Abstract:
A method and apparatus for generating a localized heating are provided, the method comprising: transmitting a spatially localized or shaped electromagnetic field via a plurality of coils to a subject and generating magnetic resonance signals; performing magnetic resonance imaging based on the magnetic resonance signals to generate an image of a region of interest of the subject; and controlling the plurality of the same imaging coils to radiate radio frequency (rf) energy to generate the localized heating on a region of interest. The invention provide a more efficient manner for generating localized heating and means for verifying the heating pattern without the need to measure temperature rises in the patient. This is useful to check the localization prior to the application of hyperthermia.

Description:
FIELD OF THE INVENTION 
     The subject matter disclosed herein relates generally to a method and an apparatus for generating a localized heating, and more particularly, to a method and an apparatus for generating a localized heating on a region of interest of a subject by a magnetic resonance imaging (MRI) system. 
     RELATED ART 
     In the field of oncology, hyperthermia is frequently used in conjunction with chemotherapy to improve an efficiency of tumor cell killing. Radio frequency (RF) hyperthermia is a standard tool in the oncology field to generate spatially controlled (localized) heating patterns within a body. Conventional RF hyperthermia uses an array of dipole antennas placed around the body and delivers the necessary energy via a continuous or pulsed RF waveform. 
     An amplitude and a phase of the RF waveform at each element is varied to provide the necessary spatial localization. Verification of the localized heating pattern is performed via invasive thermocouples that directly measure the temperature rise or non-invasively using MR or infrared thermometry. In addition, to improve the efficiency of delivering the RF energy to the patient, a water-filled bag surrounding the patient is used to increase the coupling of the RF to the body. 
     MR thermometry, using proton resonance frequency (PRF) shifts, has been used with RF hyperthermia to monitor the heating pattern and to adjust the application of RF energy so as to target only the region of interest (e.g., Kowalski M E, et al, IEEE Trans Biomed Eng 2002; 49: 1229-41). However, cumbersome water-filled bags are used and the heating pattern is adjusted and verified based on the image-based thermometry data. Therefore, an improved method and apparatus for generating a localized heating in a region of interest of a subject overcoming foregoing disadvantages is desired. 
     SUMMARY OF THE INVENTION 
     In a first aspect, a method for generating a localized heating is provided. The method includes the steps of: transmitting a spatially localized or shaped electromagnetic field via a plurality of coils to a subject and generating magnetic resonance signals; performing magnetic resonance imaging based on the magnetic resonance signals to generate an image of a region of interest of the subject; and controlling the plurality of the coils to radiate radio frequency (rf) energy to generate the localized heating in a region of interest. 
     In a second aspect, an apparatus for generating localized heating is provided. The apparatus includes: a plurality of coils configured to transmit a spatially localized or shaped electromagnetic field to a subject and to generate magnetic resonance signals; an imaging device configured to perform magnetic resonance imaging based on the magnetic resonance signals to generate an image of a region of interest of the subject; and a control device configured to control the plurality of the coils to radiate RF energy to generate the localized heating on the region of interest. 
     In a third aspect, a method for generating a localized heating is provided. The method includes: transmitting radio frequency energy via a plurality of coils to a subject; and generating unique radio frequency waveforms on each of the coils to generate an arbitrary specific absorption rate distribution in the subject to enable spatially localized heating. 
     In a fourth aspect, a method for generating a localized heating pattern and imaging is provided. The method and apparatus includes: a plurality of coils configured to transmit a spatially localized or shaped time-varying magnetic field to excite spins of interest within the body to generate magnetic resonance signals. Furthermore, the same configuration of coils is used to also transmit a spatially localized or shaped electric field to generate an arbitrary specific absorption rate distribution in the subject to enable spatial localized heating. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The features and advantages of the invention will become apparent from the following detailed description of the embodiments of the invention when read with the accompanying drawings in which: 
         FIG. 1  illustrates a block diagram of a system for generating a localized heating in accordance with certain embodiments of the invention. 
         FIG. 2  is a simplified block diagram showing a linear coil array in accordance with one embodiment of the invention. 
         FIG. 3  is a simplified block diagram showing a coil array in accordance with another embodiment of the invention. 
         FIG. 4  is a flow chart showing operation of an apparatus in accordance with one embodiment of the invention. 
         FIG. 5  illustrates a simplified block diagram of the apparatus for generating a localized heating in accordance with another embodiment of the invention. 
         FIG. 6  is a flow chart of a method in accordance with one embodiment of the invention; 
         FIG. 7  shows the specific absorption rate (SAR) pattern by using a conventional sinusoidal distribution of current in a quadrature body coil. 
         FIG. 8  shows SAR pattern by using an 8-channel parallel coil and a choice of coil weights {w m   e }. 
     
