Focused ultrasonic treatment using mechanical and electronic control along a calculated trajectory.

Abstract

Title of Invention: Focused ultrasonic treatment by mechanical and electronic control along a calculated trajectory A computer execution method for controlling a device (1) intended for use in opening the blood-brain barrier, the method comprising the steps of: calculating a trajectory; generating a focused ultrasonic beam (12) that generates a focal point (13); and controlling the device (1) to move the focal point (13) along the trajectory to cover a predetermined target volume.

Description

Technical Field

[0001] The present invention generally relates to a computer-executable method for controlling an apparatus that generates focused ultrasound. The present invention is particularly noted for applications such as the opening of the blood-brain barrier. Background

[0002] In the field of treating central nervous system diseases, techniques have been developed to temporarily disrupt the blood-brain barrier by combining focused ultrasound with the circulation of microbubbles administered by intravenous injection.

[0003] These techniques make it possible to reversibly and non-invasively open the blood-brain barrier, but generally cannot open a large volume of the blood-brain barrier, such as a large volume of tumor. More generally, known techniques are not suitable for some clinical applications.

Summary of the Invention

[0004] To overcome the limitations of the prior art, the present invention provides a computer-executable method for controlling an apparatus that generates a focused ultrasound beam that generates a focus and is configured to enable electronic and / or mechanical steering of the focus, The method is - defining a trajectory of the focus based on one or more parameters selected from a list including a trajectory pattern, a movement speed of the focus, and an acceleration of the focus; - generating the focused ultrasound beam and controlling the apparatus to move the focus along the trajectory so as to cover a predetermined target volume.

[0005] Thus, according to the present invention, it is proposed to calculate a trajectory of the focus based on a predetermined target volume.

[0006] This inverse problem type approach makes it possible to define an appropriate or optimal opening trajectory taking into account the relevant parameters. In certain embodiments, the device is a medical device intended for use in opening the blood-brain barrier. The aforementioned predetermined target volume can typically correspond to the volume required for the blood-brain barrier to open, as defined by a physician.

[0007] The inventors have found that the proposed method makes it possible to increase the open volume of the blood-brain barrier compared to conventional manual techniques. The claimed method does not have to include surgical / therapeutic steps. In some embodiments, the step of controlling the device includes combining mechanical and electronic control of the focus. By combining mechanical and electronic control, it becomes possible to cover large volumes in a short period of time, particularly in a period of time equal to or similar to the time required to cover the surface forming a slice or layer of the said volume. Preferably, the step of controlling the device includes generating a focused ultrasonic beam with a series of ultrasonic pulses. Alternatively, the step of controlling the device may include generating a continuous focused ultrasonic beam. In some embodiments, the step of controlling the device includes shifting the focus between the ultrasonic pulses. One of the advantages of this particular type of combination is that it shortens the trajectory duration of a given target volume. Of course, it is possible to combine this with other types of mechanical and electronic manipulation, such as shifting the focus during a portion of the ultrasonic pulse, or more generally, during ultrasonic beam generation. In some embodiments, the predetermined target volume is defined as a series of layers. The layers may have a planar and / or curved shape. The layers can form continuous and / or discrete surfaces. Preferably, the layers are spaced apart from each other along the reference direction. The step of controlling the device may include generating a focused ultrasonic beam along the reference direction. In some embodiments, the step of defining the trajectory includes calculating the trajectory of the focus for each of the layers.

[0008] With respect to the direction of steering, the step of shifting the focus may include electronic steering in the reference direction, also called the first direction, and / or the second direction and / or the third direction, and / or any corresponding rotation, wherein the first, second and third directions are perpendicular to each other. The step of shifting the focus may include mechanical manipulation in a first direction and / or a second direction and / or a third direction and / or any corresponding rotation. Various combinations of electronic and / or mechanical control can be implemented, including the following non-limiting examples: In some embodiments, the step of shifting the focus includes electronic control in both first, second, and third directions. In some other embodiments, the step of shifting the focus includes mechanical manipulation in both first, second, and third directions. In yet another embodiment, the step of shifting the focus includes electronic control in the first direction and mechanical control in the second and third directions. In yet another embodiment, the step of shifting the focus includes electronic control in the first and third directions and mechanical control in the second direction. In yet another embodiment, the step of shifting the focus includes electronic control in the first direction and mechanical control in the first, second, and third directions. In some embodiments, the trajectory pattern parameter includes a pattern type parameter. For example, the pattern type parameter may be a spiral pattern or a pattern that includes multiple parallel line sections. The trajectory pattern parameters include pattern type parameters and may optionally include corresponding shape factor parameters. For example, the shape factor parameter may be the distance between predetermined points in the pattern. In some embodiments, the list of one or more parameters selected includes the temporal variation of a variable representing the microbubble concentration and the temporal variation of the sound pressure field.

