Reducing electrical induction while treating subject using alternating electric field by controlling climb characteristics

Abstract

When an array of transducers (i.e., an array of electrode elements) is used to apply an alternating electric field to a subject's body, the subject may experience electrical induction. This electrical induction can be improved by changing the manner in which the voltage climbs from zero to its peak when an AC voltage is applied for the first time to any given transducer array and also when the alternating electric field switches direction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 411,725, filed on September 30, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Tumor Treating Field (TT Field) therapy is a proven method for treating tumors using alternating electric fields with frequencies between 50 kHz and 1 MHz (e.g., 150 kHz to 200 kHz). In the system, the TT field is delivered to the patient via four transducer arrays placed on the patient's skin near the tumor. These transducer arrays are arranged in two pairs, one pair of transducer arrays is located on the left and right sides of the tumor, and the other pair of transducer arrays is located on the front and back sides of the tumor. Each transducer array is connected to an AC signal generator via a multi-wire cable. The AC signal generator (a) sends an AC current through the pair of front / rear (A / P) transducer arrays for 1 second, which induces an electric field with a first direction through the tumor; then (b) sends an AC current through the pair of left / right (L / R) arrays for 1 second, which induces an electric field with a second direction through the tumor; then repeats steps (a) and (b) for the duration of the treatment. Each transducer array includes a plurality of (e.g., 9 to 30) electrode elements.

[0004] Alternating electric fields can also be used to treat medical conditions other than tumors. For example, as described in U.S. Pat. No. 10,967,167 (incorporated herein by reference in its entirety), alternating electric fields can be used to increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapeutic drugs to reach the brain.

[0005] When using an alternating electric field to treat a subject, a higher amplitude is closely associated with a higher therapeutic efficacy. However, as the amplitude of the alternating electric field increases, and / or as the frequency of the alternating electric field decreases (e.g., to around 100kHz), some subjects experience an electro-inductive effect. This electro-induction may be, for example, a sense of vibration, paresthesia, and / or a sense of twitching or contraction of muscle fibers, or a light flash (phosphene) in the eyes. Electro-induction may prevent some subjects from continuing to use an alternating electric field for their treatment. In addition, electro-induction may limit the amplitude of the alternating electric field that can be comfortably applied to a given subject, which in turn may limit the therapeutic efficacy. Summary of the invention

[0006] One aspect of the present invention relates to a first method of applying an alternating electric field in a target area of ​​a subject's body. The first method includes: (a) applying a first alternating electric field having a first orientation in the target area during a first time interval. The first alternating electric field has an amplitude that increases during multiple first segments of the first time interval and also remains constant or decreases during multiple second segments of the first time interval. Each second segment of the multiple second segments of the first time interval has a length of at least 10 ms and is immediately after a corresponding first segment of the first segment of the first time interval. The first alternating electric field has an amplitude that remains constant during a third segment of the first time interval. And the third segment of the first time interval is after the last first segment of the first segment of the first time interval.

[0007] In some examples of the first method, the first alternating electric field has an amplitude that remains constant during each of the plurality of second segments of the first time interval. In some examples of the first method, the first alternating electric field has an amplitude that decreases during each of the plurality of second segments of the first time interval. In some examples of the first method, when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

[0008] Some examples of the first method further include: (b) during the second time interval, applying a second alternating electric field having a second orientation in the target area. The second alternating electric field has an amplitude that increases during multiple first segments of the second time interval and also remains constant or decreases during multiple second segments of the second time interval. The second orientation is different from the first orientation. The length of each second segment of the multiple second segments of the second time interval is at least 10 ms and is immediately after a corresponding first segment in the first segment of the second time interval. The second alternating electric field has an amplitude that remains constant during a third segment of the second time interval. And the third segment of the second time interval is after the last first segment in the first segment of the second time interval. These examples also include repeating steps (a) and (b) in an alternating order at least 1000 times.

[0009] Optionally, in each instance of the first method described in the previous paragraph, the first alternating electric field is not applied in the target area during a time interval immediately following the first time interval, and the second alternating electric field is not applied in the target area during a time interval immediately following the second time interval.

[0010] Optionally, in each instance of the first method described in the previous paragraph, the first alternating electric field has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval; and the second alternating electric field has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is after the third segment of the second time interval.

[0011] Some examples of the first method further include: (b) during the second time interval, applying a second alternating electric field having a second orientation in the target area. The second alternating electric field has an amplitude that increases during multiple first segments of the second time interval and also remains constant or decreases during multiple second segments of the second time interval. The second orientation is different from the first orientation. The length of each second segment of the multiple second segments of the second time interval is at least 10 ms and is immediately after a corresponding first segment of the first segment of the second time interval. The second alternating electric field has an amplitude that remains constant during a third segment of the second time interval. And the third segment of the second time interval is after the last first segment of the first segment of the second time interval. These examples also include repeating steps (a) and (b) in an alternating order at least 1000 times. In these examples, when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval. And when the second time interval begins, the second alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval.

