System and method for registering images obtained using different imaging modalities

Abstract

Different imaging modalities are registered to a common coordinate reference frame or to one another by utilizing transient or clinically harmless tissue disruption caused at known anatomical locations. These are visualized by two imaging systems, thereby achieving their registration.

Description

Technical Field

[0001] The present disclosure relates to imaging, and more particularly to systems and methods for registering images acquired using various imaging modalities and / or verifying image registration. Background Art

[0002] Medical imaging of internal organs provides important anatomical and diagnostic information that medical personnel can use to make treatment decisions. Medical images can be acquired using a variety of non-invasive imaging procedures, such as computer topography (CT), magnetic resonance imaging (MRI), or ultrasound imaging. A CT system emits x-rays through the anatomical part of interest, and based on the attenuation coefficient of the x-rays, cross-sectional images ("slices") of the object can be reconstructed. Therefore, CT scans are very suitable for viewing details of bone structure, diagnosing lung and chest diseases, and detecting cancer. Advantages of CT imaging include, for example, short scan times for a complete scan (usually less than five minutes), low cost (about half the price of an MRI device), the ability to accurately outline bone tissue in the body, and fewer motion artifacts due to fast imaging speeds (less than 30 seconds per scan), etc. However, CT systems irradiate patients and therefore pose risks; therefore, CT scans are not recommended for pregnant women or children.

[0003] Ultrasound imaging, which involves transmitting high-frequency sound waves through the human body, is another widely used technology. Ultrasound waves penetrate soft tissues well, and due to the short wavelength of ultrasound waves, can be focused to a point of several millimeters in size. In a typical ultrasound examination, the transducer probe is placed directly on the skin or in a body opening. A thin layer of gel can be applied to the skin to provide direct contact between the transducer probe and the skin, and thereby to effectively transmit the ultrasonic energy into the body. Ultrasound images of internal anatomical structures can be constructed by waves reflected by these structures, specifically, for example, by the amplitude and phase of the reflected signal and / or the time required for the ultrasound wave to pass through the human body. Since the ultrasound image is captured in real time, the ultrasound image can also show the movement of the internal organs of the body and the blood flow through the blood vessels. In addition, ultrasound imaging provides high temporal resolution, high sensitivity to acoustic scatterers (such as calcification and bubbles), good visualization, low cost, portability, and no ionizing radiation exposure, and is therefore generally considered safe even for pregnant women and children. Acoustic imaging is also effective in mapping cavitation events (which occur during ultrasound therapy) in real time, but cannot accurately identify soft tissue contours through the skull and other bony structures, which introduces offsets and errors.

[0004] MRI is yet another imaging modality for visualizing internal tissues. MRI can be used in conjunction with therapeutic (as opposed to imaging) ultrasound to guide the focusing of ultrasound during therapy, as described in detail below. In short, MRI involves placing the patient in a uniform static magnetic field, thereby aligning the spins of hydrogen nuclei in the tissue. Then, by applying a radio frequency (RF) electromagnetic pulse with an appropriate frequency ("resonance frequency"), the spins can be flipped, thereby temporarily disrupting the alignment and inducing a response signal. Different tissues produce different response signals, thereby forming a contrast between these tissues in the MR image. Since the resonant frequency and the frequency of the response signal depend on the magnetic field strength, the origin and frequency of the response signal can be controlled by superimposing a magnetic gradient field on the uniform field, so that the magnetic field strength depends on the position. By using a time-varying gradient field, an MRI "scan" of the tissue can be obtained.

[0005] Many MRI protocols use time-varying gradients in two or three mutually perpendicular directions. The relative strengths and timing of the gradient fields and RF pulses are specified in the pulse sequence. Combined with the tissue dependence of the MRI response signal, the time-varying magnetic field gradient can be used to visualize, for example, a brain tumor and determine the location of the brain tumor relative to the patient's skull. The advantages of MRI include multi-planar imaging capabilities (without moving the patient), high signal-to-noise ratio, high sensitivity to subtle changes in soft tissue morphology and function, and no radiation exposure. However, MRI is very sensitive to patient movement due to long scanning times (usually 30 minutes to several hours), low image resolution of bone structures, and interference from the operation of other RF devices. MRI is also poor for real-time cavitation mapping.

[0006] Since each imaging technique has its own advantages and disadvantages and can provide different types of information, it may be advantageous to combine different imaging techniques in practice. For example, combining a CT scan with an MRI can provide detailed information about bone structure and subtle differences between soft tissues. The combination of MRI and ultrasound imaging has been shown to provide additional diagnostic information, providing better diagnosis for neurosurgical applications and breast biopsy guidance that occur during surgery. In addition, since ultrasound energy can be used therapeutically, such as to heat and ablate diseased (e.g., cancerous) tissue without causing significant damage to surrounding healthy tissue, the combination of MRI and ultrasound provides imaging capabilities during therapeutic medical procedures.

[0007] Ultrasound focusing systems generally include an acoustic transducer surface or an array of transducer surfaces to generate one or more ultrasound beams. In a transducer array, individual surfaces or "elements" are typically individually controllable, i.e., the vibration phase and / or amplitude of the individual surfaces or elements can be set independently of each other, so that the beam is steered in a desired direction and focused at a desired distance. Ultrasound systems typically also include receiving elements that are integrated into the transducer array or provided in the form of separate detectors, which help monitor ultrasound-based treatments. For example, a receiving element can detect ultrasound reflected through an interface between the transducer and the target tissue, which may be caused by bubbles on the skin, which need to be removed to avoid skin burns. Receiving elements can also be used to detect cavitation in overheated tissue (i.e., cavities formed by the collapse of bubbles formed in the fluid of the tissue).

