WO2010103469A1

WO2010103469A1 - Sonolysis of blood clots using low power, coded excitation pulses

Info

Publication number: WO2010103469A1
Application number: PCT/IB2010/051031
Authority: WO
Inventors: Jeffry E. Powers; Vijay Shamdasani
Original assignee: Koninklijke Philips Electronics, N.V.
Priority date: 2009-03-12
Filing date: 2010-03-10
Publication date: 2010-09-16

Abstract

An ultrasonic diagnostic imaging system is used to effect sonolysis of blood clots using a microbubble contrast agent. The therapeutic energy which produces sonolysis is a low energy level which gently agitates or oscillates the microbubbles without breaking them, thereby prolonging the sonolysis effect. The low energy level may be a transmit voltage level not in excess of ten volts, or a transmit MI not in excess of 0.2. Preferably the transmitted waveform is a long frequency-modulated CHIRP waveform.

Description

SONOLYSIS OF BLOOD CLOTS USING LOW POWER, CODED EXCITATION PULSES

This invention relates to medical diagnostic ultrasound systems and, in particular, to ultrasound systems which can be optimized to dissolve blood clots and similar occlusions.

International patent application publication number WO 2008/017997 (Browning et al . ) describes an ultrasonic blood clot lysis system directed to breaking up transcranial blood clots which can cause stroke. In lysis applications it has been shown that ultrasound combined with microbubbles, with or without a thrombolytic drug such as tPa, can speed dissolution of blood clots in stroke, heart attacks, and other occlusive vascular diseases. Recent results indicate that there is an optimal acoustic pressure range which maximizes the therapeutic effect while minimizing unintended bioeffects. Bubbles that are subjected to an acoustic field undergo radial expansion and contraction in response to the acoustic pressure waves. At relatively low levels of acoustic energy, this vibration is stable and can continue for considerable time, which has been demonstrated to maximize clot dissolution. This phenomenon is referred to as stable cavitation. At higher acoustic pressures, the bubbles become unstable and break into smaller bubbles and dissolve into the surrounding fluid, referred to as inertial cavitation. At even higher acoustic pressures the expansion of the bubbles can rupture very small capillaries containing the rupturing bubbles. The physiological mechanisms causing the enhanced therapeutic effect at the lower energy level are not fully understood. One commentator has speculated that the oscillation of the bubbles promotes local microstreaming of a surrounding pharmaceutical compound, increasing the penetration of the compound into an adjacent clot matrix. See "Mechanism Responsible for Ultrasound- accelerated Fibrinolysis in the Presence and Absence of Optison™, " by A. F. Prokop et al . , presented at the 2006 IEEE International Ultrasonics Symposium (October 2006) and "Correlation of Cavitation With Ultrasound Enhancement of Thrombolysis," by S. Datta, et al., UIt. in Med. & Biol., vol. 32, no. 8, p 1257- 1267 (2006) .

The blood clot lysis system shown in the Browning et al . application can be operated at acoustic output levels which are approved for diagnostic imaging. In the past, it has been believed that clot lysis is most effective when the transmitted energy is at or near the limits for diagnostic ultrasound, an MI (mechanical index) of 1.9, which delivers maximal energy to the microbubbles and was believed to produce the greatest agitation or disruption of the microbubbles. Such high power transmission is conventionally used in "flash" contrast imaging, when the high transmit energy breaks or collapses the microbubbles in the path of the ultrasound and this breakage is observed as a "flash" of the image and/or used as a prelude to evaluating the return (re-perfusion) of microbubbles into the region where the microbubbles were depleted by the flash transmission. See US Pat. 5,456,257 (Johnson et al . ) ; US Pat. 6,716,412 (Unger) ; US Pat. 6,340,348 (Krishnan et al . ) ; and EP specification 0 770 352 (Powers et al . ) However the present inventors have determined that more effective blood clot lysis can be achieved, not by strongly disrupting or breaking the microbubbles adjacent to the blood clot, but by agitating these adjacent microbubbles gently without breaking them, and thus prolong the agitation effect. Thus it is an object of the present invention to provide ultrasonic blood clot lysis at lower energy levels than those which are conventionally used or believed to be necessary. It is a further object to agitate the microbubbles for blood clot lysis with long coded pulses such as frequency modulated (CHIRP) therapy pulses. It is a further object to monitor microbubble agitation for blood clot lysis so that the desirable effect may be controlled and prolonged during therapy.