[0012] Another aspect of the present invention relates to a first device for applying an electrical signal to at least one electrode element of a first group, a second group, a third group, and a fourth group. The first device includes an AC signal generator and a controller. The AC signal generator has a first output terminal, a second output terminal, and at least one control input terminal. And the controller is configured to apply a control signal sequence to the at least one control input terminal of the AC signal generator. The control signal sequence commands the AC signal generator to perform the following operations: (a) during a first time interval, applying a first AC output signal to the first output terminal, wherein the first AC output signal has an amplitude that increases during multiple first segments of the first time interval and also remains constant or decreases during multiple second segments of the first time interval, wherein each second segment of the multiple second segments of the first time interval has a length of at least 10 ms and is immediately after a corresponding first segment of the first segment of the first time interval, wherein the first AC output signal has an amplitude that remains constant during a third segment of the first time interval, and wherein the third segment of the first time interval is after the last first segment of the first segment of the first time interval.

[0013] In some embodiments of the first device, the first AC output signal has an amplitude that remains constant during each of the plurality of second segments of the first time interval. In some embodiments of the first device, the first AC output signal has an amplitude that decreases during each of the plurality of second segments of the first time interval. In some embodiments of the first device, when the first time interval begins, the first AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

[0014] In some embodiments of the first device, the control signal sequence commands the AC signal generator to perform the following operations: (b) during a second time interval, apply a second AC output signal to the second output terminal, wherein the second AC output signal has an amplitude that increases during multiple first segments of the second time interval and also remains constant or decreases during multiple second segments of the second time interval, wherein each second segment of the multiple second segments of the second time interval has a length of at least 10 ms and is immediately followed by a corresponding first segment of the first segment of the second time interval, wherein the second AC output signal has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval is after the last first segment of the first segment of the second time interval; and (c) repeat (a) and (b) in an alternating order at least 1000 times.

[0015] Optionally, in each embodiment of the first device described in the previous paragraph, the first AC output signal is not applied to the first output terminal during the time interval immediately following the first time interval, and the second AC output signal is not applied to the second output terminal during the time interval immediately following the second time interval.

[0016] Optionally, in each embodiment of the first device described in the previous paragraph, the first AC output signal has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval; and the second AC output signal has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is after the third segment of the second time interval.

[0017] In some embodiments of the first device, the control signal sequence instructs the AC signal generator to perform the following operations: (b) during a second time interval, applying a second AC output signal to the second output terminal, wherein the second AC output signal has an amplitude that increases during a plurality of first segments of the second time interval and also remains constant or decreases during a plurality of second segments of the second time interval, wherein each second segment of the plurality of second segments of the second time interval has a length of at least 10 ms and is immediately after a corresponding first segment of the first segments of the second time interval, wherein the second AC output signal has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval is after the last first segment of the first segments of the second time interval; and (c) repeating (a) and (b) in an alternating order at least 1000 times. In these embodiments, when the first time interval begins, the first AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval. And when the second time interval begins, the second AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval.

[0018] Another aspect of the present invention relates to a second method of applying an alternating electric field in a target area of ​​a subject's body. The second method comprises: (a) applying a first alternating electric field having a first orientation in the target area during a first time interval. The first alternating electric field has an amplitude that increases at a first rate during a first segment of the first time interval and increases at a second rate slower than the first rate during a second segment of the first time interval. The second segment of the first time interval is immediately after the first segment of the first time interval. The first alternating electric field has an amplitude that remains constant during a third segment of the first time interval. And the third segment of the first time interval is after the second segment of the first time interval.

[0019] In some examples of the second method, the amplitude of the first alternating electric field increases linearly during the first segment of the first time interval, and the amplitude of the first alternating electric field increases linearly during the second segment of the first time interval. In some examples of the second method, the first-order derivative of the amplitude of the first alternating electric field decreases continuously during the second segment of the first time interval.

[0020] Some examples of the second method further include: (b) during a second time interval, applying a second alternating electric field having a second orientation in the target area. The second orientation is different from the first orientation. The second alternating electric field has an amplitude that increases at a third rate during a first segment of the second time interval and increases at a fourth rate that is slower than the third rate during a second segment of the second time interval. The second segment of the second time interval is immediately after the first segment of the second time interval. The second alternating electric field has an amplitude that remains constant during a third segment of the second time interval. And the third segment of the second time interval is after the second segment of the second time interval. In these examples, steps (a) and (b) are repeated at least 1000 times in an alternating order.

[0021] Optionally, in each instance of the second method described in the previous paragraph, the first alternating electric field is not applied in the target area during the time interval immediately following the first time interval, and the second alternating electric field is not applied in the target area during the time interval immediately following the second time interval.

[0022] Optionally, in each instance of the second method described in the previous paragraph, the first alternating electric field has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval; and the second alternating electric field has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is after the third segment of the second time interval.

[0023] Another aspect of the present invention relates to a second device for applying an electrical signal to at least one electrode element of a first group, a second group, a third group, and a fourth group. The second device includes an AC signal generator and a controller. The AC signal generator has a first output, a second output, and at least one control input. The controller is configured to apply a control signal sequence to the at least one control input of the AC signal generator, and the control signal sequence commands the AC signal generator to perform the following operations: (a) during a first time interval, a first AC output signal is applied to the first output. The first AC output signal has an amplitude that increases at a first rate during a first segment of the first time interval and increases at a second rate slower than the first rate during a second segment of the first time interval. The second segment of the first time interval is immediately after the first segment of the first time interval. The first AC output signal has an amplitude that remains constant during a third segment of the first time interval, and the third segment of the first time interval is after the second segment of the first time interval.

[0024] In some embodiments of the second device, the amplitude of the first AC output signal increases linearly during the first segment of the first time interval, and the amplitude of the first AC output signal increases linearly during the second segment of the first time interval. In some embodiments of the second device, a first-order derivative of the amplitude of the first AC output signal decreases continuously during the second segment of the first time interval.

