CARDIAC ARRHYTHMIA TREATMENT

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No.

62/682272 entitled“APPLICATION OF MRI-GUIDED HIGH-INTENSITY FOCUSED ULTRASOUND FOR CARDIAC ARRHYTHMIA TREATMENT,” filed June 8, 2018, and incorporated herein by reference in its entirety.

FIELD OF INVENTION

[0002] This application relates to non-invasive therapy using high-intensity focused ultrasound (HIFU) ablation for, for example, cardia arrhythmia, and to using HIFU ablation guided via various imaging techniques and via detection of temperature, motion, and/or electrophysiological signals.

BACKGROUND

[0003] The percutaneous catheter-guided ablation of cardiac arrhythmia is the current standard of treatment for ventricular or supraventricular arrhythmia that is refractory to medical therapy. While this method presents clear advantages over surgical approaches and produces moderate success (-50% chance of success following a single procedure in the case of atrial fibrillation, the most common form of cardiac arrhythmia), there are dramatic shortcomings: 1) Serial mapping of cardiac tissue results in long procedures and limited precision, 2) Mapping is not spatiotemporally resolved; as a result, critical

electrophysiological features (e.g., rotors) are difficult to identify, 3) There is inaccessible arrhythmogenic tissue and an inability to deliver adequate ablative energy transmurally across the myocardium. These factors limit the ability to understand complex arrhythmia, and are associated with significant morbidity and mortality.

[0004] Recent advances have enabled the noninvasive mapping of cardiac arrhythmias with electrocardiographic imaging (ECGI), which utilizes an external vest of 256 electrodes. This technique can provide detailed, noninvasive, spatiotemporally resolved mapping. However, without a complimentary noninvasive method to treat arrhythmia, much of the benefit associated with this method is mitigated. Both a noninvasive diagnostic and therapeutic method are needed to move towards a new paradigm of fully noninvasive treatment of cardiac arrhythmia. Recently, a small-scale clinical trial investigated the feasibility of combining ablative radiation with ECGI in order to perform noninvasive, catheter-free, electrophysiology-guided radioablation for ventricular tachycardia. Despite the significant findings, however, radiation therapy is intrinsically undesirable, limiting the potential impact of this approach to very sick patients. Damage to non-target organs along the radiation path is inevitable; patients in this study were noted to have inflammatory changes in the lung. Therefore, a more precise noninvasive method for ablating tissue is needed to address such limitations. There is still a critical unmet need for a safe and precise method to deliver therapeutic ablation of cardiac tissue.

SUMMARY

[0005] Various embodiments of the disclosure relate to a method combining externally applied high-intensity focused ultrasound (HIFU) and magnetic resonance (MR)- thermometry techniques for the ablation of contractile myocardial tissue while

simultaneously monitoring temperature changes in the tissue and surrounding blood. In certain embodiments, the method may further comprise using an external ECG vest to assess location of an arrhythmia non-invasively.

[0006] Various embodiments relate to a method comprising using cardiac gating to account for myocardial contractility while precisely targeting an area of interest with HIFU. The cardiac gating may involve timing of HIFU to a specific interval of the cardiac cycle with the use of electrocardiographic (ECG) signals. In certain embodiments, the method may further comprise localizing an anatomic area of interest using MR imaging.

[0007] Various embodiments relate to a method comprising using respiratory gating to account for chest wall and diaphragmatic movement in relation to the position of a heart. The respiratory gating may involve timing of the position of the region of interest in relation to the respiratory cycle using MR imaging.

[0008] Various embodiments relate to a method comprising targeting HIFU at cardiac tissue through the ribs with passive cooling or through the ribs with active cooling. In certain embodiments, the method may further comprise using a sternal cooling system to limit thermal damage as a result of sternal bone absorption of HIFU.

[0009] Various embodiments relate to a method combining the use of transesophageally- applied HIFU with MR thermometry for ablation of myocardial tissue.

[0010] Various embodiments relate to a method comprising using local tissue dosing based on models to compensate for tissue depth and cooling associated with local flow of blood to ensure uniform effective dose (ED).

[0011] Various embodiments relate to a method for non-invasive cardiac ablation. The method may comprise acquiring physiological data from a cardiac region of a subject using a physiological signal detection system. The method may comprise targeting a cardiac tissue in the cardiac region for ablation based on the physiological data. The method may comprise externally applying HIFU energy to the targeted cardiac tissue. The HIFU energy may be applied using an ultrasound probe. The HIFU energy may be applied according to a treatment parameter. The method may comprise determining one or more temperatures of the subject via magnetic resonance (MR) thermometry. The method may comprise adjusting the treatment parameter corresponding to application of the HIFU energy based on the one or more temperatures.

[0012] In certain embodiments, determining one or more temperatures of the subject may comprise determining one or more temperatures of portions of the cardiac region.

[0013] In certain embodiments, determining one or more temperatures may comprise determining one or more temperatures of blood of the subject.

[0014] In certain embodiments, the treatment parameter may be a target area of the subject at which to apply the HIFU energy emitted by an ultrasound probe.

[0015] In certain embodiments, the treatment parameter may be an intensity of the HIFU energy.

