different tissue properties (ie, T1, T2, etc.) Once acquired, each voxel’s signal evolution is matched to
such that each combination of sequence parameters yields a the dictionary of simulated signals and used to generate
unique signal evolution through time. This gives MRF an artifact-free property maps. The data were acquired in
inherent flexibility; any pulse sequence can be used with 12.3 seconds, and maps were generated in 3 minutes on a
MRF, as long as it provides sufficient signal-to-noise ratio standard desktop computer, which is a marked time

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improvement over the 5–10 minutes each required for con- echo time (TE) is also modulated. Another approach to over-
ventional T1 and T2 mapping.11 come B0 inhomogeneities proposes a pseudo-SSFP sequence,13
One potential drawback to the bSSFP-MRF method is which reduces the complexity of the MRF sequence design
the possibility that off-resonance banding artifacts obscure problem, but it is also unable to perform B0 mapping.
important anatomy. This issue can be overcome through the Sensitizing the sequence to new forms of contrast
use of an unbalanced SSFP MRF sequence,12 also referred to as beyond T1 and T2 mapping necessitated development of
FISP, GRASS, or FFE. The SSFP sequence is robust to B0 novel pulse sequences within the MRF framework. Descrip-
inhomogeneities, at the cost of reduced SNR compared with tions of many of these and their technical implementations
the bSSFP sequence, and is unable to map B0 with MRF unless can be found in the review by Mehta et al,2 and their valida-
tion approaches can be seen in Figs. 2 and 3.

Dictionary Generation
The acquired signal must be matched to a library, termed "dictio-
nary," of known signal evolutions to create property maps. Dic-
tionary signals are simulated given the FA and TR pattern and
combinations of properties such as T1, T2, and B0. The original
MRF implementation used the Bloch equation6; however other
approaches used the extended phase graph (EPG)14 formalism,
which can improve computation efficiency. The dictionary of sig-
nals and an associated look-up table are stored to relate the simu-
lated signals to the property combinations used to create them. In
most MRF applications, the dictionary need only be generated
once prior to imaging and can then be used in multiple subjects.

FIGURE 2: Chart of validation methods used with MRF FIGURE 3: Chart of validation approaches used in clinical studies
techniques, as compiled from published articles. The star with MRF, as reported in published articles. Note that Refs.
indicates repeatability experiments that explicitly mention a 25,28,39 also appear in Fig. 2, because they contain both
test–retest procedure where the subject was removed from the methods development and preliminary clinical data. The asterisk
scanner prior to reimaging. It should be noted that Jiang et al99 indicates repeatability experiments that explicitly mention a
performed this type of test–retest experiment on the SSFP-MRF test–retest procedure where the subject was removed from the
implementation, which is not listed in this chart. scanner prior to reimaging.

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Depending on the range and step size of each property performance computing cluster to generate the dictionary.
value and number of parameters and properties, dictionaries can The authors performed brute force optimization and found
become large and unwieldy, requiring storage space and long that a smoothly varying sinusoidal flip angle patterns yielded
computation times. Overcoming these limitations is an active robust metrics, while the TR pattern had little effect on the
area of research and is discussed further in Part 2 of this review.4 results. However, they noted that more rigorous optimization
could be useful and is currently being explored.
Pattern Matching The first studies with cardiac MRF in a clinical popula-
Once the dictionary is generated and signals are acquired, the tion are studying patients with nonischemic cardiomyopathy.16
through-time signal evolution from each voxel must be matched A second study is monitoring cardiac graft rejection in heart
to a signal within the dictionary. This can be achieved through transplant patients. Preliminary results were presented by Cor-
template matching,15 where the dictionary is multiplied by the istine et al19 in a small patient cohort, where quantitative differ-
acquired signal. The multiplication generates a signal vector; the ences between healthy patients and transplant recipients were
entry with the highest correlation between acquired signal and observed. Thus far, cardiac MRF results are comparable to
dictionary is considered the match, and the associated properties those obtained with conventional methods and can be obtained
from the look-up table are assigned to the given voxel. This is with reduced scan time without image registration.
repeated for every voxel in the image, generating multiple,
artifact-free property maps from one acquisition, despite image Head Imaging
artifacts from the highly undersampled acquired signal. Addi- Relaxometry measurements in the brain are useful for track-
tionally, each map is inherently coregistered to the others, elimi- ing changes related to age,20,21 distinguishing between
nating the need for post-acquisition image registration. Many healthy and cancerous tissues,22 and diagnosing diseases such
nonlinear pattern matching approaches have been explored to as epilepsy23,24 and multiple sclerosis (MS).25
accelerate the matching processes, the details of which can be Imaging in the pediatric population is limited to short
found in Part 2.4 scan times or requires sedation to avoid motion errors, which
limits the use of quantitative imaging. Acquisition of patient-
Potential Clinical Uses specific values could better inform myelin fraction models,
One of the unique aspects of MRF is the ability to adapt the which typically use average T1 and T2 from adults that may
framework to a wide variety of applications. An overview of not translate to children. Badve et al20 demonstrated that
clinical areas where the framework was applied can be seen in MRF can generate comparable results in a large cohort of
Table 1. Properties measured in various tissues with MRF com- healthy volunteers, and observed changes with age; a small
pared with those found in the literature can be found in the increase in T1 and T2 of some brain regions and a decrease in
supporting information (Supporting Information Table 1). T1 and T2 in other regions. Chen et al21 applied SSFP-MRF
successfully in a clinical pediatric setting to patients in the
Cardiovascular first 5 years of life and explored changes in T1, T2, and mye-
T1 and T2 mapping of the myocardium can provide informa- lin content. This was achieved using two dictionaries, one for
tion about fibrosis, edema, and injury16; however, clinical T1 and T2, and the other for myelin fraction, and employed
implementation is challenging due to cardiac motion and the an inversion recovery preparation module26 to avoid B1+
long acquisition times of quantitative methods. MRF could inhomogeneities. The study successfully imaged 28 patients
overcome these constraints by rapidly acquiring multiple between ages 2 months and 60 months and observed age-
maps in the heart simultaneously. While the original MRF related differences, particularly in myelination. T1 and T2
method was shown to be robust to some types of motion,1 decreased logarithmically with age and were consistent with
the time scale of cardiac motion would lead to large errors in literature values. These two studies demonstrate using MRF-
MRF maps if left unaccounted for. To address this, Hamilton derived quantitative maps to study changes with age and the
et al17 modified the MRF framework to account for cardiac potential to explore abnormalities and disease states.
and respiratory motion. The SSFP sequence acquisition was Early identification of malignant tumors is important
triggered to EKG waveforms from a breath-held patient and for prompt and successful medical treatment, and MRF has
employed a T2 preparation pulse to improve sensitivity of the been used to explore disease states. Badve et al22 used an
T2 measurement. SSFP-MRF method to rapidly and effectively differentiate
In a subsequent study, Hamilton et al18 investigated the between common types of brain tumors in a study of
effect of confounding factors on the accuracy of the T1 and 31 patients. The acquired T1 and T2 maps were used to suc-
T2 maps. Errors due to non-ideal slice profiles, inefficient cessfully differentiate low-grade gliomas from metastases and
preparation pulses, and B1+ inhomogeneities were included in from peritumoral regions of glioblastomas, suggesting that
the dictionary, improving accuracy and precision of cardiac MRF could be used for quantifiable diagnosis, provided that
MRF. This increased the dictionary size, requiring a high- the results are verified in large patient trials.