[0025] In some embodiments of the second device, the control signal sequence commands the AC signal generator to perform the following operations: (b) during a second time interval, apply a second AC output signal to the second output terminal. The second AC output signal has an amplitude that increases at a third rate during a first segment of the second time interval and increases at a fourth rate that is slower than the third rate during a second segment of the second time interval. The second segment of the second time interval is immediately after the first segment of the second time interval. The second AC output signal has an amplitude that remains constant during a third segment of the second time interval. And the third segment of the second time interval is after the second segment of the second time interval. (a) and (b) are repeated at least 1000 times in an alternating order.

[0026] Optionally, in each embodiment of the second device described in the previous paragraph, the first AC output signal is not applied to the first output terminal during the time interval immediately following the first time interval, and the second AC output signal is not applied to the second output terminal during the time interval immediately following the second time interval.

[0027] Optionally, in each embodiment of the second device described in the previous paragraph, the first AC output signal has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval; and the second AC output signal has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is after the third segment of the second time interval.

[0028] Another aspect of the present invention relates to a third method of applying an alternating electric field in a target area of ​​a subject's body. The third method comprises: (a) applying a first alternating electric field having a first orientation in the target area during a first time interval, the first alternating electric field having an amplitude that increases during a plurality of first segments of the first time interval and also remains constant or decreases during a plurality of second segments of the first time interval, wherein each second segment of the plurality of second segments of the first time interval is immediately after a corresponding first segment of the first segment of the first time interval, wherein the first alternating electric field has an amplitude that remains constant during a third segment of the first time interval, wherein the third segment of the first time interval is after the last first segment of the first segment of the first time interval, and wherein when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

[0029] Some examples of the third method further include: (b) during the second time interval, applying a second alternating electric field having a second orientation in the target area, the second alternating electric field having an amplitude that increases during a plurality of first segments of the second time interval and also remains constant or decreases during a plurality of second segments of the second time interval, wherein each second segment of the plurality of second segments of the second time interval is immediately after a corresponding first segment of the first segment of the second time interval, wherein the second alternating electric field has an amplitude that remains constant during a third segment of the second time interval, wherein the third segment of the second time interval is after the last first segment of the first segment of the second time interval, and wherein when the second time interval begins, the second alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval. These examples of the third method further include: repeating steps (a) and (b) in an alternating order at least 1000 times. In these examples of the third method, the second orientation is different from the first orientation. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Describes the prior art The AC output amplitude in both channels of the system.

[0031] Figure 2 is a block diagram of a system for driving a group of transducer arrays with an AC voltage signal, wherein the amplitude trajectory of the AC output can be controlled.

[0032] Figure 3 Depicted are examples of what may be imparted to the output of an AC signal generator to improve the amplitude trajectory of electrical induction.

[0033] Figure 4 Additional examples are depicted that may be imparted to the output of an AC signal generator to improve the amplitude trajectory of the electrical inductance.

[0034] Various embodiments are described in detail below with reference to the drawings, wherein like reference numerals refer to like elements. DETAILED DESCRIPTION

[0035] Figure 1 Describes the prior art AC output amplitudes for the L / R channels and A / P channels in the system. It is noteworthy that when the signal to the A / P transducer array or the L / R transducer array is turned on during any given one-second interval, the amplitude of the AC voltage does not immediately jump to its peak value. Instead, the amplitude of the AC voltage climbs from zero to its peak value over the course of the 50ms window. Similarly, when the signal is turned off during any given one-second interval, the amplitude of the AC voltage ramps down from its peak value to zero over the course of the 50ms window.

[0036] The inventors have determined that electrical induction is not a problem during steady-state application of an AC voltage to a given pair of transducer arrays or when the AC voltage is turned off / falling. Rather, electrical induction appears to be a problem only when the AC voltage is turned on / ramp up (which occurs when the system is first turned on and whenever the electric field switches direction). Electrical induction is believed to arise from the interaction between the alternating electric field and neural cells or fibers (i.e., neurons or axons) located near or adjacent to the transducer arrays.

[0037] The inventors have also determined that electrical induction can be improved by changing the trajectory of how the AC voltage climbs from zero to its peak value when the AC voltage is first applied to any given transducer array pair and also when the alternating electric field changes direction.

[0038] Figure 21 is a block diagram of a system for driving a set of transducer arrays with an AC voltage signal, wherein the trajectory of how the AC voltage increases from zero to its peak value can be controlled. The system includes an AC signal generator 20, which is designed to generate a first AC output and a second AC output with a frequency of 50kHz to 10MHz (e.g., 50kHz to 1MHz, 50kHz to 500kHz, 75kHz to 300kHz, or 150kHz to 250kHz). When the system is used to apply a TT field to a human body (e.g., Figure 2 ), a first AC output is applied across a first pair of transducer arrays 10L and 10R located on the left and right sides of the tumor; and a second AC output is applied across a second pair of transducer arrays 10A and 10P located on the front and back sides of the tumor.

