US-12616447-B2 - Method and system for spectral analysis and determination of a marker making it possible to ensure the safety of therapeutic ultrasound interventions

US12616447B2US 12616447 B2US12616447 B2US 12616447B2US-12616447-B2

Abstract

A method for performing spectral analysis and determining a safety marker includes an assembly via which: regularly, during shot Bb, at a series of times ta, the variation as a function of time in the spectral lines corresponding to the subharmonic and ultra-harmonic frequencies of a received acoustic-response signal of the microbubbles is measured, and the variation as a function of time, over the times ta, in a safety marker is determined and quantified, the safety marker being defined, at each time ta, by a number MDDa equal to the ratio of the sum of the areas of the spectral lines, measured at the time ta and corresponding to the subharmonic and/or ultra-harmonic frequencies of the received acoustic-response signal of the microbubbles, to the sum of the areas of the spectral lines, measured at the first time t 1 and corresponding to the subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles. A system for performing spectral analysis and determining a safety marker implements said method.

Inventors

ANTHONY NOVELL
HERMES SALLES KAMIMURA
Benoît LARRAT

Assignees

COMMISSARIAT A L'ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES

Dates

Publication Date: 20260505
Application Date: 20191016
Priority Date: 20181024

Claims (12)

1 . A system for performing spectral analysis and determining a safety marker that is representative of a state of destabilization of microbubbles contained in a region of a soft vascularized biological tissue, said microbubbles comprising an envelope and said microbubbles having an initial state, said microbubbles being subjected to an ultrasonic excitation signal at a predetermined emission frequency f 0 in order to induce localized and reversible opening of one or more biological barriers in said region, and said state of destabilization of the microbubbles being a modification of said initial state of the microbubbles associated with a buckling of the envelope of the microbubbles and detrimental to the soft vascularized biological tissue, said ultrasonic excitation signal being formed by an ultrasonic sequence composed of a predetermined integer number Nb, higher than or equal to 1, of wave trains, called “shots”; and wherein the system is configured to, after each shot Bb is triggered, b being comprised between 1 and Nb: regularly measure, during each said triggered shot Bb in a series of times ta, a variation as a function of time in one or more spectral lines corresponding to one or more subharmonic and/or ultra-harmonic frequencies of an acoustic-response signal received from the microbubbles, the acoustic-response signal being detected by a passive cavitation detector having a predetermined detection passband, and determine and quantify, the variation as a function of time, over the times ta of said series of times ta, in a safety marker that is defined, at each time ta of said series of times ta, by a number MDD a equal to a ratio of a sum of the areas of the spectral lines, measured at said time ta and corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles, to the sum of the areas of the spectral lines, measured at a first time t 1 of said series of times ta and corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles in said initial state of the microbubbles, and wherein said spectral lines corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles exploits the acoustic-response signal received in an observation window or analysis window (wa) that contains said time ta and that is included in a reception time interval corresponding to said triggered shot Bb, the system being configured, for one of the shots Bb called given shot Bb, in a first measuring and segmenting step, to break up the acoustic-response signal of the microbubbles to the given shot Bb into a predetermined integer number k, k being higher than or equal to 2, of time windows wa, a varying from 1 to k, of equal durations that allow a variation in frequency components during the given shot Bb to be determined, said acoustic-response signal being received and measured by the passive cavitation detector, the duration of the time windows wa being comprised between a duration of 8 cycles of the ultrasonic excitation signal and half a duration T B of one shot; and/or the number k of time windows wa being higher than or equal to 2 and lower than or equal to one eighth of the product of the duration TB of one shot multiplied by the predetermined emission frequency f 0 .
2 . The system of claim 1 , wherein the observation or analysis windows (wa) are adjacent or separate or partially overlap pairwise.
3 . The system of claim 1 , wherein the number k of time windows wa and their sizes tw depend directly on a duration and on the predetermined emission frequency f 0 of the given shot Bb, the duration of the given shot being comprised between at least one microsecond and hundreds of milliseconds.
4 . The system of claim 1 , configured to, a shot Bb being given with b comprised between 1 and Nb, in a spectra-computing second step, which is executed after said first measuring and segmenting step, compute, for each of the time windows wa of the shot Bb, a varying from 1 to k, a frequency spectrum of a portion, of the acoustic-response signal of the microbubbles to the shot Bb, that is contained in said window wa.
5 . The system of claim 4 , wherein the spectra-computing of the frequency spectrum uses a Fourier transform.
6 . The system of claim 4 , configured to, in a third step of computing a variation, during the shot, in a cavitation signal s(a), which step is executed after the spectra-computing second step, compute, for each time window wa, a varying from 1 to k, the cavitation signal s(a) to be the sum of the areas of the spectral lines measured at the time ta and corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles.