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TABLE 1. Overview of Clinical Applications to Which MRF Has Been Applied

Application Method Used Performance Considerations

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20 1
Brain (Normal bSSFP-MRF Identified age-related changes. Differentiated low grade gliomas No statistical significance in grading solid neuronal
and Tumors22) from metastases and healthy tissue. tumors. Limited volume coverage.
Breast37,38 3D MRF74 Obtained volumetric maps over entire breast. Differences between Small study makes determining significance
diseased and healthy tissue. difficult. Repeatable and reproducible across
scanners.38
Cardiac16,19 cMRF17,18 based Performed in single breath hold. Adapts to patient-specific heart Optimization of sequence needed to account for
on SSFP-MRF12 rate variation. confounding factors.
Cartilage10 Based on PnP-MRF39 Acquired high-resolution maps of many slices in a short scan time. Dictionary spacing may need optimization to range
of expected cartilage values.
Eye31 Cartesian MRF8 Achieved Cartesian MRF at 7T. Needs only a single receive coil. Needs optimization for accuracy of mapping long
T1 in the eye.
Epilepsy23,24 3D MRF74 or Sliding Better able to identify lesions in less time than existing methods. Nature of disease could require higher resolution.
Window76 SSFP-
MRF12
Liver Lesions35 SSFP-MRF12 with Overcomes abdominal B1+ inhomogeneities. In small patient study, Current implementation lacks volume coverage.
Bloch-Siegert B1+ noted property differences between benign and malignant tissue. Requires breath hold to avoid motion.
mapping36
Moyamoya28 ASL bSFFP MRF Joint hemodynamic and relaxation maps, allowing for improved Requires further sequence optimization for
1,32
model fit. Observed differences between healthy and improved fitting. Sensitive to choice of model.
diseased tissue.
Near Metal PnP-MRF39 Anatomy near implant visible. Maps obtained of the area. Proton-density map lacks tissue contrast. Slice
Implants39 profile can be influenced by field fluctuations.
Pediatric Brain SSFP-MRF12 and T2 Performed without sedation. Changes in tissue properties and Limited volume coverage. Validation of myelin
Development21 prep modules17 myelin water fraction with growth. water fraction needed.
Prostate32–34 SSFP-MRF12 with Aids classfication of tumor severity. Coupled measurement with Resolution too low for lesion detection.
conventional ADC conventional diffusion mapping. Misalignment between diffusion and MRF maps.

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Poorman et al.: MR Fingerprinting Review Part 1
Journal of Magnetic Resonance Imaging

Epilepsy diagnosis is particularly challenging, because it required for conventional MR relaxometry. Matrix comple-
requires full-volume, high-resolution images.23 Liao et al24 tion reconstruction was used to achieve sufficient image reso-
demonstrated that 2D MRF can be used to circumvent this lution despite the high undersampling factors, which proved
issue. Using MRF, only one out of 33 patients was misdi- to be computationally efficient and required only a single
agnosed, while 10 were misdiagnosed with conventional MRI. receive coil. Relaxation times in healthy patients were compa-
Ma et al23 used a 3D MRF sequence to acquire full brain maps rable to the literature and image reconstruction was compara-
(see Enhanced Volume Coverage) in 13.5 minutes, while con- ble to a fully-sampled scan. Differences between healthy
ventional methods required over 30 minutes. MRF and con- tissues and a uveal melanoma were observed.
ventional MRI methods identified epileptic lesions in 11 out of
15 patients, while MRF enabled the detection of lesions in the Body Imaging
remaining 4 patients. However, 3D MRF still faces potential Quantitative measurements such as T1, T2, T2*, and the
challenges from motion. apparent diffusion coefficient (ADC) can be used for many
Proton density (PD) images can be useful in imaging of body applications.
MS plaques.27 However, direct mapping of proton density Early MRF methodologies have been implemented in
requires corrections for B1+ and other forms of contrast. the clinic to study cancer in the prostate32–34 and liver.35 Yu
Rieger et al25 used MRF to account for these factors and et al used SSFP-MRF to simultaneously assess T1 and T2
image MS plaques in a proof-of-concept study. MS plaques (7.5 min), paired with a conventional ADC sequence
were distinguishable from healthy tissue on T1, T2*, and PD (4.5 min) to acquire three quantitative maps of the prostate
maps acquired with EPI-MRF (also discussed in Enhanced in 12 minutes for lesion characterization.32 This reduced the
Volume Coverage). scan time, compared with the clinical standard sequences, by
Arterial spin labeling (ASL) is often used to noninva- 9 minutes, while acquiring quantitative maps rather than
sively monitor hemodynamics in the brain, without the use weighted images. T1, T2, and ADC were significant predic-
of contrast agents. Conventional MRI ASL techniques are tors in a multivariate logistic model that differentiated
limited by low SNR, require assumptions about the timing of between prostate cancer and normal peripheral zone cancer
a labeled bolus’ entry into tissue, and use simplified signal (by comparison with histologically confirmed cancer). Panda
models that may not be accurate in abnormal tissues. et al conducted two similar studies using 2D SSFP-MRF to
Su et al28 first demonstrated a combined ASL-MRF measure T1 and T2, and combined information from those
approach to quantify hemodynamic properties simultaneously maps with quantitative ADC.33,34 In both the peripheral zone
using a two-compartment model. Using a conventional ASL and transition zone regions, the quantitative map information
sequence29 acquisition, parameters were pseudorandomly var- was useful in differentiating cancers from noncancers. The
ied and the postlabeling delay was eliminated, avoiding protocol combining MRF and diffusion may obviate the need
wasted time during the sequence. This technique generated for lesion characterization with contrast and reduce the overall
maps of seven unique hemodynamic properties in addition to scan time compared with clinical standard of care.
T1 and B1+. Relaxometry performed well in reproducibility Chen et al35 acquired 2D SSFP-MRF and a Bloch–Siegert
experiments (>95% cross-correlation); however, the cerebral 36
shift B1+ map. The B1+ measurement was incorporated in the
blood flow and bolus arrival time measures were not as reli- pattern-matching step, and the method rapidly acquired T1 and
able, suggesting that optimization of the method against vali- T2 values in the abdomen of healthy subjects that agreed with
dated standards is needed. The method was used in small literature values. B1+ correction improved the accuracy of the T2
trials of hypercapnia and Moyamoya disease. In both cases and PD measurements, as demonstrated with a phantom. The
the ASL-MRF method measured differences in perfusion T1 and T2 values obtained in metastatic adenocarcinoma were
between the control and experimental groups, without the significantly different from the surrounding liver parenchyma
use of contrast agent. Wright et al30 also implemented an relaxation times (six patients with 20 focal liver lesions) and
ASL-MRF method, using a modified pseudocontinuous ASL those in hepatic parenchyma in eight healthy volunteers. While
sequence to explore sources of error in the ASL-MRF the results using MRF to characterize cancerous tissue are prom-
sequence. They found that the T1 map and FA used were ising, the utility of these methods could be improved with 1)
larger contributors to the overall ASL signal than the hemo- faster acquisitions times of the entire volume, 2) the inclusion of
dynamic properties. Based on these results, the authors ADC in the MRF sequence, 3) fat suppression or water/fat sepa-
suggested that the acquisition scheme should be optimized to ration, and 4) the inclusion of B1+, rather than using a Bloch–
increase sensitivity to the hemodynamic properties of interest. Siegert B1+ map correction.
In addition to brain imaging, efficient acquisition times More recently, 3D MRF with Bloch–Siegert B1+ map
are important in eye imaging to reduce motion effects from correction and fat suppression was used to acquire full-volume,
blinking. Koolstra et al31 used undersampled Cartesian MRF T1 and T2 maps in the breast at a spatial resolution of 1.6 ×
to reduce the scan time to 1:16 minutes from 7:02 minutes 1.6 × 3 mm3 in ~6 minutes.37 Panda et al conducted both