    
    
     DETAILED DESCRIPTION 
     The embodiments of the invention will be described in detail with respect to the figures below. Taking into account that detailed description of some related art would confuse the invention, the detailed description thereof will not be provided herein. In the drawings, the same reference numerals are used to indicate the same elements or components performing the same functions. 
       FIG. 1  illustrates a block diagram of a system for generating the localized heating in accordance with embodiments of the invention. The system is an MR imaging system that incorporates the embodiments of the invention. The MRI system could be, for example, a GE-Signa MR scanner available from GE Medical Systems, Inc., which is adapted to perform the method of the invention, although other systems could be used as well. 
     The operation of the system is controlled from an operator console  100  which includes a keyboard and control panel  102  and a display  104 . The console  100  communicates through a link  116  with a separate computer system  120  that enables an operator to control the production and display of images on the screen  104 . The computer system  120  includes a number of modules which communicate with each other through a backplane. These modules include an image processor module  106 , a CPU module  108 , and a memory module  113 , known in the art as a frame buffer for storing image data arrays. The computer system  120  is linked to disk storage  111  and tape drive  112  for storage of image data and programs, and it communicates with a separate system control  122  through a high speed serial link  115 . 
     The system control  122  includes a set of modules connected together by a backplane. These modules include a CPU module  119  and a pulse generator module  121  which connects to the operator console  100  through a serial link  125 . It is through this link  125  that the system control  122  receives commands from the operator which indicate operations that are to be performed. The pulse generator module  121  operates the system components to carry out the desired operations. It produces data that indicate the timing, strength, and shape of the radio frequency (RF) pulses which are to be produced, and the timing of and length of the data acquisition window. The pulse generator module  121  connects to a set of gradient amplifiers  127 , to indicate the timing and shape of the gradient pulses to be produced during the scan. The pulse generator module  121  also receives subject data from a physiological acquisition controller  129  that receives signals from a number of different sensors connected to the subject  200 , such as ECG signals from electrodes or respiratory signals from a bellows. And finally, the pulse generator module  121  connects to a scan room interface circuit  133  which receives signals from various sensors associated with the condition of the subject  200  and the magnet system. It is also through the scan room interface circuit  133  that a positioning device  134  receives commands to move the subject  200  to the desired position for the scan. 
     The gradient waveforms produced by the pulse generator module  121  are applied to a gradient amplifier system  127  comprised of G x , G y  and G z  amplifiers. Each gradient amplifier excites a corresponding gradient coil in an assembly  139  generally designated to produce the magnetic field gradients used for position encoding acquired signals. The gradient coil assembly  139  forms a part of a magnet assembly  141  which includes a polarizing magnet  140  and a RF coil system  152 . Volume  142  is shown as the area within magnet assembly  141  for receiving subject  200  and includes a patient bore. As used herein, the usable volume of a MRI scanner is defined generally as the volume within volume  142  that is a contiguous area inside the patient bore where homogeneity of main, gradient and RF fields are within known, acceptable ranges for imaging. A transceiver module  150  in the system control  122  produces pulses that are amplified by a RF amplifier system  151  and coupled to the RF coil system  152  by a transmit/receive switch system  154 . The resulting signals radiated by the excited nuclei in the subject  200  can be sensed by the same RF coil system  152  and coupled through the transmit/receive switch system  154  to a preamplifier system  153 . The amplified MR signals are demodulated, filtered, and digitized in the receiver section of the transceiver  150 . The transmit/receive switch  154  is controlled by a signal from the pulse generator module  121  to electrically connect the RF amplifier system  151  to the coil system  152  during the transmit mode (i.e., during excitation) and to connect the preamplifier system  153  during the receive mode. The transmit/receive switch system  154  also enables a separate RF coil (not shown, for example, a head coil or surface coil) to be used in either the transmit mode or the receive mode. 
     In the embodiments of the invention, the RF coil system  152  is a transmit/receive coil array assembly that will be described with reference to  FIGS. 2-3 . During the transmit mode, the RF pulse waveforms produced by the pulse generator module  121  are applied to a RF amplifier system  151  comprised of multiple amplifiers. Each amplifier controls the current in a corresponding component coil of the coil system  152  in accordance with the amplifier&#39;s input RF pulse waveform. With the transmit/receive switch system  154 , the RF coil system  152  is configured to perform transmission and reception simultaneously or alternatively. 
     As used herein “adapted to”, “configured” and the like refer to mechanical or structural connections between elements to allow the elements to cooperate to provide a described effect; these terms also refer to operation capabilities of electrical elements such as analog or digital computers or application specific devices such as an application specific integrated circuit (ASIC) that is programmed to perform a sequence to provide an output in response to given input signals. 
     The MR signals picked up by the RF coil system  152  or a separate receive coil are digitized by the transceiver module  150  and transferred to a memory module  160  in the system control  122 . When the scan is completed and an entire array of data has been acquired in the memory module  160 , an array processor  161  operates to Fourier transform the data into an array of image data. These image data are conveyed through the serial link  115  to the computer system  120  where they are stored in the disk memory  111 . In response to commands received from the operator console  100 , these image data may be processed by the image processor  106  and conveyed to the operator console  100  and presented on the display  104 , or they may be further archived on the tape drive  112 . Further processing is performed by the image processor  106  that includes reconstructing acquired MR image data. 