7 . The system of claim 6 , wherein a number of ultra-harmonic and/or subharmonic components considered in the computation of the cavitation signal s(a) depends on the predetermined detection passband of one or more transducers used to detect the cavitation and that form the passive cavitation detector.
8 . The system of claim 6 , wherein said one or more ultra-harmonic and/or subharmonic components corresponds to measured peaks in said spectral lines, and wherein an amplitude of the measured peaks of the one or more ultra-harmonic and/or subharmonic components comprised in the predetermined detection passband of the passive cavitation detector are used in addition to or instead of the cavitation signal s(a) in the third step of computing.
9 . The system of claim 6 , configured to, in a fourth step of computing a variation, during the shot, in said cavitation signal s(a), which step is executed after the third step, compute, for each time window wa of the shot Bb, a varying from 1 to k, a cavitation dose safety marker defined by the number MDDa equal to a ratio of the cavitation signal s(a) in the a-th window of time windows wa to a cavitation signal s( 1 ) of a first time window w 1 , the cavitation dose being expressed on a linear or logarithmic scale.
10 . The system of claim 9 , configured to, for one of the shots Bb called given shot Bb, b being comprised between 1 and Nb, in a fifth step of computing a variation, during the shot, in a first warning parameter Al 1 ( a ) and/or in a second warning parameter Al 2 ( a ), which step is executed after the fourth step, put the first warning parameter Al 1 ( a ) in first active state when the cavitation dose safety marker exceeds a first predetermined safety threshold value Th 1 , and put the second warning parameter Al 2 ( a ) in a second active state when a number of times nf the cavitation dose safety marker has exceeded the first predetermined safety threshold value Th 1 has exceeded a second predetermined threshold value Th 2 .
11 . The system of claim 10 , configured to, in a sixth step, which step is executed after the fifth step, transmit, to a controller device that intervenes in a feedback loop controlling shot parameters: the cavitation dose delivered in the fourth step, said cavitation dose varying during the shot; and/or the variation of the first warning parameter Al 1 ( a ) and/or of the second warning parameter Al 2 ( a ) as determined in the fifth step.
12 . A system for providing ultrasonic assistance to a therapeutic treatment targeting a region of a soft vascularized biological tissue containing microbubbles, said microbubbles, said microbubbles comprising an envelope and said microbubbles having an initial state, the system comprising: an ultrasonic device configured for exciting and emitting an ultrasonic sequence of one or more excitation shots at a predetermined emission frequency f 0 , said excitation shots being focused on the region to be treated of the soft vascularized biological tissue, a passive cavitation sensor for detecting and measuring a response of the microbubbles contained in the region in response to the excitation shots of the therapeutic sequence, a system for performing spectral analysis and determining a safety marker that is representative of a state of destabilization of the microbubbles, said state of destabilization of the microbubbles being a modification of said initial state of the microbubbles associated with a buckling of the envelope of the microbubbles, and a controller device for controlling parameters of the one or more excitation shots of the ultrasonic device, the passive cavitation sensor, the system for performing spectral analysis and determining a safety marker, the controller device and the ultrasound device being placed in series in a chain so as to form a safety feedback loop, wherein the safety marker is representative of the state of destabilization of microbubbles contained in the region of the soft vascularized biological tissue, said microbubbles being subjected to an ultrasonic excitation signal at the predetermined emission frequency f 0 in order to induce localized and reversible opening of one or more biological barriers in said region, and said state of destabilization of the microbubbles being detrimental to the soft vascularized biological tissue, said ultrasonic excitation signal being formed by the ultrasonic sequence composed of a predetermined integer number Nb, higher than or equal to 1, of wave trains, called “shots”; and wherein the system for performing spectral analysis and determining a safety marker is configured to, after each shot Bb is triggered, b being comprised between 1 and Nb: regularly measure, during each of said triggered shot Bb in a series of times ta, a variation as a function of time in one or more spectral lines corresponding to one or more subharmonic and/or ultra-harmonic frequencies of an acoustic-response signal received from the microbubbles, the acoustic response signal being detected by a passive cavitation detector having a predetermined detection passband, and determine and quantify, the variation as a function of time, over the times ta of said series of times ta, in a cavitation dose safety marker that is defined, at each time ta of said series of times ta, by a number MDDa equal to a ratio of a sum of the areas of the spectral lines, measured at said time ta and corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles, to the sum of the areas of the spectral lines, measured at a first time t 1 of said series of times ta and corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles in said initial state of the microbubbles, and wherein said spectral lines corresponding to the one or more subharmonic and/or ultra-harmonic frequencies of the acoustic-response signal of the microbubbles exploits the acoustic-response signal received in an observation window or analysis window (wa) that contains said time