[0008] Focused ultrasound transducer systems may include MR tracking coils or other markers for determining the position and orientation of the transducer relative to target tissue (such as a tumor) in the MR image. Based on the calculation of the required transducer element phase and amplitude, the transducer array is then driven to focus the ultrasound on the target. The ultrasound focus itself can be visualized using MRI or acoustic resonance force imaging (ARFI), and this visualization can be used to adjust the focus position. These methods are generally referred to as magnetic resonance guided focused ultrasound (MRgFUS).

[0009] To successfully integrate two or more imaging systems and / or combine the information provided by different systems, it is necessary to register the image data that may have been acquired in different imaging coordinate systems. Traditional registration methods often involve complex computational procedures and may not provide sufficient accuracy for therapeutic purposes. For example, when using acoustic imaging in conjunction with MRI for real-time cavitation mapping to image soft tissue, both modalities may not have useful features that can be accurately identified to facilitate registration. Summary of the invention

[0010] Embodiments of the present disclosure provide systems and methods for registering different imaging modes to a common coordinate reference system or to each other. Instantaneous or clinically harmless tissue destruction is caused at a known anatomical location and visualized and registered by two imaging systems. In different embodiments, one of the imaging systems is an ultrasound system capable of delivering both imaging acoustic energy and therapeutic acoustic energy. In its imaging mode, the ultrasound system senses the reflection of an acoustic imaging pulse directed to a target location. Operating the ultrasound system in therapy mode enables targeted delivery of high-amplitude, highly focused ultrasound pulses, which produces tissue effects that can be observed by a second imaging system (e.g., an MR system). Tissue effects may be transient, such as slight and reversible tissue destruction, or may involve tissue destruction that lasts longer but is negligible. In both cases, the resulting microbleeding can be detected by MRI. Tissue effects can be produced by local cavitation events in the target tissue caused by acoustic energy deposition.

[0011] In other embodiments, the tissue effect is a detectable change in tissue permeability, such as the opening of the blood-brain barrier (BBB) ​​to allow molecules that would otherwise not be able to pass through to pass through. Such molecules may be detectable by a second imaging system, for example, the molecules may be detectably aggregated between where the BBB is sufficiently disrupted. For example, an MR contrast agent may include gadolinium ions that are easily detectable in a nuclear MR image. Ultrasound contrast agents may include micrometer-sized bubbles (microbubbles), nanometer-sized bubbles (nanobubbles), phase-shifted nanodroplets, bubbles, echogenic liposomes, and / or polymer nanoparticles; see, for example, Helfield et al., "Acoustically-Stimulated Nanobubbles: Opportunities in Medical Ultrasound Imaging and Therapy", Frontiers in Physics, May 7, 2021 (the entire disclosure of the document is hereby incorporated by reference). Additionally or alternatively, the contrast agent can be a droplet / phase shift contrast agent or a modified liposome or other lipid vesicle combined with a traditional contrast agent. Liposomes and other vesicles can be filled with drugs or attached to drugs, thus enabling not only imaging with two modalities, but also simultaneous therapy.

[0012] The precise location of the tissue effect can be determined by an ultrasound system that detects the acoustic reflections of the collapsing microbubbles due to the cavitation event using either a dedicated receiving transducer element or the same element that transmits the acoustic dose but operates in a receiving mode. The ultrasound system can produce an image of the target area or, more typically, can determine the location of the cavitation event based on a time-of-flight analysis of the received reflected signal. The acoustic reflections from a cavitation event have a unique signature that is characterized by being able to be isolated from other reflected signals.

[0013] Once the location of the cavitation event is determined using the ultrasound system, and the resulting and co-localized tissue destruction is identified by another imaging system, the two systems can be registered in a common coordinate reference system. A coordinate transformation can be established to relate the spatial reference system of each imaging system to that of the other imaging system.

[0014] Although the following discussion focuses primarily on ultrasound and MRI systems, it should be understood that the present disclosure is useful for any imaging system that can detect co-located internal markers. In addition, it is not necessary for the marker to be actually created by one of the imaging systems, although this may simplify its location. For example, a third system can induce tissue destruction at a known internal location. When tissue destruction (or its consequences, such as microbleeding or detectable permeability) is detected and spatially located by both systems, the two systems can be aligned based on the known internal location.

[0015] As used herein, the terms "approximately," "roughly," and "substantially" mean ±10%, and in some embodiments, ±5%. References throughout this specification to "one instance," "an example," "one embodiment," "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the example is included in at least one example of the technology of the present invention. Therefore, the phrases "in one example," "in an example," "one embodiment," or "an embodiment" appearing in various places throughout this specification do not necessarily all refer to the same example. In addition, particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In the accompanying drawings, the same reference numerals generally refer to the same parts in different views. In addition, the drawings are not necessarily drawn to scale, but the emphasis is generally placed on illustrating the principles of the present disclosure. In the following description, various embodiments of the present disclosure are described with reference to the following drawings, in which:

[0017] Figure 1Aschematically depicts an exemplary MRI system according to various embodiments of the present disclosure;

[0018] Figure 1B An exemplary CT system according to various embodiments of the present disclosure is schematically described;

[0019] Figure 1C schematically depicts an exemplary ultrasound system according to various embodiments of the present disclosure;

[0020] Figure 2A The two imaging systems are schematically shown for registration operation.

