WO2013104726A1

WO2013104726A1 - Ultrasound imaging using counter propagating waves

Info

Publication number: WO2013104726A1
Application number: PCT/EP2013/050424
Authority: WO
Inventors: Guillaume Renaud; Nicolaas De Jong; Johannes Gijsbertus BOSCH; Antonius Franciscus Wilhelmus Van Der Steen
Original assignee: Erasmus University Medical Center Rotterdam
Priority date: 2012-01-11
Filing date: 2013-01-10
Publication date: 2013-07-18
Also published as: GB201200411D0; GB2498519A

Abstract

An ultrasound imaging method and apparatus are described. The method comprises transmitting a reference excitation signal into a target medium and receiving first echo signals corresponding to the reference excitation signal. The method further comprises transmitting an imaging excitation signal into the target medium, transmitting a manipulation signal into the target medium, the imaging excitation signal and the manipulation signal not overlapping in time, and receiving second echo signals corresponding to the imaging excitation signal and manipulation signal and an interaction therebetween. The method further comprises generating an output signal based on a difference between the first echo signals and second echo signals.

Description

ULTRASOUND IMAGING USING COUNTER PROPAGATING WAVES

The present invention relates to methods and apparatus for ultrasound imaging. Ultrasound waves, sometimes called ultrasound signals, can be used to detect and image structures and matter. While commonly used in medical applications, ultrasound is also used in a variety of other disciplines for detection and imaging of features in materials. Contrast ultrasound imaging makes use of the ways in which sound waves can interact and are scattered or reflected from interfaces between substances. In recent years, several pulse sequences have been proposed for real-time contrast ultrasound imaging. They employ a sequence of two or three ultrasound signals to retrieve specific signatures from contrast agents, such as microbubbles. Pulse sequences of two or three waveforms, such as pulse inversion, amplitude modulation, chirp reversal, pulse subtraction time delay imaging or radial modulation (including classical surf imaging), are all dramatically impaired due to artefacts caused by nonlinear acoustic propagation which induces distortion of any transmitted waveforms.

The detection of microbubble contrast agent may be more efficient if the transmit acoustic pressure is low, such that the distortion of the waveforms due to nonlinear propagation in tissue remains as weak as possible. "Low" acoustic pressures may be considered those where the mechanical index, which is the peak negative acoustic pressure measured in MPa divided by the square root of the frequency in MHz, is less than 0.2. If the distortion of the waveforms is too great, then the suppression of signals arising from linear scattering, and hence the ability to distinguish microbubbles from tissue, may be impaired. Furthermore, when investigating a region located behind a vessel or other structure in which contrast agent (such as microbubbles) is flowing, the echo signals can become distorted, the distortion being induced by highly nonlinear wave propagation through the contrast agent. The echoes scattered by echogenic tissue (such as soft tissue) cannot be sufficiently suppressed, and the detection of microbubbles (such as contrast agent microbubbles) cannot then be reliably performed in this area. This effect is the so-called distal vessel wall artefact effect (or far wall artefact, or pseudoenhancement) . Other methods such as destructive and non-destructive subharmonic imaging, and superharmonic imaging, employ a single waveform to detect contrast agent such as contrast microbubbles. Superharmonic imaging requires a sophisticated ultrasound probe to transmit and receive the ultrasonic signals. Non-destructive subharmonic imaging requires a specific microbubble contrast agent tailored for use with this technique in order to be efficient, such as low surface tension buckling bubbles. Such specific microbubble contrast agents are not yet available on the market for clinical use. Destructive subharmonic imaging does not allow slow blood perfusion analysis.

Subharmonic imaging also reduces the artefacts present due to nonlinear acoustic propagation, but this requires the insonification of contrast microbubbles at, or at twice the microbubbles' resonant frequency. Thus, this technique is highly dependent on the type of contrast agent and the size of contrast microbubbles flowing in the probed region of interest.

A recent method, called ringdown surf imaging in this document, (R. Hansen ef a/, "Contrast imaging by non-overlapping dual frequency band transmit pulse complexes", IEEE Transactions UFFC, vol. 58 (2), pp. 290-297, 2011) uses high frequency (HF) pulses for image reconstruction, and low frequency (LF) pulses for manipulation of the scattering properties of contrast agent, such as manipulating contrast bubble diameter observed by a HF pulse. The LF manipulation pulses can be tuned to the bubble resonant frequency, but the HF imaging frequency is chosen according to the size and depth of the object being imaged. The HF and LF pulses may be non-overlapping. For a material with nonlinear elasticity, such as soft tissue, LF pulses overlapping in time with HF pulses will affect the propagation velocity for the HF pulses. However, transmitted LF pulses and HF pulses not overlapping will not manipulate the propagation velocity observed by the HF pulses.

It is an object of the present invention to provide improved ultrasonic imaging.

According to one aspect, the present invention provides an ultrasound imaging method comprising:

transmitting a reference excitation signal into a target medium;

receiving first echo signals corresponding to the reference excitation signal; transmitting an imaging excitation signal into the target medium; transmitting a manipulation signal into the target medium, the imaging excitation signal and the manipulation signal not overlapping in time;

receiving second echo signals corresponding to the imaging excitation signal and manipulation signal and an interaction therebetween; and

generating an output signal based on a difference between the first echo signals and second echo signals.

The step of receiving second echo signals corresponding to an interaction between the imaging excitation signal and the manipulation signal comprises receiving scattered echoes from the crossing of the imaging excitation signal and the manipulation signal propagating in opposite directions. In other words, the interaction corresponds to that of counter-propagation.

The method may further include varying a time delay between the transmission of the manipulation signal and transmission of the imaging excitation signal, in order to vary a depth of interaction between the imaging excitation signal and the manipulation signal in the target medium.

The method may further comprise transmitting a second imaging excitation signal into the target medium; transmitting a second manipulation signal into the target medium, the second imaging excitation signal and the second manipulation signal not overlapping in time; receiving third echo signals corresponding to the second imaging excitation signal and the second manipulation signal and an interaction therebetween; and generating a second output signal based on a difference between the first echo signals and third echo signals.

The method may further include selecting a particular time delay between the transmission of the manipulation signal and transmission of the imaging excitation signal, in order to determine a particular depth of interaction between the imaging excitation signal and the manipulation signal in the target medium.

The manipulation signal may be transmitted after the imaging excitation signal is transmitted. Alternatively, the imaging excitation signal may be transmitted after the manipulation signal is transmitted.

The steps of transmitting the reference excitation signal and receiving first echo signals may be performed after the steps of transmitting the imaging excitation signal, transmitting the manipulation signal and receiving the second echo signals. Alternatively the steps of transmitting the imaging excitation signal, transmitting the manipulation signal and receiving the second echo signals may be performed after the steps of transmitting the reference excitation signal and receiving first echo signals.

The imaging excitation signal and the manipulation signal may be of different frequencies, and the method may further comprise the step of filtering the second echo signals, to attenuate components of the manipulation signal.

