Review
Role of M agnetic Resonance Imaging in Guiding
Thermal Therapies
A Brief Technical Review
KAGAYAKI KURODA
Department of Human and Information Sciences, School of Information Science and Technology, Tokai University, 1117 Kitakaname, Hiratsuka 259-1292, Japan
Molecular Imaging Research Group, Institute of Biomedical Research and Innovation, 2-2 Minatojima-Minamimachi, Chuo, Kobe 650-0047, Japan
Abstract : For a number of reasons, Magnetic Resonance Imaging (MRI) is a unique tool for interventional use. It has a spatial resolution which is independent of the wavelength of the electromagnetic field used for imaging,has various imaging parameters which are related to the physical properties of the subject; provides a superior soft-tissue contrast; provides freedom in determining the slicing or viewing angle; and it utilizes non-ionizing radiation. This technology offers assistance in therapeutic applications such as lesion identification, treatment planning, device tracking, temperature imaging and treatment evaluation. In this article,the role of MRI in assisting thermal therapy is briefly reviewed from a technical point of view.
Key Words : magnetic resonance (MR), thermal therapy, interventional, temperature, thermometry
Introduction
Magnetic resonance imaging (MRI) has been used in therapy since the concept was first proposed and a practical open-configuration magnetic resonance (MR) system was developed in 1994. MRI is used for guidance in biopsies ,surgical operations ,focused ultrasound surgery(FUS) ,laser ablation , cryosurgery ,microwave ablation ,and radio frequency(RF)ablation . Additional applications with catheterization, endoscopic surgery, reproductive medicine, and gene therapy are currently being investigated. Among these many applications, assistance with thermal therapy is an important use of MR, primarily because MR is the only known imaging modality that can be used to visualize internal body temperatures. In this review,the features of MR applications which are of use in thermal therapies are discussed from the viewpoint of physics and engineering. In the following,the MR of protons( H) is discussed. For those who are not familiar with MR,the fundamentals of MR physics and principles are well described in available text books .
Received 31 March, 2007, Accepted 21 May 2007. Corresponding author; Tel, ＋81-463-58-1211, ext. 4671; Fax, ＋81-463-58-9461; e-mail, kagayaki＠keyaki.cc.u-tokai.ac.jp
１. MR imaging as instrumentation
MRI has unique features when compared with other imaging modalities such as X-ray computerized tomography (X-CT), Positron emission tomography (PET), Single Photon Emission Tomography (SPECT),and Ultrasound Sonography(US). In general,the spatial resolutions attained in imaging are determined by the length of the electromagnetic or compressional waves used with the various modalities . Diffraction cannot occur through an aperture or a structure whose size is smaller than the wavelength,and the spatial resolution of X-CT and US scanners are determined by this principle because the transmission, absorption, reflection and diffraction of the waves are directly observed. With these other technologies, the properties of the waves are used entirely for resolving spatial dimensions. However, the spatial resolution of MRI is not determined simply by the length of the electromagnetic waves used,which are typically 0.6-300 m (500-1 MHz)in air and much longer than the size of the human body. MRI resolution is governed by the strength of the static and gradient magnetic fields and the bandwidth of the radio frequency field. This means that the properties of the waves can be utilized for purposes other than resolution in space,and hence,MRI is capable of imaging a variety of physical and chemical properties in biological tissues. In addition, MRI s strengths are the contrast it provides between different high-water-content tissues, its non-ionizing-radiation properties, and its arbitrary selection of spatial regions to examine. Using a diverse range of parameters can yield images with high-order biological information including functional,thermal,and metabolic information in addition to simple anatomical images. MR s non-ionizing radiation property is important for long-time and/or frequent imaging during treatments. The primary drawbacks of MRI in interventional use are incompatibilities in temporal-spatial resolution and the signal to noise ratio, limitations in the use of magnetic and conductive materials in the clinical and experimental setups,and the cost of avoiding these materials. Biological reactions to the strong static magnetic fields(∼ 3T)used in the latest systems,the electric currents induced by the alternating gradient fields, and the thermal energy deposited by the RF fields are concerns, although these reactions are less significant than those of ionizing radiation. The physical values to be measured and the MR parameters corresponding to these quantities are listed in Table I.