[0009] In some embodiments, the moving velocity and / or acceleration of the focus are calculated as a function of the temporal change of a variable representing the microbubble concentration and / or the temporal change of the sound pressure field.

[0010] In some embodiments, the step of defining a trajectory includes simulating several trajectories and selecting one of these simulated trajectories.

[0011] Selecting one of the simulated trajectories is preferably done based on one or more criteria such as the duration of the trajectory to complete and / or the percentage of coverage of the target volume and / or the uniformity of exposure of the target volume. In another embodiment, the present invention is -A transducer configured to generate a focused ultrasonic beam that creates a focus, - Electronic and / or mechanical control means configured to move the focus, - To provide an apparatus having means configured to perform the steps of the method defined above. In some embodiments, the apparatus includes a robotic arm that supports a transducer and forms the mechanical maneuvering means.

[0012] In yet another aspect, the present invention provides a computer program that includes instructions causing an apparatus as defined above to perform steps of the method as defined above. In yet another aspect, the present invention provides a computer-readable storage medium storing the above-specified computer program.

[0013] The present invention, as well as all aspects, embodiments, and advantages related thereto, will become more readily apparent upon consideration of the following detailed description of specific embodiments provided below, including the accompanying drawings.

Brief Description of the Drawings

[0014] In the following, non-limiting embodiments of the present invention will be described with reference to the accompanying drawings. [Figure 1] It is a schematic diagram of the device according to the present invention. [Figure 2] It is a schematic diagram of the method according to the present invention. [Figure 3] It is a schematic diagram of a target volume defined by multiple layers. [Figure 4] It is a schematic diagram of the layer of the target volume and the locus of the focus related to this layer. [Figure 5] It is a schematic diagram of the ultrasonic treatment scheme according to the present invention. Detailed Description of the Invention

[0015] FIG. 1 schematically shows a device 1 according to a non-limiting embodiment of the present invention. In this example, the device 1 is intended to be used for opening the blood-brain barrier. The device 1 in FIG. 1 includes a robotic arm 2, a holder 3, a transducer 4, and computer control means 5.

[0016] In this embodiment, the arm 2 includes components 6 to 9 connected to each other by pivot links defining six degrees of freedom. More specifically, the component 6 forming the base of the arm 2 is connected to the component 7 by two pivot links. The components 7 and 8 are connected to each other by one pivot link. The component 8 forms the end element of the arm 2 and is connected to the element 9 by three pivot links. The transducer 4 is connected to the end element 8 of the arm 2 via the holder 3.

[0017] Figure 1 shows a first orthogonal spatial system formed by directions D1, D2, and D3, and a second orthogonal spatial system formed by directions D4, D5, and D6. The first system is associated with the base 6 of arm 2, and the second system is associated with transducer 4.

[0018] In this example, transducer 4 is a conventional medical transducer configured to generate ultrasonic pulses by an array of piezoelectric elements, the phases of which can be individually modified and together define a concave active surface 11.

[0019] As is known, such transducers 4 are typically a few millimeters in size. 3 This enables the generation of a focused ultrasonic beam 12 to produce a focal point 13 having an elliptical shape. The position of the focal point relative to the active surface 11 can be changed by controlling the phase of the piezoelectric element.

[0020] In this example, the piezoelectric elements are distributed concentrically around the axis A1 of the transducer 4, which is parallel to D4, and the focal position can be changed only with respect to the focal length, i.e., the distance between the active surface 11 and the focal point 13 along the transducer axis A1.

[0021] In the embodiment shown in Figure 1, the arm 2, as a result of its degrees of freedom, can be controlled to move the transducer 4 in any of directions D1, D2, and D3, or in any combination of these directions and corresponding rotations. Thus, the arm 2 constitutes a mechanical maneuvering means in the sense that the mechanical displacement of its parts 7, 8, and 9 relative to part 6 allows the position of the focus 13 to be changed according to D1 and / or D2 and / or D3.

[0022] In addition, the transducer 4 constitutes an electronic control means in that the phase control of its piezoelectric element allows for changing the position of the focal point 13 along the transducer axis A1 and then direction D4 in this example.