The reference excitation signal and the imaging excitation signal may be coded, and the method may further comprise the step of cross-correlating the received first echo signals and second echo signals to select components of the first echo signals corresponding to the reference excitation signal and to select components of the second echo signals corresponding to the imaging excitation signals, to discriminate from components corresponding to the manipulation signal.

The reference excitation signal and the imaging excitation signal may comprise substantially identical waveforms.

The method may further include the step of varying the relative amplitudes of the imaging excitation signal and the manipulation signal to optimise the echo signals received from a particular feature in the target medium. Ultrasound signals may be transmitted, and echoes received, by the same transducer. Alternatively, imaging excitation signals may be transmitted, and subsequent echoes received by a first transducer, whereas manipulation signals may be transmitted and subsequent echoes received by a second transducer. Alternatively, imaging excitation signals may be transmitted by a first transducer, subsequent echoes may be received by a second transducer, whereas manipulation signals may be transmitted by a third transducer. A transducer may be a single element transducer or a multi-element transducer.

The method may further comprise introduction of a microbubble contrast agent into the target medium. The reference excitation signal and/or the imaging excitation signal may comprise one or more of a waveform, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal and an amplitude-modulated signal. The manipulation signal may comprise one or more of a waveform, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal, an amplitude modulated signal, or noise.

The reference excitation signal and the imaging excitation signal may comprise a pulse sequence, the pulse sequence comprising one or more of pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, sub-harmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging. The manipulation signal may comprise a pulse sequence, the pulse sequence comprising one or more of pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, sub-harmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging.

Counter-propagation imaging can benefit from sub-harmonic emission produced by the manipulation signal. If the frequency content of the subharmonic signal produced by the manipulation wave overlaps at least partly with the frequency content of the imaging excitation signal, comparison between scattered echoes from the reference excitation signal and scattered echoes form the imaging excitation signal may allow the extraction of an additional signal that helps to detect bubbles or cracks which are the source of the subharmonic emission.

The method may include repeating the steps of transmitting and receiving signals at different angles of incidence around the target medium. The method may include repeating the steps of transmitting and receiving signals at different depths of interaction between the imaging excitation signal and manipulation signal in the target medium. The imaging excitation signal and manipulation signal may be transmitted into the target medium from opposite sides of the target medium. Such further steps may allow the performance of tomographic-type imaging. The reference excitation signal may comprise a first portion comprising a low frequency reference burst and a second portion comprising a high frequency reference burst, the bursts not overlapping in time. The imaging excitation signal may comprise a phase inverted version of the first portion of the reference excitation signal, and the manipulation signal may comprise a phase inverted version of the second portion of the reference excitation signal, the phase inverted bursts not overlapping in time. The output signal may be generated by adding the first and second echo signals.

According to another aspect, the present invention provides an ultrasound imaging apparatus comprising at least one ultrasound transducer configured for transmitting and receiving ultrasonic signals; a signal processor; and a control system configured to cause the apparatus to perform any of the method steps as described above.

Embodiments of the present invention will now be described by way of example and with reference to the accompanying drawings in which:

figures 1a-1b show a pulse sequence with a pulse used as an imaging excitation signal;

figures 2a-2b show a pulse sequence with a chirp used as an imaging excitation signal;

figure 2c shows a three-transmission phase pulse sequence, with a varied time delay between the imaging excitation signal and the manipulation signal;

figure 2d shows schematically a possible set-up for tomographic imaging; figure 2e shows schematically a possible set-up for tomographic imaging using two transducers;

figure 2f shows schematically a possible set-up for tomographic imaging using three transducers;

figure 3 shows a schematic top-down view of apparatus used in an experiment;

figure 4 shows a B-mode line obtained using the apparatus of figure 3;

figure 5 shows envelopes of radio frequency (RF) lines obtained using the apparatus of figure 3 with different pulse sequences;

figure 6 shows signal processing steps according to an embodiment using counter propagating chirp excitation as a pulse sequence;

figure 7a shows a schematic example arrangement for seismic imaging; figure 7b shows a pulse sequence used in a seismic imaging experiment with identical waveforms used as a reference excitation signal, an imaging excitation signal and a manipulation signal;

figures 7c-7d show experimental results from a seismic imaging experiment; figure 8 shows phase-inverted "bi-frequency pulse sequences" used for imaging; and

figure 9 shows experimental results from a tissue mimicking material using the pulse sequences illustrated in figure 8.

Nonlinear interaction between two acoustic signals or waves propagating in opposite directions (counter-propagation) is not efficient in homogeneous media, such as fluids and solids, as well as not being efficient in inhomogeneous media which do not contain any localised high gradients in compressibility, in density or in the amplitude- dependence of compressibility (non-linear elasticity), such as tissue in the human body, or uniform rocks containing no cracks. However, a gas microbubble in a liquid, or a crack in a solid constitutes a localised high gradient which provides a source of acoustic nonlinearity. Gas microbubbles in a liquid, or a crack in a solid, therefore provide sources of localised contrast in compressibility. Such sources of acoustic nonlinearity allow the nonlinear interaction of two counter-propagating signals (waves).

Transmitting an imaging excitation signal and a manipulation signal which are non- overlapping in time into a target medium, in the presence of an acoustic scatterer or a reflecting object in the medium, will result in the first transmitted signal scattering and changing direction, and then crossing the counter-propagating second transmitted signal. In the case where a localised contrast agent or local inhomogeneity, such as a high spatial gradient in compressibility, in density, or in the amplitude-dependence of compressibility (non-linear elasticity) is present and situated at the point where the two counter-propagating signals cross, the manipulation signal will manipulate the local acoustic properties of the medium and as a consequence, affect the propagation of the imaging excitation signal. Echo signals will be received as a result of the scattered imaging excitation signal. The imaging excitation signal may be transmitted before, or after, the manipulation signal is transmitted.

Repeating the imaging excitation signal transmission, but without the transmission of a manipulation signal provides a reference. A reference imaging (excitation) signal may be transmitted into a target medium which is then scattered to provide echo signals which are received by a transducer. These received echo signals provide a reference. We may label the received echo signals arising from scattering of a transmitted imaging excitation signal only as first echo signals. We may also label the received echo signals arising from scattering of a transmitted imaging excitation signal and of a transmitted manipulation signal, and any interaction therebetween, as second echo signals.

Comparing the first echo signals (which act as a reference) with the second echo signals allows the effect of the manipulation signal to be determined. An output signal may be generated based on a difference between the first echo signals and the second echo signals. As a result, for example, the position of an acoustic nonlinear source such as a gas bubble in a liquid or a crack in a solid can be determined. An image may be formed from the generated output signal.

The steps of transmitting the reference excitation signal and receiving first echo signals may be performed before, or after, the steps of transmitting the imaging excitation signal and transmitting the manipulation signal and receiving second echo signals.

The above method of imaging, using a reference excitation signal as a reference, and using an imaging excitation signal and a manipulation signal, may be referred to as counter-propagation based acoustic imaging.

The backscattered signals (the scattered reference excitation signal providing first echo signals and the scattered imaging excitation signal and scattered manipulation signal providing second echo signals) can be received by the same transducer as that which transmits the signals (the reference excitation signal, the imaging excitation signal and the manipulation signal).

