Abstract:
The contrast-to-tissue ratio is improved while imaging contrast infused tissue. A subject is infused with contrast medium having microbubbles at a fundamental frequency. First and second transmit pulses are transmitted into the subject. The first and second transmit pulses each comprise first, or basic, and second, or seed, signals. The basic signal has a frequency based on the fundamental frequency and the seed signal has a subharmonic frequency based on the frequency of the basic signal. The first and second transmit pulses are phase inverted with respect to each other. Received echoes from first and second transmit pulses are filtered at a subharmonic or ultraharmonic frequency to remove tissue response and pass microbubble response.

Description:
BACKGROUND OF THE INVENTION 
     Certain embodiments of the present invention relate to ultrasound imaging of the human anatomy for the purpose of medical diagnosis. In particular, certain embodiments of the present invention relate to methods and apparatus for improving the ratio of contrast signals to tissue signals in ultrasound contrast imaging. 
     Contrast agents may be used with ultrasound imaging to enhance the clinical evaluation of blood flow and perfusion, which is the circulation of blood to an organ or tissue. The contrast agents comprise microbubbles which are typically 1-10 um in size. When injected into a patient&#39;s blood, the contrast microbubbles generate nonlinear signals and increase the ultrasound echo strength in comparison to the echo strength of blood without contrast. Tissue also generates nonlinear signals, but the nonlinear tissue signals are generally weaker than the nonlinear contrast signals. 
     In order to visualize blood flow or perfusion of tissue, the tissue echo strength must be significantly reduced relative to the contrast echo strength. One way to suppress the tissue signal is to image second or high harmonics of the nonlinear signals generated by the microbubbles. In basic harmonic imaging, a narrowband signal is transmitted at a frequency, f 0 . In U.S. Pat. Nos. 5,724,979 and 5,733,527, the returned echoes are band pass filtered at 2f 0  in order to image a second harmonic signal generated by the microbubbles and tissue. Alternatively, in U.S. Pat. Nos. 5,632,277, 5,706,819, and 6,3719,914, pulse inversion permits overlap of the fundamental and harmonic bands for better spatial resolution by using two phase inverted transmit pulses to cancel the fundamental (linear) component which leaves the nonlinear components to be imaged. 
     For each of the aforementioned conventional methods, the ratio of contrast to tissue signal strength is still insufficient for imaging tissue perfusion. One method to improve the contrast-to-tissue ratio (CTR) is to reduce the transmit mechanical index (MI), because the nonlinear signal of tissue falls faster than the nonlinear signal of contrast as the MI decreases. This method, however, experiences signal-to-noise ratio (SNR) limitations. 
     Compared to techniques which use second or high harmonics, subharmonic imaging has the advantage that tissue does not produce significant subharmonic content, and thus a high CTR can be maintained. (see U.S. Pat. No. 6,117,082; James Chomas et al., “Subharmonic Phase-Inversion for Tumor Perfusion Estimation”; P. M. Shankar et al., “Advantage of Subharmonic Over Second Harmonic Backscatter for Contrast-to-Tissue Echo Enhancement”) Subharmonic imaging involves transmitting a pulse at a fundamental frequency, f 0 , and filtering the received echoes to reject echoes at f 0 , while receiving echoes at a subharmonic frequency of f 0 , e.g. f 0 /2, f 0 /3, and the like. However, the subharmonic signal level is generally much lower than the second harmonic and fundamental signal. Another problem experienced while generating the subharmonic response is that a pressure threshold exists which may be too high for low MI real-time perfusion imaging. 
     Subharmonic generation is a positive feed back loop. In U.S. Pat. No. 6,117,082, a seed signal at a subharmonic frequency is introduced to induce the positive feed back of the subharmonic signal generation during the pulsing time. To avoid tissue signal generated by the seed signal, the seed signal is put almost 40 dB down compared to the fundamental signal. The low amplitude of the seed signal limits the speed for generating a high level subharmonic signal. Thus, high pressure and a long transmit pulse are needed to generate a strong subharmonic signal. 