[0016] In certain embodiments, the treatment parameter may be a timing of HIFU energy application. [0017] In certain embodiments, the physiological signal detection system may comprise an echocardiography device. The physiological data may comprise an echocardiogram.

[0018] In certain embodiments, the physiological signal detection system may comprise an MR imaging device. The physiological data may comprise an MR image.

[0019] In certain embodiments, the physiological signal detection system may comprise an external electrocardiography (ECG) vest. The physiological data may comprise ECG signals captured using the ECG vest. The method may comprise non-invasively locating an arrhythmia to be targeted with the FQFET energy using the ECG signals.

[0020] In certain embodiments, the method may comprise gating application of HIFU energy to at least one of cardiac motion or respiratory motion.

[0021] In certain embodiments, adjusting the treatment parameter may comprise timing EHFET energy to an interval of at least one of a cardiac cycle or a respiratory cycle.

[0022] In certain embodiments, gating application of HIFU energy may comprise acquiring motion data for the subject using a motion detection system.

[0023] In certain embodiments, the motion detection system may comprise an ECG device. Acquiring motion data may comprise acquiring ECG signals from the cardiac region.

[0024] In certain embodiments, the motion detection system may comprise a motion sensor. The method may comprise adjusting the treatment parameter based on the motion data.

[0025] In certain embodiments, the method may comprise cooling the cardiac region or a portion thereof using an active cooling system.

[0026] Various embodiments may relate to a method for non-invasive cardiac ablation.

The method may comprise targeting a cardiac tissue in the cardiac region for ablation. The cardiac tissue may be targeted based on an image of a cardiac region. Alternatively or additionally, the cardiac tissue may be targeted based on ECG signals from the cardiac region. The method may comprise externally applying FUFET energy to the targeted cardiac tissue. The FUFET energy may be applied using an ultrasound probe. The method may comprise acquiring temperature data for the subject via MR thermometry. The method may comprise adjusting a treatment parameter corresponding to application of the HIFU energy based on the temperature data.

[0027] In certain embodiments, the method may comprise acquiring motion data for the targeted cardiac tissue. The method may comprise adjusting the treatment parameter based on the motion data.

[0028] In certain embodiments, the method may further comprise acquiring ECG signals from the cardiac region via an ECG device. Adjusting the treatment parameter may comprise timing EHFET energy to an interval of a cardiac cycle.

[0029] Various embodiments relate to a system for non-invasive cardiac ablation. The system may comprise a physiological signal detection system. The system may comprise a FUFET energy emitter having an ultrasound probe. The system may comprise a temperature detection system. The system may comprise a processor and a memory having instructions which, when executed by the processor, cause the processor to perform specific functions.

The system may be configured to use the physiological signal detection system to acquire physiological data. The physiological data may be acquired from a cardiac region of a subject. The system may be configured to target a cardiac tissue in the cardiac region for ablation. The cardiac tissue may be targeted based on the physiological data. The system may be configured to externally apply FUFET energy to the targeted cardiac tissue using the ultrasound probe of the FUFET energy emitter. The system may be configured to acquire temperature data for the subject using the temperature detection system. The system may be configured to adjust a treatment parameter corresponding to application of the FUFET energy based on the temperature data.

[0030] In certain embodiments, the temperature detection system comprises an MR device. The system may be configured to acquire the temperature data via MR thermometry.

[0031] In various embodiments, ultrasound, which is safer than radiation, may be used to sonicate targeted regions in the body, including the heart. High-intensity focused ultrasound may ablate tissue via thermal damage to the tissue. Imaging-guided high-intensity focused ultrasound may be used for the noninvasive treatment of various types of benign or malignant diseases. When coupled with MR-based temperature measurement (e.g., MR thermometry), energy delivery can be localized, and changes in the targeted tissue can be monitored.

Example embodiments of the disclosure involve utilization of MRI-guided EHFET (MRI- EHFET) for the treatment for cardiac arrhythmia by targeted ablation of myocardial tissue.

The disclosed approach of applying MRI-guided HIFET to the noninvasive treatment of cardiac arrhythmia, optionally coupled with electrocardiographic imaging (ECGI), may provide a new paradigm of noninvasive ablation therapy for cardiac arrhythmia.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The figures, described herein, are for illustration purposes only. It is to be understood that in some instances various aspects of the described implementations may be shown exaggerated or enlarged to facilitate an understanding of the described

implementations. In the drawings, like reference characters generally refer to like features, functionally similar and/or structurally similar elements throughout the various drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the teachings. The drawings are not intended to limit the scope of the present teachings in any way. The system and method may be better understood from the following illustrative description with reference to the following drawings in which:

[0033] FIG. 1 illustrates example systems of the disclosed approach in accordance with example embodiments.

[0034] FIG. 2 provides an example process flow for the disclosed approach in accordance with example embodiments.

[0035] FIG. 3 provides a medical image of a potential target site for illustration of the interaction of applied ultrasound waves with the potential target site in accordance with example embodiments.