Alternatively, one transducer may be used to transmit the reference excitation signals and receive the first echo responses, and a separate transducer may be used to transmit the imaging excitation signal and the manipulation signal, and receive second echo signals. Alternatively, one transducer may be used to transmit the reference excitation signals and the imaging excitation signals and a separate transducer may be used to transmit the manipulation signals. The same, or different, transducers may be used to receive the echo signals. It will be appreciated that one or more transducers may comprise an ultrasound probe. It will also be appreciated that a transducer may comprise one or more elements, such as piezoelectric elements, for example. Figure 1a is a plot 100 showing an exemplary reference excitation signal 104 plotted against time 102 in the form of a pulse. Figure 1b is a plot 110 showing an exemplary signal plotted against time 112 comprising an imaging excitation signal 114 and a manipulation signal 116. It can be seen that the reference excitation signal 104 corresponds to the imaging excitation signal 114, in that they are substantially identical waveforms. The imaging excitation signal 114 and the manipulation signal 116 do not overlap in time. In this example the imaging excitation signal 114 occurs between 0 and 1 microseconds, whereas the manipulation signal 16 occurs between 1 and 2 microseconds. The imaging excitation signal 114 and manipulation signal 116 are also in different frequency ranges.

Figure 1a illustrates a pulsing scheme which could be used to generate a B-mode ultrasonic image and a contrast mode image. Figures 1a and 1b illustrate pulsing schemes which may together be used to perform counter-propagation based acoustic imaging. Counter-propagation based acoustic imaging may be used to reveal the positions of localised high contrast, such as localised high contrast areas of compressibility due to the presence of microbubbles introduced into the target medium.

Figure 2a is a plot 200 showing another exemplary reference excitation signal 204 plotted against time 202. The reference excitation signal in this example is a chirp. Figure 2b shows a plot 210 of an exemplary excitation signal plotted against time 212, comprising an imaging excitation signal 214 and a manipulation signal 216. It can be seen that the reference excitation signal 204 corresponds to the imaging excitation signal 214 in that they are substantially identical waveforms. The imaging excitation signal 214 and the manipulation signal 216 do not overlap in time. In this example the imaging excitation signal 214 occurs between 0 and 2.5 microseconds, whereas the manipulation signal 216 occurs between 2.5 and 5 microseconds. The imaging excitation signal 214 and manipulation signal 216 are also in different frequency ranges.

The frequency ranges chosen for the imaging excitation signal 114, 214 and the manipulation signals 116, 216 have no constraint other than the frequency ranges of the imaging excitation signal 114, 214 and of the manipulation signal 116, 216 are preferably different. That is, the imaging excitation signal 114, 214 and manipulation signal 116, 216 ought each to have a significant amount of energy in a different frequency range. This is to allow for filtering of at least the second echo signals to take place during signal processing. Filtering may be performed in order to attenuate components of the manipulation signal. A typical filter applied may be a bandpass filter. The frequency range of the imaging excitation signal 114, 214 may be higher, or lower, than the frequency range of the manipulation signal 116, 216. The same filtering may also be applied to the first echo signals for convenience, although these echo signals do not have a component of a manipulation signal to remove.

The imaging excitation signal 114, 214 and the reference excitation signal 104, 204 may each comprise one or more of a waveform 114, 214, 104, 204, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal (e.g. a chirp signal) 204, 214 and an amplitude-modulated signal. The manipulation signal 116, 216 may comprise one or more of a waveform 116, 216, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal (e.g. a chirp signal), an amplitude modulated signal or noise.

The reference excitation signal, the imaging excitation signal and the manipulation signal each comprise a pulse sequence. The pulse sequence may comprise one or more of pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, sub-harmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging. More details are provided herein concerning these different pulse sequences in relation to an experiment carried out by the inventors. The imaging excitation signal can be transmitted before or after the manipulation signal. Similarly the reference excitation signal can be transmitted before or after the imaging excitation signal or the manipulation signal. The transmission of a reference excitation signal, an imaging excitation signal, and a manipulation signal (in any allowed order as specified above) can be considered to be a pulse sequence.

Other techniques may be used in conjunction with the described method of counter- propagation based acoustic imaging. Such methods include pulse amplitude modulation (also known as power modulation), pulse inversion (also known as phase inversion), pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, subharmonic excitation, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging. Counter-propagation based acoustic imaging, such as that provided by one or more embodiments described herein, uses a two transmission phase pulse sequence such as those illustrated in figure 1a and 1b (or 2a and 2b), or a three transmission phase pulse sequence such as that illustrated in figure 2c. The time interval between the transmission of the reference excitation signal 104, 204 and the transmission of the complex consisting of the imaging excitation signal 114, 214 and the manipulation signal 116, 216, is determined at least in part by the speed of sound in the probed medium, and the maximum investigated depth. If the medium is moving, this time interval must be sufficiently short so that the motion of the medium may be considered to be quasi-static for the duration of the waves' motion through it.

In the case where the imaging excitation signal is transmitted before the manipulation signal, the imaging excitation signal will be scattered and travel back to the transducer(s) while the manipulation signal propagates away from the transducer(s). Similarly, in the case where the manipulation signal is transmitted before the imaging excitation signal, the manipulation signal will be scattered and travel back to the transducer(s) while the imaging excitation signal propagates away from the transducer(s). The manipulation signal may modify the local acoustic properties of the target medium due to an inhomogeneity being present in the target medium. The inhomogeneity may, for example, be a microbubble contrast agent introduced into a body, or may be a crack in a rock or material. The inhomogeneity may also be any inhomogeneity in compressibility of the target medium, or any inhomogeneity in density of the target medium. The effect of the manipulation signal modifying the local acoustic properties of the target medium due to the presence of an inhomogeneity will affect the propagation of the imaging excitation signal.

A time interval, or time delay, may be used so that the imaging excitation signal 114, 214 and manipulation signal 1 6, 216 are transmitted, separated by the time delay. The time delay between transmission of the manipulation signal and transmission of the imaging excitation signal may be varied in order to vary a depth of interaction between the imaging excitation signal and the manipulation signal in the target medium. This effectively selects the depth into the target medium at which the two counter-propagating waves cross each other. By transmitting the manipulation signal and the imaging excitation signal, separated by a time delay, and repeating the process over a range of time delays, a range of depths of interaction is swept through in the target medium of the point of crossing of the two counter-propagating signals. In this way, the location of a particular feature, such as an inhomogeneity, may be determined. Figure 2c illustrates a three-step pulse sequence, and shows that different time delays may be used between transmission of the imaging excitation signal and the manipulation signal. Plot 250 shows a first step comprising an exemplary reference excitation signal 254 plotted against time 252. Plot 260 shows a second step comprising an imaging excitation signal 264 followed immediately by a manipulation signal 266 (that is, with a time delay 268 of substantially 0 microseconds), plotted against time 262. In plot 260 the imaging excitation signal 264 occurs between 0 and 2 microseconds, whereas the manipulation signal 266 occurs between 2 and 4 microseconds. Plot 270 shows a third step comprising an imaging excitation signal 274 followed by a time delay 278 of 6 microseconds, followed by a manipulation signal 276, plotted against time 272. In plot 270 the imaging excitation signal 274 occurs between 0 and 2 microseconds, whereas the manipulation signal 276 occurs between 8 and 10 microseconds. The imaging excitation signals 264, 274 and manipulation signals 266, 276 are in different frequency ranges. Using a pulse sequence as shown in plot 260 with no time delay may probe one particular depth in the target medium, whereas a pulse sequence as shown in plot 270 with a 6 microsecond time delay may probe a different depth in the target medium. It may be the case that only one reference excitation signal 254 is required for comparison with a series of imaging excitation signals 264, 274 and manipulation signals 266, 276 having a range of time delays between the imaging excitation signals 264, 274 and the manipulation signals 266, 276. In other circumstances, for example in a target medium which changes in time (such as a flowing medium), it may be preferable to transmit a reference excitation signal 254 corresponding to each transmission of an imaging excitation signal 264, 274 and manipulation signal 266, 276.