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repeatability and reproducibility studies in healthy subjects.38 In conventional methods and accurate T1 and T2 metrics of
the work by Chen et al,37 MRF maps were useful in character- static tissue, confirmed with literature values. However, the
izing the breast lesions: T1 and T2 relaxation times measured in sequence was unable to quantify flow in static voxels or rel-
healthy subjects agreed with previous literature, and the T2 axometry in flowing voxels due to phase effects from the
relaxation time was significantly higher in invasive ductal carci- inversion pulse. This effect also limits the velocities that can
noma than in healthy tissue.37 be encoded, limiting the method’s application to blood vessels
and static organs.
Musculoskeletal
Musculoskeletal imaging could also benefit from MRF tech- Chemical Exchange Saturation Transfer and
niques, both for the acquisition of T1 and T2 in a reasonable Magnetization Transfer
scan time and the ability to image near metal. An MRF-based Chemical exchange saturation transfer (CEST) methods can
methodology was introduced to acquire PD, T1, and T2 relaxa- measure tissue physiological properties and detect biomole-
tion time maps along radial sections of the hip10 based on the cules with water-exchangeable protons. However, there is no
plug-n-play (PnP-MRF) method.39 This method’s resolution consensus-standard method to measure CEST, nor is there a
was within the range of resolutions presented in previous hip standard phantom with which to test proposed CEST and
mapping methods,40,41 with an overall faster scan time. magnetization transfer (MT) methodologies. Given those
The PnP-MRF method can image near metal implants,39 considerations, we attempt to compare and contrast three
which is a challenge in musculoskeletal MRI previously recently proposed methods to measure CEST via MRF-based
addressed by methods such as SEMAC42 and MAVRIC.43 methods for amide46,47 and creatine protons.48
Orthopedic implants create an inhomogeneous B1+ field that MRF typically matches acquired signals to a
rapidly decays the signal, leading to voids in the image. PnP- precalculated dictionary, which can be generated using the
MRF recovers the lost signal by mapping the heterogeneous B1+ Bloch–McConnell equation for CEST.46,48 However, con-
field as part of the MRF sequence, rather than using a separate ventional CEST is already at risk of overfitting errors due to
calculation, generating both anatomical and quantitative maps the incorporation of additional properties in multiple pool
near the implant. With such techniques, the case of pain or models,47 and inclusion of all these properties in MRF would
improper function at the site of the implant could be explored result in prohibitively large dictionaries and computation
and understood with imaging before turning to surgery. times. Each of the CEST-MRF methods approaches these
challenges in different ways.
Technique Development for Clinical Zhou et al48 adapted MRF to quantify exchange rates
Applications of creatine. The saturation power and duration were varied
An overview of techniques that have been combined with while keeping TR fixed. Signals were pattern-matched with a
MRF can be seen in Table 2. label dictionary at the solute proton resonance frequency and
a reference dictionary at the opposite resonant frequency.
Blood Flow Then the CEST signals were calculated by subtracting the
Measurement of blood flow velocity can inform cardiac out- label signal from the reference signal49 and matching to the
put and vasculature health. The effect of blood flow on an corresponding CEST dictionary. The exchange rates mea-
MRI signal is complex and determined by a multitude of sured with CEST-MRF had higher agreement with the
factors,44 and thus cannot be used directly to quantify veloc- exchange rates measured by water-exchange spectroscopy than
ity. Existing methods require long acquisition times and the pulsed quantitative CEST method. The method was
encode flow in only one direction at once. Incorporating such designed to also measure the effect of MT on CEST-MRF;
techniques with MRF would enable simultaneous quantifica- however, the MT effects were not large because the saturation
tion of flow in multiple directions, yielding a velocity vector, times used were shorter than those used by pulsed quantita-
while also generating T1 and T2 mapping of the surrounding tive CEST. The lack of susceptibility to MT is an advantage
tissue. of this CEST-MRF method.
To accomplish this, Flassbeck et al45 incorporated Cohen et al46 developed a dictionary-based CEST
motion encoding gradients into an SSFP-MRF sequence, method using a two-pool model for phantom measurements
varying the FA and strength of the x, y, and z gradients each and a three-pool model for mouse measurements. Similar to
TR. Unlike the conventional MRF methods, TR was kept Zhou et al,48 saturation pulse power was varied; however, the
constant. The first five TRs were discarded prior to recon- saturation pulse duration remained unchanged. Dictionary
struction to avoid the effects of noninverted blood inflow size and uniqueness of the signals were a concern, especially
caused by the inversion pulse. The acquisition used patient- when extending to the three-pool model. To maintain a rea-
specific EKG signals to separate cardiac phases in the recon- sonable dictionary size and avoid overfitting, T1 and T2 of
struction. The sequence measured velocities comparable to the three pools (water, amide, and semisolid) were set from

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TABLE 2. Overview of Techniques That Have Been Developed With MRF

Feature Benefits Limitations


Arterial Spin Avoids model assumptions. Need to time entry of labeled bolus. Requires large dictionary. Dependent on choice of flow model.
Labeling28,30
B1+ Improves T2 estimation in particular. For Ref. 39, does not Validation of B1+ map is challenging.
Mapping39,69,71,73 require homogeneous B1+ :
Cardiac17,18 Robust to heart rate variability and confounds (e.g., slice profile Limited volume coverage. Long computation times. Susceptible to gradient
and pulse efficiency). non-linearities.
CESTand MT46–48 Dramatically reduces scan time compared to conventional Model assumptions are required to reduce dictionary size. Partial volume
Journal of Magnetic Resonance Imaging

methods. effects. Lacks ground truth for validation.