Table I. MRI parameters and the corresponding observable physical quantities
Physical quantity MR parameter Image category
Density M Morphology
Molecular motion/viscosity T , T , D
Susceptibility T , φ Functional
Chemical environment δ, MTC Metabolic
Temperature M , T , T , D, δ, φ Thermal
Velocity φ Flow/Motion
Elasticity φ Elastic
M : Thermal equilibrium magnetization, T : Spin-lattice (longitudinal) relaxation time, T : Spin-spin (transverse) relaxation time, T : T includes the effect of inhomogeneity of the external magnetic field,D : Diffusion coefficient,δ: chemical shift,φ: Phase,MTC : Magnetization Transfer Coefficient.
２. Roles of MR in thermal therapies
２.１ Detection of tumors
One of the most significant and the most widely used applications of MR is tumor detection in soft tissues. Tumor detection can be regarded as the targeting stage in thermal therapy. For brain tumors for example, the characteristic MR appearance is a hyper-intense signal (long T relaxation time) in a T -weighted image, and a low signal (long T ) in a T -weighted image. In addition to these basic contrasts, T contrast enhancement with a Gadolinium chelate is commonly used to provide a clearer tumor delineation . Fig.1 shows examples of brain tumor enhancement at 0.5 T in an open MR system. Proton magnetic resonance spectroscopy(MRS) and magnetic resonance spectroscopic imaging (MRSI) are also powerful tools for the diagnoses of malignant tumors, although the routine use of these techniques in the clinic is limited because of the time-consuming scan preparations required which include magnetic field shimming, and delicate data processing protocols such as spectral shaping. Tumors in different organs have specific properties,and hence the imaging techniques to be used have to be optimized according to the target regions to be examined. These tumor detection techniques are well reviewed in available text books .
２.２ Navigation of treatment devices
MRI can be used to help in navigating and placing interstitial or intra-cavity heating devices . Devices with paramagnetic or conductive materials normally appear as signal voids in the images,because they contain no protons or a very small numbers of protons. These materials also create a characteristic signal intensity distribution because of their magnetic properties and electrical conductivity. The signals are more notable in gradient echo sequences, in which the signal decays with the transverse relaxation time including the effect of the field inhomogeniety(T ),and is modulated with an eddy-current-induced
Fig.1.Examples of contrast-enhanced, T -weighted images showing brain tumors (arrow heads) and optical fibers penetrating into the tumors (arrows). The images were acquired at 0.5 T in an open MR system with a typical first spin echo sequence of TR/TE, 400/24 ms; echo train length, 4. Images were provided by courtesy of Prof. Ferenc Jolesz, MD and his colleagues, Department of Radiology, Brigham and Women s Hospital, Harvard Medical School.
magnetic field change. In spin-echo sequences, the effect of susceptibility-induced field inhomogeneity is reduced by the refocusing pulses. If a device is straight and rigid,detecting its tip is relatively simple. One can use a commercially available two-or three-point optical navigator , or a magnetic navigator that detects gradient fields used during image acquisition . The coordinate systems of those apparatuses are interlocked with the MR coordinate systems to enable acquisitions of images parallel with or perpendicular to the devices.
Heating devices made of diamagnetic and nonconductive materials are often unrecognizable in MR images. Flexible devices like optical fibers or catheters are sometimes even more difficult to detect and track in three-dimensional space. Such a situation is also encountered with metal devices, which can bend in tissues. In these cases, guiding a heating device to a target region becomes difficult. Various techniques for marking and navigating devices have been proposed . These techniques can be classified into two groups; passive approaches which do not use electrical currents, and active approaches using currents. In the former case,the simplest method is to make the devices appear as susceptibility artifacts in the images by putting susceptible materials on or around the devices . A variation of this type of approach uses a flexible device which can be guided and inserted into the target tissue and then act as a sheath and guide for the heating device or device of interest. In fact,the successful placements of the optical fibers shown in Fig.1 were performed by using biopsy needles. The other approach is to make a positive contrast enhancement by coating the device with a gel containing a Gadolinium chelate . Another approach, although somewhat primitive, is to wind a coil on the device and to apply a direct electrical current to the coil in order to create local magnetic field disturbances which then appear as artifacts in a image . A more sophisticated approach is to use coils,but to form inductance-capacitance resonance circuits to detect magnetic resonance signals locally,and produce hyper-intense images in the area of interest . MRI is also advantageous when compared to X-ray fluoroscopy because of MRI s non-ionizing radiation nature . The navigation techniques described briefly above are important,not only for thermal therapies but also for other minimally invasive clinical procedures such as catheterization.