The time delay between transmission of the manipulation signal and transmission of the imaging excitation signal can be selected to be a particular time delay. Determining a particular time delay will result in the cross-propagation of the two signals at a particular depth of interaction in the target medium. It may be, for example, that the position of a feature such as an inhomogeneity in the target medium is known. Alternatively, it may be desired to have the counter-propagating waves cross each other at a particular distance from a feature of known location. The time delay may be determined according to the known depth of interaction required for the two signals to cross each other at the location of the feature, and according to the speed of sound in the medium, that is the speed at which the signals will propagate, through the target medium. For example, the particular depth of interaction of the feature to be detected and/or imaged may be known as a result of other imaging procedures. The feature to be detected and/or imaged may be, for example, a vessel carrying microbubble contrast agent. The feature may also be, for example, a different contrast agent, a crack, any inhomogeneity in compressibility of the target medium, or any inhomogeneity in density of the target medium.

Therefore the region of inhomogeneities may be investigated using counter- propagation based acoustic imaging. The ability to adjust the point at which the two counter-propagating signals cross allows for detecting and imaging inhomogeneities, such as localised contrasts in compressibility located at a particular depth of interaction. Such depths of interactions where features of interest may exist can be located in regions exhibiting weak acoustic scattering, and no specular reflections may be detected if more echogenic regions exist deeper in the medium. The scattering of the imaging excitation signal may be produced deeper in the medium, which may be desirable if, for example, scattering properties are more suitable there. This may be achieved by adjusting the time delay between the transmission of the excitation signal and the manipulation signal, thus allowing for counter-propagation of the two signals at a deeper region of interest.

The amplitude of the imaging excitation signal and the manipulation signal can be adjusted separately. The amplitude of the imaging excitation signal affects the signal to noise ratio. The amplitude of the manipulation signal affects the degree of the interaction between the imaging excitation signal and the manipulation signal, that is, the contrast to tissue ratio (CTR) in the case of medical ultrasound and medical ultrasound imaging. Therefore, the relative amplitudes of the imaging excitation signal and the manipulation signal may be varied to optimise the echo signals received from a particular feature in the target medium.

The durations of the imaging excitation signal and manipulation signal can be changed to determine the spatial resolution of the images formed using counter- propagation based acoustic imaging. The spatial resolution in B-mode images depends on the duration of the excitation signal. The longer in time the reference excitation signal lasts, the coarser the spatial resolution of the B-mode image. Correspondingly, the longer in time the imaging excitation signal lasts, the coarser the spatial resolution of any generated contrast-mode image. Conversely, the shorter in time the imaging excitation signal lasts, the finer the spatial resolution of any generated contrast-mode image. In figures 1a-b it can be seen that the reference excitation signal 104, the excitation signal 114, and the manipulation signals 116 all have a duration of approximately 1 microsecond. In figures 2a-b the reference excitation signal 204, the excitation signal 214, and the manipulation signals 216 all have a duration of approximately 2.5 microseconds. The reference excitation signal, the imaging excitation signal, and the manipulation signal may all have substantially different durations to each other. It will be appreciated that in the above discussion, features discussed in relation to the imaging excitation signal also apply to the reference excitation signal, since these two signals preferably correspond to each other. That is, these two signals ideally comprise substantially identical waveforms for the counter-propagation based acoustic imaging. However, it will be understood that the reference excitation signal and the imaging excitation signal could in principle be somewhat different provided that they share sufficient known commonality that the relevant features of each can be extracted and correlated.

In an example embodiment, an output signal is generated based on a difference between the first echo signals and the second echo signals. This difference may be determined using a signal processor. A signal processor can perform the following steps in order to generate an output signal. These steps are described in more detail in the discussion which follows of an experiment carried out by the inventors. A signal processor can filter the received first echo signals and second echo signals in order to retrieve signal components corresponding to the transmitted reference excitation signal and transmitted imaging excitation signal. Such filtering therefore at least attenuates and preferably fully suppresses components of the second echo signals corresponding to the manipulation signal. From these filtered first and second echo signals, a subtraction may be performed to determine a difference between the two signals. This difference signal provides an RF line when performing contrast mode imaging. The further step may be performed of computing an envelope of the RF line in order to obtain one line of a contrast mode image.

An excellent result is obtained when performing signal processing on the received second echo signals if the signal components in the second echo signals due to the scattered manipulation signal are totally suppressed, thereby leaving only signal components due to the scattered imaging excitation signal. If the signal components due to the scattered manipulation signal are totally suppressed then the remaining signal components must relate only to the transmitted imaging excitation signal. In practice it will be appreciated that it may be difficult to achieve complete attenuation of all components of the manipulation signal but that better results are achieved if higher proportions of components of the manipulation signal are suppressed.

A chirp, or coded excitation, may be used for the imaging excitation signal (and reference excitation signal) as shown in figures 2a-b. In this case it has been determined by the inventors that further suppression of the signal components originating from the scattered manipulation signal in the second echo signals can be achieved by using a coded excitation. Consequently, the signal to noise ratio, and therefore the contrast to noise ratio (CNR) of any generated images is improved. In this case of using a chirp (a coded excitation) a different signal processing step is required. This step is the cross-correlating of the received first echo signals and second echo signals to select components of the first echo signals corresponding to the reference excitation signal, and to select components of the second echo signals corresponding to the imaging excitation signals.

If using a coded excitation such as those shown in figures 2a-b, the imaging excitation signal 214 should be designed to have as little resemblance to the manipulation signal 216 as possible. It has been determined by the inventors that designing the waves in this way dramatically reduces the amplitude of signals arising from the scattered manipulation signal. The maximum amplitude of the normalised cross-correlation between the imaging excitation signal 214 and the manipulation signal 216 should preferably be 0.01.

