Reducing electrosensory sensation when treating a subject using a rotating AC electric field by gradually increasing the amplitude of the electric field.

Abstract

When an alternating current electric field (e.g., a tumor treatment electric field or TT field) is applied to a subject's body using a transducer array (i.e., an array of electrode elements), the subject may experience an electrosensory response. The electrosensory response can be improved by altering the way the AC voltage increases from zero to its peak when it is first applied to the transducer array.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Application No. 63 / 456,104, filed Mar. 31, 2023, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Tumor treating electric fields (TTFields) therapy is a proven approach for treating tumors using alternating electric fields at frequencies of 50 kHz to 1 MHz (e.g., 150 kHz - 200 kHz). Since the effectiveness of TTFields depends on the direction of the alternating electric field with respect to the longitudinal axis of the dividing tumor cells, it is preferable to apply the alternating electric field with different orientations at different times during the treatment process.

[0003] In the prior art Optune® system, TTFields are delivered to the patient via four transducer arrays placed on the patient's skin near the tumor. The transducer arrays are arranged in two pairs, with one pair of transducer arrays positioned on the left and right of the tumor and the other pair of transducer arrays positioned in front of and behind the tumor. Each transducer array is connected to an alternating - current signal generator via a multi - wire cable. The AC signal generator (a) sends an AC current to the anterior / posterior (A / P) pair of transducer arrays for 1 second, inducing an electric field of a first orientation in the tumor, and then (b) sends an AC current to the left / right (L / R) pair of the arrays for 1 second, inducing an electric field of a second orientation in the tumor. Next, the system repeats steps (a) and (b) for the duration of the treatment, which repeatedly switches the orientation of the electric field.

[0004] Patent Document 1 (which is incorporated herein by reference in its entirety) describes another approach for changing the orientation of an alternating electric field. More specifically, when a first sine wave is applied to an A / P pair of transducer arrays and a second sine wave of the same frequency is applied to an L / R transducer array, and when the first and second sine waves are 90° out of phase with respect to each other, the orientation of the electric field rotates continuously by 360° during the course of treatment.

[0005] Alternating electric fields are also useful in treating conditions other than tumors. For example, as described in Patent Document 2 (which is incorporated herein by reference in its entirety), alternating electric fields can be used to increase the permeability of the blood-brain barrier, allowing, for example, chemotherapy drugs to reach the brain.

[0006] When treating subjects with an alternating current (AC) electric field, a larger amplitude generally leads to a greater therapeutic effect. However, as the amplitude of the AC electric field increases or its frequency decreases (for example, to around 100 kHz), some subjects may experience electrosensory effects. These electrosensations can include sensations of vibration, paresthesia, and / or muscle spasms or contractions, or flashes of light in the eyes. These electrosensations may cause some subjects to discourage continued treatment with the AC electric field. Furthermore, electrosensations may limit the amplitude of the AC electric field that can be comfortably applied to a given subject, potentially limiting the therapeutic effect. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 7565206 [Patent Document 2] U.S. Patent No. 10967167 [Overview of the project]

[0008] One aspect of the present invention relates to a first method for selectively destroying or inhibiting the proliferation of rapidly dividing cells located within a target region of a subject's body. The first method includes the step of applying an AC electric field to a target region with an electric field orientation that rotates relative to the target region. The electric field has a frequency of 50 kHz to 1 MHz and an amplitude that increases from an initial level to a final level over at least 0.1 seconds.

[0009] In some examples of the first method, when the amplitude of the electric field is at its final level, the electric field has an electric field intensity of at least 1 V / cm in at least a portion of the target region. In some examples of the first method, the electric field is applied to the target region via an insulating electrode. In some examples of the first method, the electric field has an amplitude that increases from an initial level to a final level over a period of at least 0.3 seconds.

[0010] In some examples, an electric field in at least a portion of the target region is induced by the applied voltage, and when the amplitude of the electric field is at its final level, the applied voltage is at least 50V RMS, and optionally, the applied voltage is at least 100V RMS.