     Referring to  FIG. 2 , in one embodiment, a transmit/receive coil array assembly  300  for use in the embodiment of the invention comprises a plurality of radio frequency (rf) coils  210  configured for transmitting in parallel during transmission mode and a plurality of RF amplifiers  220  coupled to the corresponding RF coils adapted to generate a controlled current in each of the RF coils, and wherein the controlled current being used for defining and steering a region of interest  230  of the subject  200  within the system. In  FIG. 2 , the placement of the coils is substantially linear. 
     Referring to  FIG. 3 , an alternative embodiment is shown, in which RF coils  210  are arranged in an equally distributed pattern about the subject  200 , such as a circle. 
     Hereinafter, the embodiments of the invention will be further described in details in conjunction with the drawings. 
       FIG. 4  is a flow chart showing the operations of the apparatus in accordance with one embodiment of the invention. 
     As shown in  FIG. 4 , the apparatus of the embodiment of the invention is used to generate the localized heating based on the magnetic resonance imaging (MRI). After the operation is started, in Step  402 , a spatially localized or shaped electromagnetic field is transmitted to the subject  200  and magnetic resonance (MR) signals are generated through a plurality of coils. Specifically, the pulse generator module  121  produces the RF pulse waveforms, and applies the RF pulse waveforms to the RF amplifier system  151  comprised of multiple amplifiers which control the current in each component coil of the coil system  152 , which comprises a plurality of coils  210  as shown in  FIGS. 2 and 3 , in accordance with the amplifier&#39;s input RF pulse waveform, so that the coil system  152  transmits the electromagnetic field to the subject  200  and generates MR signals. 
     Then, in Step  404 , the MR imaging is performed based on the MR signals to generate image of a region of interest  230  of the subject  200 . Specifically, the coil system  152  picks up the MR signals. With the transmit/receive switch system  154 , the MR signals picked up by the coil system  152  are digitized by the transceiver module  150  and transferred to a memory module  160  of the system control  122 . 
     When an entire array of data has been acquired in the memory module  160 , an array processor  161  operates to Fourier transform the data into an array of image data. These image data are conveyed through the serial link  115  to the computer system  120  where they are stored in the disk memory  111 . In response to commands received from the operator console  100 , or automatically, these image data are further processed by the image processor  106  and conveyed to the operator console  100  and presented on the display  104 . In addition, these image data may also be archived on the tape drive  112 . Here, the image processor  106  performs MR imaging based on the MR signals to generate image of the region of interest  230  of the subject  200 . 
     Then, in Step  406 , the plurality of coils  210  are controlled to radiate radio frequency energy via a RF waveform to generate localized heating in the region of interest  230 . Specifically, the pulse generator  121  and the coil system  152  are controlled by the CPU module  108  and/or the CPU module  119  to radiate radio frequency energy via the RF pulse waveform to generate localized heating within a range of the region of interest  230  based on the image of the region of interest  230 . 
     Implicit in the preceding description of the work flow is the incorporation of a calibration step wherein the B 1  field distribution for each of the coil elements  210  in the multiple element coil array is measured. This information is used to compute the radio frequency amplitudes and phase for each coil element in order to generate the appropriate distribution of the electric field in the subject  240 , and consequently, the heating or specific absorption rate distribution in the subject  240 . 
     In one embodiment, a localized heating is generated by the apparatus of the embodiment of the invention based on the electromagnetic field. Specifically, a set of weights (radio frequency coil amplitude and phase for each coil element  210 ) are calculated by CPU  108  or  119  such that the magnitude of the magnetic field equals that of a desired magnetic field within the region of interest  230 . A magnetic field excitation pattern that can be observed in the image is generated by means of the radio frequency energy based on the set of weights. The corresponding radio frequency electric field distribution is inferred by comparing the radio frequency magnetic field excitation pattern in the image. Then, the spatially localized heating pattern is predicted by the inferred radio frequency electric field distribution. The localized heating pattern can also be generated by using unique radio frequency (rf) waveforms in each of the plurality of coils  210  and/or simultaneously adjusting the amplitude and phase of the unique radio frequency waveforms. In either case, the individual coil element weights (amplitude and phase) that results in a desired localized heating pattern or distribution will also yield a unique magnetic (B 1 ) field excitation pattern that can be visualized in a magnetic resonance image. The heating pattern (electric field distribution) then corresponds to the MR B 1 -field excitation pattern. In one embodiment, the unique radio frequency waveform is a unit radio frequency sinusoidal pulse. The use of other waveforms will also yield similar results. 
     In other words, a set of weights (amplitude and phase of each coil element  210 ) are calculated by CPU  108  or  119  such that the magnitude of the magnetic field equals that of a desired magnetic field within the region of interest  230 , an electric field is generated by the plurality of coils based on the same set of weights, and the localized heating is generated by the apparatus based on the applied electromagnetic field with the same set of computed weights. 
     Specifically, the above procedure will be further described in detail as below. 
     The embodiment of the invention is based on the parallel transmit technique that was originally intended to provide a more homogeneous transmit B 1 -field (B 1 +) and also to reduce the overall SAR. Note that 
     