Advantages of one or more aspects of the above described methods of counter- propagating based acoustic imaging are that B-mode images, and contrast mode images, can be constructed with a high frame rate. Contrast mode images may be constructed with sensitive and accurate detection of localised inhomogeneities, such as regions of local high contrast in compressibility (for example, bubbles or cracks). Contrast mode images may also be constructed which are substantially free from artefacts due to nonlinear acoustic propagation, which induces distortion of transmitted waveforms, particularly distal vessel wall artefacts. Blood flow and perfusion measurements may be performed using counter-propagating based acoustic imaging methods. Detection and classification of emboli may be performed using counter-propagating based acoustic imaging methods. Counter-propagating based acoustic imaging also allows for improved detection of angiogenesis within atherosclerotic plaques.

Advantages also include that at least some of the methods described above do not require the excitation of any mechanical resonance in an inhomogeneity or contrast medium. Consequently, it is not necessary to tune the frequency of the transmitted signals in order to correspond to a resonant frequency of an inhomogeneity or contrast medium, such as a bubble or crack. The efficacy of methods described herein can benefit by exciting the resonant frequency of a contrast medium such as a microbubble, but such methods are not dependent on exciting resonant frequencies. Further, imaging using one or more of the methods disclosed herein can produce contrast-mode images which are substantially free from artefacts due to acoustic propagation which induce distortion of transmitted waveforms. Further still, imaging using one or more of the methods described above can be achieved advantageously using an ultrasound probe which comprises identical elements, or transducers, for both transmitting and receiving the (reference) imaging excitation signal and manipulation signal. Even the same transducer may be used for both transmitting and receiving the (reference) imaging excitation signal and manipulation signal.

It may be the case that acoustic scattering is too weak (that is, the scattering only provides weak backscattered signals which cannot be used to generate high quality images). Such cases may arise when probing homogeneous tissue, or a scatterer- free liquid. This may be overcome, for example, by adjusting the amplitude of the imaging excitation signal and manipulation signal. Since the amplitude of these signals can be adjusted separately, increasing the amplitude of the imaging excitation signal with respect to the manipulation signal amplitude can contribute towards solving the problem of weak acoustic scattering.

The location at which the two signals cross each other can be determined, if desired, to be the location of an inhomogeneity located at a particular known depth of interaction, such as an area of localised contrast in compressibility (such as a microbubble). Adjusting the depth/location at which the two counter-propagating signals cross allows for detecting localised contrasts which are situated in a region which exhibits weaker acoustic scattering and in which no specular reflections occur if more echogenic regions are present deeper in the medium.

Adjusting/varying the time delay between the transmission of the manipulation signal and the imaging excitation signal over a particular range determines a range of depths over which the counter propagating signals will meet. In this way, by probing a range of depths in the target medium the location of any inhomogeneity may be determined if not already known. A compound image may be constructed from several contrast-images obtained using different time delays between the imaging excitation signal and the manipulation signal in order to probe different depths in the medium. Such compound image formation may solve the problem of weak acoustic scattering.

Since the intensity of the generated output signal, and consequently of any image formed therefrom, is related to both the local echogenicity and the strength of interaction between the counter-propagating signals, the output signal can be compressed in order to compensate for the heterogeneity of the scattering properties of the probed medium. Doing this means that the contrast image generated from the output signal highlights only the strength of the interaction between the counter- propagating signals. Compensating in this way is relatively straightforward if using a B-mode image constructed using signals received from the same transmitted pulse sequence (that is, from the first echo signals) as those used in counter-propagation based acoustic imaging (that is, from the second echo signals). In fact, the B-mode image provides a map of the heterogeneity of the scattering of the investigated medium. The methods of counter-propagation based acoustic imaging as discussed herein can be implemented within current standards. Standards relating to ultrasound medical imaging, such as mechanical index (<1.9 for the described methods) and thermal index (<3 for the described methods) are respected. The described methods also work with low-amplitude acoustic pressure waves and short timescale signals, so standards relating to these aspects are also respected. The methods of counter-propagation based acoustic imaging as discussed herein may result in reduced and/or suppressed nonlinear acoustic propagation artefacts arising from distortion of the waveforms. Further, the methods may also provide for an ultrasonic imaging technique which is substantially free from distal vessel wall artefacts. Such a technique may result in improved detection of contrast agent flowing close to and behind a vessel or vessels around which contrast agent is also circulating. Such a situation may arise when detecting and/or imaging microvessels within atherosclerotic plaques, or during perfusion analyses. The methods of counter-propagation based acoustic imaging discussed may be implemented by an apparatus, which comprises at least one ultrasound transducer configured for transmission and receipt of ultrasonic signals, at least one signal processor, and at least one control means, the control means configured to perform the steps of the method as provided above.

The potential applications of the methods described herein include external noninvasive and invasive/internal ultrasound contrast imaging for medical diagnosis of diseases and monitoring of therapeutic procedures. Internal imaging may be transoesophageal, intravascular, intracardiac, intraluminal, endorectal, or endovaginal. Potential applications also include in-vivo detection of microcracks in bone tissue (non-invasive assessment of bone micro-damage) and the monitoring of bone fracture healing. Potential applications in geophysics include imaging of the extent of damage of rocks and other structures, and the detection of localised damaged regions in rocks and other structure. An example is identifying damaged rock regions related to oil extraction or well drilling. Another example is the assessment of seismic hazard. The methods may find application in non-destructive testing of cements and concrete structures, such as detecting and imaging the extent of damage in cement/concrete, detecting and imaging cracks and other dislocations in cement/concrete, detecting and imaging debonding between reinforcement bard/grids/plates and concrete in reinforced concrete, and applications related to safety controls in concrete structures such as nuclear power plants. An experiment performed by the inventors in relation to imaging a rock sample is discussed in relation to figures 7a-7d. Further examples of the application of the methods described herein include acoustical contrast tomography. In this application, one emitter/receiver may be used. Another possibility is to use two acoustic emitter/receiver devices placed face to face about the object to be investigated. In such tomographic imaging, the transmitter(s)/receiver(s), is/are able to rotate about the object (that is, around the target medium). Thus signals are transmitted and received at different angles of incidence around the target medium. In the example of using two devices face to face about the object to be investigated, the two devices each transmit acoustic signals, identical or different, with a predetermined time delay between the two transmissions. Adjusting the time delay between transmissions allows for varying the depth of interaction between the imaging excitation signal and the manipulation signal, thereby selecting the region in the object where the two acoustic signals cross. In the presence of a localised inhomogeneity where the signals cross, the propagation of the signals is affected. Repeating the procedure with one transmitted signal provides a reference. Comparing the signals received in the two configurations allows for detecting localised inhomogeneities, and a tomographic image may be obtained by rotating the two devices around the target medium, and modifying the time delay between signal transmissions. A possible application of tomography performed in this way is ultrasound breast imaging.

Figure 2d illustrates schematically a possible set up for backscattering tomographic imaging 280 using counter-propagation based acoustic imaging as described herein. A target medium 282 containing features of interest 289 and having a tomographic axis 284 is shown. The transmitter/receiver 286 may be used to transmit and receive signals to access different depths of interaction between the imaging excitation signal and manipulation signal in the target medium. By accessing a range of depths of interaction, a line through the target medium 282 may be probed. A transmitter/receiver 286 may be rotated to different angles of incidence Θ, 288 about the tomographic axis 284 of the target medium 282 to perform imaging at each angle of incidence Θ, 288.