[0039] When the AC signal generator 20 applies a voltage between the transducer arrays 10L, 10R, an alternating electric field having field lines extending generally from left to right is induced through the target area. And when the AC signal generator 20 applies a voltage between the transducer arrays 10A, 10P, an alternating electric field having field lines extending generally from front to back is induced through the target area. The frequency of the alternating electric field will match the frequency of the AC signal generator 20. The electrode elements in the transducer array 10 may be capacitively coupled electrode elements (i.e., electrode elements comprising a thin dielectric layer that contacts the subject's body) or conductive electrode elements (i.e., electrode elements comprising a conductive surface that contacts the subject's body).

[0040] In some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of at least 1 V / cm in at least a portion of the cells. In some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of 1 V / cm to 10 V / cm in at least a portion of the cells.

[0041] Compared with the existing technology As in the system, (a) the first AC output is applied to the L / R transducer array for 1 second; (b) the second AC output is applied to the A / P transducer array for 1 second; and the two-step sequence (a) and (b) are repeated for the duration of the treatment. Figure 2 The trajectory of how the AC voltage increases from zero to its peak value in the example is The climbing trajectories used in the study differed in ways that helped improve the electrical induction experienced by the subjects.

[0042] The AC signal generator 20 is configured to generate a first AC output and a second AC output, the amplitude of the first AC output and the second AC output depending on the state of at least one control input. The controller 30 quickly (e.g., at a rate of 1 control signal per ms) sends sequential control signals to the at least one control input to generate the amplitude trajectory described herein. It should be noted that although Figure 2 The controller 30 and the AC signal generator 20 are depicted as two distinct blocks, but the two blocks may be integrated into a single hardware device.

[0043] The structural details of the controller 30 and the nature of the control signals will depend on the design of the AC signal generator 20. In one example, the design of the AC signal generator 20 is similar to the AC signal generator described in U.S. Pat. No. 9,910,453, which is incorporated herein by reference in its entirety. The AC signal generator has two output channels (i.e., a first channel for L / R and a second channel for A / P). The instantaneous AC output voltage on either channel depends on the instantaneous output voltage of the DC-DC converter, and the output voltage of the DC-DC converter is controlled by writing a control word to a digital-to-analog converter (DAC) at a rate of, for example, 1 control signal per ms.

[0044] Therefore, the AC signal generator can be used to increase the AC output voltage at any desired rate and using any trajectory by sending appropriate control words to the DAC in sequence.

[0045] Figure 3 Depicted may be given to the AC signal generator 20 ( Figure 2 An example of an amplitude trace of an L / R output channel and an A / P output channel of an AC signal generator 20 (as shown) to improve electrical induction. More specifically, trace 51 depicts how the amplitude of the AC voltage of the L / R channel varies with time, and trace 52 depicts how the amplitude of the AC voltage of the A / P channel varies with time. Sub-figure A is an enlarged version of the climbing interval of trace 51 for the L / R channel. In this example, the amplitude increases during interval 1, then remains constant for at least 10 ms during interval 2, then increases further during interval 1', then remains constant for at least 10 ms during interval 2', and then increases further during interval 1". To generate this amplitude trace, the controller 30 sends control words to the AC signal generator 20 in sequence (e.g., once every ms). When the AC signal generator 20 receives these control words, it will generate an output having the same amplitude as Figure 3 A similar sequence of control words is used to control the A / P channel. Note that if the controller 30 sends control words to the AC signal generator at a rate of one control word per ms, the intervals 1, 1', 1" will not be true ramps (e.g. Figure 3Instead, the intervals will be steps with very small step heights, which in a zoomed out view will be Figure 3 The slopes depicted are similar.

[0046] When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, a first alternating electric field having a first orientation is applied in the target area during a first time interval. The first alternating electric field has an amplitude that increases during a plurality of first segments 1, 1', 1" of the first time interval and remains constant for at least 10 ms during a plurality of second segments 2, 2' of the first time interval. Each of the plurality of second segments 2, 2' of the first time interval is immediately followed by a corresponding one of the first segments 1, 1' of the first time interval. The rationale for including the second segments 2, 2' of the first time interval in the trajectory, each of which has a length of at least 10 ms, is to allow the subject to adapt to a given voltage setting before the voltage is further increased. In some embodiments, the length of each of these intervals is at least 20 ms or at least 40 ms.

[0047] Note that while the first segments 1, 1', 1" of the first time interval in the example depicted in sub-figure A together occupy more than half of the first time interval, the first segments 1, 1', 1" (during which the amplitude increases) may be significantly shorter. For example, in some embodiments, these segments may be as short as 1 ms, as short as 1 μs, or even shorter than 1 μs. And since each of the second segments 2, 2' in these embodiments is much longer (i.e., at least 10 ms in length), the resulting waveform during the first time interval will resemble a staircase with vertical edges. In these embodiments, the transition from one amplitude to the next can be achieved by writing a single control word to the AC signal generator 20. When the AC signal generator 20 receives the single control word, its output will jump to the next step of the staircase as quickly as possible, limited only by the response time of the AC signal generator 20, which may be as short as 1 μs or even shorter than 1 μs. In these embodiments, the duration of each first segment 1, 1', 1" will be relatively short.

[0048] After the ramp-up period (which includes segments 1, 2, 1', 2', and 1" of the first time interval), the output of the AC signal generator 20 remains constant during interval 3. Interval 3 follows the last first segment in the first segment 1". After interval 3, the output of the AC signal generator 20 drops during interval 4. When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, the first alternating electric field will have an amplitude that remains constant during the third segment 3 of the first time interval. The third segment 3 of the first time interval follows (although not *immediately* following in this example) the last first segment in the first segment 1" of the first time interval.