DETAILED DESCRIPTION

[0036] The various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the described concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes. [0037] Disclosed are approaches for applying MRI-guided high-intensity focused ultrasound for (HIFU) for treatment of cardiac arrhythmia. The use of externally-applied HIFU may be combined with magnetic resonance (MR)-thermometry techniques for the ablation of contractile myocardial tissue while simultaneously monitoring the temperature changes in the tissue and surrounding blood. Cardiac gating may be used in order to account for myocardial contractility while precisely targeting the area of interest with HIFU. Cardiac gating may involve timing of HIFU to a specific interval of the cardiac cycle with the use of electrocardiographic (ECG) signals, in addition to localization of the anatomic area of interest using MR imaging. Respiratory gating may be used in order to account for chest wall and diaphragmatic movement in relation to the position of the heart. Respiratory gating may involve timing of the position of the region of interest in relation to the respiratory cycle using MR imaging. A sternal cooling system may be used in order to limit thermal damage as a result of sternal bone absorption. HIFU of cardiac tissue may be achieved through the ribs with passive cooling or through the ribs with active cooling. The use of

transesophageally-applied HIFU may be combined with MR thermometry for the ablation of myocardial tissue. An external ECG vest may be used to assess location of arrhythmia non- invasively. Local tissue dosing may be based on models to compensate for tissue depth and cooling associated with local flow of blood to ensure uniform“effective dose” after compensating for the effects of blood flow.

[0038] Various embodiments of the disclosure involve the application of HIFU through a custom made MRI-compatible vest that tightly fits the individual without space between the vest and the chest wall. The vest may be fitted with ECG leads and a motion sensor for cardiac and respiratory gating, respectively. HIFU may be focused onto myocardial tissue through an ultrasound probe that is placed directly over the heart and can sonicate the different heart cavities through the acoustic window. The position of the ultrasound probe may be controlled by a high-precision positioning system. The positioning system enables delivery of focused ultrasound energy to precise locations within the heart. Temperature- sensitive magnetic resonance (MR) images obtained during the sonication process may be used to estimate the temperature and thermal dose. During sonication, the chest wall vest may be fitted with an active cooling system that may help dissipate thermal temperature as a result of chest wall absorption of ultrasound waves. [0039] Referring to FIG. 1, an example non-invasive therapeutic system 100 comprises a computing system 110 and one or more of an energy emission system 130, an imaging system 140, a gating and motion detection system 150, a temperature detection system 160, and an active cooling system 170. Computing system 110 (or multiple computing systems) is capable of communicating with systems 130, 140, 150, 160, and/or 170, directly or indirectly. In some embodiments, systems 130, 140, 150, 160, and/or 170 are able to communicate with each other, directly or indirectly (e.g., via computing system 110). Computing system 110 may be capable of transmitting instructions or other data to systems 130, 140, 150, 160, and 170, and receiving signals, readings, or other data therefrom.

[0040] Computing system 110 may include a controller 112 with one or more processors and one or more volatile and non-volatile memories for storing computing code, captured data, etc. The controller 112 may be capable of exchanging control signals with systems 140, 150, 160, and/or 170, allowing the computing system 110 to be used to control the acquisition of physiological or other data related to a subject, such as capture of images / signals via the sensors thereof. The controller 112 may be capable of exchanging control signals with energy emission system 130 to control application of thermal or other energy to a subject (e.g., energy level, timing, and/or aim), and with active cooling system 170 to reduce the temperature of one or more areas of the subject. The computing system 112 may also include a signal processor 114 that may perform computations and analyses using data from systems 130, 140, 150, 160, and 170. A transceiver 116 allows the computing system 110 to exchange readings, control commands, and/or other data with systems 130, 140, 150, 160, and/or 170, wirelessly or via wires. One or more user interfaces 118 allow the computing system to receive user inputs (e.g., via a keyboard, touchscreen, microphone, camera, etc.) and provide outputs (e.g., via a display screen, audio speakers, etc.). The computing system 110 may include treatment parameter adjuster 120 that may receive data from, for example, signal processor 114, determine suitable changes to treatment parameters, such as timing, targeting (aim), and intensity, and generate suitable control signals to instruct (e.g., via transceiver 116) systems 130, 140, 150, 160, and/or 170 to implement parameter adjustments or otherwise perform specified functions. The computing system 110 may also include one or more databases for storing, for example, signals acquired via one or more sensors of system 100. [0041] In various embodiments, energy emission system 130 of system 100 may comprise one or more ultrasound devices capable of emitting HIFU energy (e.g., via an ultrasound probe). In some implementations, the energy emission system 130 may additionally or alternatively comprise other sources of energy (thermal or otherwise).

[0042] In various embodiments, imaging system 140 may comprise any devices enabling mapping or visualization of anatomical or physiological features or processes. In various embodiments, imaging system 140 may include, for example, MR devices, echocardiography devices, computed tomography (CT) devices, or other imaging devices or sensors.