A combination of changing the angle of incidence Θ, 288, and the depths of interaction between the imaging excitation signals and manipulation signals in the target medium, may be used to record a series of probed lines at different angles of incidence. Such lines may be used to reconstruct a tomographic image using counter-propagation based acoustic imaging. Transmission tomographic imaging may also be performed using two transmitters/receivers 290 as shown in figure 2e. Two transmitters/receivers 296, 298 are shown for use in transmitting imaging excitation signals and manipulation signals into the target medium 292 from opposite sides of the target medium in order to image features of interest 294 within the target medium 292.

Figure 2f illustrates that the imaging excitation signals may be transmitted into a target medium 2002 containing features of interest 2004 by one transducer 2006 and received by a second transducer 2008, or by a third transducer 2010, whereas manipulation signals may be transmitted by transducer 2008 or by a third transducer 2010. As another example, imaging excitation signals may be transmitted from opposite sides of the target medium 2002 by two transducers 2006, 2008, and manipulation signals may be transmitted by a third transducer 2010. This third transducer may insonify the target medium from a different direction to the propagation direction of the imaging excitation signals. Other combinations are possible. Three transducers may be used in this way for tomographic imaging, or for non-tomographic counter-propagation acoustic based imaging.

An experimental study was carried out to identify the best pulse sequences for use in ultrasound contrast imaging of the carotid artery, by comparing a series of reported pulse sequences and by using one or more methods as provided in this disclosure. A good candidate pulse sequence should provide sensitive detection of contrast microbubbles (which provide inhomogeneities presenting a high contrast in compressibility in regard to the medium), provide efficient suppression of echoes arising from linear scattering, prevent artefacts from being present in the resulting output signal, and be a simple enough method to allow for high frame rate imaging. In particular, distal vessel wall artefacts caused by nonlinear propagation through contrast agent (microbubbles) can dramatically impair the detection of microbubbles in any region located behind a vessel with respect to the transducer.

Figure 3 illustrates a top-down view of apparatus 300 used in this experiment. A focussed single element transducer 302 was positioned next to a water tank 304. The water tank 304 contained a thin metallic wire 306, a thin walled tube 308 which contained contrast agent 310 and a magnetic stirrer 312, and a rubber block 314.

The focussed single-element transducer was used in pulse-echo mode to transmit ultrasonic excitation signals 316 and receive ultrasonic scattered echo signals 318. The frequency range of the signals was between 3 MHz and 8 MHz in this experiment. The transducer was focussed at 50 mm. The excitation signals 316 were designed with a low mechanical index of between 0.1 and 0.2. In the water tank 304, the transducer 302 received echo signals 318 through a thin walled tube 308 which contained contrast agent 310 (SonoVue, Bracco) diluted in a ratio of 1 :5000. A thin metallic wire 306 was placed between the transducer 302 and the tube 308 to act as a linear scatterer. A block of rubber 314 was placed on the other side of the tube 308 to the wire 306 to also act as a linear scatterer, and to evaluate the contrast to tissue ratio (CTR) and the contrast to artefact ratio (CAR). The contrast to noise ratio (CNR) was also determined by comparing received echo signals obtained from contrast agent 310 with received echo signals using pure water in the place of contrast agent 310. From the echo signals 318 received by the transducer 302, a single RF line was generated.

By transmitting an imaging excitation signal such as that shown in figure 1a, a B- mode line was obtained from the excitation signal propagating through the thin metallic wire, the tube filled with diluted contrast agent, and the rubber block, thereby generating scattered echo signals. The obtained B-mode line is shown in figure 4.

Figure 4 shows a B-mode line 400 obtained using the experimental setup described above using a pulse imaging excitation signal as an excitation signal. The distance (in mm) away from the transducer of the various elements in the experimental arrangement can be seen in the B-mode image. Peak echo signals are seen corresponding to the thin metallic wire (peak 402), the proximal tube wall (i.e. the tube wall closest to the transducer (peak 404)), the distal tube wall (i.e. the tube wall farthest from the transducer (peak 408)) and the rubber block (peak 410). A weaker echo signal is also detected corresponding to the microbubble contrast agent present in the tube (peaks 406) between the determined distances of approximately 42 mm and approximately 56 mm.

By transmitting various pulse sequences, various contrast mode line scans were obtained 502-516. Pulse sequences used in this experiment were pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, subharmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, ringdown surf imaging and counter- propagation chirp imaging. Contrast mode line scans obtained using these various pulse sequences 500 are illustrated in figure 5 (note that scans obtained using pulse inversion, pulse inversion amplitude modulation and radial modulation are not shown in figure 5). Each contrast mode image line shown in figure 5 has been obtained by averaging the contrast mode image lines obtained from 20 successive acquisitions. The signal processing in relation to using counter-propagating chirp imaging as a pulse sequence is illustrated in more detail in figure 6. The signal processing provides the contrast mode line 516. Figure 6 illustrates the signal processing steps carried out for counter-propagating chirp imaging performed on a single measurement. A first echo signal 602 corresponding to the transmitted reference excitation signal, and a second echo signal corresponding to the transmitted imaging excitation signal 604 are shown. The first echo signals and second echo signals are RF data lines.

Since the excitation signal and reference excitation signal in this example are chirp excitations, and therefore coded excitations, a decoding step is performed for each received response. The first echo signals 602 were decoded by cross-correlating the received reference response with the transmitted reference excitation signal to give a first line of decoded RF data 606. Similarly, the second echo signals 604 were low- pass filtered (to attenuate echoes from the manipulation signal) and decoded by cross-correlating the received response with the transmitted excitation signal to give a second line of decoded RF data 608. The decoding in this example was performed as chirp compression, since the reference excitation signal and excitation signal were both chirp signals.

A difference was obtained between the decoded first echo signals and the decoded second echo signals by subtracting the second line 608 from the first line 606 of decoded RF data. This difference provides RF data 610 giving a contrast mode line 612 by applying an envelope to the RF data 610.

Returning now to figure 5, it can be seen that contrast mode line scans were obtained by using pulse amplitude modulation 502, chirp amplitude modulation 504, chirp reversal 506, chirp reversal amplitude modulation 508, pulse subtraction time delay imaging 510, subharmonic imaging 512, ringdown surf imaging 514 and counter-propagation chirp imaging 516. Artefacts 518 due to the nonlinear propagation of ultrasonic signals in water are seen in some of the contrast mode line scans, most obviously in scans obtained using pulse amplitude modulation 502, chirp amplitude modulation 504 and chirp reversal amplitude modulation 508. Distal vessel wall artefacts 520 are also observed in many of the contrast mode line scans. Only subharmonic imaging 512, ringdown surf imaging 514 and counter-propagation chirp imaging 516 are substantially free of distal vessel wall artefacts. Table 1 shows the contrast scores obtained for various imaging pulses used according to the experimental setup in figure 3. The contrast scores are calculated by summing the contrast to noise ratio (CNR), contrast to artefact ratio (CAR) and contrast to tissue ratio (CTR) determined from an average of 160 acquisitions per pulse sequence type. The ratios are in units of decibel (dB).

