JP2001518360A - Ultrasonic bubble recognition imaging method - Google Patents

Abstract

  (57) [Summary] In a method for identifying gaseous bubbles in a liquid, an ultrasound contrast agent is injected into the liquid to create gaseous bubbles in the liquid. By directing a first ultrasonic pulse centered on a first frequency to the bubble, the bubble causes a change in the first vibration size and a first vibration corresponding to the change in the first vibration size of the bubble. Generate an echo signal. A first vibration echo signal generated by the bubble is detected, and the bubble is identified based on the detected first echo signal.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the field of ultrasound contrast agents (Ultrasonic Contrast Agent).

Description of the Background Art [0002] Physicians and physiologists have been diagnosed with local perfusion (perfusion) in the diagnosis of injury healing, the survival of diabetes, transplanted tissues and regeneratively transplanted limbs, and the diagnosis of cancer lesions, and the diagnosis of cardiovascular function. ) Has long been recognized, but to date there is no direct diagnosis method. It is clear that the underlying changes in tissue perfusion are associated with disease progression or, in some cases, disease development. Many imaging techniques have been developed to indirectly detect ischemia, such as, for example, ultrasound and magnetic resonance techniques that assess the range and magnitude of local motion of a beating heart. The echoes from the blood are now much more intense, and the local bubble destruction can map the transition times of microvessels on a much smaller scale, so that the second
And the opportunity for ultrasound imaging assisted (contrast-assisted) using third-generation contrast agents (contrast agents) and new imaging strategies. In addition, it is possible to remotely control the contrast agent in the body by the power of radiation. Imaging using contrast effects is also less costly than alternative vascular imaging techniques.

[0003] Imaging methods using the contrast effect include a lack of basic understanding of the interaction between ultrasound and microbubbles, and the difficulties associated with any artifacts that may occur. Has not been able to achieve the expected results. In cardiology, the use of the amplitude of the return signal has been particularly difficult because contrast agents also can attenuate the signal and thus make it difficult to interpret amplitude variations.

[0004] Cancer currently accounts for 15.8% of the US mortality rate. Mass in malignant breast (
mass) can often be distinguished by increased echo attenuation and reduced backscatter using ultrasound, but these changes are not observed in about 10% of the malignant mass.

[0005] More than 60 million people in the United States have some form of cardiovascular (myocardial) disease (CVD)
And CVD is the leading cause of death for over 954,000 people annually. This accounts for over 42% of US deaths each year. Although ultrasound is still the primary imaging modality for CVD detection and diagnosis, it is currently not possible to map blood flow in coronary arteries or map cardiovascular perfusion with ultrasound. It is a serious constraint.

[0006] While ultrasound-enhanced (contrast) imaging has the potential to address these current limitations, medically acceptable improvements have been made with improved detection of bubbles. Signal processing is required.

Although ultrasound contrast agents were first conceived in 1968, the development of longer-lasting contrast agents has provided exciting new opportunities for imaging microvasculature. In the past few years, microbubbles have been developed that can remain in the circulation for a longer period of time. New contrast agents include high molecular weight gases that have low diffusion constants and are incorporated into lipid or albumin shells. Drugs under development include substances that attach to certain tissues and improve the detection of diseased or tumor-bearing vessels.

[0008] Also, while contrast agents have been used to increase the amplitude of scattering since 1970, techniques for distinguishing bubbles and tissue echoes have only recently been proposed. After that. The scattering and attenuation properties of certain contrast agents have been studied. Experiments have shown that with transmission of pressure, the scattering of the echo increases linearly and the harmonic signal changes. The use of in-vitro harmonic imaging has proven effective and has demonstrated the ability to use cross-correlation to track microbubbles. The use of transmission at 5 MHz and subharmonic reception at 2.5 MHz has been evaluated, demonstrating that subharmonic peaks from the contrast agent Albnex® can be detected in vitro. Attenuation and transmission studies have shown high attenuation of acoustic contrast agents, which is an important factor in cardiac imaging. Many recent conference proceedings summaries show new drugs.

According to the medical evaluation of the imaging technique using the current contrast (contrast) action,
Artifacts have been shown to reduce the effectiveness of assessing cardiovascular perfusion. In particular, attenuation and rib artifacts are problematic for modes of operation that evaluate perfusion based on the video intensity of the return signal to map perfusion. Security issues have been reported, especially at high strengths and low frequencies (<2 MHz). There remains a need in the art for improvements in ultrasound technology.

SUMMARY OF THE INVENTION According to the present invention, a method for identifying gaseous bubbles in a liquid includes injecting an ultrasonic contrast agent into the liquid to form gaseous bubbles in the liquid. including. A first ultrasonic pulse generated at a first frequency is directed to the bubble, the bubble causing a change in a first vibration size, and a first vibration echo signal corresponding to the change in the first vibration size of the bubble. To occur. A first vibration echo signal generated by the bubble is detected, and the bubble is identified based on the detected first echo signal.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, an ultrasound contrast agent generates a unique echo that can be distinguished from surrounding tissue using, for example, time domain recognition techniques. The identification of these echoes facilitates powerful ultrasound imaging using contrast.