[0043] In various embodiments, gating and motion detection system 150 may include any devices capable of providing data on movements (rhythmic or otherwise) or changes in position. In various embodiments, gating and motion detection system 150 may comprise, for example one or more ECG devices that capture ECG signals corresponding with cardiac cycles (during which contraction and relaxation of heart muscle causes the heart to move) and stages or features thereof. In certain embodiments, ECG sensors may be incorporated into, for example, a wearable ECG vest that incorporates electrodes capable of detecting ECG signals when in contact with the skin of the subject. In certain embodiments, gating and motion detection system 150 may, alternatively or additionally, comprise motion sensors, sound sensors, and/or other sensors that inform on movements and changes in position. For example, motion and/or sound sensors may be used to detect breathing and identify respiratory cycles that affect changes in the position of an anatomical feature being targeted via energy emission system 130.

[0044] In various embodiments, temperature detection system 160 may include any devices capable of detecting or determining temperature or changes in temperature. Temperature detection system 160 may comprise, for example, one or more MR or other devices used to determine temperature using MR thermometry. Temperature may be monitored non- invasively using MR imaging based on temperature-sensitive MR parameters such as the proton resonance frequency, diffusion coefficient, Ti and T ₂ relaxation times, magnetization transfer, and proton density. In certain embodiments, temperature detection system 160 may, alternatively or additionally, comprise one or more temperature sensors capable of providing temperature data to determine, for example, how much thermal energy has been received by a subject (e.g., via energy emission system 130). In some embodiments, temperature detection system 160 may comprise a vest with temperature sensors secured thereto. In other embodiments, temperature detection system 160 may be part of such a vest.

[0045] In various embodiments, active cooling system 170 may include any devices capable of reducing a temperature of a subject and/or area. The active cooling system 170 may comprise cooling pads, vests, or any other suitable devices. Active cooling systems 170 are capable of implementing different levels of cooling. A level of cooling by active cooling system 170 may be changed automatically based on, for example, detected temperatures (which may be received from temperature detection system 160 and/or computing system 110), or on an as-instructed basis according to commands and instructions (from, e.g., computing system 110) regarding a degree to which an area is to be cooled based on various factors.

[0046] Referring to FIG. 2, an example process 200 for non-invasive application of thermal energy is illustrated according to potential embodiments. In various embodiments, process 200 may be implemented using system 100. At 205, computing system 110 may locate and/or identify a tissue to be targeted. In various implementations, the tissue may be cardiac tissue associated with an arrhythmia. The computing system 110 may control the imaging system 140 to image and/or map a region of interest (ROI), such as a cardiac region of a subject. For example, the computing system 110 may instruct an MR device to acquire an MRI image, an echocardiography device to acquire an echocardiogram, an

electrophysiology device (such as an ECG device) to acquire electrophysiological signals (such as ECG signals), and/or another device to acquire physiological data. In various implementations, computing system 110 (e.g., via signal processor 114) may use the imagery, signals, and/or other physiological data to locate myocardial or other tissue, and/or to identify an arrhythmia or other condition, to be treated.

[0047] At 210, the computing system 110 may, based on the physiological data received at 205, target the tissue or condition to be treated using energy emission system 130. In various embodiments, the computing system 110 may, for example, change a position of a subject (e.g., by moving a treatment or imaging platform on which the subject has been located for imaging and/or treatment) such that a tissue target is aligned with a path of the energy to be emitted using energy emission system 130. Alternatively or additionally, the computing system 110 may change the position of the energy emission system 130 (or one or more components thereof), with or without repositioning the subject, such that the energy from the energy source is aimed at the targeted tissue. For example, the computing system 130 may change a position of a HIFU probe (i.e., an ultrasound probe capable of emitting HIFU energy) or set a direction in which HIFU energy is directed from the HIFU probe (via, e.g., a high-precision positioning system).

[0048] At 215, the computing system 110 may check an aim of an energy emission device such as a HIFU probe. Aim may be ascertained based on, for example, alignment of a center of a targeted tissue with a center of an energy path, and/or on the degree of overlap of the target tissue with an energy beam from a probe or other emitter. In various embodiments, treatment parameter adjuster 120 may acquire imagery from imaging system 140, position data (e.g., data that is indicative of where an energy beam is aimed) from energy emission system 130, motion data from gating and motion detection system 150, and/or temperature data from temperature detection system 160. If energy has already been applied, aim may be checked using temperature data from temperature detection system 160. In such a case, the computing system 110 may ascertain the aim of the energy emission system 130 by determining, for example, which areas have experienced the greatest change (e.g., increase) in temperature. The computing system 110 may identify areas determined to have heated up the most being as likely being in the path of the energy beam. In some implementations, system 100 may include a 3D scanner, and the computing system 110 may use the 3D scanner or other positioning or orientation devices to determine the position, orientation, and/or posture of the subject in comparison with where the energy is directed by energy emission system 130.