[0023] Referring to Figure 1, the computer control means 5 is configured to control both the arm 2 and the transducer 4 in order to move the focus 13 mechanically and / or electronically.

[0024] Means 5 include a computer-readable storage medium storing a computer program for controlling the arm 2 and transducer 4 as described below, or in accordance with any other method of carrying out the present invention. Referring to Figure 2, the present invention relates to a computer execution method 20 for controlling the apparatus 1 of Figure 1, or any other apparatus suitable for performing such an operation.

[0025] In this example, method 20 includes a step 21 for determining a target volume, a step 22 for defining the trajectory of the focal point 13, and a step 23 for controlling the apparatus 1, the latter of which is broken down into a step 24 for generating the focused ultrasonic beam 12 using the transducer 4, and a step 25 for moving the focal point 13 along the trajectory defined in step 22 to cover the target volume determined in step 21. Determination of target volume In applications of opening the blood-brain barrier, the target volume can be predetermined by a physician, typically using medical imaging. Referring to Figure 3, the target volume 30 can have a relatively complex geometric shape and can be approximated by an irregular polyhedral structure. In this example, the computer program of the present invention is an algorithm that defines the target volume 30 as a series of layers 31.

[0026] In the example shown in Figure 3, the target volume 30 is defined here using five planar layers 31 spaced apart from each other along the reference direction, which in this case corresponds to direction D4. Thus, each of the layers 31 extends parallel to directions D5 and D6. The algorithm determines the number of layers 31 required to cover the target volume 30. This can be done using a predetermined distance between each pair of adjacent layers 31. Trajectory definition In this example, the locus solution for focus 13 is calculated for each of the layers 31. Figure 4 shows an example of the locus 32 for one layer 31. The trajectory solution can be explained in terms of the trajectory pattern and the velocity and / or acceleration of the focal point 13. The values ​​of one or more of these parameters are typically stored and selected by an algorithm.

[0027] For example, with respect to the velocity or acceleration parameter of the focus 13, the moving velocity may be constant over time in correspondence with the zero acceleration of the focus 13, or it may decrease over time as a function of time, for example, constantly or exponentially.

[0028] In the example of blood-brain barrier opening applications, the movement speed and acceleration of the focus 13 are preferably calculated as a function of the temporal change of a variable representing the microbubble concentration. In fact, it is known in the art that the concentration of microbubbles decreases exponentially over time after their injection. Therefore, the speed of the focus 13 can be decreased in response to the passage of time to allow for a longer sonication period over tissues with lower microbubble concentrations, ensuring compensation for the decreasing microbubble concentration. Referring to the trajectory 32 in Figure 4, the movement speed of the focus 13 decreases over time from the starting point 33 to the ending point 34 of the trajectory 32. In this application, the velocity and acceleration of focus 13 can also be calculated as a function of the sound pressure field, which can be estimated using known techniques. Regarding the trajectory pattern parameters, this example will explain the pattern type and the corresponding shape factors.

[0029] In the example in Figure 4, the pattern type of the trajectory 32 is a spiral shape, i.e., a curve that wraps around a point through which, for example, transducer axis A1 passes, gradually becoming closer together and thus forming loops that extend radially from one another.

[0030] The distance between the loops, in other words, the distance between a predetermined portion or point I1, I2, I3... that can be formed by the intersection of the straight line L1, which is parallel to directions D5 and D6 and extends radially, and the trajectory 32, can define the shape factor of the trajectory pattern. In the example in Figure 4, the distance between two adjacent points I1, I2, I3... decreases overall from the outside to the inside of the pattern, i.e., from the start point 33 to the end point 34 of the trajectory 32.

[0031] In this example of a spiral pattern, the distance between the spiral loops decreases overall as sonication progresses, which can result in overlap of sonication regions that take into account the decrease in microbubble concentration over time.

[0032] In other words, both the velocity / acceleration parameter and the trajectory pattern parameter can be calculated as a function of the change in microbubble concentration, and the decrease in microbubble concentration over time requires longer sonication to achieve opening of the blood-brain barrier in this example.

[0033] Therefore, the algorithm can first simulate trajectory solutions using several parameters, in this example, the moving velocity / acceleration of focus 13, the trajectory pattern, the temporal change in microbubble concentration, and the sound pressure field. The algorithm can then compare these simulated trajectory solutions to identify, for example, the trajectory with the best balance between overlap and ultrasonic processing speed.

[0034] In this example, the algorithm calculates the trajectory solution for each layer 31 based on the displacement of the focal point 13 from one layer 31 to another between ultrasonic pulses, and the ultrasonic processing is pulse-width modulated with a duty cycle in the range of, for example, 1% to 10% in this example.