In addition, the echo from the ultrasound contrast agent is generated by a transmitted dilution cycle and compression cycle pair, and a strong echo is generated by a pair of half cycles in that order (dilute-compression). It turns out that. In this way, contrast agents can be identified from tissue using transmission strategies that vary the order and number of half cycles, as well as their intensity and frequency. Bubbles and tissues generate higher frequency terms when the bubbles insonify at their resonant frequency. Shell-structured bubbles do not respond to the first half cycle of acoustic compression, but rather require expansion caused by dilution to proceed with compression.

The present invention overcomes many of the problems that limit the usefulness of ultrasound contrast agents. In particular, the present invention is powerful even in the presence of intervening attenuation, tissue movement, and bubble collapse.

The present invention enables wideband signal transmission that significantly improves spatial resolution as compared to the narrowband transmission strategy required for harmonic imaging methods. Broadband signaling produces echoes of equal or greater intensity than narrowband signaling.
For second generation contrast agents, the spatial resolution achieved by broadband and higher frequency insonations is superior to narrowband or low frequency techniques.

[0015] Suitable contrast agents include gases. The gas may be any suitable gas, such as air, but a high molecular weight gas is preferred. The preferred embodiment of the present invention relies on the compressibility of the generated bubbles, with a preferred degree of compression of about 5 × 10 −7 m 2 / N or more. Examples of suitable contrast agents are Mallinckrodt, Inc., and the products Albunex® and Optison®, commercially available from Molecular Biosystems, Inc.
, Both having a gas core and albumin shell, wherein the gas core is air or perfluoropropane.

[0016] The shell of the bubble may be any suitable material, such as a protein, lipid, or other material.

A suitable bubble diameter range may be about 1-12 microns, for example about 2 microns.

[0018] The duration of a suitable bubble in vivo may be about 10-60 minutes, for example about 20 minutes.

The resonant frequency of a bubble is typically determined by finding the frequency at which echo attenuation and backscatter are greatest. A typical bubble resonance frequency is about 1.5-
5 MHz.

In order to recognize a bubble signal, the present invention can be applied as follows.

The generation of the required echo (es) can be achieved by injecting a suitable ultrasound contrast agent and transmitting short (broadband) ultrasound pulses at the resonant frequency of the bubble. A typical "short" pulse is about three cycles of the center frequency or less. The preferred wavelength is about 1.5 cycles. The bandwidth of this pulse is about 0.6 MHz or more for a center frequency of about 2 MHz and about 1.6 MHz for a center frequency of 5 MHz.

[0022] To facilitate the identification of bubbles, another pulse is transmitted after the initial transmission in which the compression and dilution, the number of dilution or compression cycles, or the intensity of the compression and dilution cycles are altered. The preferred signal is a transmission signal of about 1.5 cycles. One method of incorporating multiple pulses is to transmit the signal with one dilution and one compression, followed by one dilution cycle, and then change the excitation order, Signal is 1
One compression, one dilution, and one subsequent compression cycle. Next, the two resulting echoes (E1 and E2) are processed as described below.

Bubbles can be recognized in any of several signal processing embodiments. Some examples begin by correlating the echo signal with the bubble identification signal, an example of which is shown in FIG. 1 for an example of a contrast agent excited at 2 MHz. A bubble identification signal, which is a reference echo signal indicative of a particular contrast agent bubble, is obtained by recording the echo from a single bubble for a particular set of imaging parameters. Thus, for a particular transmission intensity (eg, 1 MPa), a particular transmission pulse (eg, 1.5 cycles), and a particular center frequency (eg, 2 or 5 MHz), a bubble identification signal is recorded for each contrast agent. .

Further assurance is obtained by incorporating information from the second frequency. To incorporate frequency information, two echoes from the two transmit frequencies are processed by correlating the signal with the bubble identification signal as described above.

The transmission of the bubble at the resonant frequency is performed after the transmission at the second frequency, reducing the chance of the bubble breaking. Boolean logic is used to determine whether a bubble has been found at one or both frequencies. As the two frequencies, a resonance frequency and a frequency higher or lower than the resonance frequency are selected. For a contrast agent having a resonance frequency of about 5 MHz, the second frequency could be about 2 MHz or about 9 MHz, depending on the depth of the imaged area. In either case, the bubble identification signal is recorded as described above. If the target site is in a region near the surface, 9 MHz can be selected as the second frequency, and 2 MHz can be selected for a deep target.