[0049] At 220, the computing system 110 may determine whether the aim (determined at 215) is acceptable. In various embodiments, the computing system 110 may determine that aim is acceptable if, for example, a fraction of the energy reaching areas other than the tissue being targeted is sufficiently small, such as 20%, 10%, 5%, or less. The computing system 110 may use, for example, temperature data from temperature detection system 160, to determine whether areas other than a targeted tissue have been heated. In some

implementations, the computing system 110 may determine the aim to be acceptable if, for example, the largest detected temperature increases (e.g., at least 66%, 75%, 90%, or more) are in targeted tissue as opposed to, for example, tissue surrounding targeted tissue. In some implementations, the computing system 110 may determine the aim to be acceptable if, for example, a fraction of a heated area that is targeted tissue is sufficiently high relative to the fraction that is non-targeted tissue (e.g., at least 66%, 75%, 90%, or more of tissue that has been heated up was the intended target). The computing system 110 may, in some implementations, identify the non-targeted tissue (e.g., non-targeted tissue surrounding the targeted tissue, such as a sternum, lung, air cavity, or non-targeted chamber of the heart) that has heated up, and assess a risk of or sensitivity to heating of the non-target tissue. For example, aim may be determined to be acceptable if the sternum has heated up a certain number of degrees (e.g., 15 degrees) but unacceptable if non-targeted myocardial tissue adjacent to the targeted myocardial tissue has heated up a certain lower number of degrees (e.g., 5 degrees).

[0050] If the computing system 110 determines that the aim is not acceptable at 220, process 200 may return to 215 to recheck the aim, and/or may return to 210 to re-aim the energy emitter system 130. In certain embodiments, the computing system 110 may pause before (i.e., delay) aim recheck at 215 or re-aiming at 210, by default or based on various factors. The computing system 110 may delay aim recheck (215) or re-aim (210) in case the aim of the energy emitter was off-target (or otherwise unacceptable) due to an ephemeral state (e.g., a bump of the subject or of the equipment). In some embodiments, the computing system 110 may delay aim recheck (215) or re-aim (210) if, based on data from gating and motion detection system 150, the computing system 110 determines that the subject was in motion when the computing system 110 determined that the aim was unacceptable at 220. Alternatively or additionally, the computing system 110 may delay aim recheck (215) or re aim (210) if, based on data from gating and motion detection system 150, the computing system 110 predicts that, based on past movements (e.g., due to heartbeat, breathing, muscle contractions, etc.), a subsequent, impending movement is likely to realign the targeted tissue with the energy beam, rendering the aim acceptable without any change to the position of the subject (e.g., by moving a platform or on which a subject is positioned) or to where the energy beam is directed.

[0051] If aim is determined to be acceptable at 220, then process 200 may proceed to energy delivery at 250. The computing system 110 (via, e.g., the treatment parameter adjuster 120) may control the energy emission system 130 to apply energy at the targeted tissue. In various implementations, the treatment parameter adjuster 120 may determine a timing of energy emission. Timing of energy emission may comprise a duration for which energy is emitted (e.g., 5 seconds, 10 seconds, 30 second, etc.), and/or a pattern of emission (e.g., short or long bursts of energy, continuous energy emission, etc.). The treatment parameter adjuster 120 may, alternatively or additionally, determine an intensity for emitted energy. Intensity may comprise an energy level (e.g., in Watts), and/or may comprise a beam width for the energy emission (e.g., 0.25 millimeter, 1 millimeter, etc.). Where applicable, treatment parameter adjuster 120 may, alternatively or additionally, determine type or types of energy (if multiple energy sources are used), wavelengths of light, or any other parameter applicable to application of energy using energy emission system 130. In various

implementations, delivering energy at 250 comprises delivering thermal energy by sonicating myocardial tissue for, for example, ablation therapy for cardiac arrhythmia. Once energy is delivered according to selected treatment parameters (e.g., 9 seconds of HIFU at 400W directed at a side of a central fibrous body), process 200 may, in some implementations, return to checking of aim at 215.

[0052] At 225, the computing system 110 (via, e.g., treatment parameter adjuster 120) may set one or more treatment parameters (e.g., timing and/or intensity of energy to be delivered). In various embodiments, this may occur once a target tissue is located and/or identified at 225, once the energy emission system 130 is aimed at 210, once a certain amount of energy has been delivered at 250, and/or at another point. Treatment parameters may be based on data from, for example, imaging system 140, gating and motion detection system 150, temperature detection system 160, and/or other components of system 100.

[0053] In various implementations, step 225 may additionally or alternatively involve setting a cooling level for active cooling system 170. The computing system 110 may, for example, activate the active cooling system 170 if not active, or change a temperature of a component of the active cooling system 170 (e.g., the temperature of one or more cooling pads of the active cooling system 170, which may be part of a vest worn by the subject) to, for example, cool a tissue of the subject surrounding the targeted tissue to avoid or reduce damage to untargeted regions.

[0054] At 230, the computing system 110 may determine temperatures for various regions of interest of the subject. The computing system 110 may, for example, acquire temperature data from the temperature detection system 160 or a component thereof. The temperature data may be a temperature profile for a region, showing different temperatures and/or temperature changes for one or more regions of interest. The computing system 110 may, alternatively or additionally, acquire temperature readings from one or more temperature sensors located at different places on the subject. In some implementations, temperature sensors may be incorporated in a vest worn by the subject (e.g., the ECG vest).