ta and that is included in a reception time interval corresponding to said triggered shot Bb, the system for performing spectral analysis and determining a safety marker being configured, for one of the shots Bb called given shot Bb, in a first measuring and segmenting step, to break up the acoustic-response signal of the microbubbles to the given shot Bb into a predetermined integer number k, k being higher than or equal to 2, of time windows wa, a varying from 1 to k, of equal durations that allow a variation in frequency components during the given shot Bb to be determined, said acoustic-response signal being received and measured by the passive cavitation detector, the duration of the time windows wa being comprised between a duration of 8 cycles of the ultrasonic excitation signal and half a duration T B of one shot; and/or the number k of time windows wa being higher than or equal to 2 and lower than or equal to one eighth of the product of the duration T B of one shot multiplied by the predetermined emission frequency f 0 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a National Stage of International patent application PCT/EP2019/078098, filed on Oct. 16, 2019, which claims priority to foreign French patent application No. FR 1859826, filed on Oct. 24, 2018, the disclosures of which are incorporated by reference in their entirety. FIELD OF THE INVENTION The present invention relates to a method for performing spectral analysis of the acoustic response of a biological tissue and for determining a safety marker allowing the safety of therapeutic ultrasound interventions to be ensured. The invention also relates to a corresponding system for performing spectral analysis of the acoustic response of a biological tissue and for determining a safety marker allowing the safety of therapeutic ultrasound interventions to be ensured. BACKGROUND The biological tissue is any soft vascularized biological tissue, for example a tissue comprised in the set of the tissues of the brain, liver, heart, muscles, breasts, kidneys, eyes, thyroid, prostate, uterus, tendons, pancreas, and skin, and preferably a brain tissue. Despite the increase in the number of active drugs and the emergence of targeted therapies in oncology, the therapeutic progress that has been made with respect to brain diseases (cancer included) still remains modest. One of the major obstacles resides in the inability to deliver therapeutic molecules to the tissues in a specific and controlled manner. Specifically, the walls of the blood vessels of the brain form a very effective endothelial barrier called the blood-brain barrier. This barrier limits the passage of molecules from the blood to the cells to be treated. Current methods for administering therapeutic agents are invasive, non-localized, or pose a high risk to the patient. Furthermore, the free circulation of therapeutic substances through the organism has undesirable effects on healthy tissues. Efficient, specific and localized delivery of therapeutic molecules is therefore a major challenge. Since 2000, many studies have demonstrated that focused ultrasound may be used to accomplish this task. Combined with the intravenous injection of gas microbubbles, ultrasound may be used to induce localized and reversible opening of biological barriers. Specifically, the mechanical forces (i.e., micro-flows and oscillations) resulting from the bubble-ultrasound interactions (cavitation) weaken the barrier and promote the passage of molecules into the brain tissue in general, and in particular into the diseased region that it is sought to treat if the latter is correctly targeted by the ultrasound beam. The treatment possibly lasting several hours, how effectively the barrier is kept open in terms of passage of large molecules and the safety of the technique may be controlled by modifying ultrasonic parameters. The delivered “cavitation dose” plays a major role in the effectiveness and safety of this technology. The acoustic pressure within the treated tissue must be sufficient to cause a controlled oscillation of the microbubbles (stable cavitation regime) and to generate a reversible and non-lesional permeabilization of the vascular walls. In contrast, subjected to excessively high acoustic pressures, the microbubbles then enter into an inertial cavitation regime involving locally violent physical effects (i.e. shock waves, micro-jets, local implosion of the bubble) that may lead to deterioration of tissues and to the onset of serious side effects (e.g., inflammation, hemorrhaging). The difference between an effective dose and a lesional dose is small and hence new precise in situ dosimetry methods need to be developed. As this technology is about to start clinical trials, it would be highly desirable to be able to control cavitation dose in real time. In the context of opening of the blood-brain barrier by ultrasound, the objective is to keep a high degree of stable cavitation (effectiveness) during the treatment while keeping inertial cavitation at a low level (safety). In trans-skull ultrasound therapy, the non-uniformity of the skull may have an undesirable influence on the effectiveness and safety of the technique. Specifically, since the thickness of the skull varies depending on the region, the attenuation of the ultrasound beam is correspondingly modified. The amplitude of the ultrasonic wave may easily vary by a factor of 2 from one point to another in humans. For large animals and more particularly non-human primates, the presence of tissues (e.g. muscles) between the skin and the skull may also affect the ultrasound beam. Thus, when the ultrasound is transmitted through a region that is thicker than expected, the amplitude of the ultrasonic wave in the region of interest will be lower and the treatment potentially ineffective (i.e., the acoustic pressure will be insufficient to allow a noticeable oscillation of the microbubbles to be achieved). In contrast, if the region is thinner, the amplitude of th