AR INSIGHTS. Technical Review, Types of Imaging, Part 4 Magnetic Resonance Imaging

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1 AR INSIGHTS THE ANATOMICAL RECORD 297: (2014) AR INSIGHTS Technical Review, Types of Imaging, Part 4 Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is based on nuclear magnetic resonance, which was independently discovered in 1946 by Bloch et al. (1946) and Purcell et al. (1946). Therefore, the first scanners to use nuclear magnetic resonance to obtain medical images were called nuclear magnetic resonance scanners. The phenomenon of nuclear magnetic resonance is based on the interaction between an external magnetic field and nuclei. However, patients were concerned about the use of the word nuclear because they associated nuclear with radioactivity, even though no radioactivity or ionizing radiation is involved; therefore, the term MRI came into use. MRI shows contrast between soft tissues and has high spatial resolution (Kuperman, 2000). This technique has rapidly evolved over the last 30 years to become an important imaging modality. Approximately 60 million MRI scans are carried out throughout the world every year. PRINCIPLES OF MRI Properties of the Hydrogen Nucleus are Important to MRI Magnetic resonance occurs when a magnet interacts with a magnetic field (Oldendorf and Oldendorf, 1988). MRI is possible because tissue in the body is composed of lots of water. Water molecules are composed of hydrogen nuclei (protons). A hydrogen atom comprises a nucleus with one proton and one electron that orbit the nucleus. The proton is able to spin and behaves like a small magnet. Hydrogen has a highly magnetic nucleus and makes up two thirds of the atoms in tissues. Hydrogen nuclei are the best target for in vivo MRI because, among all types of nuclei in tissues, they provide the highest nuclear magnetic resonance signal and achieve good contrast between different tissues in vivo. (Kuperman, 2000). In the nucleus of hydrogen, movement in electric charge results in a magnetic field. The hydrogen nucleus spins about an axis, and therefore, this moving charge behaves similar to current in a loop of wire, producing a magnetic field. This is termed nuclear magnetism, which can be used for imaging. When the hydrogen nucleus is exposed to a strong magnetic field, it has properties that are comparable with those of a compass needle in the Earth s magnetic field. First, the hydrogen nucleus tends to align with a magnetic field. Second, the hydrogen nucleus has a resonant frequency proportional to the external field strength. Third, the hydrogen nucleus absorbs energy if this energy is at the resonant frequency, and this energy will subsequently be re-emitted. In the presence of a gradient magnetic field, the location of hydrogen nuclei in the gradient is indicated by their resonant frequency. When an atomic nucleus becomes a resonating magnetic object, this is termed nuclear magnetic resonance. When the nucleus in a hydrogen atom is stimulated by radio waves, which have a weak magnetic field, the absorption of energy from radio waves by a magnetic atomic nucleus constitutes the phenomenon of nuclear magnetic resonance. The term resonant frequency is the number of times per second that the hydrogen nucleus wobbles or precesses (oscillation in a wobbling motion). As mentioned above, some protons will align in the direction of the magnetic field, but some will align in the opposite direction to the magnetic field. Magnetic fields from many of these protons will be cancelled out, but more protons will tend to be aligned with the main magnetic field, which produces a net magnetization that is aligned parallel to the main magnetic field. This net magnetization is the source of the MR signal (Pooley, 2005). When energy is absorbed from a radiofrequency pulse, this net magnetization rotates away from the longitudinal direction. The duration and strength of the radiofrequency pulse determines the amount of this rotation, which is called the flip angle. When net magnetization is rotated into the transverse plane (transverse magnetization) by a radiofrequency pulse, this is called a 90 radiofrequency pulse. When net magnetization is rotated 180 into the longitudinal direction (longitudinal magnetization), this is called a 180 radiofrequency pulse. Imaging MRI instrumentation. The main components of an MRI system comprise the following: (1) a strong magnet for generating a static magnetic field; (2) a gradient system comprising three coils for producing a linear field in the X-, Y-, and Z-directions (see Basic Scans below for discussion of these axes) and the corresponding amplifiers; (3) a radiofrequency transmitter including a transmit coil in the scanner; (4) a sensitive radiofrequency transmitter receiver for picking up and amplifying the MR signal; (5) coils for either receiving or transmitting; and (6) computers for regulating the scanner and the gradients, for creating the MR images (array processor), and for coordination of all processes. (Weishaupt et al., 2006). VC 2014 WILEY PERIODICALS, INC.