[0055] At 235, the computing system 110 may determine whether one or more

temperatures of one or more regions of interest are acceptable. This may involve, for example, determining whether a temperature is too high (risking unintended tissue damage), or too low for effectiveness (e.g., not hot enough for an intended ablative therapy). In various embodiments, the computing system 110 may determine that a temperature is acceptable depending on the particular tissue. For example, a certain temperature increase may be deemed unacceptable for one tissue or tissue type (e.g., myocardial tissue adjacent to the targeted tissue), but may be deemed acceptable for another tissue or tissue type (e.g., bone).

[0056] If detected temperatures are determined to be acceptable at 235, then process 200 may proceed to energy delivery at 250. If the computing system 110 determines that one or more detected temperatures are not acceptable at 235, process 200 may return to 230 to recheck the temperature, and/or may return to 225 to reset or modify one or more treatment parameters and/or to change cooling level. In certain embodiments, the computing system 110 may pause (e.g., delay) temperature recheck at 230 or parameter change at 225. The computing system 110 may delay temperature recheck at 225 or parameter change at 225 if, for example, a region determined to be too hot is predicted to cool fairly rapidly (e.g., using a prior setting of active cooling system 170, or due to high blood flow in the area).

[0057] Computing system 110 may perform various steps of process 200 sequentially or in parallel in different embodiments. For example, the computing system may target tissue at 210 and set parameters at 225 at the same time or one step after the other. Similarly, computing system 110 may check aim at 215 (and/or determine its acceptability at 220) and, substantially at the same time, check temperature at 230 (and/or determine its acceptability at 235).

[0058] In various embodiments, two or more components, devices, or sub-systems of system 100 may be combined into one component, device, or sub-system. Similarly, one or more components, devices, or sub-systems of system 100 may be split into two or more components, devices, or sub-systems. Also, one component or device in system 100 may be used as part of two or more sub-systems. For example, an MR device may function as part of imaging system 140 for capturing MRI images used to locate a target, and may also function as part of temperature detection system 160 for determining temperature via MR- thermometry techniques. Moreover, various embodiments of system 100 may include only a subset of the sub-systems in FIG. 1, or may include additional sub-systems, components, and/or devices not depicted in FIG. 1.

[0059] Referring to FIG. 3, externally-applied ultrasound waves may interact with subjects in one of multiple ways. A certain fraction of incident ultrasound waves (302) may be reflected (304) without reaching a region of interest. Certain ultrasound waves (312) may be refracted (314), missing the targeted myocardial tissue. Ultrasound energy may be dissipated through circulating blood (322). Ultrasound waves (332) may also be absorbed by, for example, the sternum of the subject. A fraction of ultrasound waves (342) may reach the targeted myocardial tissue. An algorithm based on an individual’s anatomy and body habitus may be used in order to determine the optimal approach and required compensation in energy delivery as a result of ultrasound wave reflection, refraction and absorption in addition to heat dissipation by circulating blood.

[0060] One of the challenges associated with the use of ultrasound waves for myocardial ablation, according to various potential embodiments, involves overcoming absorption of ultrasound wave by bone and reflection by air-filled lung tissue. In alternative versions, different approaches may be used for ultrasound delivery. In some implementations, a direct pathway through the ribs / sternum with passive cooling may be used. In certain

implementations, a direct pathway through the ribs/sternum with active cooling may be used. In various embodiments, transesophageal HIFU with direct approach to the heart may be used.

[0061] The ability to precisely focus the ultrasound beam to a target region of interest, while simultaneously tracking temperature changes during therapy administration, represents a fundamental difference, and a novel application, of MRI-guided HIFU for the noninvasive ablation of cardiac arrhythmia, compared to currently described methodologies. In various embodiments, the disclosed approach may be used to treat a multitude of arrhythmogenic conditions, including both supraventricular and ventricular conditions, such as: atrial fibrillation, atrial tachycardia, atrial flutter, ventricular tachycardia, ventricular fibrillation, ventricular and atrial premature beats. [0062] Technological considerations in applying the disclosed approach to cardiac arrhythmia include the following: 1) Ultrasonic energy is absorbed by bone and reflected by air-filled structures, such as the lungs, and these structures may need to be avoided or the attenuation and heating associated with them accounted for; 2) Cardiac tissue is in constant contact with flowing blood, dramatically impacting heat transfer, depending on the flow of the blood and the depth of the tissue, and understanding these changes helps prevent adverse events, such as a cerebrovascular event, associated with heating of blood; 3) The heart is contractile, and accounting for motion and ensuring sonication is still precise and controlled is not addressed by other applications of HIFU.

[0063] An example procedural workflow for the noninvasive application of MRI-guided HIFU for myocardial ablation will now be discussed. This may involve evaluating the ability of HIFU to ablate myocardial tissue under static conditions with and without flow. MRI- guided HIFU can be targeted to an ex vivo phantom model of the heart, which may comprise a flow loop that circulates blood over myocardial tissue (taken from different regions of an explanted porcine heart). This may help characterize technical capabilities of the HIFU equipment, such as determination of maximal focal length and minimum spot size of the HIFU transducer within myocardial tissue. Here, in a very controlled manner, the relationship between the instrument target spot size and the produced lesion within the tissue can be understood. Furthermore, by providing a controlled flow loop to circulate blood, the flow dependent reduction in tissue heating can be evaluated as a function of tissue depth as well as the effect of tissue type. This helps ensure that all tissue, regardless of depth and local flow, receive the same effective dose. Furthermore, this approach allows for the study of these effects independent of confounding anatomic structures and cardiac motion that are present in small animals.