[0035] Such an ultrasonic treatment scheme, as shown in Figure 5, increases efficiency and ensures focused ultrasonic energy delivery for cavitation at multiple depths during the same pulse width modulation period.

[0036] Figure 5 shows the ultrasonic processing scheme in a chart where the horizontal axis XX defines time and the vertical axis YY defines focused ultrasonic output. The period from time X1 to time X11 corresponds to the pulse width modulation period. The periods between X1 and X2, between X3 and X4, between X5 and X6, between X7 and X8, and between X9 and X10 correspond to the periods during which the first, second, third, fourth, and fifth layers of the layer 31 are ultrasonically processed, respectively. The focal point 13 is displaced from one layer 31 to another between ultrasonic pulses, i.e., between X2 and X3, between X4 and X5, between X6 and X7, between X8 and X9, and between X10 and X11.

[0037] Therefore, referring to Figures 3 and 4, the resulting trajectory is the convolution of the displacement of the focal point 13 in directions D5 and / or D6 during the ultrasonic pulse and the displacement of the focal point 13 in direction D4 between ultrasonic pulses. Simulation and optimization

[0038] The three-dimensional trajectory of focus 13 can be written in a parametric form in which the elements of vector Λ are formed by parameters such as the velocity of focus 13 in a given layer 31, shape factors such as helical width attenuation and initial values ​​of the shape factors, and the distance between layers 31. Such a parametric form makes it possible to design an optimization scheme that iteratively changes the parameters of vector Λ.

[0039] In this example, a simulator is implemented to test each candidate trajectory. The simulator is preferably encapsulated within a loss function for feedback to the optimization loop. The loss function can be a combination of total sonication time, coverage, and uniformity, as defined by the following equation. L G (Λ)=Q(f(T),g(C),h(H))

[0040] In the formula, G is the physical configuration (e.g., transducer and microbubble setup), T is the sonication duration, C is the coverage percentage defined as a floating-point number ∈[0,1] equal to the area divided by the target volume when the sonication is greater than a predetermined threshold, and H is the area within the target volume.

[0041]

number

[0042] The uniformity descriptors correspond to the standard deviation of (see below), and the functions f, g, and h are designed to guide the optimizer toward good points for different optimization targets. In this example, these functions are simple linear functions with different weight values. T is integral

[0043]

number

[0044] It can be calculated as follows, where B is the locus length. Q is the result L obtained by combining functions f, g, and h. G This is a relational function that creates an additive and / or multiplicative relation between f, g, and h. For example, but not limited to this, Q can result in an additive and / or multiplicative relation between f, g, and h.

[0045] The duration τ under a sound pressure field p(X, t) with microbubble concentration c(t) t To quantify the transmittance of point X at time t after ultrasonic treatment, the following formula can be used.

[0046]

number

[0047]

number

[0048] The quantity Γ can be rewritten as the sum of exposure periods collected only when p(X,t)>0 over the entire sonication period, i.e., when point X is within the effective pressure field. Since some sonication can deliver ultrasonic cavitation energy to point X within the overlapping region, the quantity Γ can be written in vectorized discrete form. The subscript k below indicates the time samples combined to achieve a complete simulation iteration. Square brackets and parentheses are for spatial vectorization and temporal discretization, respectively.

[0049]

number

[0050] The duration of ultrasonic treatment can be controlled by changing the speed of transducer 4. For W and the focal volume width in the direction of movement of transducer 4 at speed v(t), the resulting ultrasonic treatment time is

[0051]

number

[0052] After generating simulations of candidate trajectories described by the vector Λ, other trajectories can be computed using a pattern search algorithm, such as the so-called Hooke-Jeeves pattern search algorithm.

[0053] The simulator output for the trajectory can be evaluated using appropriate metrics, such as operating time, exposure uniformity, and coverage percentage. These metrics can be adjusted by the physician. The evaluation of the trajectory can be calculated, and the optimizer can adjust to a better point Λ by changing the trajectory parameters. The optimization iteration can be stopped after convergence. A suitable trajectory covering the target volume 30 can be defined using the above principles, but not limited to them. Focus formation and shift

[0054] In the examples shown in Figures 1 and 2, transducer 4 is controlled to generate a focused ultrasonic beam 12 along axis A1 using a series of ultrasonic pulses to produce a focal point 13, and both arm 2 and transducer 4 are controlled to move the focal point 13 along the trajectory defined in step 22 to cover the target volume 30.