２.３ Temperature imaging Overview
One of the most significant features of MR in assisting thermal therapies is noninvasive thermometry. Evaluation of temperatures at the target, protection of surrounding normal tissues, control of heating power,and assessment of therapeutic effects all require temperature information. Invasive thermometric tools such as thermocouples and optical fiber thermometers detect only the temperature information around the probe points,and cannot detect hot spots distant from the probe. Thermometry techniques have to be noninvasive in order to image temperature distributions in the target region, because the insertion of a large number of probes would circumvent the non-invasive approach to therapy and is obviously not practical. There are also interactions between probes and electromagnetic waves or sound waves used for heating. Several noninvasive techniques using X-CT, US, microwave tomography, radiometry,and MRI have been introduced in the last 20 years . However recently,MRI has come to be considered as the only practical modality for noninvasive temperature imaging, after water proton
resonance frequencies were found to be a reliable measure of temperatures ,and permited a temperature imaging strategy to be designed .
Most of the proton MR parameters used for water such as the spin-lattice relaxation time T , spin-spin relaxation time, T , proton density or thermal equilibrium magnetization, M , diffusion coefficient,D ,and chemical shift,δ ,are known to be temperature-dependent. Among these parameters,the chemical shift of the water proton has recently been recognized as the most reliable and practical indicator of temperature .
Principles and techniques
The temperature dependence of the proton chemical shift occurs when the proton system has hydrogen bonds . The most abundant hydrogen-bonded proton system in biological tissues is water. The resonance frequency of a proton at a certain temperature is determined by the strength of the magnetic flux density,B ,of an external field,and the shielding effect,σ,caused by the currents induced in the electron cloud in a direction which cancels the external field. When temperature rises,the motion of water molecules intensifies, distorting, extending and/or breaking the hydrogen bonds of the molecules; thus,an electron cloud at higher temperatures is freer from the restraint of electrical bonding forces than at lower temperatures. The attenuation of hydrogen bonding induces more currents in the electron cloud, strengthening the shielding effect. As the result, the resonance frequency of the water proton becomes lower. The difference of the temperature coefficient of the water proton resonance frequency,compared to the reference resonance frequency or the center frequency of the RF system in the MR scanner,is called the chemical shift,and this has been determined to -0.01 ppm/℃ for pure water . In biological tissues, this coefficient was found to be similar to that of pure water .
Temperature imaging based on the water proton chemical shift originated from spectroscopy techniques and evolved into two methods: the spectroscopic imaging and phase mapping methods. Phase mapping has now been widely accepted for monitoring tissue temperature changes while using thermal therapies after initial feasibility reports . This is a practical approach because normal gradient echo sequences,which are available on most of the clinical scanners, can be used. A reference phase image is taken before heating, and then the phase change due to temperature elevation is obtained by subtracting the reference reading from the phase image after heating. Hence the temperature change ΔT can be obtained by the phase change Δφ as the following equation .
ΔT ＝ Δδ α ＝
Δφ ω ・TE・α
Where Δδis the change in the water proton chemical shift, α［ppm/℃］is the temperature coefficient of the chemical shift, ω is the reference frequency of the radio frequency(RF) system, and TE［sec］ is the echo time or the time interval between the excitation pulse and the echo signal. In practice, the phase subtraction is implicitly performed by using the following subtraction formula to avoid phase wrapping .