Contrast Detect multiple contrast agents simultaneously. Acquire Blood flow can confound T2 measurement. High spatial resolution
Enhancement26,50 colocalized maps faster than conventional methods. requirements limit undersampling.
Diffusion Improves accuracy of T2 measurements Allows for simultaneous Increases size of dictionary. Sequence sensitivity to diffusion could be
Mapping51 diffusion mapping. improved.
Flow Mapping45 Quantifies all velocity components simultaneously. Confounded by motion unrelated to blood flow.
85–89
Motion MRF inherently robust to some motion types. Data processing Cannot account for through-plane motion in 2D. Error severity depends on
pipeline can account for in-plane errors. when in the sequence motion occurs.
Patient Comfort55 Calm patient and make MRI more comfortable. Acquisition pattern limited to specific order.
Spectroscopy56,57 Subject-specific T1 and T2 improves model quantification of Confounded by multiple tissues in a voxel and low SNR. Requires
metabolites. large dictionaries.
T*2 Contrast9,59–61 T*2 enables use of MRF for iron detection in heart, liver diseases. Lose some accuracy of T2 in vivo. Needs pulse sequence optimization.
Volume Coverage Acquire full volume at once. Increase in SNR over 2D method Sliding window reduces temporal sensitivity for Ref. 75. Needs correction
(3D)74,75,78 allows finer resolution. for B1+ .
Volume Coverage Up to 3x acceleration of image acquisition. Fast algorithm Noise amplification and signal leakage between slices. Requires training data.
(SMS)34,80,83 training time. Requires multiple coils for high multiband factors.
Volume Coverage Slice interleaving allows spacing slices over area of interest. Up to Needs slice profile estimation to improve precision. Currently does not
(EPI)25 4x acceleration factor. account for T2.
Water-Fat Provides accurate fat fraction and property maps. Methods vary in accuracy, particularly at very small and very large fat
Separation39,62,63 fractions. Fixed fat model could lead to errors.

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experimentally-measured values. Finally, based on a Monte that simultaneously maps contributions from two contrast
Carlo sensitivity analysis, the worst error in the amide agents, based on their different relaxivities (r1, r2), which is
exchange rate was 27%, with the greatest contribution to this the change in relaxation rate as a function of concentration.
error from the measured water T1. DC-MRF allowed the use of multiple contrast agents to be
Heo et al47 developed a dictionary-free method to quan- used to observe more than one, possibly related, pathological
tify CEST with a reduced dataset using the simplifying assump- process at a time. For example, both a T1 and T2 contrast
tion of subgrouping proton exchange models (MRF-SPEM). agent could be used to track with one agent the delivery of a
Similar to the other CEST-MRF methods,46,48 two-pool and pharmacological treatment and with the second agent the
three-pool models were studied using variable saturation pulse resulting tumor cell death.
power. Differing from other methods, MRF-SPEM consists of
two distinct datasets: magnetization transfer contrast far off- Diffusion Mapping
resonance frequency offsets, which were fit to the two-pool Additional tissue properties, such as diffusion, can be important
model, and amide proton transfer weighted data acquired at for tissue characterization. However, the repeatability of this
near off-resonance frequency offsets, which were fit with a approach is limited because of the challenge of registering images
three-pool exchange model. The two-pool properties were from distinct methods.32 Additionally, diffusion effects influence
incorporated in the three-pool model as known information, the accuracy of MRF sequences, particularly when spoiling gradi-
reducing the number of parameters and fitting uncertainty. ents are applied, as in SSFP-MRF.51 Kobayashi and Terada deter-
One limitation of this work is the observed partial volume mined that including ADC in the dictionary could counteract
effect—in vivo studies found MT contrast in the ventricles, this effect and improve T2 measurements.51 The authors used the
where it is known not to be present. To overcome these limi- extended phase graph formalism to generate the dictionary. Incor-
tations, the authors suggested additional MT contrast acquisi- porating these approaches can improve the accuracy of rel-
tion with varied RF saturation parameters may be required or axometry and provide information about the diffusion properties
introduction of interpulse delay times to increase the specific- of a tissue. However, as with many MRF methods, incorporation
ity of affected proton exchange rates. of additional factors such as diffusion can prohibitively increase
CEST is currently limited in clinical application because the dictionary size and processing time. Additionally, using a dif-
scan and processing times are lengthy. CEST-MRF methods fusion MRF approach with a sequence that is not optimized for
resulted in reduced scan times: CEST fingerprinting decreased diffusion can limit the sensitivity. Research is ongoing to formu-
the scan time to 10 minutes from 50 minutes48; single-slice late an isotropic diffusion Bloch simulator for the problem52,53
CEST-MRF acquisition was ~2 minutes, although T1, T2, and and to optimize the sequence for sensitivity to diffusion.54
T2* maps are also required46; and MRF-SPEM including B0
and B1+ mapping was ~3 minutes compared with ~11 minutes Patient Comfort
for extrapolated a semisolid MT reference method.47 MRF-based In an effort to improve patient comfort, Ma et al55 developed a
methods could move CEST to clinical possibility, especially if technique to replace unpleasant clanging that results from gradi-
the methods can be validated by an agreed-upon methodology ent switching during traditional MRI with music. Instead of
and phantom, and if the processing times decrease. the repetitive gradient switching scheme used in traditional
MRI, a gradient switching scheme is created to generate sounds
Contrast Enhancement at frequencies that mimic a tune. An audio file is compressed,
Contrast agents can be used to sensitize MRI signal to static and filtered to remove frequencies over 4 kHz, intensity matched to
dynamic pathological processes in the body. Dynamic contrast the gradient amplitude, and then implemented in a bSSFP-
enhancement (DCE) methods either rapidly acquire T1-weighted MRF sequence. Volunteers were found to be more comfortable
images with high spatial resolution or acquire T1 maps with low during the MRF-MUSIC scans than during the other conven-
temporal resolution. MRF can acquire quantitative maps with suffi- tional methods. The method was performed using both 2D
ciently high spatial and temporal resolution to use advanced kinetic and 3D MRF, and the 3D scheme had better spatial resolution,
models that better characterize tissue. Gu et al50 assessed DCE- higher through-plane resolution, and better sound quality.55
based MRF (both SSFP and bSSFP implementations) at 7T. The Such techniques could be particularly useful in a pediatric pop-
phantom was used to validate data undersampling up to a factor of ulation to keep patients calm and avoid sedation.
eight without loss of accuracy, which enabled 2-minute temporal
resolution in mouse brains. However, optimization is needed to Spectroscopy
sensitize the MRF method to short T2 species, especially when MR spectroscopy can be used to measure metabolics and
using a T2 contrast agent (eg, dysprosium) that further shortens T2. chemical signatures of tissues within the body, such as dis-
The simultaneous T1 and T2 mapping by MRF could tinguishing benign from malignant tumors. Quantitative
broaden applications of contrast agent imaging. Anderson approaches to spectroscopy use the T1 and T2 of a given tissue
et al26 created the dual contrast MRF (DC-MRF) sequence to build mathematical models that allow direct computation