[0049] The operation of the front / rear channel (and the second alternating electric field) is similar to the operation of the left / right channel (and the first alternating electric field) described above, except that the two channels are activated in an alternating sequence (e.g., at least 1000 times) and the phases of the two channels are different. When one channel is activated, the other channel is turned off. Therefore, during the time interval immediately following the first time interval, the first alternating electric field is not applied in the target area, and during the time interval immediately following the second time interval, the second alternating electric field is not applied in the target area.

[0050] As long as the controller 30 is capable of controlling the AC signal generator 20, various alternative designs of the AC signal generator 20 and the controller 30 may replace the examples provided above. For example, if the AC signal generator is designed to respond to analog control signals, the controller 30 must generate any analog control signal sequence required to cause the AC signal generator 20 to output the desired waveform. In this case, the controller 30 may be implemented using a microprocessor or microcontroller that is programmed to write the appropriate control word to a digital-to-analog converter, the output of which generates an analog control signal that causes the AC signal generator 20 to generate the desired waveform. Alternatively, the controller 30 may be implemented using an analog circuit that automatically generates an appropriate sequence of control signals (which are then applied to the control input of the AC signal generator).

[0051] Figure 3 The trajectory of how the AC voltage increases from zero to its peak value depicted in sub-graph A of is not the only trajectory that can be used to improve the inductance. Instead, various alternative trajectories can be used. Figure 3 Sub-figure B of FIG. 1 depicts an example of an alternative trajectory that can be used to improve electrical induction. This example is similar to the above combined Figure 3The embodiment described in sub-figure A of , except that the amplitude of AC signal generator 20 decreases during intervals 2 and 2' for at least 10 ms instead of being kept constant during intervals 2 and 2' for at least 10 ms. To generate this amplitude trajectory, controller 30 sends control words to AC signal generator 20 in sequence (e.g., once every millisecond). When AC signal generator 20 receives these control words, it will generate an output having the same Figure 3 The waveform depicted in sub-graph B is of similar amplitude. A similar control word sequence is used to control the A / P channel.

[0052] When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R in these embodiments, a first alternating electric field having a first orientation is applied in the target area during a first time interval. The first alternating electric field has an amplitude that increases during a plurality of first segments 1, 1', 1" of the first time interval and decreases during a plurality of second segments 2, 2' of the first time interval for at least 10 ms. Each of the plurality of second segments 2, 2' of the first time interval is immediately followed by a corresponding one of the first segments 1, 1' of the first time interval. A similar sequence occurs at the A / P channel. Here, the rationale for including the second segments 2, 2' of the first time interval in the trajectory (each of which has a length of at least 10 ms) is to allow the subject to adapt to a given voltage setting before the voltage is further increased. In some embodiments, the length of each of these intervals is at least 20 ms or at least 40 ms.

[0053] Figure 3 Subgraph C of depicts another example of how the AC voltage increases from zero to its peak value, which can be used to improve the induction experienced by the subject. This example is similar to the above combined Figure 3 The embodiment described in sub-figure A of , except that: the amplitude of the AC signal generator 20 increases at a first rate during the first segment 1 of the first time interval and increases at a second rate slower than the first rate during the second segment 2 of the first time interval. The increase during the first segment of the first time interval can be a linear increase (as depicted in sub-figure C) or a nonlinear increase. Similarly, the increase during the second segment of the first time interval can be a linear increase (as depicted in sub-figure C) or a nonlinear increase (as depicted in sub-figure D).

[0054] The second segment of the first time interval is immediately after the first segment of the first time interval. The third and fourth segments of the first time interval in this embodiment are similar to the corresponding segments of the embodiment of sub-figure A described above. To generate the amplitude trajectory, the controller 30 sends control words to the AC signal generator 20 in sequence (for example, once every millisecond). When the AC signal generator 20 receives these control words, it will generate an output having the same Figure 3 The waveforms depicted in sub-figures C or D are of similar amplitude. A similar control word sequence is used to control the A / P channel.

[0055] When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R in these embodiments, a first alternating electric field having a first orientation is applied in the target area during a first time interval. The first alternating electric field has an amplitude that increases at a first rate during a first segment 1 of the first time interval and increases at a second rate slower than the first rate during a second segment 2 of the first time interval. A similar sequence occurs at the A / P channel.

[0056] In the examples described above, the AC voltage generator 20 is configured to use the same trajectory each time (eg, (a) always using the above combined Figure 3 (a) the output voltage of the AC voltage generator 20 is increased by (i) the trajectory described in sub-graph A in the above text; (b) always using the trajectory described in conjunction with sub-graph B above; (c) always using the trajectory described in conjunction with sub-graph C above; or (d) always using the trajectory described in conjunction with sub-graph D above). However, in alternative embodiments, the AC voltage generator 20 may be configured to control how the AC voltage increases from zero to its peak value in different ways at different times. For example, by using the trajectories of sub-graphs A and B at different times; by using the trajectories of sub-graphs A and C at different times; by using the trajectories of sub-graphs A, B, and C at different times; or by using the trajectories of sub-graphs A, B, C, and D at different times; and so on.

[0057] exist Figure 3 In all the examples depicted, when the first time interval and the second time interval begin, the amplitudes of both the first output terminal and the second output terminal of the AC signal generator are very small (e.g., less than 1% of the constant level applied during the third segment of the corresponding time interval). Similarly, when the first time interval and the second time interval begin, both the first alternating electric field and the second alternating electric field are very small (e.g., less than 1% of the constant level applied during the third segment of the corresponding time interval).