     Recently, a phase inverted subharmonic imaging method was developed to further enhance the CTR. It was found that the threshold to generate subharmonic vibration could be low when the transmit frequency is at two times the microbubble resonance frequency. (James Chomas et al., “Subharmonic Phase-Inversion for Tumor Perfusion Estimation”). However, a seed subharmonic signal is not employed, so a high pressure is still needed to generate enough subharmonic signal for imaging. 
     For many contrast applications, and especially for perfusion imaging, bubble destruction has to be avoided. Contrast microbubbles are destroyed by high-MI ultrasound pulses, therefore, low-MI pulses are desired in order to not destroy contrast agents and in order to maintain a longer duration over which the contrast agents may be imaged. 
     Therefore, a need exists for a method to perform ultrasound imaging using contrast which generates a strong subharmonic signal and which improves the ratio of contrast echo signals to tissue echo signals, while not destroying the contrast microbubbles for continued imaging of microbubbles. It is an object of certain embodiments of the present invention to meet these needs and other objectives that will become apparent from the description and drawings set forth below. 
     BRIEF SUMMARY OF THE INVENTION 
     A method for improving contrast-to-tissue ratio while imaging contrast infused tissue and blood vessels is provided. The method includes infusing a subject with contrast medium having microbubbles having a fundamental frequency. A first transmit pulse comprising first and second signals is transmitted into the subject. The first signal has a first frequency based on the fundamental frequency and the second signal has a second frequency based on the first frequency and is lower than the first frequency. A second transmit pulse comprising third and fourth signals having the first and second frequencies, respectively, is transmitted into the subject. The third and fourth signals are phase inverted with respect to the first and second signals. 
     A method of imaging a patient using diagnostic ultrasound is provided including generating first and second signals having first and second frequencies, respectively. The second frequency is a subharmonic frequency with respect to the first frequency. The method further includes combining the first and second signals to create a first transmit pulse. Third and fourth signals are generated with the first and second frequencies, respectively, and the third and fourth signals are phase inverted with respect to the first and second signals. The third and fourth signals are combined to create a second transmit pulse. 
     A system for improving a contrast-to-tissue ratio while imaging contrast infused tissue and blood vessels is provided. The system includes a seeded waveform generator generating first and second transmit pulses comprising basic and seed signals. The basic signal has a first frequency and the seed signal has a second frequency which is a subharmonic frequency of the first frequency. The first and second transmit pulses are phase inverted with respect to each other. The system further includes a transmitter transmitting the first and second transmit pulses into a patient having tissue and blood vessels infused with contrast agent comprising microbubbles. A receiver receives first and second sets of echoes based on the first and second transmit pulses, respectively. A filter being centered at a frequency based on the second frequency filters the first and second sets of echoes to create filtered signals representing a response from the microbubbles. 
    
    
     BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS 
     FIG. 1 illustrates a block diagram of an ultrasonic diagnostic imaging system formed in accordance with an embodiment of the present invention. 
     FIG. 2 illustrates how two consecutive seeded transmit pulses may be formed in accordance with an embodiment of the present invention. 
     FIG. 3 illustrates the seeded waveform generator of FIG. 1 formed in accordance with an embodiment of the present invention. 
     FIG. 4 illustrates an alternative seeded waveform generator formed in accordance with an embodiment of the present invention. 
     FIG. 5 illustrates a simulated power spectra of echoes received from the tissue and the contrast microbubbles when the seeded transmit waveform is transmitted. 
     FIG. 6 illustrates a simulated power spectra of echoes received from the tissue and the contrast microbubbles when the basic signal and the phase inverted basic signal are transmitted. 
     FIG. 7 illustrates a simulated power spectra of echoes received from tissue and contrast microbubbles when seeded transmit pulse and phase inverted seeded transmit pulse are transmitted in accordance with an embodiment of the present invention. 
     FIG. 8 illustrates a block diagram of a coherent beam forming ultrasonic diagnostic imaging system formed in accordance with an embodiment of the present invention. 
     FIG. 9 illustrates how coherent beam forming may be implemented with seeded subharmonic phase inversion in accordance with an embodiment of the present invention. 
    
    
     The foregoing summary, as well as the following detailed description of certain embodiments of the present invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there is shown in the drawings, certain embodiments. It should be understood, however, that the present invention is not limited to the arrangements and instrumentality shown in the attached drawings. 