2 974 JENSEN The magnetic field produced by the magnet must have adequate strength, which usually ranges from 0.1 to 3 Teslas (T) in medical imaging. Most of the MRI scanners used operate at 1.5 T, but 3-T scanners are becoming more common in the clinical setting. In addition, some 7-T scanners are being used in universities, particularly for small animal imaging research. The MRI scanner contains a radio transmitter for producing stimulation. This scanner produces the strong fields required to align the hydrogen nuclei. The scanner also produces gradient fields to localize the nuclei. An individual nucleus emits a signal that is too weak for measurement by an MRI scanner, but the radio waves re-emitted by millions of nuclei can be sensed by an antenna of the scanner after stimulation. Magnetization needs to be large enough to acquire a signal because the MR signal is weak (Weishaupt et al., 2006). TYPES OF MRI SCANS Basic Scans An imaginary construct called the magnetization vector is used for describing the behavior of hydrogen nuclei during MRI. This is a single vector, representing the behavior of all of the hydrogen nuclei in a small region of tissue. The magnetization vector uses a coordinate system in which the X-, Y-, and Z-axes correspond to those of the magnetic field of the scanner. Imaging a transverse slice of tissue is the most common in MRI (Oldendorf and Oldendorf, 1988). To image a transverse slice, the slice must first be isolated from other tissues. This is achieved by the scanner creating a magnetic gradient longitudinally through the body, along what is called the Z-axis. The direction parallel to the main magnetic field is defined as the longitudinal direction. The hydrogen nuclei become spatially encoded when this gradient is present. In adjacent tissue slices, hydrogen nuclei are unstimulated. A second gradient is then produced at right angles to the Z-axis after the first Z- axis gradient is turned off. This results in fields of different strengths. Consequently, the radio signal emitted from the plane comprises a mixture of frequencies. The amount of hydrogen along each line in the tissue slice can be obtained by measuring the radio signal strength at different frequencies. To obtain sufficient data for forming an image, a tissue slice needs to be examined multiple times. Therefore, following a stimulating pulse, the Z-axis gradient is switched off again, and a transverse gradient is given across the tissue slice, but in a slightly different direction to the previous gradient. The plane perpendicular to the Z direction is called the transverse plane (X Y plane). This process must be repeated so that the single slice of tissue is finally cut into several hundred sets of parallel lines, and each set crosses at a different angle on the plane of the slice. The first gradient can also be transversely applied across the body for producing a sagittal section or it can be applied front-to-back to obtain a coronal section. The final step of the imaging process is achieved by computer. To obtain an image, the Fourier transform is performed. T1- and T2-weighted MRI Hydrogen nuclei are affected by their chemical environment. This environment alters the behavior of hydrogen nuclei, leading to changes in the radio signal quality emitted by tissues. When the hydrogen nucleus is exposed to a magnetic field, it is subject to small local variation in the strength of the magnetic field. MRI has good diagnostic potential because of its ability to determine differences in the magnetic environment surrounding hydrogen nuclei. Changes in the magnetic environment alter the signal received after excitation. Two types of behavior of the hydrogen nucleus are influenced by the local magnetic environment. These are called time constants T1 and T2, and are also known as relaxation times because they represent the time it takes for the emitted signal to fade following stimulation. Longitudinal magnetization is zero following a 90 radiofrequency pulse. Longitudinal magnetization is then slowly restored, and this process is known as longitudinal relaxation or T1 relaxation (Weishaupt et al., 2006). More precisely, T1 is defined as the time that it takes for longitudinal magnetization to reach 63% of its final value when there is a 90 radiofrequency pulse. The rate at which T1 relaxation occurs is different for protons in different tissues. This situation results in contrast in T1-weighted images. Fluids have a long T1 (1,500 2,000 ms), water-based tissues have an intermediate T1 (400 1,200 ms), and fat-based tissues have a short T1 ( ms). An example of this type of contrast can be found in the brain. White matter has a short T1 time and rapidly relaxes. In contrast, cerebrospinal fluid has a long T1 and slowly relaxes. The T1 time in gray matter is intermediate and has an intermediate relaxation rate. If an image is produced when these relaxation curves are widely separated, this results in an image with high contrast between the tissues. Consequently, white matter is shown as light pixels, cerebrospinal fluid shows dark pixels, and gray matter shows pixels with shades of gray. A representative T1 image is shown in Fig. 1. T2 represents how long transverse magnetization would last in a perfectly uniform external magnetic field. In other words, T2 is a measure of the length of time that resonating protons are coherent or rotate in phase after a 90 radiofrequency pulse. This process is known as transverse relaxation or T2 relaxation. More precisely, T2 is defined as the time that it takes for transverse magnetization to decay to 37% of its original value. Transverse relaxation is defined as the decay in transverse magnetization because spins lose coherence