As described above, the echo E1 obtained by the transmission at 2 MHz is correlated with the bubble identification signal recorded for the transmission at 2 MHz. The echo E2 obtained from the 5 MHz transmission is correlated with the bubble identification signal recorded for the 5 MHz transmission. As a result of the correlation at each frequency (normalized by the transmit power), if a predetermined threshold is exceeded, a bubble is identified.

Further certainty of finding bubbles can also be obtained by incorporating information from additional pulses. Supplementally transmitted pulses such as those described above may use different ordering of compression and dilution cycles in a predictable manner.
Such changes in the transmitted pulse can be small and can significantly alter the echo from the bubble, but do not alter the echo from surrounding tissue. With a suitable combination of transmitted pulses, the echo from the fixed target (tissue) surrounding the bubble changes only minimally, changing the echo from the bubble. One such example involves changing the order of the compression and leaning cycles. The same can be achieved with small changes in the transmitted amplitude. For example, a signal with a small half cycle of compression and a large half cycle of leaning can be transmitted, and then transmitted in reverse order with about twice the amplitude change. Reversing the transmission order of the half cycles creates an extra half cycle in the received signal.

The resulting echo is then correlated with the appropriate bubble identification signal (ie, prototype) for that particular transmit pulse. The correlation results are shifted in time as needed to accommodate the delay of the first transmission. In the example of changing the order of compression and dilution, the pulses are delayed so that the echoes received from the center point of the pulse in each case are aligned.

Alternatively, after removing any relative delays in transmission, the echoes from the first and subsequent pulses can be summed sequentially by appropriately delaying the echoes. As a result, the presence of air bubbles is greatly increased, thereby removing echoes from the tissue.

For example, by changing the order of the compression and dilution cycles, the pulses are delayed so that in each case the echo received from the center of the pulse is aligned. The sum result is then correlated with the bubble identification signal (FIG. 11).

Another method is to calculate the phase of each echo as a function of depth. The phases of the echo pairs are then subtracted as a function of depth. Next, the relative phase between the pulses E1 (t) and E2 (t) is detected at a depth portion that is not equal to the difference between the transmission phases at the two depth portions. This embodiment is shown in FIG. 12, where it is not necessary to recognize the envelope of the bubbles. A wall filter may precede this processing. This is a high-pass filter known in ultrasonic signal processing. In this case, a set of 4-16 echoes with E1 characteristics is captured. The E1 and E2 arrays pass through a high-pass (wall) filter before phase subtraction. The preferred pulse is the 1.5 pulse described above, but the reordering of the compression and leaning half cycles would produce E1 (t) and E2 (t).

Yet another method is to sequentially cross-correlate the signals E1 (t) and E2 (t) with zero delay. Thus, echoes from tissue show a negative correlation, echoes from the bubble show a positive correlation, and the magnitude of this correlation indicates the certainty of bubble detection (FIG. 13).

As mentioned above, the transmission of a short pulse of ultrasound (as opposed to a bubble breaking echo) produces a unique bubble echo according to the present invention. Bubble echoes are unique echoes (distinguished from tissue-generated echoes) and change uniquely with a shift (shift) of the transmitted center frequency or a change in the transmitted waveform.
Unique features include phase and positive and negative half-cycle height consistency.
The first half cycle in the bubble echo appears consistently as a positive voltage corresponding to the expansion of the bubble. The first half cycle appears as about one-third to one-half the size of the second half cycle if the transmitted pulse is 1.5 cycles. In most cases,
The third half cycle contains two harmonics rectified as shown in FIG.

The present invention recognizes the detection of these echoes from bubbles, especially based on unique time-domain signatures.

The signal detector may use a matched filter, a best-accuracy detector, a cross-correlation detector, and / or an estimator to detect a bubble echo based on a particular known (non-linear) physical response of the bubble. Can be used to recognize.

The difference between the echo responses to a plurality of frequency excitations can be used to identify unique echoes from bubbles. This does not require "harmonic" signal processing or non-linear characteristics.

The unique echo response to multiple transmitted signals with varying combinations of compression and dilution cycles can be used to recognize bubble echo. This does not require harmonic signal processing, can take several forms, and is independent of the "non-linear" properties of the bubbles.

One of the processing methods is to calculate the phase of each echo as a function of depth. Next, the phases of the echo pairs are compared as a function of depth. Then the bubbles
The relative phase between successive pulses is detected at a depth location that is not equal to the difference between the transmission phases at the two depth locations. In this embodiment, there is no need to recognize the envelope of the bubble.

In another method, echoes from successive pulses differing in the number, order and amplitude of the compression and dilution cycles are added, producing a higher number at each bubble location.

Recognition and / or rejection of tissue echoes may be determined by using a matched filter, a most probable detector, a cross-correlation detector, and / or an estimator to identify certain well-known (non-linear) physical types of bubbles. It can be based on the use of a bubble identification scheme that distinguishes these tissues from bubbles based on the response.