[0055] Referring to Figures 1, 3, and 4, and the above description, the displacement of the focal point 13 within a given layer 31 is achieved by moving arm 2 so as to displace the focal point 13 in directions D5 and D6. In other words, ultrasonic treatment of a given layer 31 is achieved by mechanical manipulation of transducer 4. The displacement of the focal point 13 from one layer 31 to another is achieved by electronic manipulation between ultrasonic pulses. Therefore, in this example, device 1 is controlled to combine mechanical and electronic control.

[0056] Many modifications can be made to the embodiments and principles described above. For example, the transducer 4 may include piezoelectric elements distributed both circumferentially and radially with respect to the transducer axis A1, allowing the focus 13 to be changed in both directions D4, D5, and D6. More generally, the focus 13 can be moved using any combination of mechanical and electronic control, for example, mechanical control in only one of directions D4, D5, and D6 and electronic control in the other two directions.

[0057] As a non-limiting alternative, the transducer 4 can be controlled to generate a continuous focused ultrasonic beam 12, and / or the target volume can be defined using a non-planar layer, such as a curved layer, and / or the pattern type parameter can include a pattern having multiple line portions parallel to each other.

Claims

1. A computer execution method (20) for controlling a device (1), a medical device in particular intended to be used to open the blood-brain barrier, The apparatus (1) is configured to generate a focused ultrasonic beam (12) that generates a focal point (13), and to enable electronic and / or mechanical manipulation of the focal point (13), and the method (20) is, - A step (22) of defining the trajectory (32) of the focus (13) based on one or more parameters selected from a list including a trajectory pattern, the moving speed of the focus (13), and the acceleration of the focus (13), A method comprising: a step (23) of controlling the apparatus (1) to generate (24) the focused ultrasonic beam (12) and to move (25) the focal point (13) along the trajectory (32) so as to cover a predetermined target volume (30), wherein the step (23) of controlling the apparatus (1) includes a step (23) of combining mechanical and electronic control of the focal point (13).

2. The method according to claim 1 (20), wherein the step (23) of controlling the apparatus (1) includes (24) generating the focused ultrasonic beam (12) with a series of ultrasonic pulses.

3. The method (20) of claim 2, wherein the step (23) of controlling the apparatus (1) includes moving the focal point (13) between the ultrasonic pulses (25).

4. The method according to any one of claims 1 to 3 (20), wherein the predetermined target volume (30) is defined as a series of layers (31).

5. The method according to claim 4 (20), wherein the layers (31) are spaced apart from each other along a reference direction (D4), and the step (23) of controlling the apparatus (1) preferably includes generating the focused ultrasonic beam (12) along the reference direction (D4) (24).

6. The method (20) of claim 4 or 5, wherein the step (22) of defining the trajectory (32) includes calculating the trajectory of the focus (13) for each of the layers (31).

7. The aforementioned trajectory pattern parameters are, - Pattern type parameter, for example, a spiral pattern, or a pattern containing multiple parallel line sections, and optionally, - The method according to any one of claims 1 to 6, including a corresponding shape factor parameter, for example, the distance between predetermined points of the pattern (20).

8. The method according to any one of claims 1 to 7 (20), wherein the list from which one or more parameters are selected includes a temporal change in a variable representing the microbubble concentration and the sound pressure field.

9. The method according to claim 8 (20), wherein the moving velocity and / or acceleration of the focus (13) is calculated as a function of the temporal change of a variable representing the microbubble concentration and / or the sound pressure field.

10. The method (20) according to any one of claims 1 to 9, wherein the step (22) defining the trajectory (32) includes simulating several trajectories and selecting one of the simulated trajectories based on one or more criteria such as the time to complete the trajectory (32) and / or the percentage of coverage of the target volume (30) and / or a factor of uniformity of exposure of the target volume (30).

11. - A transducer (4) configured to generate (24) a focused ultrasonic beam (12) that creates a focal point (13), - Electronic and / or mechanical control means (2, 4) configured to move (25) the focal point (13), Apparatus (1) having means (5) configured to carry out the steps (20) of the method described in any one of claims 1 to 10.

12. The apparatus (1) according to claim 11, comprising a robotic arm (2) that supports the transducer (4) and forms the mechanical operating means.

13. A computer program comprising instructions causing the apparatus (1) according to claim 11 or 12 to perform the steps of the method (20) according to any one of claims 1 to 10.

14. A computer-readable storage medium storing the computer program described in claim 13.

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