3 AR INSIGHTS 975 Fig. 1. T1 sagittal image of the human cervical spine. A turbo-spin echo sequence was used. White matter is shown as light pixels and cerebrospinal fluid as dark pixels. T1 images are useful for examining the cerebral cortex, identifying fatty tissue, and for post-contrast imaging. C: cerebellum; M: medulla; P: pons; S: spine. Fig. 3. T2 coronal image of the human brain. A turbo-spin echo sequence was used. This image shows a different plane (coronal vs. axial) to that in Fig. 2. FL: frontal lobe; LP: lateral pterygoid muscle; LV: lateral ventricle; PL: parietal lobe; SS: sphenoid sinus; TL: temporal lobe; WM: white matter. Fig. 2. T2 axial image of the human brain. A turbo-spin echo sequence was used. In contrast to T1, fat is darker and fluid is lighter in T2.T2 images are useful for detecting edema and showing white matter lesions. FL: frontal lobe; LV: lateral ventricle; OL: occipital lobe; T: thalamus; WM: white matter. (known as dephasing). Transverse relaxation is different from longitudinal relaxation in that the spins exchange energy with each other instead of energy being dissipated to their surroundings. Similar to T1, different tissues have different T2 values and dephase at different rates. Fat is differentiated from water, but in contrast to T1, in T2, fat is darker, and fluid is lighter. Representative T2 images are shown in Figs. 2 and 3. The features that affect signal intensity or brightness of a biological tissue on an MR image, and consequently image contrast, are proton density and T1 and T2 times (Weishaupt et al., 2006). These features can greatly vary between tissues. By varying which of these parameters is emphasized in an MR sequence, this determines how the resulting images are different in their contrast. This process is the basis for the fine discernment of soft tissue and diagnostic potential of MRI. T1 and T2 relaxation are independent of each other, but occur simultaneously. In addition, the time to echo and repetition time (see Types of Pulse Sequences below) are useful for controlling the amount of weighting of T1 and T2 effects in the image (Pooley, 2005).

4 976 JENSEN Fig. 5. Three-dimensional volume-rendered time-of-flight magnetic resonance angiogram of the human brain. Maximum intensity frontal projection. Fig. 4. FLAIR image of the human brain. A T2 axial image with an inversion pulse is shown. Normally in T2, fluid is light, but in this technique, fluid is shown in black. Structures are as labeled in Fig. 2. FLAIR is an inversion-recovery pulse sequence, which is used to suppress the signal from fluids. This technique is useful for identifying pathology (shown as bright areas when present). Types of Pulse Sequences MRI using a single pulse shows the distribution of hydrogen throughout the body and is not useful for diagnostics (Oldendorf and Oldendorf, 1988). However, MRI is usually used to address more complex issues. To investigate these complex issues, pulse sequencing is carried out instead of a single pulse. For pulse sequencing, two or more radio pulses are applied to tissue in quick succession. A parameter involved in pulse sequencing is called the repetition time, which is the time taken to go once through the pulse sequence. Researchers need a lot of experience to interpret scans made with various pulse sequences. This is because many different images can be obtained of the same scan slice with different pulse sequences. Many pulse sequences have been developed, but only some of the more common ones used in MRI are discussed below. Future development of MRI is likely to involve new pulse sequences because many variables can be used. Spin Echo The spin echo pulse sequence is a common type, in which a 90 pulse is followed by a 180 pulse. Following the 90 radio frequency pulse, protons in phase begin to diphase. The protons begin to rephase after the 180 pulse. This rephasing of the spins causes formation of an echo, termed a spin echo. The time between the peak of the 90 radio frequency pulse and the peak of the echo is termed the time to echo. For clinical MRI, scans are usually created from spin-echo pulse sequences. Another type of spin echo pulse sequence is multiecho spin echo, in which multiple 180 radio frequency pulses are performed to form multiple echoes. Each of these echoes is used for constructing a separate image data set with different contrast weighting. Turbo-spin echo, otherwise known as fast-spin echo, also uses multiple 180 radio frequency pulses to create multiple echoes. However, rather than each echo producing a different image data set, all of the echoes are included to achieve a single image data set in a faster time. The turbo-spin echo pulse sequence is useful for producing T1 and T2 contrast weighting (Figs. 1 3). Each echo still occurs at a different time to echo and thus has a different contrast weighting. Inversion-recovery Another common pulse sequence used clinically is inversion-recovery. This type of sequence measures T1 and mostly eliminates T2 effects from the scan. This enables greater anatomical details and better gray-white matter contrast than T2-weighted scans. Inversionrecovery is used to suppress undesired signals in MRI (e.g., signals from fat or fluid). Selecting time to echo and repetition time can still be performed to control contrast weighting. The inversion-recovery pulse sequence is different from the spin-echo pulse sequence in that a 180 radio frequency pulse is given before the regular spin-echo pulse sequence of 90.