[0058] However, in alternative embodiments (e.g., Figure 4), the amplitudes of the first output terminal and the second output terminal of the AC signal generator can immediately jump to an initial level Vi, which is 20% to 80% of the constant level Vf applied during the third segment of the corresponding time interval. Similarly, the amplitudes of the first alternating electric field and the second alternating electric field can immediately jump to an initial level Vi, which is 20% to 80% of the constant level Vf applied during the third segment of the corresponding time interval. After the initial jump to the initial level Vi, using, for example Figure 4 The trajectory depicted by the subgraph A of Figure 3 The trajectory in sub-graph A of FIG. 1 , but offset by Vi) increases the amplitude from Vi to Vf. Furthermore, these embodiments are not limited to the single amplitude trajectory depicted by sub-graph A. Instead, various other trajectories for changing the amplitude after the initial jump to Vi may be used in place of the trajectory depicted by sub-graph A, including but not limited to Figure 3 The amplitude traces depicted by sub-figures B, C and D of (but with the addition of offset Vi).

[0059] These embodiments are advantageous because induction is relatively rare when the voltage is below a threshold level (e.g., 40 V). Therefore, when the first time interval and the second time interval begin, the voltage jumps from 0 V to the initial voltage Vi (e.g., 40 V) immediately (e.g., in less than 200 μs) (e.g., Figure 4 ) will not cause electroinduction in the vast majority of patients. And because no time is wasted climbing from 0 V to Vi, more time will be available to climb from Vi to the final voltage Vf (which may be in excess of 100 V, for example). This will advantageously (a) increase the average field strength applied to the subject, and (b) provide the subject with more time to adapt to each new voltage level before the voltage is increased to the next level, further improving electroinduction.

[0060] In some embodiments, the value of the initial level Vi will be the same for all patients (e.g., 40V). In other embodiments, the value of the initial level Vi may be patient-specific and may be set via a suitable user interface that communicates with the controller 30. In the latter embodiment, the controller 30 may be programmed to apply different voltage levels to the subject in order to determine the threshold voltage Vth at which electroinduction begins for the particular subject to be treated. The initial level Vi is then set below the threshold Vth during the treatment process for that particular subject.

[0061] These embodiments in which the amplitude jumps to the initial level Vi are similar to the above embodiments in conjunction with Figures 2 to 3The embodiment described above has two exceptions. First, at the beginning of each first time interval and each second time interval, the amplitude immediately jumps to the initial level Vi and then follows the subsequent trajectory until it reaches the final level Vf. Second, the duration of (a) each of the plurality of second segments of the first time interval and (b) each of the plurality of second segments of the second time interval may be (i) at least 10 ms (as described above in conjunction with Figures 2 to 3 The above) or less than 10ms (e.g., 5ms to 10ms, or even less than 5ms).

[0062] In the example described above, the direction of the alternating electric field is switched between the L / R channel and the A / P channel every second, which means that the length of each time interval is 1 second. However, in alternative embodiments, the direction of the alternating electric field can be switched at a faster rate (e.g., every 1 ms to 1000 ms) or a slower rate (e.g., every 1 second to 360 seconds), in which case the duration of each interval will be shorter or longer than 1 second. Optionally, the entire treatment duration can be interrupted by a pause.

[0063] In the examples described above, the direction of the alternating electric field is switched between two directions. However, in alternative embodiments, the direction of the alternating electric field can be switched between three or more directions (assuming that additional transducer array pairs are provided). For example, the direction of the alternating electric field can be switched between three directions, each of which is determined by the placement of its own pair of transducer arrays. In other alternative embodiments, the transducer arrays do not need to be arranged in pairs. For example, see the transducer array positioning described in U.S. Patent 7,565,205, which is incorporated herein by reference. However, regardless of the arrangement of the transducer arrays, each time a given transducer array is activated, one of the modified trajectories described herein is used.

[0064] In some anatomical locations, the transducer array is not located on the subject's skin. Instead, the transducer array is implanted into the subject's body (e.g., just below the subject's skin) so that applying an AC voltage between the transducer arrays will apply an alternating electric field in a target area of ​​the subject's body.

[0065] Finally, in some anatomical locations, an electric field with a constant orientation may be used, rather than switching the orientation of an alternating electric field back and forth between two or more different directions. Embodiments used with these locations are similar to Figure 2 In these embodiments, the AC voltage generator is configured to: when initially turned on, use the above (for example, in combination with Figure 3The output voltage of the AC voltage generator is increased by any of the trajectories described in the sub-graphs A, B, C or D in the above description and then maintained at a fixed level for the duration of the treatment, or a single output terminal is repeatedly turned on and off (e.g., turned on for 1s to 10s and turned off for 0.1s to 10s). In the latter case, each time the AC voltage generator is turned on again, it uses the above (e.g., in combination with Figure 3 Any of the trajectories described in sub-figure A, sub-figure B, sub-figure C or sub-figure D) in the figure can be used to increase its output voltage.

[0066] Although the present invention has been disclosed with reference to certain embodiments, many modifications, variations and changes to the described embodiments are possible without departing from the field and scope of the invention as defined by the appended claims. Therefore, it is intended that the present invention is not limited to the described embodiments, but has the full scope defined by the language of the appended claims and their equivalents.