[0021] Figure 2B Two imaging systems operating without registration are shown schematically.

[0022] Figure 2C and 2D The effect of aberrations in causing the ultrasound focus to deviate from the intended target position is schematically illustrated.

[0023] Figure 3 A flow chart is shown of an example method for registering imaging systems while providing focused ultrasound to a target region in accordance with some embodiments. DETAILED DESCRIPTION

[0024] Representative imaging environments

[0025] Figure 1AAn exemplary MRI device 102 is shown. The device 102 may include a cylindrical electromagnet 104 that generates a necessary static magnetic field within a bore 106 of the electromagnet 104. During a medical procedure, a patient is placed within the bore 106 on a movable support table 108. An area of ​​interest 110 in the patient's body (e.g., the patient's head) may be positioned within an imaging region 112, where the electromagnet 104 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 113 may also be provided within the bore 106 and around the patient. The gradient coils 113 generate magnetic field gradients with predetermined amplitudes at predetermined times and in three mutually orthogonal directions. Using the field gradients, different spatial locations may be associated with different precession frequencies, thereby providing the MR image with its spatial resolution. An RF transmitter coil 114 surrounding the imaging region 112 transmits RF pulses into the imaging region 112 to cause the patient's tissue to emit magnetic resonance (MR) response signals. The raw MR response signals are sensed by the RF coil 114 and passed to the MR controller 116, which then calculates an MR image that can be displayed to a user. Alternatively, separate MR transmitter and receiver coils can be used. Images acquired using the MRI device 102 can provide radiologists and physicians with visual contrast between different tissues and detailed internal views of the patient's anatomical structures that cannot be visualized using conventional x-ray techniques.

[0026] The MRI controller 116 can control the pulse sequence, that is, the relative timing and intensity of the magnetic field gradient and the RF excitation pulse and the response detection period. The MR response signal is amplified, regulated and digitized into raw data using a conventional image processing system, and is further converted into an image data array by methods known to those of ordinary skill in the art. Based on the image data, the treatment area (e.g., a tumor) is determined. The image processing system can be a part of the MRI controller 116, or it can be an independent device (e.g., a general-purpose computer containing image processing software) that communicates with the MRI controller 116. In some embodiments, one or more ultrasound systems 120 or one or more sensors 122 are displaced within the bore 106 of the MRI device 102, as further described below.

[0027] Figure 1BAn exemplary CT system 130 according to an embodiment of the present disclosure is shown. The CT system 130 includes a scanner 132 having a support structure 134, an x-ray source 136, and an x-ray detector 138 located on the same side or opposite side of the source 136. The scanner 132 is configured to receive a table 140 of a patient to be scanned. The table 140 can be moved through a hole in the scanner 132 so as to properly position the patient in an imaging volume or scanning plane during an imaging sequence. The CT system 130 further includes a radiation source controller 143, a data acquisition controller 144, and a table controller 145. The radiation source controller 143 regulates the timing of the emission of x-ray radiation from the x-ray source 136 toward the patient. The data acquisition controller 144 communicates with the x-ray detector 138 to measure x-ray intensity data that passes through the patient or is reflected from the patient. The acquired intensity data is processed by the data acquisition controller 144 or the system controller 146 for CT image reconstruction. The table controller 145 is used to adjust the table position during or between imaging sequences, depending on the imaging protocol used. The controllers 143, 144, 145, 146 may be separate units or integrated into one unit.

[0028] In addition, the system controller 146 may also be connected to a user interface 147 and a memory device 148. The user interface 147 may be integrated with the system controller 146 and may typically include a user workstation for initiating imaging sequences, controlling such sequences, and manipulating data acquired during imaging sequences. The memory device 148 may be local to the imaging system, or partially or completely remote from the system, and may be configured to receive raw, partially processed, or fully processed data for CT image reconstruction.

[0029] During a typical CT scan, the x-ray scanner 132 rotates around the patient at a predetermined speed, and the x-ray source 136 emits a narrow x-ray beam that passes through the body. The intensity of the x-rays emitted through or reflected from the patient at different angles relative to the patient's body is measured by the detector 138. Based on the beam angle and intensity of the detected x-rays, a two-dimensional tomographic image (i.e., "slice") of the patient can be created. The multiple slices obtained at different angles can then be processed to reconstruct a CT image. In some embodiments, the CT image of the patient is acquired in the planning stage (i.e., before thermal treatment) so that there is time to prepare a treatment plan.

[0030] Figure 1C An exemplary ultrasound system 150 (eg, corresponding to 120, Figure 1A). As shown, the ultrasound system includes a plurality of ultrasonic transducer elements 152, which are arranged on the surface of a housing 154 in the form of an array 153. The array may include a single row or matrix transducer elements 152. In an alternative embodiment, the transducer elements 152 may be arranged uncoordinated, i.e., the transducer elements do not have to be regularly spaced or arranged in a regular pattern. As shown, the array may have a curved (e.g., spherical or parabolic) shape, or may include one or more planes or other shaped portions. Its size may vary between millimeters and tens of centimeters depending on the application. The transducer element 152 may be a piezoelectric ceramic element. Piezoelectric composites may also be used, or substantially any material capable of converting electrical energy into acoustic energy. In order to prevent mechanical coupling between the elements 152, silicone rubber or any other suitable damping material may be used to mount the element on the housing 154.