The recognition and / or rejection of the tissue echo can also be based on the transmission of a plurality of pulses that differ in the number or order of half cycles of compression and dilution, after which the received echo is processed and the tissue echo is processed. Are rejected or tissue echoes are recognized.

One of the processing methods is to calculate the phase of each echo as a function of depth. Next, the phases of the echo pairs are compared as a function of depth. Bubbles are then detected at depths where the relative phase between successive pulses is not equal to the difference between the transmit phases.

Another method is to align the signals and then successively subtract the echoes.

The transmission of multiple frequencies can be used to improve the recognition of bubble echoes. The echoes from these multiple transmission frequencies are then combined. One combining method involves using a matched filter to recognize bubble echoes at each frequency, after which the two filtered signals are combined.

The present invention is further described with reference to the following drawings, which are not intended to limit the invention.

FIG. 1 shows a hydrophone recording of a transmitted signal and echoes of a contrast agent from this signal. FIG. 1 shows a unique echo following a broadband, high intensity insonation of a contrast agent bubble. 2M for 1 + ／ cycle
A center frequency of Hz is transmitted and then the reflected echo is heard. The transmitted signal includes a lean phase, a compressed phase, and a subsequent lean phase. The reflected echo contains a positive pressure peak corresponding to the time during which the bubble expands (transmitted dilution), followed by a very large time corresponding to the time during which the bubble contracts (transmitted compression). A negative pressure peak follows. The contraction is followed by two cycles of expansion, one of these cycles being elastic rebound.

FIG. 2 shows a correlation between a hydrophone having a transmission center frequency of 2 MHz and an echo signal, and a change in bubble diameter. 2a and 2b detail the correlation between transmitted pressure, echo amplitude and bubble radius.

FIG. 3 shows the M-mode and A-line corresponding to a bubble traversing a transducer beam with a transmission center frequency of 2 MHz. FIG. 3a shows depth on the horizontal axis,
It is a small M-mode image in which the pulse index is shown on the horizontal axis. Bubbles enter the beam at a depth of 800 during pulse 44. The amplitude of the echo then increases significantly as the bubble enters the center of the beam, which corresponds to approximately 500 depths. The intensity of the ultrasonic pulse striking the bubble increased until the bubble reached the center of the beam, and then decreased again. When the pulse intensity increases, an echo occurs, and FIG.
2 presents the identification characteristics of FIG.

FIG. 4 shows the M-mode and A-line corresponding to two bubbles traversing the transducer beam with a center frequency of transmission of 2 MHz. Two separate tracks are visualized in the M-mode image corresponding to the two bubbles traversing the beam.
The first echo from the first of these bubbles, starting from a linear echo, is shown in FIG. 4b. As the bubble crosses the beam, the signature of the echo changes and again assumes the signature shown in FIG. In FIG. 4f, a second bubble appears at a depth of about 700, in addition to the bubble from above, which was at a depth of 500. When this second bubble traverses the beam (FIG. 4g, which is located at the center of the beam), the signature of the echo again assumes the form shown in FIGS.

FIG. 5 shows the M-mode and A-line corresponding to two bubbles traversing the transducer beam with a center frequency of transmission of 5 MHz. The resonance frequency of the bubble shown in this figure is 5 MHz. Again, the bubbles enter from a deeper depth, in this case near the index 600. As the bubble moves across the transducer beam, the echo intensity increases, producing the same signature as shown in FIGS. The echo phase again corresponds initially to the expansion of the bubble (positive voltage) and then to a large negative voltage corresponding to the elastic rebound of the bubble radius. This repeatable signature was recognized and this information was combined with the information obtained from the 2 MHz transmission.

FIG. 6 shows the effect of the change of the transmission signal. In this case, a complete three-cycle compression and dilution (compression-dilution-compression-dilution-compression-dilution) waveform is transmitted, and therefore differs from the waveform shown in FIG. ing. The echoes received at such low intensity are slightly different from the shapes shown in FIGS.
The effect of the phase displacement in this case was tested. In FIG. 6a, a hydrophone echo was observed for this transmitted signal containing three amplitude-modulated cycles. Although FIG. 6b shows an echo from a fixed metal reflector, it is noted that the phase of the echo is, as expected, the same as the phase of the transmitted signal. FIG. 6c shows echoes from a large bubble (> 200 microns) traveling through the flow system of the present invention, but again note that the phase is the same as the phase of the transmitted signal. FIG.
Note that the echo from a single contrast bubble is shown, but the phase is the same as the transmitted signal. Bubble echoes also have a falling cycle that is consistently generated by a particular excitation pulse. The contrast agent echo has three positive peaks, with the central peak being significantly larger.