Claims

1. A method of applying an alternating electric field to a target area of ​​a subject's body, the method comprising: (a) During a first time interval, applying a first alternating electric field having a first orientation in the target area, the first alternating electric field having an amplitude that increases during a plurality of first segments of the first time interval and also remains constant or decreases during a plurality of second segments of the first time interval, wherein each of the plurality of second segments of the first time interval has a length of at least 10 ms and is immediately followed by a corresponding first segment of the first segments of the first time interval, wherein the first alternating electric field has an amplitude that remains constant during a third segment of the first time interval, and wherein the third segment of the first time interval is after the last first segment of the first segments of the first time interval. 2 . The method of claim 1 , wherein the first alternating electric field has an amplitude that remains constant during each of the plurality of second segments of the first time interval. 3 . The method of claim 1 , wherein the first alternating electric field has an amplitude that decreases during each of the plurality of second segments of the first time interval.

4. The method of claim 1, wherein when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

5. The method according to claim 1, further comprising: (b) during a second time interval, applying a second alternating electric field having a second orientation in the target area, the second alternating electric field having an amplitude that increases during a plurality of first segments of the second time interval and also remains constant or decreases during a plurality of second segments of the second time interval, wherein each second segment of the plurality of second segments of the second time interval has a length of at least 10 ms and is immediately after a corresponding one of the first segments of the second time interval, wherein the second alternating electric field has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval is after a last first segment of the first segments of the second time interval; as well as Repeat steps (a) and (b) in alternating order at least 1000 times, The second orientation is different from the first orientation.

6. The method of claim 5, wherein during a time interval immediately following the first time interval, the first alternating electric field is not applied in the target area, and wherein during a time interval immediately following the second time interval, the second alternating electric field is not applied in the target area.

7. The method of claim 5, wherein the first alternating electric field has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval follows the third segment of the first time interval, wherein during a time interval immediately following said first time interval, said first alternating electric field is not applied in said target area, wherein the second alternating electric field has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is subsequent to the third segment of the second time interval, and wherein during a time interval immediately following the second time interval, the second alternating electric field is not applied in the target area.

8. The method of claim 5, wherein when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval, and Wherein when the second time interval begins, the second alternating electric field has an initial amplitude, and the initial amplitude is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval.

9. A device for applying an electrical signal to at least one electrode element of a first group, a second group, a third group, and a fourth group, the device comprising: an AC signal generator having a first output terminal, a second output terminal and at least one control input terminal; and a controller configured to apply a sequence of control signals to the at least one control input of the AC signal generator, The control signal sequence instructs the AC signal generator to perform the following operations: (a) During a first time interval, applying a first AC output signal to the first output terminal, wherein the first AC output signal has an amplitude that increases during a plurality of first segments of the first time interval and also remains constant or decreases during a plurality of second segments of the first time interval, wherein each of the plurality of second segments of the first time interval has a length of at least 10 ms and is immediately following a corresponding one of the first segments of the first time interval, wherein the first AC output signal has an amplitude that remains constant during a third segment of the first time interval, and wherein the third segment of the first time interval is after the last first segment of the first segments of the first time interval.

10. The apparatus of claim 9, wherein the first AC output signal has an amplitude that remains constant during each of the plurality of second segments of the first time interval.

11. The apparatus of claim 9, wherein the first AC output signal has an amplitude that decreases during each of the plurality of second segments of the first time interval.

12. The apparatus of claim 9, wherein when the first time interval begins, the first AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

13. The apparatus of claim 9, wherein the control signal sequence instructs the AC signal generator to: (b) during a second time interval, applying a second AC output signal to the second output terminal, wherein the second AC output signal has an amplitude that increases during a plurality of first segments of the second time interval and also remains constant or decreases during a plurality of second segments of the second time interval, wherein each of the plurality of second segments of the second time interval has a length of at least 10 ms and is immediately after a corresponding one of the first segments of the second time interval, wherein the second AC output signal has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval is after a last first segment of the first segments of the second time interval, and Steps (a) and (b) were repeated at least 1000 times in alternating order.

14. The apparatus of claim 13, wherein during a time interval immediately following the first time interval, the first AC output signal is not applied to the first output terminal, and Wherein during a time interval immediately following the second time interval, the second AC output signal is not applied to the second output terminal.

15. The apparatus of claim 13, wherein the first AC output signal has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval, wherein during a time interval immediately following the first time interval, the first AC output signal is not applied to the first output terminal, wherein the second AC output signal has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is subsequent to the third segment of the second time interval, and Wherein during a time interval immediately following the second time interval, the second AC output signal is not applied to the second output terminal.

16. The apparatus of claim 13, wherein when the first time interval begins, the first AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval, and Wherein when the second time interval begins, the second AC output signal has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval.

17. A method of applying an alternating electric field to a target area of ​​a subject's body, the method comprising: (a) during a first time interval, applying a first alternating electric field having a first orientation in the target area, the first alternating electric field having an amplitude that increases at a first rate during a first segment of the first time interval and increases at a second rate slower than the first rate during a second segment of the first time interval, wherein the second segment of the first time interval is immediately after the first segment of the first time interval, wherein the first alternating electric field has an amplitude that remains constant during a third segment of the first time interval, and wherein the third segment of the first time interval is after the second segment of the first time interval.