In accordance with the principles of the present invention, a diagnostic ultrasound system and method are described which promote ultrasonic blood clot lysis by gently agitating microbubbles adjacent to a blood clot in a blood vessel. Low transmit energy is used so that the microbubbles are gently jiggled or oscillated or vibrated with reduced microbubble destruction. Preferably the voltage of the transmitted ultrasound pulses is ten volts or less and/or the in situ MI of the transmit pulses is at or below an MI of 0.1. The pulses transmitted for microbubble oscillation are preferably coded pulses such as frequency modulated (CHIRP) pulses. The coded pulses can be transmitted as discrete pulses or as a continuous wave (CW) modulated signal. Apparatus and methods are described for monitoring the effects of the microbubble agitation through reception of subharmonic, ultraharmonic or Doppler (motion detection) signals, which enable the microbubble agitation to be controlled either manually or automatically. In the drawings: FIGURE 1 illustrates in block diagram form an ultrasonic diagnostic imaging system constructed in accordance with the principles of the present invention .

FIGURE 2 illustrates three dimensional ultrasonic transcranial diagnosis in accordance with the present invention.

FIGURE 3 illustrates two dimensional ultrasonic transcranial diagnosis in accordance with the present invention . FIGURE 4 illustrates the transmission of low energy CHIRP pulses to produce sonolysis of a transcranial blood clot.

FIGURES 5a-5d illustrate various CHIRP pulses which may be used in a constructed embodiment of the present invention.

FIGURE 6 illustrates a method for manual control of sonolysis in accordance with the present invention .

FIGURE 7 illustrates a first automatic method for feedback control of sonolysis.

FIGURE 8 illustrates in block diagram form the monitoring portion of a sonolysis ultrasound system constructed in accordance with the principles of the present invention. FIGURES 9a-9c illustrate received ultrasound signals and passbands which may be employed in an implementation of the system of FIGURE 8.

FIGURE 10 illustrates a second automatic method for feedback control of sonolysis. FIGURE 11 is an example of a display produced by an ultrasound system or method in accordance with the principles of the present invention.

Referring first to FIGURE 1, an ultrasound system constructed in accordance with the principles of the present invention is shown in block diagram form. The example of FIGURE 1 is a system for diagnosing and treating cranial blood clots which may cause stroke. The present invention may be employed to treat occlusions in other parts of the body such as myocardial, peripheral vascular, and renal occlusions. In FIGURE 1 two transducer arrays 10a and 10b are provided for transmitting ultrasonic waves and receiving echo information. In this example the arrays shown are two dimensional arrays of transducer elements capable of scanning in three dimensions for 3D imaging and treatment, although an implementation of the present invention may also use one dimensional arrays of transducer element which produce 2D (planar) images and treatment beams. The transducer arrays are coupled to microbeamformers 12a and 12b which control the transmission and reception of ultrasound signals by the array elements. Microbeamformers are also capable of at least partial beamforming of the signals received by groups or "patches" of transducer elements as described in US Pats. 5,997,479 (Savord et al . ) , 6,013,032 (Savord), and 6,623,432 (Powers et al . ) Signals are routed to and from the microbeamformers by a multiplexer 14 by time-interleaving signals. The multiplexer is coupled to a transmit/receive (T/R) switch 16 which switches between transmission and reception and protects the main beamformer 20 from high energy transmit signals. The transmission of ultrasonic beams from the transducer arrays 10a and 10b under control of the microbeamformers 12a and 12b is directed by the transmit controller 18 coupled to the T/R switch, which receives input from the user's operation of the user interface or control panel 38. By varying system setting from the control panel the user can control transmit parameters such as transmit voltage, MI, frequency modulation, pulse length, PRF (pulse repetition frequency), and the like.

The partially beamformed signals produced by the microbeamformers 12a, 12b are coupled to a main beamformer 20 where partially beamformed signals from the individual patches of elements are combined into a fully beamformed signal. For example, the main beamformer 20 may have 128 channels, each of which receives a partially beamformed signal from a patch of 12 transducer elements. In this way the signals received by over 1500 transducer elements of a two dimensional array transducer can contribute efficiently to a single beamformed signal.

The beamformed signals are coupled to a fundamental/harmonic signal separator 22. The separator 22 acts to separate linear and nonlinear signals so as to enable the identification of the strongly nonlinear echo signals returned from microbubbles . The separator 22 may operate in a variety of ways such as by bandpass filtering the received signals in fundamental frequency and harmonic frequency bands, or by a process known as pulse inversion harmonic separation. A suitable fundamental/harmonic signal separator is shown and described in international patent publication WO