5 AR INSIGHTS 977 Fig. 6. T1 saggital section of the human brain. (A) Gadolinium contrast was used. (B) No contrast was used. BA: basilar artery; CA: cerebral artery (anterior); P: pituitary gland. Specialized MRI Techniques There are many specialized MRI techniques, such as diffusion-weighted MRI, fluid attenuated inversion recovery (FLAIR) (Fig. 4), time-of-flight magnetic resonance angiogram (Fig. 5) magnetic resonance spectroscopy, functional MRI, magnetic resonance angiography, T1rho MRI, real-time MRI, and magnetization transfer MRI. However, discussion of these techniques is outside the scope of this article. Some of these techniques will be covered in future Insight articles. CONTRAST AGENTS Contrast agents enhance contrast in MR images by altering T1 and T2 relaxation times (Kuperman, 2000). They are often administered in MRI for improving assessment of local physiological and anatomical conditions or for improving detection of malignancy. Contrast agents are usually administered internally, and should have low toxicity with easy excretion from the body. Contrast agents for MRI indirectly affect the signal by interacting with hydrogen nuclei. Many MRI contrast agents change the T1 and T2 relaxation times in tissue via dipole-dipole interaction with water protons. Some of the more commonly used contrast agents are discussed below. Paramagnetic ions with unpaired electrons (e.g., Gd 31 and Mn 21) are often applied as MRI contrast agents because of their high relaxivities. However, these agents can be toxic, and to reduce this effect for in vivo use, they can be chelated to particular molecules. Gadolinium-diethylenetriaminepentaacetic acid (DTPA) is the most well-known MRI contrast agent (Fig. 6). Gadolinium-enhanced MRI is useful for detecting tissue abnormalities (e.g., brain and breast). Gadolinium-DTPA is a chelate composed of gadolinium ions and DTPA. Gadolinium-DTPA has a high margin of safety (Kanal et al., 1990), with a low prevalence of adverse reactions (2.4%). There are two types of iron oxide contrast agents, including superparamagnetic iron oxide and ultrasmall superparamagnetic iron oxide. These contrast agents comprise suspended colloids of iron oxide nanoparticles. When they are injected while imaging, they reduce the T2 signals of absorbing tissues. Superparamagnetic iron oxide is used for clinical liver imaging. Superparamagnetic iron oxide is detectable at much lower concentrations than with paramagnetic agents (e.g., gadolinium). Superparamagnetic iron oxide is nontoxic to cells, is biodegradable in vivo (Arbab et al., 2005; Farrell et al., 2009), and has been shown to be safe for intravenous administration in humans (Richards et al., 2012). The desire to improve enhancement of lymph nodes on MRI led to the development of ultrasmall superparamagnetic iron oxide particles from size fractionation of polydispersed superparamagnetic iron oxide (Bernd et al., 2009). USES OF MRI MRI is applied in imaging every area of the body. In particular, MRI is useful for tissues with many hydrogen nuclei and little contrast density (e.g., brain and muscle). Clinically, MRI is used to discriminate pathological tissue from healthy tissue. T2-weighted sequences are especially sensitive for pathology, and are useful for distinguishing pathological tissue from normal tissue. Advantages and Disadvantages of MRI MRI has a number of advantages as follows (Oldendorf and Oldendorf, 1988). (1) Tissue can be characterized in various ways using MRI. (2) MRI can image any plane, as discussed above. (3) The radio signals and magnetic fields used in MRI do not interact with bone. Compact bone is mostly not able to be seen with MRI because it has a low water content. Only fatty bone marrow is able to be