FIG. 7 shows the effect of the phase shift of the transmission signal. In this case, the waveform is different from the waveform shown in FIG. 6 because a significant two-cycle compressed-diluted waveform (compression-dilute-compression-dilute) is transmitted. Note that there are only two significant negative half cycles. In FIG. 7a, a hydrophone echo in this case was observed. FIG. 7b shows the echo from the fixed metal reflector, but note that the phase of this echo is, as expected, the same as the phase of the transmitted signal. FIG. 7c shows echoes from large bubbles (> 200 microns) traveling through the flow system of the present invention, but again note that the phase is the same as the phase of the transmitted signal. Note that in FIG. 7d, an echo from a single contrast bubble is shown, which is out of phase with the transmitted signal and identical to the phase of FIG. 6d. The contrast bubble echo has a positive peak (the first peak is small) corresponding to two substantially negative peaks in the hydrophone signal. Note that the signal is shorter than the signal in FIG. 6d. Thus, the received echo could be subtracted from a single bubble utilizing the two transmit pulses shown in FIGS. 6a and 7a to produce the extra half cycle shown in FIG.

FIG. 8 overlaps the two echoes shown in FIGS. 6 and 7d to demonstrate that the phases are similar and the shapes of the echoes are similar. These two echoes are echoes from two different bubbles due to the transmission pulses shown in FIGS.

The average frequency of the bubble echo changes as a function of the transmitted pulse, a change that is large enough to enhance the discrimination of the echo from bubbles and tissue.

The present invention is further described by the following examples, which are not intended to limit the invention.

Example 1 The order of the half cycle of compression and dilution in the transmitted pulse affects the time and frequency domain characteristics of the echo received from the ultrasound contrast agent. These effects can be used to distinguish between air bubbles and echoes from tissue.

With this method, both optical and acoustic observations of the ultrafine bubbles of the contrast agent are possible. The test system used two vertical transducers focused on each other on a 200 micron diameter cellulose phantom tube which was at a 45 ° angle to the two transducers. One transducer (Paname
trics® V305) is used to transmit pulses at a center frequency of 2.25 MHz, while (Panametrics® V309) uses a 5 MHz center frequency to scatter from bubbles in the container. Received a signal. The phantom was also connected to a microscope for optical observation of microbubbles. Transmit pulses were generated using an arbitrary waveform generator (TekronicsTMAWG2021) and then amplified using an RF output amplifier (ENITM325LA). Bubble echo was received using a broadband receiver (Ritec TMBR-640). The transmitted negative peak pressure was about 700 kpa. These experiments use a contrast agent suspended in saline at a very low concentration of about 1 sphere / microL, and have a volume of about 0.04 micron in the experimental system of the present invention using small diameter tubes. A sample filled with L contrast agent was produced. Similar results were obtained with some contrast agents, but the results presented here were obtained using a test agent having a lipid shell and a perfluorohydrocarbon core.

The transducer has a phase of 0 ° (half cycle of compression followed by half cycle of dilution)
, And a single cycle pulse of 180 ° (half cycle of dilution followed by half cycle of compression). Echoes received from a single bubble were recorded from more than 200 transmissions for each phase. Echoes received from transmit pulse pairs spaced approximately 3 microseconds apart (as shown in FIG. 1) were also recorded. Approximately 50 echoes were evaluated for each of the following three transmission sequences. That is, both pulses are at 0 ° phase; 180 ° after this 0 ° phase; and 180 °
The phase is 0 ° after the phase of. Using this data, both time and frequency domain properties were evaluated. Echo recordings were also compared to optical images of the change in bubble radius during the insonation of microbubbles anchored to a polystyrene plate.

The influence of the transmission phase on the frequency spectrum and the time domain envelope of the bubble echo is as follows. The average frequency of the bubble echo was lower when a 0 ° pulse was transmitted. Specifically, when a pulse of 0 ° is transmitted, 3.9 MH
An average frequency of z is observed, while 4.3 if the phase of the transmitted pulse is 180 °.
An average frequency of MHz was observed. In addition, in the case of 0 °, the time domain envelope was often long.

Table 1 below shows that the time interval between the first major diluted peak of the two received echoes corresponds to the time interval between the transmitted diluted peaks. The average reception time interval was added together with the transmission pulse time interval measured by the hydrophone. The results show that the timing of the received echo depends on the half cycle of the dilution. Specifically, as the transmitted dilution half cycle is shortened, as in the case of 0 ° -180 ° phase, the time measured between the received dilution peaks is proportionally reduced. The results show that a significant part of the bubble echo coincides with the first major dilution half cycle of the transmitted signal.

Table 1 Time interval between the first major dilution peak of the pulses of each pair of transmit and receive queries. Transmitted Transmit: Receive echo: Phase combination. The first major diluted peak of time The time between diluted peaks The time interval between microseconds (microseconds) The interval (microseconds) 0-0 2.95 2.94 0-180 2.72 2.70 180-0 3.16 3.20

FIGS. 19 a, 19 b, and 19 c show a transmit signal used to excite a broadband transducer. FIG. 19a shows two identical pulses of compression followed by dilution. FIG. 19b shows a pulse pair with compression in the first pulse followed by dilution and a pulse pair in the second pulse followed by compression. FIG. 19c shows a pulse pair in the first pulse followed by a dilution followed by compression, and a pulse pair in the second pulse followed by a dilution.