2005/074805 (Bruce et al . ) The separated signals are coupled to a signal processor 24 where they may undergo additional enhancement such as speckle removal, signal compounding, and noise elimination. The processed signals are coupled to a B mode processor 26 and a Doppler processor 28. The B mode processor 26 employs amplitude detection for the imaging of structures in the body such as muscle, tissue, and blood cells. B mode images of structure of the body may be formed in either the harmonic mode or the fundamental mode or a combination of both as described in US Pat. 6,283,919 (Roundhill et al.) and US Pat. 6,458,083 (Jago et al . ) Tissues in the body and microbubbles both return both types of signals and the stronger harmonic returns of microbubbles enable microbubbles to be clearly segmented in an image in most applications. The Doppler processor processes temporally distinct signals from tissue and blood flow for the detection of motion of substances in the image field including microbubbles. The structural and motion signals produced by these processors are coupled to a scan converter 32 and a volume renderer 34, which produce image data of tissue structure, flow, or a combined image of both characteristics. The scan converter will convert echo signals with polar coordinates into image signals of the desired image format such as a sector image in Cartesian coordinates. The volume renderer 34 will convert a 3D data set into a projected 3D image as viewed from a given reference point as described in US Pat. 6,530,885 (Entrekin et al . ) As described therein, when the reference point of the rendering is changed the 3D image can appear to rotate in what is known as a kinetic parallax display. This image manipulation is controlled by the user as indicated by the Display Control line between the user interface 38 and the volume renderer 34. Also described is the representation of a 3D volume by planar images of different image planes, a technique known as multiplanar reformatting. The volume renderer 34 can operate on image data in either rectilinear or polar coordinates as described in US Pat. 6,723,050 (Dow et al . ) The 2D or 3D images are coupled from the scan converter and volume renderer to an image processor 30 for further enhancement, buffering and temporary storage for display on an image display 40.

A graphics processor 36 is also coupled to the image processor 30 which generates graphic overlays for displaying with the ultrasound images. These graphic overlays can contain standard identifying information such as patient name, date and time of the image, imaging parameters, and the like, and can also produce a graphic overlay of a spatial indication of cavitation as described below. For these purposes the graphics processor receives input from the user interface 38. The user interface is also coupled to the transmit controller 18 to control the generation of ultrasound signals from the transducer arrays 10a and 10b and hence the images produced by and therapy applied by the transducer arrays. The transmit parameters controlled in response to user adjustment include those mentioned above, as well as the steering of the transmitted beams for image positioning and/or positioning

(steering) of a therapy beam as discussed below. As explained in greater detail below, the transmit voltage or MI is controlled during therapy to prolong the gentle jiggling or vibration of the microbubbles without causing their destruction, which would result in a cessation of the desired therapeutic effect.

The transducer arrays 10a and 10b transmit ultrasonic waves into the cranium of a patient from opposite sides of the head, although other locations may also or alternately be employed such as the front of the head or the sub-occipital acoustic window at the back of the skull. The sides of the head of most patients advantageously provide suitable acoustic windows for transcranial ultrasound through the skull at the temporal bones around and above the ears on either side of the head. In order to transmit and receive echoes through these acoustic windows the transducer arrays must be in good acoustic contact at these locations, which may be done by holding the transducer arrays against the head with a headset . One acceptable way to do this is with a headset as described in the aforementioned publication number WO 2008/017997 (Browning et al . ) , the contents of which is incorporated herein by reference. With the transducer arrays in good acoustic contact with the temple regions of the skull 100, 3D acoustic fields 102 and 104 can be scanned and imaged as shown in FIGURE 2. In the depiction of FIGURE 2, each image field 102, 104 is seen to extend almost halfway across the cranium, which is a balance between the size of the image field and the acoustic penetration and attenuation which may be expected through the bone at the temporal acoustic window. For some patients, low attenuation effects may enable an image field to extend fully across the cranium, allowing the clinician to examine the vascular structure near the skull bone on the opposite side of the cranium. By alternately examining image fields of both transducer arrays, the vasculature across the full cranium may be effectively examined. It is possible to acquire extended image fields which cover the same central region of the cranium but image from opposite sides of the head. These images can be correlated and compounded together, forming a fused image that may reveal additional characteristics of the brain. If examination finds a blood vessel occluded by a blood clot, a therapeutic beam 110 or 112 is transmitted and steered at the clot to break it up (sonolysis) either with the ultrasonic energy alone, but preferably in combination with microbubbles introduced into the bloodstream. The infusion of microbubbles may also be accompanied by application of a thrombolytic drug such as tissue plasminogen activator (tPA) . The therapeutic beam 110,112 can also be transmitted from both sides of the head, enabling breakup of a clot from both sides of the clot. Rather than be limited to reflective ultrasound imaging, through-transmission imaging can be performed by transmitting ultrasound from one transducer array and receiving the remaining unabsorbed ultrasonic energy at the other transducer array, which may reveal yet other characteristics of the brain tissue.