[0031] The transducer elements 152 are individually controllable, i.e., each of the transducer elements is capable of emitting ultrasound waves at an amplitude and / or phase that is independent of the amplitude and / or phase of other transducers. A transducer controller 156 is used to drive the transducer elements 152. For n transducer elements, the controller 156 may include n control circuits, each of which includes an amplifier and a phase delay circuit, each control circuit driving one of the transducer elements. The controller 156 may divide the RF input signal (typically in the range of 0.1 MHz to 4 MHz) into n channels for the n control circuits. The controller may be configured to drive a single transducer element 152 in an array having the same frequency but different phases and different amplitudes, so that the transducer elements collectively generate a focused ultrasound beam. The transducer controller 156 desirably provides a computing function that may be implemented in software, hardware, firmware, hard wiring, or any combination thereof, to calculate a desired focal position 158 (e.g., corresponding to 110, Figure 1A ) The controller 156 may typically include several separable devices, such as a frequency generator, a beamformer including an amplifier and phase delay circuit, and a computer (e.g., a general purpose computer) that performs calculations and communicates the phase and amplitude of each transducer element 152 to the beamformer. Such systems are readily available or can be implemented without undue experimentation.

[0032] In order to perform ultrasound imaging, the controller 156 drives the transducer elements 152 to transmit acoustic signals to the imaged area and receive reflected signals from various structures and organs in the patient's body. By appropriately delaying the pulses applied to each transducer element 152, the focused ultrasound beam can be emitted along the desired scan line. The acoustic signals reflected from a given point in the patient's body are received by the transducer elements 152 at different times. The transducer elements can then convert the received acoustic signals into electrical signals and provide them to the beamformer. The delayed signals from each transducer element 152 are summed by the beamformer to provide a scanner signal, which represents the reflected energy level along a given scan line. This process is repeated on multiple scan lines to provide signals to generate an image of a specified area of ​​the patient's body. Typically, the scanning mode is a sector scan, in which the scan line starts from the center of the ultrasound transducer and points to different angles. Linear, curvilinear or any other scanning mode may also be used.

[0033] Focused ultrasound can also be used therapeutically on in vivo tissues within a patient, and as described below, therapeutic applications can supplement imaging by creating markers visible to imaging systems. Specifically, ultrasound can be used for applications involving ablation of tumors, thereby eliminating the need for invasive surgery, targeted drug delivery, control of the blood-brain barrier, lysis of blood clots, and other surgical procedures. During tumor ablation, focused ultrasound energy is deposited at a level sufficient to ablate tissue. This procedure is generally referred to as high-intensity focused ultrasound (HIFU) therapy and is described in detail, for example, in PCT application No. WO 2021 / 123906 filed on December 18, 2020, the entire disclosure of which is hereby incorporated by reference.

[0034] Alternatively, the transducer array 153 can be operated at a sufficiently high power to produce cavitation at the target location. One such procedure is tissue destruction, which involves delivering acoustic energy in the form of short (generally less than 50 microseconds), high amplitude pulses, depositing relatively low total energy at a higher peak pressure. This induces transient cavitation to mechanically disrupt the targeted tissue. Cavitation occurs when sufficient negative pressure is applied to the tissue to vaporize the fluid to form microbubbles and release dissolved gases. Once formed, the microbubbles exhibit highly dynamic oscillation modes and inertial collapse, resulting in cell and tissue destruction. Although pathological applications such as HIFU are sensitive to the amount of energy reaching the target, tissue destruction is more sensitive to negative peak pressures.

[0035] Another therapeutic application of focused ultrasound involves enhancing tissue permeability in a target area. For example, a target tissue is typically permeable to molecules less than 400 Daltons in size, but a therapeutic agent may be 1,000 Daltons or larger in size and is therefore blocked from entering the target area. When ultrasound is applied, tissue within a target area (e.g., the BBB) or tissue that regulates access to the target area may be damaged, and therefore its permeability may increase. The permeability level and / or the size of the tissue area in which the permeability is increased may depend on the intensity and / or duration of the ultrasound application. Therefore, by adjusting ultrasound parameters, the tissue permeability of the target area can be increased to a desired degree to allow the therapeutic agent to penetrate and / or diffuse therein. The degree of tissue permeability can be monitored using molecules or molecular complexes of known size combined with a visualization agent (the molecules or molecular complexes are too large to penetrate the intact BBB). The visualization agent can be a contrast agent, for example, a liposome labeled with a fluorophore or Gd; see, for example, U.S. Serial No. 63 / 322,617, filed on March 22, 2022 and entitled "Monitoring Tissue Permeability During Ultrasound Procedures," the entire disclosure of which is hereby incorporated by reference. The molecule or molecular complex can be a liposome, a quantum dot, or a dextran. If the size of the molecule or molecular complex is similar to that of the therapeutic agent (e.g., an antibody or other biologic), detection of the passage of the visualization agent indicates that the BBB has sufficient openings to accommodate the therapeutic agent.