[0064] A computer controlled focused ultrasound system may be used for myocardial sonication. The system is capable of delivering exposures ranging from high-power continuous sonications for thermal coagulation of soft tissues, to pulsed sonications suitable for applications such as tissue lysis. The system is designed to be flexible, and is fully MRI- compatible, enabling the application of real-time imaging with MRI and subsequent monitoring of sonication effect on myocardial tissue after the administration of the therapeutic ultrasound doses. [0065] During sonication, MR imaging may be used to monitor any temperature change at the target area using a proton resonance frequency (PRF) shift technique known as MR thermometry. MR thermometry may be used in detecting changes in myocardial tissue temperature and adjacent blood, which may be simultaneously assessed by temperature sensors located near the target site. After sonication, the MR-HIFU system may calculate the thermal dose and show the area where the lethal thermal dose was delivered.

[0066] Example implementations may involve custom hardware that provides a seamless fluid filled interface between the HIFU tool and the tissue, while providing for controlled flow on the opposite tissue surface. Creation of these types of setups may involve highly customized chambers, experience with tissue and with sealed flow loops. Custom in vitro flow loops may be created based on 3D printed structures and cadaver tissue, specifically for the development of cardiac devices, thus supporting their suitability to develop the tools suited to this challenge.

[0067] Bone and air-containing tissue may also impact effectiveness of cardiac sonication. With conditions optimized or otherwise enhanced for performing cardiac sonication, the effects of anatomic features such as the ribs and lungs, which absorb and reflect ultrasound energy respectively, may be taken into account. To accomplish this, cadaver flow loops may be used that incorporate tissue with embedded bone and/or lungs (or synthetic, porous, air filled structures meant to simulate lung tissue). The disruption of targeted ultrasound may be assessed, and the extent of heating associated with bone structures may be used to calibrate system parameters. This methodology may help set the optimal path for HIFU sonication through the ribs of different subjects. Different approaches to active cooling may be used. HIFU of cardiac tissue can be achieved through the ribs with passive cooling, HIFU of cardiac tissue can be achieved through the ribs with active cooling, or a more complex approach such as transesophageal HIFU may be more suitable.

[0068] The disclosed approach provides the ability to ablate myocardial tissue in beating hearts. In addition, the approach accounts for cardiac motion, and what type of pulse dynamics (duration, frequency, intensity, etc.) result in the most reliable and localized ablation. Ultrasound wave delivery to the myocardium may be varied in the presence of atrial and ventricular arrhythmia that result in irregular cardiac pulsation (such as atrial fibrillation or ventricular tachycardia). Respiratory motion, pulse dynamics, and sonication route may be adjusted in order to accommodate for chest wall movement. [0069] In subjects with myocardial scarring and cardiac arrhythmia, electroanatomic mapping (with the help of ECGI) may be used to specifically target the arrhythmogenic focus, while monitoring for improvement and/or resolution of ectopic beats. Interactions between cardiopulmonary conditions (presence of lung disease), systemic diseases (presence of anemia and or inflammation), and other miscellaneous conditions (osteoporosis, presence of central venous catheters) may impact delivery of ultrasound waves for successful myocardial ablation in different subjects.

[0070] In various implementations, application of HIFU across the chest wall achieves enough penetration to ablate myocardial tissue despite the expected bone and lung

attenuation. Focused ultrasound waves may be gated to cardiac motion and respiratory movement.

[0071] In some implementations of the disclosed approach, an MRI-compatible image- guided focused ultrasound system may be incorporated into the overall system. The MRI- compatible image-guided focused ultrasound system may include a computer-controlled high-precision three-axis positioning system and a high-power focused ultrasound transducer coupled. The positioning system may enable delivery of focused ultrasound energy to precise locations in soft tissue. The system may fit within the bore of a clinical MR or CT scanner for image-guided treatment planning and delivery. The system may be completely non magnetic, enabling it to function within a high-field magnetic resonance imager for image- guided treatment planning and monitoring of ultrasound exposures. The system may additionally be compatible with x-ray CT imaging. The non-magnetic positioning system may be able to translate the transducer along arbitrary 3D paths during imaging. The delivery of ultrasound exposures may be achieved using images acquired with MRI or CT, depending on the configuration of the system. Real-time monitoring of forward and reflected electrical power to the transducer may enable consistent delivery of energy. The system is capable of delivering exposures ranging from high-power continuous sonications for thermal coagulation of soft tissues, to pulsed sonications suitable for applications such as tissue lysis, drug delivery, or vascular permeabilization.

[0072] Non-limiting examples of various embodiments are disclosed herein. Features from one or more embodiments disclosed herein may be combined with features of one or more other embodiments disclosed herein as someone of ordinary skill in the art would understand. [0073] As utilized herein, the terms“approximately,”“about,”“substantially” and similar terms are intended to have a broad meaning in harmony with the common and accepted usage by those of ordinary skill in the art to which the subject matter of this disclosure pertains. It should be understood by those of skill in the art who review this disclosure that these terms are intended to allow a description of certain features described without restricting the scope of these features to the precise numerical ranges provided. Accordingly, these terms should be interpreted as indicating that insubstantial or inconsequential modifications or alterations of the subject matter described and are considered to be within the scope of the disclosure.