FIGURE 3 illustrates a two dimensional imaging example of the present invention. In this example the transducer array 122 is a one dimensional array or portion of a 2D array which performs 2D imaging. The array may be configured as a circular phased array transducer as described in US Pat. 5,226,422. This transducer array, like the other arrays described herein, is covered with a lens 124 which electrically insulates the patient from the transducer array and in the case of a one dimensional array may also provide focusing in the elevation (orthogonal to the plane) dimension. The transducer array 122 is backed with acoustic damping material 126 which attenuates acoustic waves emanating from the back of the array to prevent their reflection back into the transducer elements. Behind this transducer stack is a device 130 for rotating the image plane 140 of the array. The device 130 may be a simple knob or tab which may be grasped by the clinician to manually rotate the circular array transducer in its rotatable transducer mount (not shown) . The device 130 may also be a motor which is energized through a conductor 132 to mechanically rotate the transducer as discussed in US Pat. 5,181,514 (Solomon et al . ) Rotating the one dimensional array transducer 122 as indicated by arrow 144 will cause its image plane 140 to pivot around its central axis, enabling the repositioning of the image plane for full examination of the vasculature in front of and in the imaging plane of the transducer array. As discussed in the '514 patent, the planes acquired during at least a 180° rotation of the array will occupy a conical volume in front of the transducer array, which may be rendered into a 3D image of that volumetric region. Other planes outside this volumetric region may be imaged by repositioning, rocking or tilting the transducer array in its headset in relation to the skull 100. If a stenosis is found in the image of the plane being imaged, the therapeutic beam vector graphic 142 can be steered by the clinician to aim the therapeutic beam at the stenosis and therapeutic pulses applied to disrupt the microbubbles at the site of the stenosis.

In accordance with the principles of the present invention, low energy transmission is used during sonolysis to prolong the therapeutic effect by vibrating or oscillating or jiggling the microbubbles without causing extensive destruction of the microbubbles. A standard cart-mounted ultrasound system with conventional piezoelectric ceramic transducers may drive the transducer elements with voltages up to 200 volts and still be within the regulatory limits of diagnostic ultrasound. In a constructed embodiment of the present invention the transducer elements are driven with much lower transmit voltages, preferably less than ten volts. Typical low voltage ranges may be 3-4 volts or 5-6 volts, for instance. Another parameter which may be controlled to maintain low energy transmission is the mechanical index (MI) of the transmit waveforms. The mechanical index is a measure of the peak negative pressure of a transmit waveform divided by the square root of the frequency of the waveform. The MI provides an indicator which is a measure of the cavitational effects of the transmitted ultrasound. The maximum limit of the MI for diagnostic ultrasound in the United States is an MI = 1.9. For low energy transmission in accordance with the present invention a much lower MI of 0.1 or lower is used. Preferably this is the MI of the pulse waveform in situ, that is, at the microbubbles where the ultrasound energy is being delivered. In a transcranial application as described above, the transmitted waveform will experience a substantial amount of attenuation as it travels through the skull. Thus, to deliver an MI of 0.1 in situ, it may be necessary to use a transmit MI of 0.18 - 0.2. , based on normal derating assumptions. It should be noted that the above parameters are effective for the microbubble contrast agents currently available. In the future, new microbubble agents may be developed with different characteristics which permit variation from these ranges of parameters. For instance if a microbubble agent with a stiffer, more robust microbubble shells are developed, such microbubbles would be able to withstand excitation with higher energy levels of ultrasound without breaking or severe disruption of the microbubbles. The desired gentle agitation could be performed at higher energy levels than those given above . In accordance with a further aspect of the present invention, the low energy therapeutic transmit pulses are transmitted as long pulses which jiggle or vibrate the microbubbles with a relatively long interval of low energy. When ultrasound imaging is performed at or near a high MI setting such as MI = 1.9, the transmit pulses are generally very short, only a cycle or two. This provides a broad signal bandwidth but is also mandated by the other regulatory limit, the thermal limit. Only a few cycles of a transmit pulse at high MI are required before unacceptable heating of the probe occurs and the SPTA limit is exceeded. However, with a low energy pulse such as three to ten volts or an MI of 0.1 to 0.2, the transmit level is too low to cause rapid heating and hence the transmit waveform can be extended over many cycles. Thus, a sonolysis therapeutic pulse of the present invention may be dozens or hundreds of cycles long. Preferably the transmit pulse frequency is in the range of 500 kiloHertz to 2 MHz. The pulse length can range from 5-10 microseconds to very long pulses for near continuous operation.

In accordance with yet another aspect of the present invention the transmitted therapeutic pulse is frequency modulated. A preferred frequency modulated pulse is a CHIRP pulse, which starts at a low frequency and is modulated up to a higher frequency during successive cycles of the transmit waveform, or vice versa. There are two advantages of the use of a frequency modulated pulse. One is that microbubbles of different sizes are resonant at different frequencies and thus are more responsive to select transmit frequencies. Transmitting a frequency modulated pulse causes microbubbles of a greater variation in sizes to be energized into vibration or oscillation. The second advantage of a frequency modulated pulse such as a CHIRP pulse is greater resolution when imaging is performed during the therapy. The correlation of a CHIRP waveform and its resulting echo signal closely approximates an impulse response, which provides a sharp delineation of the round-trip travel time of the pulse and thus good axial resolution during ultrasound imaging. This correlation can be performed by a matched filter and, as discussed below, by the quadrature bandpass filter (QBP) which can be used for ultrasound signal demodulation as described in US Pat. 6,050,942 (Rust et al . ) The combination of these two benefits leads to the choice of a CHIRP waveform for a low energy sonolysis therapeutic pulse as shown in the 2D example of FIGURE 4. In this example a CHIRP pulse 312 is directed toward the microbubbles 204 which are adjacent to a blood clot 202 in a cranial blood vessel 200. The low energy delivered by the long CHIRP pulse 312 causes the microbubbles 204 to gently vibrate without substantial breakage, thereby delivering a prolonged therapeutic effect to break up the blood clot 2002.