Table 1 - contrast scores obtained for various imaging pulses used according to the experimental setup in figure 3 over 160 acquisitions per pulse sequence type.

It can be seen from the experiments carried out that only subharmonic imaging ringdown surf imaging and counter-propagating chirp imaging are free from distal vessel wall artefacts. The contrast score (CNR + CAR + CTR) for counter- propagating chirp imaging is the highest at 24 dB, indicating that using this type of pulse sequence may be considered to be the best candidate for imaging using the methods described.

Figure 7a shows a schematic example arrangement for seismic imaging. A rock sample 700 and transducer 702 are positioned as shown in figure 7a. A 19mm diameter active mono-element transducer 702 with a centre frequency of 0.5 MHz was positioned in contact with one end of a rock sample 700. The rock sample 700 was a room-dry Meule sandstone sample, 13cm in length and 25mm in diameter. The transducer 702 was used in pulse-echo mode to transmit a pulse sequence, and to receive the echoes backscattered from microstructures in the rock. Coupling gel was applied between the transducer 702 and the sample 700. The surface of the sample 700 was previously coated with nail varnish to prevent the coupling gel from entering the rock due to capillary action.

Figure 7b shows the pulse sequence used in the seismic imaging experiment as shown in figure 7a. Plot 710 shows a reference excitation signal 714 plotted against time 712. Plot 720 shows an imaging excitation signal 724 and a manipulation signal 726 plotted against time 722. The reference excitation signal 714 corresponds to the imaging excitation signal 724 (in this example, all three signals 714, 724, 726 are a six microsecond 0.5 MHz pulse). The reference excitation signal 714, and the imaging excitation signal 724 plus manipulation signal 726 complex, are separated by a 500 microsecond silence. That is, the reference excitation pulse 714 was transmitted first, then after 500 microseconds the imaging excitation signal 724 and manipulation signal 726 were transmitted with no overlap in time between them. The pulsing scheme (reference excitation signal 714, imaging excitation signal 724 and manipulation signal 726) was repeated four times. Measurements were performed at both ends of the sample 700 and averaged over 20 measurements. The maximum dynamic strain amplitude generated in the rock sample was approximately 10^"6.

Figures 7c-7d show experimental results from the seismic imaging experiment. Figure 7c shows results 730, 732, 734 measured against distance 736 from one end of the sample 700, and figure 7d shows results 760, 762, 764 measured against distance 766 from the other end of the sample 700.

Plots of received first echo signals 730, 760 from the four reference excitation signals against distance 736, 766 each show backscattered waves and an echo 738, 768 from the other end of the sample 700. These four plots show the excellent reproducibility of the response to the reference excitation signal.

Plots of subtraction echoes 732, 762 from the first and fourth reference excitation signals as a percentage of the maximum amplitude of the first echo signals (as shown in the plots 730, 760) against distance 736, 766 are shown. These plots 732, 762 show that the background noise level is close to 0.5% in plot 732 and close to 0.2% in plot 762. Plots of the counter-propagation interaction signal 734, 764 from the interaction of the counter-propagating imaging excitation signal and manipulation signal, as a percentage of the B-mode signal, against distance 736, 766 are given. These plots 734, 764 show the excellent reproducibility of the counter-propagation interaction signal. Because of the high attenuation of ultrasound signals in the rock sample, a maximum depth of 70mm was investigated. Plot 734 indicates a highly damaged region between 20mm and 30mm from the first end of the sample. Plot 764 shows a uniformly damaged region between 20mm and 60mm from the other end of the sample.

Significant interaction between counter-propagating waves (that is, echoes in response to the imaging excitation signal 724 being backscattered and the forward propagation manipulation signal 726) is expected if the elastic nonlinearity (and/or material nonlinear conditioning induced by the manipulation pulse) is important at the location where counter-propagating waves meet each other.

Elastic nonlinearity in the rock sample 700 is primarily due to damage, for example in the form of cracks and other features of the microstructure (inter-grain cement). Therefore scanning the magnitude of the interaction between counter-propagating waves allows the importance of damage or the presence of specific microstructure features to be imaged.

A signal quantifying the magnitude of the interaction can be constructed by calculating an output signal based on a difference between a synthetic signal based on the first echoes received in response to the reference excitation signal 714 (in the absence of counter-propagating wave interactions), and second echoes received in response to the transmission of the imaging excitation signal 724 and manipulation signal 726. The synthetic signal based on the first echo signals in response to the reference excitation signal in this example is obtained by summing the echoes received in response to the reference excitation signal with the same echoes delayed by six microseconds.

A pulse sequence with two frequencies as shown in figure 8 may be labelled a "bi- frequency pulse sequence". Such bi-frequency pulse sequences for detection of contrast agent are affected by nonlinear propagation artefacts when the two frequencies coexist in time. Subharmonic imaging is substantially free from nonlinear propagation artefacts. Thus it may be possible to improve the efficiency of subharmonic imaging by using bi-frequency pulse sequences such as those illustrated in figure 8.

Figure 8 shows a complex which may be regarded as a reference excitation signal 802 (labelled as a "First transmitted signal") which comprises a first portion 804 comprising a low frequency reference burst and a second portion 806 comprising a high frequency reference burst. The bursts 804, 806 are not overlapping in time. The low frequency reference burst 804 in this example is a 3.5 MHz sine wave burst. The high frequency reference burst 806 is an 8 MHz sine wave burst. The high frequency burst in the second portion 806 of the reference excitation signal 802 may be considered as a reference manipulation signal. This complex 802 generates the first echo signals, similar to previously described embodiments.

Figure 8 also shows a complex 812 (labelled as a "Second transmitted signal") comprising an imaging excitation signal 814 and a manipulation signal 816. The imaging excitation signal 814 comprises a phase inverted version of the first portion 804 of the reference excitation signal. The manipulation signal 816 comprises a phase inverted version of the second portion 806 of the reference excitation signal. The phase inverted bursts (imaging excitation signal 814 and manipulation signal 816) are not overlapping in time. This complex 812 generates the second echo signals, similar to previously described embodiments.

Thus two different frequency bursts 804, 806 are used in the reference excitation signal 802, and for the imaging excitation signal 814 plus manipulation signal 816 pulse sequence 812. The second complex 812 is essentially the same as the first complex 802 but in anti-phase.

The output signal is generated by adding the first and second echo signals (that is, by summing the first and second backscattered responses). Any difference between the first echo signals and second echo signals will become apparent by cancellation of the phase and phase-inverted versions of the two complexes when adding the first and second echo signals.