FIGS. 20 a, 20 b, 20 c and 20 d show echoes received from individual bubbles and demonstrate the consequences of a change in the transmission phase. 20a and 20b show a combination of phases transmitted at 0 ° -180 ° phase. 20c and 20d are examples of combinations of phases transmitted at 180 ° -0 ° phase. To facilitate comparison of the echo timing, the first compression peak is aligned in two cases.

FIG. 20 includes two echoes received according to a 180 ° -0 ° transmission phase combination and two echoes received according to a 0 ° -180 ° transmission phase combination, The echo from this bubble insonated with a pair of pulses is shown. Note that the echo resulting from each transmission phase was similar in all cases. This, in turn, demonstrates that for all short transmissions, the time domain envelope from a single bubble echo can be predicted. This shows that the received echo can be recognized by correlating it with the prototype of the bubble echo.

The characteristics of the bubble echo, including the recognition characteristics in the average frequency, duration and time domain, change with the phase change of the transmitted signal, indicating that there is a high correlation between successive echoes. The transmission of several signal phases can be used to identify bubbles in vivo.

Example 2 Measurements were made on several contrast agents having both albumin and lipid shells,
The average frequency of the bubble echo changes as a function of the transmission phase, and it has been demonstrated that this change is a change large enough to enhance the distinction between echoes from bubbles and those from tissue. However, the average frequency is slightly different between albumin and lipid shell contrast agents as shown in Table 2.

Table 2 Albumin shell Lipid shell Transmission phase 0 180 0 180 Number of bubbles 72 72 75 75 Average frequency (MHz) 3.45 3.98 3.74 4.42

Filtering air bubbles to achieve a limited distribution greatly reduces the standard deviation of the average frequency estimate.

In order to utilize the above results for signal processing, the following steps are used. Echoes from the tissue are rejected by filtering the walls or using a wide-pass filter to remove frequencies near the fundamental frequency. The average frequency is evaluated to identify the presence of bubbles. The average frequency is calculated as a function of depth for the 0 ° and 180 ° pulses, and a significant displacement of this frequency is indicative of the presence of the bubble (s).

FIG. 15 shows echoes scattered from bubbles of the contrast agent having transmission phases of 0 ° and 180 °. The phase of the transmitted signal is inverted, but the phase of the received echo is not inverted. The average frequency is different for the two echoes. When observed with shorter pulses, the average frequency for a 180 ° transmission is higher.

FIGS. 16 a and 16 b show the hydrophone recording of the transmitted signal for 0 ° and 180 °. Note that they are inverted. Echoes recorded from the contrast agent in two cases are shown. Note that they have the envelope shown in FIG. 16, but that the echo from the 180 ° transmission is delayed and in each case occurs during the half cycle of dilution.

FIGS. 17 a and 17 b show two sets of recordings of echoes from four pulses separated by 1.25 microseconds. The echo is generated by a single albumin bubble. The pulses were transmitted alternately at 0 ° and 180 °, and the intervals between transmitted pulses were uniform. Note that the received echo alternates between the two delays (the intervals between the echoes are non-uniform, corresponding to the timing of the transmitted dilution). The echo also alternates between two average frequencies at 0 ° and 180 °. Also note that the echo intensity weakens the bubbles in the albumin shell and grows between successive pulses.

FIGS. 18 a and 18 b show two sets of recordings of echoes from four pulses separated by 1.25 microseconds. The echo is generated from a single lipid bubble. The transmission of the pulses alternated between 0 ° and 180 °, and the transmitted pulses were equally spaced. Note that the received echo alternates between the two delays (the intervals between the echoes are non-uniform, corresponding to the timing of the transmitted dilution). The echo also alternates between two average frequencies at 0 ° and 180 °. Also note that the echo intensity does not grow between consecutive pulses in the case of lipid shells.

FIGS. 17 and 18 show the consistency of the results and show that these characteristics can be used to inject two different contrast agents to distinguish their echoes.

As mentioned above, the present invention can provide a number of advantages over the prior art.

One of the immediate medical benefits of the present invention with respect to detecting breast cancer is that
The new ability to guide a needle biopsy in any patient, not just those with low echo tumors. Local vascular changes are seen in patients with no detectable mass and with cancerous tumors. More generally, the present invention greatly improves the positive predictive value of ultrasound diagnosis of identified masses.

The present invention also has great implications for the study of cardiovascular disease (CVD), as it can be applied to the assessment of myocardial perfusion.

[Brief description of the drawings]

FIG. 1 is a graph showing a hydrophone recording from a transmitted signal and a contrast agent echo from the signal.