FIGURE 5 illustrates several modulation techniques which can be used to produce a therapeutic CHIRP pulse for sonolysis. FIGURE 5a illustrates a linear CHIRP pulse 312 in which the frequency of the waveform is incremented linearly from a low frequency to a high frequency as indicated by line 314 in FIGURE 5b. Another way to modulate the CHIRP pulse is quadratically as shown by the quadratic CHIRP pulse 322 in FIGURE 5c. This CHIRP pulse is produced by modulating the waveform frequency non-linearly as shown by the curve 324 in FIGURE 5d. As previously mentioned the frequency modulation of the CHIRP therapeutic pulse can be from a low frequency to a high frequency or from a high frequency to a low frequency. Multiple long CHIRP pulses can be repeated, with one CHIRP pulse being produced immediately following another, thereby creating an even longer CHIRP pulse. The frequency modulation can be the same for each successive CHIRP pulse, or can be alternated or varied from pulse to pulse in the long multiple-pulse sequence. CHIRP waveforms can be transmitted one after the other for (nearly) continuous therapeutic operation.

FIGURE 6 illustrates a method for delivering sonolysis therapy in accordance with the present invention. A transducer 122, 10a, or 10b is coupled to the body of the patient and the region of the body which may contain a blood clot is imaged to locate a clot 202, such as by detection of a blockage of blood flow in a vessel 200 with Doppler ultrasound. Microbubbles 204 are infused into the patient's blood stream at step 602 and flow to the site of the obstruction. The ultrasound energy is then increased in step 604 until it is observed or detected that the microbubbles are being disrupted. When significant disruption has been observed or detected, the user dials back the energy control of the ultrasound system to a low energy level at step 606, which stabilizes the microbubbles in a state in which they are being gently agitated at the site of the blockage. Depending upon it size, the blood clot should be broken up in a few minutes by ultrasonic blood clot lysis.

FIGURE 7 illustrates an automated method for performing blood clot lysis in accordance with the present invention. The blood clot 202 is detected in the ultrasound imaging field 102, 104, or 140 and microbubbles 204 are infused into the blood stream of the patient and flow to the site of the blockage in step 702. The microbubbles are insonified with ultrasound energy and the ultraharmonic and/or subharmonic content of the echo signals is measured at step 708. An indication of ultraharmonic or subharmonic content is indicative of stable cavitation, whereas a return of broadband noise is indicative of inertial cavitation, in which the microbubbles are being excessively agitated and severely disrupted. If inertial cavitation is detected, the energy level of the therapeutic ultrasound is reduced to a lower level at step 710 to stabilize the microbubbles in a state of stable cavitation. Thus, feedback of the measurement of the ultraharmonic or subharmonic content is used to maintain a steady jiggling or oscillation of the microbubbles 204 for blood clot lysis.

The portion of the ultrasound system which detects the type of cavitation and alerts the user accordingly or automatically controls the energy level of the therapeutic ultrasound is illustrated in block diagram form in FIGURE 8. An ultrasound probe 60 has a transducer array 10 coupled by T/R switch 16 to a transmit beamformer 20a which controls the transmission of therapeutic beams by the transducer array 10 and to a receive beamformer 20b which beamforms echo signals received from the transducer array elements 10. The beamformed echo signals are processed by a quadrature bandpass (QBP) filter 62. QBP filters are commonly used in ultrasound systems to filter received echo signals, produce I and Q quadrature signal components for Doppler and coherent image processing and provide sampling decimation. The QBP filter can also perform correlation of transmitted and received CHIRP waveforms to detect CHIRP echoes and image the microbubbles and surrounding tissue. QBP filters are generally described in US Pat. 6,050,942 (Rust et al . ) , for example. In this implementation the QBP filter also filters the echo signals into two passbands, an SC band and an IC band such as those shown in FIGURE 9. The signal content of the SC and IC bands is then analyzed by a cavitation comparator 70 which may analyze the SC signal content alone for its energy content or in comparison with a threshold level, or may analyze the SC signal content in comparison with the IC signal content. The result of the analysis will indicate the presence of stable cavitation, inertial cavitation, or both or neither.