       
         
           
             
               
                 
                   
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     wherein σ is the tissue conductivity and |E| 2  denotes the magnitude squared of the associated E-field, where |E| 2 =√(E x   2 +E y   2 +E z   2 ). 
     The CPU module  108  calculates a set of weights such that the magnitude-squared difference between the generated magnetic field and a desired magnetic field, which is determined based on the image, is minimized within the region of interest  230 . For example, for an array of N coils (N denotes number of coils, m is coil index, and n is the index for spatial location), in parallel transmit, the resulting magnetic field is given as the weighted sum of the individual transmit coils&#39; magnetic fields 
     
       
         
           
             
               
                 
                   
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     wherein B n,m  is the magnetic field generated at location n by coil m when the coil alone is driven by a unit radiofrequency sinusoidal pulse. w m , a complex scalar capturing the amplitude and phase control of a radio frequency sinusoidal pulse that drives the mth coil, effectively represents the weight for the mth coil in generating the net magnetic field at discrete points n. 
     With the array of N coils, the method of the embodiment of the invention for generating localized heating patterns relies on the application of unique RF waveforms, such as a unit radio frequency sinusoidal pulse, to each individual coil. This is in contrast to the conventional RF hyperthermia techniques that only modulate the amplitude and phase of the same waveform to each coil. Our invention allows the modulation of amplitude and phase of waveforms to each coil without restricting the same waveform to all coil elements. 
     For a parallel transmit approach seeking to generate as homogeneous a B 1 + field as possible, the set of weights {w m } can be calculated such that the magnitude squared difference between the b n  and the desired b n ′ field, which is determined based on the image of a given region-of-interest (ROI)  230  of the subject  200  by experiment, as small as possible within the ROI. That is to calculate the set of weights such that the least-squared difference is as small as possible, i.e.,:
 
| b   n   ′b   n | 2 →0  (3)
 
wherein b n  is the magnetic field generated by the multiple coils array defined in Equation (2), while b n ′ is the desired magnetic field distribution.
 