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of analyte concentrations. However, due to acquisition time MRF with quadratic RF (qRF) to create high T2* sensitivity.
constraints, the models use population-level tabulated values The signal model was modified to include an irreversible signal
of T1 and T2, leading to errors. Combining spectroscopy with decay time constant based on a Lorentzian distribution, Γ, to
MRF could allow patient-specific T1 and T2 values to be used. account for nonrefocused transverse magnetization. The com-
Wang et al56 developed a bSSFP-MRF sequence for 31P plete model also included background off-resonance (δf), simi-
measurement of creatine kinase reactions, evaluated in simula- lar to Wyatt et al.59 Unlike Wyatt et al, δf was included in the
tions and in vivo in rat limbs. Acquisition time and reproduc- dictionary, along with T1, T2, and Γ. Then the relationship
ibility of creatine kinase rate quantification improved compared between T2 and Γ was used to compute T2*. The authors
with conventional methods. However, the authors noted that noted that optimization is needed to determine the appropriate
certain properties, such as the T1 and T2 of some chemical spe- number of bSSFP and qRF blocks to obtain sensitivity to all
cies and B1+ effects, were held constant to avoid large dictionar- relaxation properties. Hong et al61 also used a hybrid MRF
ies and reduce computation requirements. This constraint was sequence, alternating SSFP and SPGR MRF schemes to sensi-
found to introduce up to 30% error into the final measure- tize to T2 and T2*, and compensated background field inho-
ment, depending on pathophysiological conditions. mogeneity with z-shim gradients. The gradient compensation
Kulpanovich and Tal57 extended MRF spectroscopy to is unique to this method and restored T2 and T2* measure-
1
H, which is more commonly used in MRI, to map T1, T2, ment signal by removing macroscopic field inhomogeneity
and B1+ and simultaneously quantify metabolite concentra- induced by hardware imperfections or naturally occurring
tion. The study confirmed that using patient-specific T1 and inhomogeneities, such as at the air–tissue boundaries.
T2 values offered the highest sensitivity and specificity,
whereas using a population average offered little improvement Water/Fat Separation
over excluding T1 and T2 entirely. The authors explored the Water/fat separation is important for quantifying fat concentra-
effect of acquisition scheme optimization58 on bias and vari- tion, as well as reducing biases in property estimation that can
ance introduced into the final estimation. result if fat is not considered. To date, three approaches to wat-
er/fat separation using MRF have been published,39,62,63 each
T2 * approaching the problem differently with varied success.
T2* measurement is useful for understanding disease processes Cencini et al62 developed a dictionary-based water/fat
that involve iron accumulation in the body. Each of the MRF separation MRF method (DBWF-MRF) to determine fat
methods to determine T2* presents a unique solution with fraction, water T1, fat T1, B0, and B1+ maps. To reduce the
advantages and disadvantages, and similar to CEST, there is no size of the dictionary, the authors used RF spoiling to
consensus-standard method nor standard phantom. decrease T2 sensitivity and thus omitted T2 relaxation time
One method to sensitize MRF to T2* is to substantially from the dictionary. The authors compared their results to
modulate TE, in contrast to the original MRF method, where both an MRF-Dixon based method64 and IDEAL.65 In
TE was constant and as short as possible to maximize SNR phantoms and in vivo, DBWF-MRF had comparable separa-
and minimize phase contributions.1 Rieger et al9 presented an tion results to IDEAL, with an improved image acquisition
echo-planar imaging (EPI) MRF method for simultaneous time. However, the method has definite limitations, including
assessment of T1, T2*, and PD, accelerated by a factor of four that it fails with large field inhomogeneities, and there are
using an interleaved slice acquisition pattern.25 However, the challenges at the water/fat boundaries due to blurring. The
long TEs necessitated by EPI may make the method insensi- measured water and fat T1 values are accurate and reliable
tive to short T2* species when SNR is below five,9 which was only within the bounds of 25–75% fat, as shown with a
not fully explored by the authors. The dictionary spans T2 Cramér–Rao lower bound analysis.
10–300 msec; however, the phantom does not test the lower In the supplementary material of Cloos et al,39 they
bound of the dictionary, since the shortest reported T2 for report a method to estimate fat fraction using two PnP-MRF
the phantom is ~40 msec. Alternatively, Wyatt et al59 used acquisitions using two echo times. This dual echo method was
SSFP-MRF and modulated TE to sensitize signals to T2* in tested in a single, healthy subject, and the T1 and T2 values of
magnitude and B0 in phase, allowing the fit of T1, T2, T2*, the water and fat agreed with the literature,66 although the fat
and δf, the resonant frequency offset. Due to the broad range fraction was overestimated compared with IDEAL.65
of δf field variations, a two-step dictionary method was used. Ostenson et al63 demonstrated that a k-space-based wat-
The MRF estimates of T1, T2, T2*, and δf were compared er/fat separation technique67 can be adapted to MRF, using a
with their conventionally measured counterparts in a phan- variable TE and static TR to encode the chemical shift. The
tom and in vivo. method was used to quantify T1, T2, B0, and the fat fraction,
Another approach is to create a hybrid MRF sequence and demonstrated accurate quantification in fat fractions from
using multiple MRF base sequences that modulate the signal 0% to 90% in phantoms, when water/fat separation was
to be sensitized to T2*. Wang et al60 incorporated bSSFP- applied, and up to 100% in simulation. The method was