[0036] The ultrasound system 150 may be placed within the bore 106 of the MRI device 102 or placed near the MRI device 102. The combined MRI-ultrasound system is capable of monitoring the use of ultrasound for therapeutic and / or safety purposes. In order to determine the relative position of the ultrasound system 150 and the MRI device 102, the ultrasound system 150 may further include an MR tracker 160 associated therewith, each of which is arranged at a fixed position and orientation relative to the ultrasound system 150. For example, the tracker 160 may be integrated into the ultrasound system housing 154 or connected to the ultrasound system housing. If the relative position and orientation of the MR tracker 160 and the ultrasound system 150 are known, the MR scan of the MR tracker 160 is included in the resulting image to implicitly display the position of the ultrasound system 150 with MRI coordinates (in the coordinate system of the MRI device 102). In some embodiments, in order to help relate the ultrasound coordinate system to the MRI coordinate system, an MR image including at least a portion of the ultrasound system 150 (e.g., some transducer elements) is acquired. This MR image can be combined with the known spatial arrangement of the ultrasound transducer elements to determine the positions of the transducer elements (not necessarily all of which are included in the acquired MR image) in the MRI coordinate system, as described further below.

[0037] When penetrating the patient, ultrasound waves usually encounter multiple layers of tissue, such as bone, muscle or fat, which have different densities and structures, and therefore different propagation characteristics of ultrasound. Due to the inhomogeneity and anisotropy of the tissue, the ultrasound front tends to be distorted. In addition, the signals from different transducer elements may encounter materials with different thicknesses and contours, and there may be air-filled or liquid-filled gaps between the transducer elements and the area to be imaged or treated, resulting in different phase shifts and attenuations. Therefore, it is very important to understand the structure, density and / or thickness of the multi-layer tissue structure to compensate for these effects and avoid deterioration of the focusing characteristics by applying appropriate phase shifts and magnification factors to the transducer elements. MRI generally provides high-sensitivity images of soft tissues (e.g., the brain), while CT scans create images with more details about bone structures (e.g., the skull). Therefore, it may be beneficial to combine the image information obtained from the MRI device 102 and the CT system 130. To do this, of course, the images need to be registered, and therefore the MRI and CT coordinate systems also need to be registered.

[0038] Device registration

[0039] The following disclosure describes the registration of two or more imaging devices. It should first be noted that an "imaging device" may be capable of being used for applications other than imaging, for example, an ultrasound system may be operated to perform various therapeutic applications as described above. Imaging systems referred to herein refer generally to such systems, regardless of whether they are actually used to create images. In addition, although the present discussion focuses on ultrasound and MR imaging, this is only for illustrative purposes. The present disclosure is applicable to other imaging modalities, such as CT, optical, and positron emission tomography (PET).

[0040] refer to Figure 2A , ultrasonic transducer system 205 (eg, corresponding to system 150, Figure 1C ) has an associated coordinate system CS US , so that events recorded by the ultrasound transducer system are located relative to this coordinate system. MRI system 210 (eg, corresponding to system 102, Figure 1A ) has an associated coordinate system CS MR , so that the events recorded by the system are located relative to this coordinate system. In operation, the ultrasonic transducer system 205 is controlled by a controller (e.g., controller 156, Figure 1C ) operates to generate, for example, a cavitation event by emitting ultrasound along vector arrow Tx and focusing at a target F (also referred to as focus F). In practice, this will involve emitting ultrasound from various spatially distributed transducer elements (e.g., element 152, Figure 1C ) with its output concentrated at the target F, but for illustration purposes the transducer elements are shown as if transmitting along a single path Tx. Figure 2A As shown in US and CS MR at the same point in the graph (for example, the origin as shown in the figure).

[0041] Detectable events such as cavitation can be induced and monitored by the ultrasound system 205, as described, for example, in U.S. Patent Publication No. 2022 / 0043143, the entire disclosure of which is hereby incorporated by reference. As described therein, one or more transient acoustic reflectors can be generated at or near the focus F by operating the ultrasound system 205 to emit high-power pulses that create cavitation events and generate microbubbles that serve as transient acoustic reflectors. Subsequently, the ultrasonic transducer system 205 operates to generate a focus at the same location and receives signals reflected from the transient reflectors by switching to operation in a receive mode by the transducer element itself or by other transducer elements that do not emit high-power pulses or by one or more acoustic signal detectors. As used herein, a "transient reflector" refers to an acoustic reflector that dissipates or evolves over time during sonication. The term "imaging" includes this operation and similar positioning operations, and for purposes of this article, a positioning event is an "image."

[0042] The position of the transient reflector on the target F can be determined using the time-of-flight technique. Since the relative spatial positions of all ultrasonic transducer elements are known in advance, the signal's time-of-flight (i.e., the interval between the ultrasonic emission and the detection of the reflection by each monitoring (receiving) transducer) can be used to locate the coordinate system CS US The detected events in .

[0043] If a detectable event E at a target F not only produces a transient reflector but also produces tissue destruction at the same location and is detectable by the MRI system 210, the coordinate systems CS can be registered by assigning the same location in each coordinate system to the target F (detectable event E). US and CS MR This process depends on the accurate arrangement of the ultrasound system 205 for the detectable events. Figure 2B As shown, if event E occurs at a location that is offset from target F (i.e., where the ultrasound transmission is actually focused or is believed to be focused), then this will affect the registration; therefore, it is important to ensure consistency between the transmission location and the reflection location using a calibration procedure such as described in the '3143 application.