     Then, a magnetic field excitation pattern that can be observed in the image is generated by the computer system  120  by means of the radio frequency energy based on the set of weights. 
     Then, the corresponding radio frequency electric field distribution is inferred by comparing the radio frequency magnetic field excitation pattern in the image. Specifically, the CPU module  108  calculates an electric field distribution generated by the coil system  152  based on the same set of calculated weights such that the electric field is maximum in the region of interest  230  and minimum outside the region of interest  230 . 
     The net electric field that is produced by the multiple transmit coils can be written as 
                     e   n     =       ∑     m   =   1       #   ⁢   coils       ⁢       E     n   ,   m       *     w   m                 (   4   )               
wherein E n,m  is the electric field generated at location n by coil m when the coil alone is driven by the unit radiofrequency sinusoidal pulse. Based on equation (4), the set of weights may also be calculated such that the magnitude of the electric field equals that of a desired electric field within the region of interest.
 
     According to the above equation (4) and based on the set of weights {w m } which is previously calculated, the electric field distribution that is produced in the meanwhile by the multiple transmit coils can be obtained. 
     In order to modify the SAR distribution, we can compute the new cost function to maximize the SAR in the given ROI  230  while minimizing the SAR in other areas (outside the ROI  230 ). The cost function can then be
 
| e   n ′| 2   −|e   n | 2 →0  (5)
 
wherein e n  is the net electric field generated by the multiple transmit array, while e n ′ is the desired electric field distribution. Note that over the given ROI, |e n ′| 2  is maximum, and in other areas, |e n ′| 2  is minimum.
 
     In addition, the electric field distribution may also be predicted by means of the magnetic field based on the following Maxwell&#39;s equations:
 
 {right arrow over (E)} =(μ(σ− j ω∈)) −1   ∇×{right arrow over (B)}   (6)
 
where μ is the magnetic permeability, σ is the conductivity, and δ is the dielectric constant (permittivity), with ω as the resonant frequency, and j=(−1) 1/2 . B 1  field calibration or mapping procedure can be performed to determine the B n,m  fields, i.e. {right arrow over (B)}, for each transmit coil. Then, from the equation (6), E n,m  can be approximated together with using representative values for the tissue constants and the value of the {right arrow over (B)}.
 