FIG. 2 is a diagram comparing the graph of FIG. 1 with the bubble size.

FIG. 3 is a graph showing an M mode and an A mode corresponding to bubbles.

FIG. 4 is a graph showing an M mode and an A mode corresponding to two bubbles.

FIG. 5 is a graph showing an M mode and an A mode corresponding to another pair of bubbles.

FIG. 6a is a graph showing the effect of a change in a transmission signal.

FIG. 6b is a graph showing the effect of a change in a transmission signal.

FIG. 6c is a graph showing the effect of a change in a transmission signal.

FIG. 6d is a graph showing the effect of a change in the transmission signal.

FIG. 7a is a graph showing the effect of a phase shift of a transmission signal.

FIG. 7b is a graph showing the effect of a phase shift of a transmission signal.

FIG. 7c is a graph showing the effect of a phase shift of a transmission signal.

FIG. 7D is a graph showing the influence of the phase shift of the transmission signal.

8 is a graph showing a comparison between the echo shown in FIG. 6 and the echo shown in FIG. 7 (d).

FIG. 9 is a block diagram illustrating a comparison of a correlation receiver for transmission of two pulses.

FIG. 10 is a block diagram illustrating a matched filter used in accordance with the present invention.

FIG. 11 is a block diagram of an alternative method according to one embodiment of the present invention.

FIG. 12 is a block diagram illustrating the calculation of the phase of an echo as a function of depth.

FIG. 13 is a block diagram illustrating cross-correlation of signals.

FIG. 14 is a graph showing M mode and A line corresponding to bubbles versus non-contrast agents according to the present invention.

FIG. 15 is a graph showing echoes scattered from bubbles of a contrast agent at transmission phases of 0 ° and 180 °.

16A is a graph showing the amplitude of the hydrophone recording pulse and the amplitude of the echo of the transmission signal of 0 °, and FIG. It is a graph shown.

FIG. 17 is a duplicate set of recordings from four pulses, separated by 1.25 microseconds, generated by a single albumin shell bubble.

FIG. 18 is a set of two recordings of echoes from four pulses separated by 1.25 microseconds, generated by a single lipid shell bubble.

FIG. 19 is a graph showing a set of transmitted signals from a lipid shell bubble having a perfluorohydrocarbon core to excite a broadband transducer.

FIG. 20 is a graph showing the aggregation of transmitted signals from individual lipid shell bubbles having a perfluorohydrocarbon core.

[Procedure amendment]

[Submission Date] April 19, 2000 (2000.4.19)

[Procedure amendment 1]

[Document name to be amended] Drawing

[Correction target item name] All figures

[Correction method] Change

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FIG.

FIG.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (71) Applicant 1224 West Main Street # 1-110, Charlottesville, VA 22903, U.S.A. S. A. (72) Inventor Morgan, Karen Elizabeth United States, Virginia, Charlottesville, CABer Avenue 824A Terms (reference) 4C085 HH09 JJ05 JJ16 LL01 4C301 DD01 EE20 JB22 JB28 5J083 AA02 AB17 AE00 AE08 BA09 BB12 DC07

Claims (40)