[0044] It is well known that tissue inhomogeneities may cause sound energy to refract at the boundaries of tissue regions with different sound velocities. Refraction may reduce constructive interference and therefore reduce the intensity of the sound energy at the lesion, especially when the sound energy passes through bone. Therefore, inhomogeneous tissue structure may produce beam aberrations and refractions, which may distort or shift the focus. This is shown as Figure 2C and 2D The “medium effect” 220 in the figure means that the tissue is the medium through which the measured ultrasound signal passes. Because tissue homogeneity has the same effect on the transmitted ultrasound (Tx) and the reflected ultrasound (Rx), Figure 2D As shown in , even a perfectly calibrated ultrasound system 205 does not take into account focus shifts caused by aberrations. In fact, the ultrasound controller 156 does not "know" what effect the medium will have on the focus position.

[0045] Various techniques have been developed to correct for distortion or offset caused by aberrations; see, e.g., U.S. Pat. Nos. 8,088,067 and 11,291,430 and U.S. Patent Publication No. 2020 / 0085409, the disclosures of which are incorporated herein by reference. These techniques are important for treatment as long as the images produced by the MRI system are not subject to identical registration, but are not necessarily important for aberrations in the ultrasound and MRI coordinate systems. This is usually not the case, since changes in tissue density affect neither the nuclear magnetic resonance phenomenon nor its electromagnetic detection. If the difference between the true ultrasound coordinates and the apparent ultrasound coordinates is small, or if the treatment procedure typically includes aberration correction, then the true MRI coordinates CS MR With the mobile ultrasound coordinate CS' US In the latter case, as long as the correction is done for processing, it is usually not necessary to also apply this correction to the registration, since the shifted coordinate system CS' US is the coordinate system in which the processing is performed.

[0046] As explained above, the co-localized tissue effect enables visibility in both the ultrasound imaging system 205 and the MR imaging system 210. In one embodiment, the ultrasound transducer array is operated at a sufficiently high power to produce cavitation at the focal point F. One such procedure is tissue destruction, in which acoustic energy is delivered in short (generally less than 50 microseconds), high amplitude pulses to induce transient cavitation to mechanically disrupt the targeted tissue. Cavitation occurs when sufficient negative pressure is applied to the tissue to vaporize the fluid to form microbubbles and release dissolved gases. See, e.g., Xu et al., "Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound", Int. J. Hyperthermia, 2021, 38(1):561-575; Roberts, "Development and Translation of Histotripsy: Current Status and Future Directions", Curr. Opin. Urol., Jan. 2014, 24(1):104-110. Once formed, microbubbles exhibit highly dynamic oscillation patterns and inertial collapse, which produces cell and tissue destruction, resulting in small (e.g., 2 mm or less) hemorrhage areas that heal quickly but can be detected in MR images. See, e.g., Mitchell et al., "Detection of subarachnoid hemorrhage with magnetic resonance imaging," J. Neurol. Neurosurg. Psychiatry, 2001, 70:205-211. A gradient echo T2* sequence is known to show good sensitivity for internal hemorrhage. Ibid. Other sequences, such as T2 and fluid attenuated inversion recovery (FLAIR), may also be used or used alternatively. More generally, MRI images are complex, and features therein may be detected in a variety of ways—for example, an MRI image may be a graph of the amplitude of an MR response signal or a graph of the phase of the signal; a feature may be detectable based on the amplitude of a pixel associated with the feature, the phase of a pixel associated with the feature, or a phase difference relative to a baseline image, or a combination of the foregoing.

[0047] The use of ultrasound contrast agents (usually dispersions of gas microbubbles) can reduce the energy intensity and pressure required to induce cavitation. This in turn reduces the risk of excessive tissue damage. For example, in the presence of contrast agents, the peak focus pressure required for tissue destruction can be reduced from about 20MP to 1MP. U.S. Serial No. 16 / 378,945 (the entire disclosure of the application is incorporated by reference) describes an administration system for contrast agents, including customizing microbubble properties according to specific applications. Similar systems can also be used to administer MRI contrast agents. Alternatively, contrast agents can also be administered parenterally by a syringe or intravenous device.

[0048] In another embodiment, the tissue damage detectable by MRI is increased permeability. The use of HIFU to enhance permeability across tissue barriers (e.g., BBB) has been recognized; see, for example, Burgess et al., "Drug delivery across the blood-brain barrier using focused ultrasound", Expert Opin. Drug Deliv., 2014, 11(5):711-721. The permeability enhancement can be detected using MRI contrast agents such as nanoparticles, which include gadolinium (see Conti et al., "Empirical and Theoretical Characterization of the Diffusion Process of Different Gadolinium-Based Nanoparticles within the Brain Tissue after Ultrasound-Induced Permeabilization of the Blood-Brain Barrier", Contrast Media and Mol. Im., 2019, Article No. 6341545, the entire disclosure of which is hereby incorporated by reference), fluorophores, or a combination thereof, wherein the nanoparticles are typically encapsulated in liposomes (see, e.g., Aryal et al., "MRI Monitoring and Quantification of Ultrasound-Mediated Delivery of Liposomes Dually Labeled with Gadolinium and Fluorophores across the Blood-Brain Barrier"). Fluorophore through the Blood-Brain Barrier", Ultrasound Med. Biol., 2019, 45(7): 1733-1742, the entire disclosure of which is hereby incorporated by reference).