The result of the cavitation analysis is used in an automated implementation to control the transmit energy level of the transducer array 10. This is done in this example by coupling a cavitation control signal from the cavitation comparator 70 to the power control input of the transmit beamformer 20a. When it is desired to produce stable cavitation of microbubbles the cavitation control signal will vary the transmit power until a maximum response is detected in the SC passband, at which point that transmit power level is maintained to maintain stable cavitation. Alternatively or additionally, the response of the SC passband can be compared with that of the IC passband and the transmit power level controlled to obtain the desired SC to IC band ratio. In a manual implementation the user will control the transmit power from the transmit power control of the user interface 38 as shown in step 606 of FIGURE 6. As the user increases power from a low power setting with microbubbles present, stable cavitation will begin to occur, producing subharmonic energy in the SC passband which is detected by the cavitation comparator, either alone or in combination with higher frequency energy of the IC passband. When stable cavitation is identified by the cavitation comparator 70 a control signal is coupled to a user alert 72 which issues an audible or visual alert to the user. The audible alert can comprise a tone of a given frequency or amplitude from a speaker 42 when stable cavitation is detected, and can change to or be mixed with a tone of a different frequency or sound when inertial cavitation is detected. The user will then adjust the power level until the stable cavitation tone is continuously heard without interruption by the inertial cavitation tone.

Alternatively or in addition, a visual indication 44 can be presented, such as a green light when stable cavitation is detected and changing to a red light when inertial cavitation is present. The user will adjust the power for a solid green light in that example .

FIGURES 9a-9c illustrate the signal processing of the subharmonic and ultraharmonic echo content. FIGURE 9a illustrates a range of frequencies for a transmit pulse or wave and its echo components. In a typical implementation the therapeutic transmit pulse f_tr is a long CHIRP pulse (long sample volume) directed at a blood clot. When a transmit pulse f_tr is reflected by a microbubble the reflected echo will have significant harmonic content due to the nonlinear behavior of the microbubble in the acoustic field. The second harmonic component 2f_tr and the third harmonic, 3f_tr? are also illustrated in FIGURE 9a. The transmitted wave will also be distorted by its passage through tissue which will also generate nonlinear echo returns, but generally at lower levels than the harmonic echo returns from microbubbles . The tissue harmonic components are most prevalent at the integer harmonic frequencies 2f_tr and 3f_tr, with successively higher harmonics being of decreasing amplitude .

At different transmit power (MI, voltage) levels microbubbles will exhibit different behavior. The microbubbles in the body will exhibit radial expansion and contraction in response to the transmitted acoustic pressure waves. At relatively low levels of acoustic energy, this oscillation is stable and can continue for a considerable amount of time. This continual agitation by the oscillating bubbles (stable cavitation) may be a phenomenon that contributes to the effectiveness of the microbubbles in breaking up a clot. Stable cavitation is maintained by maintaining the energy of the acoustic pressure waves at an intensity which produces this effect. At higher acoustic pressures, the microbubbles become unstable and break into smaller bubbles and dissolve into the surrounding blood, and at even higher acoustic pressures even within diagnostic power limits the bubbles can rupture violently and disappear. This removal of the bubbles may be a factor contributing to the relative ineffectiveness of these inertial cavitation pressure levels in promoting clot dissolution. Thus it is desirable to maintain the transmit acoustic energy at a level which sustains stable cavitation without the onset of significant inertial cavitation.

Microbubbles which are in stable cavitation will return echo signals with significant subharmonic content below the fundamental transmit frequency f_tr • For instance, echoes from stable cavitation can be expected to return echo signals with frequencies at a frequency of 0.5f_tr as indicated in FIGURE 9a. The frequency content of echoes can be analyzed to determine whether there is significant frequency content about this subharmonic frequency. A bandpass filter of the QBP with a center frequency of 0.5f_tr will perform this function as indicated in FIGURE 9b, in which a passband centered at this frequency will pass signal energy about this frequency. The energy content of this SC passband can be examined for significant subharmonic energy content and used as an indication of stable cavitation. The transmit power of the acoustic energy is then adjusted or maintained to maximize the energy content of the SC passband, thereby establishing and maintaining stable cavitation. The analysis of the SC passband can be performed with respect to a predetermined threshold or by adjusting the transmit energy until a maximum response in the SC passband is produced. The SC passband energy can also be compared with the energy of a frequency spectrum characteristic of inertial cavitation. For instance, since a signature of inertial cavitation is broadband frequency content above the fundamental frequency f_tr, a passband can be established at these higher frequencies such as the IC passband illustrated in FIGURE 9b at 1.5f_tr- This ultraharmonic frequency is used to reduce contributions from tissue harmonic echo returns, which exhibit significant frequency content at integer harmonic frequencies such as the second harmonic 2f_tr- One technique of using both frequencies is to adjust the transmit power until a maximum ratio of the SC band energy to the IC energy is obtained. Another approach is to increase transmit power to a level just below the occurrence of significant or detectable energy in the IC band. Thus, stable cavitation is maintained without the onset of undesired inertial cavitation. This is of considerable benefit in transcranial applications because the skull is highly attenuative and varies from person to person. It is very difficult to predict in advance the transmit power level needed to maintain stable cavitation in the head of a particular patient. The present invention solves this problem by detecting and identifying the type of cavitation, then allowing the user to automatically or manually control the cavitation mode.