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compared with conventional water/fat separation68 and Buonincontri and Sawiak69 created sensitivity to B1+ by
shown to be less biased than MRF without water/fat separa- modifying a 3D SSFP-MRF sequence with abrupt FA
tion. The authors note that variations in the measured prop- changes between 0 and 90 at the end of the sequence to cap-
erty maps arise from residual undersampling aliasing and ture the signal’s oscillatory behavior. This approach was also
suggest that this could be improved with alternative recon- applied at 7T, where T1, T2, and B1+ were successfully
struction approaches beyond dictionary matching. corrected in vivo.70
Cloos et al39 noted that direct incorporation of B1+ into
Current Sequence Challenges the dictionary could fail in areas where B1+ distortions are
B1+ Mapping large enough to cause complete signal loss. To overcome this,
Field inhomogeneities must be accounted for in MRF to they created the PnP-MRF sequence that leveraged parallel
avoid errors in property maps resulting from poor dictionary transmission to allow acquisition even in areas of nulled sig-
matches. B1+ and B0 field inhomogeneities are especially nal. This was accomplished by using multiple coil modes and
problematic at high field strengths (>3T) and large fields of multiple echo types to incorporate B1+ in the dictionary. This
view (FOVs), such as abdominal imaging.35 Several method was demonstrated near metal and in the presence of
approaches were developed to correct MRF for these inhomo- adipose tissue. Recently, Körzdörfer et al71 proposed to mod-
geneities, either by acquiring a separate B1+ map for correc- ify a conventional bSSFP-MRF framework for B1+ quantifica-
tion35 or incorporating B1+ sensitivity into the MRF tion, by combining it with a fast low angle shot (FLASH,
sequence and dictionary.39,69–71 An example of such artifacts SPGR, T1-FFE) and SSFP sequence. Additionally, in vivo
and their correction can be seen in Fig. 4. measurements showed a greater standard deviation using the
Chen et al35 used the Bloch–Siegert shift to map B1+ proposed technique than values acquired with a separate B1+
outside of the MRF acquisition, incorporating the measure- correction. It should be noted that with these three methods,
ment into the pattern matching step. Accurate T1 and T2 each added dimension requires exponentially more finger-
maps were obtained with 12-fold acceleration, despite inho- prints to be simulated in the dictionary, requiring greater
mogeneous fields in the abdomen (previously in Body Imag- computational power.71
ing). When using this correction approach, noise propagation While traditionally a challenge in conventional MR
from the B1+ mapping technique is a potential issue, eg, in studies, these results indicate that inhomogeneities in MRF
variable FA T1 mapping, noise in the B1+ map increases noise can be advantageous. Field maps not only improve T1 and T2
in the T1 map.72 Thus, it is preferable to incorporate B1+ measurements, they also can be used to image near metal,39
simulation into the dictionary to account for these errors.73 estimate tissue susceptibility,71 and map electrical properties.39

FIGURE 4: Example of B1+-induced MRI artifacts in the leg near an orthopedic implant. Conventional, spin echo images have large
signal voids near the implant and in the contralateral leg. PnP-MRF is able to account for the inhomogeneities to reconstruct high-
quality, quantitative PD, T1, T2, and B1+ maps. Figure adapted with permission from Ref. 39.

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Enhanced Volume Coverage bulk motion as well as periodic cardiac and respiratory motion.
Quantitative MRI is often neglected in clinical protocols Flow in areas such as the cerebrospinal fluid and blood vessels
because of the long acquisition times required to obtain high- can cause artifacts in MRF due to unbalanced gradients and
resolution, quantitative maps. Efforts have been made to accel- through-plane magnetization, causing these voxels to be mis-
erate MRF acquisition to enable enhanced volume coverage in classified. An example of motion errors and a correction
a clinically-usable timeframe. The methods can be classified as method can be seen in Fig. 5.
3D, simultaneous multislice (SMS), or slice interleaving. Ma et al1 demonstrated that MRF is insensitive to non-
Ma et al74 extended MRF to a 3D acquisition such that var- periodic motion at the end of a scan, because the motion-
iable density spirals were acquired in the kx-y plane for every step corrupted data were filtered out by the pattern matching
in kz in a stack of spirals strategy. This enabled a full-volume algorithm. Building on this work, Yu et al85 confirmed that T1
MRF acquisition in less than 5 minutes, preceded by a 3D measured using MRF with a nonselective inversion pulse was
Bloch–Siegert B1+ map that required 1.6 minutes. Liao et al75 fur- relatively insensitive to in-plane motion but was sensitive to
ther accelerated the stack of spirals 3D acquisition by combining a through-plane motion in the middle of a scan, where larger flip
sliding window reconstruction76 with generalized autocalibrating angles were used. Mehta et al86 developed in-plane motion cor-
partially parallel acquisitions (GRAPPA).77 This combination rection that occurs during any part of the acquisition. The
allowed reconstruction of artifact-free images for dictionary method, MOtion insensitive MRF (MORF), identified and
matching and reduced the number of repetitions required for pat- corrected motion-compromised data by iterating between pat-
tern matching. Full-volume T1, T2, and PD brain maps were tern matching,1 identification of motion corrupted frames, and
acquired in 7.5 minutes. However, these modifications resulted in motion estimation. MORF allowed motion correction during
a reconstruction time of 20 hours with multiple computing cores the entirety of the acquisition; however, it required longer and
running in parallel.75 Cao et al78 enabled further acceleration by more intense computations. MORF also generated a map of
undersampling in all dimensions using multiaxis spiral projection displacements, which could be beneficial to other applications
imaging,79 with an acquisition time of 5 minutes. such as cardiac and abdominal imaging.86
Ye et al80 proposed simultaneous multislice acquisition Anderson et al87 addressed the need for respiratory and pul-
combined with bSSFP-MRF to increase volume coverage by satile motion correction in Cartesian MRF. The proposed RIPE-
accelerating 2D acquisitions. This method used a gradient- MRF method linearly incremented the phase-encoding line in
blipped CAIPIRINHA acquisition to encode unique phases into k-space to add temporal incoherence to the motion. RIPE-MRF
each slice81 and a SENSE reconstruction.82 It was shown to be reduced the artifact-to-noise ratio without increasing the acquisi-
accurate in simulations and in vivo against conventional MRI tion time.87 The authors noted that additional work is needed in
methods, requiring only 5 s/slice, but struggled at multiband fac- regions of high frequency pulsatility and rapid motion.87
tors greater than two. The method was later supplemented with Cruz et al88 proposed a method for 2D in-plane motion
GRAPPA to allow a multiband factor of three with an acquisition correction during reconstruction. The method (MC-MRF)
time of 3.8 s/slice, but was prone to noise amplification at higher used a sliding window reconstruction76 to estimate rigid body
factors.83 To avoid the need for parallel arrays required by these motion, corrected the k-space data, and performed low rank
methods, Jiang et al84 modulated the applied FA pattern of an reconstruction. Errors due to in-plane motion were reduced,
SSFP-MRF sequence to encode slice phases with RF instead of although through-plane motion remained a challenge, particu-
gradients. The work was validated against conventional methods larly for small structures in T2 maps. Xu et al89 developed a
in a phantom and between single-slice and SMS-MRF in vivo, similar method comprised of motion recognition and correc-
and required 18 seconds to acquire two slices. A multiband factor tion in k-space prior to reconstruction. The proposed method
of two was achieved with a single coil, suggesting that higher fac- suppressed errors from in-plane motion artifacts in a phantom
tors could be achieved when more coils are present. and in vivo, but it did not substantially improve through-plane
Rieger et al9 combined MRF with EPI to accelerate motion errors. The authors suggest that using a 3D acquisition
Cartesian acquisitions and acquire T1, T2*, and PD (see could aid through-plane correction.
T2*). MRF-EPI achieved accuracy in a phantom and in vivo
comparable to conventional scans, in less time than a fully-
sampled acquisition. The authors note that this EPI method Barriers to Clinical Adaptation and
was slower than the typical spiral readout. However, it was Recommendations for Progress
extended to cover a full volume using a slice interleaved As summarized in this review, MRF has many possible uses for
acquisition and acquired 32 slices in 3:36 minutes in vivo.25 diagnostics, and there is ongoing work to address challenges such
as incorporation of B1+ compensation,35,39,69–71 enhancing vol-
Motion Compensation ume coverage,9,25,75,80,83 and motion compensation.85–89 A key
Motion is a challenge in MRI, as it results in blurring and arti- advantage of MRF is that it can acquire data in a rapid fashion,
facts. If left unaccounted, errors can result from nonperiodic, although the overall time between patient positioning and image