[0049] For example, MRI has been used to detect the presence of contrast agents in the extracellular space of the brain after ultrasound-induced BBB permeation. The accumulation of contrast agents detectable by MRI at the site of the ultrasound focus can be used to align the ultrasound and MRI coordinate reference systems accordingly. More generally, the molecules or molecular complexes detectable by MRI can be liposomes, quantum dots, or dextran. This method avoids tissue destruction because the destruction is completely reversible and does not require healing. In addition, MRI contrast agents may contain microbubbles or other substances, which reduce the threshold ultrasound intensity required to induce cavitation and thus enhance tissue permeability and detectable reflection of ultrasound signals. That is, a single contrast agent can provide both acoustic response and MRI response. Alternatively, MRI contrast agents and ultrasound contrast agents can be used in combination, or otherwise administered together near the area of ​​interest (or can be formulated to focus on the area of ​​interest) to provide ultrasound visibility and MR visibility. Contrast agents (and / or controlled imaging systems) can be administered so that the contrast agent appears in the recorded target area image.

[0050] Once the ultrasound imaging system and the MR imaging system have determined the position of the target F in their respective coordinate reference systems, the device controllers 146, 156 can communicate to share this information, and either of the device controllers 146, 156 can establish a coordinate transformation to relate the spatial reference system of each imaging system to the other (or another reference coordinate system) and pass the parameters to the other device controller. For example, this coordinate transformation can be in the form of a matrix or a system of linear equations. The images generated by the two imaging systems can then be registered and merged into a single image. Similarly, features detected using the MRI system 210 but not resolved by the ultrasound system 205 in the imaging mode can be used to guide the therapeutic use of the ultrasound system 205.

[0051] Figure 3 A flowchart of an example method for aligning an imaging system while providing focused ultrasound to a target area according to some embodiments is shown. The process may be controlled by instructions stored in a computer memory or a non-transitory computer-readable storage medium. These instructions may be included in one or more programs stored in a non-transitory computer-readable storage medium. When executed by one or more processors (e.g., 116; 146; 156; and / or a processor that controls 116, 146, and / or 156), these instructions cause the system to execute the process. The non-transitory computer-readable storage medium may include one or more solid-state storage devices (e.g., flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors.

[0052] In operation 302, one or more processors (e.g., 116; 146; 156; and / or a processor controlling 116, 146, and / or 156) operate a first device (e.g., ultrasound system 150) to cause tissue destruction at a target area in internal anatomical tissue (e.g., 110).

[0053] In operation 304 , one or more processors operate a first device (eg, a transducer element 152 configured to receive a signal) to detect a location of tissue destruction in a target area.

[0054] In operation 306 , the one or more processors operate a second device (eg, the MRI apparatus 102 ) to acquire an image of the target region (eg, 110 ).

[0055] In operation 308 , the one or more processors operate the second device to detect a location of tissue destruction in the image.

[0056] In operation 308, one or more processors align a first coordinate reference system of the first device and a second coordinate reference system of the second device to a common coordinate reference system based on (i) the location of tissue damage in the target area detected by the first device and (ii) the location of tissue damage in the image detected by the second device.

[0057] In some embodiments, the one or more processors are configured to generate a coordinate system by placing the same position (e.g., Figures 2A-2D F) is assigned to the tissue destruction in the target area to align the first coordinate reference system and the second coordinate reference system to the common coordinate reference system.

[0058] In some embodiments, the one or more processors are configured to align the first coordinate reference system and the second coordinate reference system to the common coordinate reference system by establishing a coordinate transformation to associate one of the first coordinate reference system and the second coordinate reference system with the other of the first coordinate reference system and the second coordinate reference system. In some embodiments, the one or more processors are configured to operate one of the first device and the second device to communicate the coordinate transformation to the other of the first device and the second device.

[0059] In some embodiments, the tissue destruction can be visualized by MRI and / or can be detected computationally in a T2 MR image or in a T2*MR image.In some embodiments, the tissue destruction is transient destruction.

[0060] In some embodiments, the one or more processors are configured to operate the ultrasound transducer system to induce acoustic cavitation at the target area, and the tissue destruction is mechanical disruption of tissue caused by the acoustic cavitation.

[0061] In some embodiments, the one or more processors are configured to: (i) operate a source of an ultrasound contrast agent comprising a suspension of microbubbles; and (ii) cause the ultrasound contrast agent to be administered so that the ultrasound contrast agent reaches the target area before operating the first device to cause the tissue destruction at the target area.

[0062] In some embodiments, the one or more processors are configured to operate the ultrasound transducer system to increase the permeability of the tissue at the target area, and the tissue disruption is an increase in permeability. In some embodiments, the tissue is a blood-brain barrier. In some embodiments, the one or more processors are configured to cause an MRI contrast agent to be administered such that the MRI contrast agent is present at the target area when the second device is operated to acquire the image.

[0063] In some embodiments, the one or more processors are configured to operate a source of an ultrasound contrast agent comprising a suspension of microbubbles and a source of an MRI contrast agent such that when the second device is operated to acquire the image, the ultrasound contrast agent and the MRI contrast agent are present at the target area.