6 978 JENSEN imaged, being the only bone structure that can be visualized. (4) Contrast medium is not always needed. (5) Finally, unlike computed tomography scans and X-rays, MRI does not use ionizing radiation. MRI has comparable resolution to computed tomography but has much better contrast resolution. There are some disadvantages of MRI as follows. (1) MRI is complex and expensive. (2) MRI involves long scan times. (3) Noise, isolation, and confinement can be stressful to patients while scanning. (4) Patients who have pacemakers and metallic artifacts are unable to undergo MRI. SAFETY CONSIDERATIONS FOR USING MRI IN HUMANS There are various health and safety concerns for both patients and doctors/researchers because of the way in which clinical MR imaging is currently performed. These concerns can be categorized into the following four main areas: (1) static magnetic field effects (e.g., biological effects and safety considerations [physical effects] related to attractive forces of the static magnetic field; (2) effects from time-varying extremely low frequency magnetic fields (e.g., altered synthesis of DNA); (3) effects of rapid changes in magnetic field gradients, which can induce voltages in the body; and (4) other concerns that are not directly related to magnetic fields (e.g., contrast agents and psychological effects; see safety_article.asp?subject5172) (Kanal et al., 1990). Occupational Exposure to MRI Safety guidelines for occupational exposure to MRI have been published in the USA (e.g., ACR Guidance Document for Safe MR Practices, Sentinel Event Alert #38 by the Joint Commission, and MRI Design Guide by the United States Veterans Administration) and Europe (e.g., EU directive 2004/40/EC on physical agents [electromagnetic fields]). Exposure limits are usually expressed as root mean square values. In most guidelines, restrictions are established to avoid short-term adverse effects and are defined in terms of root mean square-induced electric field components in tissue. However, despite guidelines being issued, little is known regarding the actual levels of electromagnetic field exposure in workers involved with using MRI (McRobbie, 2012). ACKNOWLEDGEMENTS The author thanks Angela Harrison and Anna-Maria Lydon atthecentreforadvancedmri,theuniversityofauckland, and Ayton Hope for kindly providing the images. ELLEN C. JENSEN 35 Southern Cross Road Kohimarama Auckland 1071 New Zealand LITERATURE CITED Arbab AS, Yocum GT, Rad AM, Khakoo AY, Fellowes V, Read EJ, Frank JA Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed 18: Bernd H, De Kerviler E, Gaillard S, Bonnemain B Safety and tolerability of ultrasmall superparamagnetic iron oxide contrast agent: comprehensive analysis of a clinical development program. Invest Radiol 44: Bloch F, Hansen WW, Packard M Nuclear induction. Phys Rev 69:127. Farrell E, Wielopolski P, Pavljasevic P, Kops N, Weinans H, Bernsen MR, van Osch GJ Cell labelling with superparamagnetic iron oxide has no effect on chondrocyte behaviour. Osteoarthr Cartil 17: Kanal E, Shellock FG, Talagala L Safety considerations in MR imaging. Radiology 176: Kuperman V Magnetic resonance imaging: physical principles and applications. San Diego: Academic Press. McRobbie DW Occupational exposure in MRI. Br J Radiol 85: Oldendorf MD, Oldendorf JR Basics of magnetic resonance imaging. Boston: Martinus Nijhoff Publishing. Pooley RA Fundamental physics of MR imaging. Radio- Graphics 25: Purcell EM, Torrey HC, Pound RV Resonance absorption by nuclear magnetic moments in a solid. Phys Rev 69:37. Richards JM, Shaw CA, Lang NN, Williams MC, Semple SI, MacGillivray TJ, Gray C, Crawford JH, Alam SR, Atkinson AP, Forrest EK, Bienek C, Mills NL, Burdess A, Dhaliwal K, Simpson AJ, Wallace WA, Hill AT, Roddie PH, McKillop G, Connolly TA, Feuerstein GZ, Barclay GR, Turner ML, Newby DE In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide: feasibility and safety in humans. Circ Cardiovasc Imaging 4: Weishaupt D, K ochli VD, Marincek B How does MRI work?: An introduction to the physics and function of magnetic resonance imaging. 2nd edn. Berlin Heidelberg: Springer. *Correspondence to: Ellen Jensen, 35 Southern Cross Rd., Kohimarama, Auckland, New Zealand, ellen_knapp2004@yahoo.com.au Received 9 November 2013; Accepted 6 March DOI /ar Published online 19 April 2014 in Wiley Online Library (wileyonlinelibrary.com).