Yet another approach is to use a wider passband in order to be more sensitive to energy at subharmonic and ultraharmonic frequencies as shown in FIGURE 9c. In this example the SC passband 202 rolls off below 0.5f_tr at the low end and just before the fundamental frequency f_tr • For inertial cavitation detection a broader passband is used to take advantage of the wide frequency content returned from inertial cavitation events. In this example the first sub-band 204a of the IC band has a lower cutoff above the fundamental frequency f_tr and below 1.5f_tr- The passband is notched out at the second harmonic 2f_tr and continues with a second sub-band 204b above the second harmonic frequency and below the third harmonic frequency 3f_tr- Additional sub-bands such as 204c can also be used. This IC passband captures the ultraharmonic energy of inertial cavitation events with reduced response to tissue harmonic energy at the integer harmonic frequencies.

A further approach is to use a narrower passband in the subharmonic range and a broader passband in the ultraharmonic range. For example a narrow passband such as the SC passband of FIGURE 9b can be used for stable cavitation detection, and a broader passband such as passband 204a of FIGURE 9c can be used for inertial cavitation detection.

FIGURE 10 illustrates a Doppler-like technique in which the microbubbles are maintained in a gently agitated state without excessive disruption. Similar to Doppler processing, this technique analyzes ensembles of temporally discrete echo signals returned from specific locations in the image field. The ensembles may be acquired over a range of PRFs such as 5kHz to 1OkHz. As before, a blood clot is imaged with the ultrasound probe 60 and microbubbles 204 are infused into the patient's blood stream in step 1002. Echo ensembles are then acquired around the location of the blood clot. The echoes of an ensemble from a given location are compared pulse-to- pulse in step 1004 (e.g., consecutive echoes) and subtracted to eliminate echo returns from stationary materials. The resulting difference values thus represent the effects of motion at the ensemble location. Successive difference values are then compared in step 1006 to ascertain their consistency from measurement to measurement. When the microbubbles are being gently vibrated or oscillated to cause the desired sonolysis, there will be microbubble motion which will manifest itself as nonzero values resulting from the step 1004 comparison. When this desired motion continues the measurements from pulse-to-pulse in step 1006 will be relatively constant and stable. But if excessive energy is being applied and the microbubbles are being strongly disrupted or bursting, the difference values will vary as microbubbles are broken up into smaller microbubbles or are dissolved or disappear entirely. An uneven series of measured difference values is thus an indication of excessive ultrasound energy and the transmitted therapeutic energy is adjusted to stabilize the microbubbles in their desired gently agitated state in 1008. As before, the operating state can be alerted to the user for manual user intervention or can be automatically adjusted and maintained by the ultrasound system.

FIGURE 11 illustrates the ultrasound system display screen 300 of an ultrasound system constructed in accordance with the present invention. The display 300 in this example is displaying an ultrasound image 302 which includes tissue and vasculature. The vasculature includes a major blood vessel 80, off of which is branching a smaller vessel 82 which branches into smaller capillaries 84 and 86. The blood vessels will appear black in grayscale due to the low level echo returns from the blood, but can be shown in color in Doppler mode with the color indicating the motion of the blood. As the probe 60 scans the region of the body producing the image, the B mode signals from the vessels will change from black (low level) to bright (high level) when the blood flow begins to contain appreciable amounts of microbubbles. The arrival of microbubbles in the blood flow can be detected adaptively from this change or the system can be baselined manually by placing a sample volume over a vessel without microbubbles and measuring the signal content, then placing the sample volume over a vessel when microbubbles are present to measure the signal content from the microbubbles. Either the adaptive or manual technique can be used, in conjunction with the flow (Doppler) information if desired, to detect signals coming from microbubbles. When a microbubble has been detected at a spatial location in the image, the "bubble detect" signal triggers the graphics processor 36 in FIGURE 8 to place a color in a color overlay of the image 302 which indicates the type of cavitation at each bubble location. The color is determined by a cavitation signal coupled to the graphics processor from the cavitation comparator 70. For instance, if the SC signal or SC/IC ratio indicates the presence of stable cavitation at a location where a bubble is detected, a green color is added to the overlay at that bubble location, as indicated by the single hatching 90 in FIGURE 11. But when inertial cavitation is detected by the cavitation comparator, a different color is added to the overlay such as a red color at that bubble location. The red color is indicated by cross- hatching 92 in FIGURE 11. When no cavitation is detected as will occur in signals returned from tissue or blood without microbubbles, no overlay color is added and the ultrasound image will appear conventional at those locations. The cavitation color overlay is combined with the ultrasound image by the ultrasound image processor 30.