18. The method of claim 17, wherein the amplitude of the first alternating electric field increases linearly during the first segment of the first time interval, and Wherein the amplitude of the first alternating electric field increases linearly during the second segment of the first time interval.

19. The method of claim 17, wherein a first-order derivative of the amplitude of the first alternating electric field continuously decreases during the second segment of the first time interval.

20. The method according to claim 17, further comprising: (b) during a second time interval, applying a second alternating electric field having a second orientation in the target area, the second alternating electric field having an amplitude that increases at a third rate during a first segment of the second time interval and increases at a fourth rate that is slower than the third rate during a second segment of the second time interval, wherein the second segment of the second time interval immediately follows the first segment of the second time interval, wherein the second alternating electric field has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval follows the second segment of the second time interval; as well as Repeat steps (a) and (b) in alternating order at least 1000 times, The second orientation is different from the first orientation.

21. The method of claim 20, wherein during a time interval immediately following the first time interval, the first alternating electric field is not applied in the target area, and wherein during a time interval immediately following the second time interval, the second alternating electric field is not applied in the target area.

22. The method of claim 20, wherein the first alternating electric field has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval follows the third segment of the first time interval, wherein during a time interval immediately following said first time interval, said first alternating electric field is not applied in said target area, wherein the second alternating electric field has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is subsequent to the third segment of the second time interval, and wherein during a time interval immediately following the second time interval, the second alternating electric field is not applied in the target area.

23. A device for applying an electrical signal to at least one electrode element of a first group, a second group, a third group, and a fourth group, the device comprising: an AC signal generator having a first output terminal, a second output terminal and at least one control input terminal; and a controller configured to apply a sequence of control signals to the at least one control input of the AC signal generator, The control signal sequence instructs the AC signal generator to perform the following operations: (a) applying a first AC output signal to the first output terminal during a first time interval, wherein the first AC output signal has an amplitude that increases at a first rate during a first segment of the first time interval and increases at a second rate slower than the first rate during a second segment of the first time interval, wherein the second segment of the first time interval is immediately after the first segment of the first time interval, wherein the first AC output signal has an amplitude that remains constant during a third segment of the first time interval, and wherein the third segment of the first time interval is after the second segment of the first time interval.

24. The apparatus of claim 23, wherein the amplitude of the first AC output signal increases linearly during the first segment of the first time interval, and Wherein the amplitude of the first AC output signal increases linearly during the second segment of the first time interval.

25. The apparatus of claim 23, wherein a first order derivative of the amplitude of the first AC output signal decreases continuously during the second segment of the first time interval.

26. The apparatus of claim 23, wherein the sequence of control signals instructs the AC signal generator to: (b) applying a second AC output signal to the second output terminal during a second time interval, wherein the second AC output signal has an amplitude that increases at a third rate during a first segment of the second time interval and increases at a fourth rate that is slower than the third rate during a second segment of the second time interval, wherein the second segment of the second time interval is immediately after the first segment of the second time interval, wherein the second AC output signal has an amplitude that remains constant during a third segment of the second time interval, and wherein the third segment of the second time interval is after the second segment of the second time interval, and Steps (a) and (b) were repeated at least 1000 times in alternating order.

27. The apparatus of claim 26, wherein during a time interval immediately following the first time interval, the first AC output signal is not applied to the first output terminal, and Wherein during a time interval immediately following the second time interval, the second AC output signal is not applied to the second output terminal.

28. The apparatus of claim 26, wherein the first AC output signal has an amplitude that decreases during a fourth segment of the first time interval, wherein the fourth segment of the first time interval is after the third segment of the first time interval, wherein during a time interval immediately following the first time interval, the first AC output signal is not applied to the first output terminal, wherein the second AC output signal has an amplitude that decreases during a fourth segment of the second time interval, wherein the fourth segment of the second time interval is subsequent to the third segment of the second time interval, and Wherein during a time interval immediately following the second time interval, the second AC output signal is not applied to the second output terminal.

29. A method of applying an alternating electric field to a target area of ​​a subject's body, the method comprising: (a) during a first time interval, applying a first alternating electric field having a first orientation in the target area, the first alternating electric field having an amplitude that increases during a plurality of first segments of the first time interval and also remains constant or decreases during a plurality of second segments of the first time interval, wherein each of the plurality of second segments of the first time interval is immediately followed by a corresponding first segment of the first segments of the first time interval, wherein the first alternating electric field has an amplitude that remains constant during a third segment of the first time interval, wherein the third segment of the first time interval is after the last first segment of the first segments of the first time interval, and wherein when the first time interval begins, the first alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the first time interval.

30. The method of claim 29, further comprising: (b) during a second time interval, applying a second alternating electric field having a second orientation in the target area, the second alternating electric field having an amplitude that increases during a plurality of first segments of the second time interval and also remains constant or decreases during a plurality of second segments of the second time interval, wherein each of the plurality of second segments of the second time interval is immediately after a corresponding one of the first segments of the second time interval, wherein the second alternating electric field has an amplitude that remains constant during a third segment of the second time interval, wherein the third segment of the second time interval is after a last one of the first segments of the second time interval, and wherein when the second time interval begins, the second alternating electric field has an initial amplitude that is 20% to 80% of the amplitude that remains constant during the third segment of the second time interval; as well as Steps (a) and (b) are repeated at least 1000 times in an alternating order, wherein the second orientation is different from the first orientation.

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