     DETAILED DESCRIPTION OF THE INVENTION 
     FIG. 1 illustrates a block diagram of an ultrasonic diagnostic imaging system  100  formed in accordance with an embodiment of the present invention. The system  100  includes a transducer array  102  contained within an ultrasonic probe  103 . The transducer array  102  is coupled via a transmit/receive switch  104  to a transmitter  106  and a receiver  108 . The transmitter  106  drives the transducer array  102  to fire pulses, or emit pulsed ultrasonic signals, into an object or body. A seeded waveform generator  110  generates seeded waveforms which are further discussed below. Seeded waveforms may be transmitted sequentially in time, along the same spatial line, by the transmitter  106 , which is controlled by transmitter controller  112 . 
     The ultrasonic signals are backscattered from structures in the body, like blood cells, muscular tissue or contrast microbubbles, to produce echoes which are detected by the transducer array  102 . The echoes from each transmit pulse are received sequentially by receiver  108 . The received echoes are passed through a beamformer  114 , which performs beamforming and filtering operations and is controlled by a receiver controller  116 . The received signals are then stored in memory  118 . A central controller  126  coordinates higher-level functions of the ultrasound imaging system, such as user inputs from a user control panel  128 , display of data on a display  124 , and the like. 
     FIG. 2 illustrates how two consecutive seeded transmit pulses may be formed. The seeded waveform generator  110  generates a first signal, basic signal  130 , and a second signal, seed signal  132 . The basic signal  130  and seed signal  132  are then combined by a combining operation  134  within the seeded waveform generator  110  to produce a seeded transmit pulse  136 . The combining operation may comprise adding, subtracting, coherent synthesizing, or other functions. The basic signal  130  may have a basic frequency 2f 0 , wherein f 0  is the resonance frequency of the contrast microbubbles. The seed signal  132  is at a subharmonic frequency of 2f 0 , such as f 0 , 2f 0 /3, and the like. Alternatively, the basic signal  130  may have a basic frequency f 0 , while the seed signal  132  has a subharmonic frequency of f 0 , such as f 0 /2. In the example of FIG. 2, the basic signal  130  has a transmit frequency of 6 Mhz, and seed signal  132  has a transmit frequency of 3 MHz. 
     As described in the background, subharmonic generation is a positive feed back response. Here, seed signal  132  is introduced to start the positive feed back loop of subharmonic generation. The amplitude of the seed signal  132  is between approximately −10 dB to approximately −30 dB with respect to the basic signal  130 . At the amplitude level used here, the subharmonic signal can be generated to high amplitude in a short pulse duration time such as 4 or 6 cycles with 6 MHz, for example, that makes it practical to be applied in the current commercial probes. Also, since when the microbubble is insonated with 2 times the microbubble&#39;s resonance frequency, the threshold level for subharmonic generation could be very low, thus low MI value can be easily reached with good subharmonic response. 
     The aforementioned process is repeated to generate phase inverted basic signal  138  and phase inverted seed signal  140 . The phase inverted basic signal  138  and phase inverted seed signal  140  are combined by a combining operation  142  to form phase inverted seeded transmit pulse  144 . The combining operation  142  may be the same operation and/or structure as the combining operation  134 . 
     Basic signal  138  is a phase inverted version of basic signal  130 . Seed signal  140  is a phase inverted version of seed signal  132 . Thus, it should be recognized that the phase relation between the basic signal  130  and seed signal  132  is the same as the phase relation between the phase inverted basic signal  138  and phase inverted seed signal  140 . In other words, the phase inverted seeded transmit pulse  144  of the second firing is phase inverted, or negative, with respect to the seeded transmit pulse  136  of the first firing, which is positive. Alternatively, the phase inverted seeded transmit pulse  144  may be generated by phase inverting the seeded transmit pulse  136 . 
     Returning to FIG. 1, after the two phase inverted received signals are processed and stored in memory  118 , the two phase inverted received signals are integrated together with coherent synthesizing by the signal processor  120 . The signal processor  120  then filters the integrated signals at the subharmonic frequency band, such as f 0  or at an ultraharmonic frequency band, such as 4f 0 /3. The resultant processed signals are envelope detected and log compressed, then sent by the signal processor  120  to the scan converter  122 . The processed signals are then displayed by the display  124 . 