[0064] In some embodiments, the one or more processors are configured to operate the first device to record signals from tissue at the target area and detect the location of the tissue destruction based at least in part on the signals recorded by the first device.

[0065] In some embodiments, the one or more processors are configured to operate the first device to generate a second image of the target area based on the signals recorded by the first device, and detect the location of the tissue destruction in the second image.

[0066] As previously described, the above methods can be applied to any two or more imaging modalities that can resolve different but coexisting tissue events. For example, PET biomarkers that are normally unable to penetrate the BBB can be administered; once the BBB is opened at one or more specific locations as described above, the passage of the PET biomarker can be detected to allow registration of the PET and ultrasound (or other) systems. Suitable PET biomarkers include [68Ga]DTPA, 2-amino-[3-11C]isobutyric acid, and Gd nanoparticles.

[0067] In addition, it should be understood that the features of the various embodiments described herein are not necessarily mutually exclusive and may exist in various combinations and arrangements, even if such combinations or arrangements are not expressly disclosed herein, without departing from the spirit and scope of the present disclosure. In fact, for those of ordinary skill in the art, changes, modifications and other embodiments of the contents described herein will occur without departing from the spirit and scope of the present disclosure.

[0068] In general, the functions for evaluating and / or calculating the imaging registration between two or more imaging systems and controlling the operation of these systems can be constructed in one or more modules implemented in hardware, software, or a combination of the two. For embodiments in which the functions are provided as one or more software programs, the programs can be written in a variety of high-level languages, such as FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. In addition, the software can be implemented in an assembly language for a microprocessor retained on the target computer; for example, if the software is configured to run on an IBM PC or a PC clone, it can be implemented in Intel 80x86 assembly language. The software can be embodied in an article of manufacture or industrial product, including but not limited to a floppy disk, a jump drive, a hard disk, an optical disk, a tape, a PROM, an EPROM, an EEPROM, a field programmable gate array, or a CD-ROM. For example, an embodiment using hardware circuits can be implemented using one or more FPGA, CPLD, or ASIC processors.

Claims

1. A system for registering a first device and a second device affecting internal anatomical tissue, the system comprising one or more processors, the one or more processors being configured to: The first device is operated to: causing tissue destruction at a target area in the internal anatomical tissue; and detecting a location of the tissue destruction in the target area; The second device is operated to: Acquire an image of the target area; and detecting a location of the tissue destruction in the image; Based on (i) the location of the tissue damage in the target area detected by the first device and (ii) the location of the tissue damage in the image detected by the second device, a first coordinate reference system of the first device and a second coordinate reference system of the second device are aligned to a common coordinate reference system.

2. The system of claim 1, wherein the first device is an ultrasound transducer system and the second device is a magnetic resonance imaging (MRI) system.

3. A system according to claim 1 or claim 2, wherein the one or more processors are configured to align the first coordinate reference system and the second coordinate reference system to the common coordinate reference system by assigning the same position in each of the first coordinate reference system and the second coordinate reference system to the tissue destruction in the target area.

4. The system of claim 1 or claim 2, wherein the one or more processors are configured to align the first coordinate reference system and the second coordinate reference system to the common coordinate reference system by establishing a coordinate transformation to associate one of the first coordinate reference system and the second coordinate reference system with the other of the first coordinate reference system and the second coordinate reference system. 5 . The system of claim 4 , wherein the one or more processors are configured to operate one of the first device and the second device to communicate the coordinate transformation to the other of the first device and the second device.

6. The system according to any one of claims 2 to 5, wherein the tissue destruction can be visualized by MRI and / or can be detected computationally in a T2 MR image or in a T2* MR image.

7. The system of any one of claims 2 to 6, wherein the tissue destruction is instantaneous destruction.

8. The system of any one of claims 2 to 7, wherein the one or more processors are configured to operate the ultrasound transducer system to induce acoustic cavitation at the target area, and the tissue damage is mechanically disrupted tissue caused by the acoustic cavitation.

9. A system according to any one of claims 2 to 7, wherein the one or more processors are configured to: (i) operate a source of an ultrasound contrast agent comprising a suspension of microbubbles; and (ii) cause the ultrasound contrast agent to be administered so that the ultrasound contrast agent reaches the target area before operating the first device to cause the tissue destruction at the target area.

10. The system of any one of claims 2 to 7, wherein the one or more processors are configured to operate the ultrasound transducer system to increase the permeability of tissue at the target area, and the tissue destruction is an increase in permeability.

11. The system of claim 10, wherein the tissue is the blood-brain barrier.

12. The system of claim 11, wherein the one or more processors are configured to cause an MRI contrast agent to be administered such that the MRI contrast agent is present at the target region when the second device is operated to acquire the image.

13. A system according to any one of claims 2 to 7, wherein the one or more processors are configured to operate a source of an ultrasound contrast agent comprising a suspension of microbubbles and a source of an MRI contrast agent so that when the second device is operated to acquire the image, the ultrasound contrast agent and the MRI contrast agent are present at the target area.

14. A system according to any one of claims 1 to 13, wherein the one or more processors are configured to operate the first device to record signals from tissue at the target area and detect the location of the tissue destruction based at least in part on the signals recorded by the first device.

15. The system of claim 14, wherein the one or more processors are configured to operate the first device to generate a second image of the target area based on the signals recorded by the first device, and detect the location of the tissue destruction in the second image.

Images