Δφ＝ tan S R-ref・S^I-tar− S^R-tar・S I-ref S R-ref・S^R-tar＋ S I−ref・S^I−tar
Although any non-water component present,for instance lipids,contributing to the signal can be a source of error in this calculation, signal suppression techniques work well for reducing such errors.
There are many variant techniques of the phase mapping method. In the multiple gradient echo technique, several gradient echo signals are acquired during a repetition time (TR) in order to reduce errors in the chemical shift change using a least squares analysis . In the echo-shift approach,TE can be longer than TR, yielding short acquisition times and sufficient temperature sensitivity simultaneously . Similarly, echo-shifted first spin-echos can be applied to thermometry . Techniques using balanced steady-state free precession (balanced SSFP) sequences have also been proposed .
The phase mapping technique can be affected by tissue susceptibility changes and body movement because it basically depends on the voxel-by-voxel subtraction between objective and baseline phase values. Recently,efforts have been made to analyze and reduce the effect of body motion or deformation. This will be discussed in the next section.
The other concept used to avoid errors induced in phase mapping methods is to use spectroscopic imaging techniques which utilize a temperature-insensitive proton component as an internal reference to measure the water proton chemical shift. To improve the temporal resolution, methods using Echo Planar Spectroscopic Imaging (EPSI) and Line Scan Echo Planar Spectroscopic Imaging (LSEPSI) have been proposed. Techniques using the proton chemical shifts of paramagnetic lanthanide complexes have also been intensively investigated . These non-water techniques may be advantageous in terms of temperature sensitivity and/or the possible absolute temperature measurements.
Measurement of adipose tissue temperature is another important issue. However, to date, few studies have been conducted on this topic .
Application to the mobile organs
In the field of MR intervention, thermal treatment of a mobile organ such as the liver is currently an important topic . Since the phase mapping technique relies on voxel-by-voxel subtraction of the phase of the complex MR images,other factors producing phase changes can be sources of temperature error. The most significant of these factors is inter-scan motion,which refers to body or organ movement between a pair of scans at two different temperature observation time points. Intra-scan motion, or movement during image acquisition, on the other hand, is relatively insignificant because it can be avoided by using rapid scan techniques combined with breath holding. There are two primary effects of interscan motion. First,tissue motion and/or deformation can cause the protons in a voxel to move relative to another voxel(s). Second, there might be a distortion of the magnetic flux of the external magnetic field. A few techniques for compensating for these motion effects in temperature imaging have been previously proposed . However,these methods are effective only when the motion is translational, periodic, in-plane, and/or without deformation.
organ is appropriate,because the external magnetic flux density distribution does not suffer from spatial discontinuity of susceptibility. In addition, the size of the heated region in the liver is relatively small compared to the size of the entire organ when localized heating is applied with microwaves, radio frequencies (RF), lasers, or focused ultrasound (FUS). These facts suggest that phase changes induced by thermal effects can be detected as local phase changes in the smooth phase distribution. Using this principle, a temperature imaging technique called Referenceless PRF thermometry , or the Self-reference method ,was devised,in which first a region of interest or ROI covering the heated area is set,and then the phase distribution in the ROI is estimated in a doughnut-like surrounding region for estimation or RFE. The estimated reference phase image is then deducted from the original phase image,and the temperature change distribution in the ROI is obtained. Since this technique,unlike the conventional method,does not require any external baseline images to be taken before heating,it reduces the effects of inter-scan motion . Fig.2 shows temperature elevation maps obtained with the self-referenced method in uterine fibroids with FUS. Although tissue motion was not significant in this case, the images were sufficient for demonstrating that the method can visualize the temperature distribution around the focus without making a baseline reading. There is still a remaining problem; the image has to be taken at a slice located directly through the heated volume. If the slice plane is not located through the heated volume, then the estimated phase change loses its temperature information. In the case of microwave or RF heating,the heating needles serve as a landmark for tracking the heating position . For FUS, several new techniques been introduced recently .
Fig.2.Temperature elevation images in uterine fibroids under focused ultrasound heating (83 W) obtained with the self-reference thermometry technique . Coronal (a-c) and sagittal views (d-f) of the elevations are superimposed over the corresponding T1-weighted,spoiled gradient echo images acquired with TR/TE,25.2/12.5 ms for coronal and 25.7/12.8 ms for sagittal images.