     FIG. 3 illustrates the seeded waveform generator  110  of FIG.  1 . The seeded waveform generator  110  includes a basic waveform generator  150  and seed waveform generator  152 . The basic waveform generator  150  generates the basic signal  130  at a first frequency, and the seed waveform generator  152  generates the seed signal  132  at a subharmonic frequency of the first frequency. The basic signal  130  and seed signal  132  are shown for reference. The basic waveform generator  150  outputs the basic signal  130  at output  154  and the seed waveform generator  152  outputs the seed signal  132  at output  156 . The basic signal  130  and seed signal  132  are then combined to form the seeded transmit pulse  136  (FIG. 2) by the combining operation  134 . The seeded transmit pulse  136  is then stored in a waveform memory  158  until being transmitted. The phase inverted version of the signal, such as phase inverted basic signal  138  and phase inverted seed signal  140  (FIG.  2 ), are generated, combined and stored in the same manner to produce phase inverted seeded transmit pulse  144 . 
     FIG. 4 illustrates an alternative seeded waveform generator  160 . In FIG. 4, a single waveform generator  162  generates the seeded transmit pulse  136  by using predefined parameters stored, for example, by the central controller  126 , or parameters input through a user control panel  128 . The seeded transmit pulse  136  is then saved in a waveform memory  164  until being transmitted. The phase inverted seeded transmit pulse  144  is generated in the same manner as the corresponding seeded transmit pulse  136 . Therefore, a person of ordinary skill in the art would recognize that the seeded transmit pulse  136  and phase inverted seeded transmit pulse  144  may be generated using a number of different methods and/or apparatus, and thus should not be limited to the embodiments discussed herein. In addition, it should be understood that the phase, bandwidth and amplitude of the basic and seed signals  130  and  132 , and the phase inverted basic and phase inverted seed signals  138  and  140  may be changed, and also the time the seed signal  132 ,  140  is merged into the basic signal  130 ,  138 , respectively, may be changed for optimization of subharmonic signal generation. 
     FIG. 5 illustrates a simulated power spectra of echoes received from the tissue and the contrast microbubbles when the seeded transmit waveform  136  is transmitted. In FIG. 5, seeded transmit waveform  136  comprises the basic signal being transmitted at 6 MHz, 2f 0 , and the seed signal  132  being transmitted at 3 MHz, or f 0 . The bubble concentration is modulated to make the total microbubble echoes have the same level response with the tissue at fundamental frequency 2f 0 . Line  170  illustrates the power spectrum of a set of echoes received by the receiver  108  from the contrast microbubbles. Line  172  illustrates the power spectrum of a set of echoes received by the receiver  108  from the tissue. The contrast microbubble response, line  170 , has approximately the same level of response as the tissue response, line  172 , at 6 MHz, or 2f 0 . Also, it can be seen that the linear response of the tissue is strong at the frequency of the seed signal f 0  (3 MHz), thus there is only a small difference between the bubble and tissue responses at the subharmonic frequency f 0 . As a result, the CTR of the image is very low when imaging with the seeded transmit pulse  136  alone. 
     FIG. 6 illustrates a simulated power spectra of echoes received from the tissue and the contrast microbubbles when the basic signal  130  and the phase inverted basic signal  138  are transmitted. In FIG. 6, the basic signal  130  and phase inverted basic signal  138  are transmitted at frequency 2f 0 , or 6 MHz, wherein f 0  is the resonant frequency of the contrast microbubbles. Line  166  illustrates the power spectrum of the combined set of echoes received by the receiver  108  from the contrast microbubbles insonated by basic signal  130  and phase inverted basic signal  138 . Line  168  illustrates the power spectrum of the combined set of echoes received by the receiver  108  from the tissue insonated by basic signal  130  and phase inverted basic signal  138 . The simulation was done with the transmit signals at the same amplitude level of the signal simulated in FIG.  5 . It can be seen that at the subharmonic frequency band, which in this case is around 3 MHz, the CTR is also very low. 