Figure 8 shows that, after summation, the first and second backscattered responses are cross-correlated with a waveform or matched filter as shown in plots 822 and 832, in order to extract the ultraharmonic and subharmonic signals respectively (nonlinear components), and recover a good spatial resolution. A low pass filter is not required to remove high frequency components from low frequency components/signals. Excitation at two frequencies, for example at 3.5 MHz and 8 MHz as shown, enhances the chance of producing ultraharmonic and subharmonic responses of a contrast agent containing a size distribution of microbubbles within the frequency bandwidth of an ultrasound transducer. In addition, the subharmonic response of a contrast agent may be further enhanced by the effect of counter- propagation interaction between the 8 MHz sine wave burst and the echoes backscattered in response to the 3.5 MHz sine wave burst. Thus generally, figure 8 illustrates transmitting a reference excitation signal which comprises a first portion comprising a relatively low frequency reference burst and a second portion comprising a relatively high frequency reference burst, the bursts not overlapping in time. First echo signals corresponding to the reference excitation signal are received. An imaging excitation signal is transmitted which comprises a phase inverted version of the first portion of the reference excitation signal. A manipulation signal is transmitted which comprises a phase inverted version of the second portion of the reference excitation signal. The phase inverted bursts (imaging excitation signal and manipulation signal) are not overlapping in time. Second echo signals are received which correspond to the imaging excitation signal and manipulation signal. The output signal is generated by adding the first and second received echo signals.

Experimental results are shown in figure 9 which were obtained using the pulse sequences of figure 8. The method was as follows; a focused single-element transducer transmitted and received ultrasound signals in a tissue mimicking material containing a 13 mm diameter cavity filled with diluted (1:2000) contrast agent (SonoVue, Bracco). Transmitted waveforms had a peak acoustic pressure of 200 kPa. Pulse inversion (by the use of two 1.25 ps 3.5 MHz waveforms in anti-phase; the first portion of the reference excitation signal and the imaging excitation signal) and subharmonic imaging (by the use of two 1.25 ps 8 MHz waveforms in anti-phase; the second portion of the reference excitation signal and the manipulation signal) as described in relation to figure 8 were performed.

The results of figure 9 shows B-mode line 902 and contrast-mode lines 904, 906, 908 acquired in the tissue mimicking material (denoted TMM in figure 9). Figure 9 shows that combined ultraharmonic and subharmonic (UH-SH) imaging 906 employing the pulse sequence described in figure 8 provides a higher contrast-to-tissue ratio (CTR) at 15 dB than pulse inversion (PI) imaging 904 alone (CTR of 12 dB) or subharmonic (SH) imaging 908 alone (CTR of 12 dB).

It will be appreciated that throughout the disclosure, the term "signal" may be used to describe a wave, and similarly the term "wave" may be used to describe a signal. Other embodiments are intentionally within the scope of the accompanying claims.

Claims

1. An ultrasound imaging method comprising:

transmitting a reference excitation signal into a target medium;

receiving first echo signals corresponding to the reference excitation signal; transmitting an imaging excitation signal into the target medium;

transmitting a manipulation signal into the target medium, the imaging excitation signal and the manipulation signal not overlapping in time;

2. The method of claim 1 , further including varying a time delay between the transmission of the manipulation signal and transmission of the imaging excitation signal, in order to vary a depth of interaction between the imaging excitation signal and the manipulation signal in the target medium.

3. The method of claim 1 , further comprising-.

transmitting a second imaging excitation signal into the target medium;

transmitting a second manipulation signal into the target medium, the second imaging excitation signal and the second manipulation signal not overlapping in time; receiving third echo signals corresponding to the second imaging excitation signal and the second manipulation signal and an interaction therebetween; and

generating a second output signal based on a difference between the first echo signals and third echo signals.

4. The method of claim 1, further including selecting a particular time delay between the transmission of the manipulation signal and transmission of the imaging excitation signal, in order to determine a particular depth of interaction between the imaging excitation signal and the manipulation signal in the target medium.

5. The method of claim 1 , in which the manipulation signal is transmitted after the imaging excitation signal is transmitted, or in which the imaging excitation signal is transmitted after the manipulation signal is transmitted.

6. The method of claim 1, in which the steps of transmitting the reference excitation signal and receiving first echo signals are performed after the steps of transmitting the imaging excitation signal, transmitting the manipulation signal and receiving the second echo signals, or in which the steps of transmitting the imaging excitation signal, transmitting the manipulation signal and receiving the second echo signals are performed after the steps of transmitting the reference excitation signal and receiving first echo signals.

7. The method of claim 1 , in which the imaging excitation signal and the manipulation signal are of different frequencies, and further comprising the step of: filtering the second echo signals to attenuate components of the manipulation signal prior to generating the output signal.

8. The method of claim 1 , in which the reference excitation signal and the imaging excitation signal are coded, and further comprising the step of:

cross-correlating the received first echo signals and second echo signals to select components of the first echo signals corresponding to the reference excitation signal and to select components of the second echo signals corresponding to the imaging excitation signals, to discriminate from components corresponding to the manipulation signal.

9. The method of claim 1 , in which the reference excitation signal and the imaging excitation signal comprise substantially identical waveforms.

10. The method of claim 1, further including the step of varying the relative amplitudes of the imaging excitation signal and the manipulation signal to optimise the echo signals received from a particular feature in the target medium.

11. The method of claim 1 , further comprising introduction of a microbubble contrast agent into the target medium.

12. The method of claim 1 , in which:

the reference excitation signal and/or the imaging excitation signal comprises one or more of a waveform, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal and an amplitude-modulated signal; and the manipulation signal comprises one or more of a waveform, a pulse, a burst, a periodic signal of one or more cycles, a coded signal, a frequency-modulated signal, an amplitude-modulated signal, or noise.

13. The method of claim 1 , in which the reference excitation signal and the imaging excitation signal comprise a pulse sequence, the pulse sequence comprising one or more of pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, sub-harmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging.

14. The method of claim 13, in which the manipulation signal comprises a pulse sequence, the pulse sequence comprising one or more of pulse amplitude modulation, pulse inversion, pulse inversion amplitude modulation, pulse subtraction time delay, radial modulation, sub-harmonic, chirp reversal, chirp amplitude modulation, chirp reversal amplitude modulation, and ringdown surf imaging.

15. The method of claim 1 , further including repeating the steps of transmitting and receiving signals at different angles of incidence around the target medium.

16. The method of claim 1 , including repeating the steps of transmitting and receiving signals at different depths of interaction between the imaging excitation signal and manipulation signal in the target medium.

17. The method of claim 1 wherein the imaging excitation signal and manipulation signal are transmitted into the target medium from opposite sides of the target medium.

18. The method of claim 1 , wherein:

the reference excitation signal comprises a first portion comprising a low frequency reference burst and a second portion comprising a high frequency reference burst, the bursts not overlapping in time;

the imaging excitation signal comprises a phase inverted version of the first portion of the reference excitation signal, and the manipulation signal comprises a phase inverted version of the second portion of the reference excitation signal, the phase inverted bursts not overlapping in time; and

the output signal is generated by adding the first and second echo signals.

19. An ultrasound imaging apparatus comprising;

at least one ultrasound transducer configured for transmitting and receiving ultrasonic signals;

a signal processor; and

a control system configured to cause the apparatus to:

perform the method of any one of claims 1 to 9, and claims 11 to 18.