     Then, the spatially localized heating pattern is predicted by the computer system  120  by means of the inferred radio frequency electric field distribution by the measured radio frequency magnetic field excitation pattern in the image. 
     Further, the electric field distribution can be predicted from the magnetic field excitation pattern in the image using an approximation of the z-component of the magnetic (B 1 ) field. The approximation of the z-component of the magnetic (B 1 ) field is constrained to a subset of allowable solutions by the boundary values set by the imaging experiment. 
     Finally, the CPU module  108  controls the pulse generator  121  and the coil system  152  (the plurality of coils  210 ) to generate the localized heating by generating unique radio frequency (rf) waveforms in each of the plurality of coils  210  or adjusting the amplitude and phase of the unique radio frequency waveforms based on the predicted spatially localized heating pattern and/or the calculated electric field distribution. In the embodiment, the unique radio frequency waveform is a unit radio frequency sinusoidal pulse, but any other waveform can also be used. 
     As stated above, in order to localize the heating pattern within the ROI, it could be verified that the B 1 + field generated is as expected. The verification can be performed based on equation (2) by using an imaging experiment and matching the expected B 1 + field pattern with the result of the experiment. This can be performed while keeping the power levels sufficiently below that needed to cause heating or temperature rises. Note that in this configuration, the same coil array is used both for MR imaging and also for generating the localized heating pattern. In addition, the large water-filled coupling bags are no longer necessary. 
     In one embodiment, the MR imaging and the localized heating is performed simultaneously. Specifically, with the transmit/receive switch  154 , the transceiver module  150  radiates RF energy via the RF waveform and receives MR signals simultaneously. In another embodiment, the MR imaging and the localized heating is performed in an interleaved fashion. Specifically, with the transmit/receive switch  154 , the transceiver module  150  radiates RF energy via the RF waveform and receives MR signals alternatively. The localized heating and MR imaging can also be interleaved by first applying a series of weights and waveforms that optimizes localized heating in a region of interest, and then applying a different series of weights and waveforms that optimizes imaging in the same region of interest. 
     The specific structure of the apparatus of the embodiment as shown in  FIG. 1  does not set a limitation to the scope of the invention. For example,  FIG. 5  illustrates a simplified block diagram of an apparatus for generating a localized heating in accordance with another embodiment of the invention. 
     As shown in  FIG. 5 , the apparatus of the embodiment of the invention for generating a localized heating may comprises a plurality of coils  503  configured to transmit a spatially localized or shaped electromagnetic field to the subject  504  and to generate MR signals, an imaging device  501  configured to perform MR imaging based on the MR signals to generate an image of a region of interest of the subject  504 , and a control device  502  configured to control the plurality of coils  503  to radiate radio frequency energy via a RF pulse waveform to generate the localized heating in the region of interest  230  based on the image. 
     In one embodiment, the control device  502  generates unique radio frequency waveforms for each of said coils or adjusts the amplitude and phase of the unique radio frequency waveforms. In one embodiment, the control device  502  is further configured to calculate a set of weights such that the magnitude of the magnetic field equals that of a desired magnetic field within the region of interest. In one embodiment, the control device  502  is further configured to calculate a set of weights such that the magnitude of the electric field equals that of a desired electric field within the region of interest. In one embodiment, the control device  502  is further configured to generate localized heating pattern based on the electric field. 
     In one embodiment, the control device  502  is further configured to generate localized heating pattern based on the electric field, wherein the radio frequency energy also generates a magnetic field excitation pattern that can be observed in the image. In one embodiment, the control device  502  is further configured to compare the spatially localized heating pattern with the radio frequency excitation pattern in the image. In one embodiment, the control device  502  is further configured to calculate an electric field generated by the plurality of coils  503  based on the set of weights, and control to generate the localized heating based on the electric field. In one embodiment, the control device  502  is further configured to calculate an electric field generated by the plurality of coils  503  based on the set of weights, and control to generate the corresponding desired electric field excitation pattern that is determined from optimizing the magnetic field excitation pattern. 
     Taking into account that detailed description of the above operations have been described above with reference to  FIGS. 1-4 , the detailed description thereof will not be provided herein. 
       FIG. 6  is a flow chart of a method in accordance with a further embodiment of the invention. As shown in  FIG. 6 , in step  601 , radio frequency energy is transmitted via a plurality of coils  503  to a subject  504 , then in step  602 , unique radio frequency waveforms are generated for each of the coils  503  to generate an arbitrary specific absorption rate (SAR) distribution in the subject  504  to enable spatially localized heating. Calibration of the B 1 -field distribution of each coil element in  503  is implicit in the preceding discussion. 
     In the above embodiment, the plurality of coils  503  used to transmit radio frequency energy with unique radio frequency waveforms for each of the coils or unique magnitude and phase weights for each coil to generate an arbitrary specific absorption rate distribution in the subject  504  to enable spatially localized heating is also used to generate a magnetic resonance image. 
     In the above embodiment, the plurality of coils  503  used to transmit radio frequency energy with unique radio frequency waveforms for each of the coils or unique magnitude and phase weights that generate a spatially localized heating pattern also generates a unique radio frequency excitation pattern in the image. 
     In the above embodiment, the plurality of coils  503  used to transmit radio frequency energy with unique radio frequency waveforms for each of the coils or unique magnitude and phase weights that generate a spatially localized heating pattern can be array around the subject  504  in any appropriate pattern that permits full coverage of all regions of interest within the subject  504 . 
     Taking into account that detailed description of the above operations have been described above with reference to  FIGS. 1-4 , the detailed description thereof will not be provided herein. 
       FIG. 7  shows the SAR pattern by using a conventional sinusoidal distribution of current in a quadrature body coil.  FIG. 8  shows the SAR pattern by using an 8-channel parallel transmit coil and a choice of coil weights, {w m   e }. The SAR pattern in  FIG. 8  is noticeably altered to favor greater power deposition (and heating) in the anterior right side of the body. These results demonstrate a proof-of-concept of the method for adjusting or localizing the heating pattern within the body by using multiple coils. 
     This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.