     FIG. 7 illustrates a simulated power spectra of echoes received from tissue and contrast microbubbles when seeded transmit pulse  136  and phase inverted seeded transmit pulse  144  are both transmitted. Line  174  illustrates the power spectrum of the combined set of echoes received from the contrast microbubbles, and line  176  illustrates the power spectrum of the combined set of echoes received from the tissue. In simulation, the contrast microbubble concentration is the same as the contrast microbubble concentration employed in FIG.  6  and FIG.  5 . The difference between the tissue signal (line  176 ) and the bubble signal (line  174 ) has been significantly improved in the subharmonic frequency band f 0 , resulting in a much higher CTR compared to the result of the single firing of seeded transmit pulse  136  shown in FIG.  5  and phase-inversion firings with only basic signal  130  and phase inverted basic signal  138  shown in FIG.  6 . 
     FIGS. 5,  6  and  7  illustrate that the seeded subharmonic phase inversion method employed in FIG. 7 improves the CTR in ultrasound contrast imaging. The −20 dB to −13 dB seeded signal level helps the positive feed back loop to start and reach a very high level, even saturation, within a short pulse duration time and with a low MI setting, while the phase inversion helps to eliminate the strong linear tissue signal generated by the seed signal inside the tissue. Additionally, the contrast imaging performance may be greatly improved when using high frequency probes (above or equal to 5 MHz) with low MI settings. As an example, the ability to image blood flow and regional micro-vascular perfusion in tissue is improved where high frequency probes are needed, such as the breast, prostrate, and thyroid. 
     FIG. 8 illustrates a block diagram of a coherent beam forming ultrasonic diagnostic imaging system  180  formed in accordance with an embodiment of the present invention. The system  180  utilizes some of the same components as the system  100 , which are illustrated with the same reference numbers. By using coherent beamforming technology, the frame rate can be increased (e.g., doubled) when compared to the frame rate of system  100 . 
     FIG. 9 illustrates how coherent beam forming may be implemented with seeded subharmonic phase inversion. FIGS. 8 and 9 will be discussed together. In FIG. 8, the seeded waveform generator  110  generates the seeded transmit pulse  136  and phase inverted seeded transmit pulse  144  as previously discussed. In coherent beamforming system  180 , instead of transmitting  136  and  144  sequentially in time along the same spatial line as in system  100 , seeded pulse  136  is transmitted along line  182 , Tx 0 , while seeded pulse  144  is transmitted along line  188 , Tx 1 . Echoes from microbubbles insonated by seeded transmit pulse  136  will be received along the same spatial line as line  182  and echoes from microbubbles insonated by the phase inverted seeded transmit pulse  144  will be received along the same spatial line as line  188  shown in FIG.  9 . This scan sequence will continue, transmitting seeded transmit pulse  136  along line  194 , Tx 2 , receiving echoes along line  188 , Rx 2 , transmitting phase inverted seeded transmit pulse  144  along line  200 , Tx 3 , receiving echoes along line  190 , Rx 3 , and so on, until an entire image is formed. 
     Echo signals received by receiver  108  will be beamformed by beamformer  206 , then sent to line memory  208 . An RF synthesizer  214  then coherently synthesizes neighboring received lines, resulting in a set of new synthetic lines SN  192 ,  196 ,  198 ,  202 , in between the transmitting and receiving lines. The new synthetic lines SN  192 ,  196 ,  198 ,  202  are a combination of echoes from microbubbles insonated by seeded transmit pulse  136  and phase inverted seeded transmit pulse  144 . Therefore, phase inversion is implemented in one frame scanning without two firings along the same spatial line. Thus, the frame rate can be doubled. The RF synthesizer  214  outputs the coherently synthesized phase inversion signals SN (N=1, 2, . . . ) to the signal processor  120 . The signal processor  120  performs further filtering at the subharmonic or ultraharmonic band, then the signal is envelope detected and log compressed. The signal is then sent to the scan converter  122  and then to the display  124 . The central controller  126  coordinates all higher-level functions of the system  180 , similar to the central controller  126  of system  100 . 
     While the invention has been described with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.