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FIGURE 5: MRF results from motion-corrupted data using a noncorrected method (IMS) and correction algorithm (MORF).
Conventional MRF is prone to errors in the presence of motion, which can be corrected using an MRF motion-correction algorithm.
Motion artifacts obscure the brain in conventional weighted imaging, but parameter maps from motion-corrected MRF can be used
to synthesize an artifact-free weighted image. Figure adapted with permission from Ref. 86.

viewing by the radiologist may not be fast enough in some cases literature. Phantoms can be used to test the sequence on MRI
due to postprocessing time. hardware, but MRF measures multiple properties, which
Optimization of the MRF sequence can enable requires a phantom that represents multiple properties. This
reduced scan times and/or improve the quality of acquired necessitates construction of custom phantoms, such as that
data.58,71,90,91 However, the postprocessing computational used by Kobayashi and Terada.51 Standardized and well-
power needed for generating dictionaries and pattern- characterized phantoms are widely available, including
matching is still a limitation. For example, the cardiac MRF ADNI,92 ACR,93 and ISMRM/NIST94 phantoms. Yet many
methodology proposed patient-specific dictionaries, but of these do not replicate the T1/T2 ratios found in most tis-
required a high-performance computing cluster to achieve sues. Finally, a challenge that was emphasized in the discussion
reasonable dictionary generation times.18 It is preferred for maps of CEST is the lack of gold standard methodology and phan-
to be generated near instantaneously, but current MRF methods toms, which can inhibit the ability to present a singular valida-
take on the order of 3 minutes to reconstruct per 2D section35 tion method.47
and in the case of 3D acquisitions, more than 2 hours23 or as We summarize the validation approaches used in various
long as 20 hours.75 Sequence optimization, algorithm perfor- implementations of MRF applications (Fig. 2) and initial clini-
mance metrics, and these computational limitations are an ongo- cal studies (Fig. 3), as well as comparisons of MRF values to
ing area of development and will be addressed in more detail in quantitative MRI measures from the literature (Supporting
Part 2 of this review.4 Information Table 1). In this review, 16 clinical studies and
Beyond the technological hurdles, there are certain steps 36 applications development studies were presented. The
to be taken such that the proposed methods and resulting majority of MRF applications presented to date validated the
maps can be compared across clinical centers and over time. method by comparison of their measured in vivo values to
Here we discuss recommendations for validation, repeatability standard method measurements in the same subjects, and most
and reproducibility studies, and standardized reporting. validated by either numerical simulation or the use of a custom
phantom (Fig. 2). In the literature, there can be discrepancies
Validation, Repeatability, and Reproducibility between the MRF-measured value and those by other tech-
Validation is required of any new technique using digital phan- niques, which is possibly due to the challenge of implementing
toms and simulations, using phantoms with ground truth mea- quantitative MR in vivo. The spin-echo methods to measure
surements, through comparison of measured in vivo values to T1 and T2 are time-consuming to acquire in the clinic, so
standard method measurements in the same subjects, or abbreviated protocols are used. These abbreviated protocols
through comparison of measured in vivo values to the can be confounded themselves by B1 effects and slice profile

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effects, stimulated echoes, and magnetization transfer. As a repeatability and reproducibility studies in the breast of healthy
result, we are not surprised that there are discrepancies between subjects, and they determined the coefficient of repeatability
MRF and literature measurements. MRF is typically used as a for T1 to be 290 msec and for T2 to be 14 msec.38 Thus, if an
research tool in a clinical setting, often with a comparison to a observed change was greater than the coefficient of repeatabil-
standard method (Fig. 3) to demonstrate the utility of the tech- ity (eg, ΔT1 >290 msec or ΔT2 >14 msec), it can be consid-
nique. The growing variety of clinical applications in the litera- ered notable. From the reproducibility study across two
ture could lead to more routine adaptation in the future. models of the same vendor, there was no difference in mea-
However, repeatability and reproducibility studies on MRF sured values. In vivo studies of MRF repeatability and clinical
methods are lacking. application have been limited to small patient cohorts, which
Repeatability and reproducibility studies are highly rec- limits the clinical impact of MRF. To date, reproducibility
ommended to demonstrate the robustness of the technique studies compared different platforms within the same vendor,
and readiness for clinical use. The Radiological Society of but methods must also be compared across vendors. Additional
North America – Quantitative Imaging Biomarkers Alliance work is needed, and several studies are under way.100–102
(RSNA-QIBA) carefully developed recommendations for Without repeatability and reproducibility studies to
repeatability and reproducibility studies95 and the statistical demonstrate consistency, accuracy, and precision of MRF
analysis of results.96–98 Repeatability and reproducibility stud- across time, location, operator, etc., the method cannot be
ies can be completed using phantoms or in vivo and should be implemented in the clinic. Beyond the demonstration of con-
the next step following validation. In a phantom, when ground sistency, accuracy, and precision, protocols need to exist to
truth values are available, the bias of that method from the gro- ensure the quality of MRF data, which may exceed the qual-
und truth values should be presented, as shown in Fig. 6 using ity assurance (QA) protocols currently in place. Geethanath
data from Ma et al.23 Ideally, the phantom is used not for a sin- et al103 presented a short QA protocol for use prior to clinical
gle validation, but repeatedly removed and then positioned in studies using MRF using the ACR and ADNI phantoms.
the scanner and imaged to generate repeatability data, as done Alternatively, we suggest using a phantom that represents
in one day by Anderson et al,26 over multiple days on one sys- multiple properties; for example, the T1, T2, and ADC or
tem by Jiang et al,99 and reproducibility data, as done across T2* of various tissues. Then use of this phantom could be
three MRI systems by Cloos et al.10 Repeatability and repro- incorporated into the regular QA protocol, ideally weekly or
ducibility data are also needed in vivo, and some studies were even daily to quickly identify errors in the measurements of
recently completed.10,23,28,38,74 Cloos et al10 presented results any of the multiple properties, which can go unnoticed by
from a small study using three healthy controls, with two mea- the human eye and the existing SNR and contrast-based QA.
surements across three systems. Using the high-resolution 3D
MRF method, Ma et al74 performed repeatability studies using Standardized Reporting
the ISMRM/NIST system phantom, and test–retest studies Standardized reporting, when possible, will allow the field to
were completed in healthy volunteers.23 Panda et al conducted more easily compare and contrast methodologies. We

a b

FIGURE 6: Results from a test–retest study using 3D MRF with the ISMRM/NIST phantom94 for T1 (a) and T2 (b). This sort of study
can be used to assess bias in the measurement technique. Data for this figure were reproduced with permission from Ref. 23.