２.４ Evaluation of Thermal Damage
Temperature elevation maps obtained with MR at different time points allows the construction of thermal dose maps using the following equations ;
TD＝ t 2t 1 R 43-T(t)dt
where TD is the equivalent time the tissue has spent at 43℃ in minutes, T(t) is tissue temperature at time point t,t1 and t2 are the time points of the treatments beginning and end. R is a constant which is empirically determined as below ;
R＝0.25 (T(t)＜43℃) R＝0.5 (T(t)＞43℃).
It is accepted that 240 min of heating at 43℃ is a criteria for a sufficient thermal treatment. Relaxation times of the MR signal can serve as an index for the thermal denaturation of tissues. Spin-spin relaxation time(T )weighted or contrast enhanced spin-lattice(T )weighted images have been proven to correlate well with histological tissue analysis .
２.５ System integration
The above-mentioned ability of MR has been combined with heating devices to form integrated heating-imaging systems. One of the most sophisticated systems is MR-guided focused ultrasound surgery . These devices are already commercially available and widely used for the clinical treatment of uterine fibroids . It is advantageous to use MR with ultrasound because the interaction between ultrasound and MR is practically negligible. Another recent improvement in such system integration is RF heating with magnetic resonance imaging . In the prototype system,electromagnetic interference between the heating RF field at 13.56 MHz and the imaging RF field at 64 MHz is sufficiently suppressed with filter techniques making simultaneous heating and monitoring possible.
２.６ Molecular imaging
MR is expanding into another area: molecular imaging for thermal therapies. Chemical shift imaging techniques, contrast-enhanced imaging with paramagnetic and super-paramagnetic compounds, or thermometric techniques with lanthanide complexes can be regarded as molecular imaging methods, and have already been mentioned above. In addition to these methods, other topics should also be mentioned.
One is the use of magnetic nano-particles packaged with specifically designed liposomes. Paramagnetic Thermosensitive Liposomes (TSL) are designed to have a membrane whose permeability increases rapidly at a gel-to-liquid crystalline phase transition temperature . When a tissue reaches this transition temperature from heating,Gadolinium or Manganese compounds contained in the liposomes are released, and undergo an acute paramagnetic relaxation effect giving a hyper-intense signal in the coagulated or heated tissue region in the T -weighted image . Thus,TSL can be used as an indicator of target temperatures. Another type of liposome is the Magnetic Cationic Liposome (MCLs) , which is designed to be injected into a tumor. The surfaces of the liposomes are positively charged in
order to be attracted by the negatively charged tumor cell surfaces. Once the MCLs have accumulated in the tumor,they yield a negative contrast enhancement in T -weighted images. When an alternative magnetic field, whose frequency is on the order of 100 KHz, is applied, they create heat with hysteresis loss. Thus MCLs can be used for both target imaging and hypthermic treatment. A similar configuration of liposomes is Antibody-conjugated Magnetoliposomes (AMLs) . Rather than using an electrically charged surface, the surface of AMLs are coated with antibodies, which allows the liposomes to accumulate on tumor cells.
Another MR application is the induction and control of transgene expression by combining MR-guided focused ultrasound heating with a heat-sensitive promoter . Significant HSP70 and GFP expression has been observed after hyperthermia at 50℃ within 3 min .
３. Summary
The role of MRI in guiding thermal therapies was briefly reviewed,primarily from the viewpoint of physical instrumentation. The applications introduced here are just a part of the enormous and growing field of MRI and its applications. However, in order to establish thermal therapies as a major and reliable therapeutic choice, and to expand the basic science of thermal medicine, more effort is still required for thermal-related MR research.
Acknowledgements
Part of this review work was conducted under the auspices of the Medical-Engineering Cooperative Research Project of the New Energy and Industrial Technology Organization (NEDO),Japan,and was supported in part by a Grant-in-Aid of the Ministry of Education, Sciences and Culture of Japan, # 15500325.
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