In the example of FIGURE 11 it is seen that stable cavitation (single hatching 90) is occurring in the lateral extremes of the major vessel 80 and into the smaller vessel 82, but that inertial cavitation (cross-hatching 92) is occurring in the center of the major vessel 80. A user trying to maintain stable cavitation will then turn down the transmit power until the red color 92 is replaced with the green color 90, indicating the presence of only stable cavitation in the vasculature. This would be an optimal operating condition to dissolve a blood clot located at the junction of the major vessel 80 and the smaller vessel 82, for instance, as microbubbles at that junction would then be gently agitated at the site to prolong the sonolysis effect.

FIGURE 11 also shows a display indicator 304 which displays the type of cavitation detected. The pointer 306 of the display indicator can point at zero, SC, or IC or between these indications. The instantaneous setting of the pointer 306 is determined by a signal from the cavitation comparator to indicate the predominant type of cavitation detected. If no cavitation is detected in the image the pointer will point to zero. As stable cavitation begins to manifest itself the pointer will move to the SC indication, and if the power is turned too high and inertial cavitation begins, the pointer will move to the IC indication. The pointer can indicate an average or overall cavitation content of the vasculature by summing or integrating the cavitation signals over the points in the image where microbubbles have been detected. Alternatively, the user can place a sample volume at the site of the blood clot and the indicator 304 will report on the type of cavitation at the therapy site. The user adjusts the transmit power level to keep the pointer 306 pointing continually at the SC indication.

Claims

WHAT IS CLAIMED IS:

1. An ultrasonic diagnostic imaging system which produces microbubble sonolysis comprising: a transducer array which operates to transmit and receive echo signals from a region of a subject which contains microbubbles; a transmitter coupled to the transducer array with a power control input which acts to control the acoustic energy level transmitted by the transducer array; and a transmit energy controller, coupled to the power control input, which causes the transmitter to transmit a low energy level below the maximum allowable energy level for diagnostic imaging to agitate microbubbles in a stable state during sonolysis .

2. The ultrasonic diagnostic imaging system of Claim 1, wherein the low energy level is not in excess of an in situ MI of 0.1.

3. The ultrasonic diagnostic imaging system of Claim 1, wherein the low energy level is not in excess of a transmitted MI of 0.2.

4. The ultrasonic diagnostic imaging system of Claim 1, wherein the low energy level is not in excess of a transmit waveform voltage level of ten volts.

5. The ultrasonic diagnostic imaging system of Claim 4, wherein the transmit waveform voltage level is in the range of three to six volts.

6. The ultrasonic diagnostic imaging system of Claim 1, wherein the transmitter is further operable to transmit a sonolysis therapy pulse as a frequency- modulated waveform.

7. The ultrasonic diagnostic imaging system of Claim 1, wherein the transmit energy controller further comprises a manual user control which adjusts the MI and/or the voltage level of a sonolysis transmit waveform.

8. The ultrasonic diagnostic imaging system of Claim 6, wherein the frequency-modulated waveform is a low energy CHIRP waveform.

9. The ultrasonic diagnostic imaging system of Claim 8, wherein the CHIRP waveform further comprises a sequence of CHIRP waveforms.

10. A method of performing sonolysis comprising: locating a blood clot in an ultrasound image field; supplying microbubbles to the site of the blood clot; directing a sonolysis waveform to the microbubbles at the site of the blood clot; increasing the energy of the sonolysis waveform until the microbubbles are strongly agitated or disrupted; and decreasing the energy of the sonolysis waveform until the microbubbles are gently agitated without significant microbubble rupturing.

11. The method of Claim 10, wherein increasing and decreasing are performed by adjustment of a manual transmit energy control.

12. The method of Claim 10, further comprising: receiving echo signals from the microbubbles in response to a sonolysis waveform; and analyzing the echo signals to determine whether the microbubbles are being strongly agitated or disrupted, or gently agitated by the sonolysis waveform.

13. The method of Claim 12, wherein analyzing further comprises analyzing at least one of the ultraharmonic and subharmonic content of the echo signals.

14. The method of Claim 12, wherein receiving further comprises receiving an ensemble of temporally discrete echo signals from a given location in the image field; and wherein analyzing further comprises measuring pulse-to-pulse differences of echo signals of the ensemble .

15. The method of Claim 12, wherein decreasing further comprises automatically decreasing the energy of the sonolysis waveform in response to a result of the step of analyzing that the microbubbles are being strongly agitated or disrupted.