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FIGURE 7: An example layout for reporting the pulse sequence diagram, relevant parameters, and k-space pattern. We also
recommend labeling the parameters of interest (FA and TR for this particular sequence) in the pulse sequence diagram. This figure is
reproduced with permission from Ref. 12.

recommend including a pulse sequence diagram with labels created, it is easier to compare data using the same color
on each varied acquisition parameter, plots of all parameters schemes for each property map. We recommend using per-
that are varied, and details of the sampling pattern in every ceptually uniform color maps, such as those recommended by
publication. One example of a figure layout containing this Griswold et al,105 including a color bar next to each map and
information can be seen in Fig. 7, which originally appeared in the units of the map property.
Jiang et al.12 However, the pulse sequence diagram should
include labels of the variables of interest: in this example, repe-
tition time and flip angle. An example of such labeling can be Conclusion
found in Fig. 1 of Ma et al,1 where each parameter was labeled Magnetic resonance fingerprinting is a powerful new
from repetition 1 to N. To aid reproducibility and comparison approach to quantitative MRI. With a flexible framework that
of algorithms, the variation patterns should be specified in a can be adapted to many applications, this technique has yet
text file in supplementary information. It should be acknowl- to explore its full potential. MRF offers the ability to acquire
edged that this exact figure format may not be conducive to multiple property maps simultaneously in just a few minutes,
every MRF implementation, eg, CEST MRF implementations without the need for image registration, allowing quantitative
do not vary TR. In these cases, plots of the parameters being MRI to be used in the clinic. One can imagine many future
varied should be displayed instead of FA and TR. Efforts possibilities for MRF beyond what is presented here. For
should be made to include these parameters in a pulse sequence example, the ability to quantify multiple properties simulta-
diagram with corresponding labels, such as in Fig. 1 of Zhou neously with MRF could allow synthetic MRI to be used to
et al.48 Finally, when possible, sharing repositories of code is generate conventional, weighted MR images with any form of
extremely helpful to allow others to reproduce results. Exam- tissue contrast, as well as quantitative maps.106 Using CEST-
ples of such resources can be found in Refs. 1,39,63,76,104. MRF, the fast acquisition time and sensitivity to chemical
Standardized reporting extends beyond pulse sequence effects could enable real-time assessment of MRI biomarkers
specifications to reporting of results. Metrics of the methodol- in vivo to monitor disease progression and treatment efficacy,
ogy need to be included, such as computation times and allowing MRI to be used as a screening tool for disease, rather
memory requirements of the dictionary (including computer than reserved for use only in high-risk cases.
specifications). Computation times and specifications should MRF has already enabled some interesting findings, and
be included for the reconstruction of property maps. Metrics we are excited about the future possibilities. In spectroscopy,
for this analysis are still under development and will be dis- for example, MRF enabled accurate quantification of absolute
cussed in Part 2.4 When, at last, quantitative maps are metabolite concentrations.57 This had not previously been

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accomplished, because patient-specific T1 and T2 could 8. Gao Y, Chen Y, Ma D, et al. Preclinical magnetic resonance finger-
printing (MRF) at 7 T: Effective quantitative imaging for rodent disease
not be acquired in a realistic timeframe, and as a result models. NMR Biomed 2015;28:384–394.
population-average values were used in models.57 Patient- 9. Rieger B, Zimmer F, Zapp J, Weingärtner S, Schad LR. Magnetic reso-
specific modeling of cancer progression, including multiple nance fingerprinting using echo-planar imaging: Joint quantification
MR-measured properties, is an active area of research,107 of T1 and T2* relaxation times. Magn Reson Med 2017;78:
1724–1733.
which could become clinically feasible with the application of
10. Cloos MA, Assländer J, Abbas B, et al. Rapid radial T1 and T2 map-
MRF for fast, quantitative mapping. Another area of interest ping of the hip articular cartilage with magnetic resonance fingerprint-
is defining normal ranges of MRI biomarkers. Studies such as ing. J Magn Reson Imaging 2018;1–6.

Badve et al20 and Chen et al21 demonstrated the sensitivity of 11. Deoni SCL, Rutt BK, Peters TM. Rapid combined T1 and T2 mapping
using gradient recalled acquisition in the steady state. Magn Reson
MRF techniques to normal tissue variations with age. Larger Med 2003;49:515–526.
studies are needed to define a baseline for quantitative mea-
12. Jiang Y, Seiberlich N, Gulani V, Griswold MA. MR fingerprinting using
surement that could fully allow quantitative MR biomarkers fast imaging with steady state precession (FISP) with spiral readout.
to be used in diagnosis and screening. Magn Reson Med 2015;74:1621–1631.

Much work in MRF was devoted to the development of 13. Assländer J, Glaser SJ, Hennig J. Pseudo steady-state free precession
for MR-fingerprinting. Magn Reson Med 2017;77:1151–1161.
methods for clinical applications, including relaxometry and
functional metrics in cardiovascular, body, and head applica- 14. Weigel M. Extended phase graphs: Dephasing, RF pulses, and
echoes — Pure and simple. J Magn Reson Imaging 2015;41:266–295.
tions. However, current methods face challenges in vivo from
15. Tropp JA, Gilbert AC. Signal recovery from random measurements via
B1+ inhomogeneities, motion, and volume coverage, which orthogonal matching pursuit. IEEE Trans Inf Theory 2007;53:
are active areas of research. Technical considerations such as 4655–4666.
pulse sequence optimization, computational power, and met- 16. Liu Y, Hamilton J, Rajagopalan S, Seiberlich N. Cardiac magnetic reso-
nance fingerprinting: Technical overview and initial results. JACC
rics for error analysis are also barriers to the widespread use of
Cardiovasc Imaging 2018;11:1837–1853.
MRF. Additionally, the field needs more studies on repeat-
17. Hamilton JI, Jiang Y, Chen Y, et al. MR fingerprinting for rapid quanti-
ability, reproducibility, and validation of this technique before fication of myocardial T1, T2, and proton spin density. Magn Reson
it can become a reliable clinical tool. We call on the MRF Med 2017;77:1446–1458.

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