[Claims] 1. A method for identifying gaseous bubbles in a liquid, comprising: a) injecting an ultrasonic contrast agent into the liquid so that gaseous bubbles are formed in the liquid; Directing a first ultrasonic pulse centered on frequency to the bubble causes a change in a first vibration size of the bubble and a first vibration corresponding to a change in the first vibration size of the bubble. Generating an echo signal; c) detecting a first oscillating echo signal generated by the bubble; and d) identifying the bubble based on the detected first echo signal. . 2. The method of claim 1, further comprising comparing the first echo signal with a first reference echo signal representing the bubble to identify the bubble. 3. The method according to claim 1, wherein said first frequency is substantially a resonance frequency of said bubble.
The method described in. 4. The method of claim 3, wherein said resonance frequency is about 1.5-5 MHz. 5. The method of claim 1, wherein the first pulse has a duration that is approximately equal to or less than three cycles of a center frequency of the first pulse. 6. The method of claim 5, wherein said first pulse has a duration of about 1.5 cycles of a center frequency of said first pulse. 7. Directing a second ultrasonic pulse, centered on a second frequency, to said bubble causes a change in a second vibration size of said bubble and a change in a second vibration size of said bubble. Generating a second vibration echo signal corresponding to the following: detecting the second vibration echo signal generated by the bubble; and further identifying the bubble based on the detected second echo signal. ,
The method of claim 1, further comprising: 8. The method of claim 7, further comprising comparing the first and second echo signals with first and second reference echo signals representing the bubble to identify the bubble. 9. The method of claim 7, wherein said second frequency is within about 5 MHz of said first frequency. 10. The method of claim 9, wherein said second frequency is in a range about 4 MHz higher than said first frequency. 11. The method of claim 9, wherein the second frequency is in a range about 3 MHz below the first frequency. 12. The method according to claim 7, wherein said first and second echo signals have a significant difference. 13. Directing another ultrasonic pulse centered on said first frequency to said bubble causes another change in vibration size of said bubble and causes another change in vibration size of said bubble. Generating another corresponding vibration echo signal; detecting another vibration echo signal generated by the bubble; and further identifying the bubble based on the detected another echo signal. The method of claim 1 comprising: 14. The method of claim 13, further comprising comparing the first echo signal with the another echo signal to identify the bubble. 15. The method of claim 13, wherein said another ultrasound pulse differs from said first ultrasound pulse in characteristics selected from the group consisting of phase, amplitude, and combinations thereof. 16. Generating a plurality of different vibration echo signals by directing a plurality of different ultrasonic pulses to the bubble, and detecting a plurality of different vibration echo signals generated by the bubble. 14. The method of claim 13, further comprising the step of: further identifying the air bubble based on the detected another echo signal. 17. The method of claim 16, further comprising comparing the first echo signal with the another echo signal to identify the bubble. 18. The method of claim 17, wherein the plurality of other ultrasound pulses differ from the first ultrasound pulse in features selected from the group consisting of phase, amplitude, and combinations thereof. . 19. A method of mapping a patient's tissue, comprising: injecting an ultrasound contrast agent into a body fluid within a patient's vasculature such that gaseous bubbles are formed in the liquid; Directing a first ultrasonic pulse centered at one frequency to the bubble causes a change in a first vibration size of the bubble and a first vibration corresponding to a change in the first vibration size of the bubble. Generating an echo signal; detecting a first vibration echo signal generated by the bubble; identifying the bubble based on the detected first echo signal; and identifying the bubble. Mapping the patient's tissue with the patient. 20. The method of claim 19, further comprising comparing the first echo signal with a first reference echo signal representing the bubble to identify the bubble. 21. Directing a second ultrasonic pulse centered on a second frequency different from the first frequency to the bubble to cause a change in a second vibration size in the bubble, and Generating a second vibration echo signal corresponding to a change in the second vibration size; detecting a second vibration echo signal generated by the bubble; and detecting the bubble based on the detected second echo signal. 20. The method of claim 19, further comprising: identifying. 22. The method of claim 21, further comprising comparing the first and second echo signals with first and second reference echo signals representing the bubble, respectively, to identify the bubble. . 23. Directing another ultrasonic pulse centered on said first frequency to said bubble causes another change in vibration size of said bubble and causes another change in vibration size of said bubble. Generating another corresponding vibration echo signal; detecting another vibration echo signal generated by the bubble; and further identifying the bubble based on the detected another echo signal. 20. The method of claim 19, comprising: 24. The method of claim 23, further comprising comparing the first echo signal with the another echo signal to identify the bubble. 25. The method of claim 23, wherein said another ultrasonic pulse differs from said first ultrasonic pulse in a feature selected from the group consisting of phase, amplitude, and a combination thereof. 26. Generating a plurality of different vibration echo signals by directing a plurality of different ultrasonic pulses to the bubble; and detecting a plurality of different vibration echo signals generated by the bubble. 24. The method of claim 23, further comprising the step of: further identifying the bubble based on another detected echo signal. 27. The method of claim 26, further comprising comparing the first echo signal with the another echo signal to identify the bubble. 28. The method of claim 27, wherein the plurality of other ultrasound pulses differ from the first ultrasound pulse in features selected from the group consisting of phase, amplitude, and combinations thereof. . 29. The method of claim 1, wherein the bubbles are identified by detecting a frequency displacement of the first echo signal. 30. The method of claim 7, wherein the bubbles are further identified by detecting a frequency displacement of the second echo signal. 31. The method of claim 13, wherein the bubbles are further identified by detecting a frequency displacement of the another echo signal. 32. The method of claim 16, wherein said bubbles are further identified by detecting a frequency displacement of said another echo signal. 33. The method of claim 19, wherein said bubbles are further identified by detecting a frequency displacement of said first echo signal. 34. The method of claim 21, wherein said bubbles are further identified by detecting a frequency displacement of said second echo signal. 35. The method of claim 23, wherein said bubbles are further identified by detecting a frequency displacement of said another echo signal. 36. The method of claim 26, wherein the bubbles are further identified by detecting a frequency displacement of the another echo signal. 37. The method of claim 13, wherein said another ultrasonic pulse differs from said first ultrasonic pulse by a displacement of a center frequency. 38. The method of claim 17, wherein the plurality of other ultrasonic pulses differ from the first ultrasonic pulse by a displacement of a center frequency. 39. The method of claim 23, wherein said another ultrasonic pulse differs from said first ultrasonic pulse by a displacement of a center frequency. 40. The method of claim 27, wherein the plurality of other ultrasonic pulses differ from the first ultrasonic pulse by a shift in center frequency.