[0074] For the purpose of this disclosure, the term“coupled” means the joining of two members directly or indirectly to one another. Physical joining may be stationary or moveable in nature. Such joining may be achieved with the two members or the two members and any additional intermediate members being integrally formed as a single unitary body with one another or with the two members or the two members and any additional intermediate members being attached to one another. Such joining may be permanent in nature or may be removable or releasable in nature. Communicative coupling involves the ability to communicate to exchange data, such as commands, instructions to perform functions or operations, data captured using devices with sensors, etc. Data may be exchanged wireless or via wires.

[0075] It should be noted that the orientation of various elements may differ according to other exemplary embodiments, and that such variations are intended to be encompassed by the present disclosure. It is recognized that features of the disclosed embodiments can be incorporated into other disclosed embodiments.

[0076] It is important to note that the constructions and arrangements of apparatuses or the components thereof as shown in the various exemplary embodiments are illustrative only. Although only a few embodiments have been described in detail in this disclosure, those skilled in the art who review this disclosure will readily appreciate that many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.) without materially departing from the novel teachings and advantages of the subject matter disclosed. For example, elements shown as integrally formed may be constructed of multiple parts or elements, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various exemplary embodiments without departing from the scope of the present disclosure.

[0077] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other mechanisms and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that, unless otherwise noted, any parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein.

It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0078] Also, the technology described herein may be embodied as a method, of which at least one example has been provided. The acts performed as part of the method may be ordered in any suitable way unless otherwise specifically noted. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0079] The indefinite articles“a” and“an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean“at least one.” As used herein in the specification and in the claims,“or” should be understood to have the same meaning as“and/or” as defined above. For example, when separating items in a list, “or” or“and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as“only one of’ or“exactly one of’ will refer to the inclusion of exactly one element of a number or list of elements. In general, the term“or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e.“one or the other but not both”) when preceded by terms of exclusivity, such as“either,”“one of,”“only one of,” or“exactly one of.”

[0080] As used herein in the specification and in the claims, the phrase“at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase“at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example,“at least one of A and B” (or, equivalently,“at least one of A or B,” or, equivalently“at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another

embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one,

B (and optionally including other elements); etc.

[0081] Embodiments of the present disclosure can be realized using any combination of dedicated components and/or programmable processors and/or other programmable devices. The various processes described herein can be implemented on the same processor or different processors in any combination. Where components are described as being configured to perform certain operations, such configuration can be accomplished, e.g., by designing electronic circuits to perform the operation, by programming programmable electronic circuits (such as microprocessors) to perform the operation, or any combination thereof. Further, while the embodiments described above may make reference to specific hardware and software components, those skilled in the art will appreciate that different combinations of hardware and/or software components may also be used and that particular operations described as being implemented in hardware might also be implemented in software or vice versa.

[0082] Computer programs incorporating various features of the present disclosure may be encoded and stored on various computer readable storage media; suitable media include magnetic disk or tape, optical storage media such as compact disk (CD) or DVD (digital versatile disk), flash memory, and other non-transitory media. Computer readable media encoded with the program code may be packaged with a compatible electronic device, or the program code may be provided separately from electronic devices (e.g., via Internet download or as a separately packaged computer-readable storage medium).

[0083] Embodiments of the disclosure relate to a non-transitory computer-readable storage medium having computer code thereon for performing various computer-implemented operations. The term“computer-readable storage medium” is used herein to include any medium that is capable of storing or encoding a sequence of instructions or computer codes for performing the operations, methodologies, and techniques described herein. The media and computer code may be those specially designed and constructed for the purposes of the embodiments of the disclosure, or they may be of the kind well known and available to those having skill in the computer software arts. Examples of computer-readable storage media include, but are not limited to: magnetic media such as hard disks, floppy disks, and magnetic tape; optical media such as CD-ROMs and holographic devices; magneto-optical media such as optical disks; and hardware devices that are specially configured to store and execute program code, such as application-specific integrated circuits (ASICs), programmable logic devices (PLDs), and ROM and RAM devices.

[0084] Examples of computer code include machine code, such as produced by a compiler, and files containing higher-level code that are executed by a computer using an interpreter or a compiler. For example, an embodiment of the disclosure may be implemented using Java, C++, or other object-oriented programming language and development tools. Additional examples of computer code include encrypted code and compressed code. Moreover, an embodiment of the disclosure may be downloaded as a computer program product, which may be transferred from a remote computer (e.g., a server computer) to a requesting computer (e.g., a client computer or a different server computer) via a transmission channel. Another embodiment of the disclosure may be implemented in hardwired circuitry in place of, or in combination with, machine-executable software instructions.

[0085] Although the disclosure has been described with respect to specific embodiments, it will be appreciated that the disclosure is intended to cover all modifications and equivalents within the scope of the following claims.