[0011] In some examples of the first method, the electric field has an amplitude that increases from an initial level to a final level over a period of at least one second. Optionally, in these examples, when the amplitude of the electric field is at its final level, the electric field has an electric field intensity of at least 5 V / cm in at least a portion of the target region.

[0012] In some examples of the first method, the electric field has an amplitude that increases from an initial level to a final level over a period of at least 0.3 seconds. When the amplitude of the electric field is at the final level, the electric field has an electric field intensity of at least 5 V / cm in at least a portion of the target region. The frequency of the electric field is 80 kHz to 300 kHz.

[0013] In some examples of the first method, the electric field has a frequency of 80 kHz to 300 kHz. In some examples of the first method, the electric field has an amplitude that is maintained at the final level for at least 100 seconds. In some examples of the first method, rotation of the AC electric field is achieved by simultaneously applying AC voltages with different phases to at least three electrodes. In some examples of the first method, the increase in amplitude from the initial level to the final level is linear.

[0014] Another aspect of the present invention relates to a first device for selectively destroying or inhibiting the proliferation of rapidly dividing cells located within a target area of ​​a subject's body. The first device includes at least three electrodes, each having a surface configured to be positioned relative to the subject's body, and an AC voltage source having at least three outputs, each electrically connected to one of the individual electrodes. Each of the at least three outputs has a frequency of 50 kHz to 1 MHz, and each of the at least three outputs has an amplitude that increases from at least an initial level to a final level of 50 V RMS over at least 0.1 seconds.

[0015] In some embodiments of the first apparatus, each of at least three outputs has an amplitude that is maintained at the final level for at least 30 seconds. In some embodiments of the first apparatus, each of at least three electrodes includes a conductive substrate, and each surface configured to be placed against the subject's body includes an insulating material having a dielectric constant of at least 20, placed on a separate conductive substrate.

[0016] In some embodiments of the first apparatus, each of at least three outputs has an amplitude that increases from an initial level to a final level over a period of at least 0.3 seconds, the final level being at least 100 V RMS.

[0017] In some embodiments of the first apparatus, each of the at least three outputs has an amplitude that increases from an initial level to a final level over at least one second, and the final level is at least 100 V RMS. Optionally, in these embodiments, each of the at least three outputs has a frequency between 80 kHz and 300 kHz.

[0018] In some embodiments of the first apparatus, each of the at least three outputs has a frequency between 80 kHz and 300 kHz. In some embodiments of the first apparatus, each of the at least three outputs has an amplitude that is maintained at the final level for at least 100 seconds.

[0019] In some embodiments of the first apparatus, the AC voltage source has a first output of a given frequency, a second output of a given frequency offset by 120° relative to the first output, and a third output of a given frequency offset by 240° relative to the first output. In some embodiments of the first apparatus, the AC voltage source has a first output of a given frequency, a second output of a given frequency offset by 90° relative to the first output, a third output of a given frequency offset by 180° relative to the first output, and a fourth output of a given frequency offset by 270° relative to the first output.

[0020] In some embodiments of the first apparatus, an AC voltage source simultaneously applies a sinusoidal signal of a first frequency to each of at least three outputs, the signal applied to each of the at least three outputs being modulated by a sinusoidal wave of a second frequency at least 10 times lower than the first frequency, and the modulated sinusoidal wave is phase-shifted. In some embodiments of the first apparatus, the amplitude increase from the initial level to the final level is linear.

[0021] In another aspect of the present invention, there is provided an AC electric field for use in a method of selectively destroying or inhibiting the growth of rapidly dividing cells located within a target region of a subject's body, the method comprising the step of rotating the AC electric field in the target region. The electric field orientation rotates with respect to the target region. The electric field has a frequency of 50 kHz to 1 MHz. The electric field has an amplitude that increases from an initial level to a final level over at least 0.1 seconds.

[0022] In yet another aspect of the present invention, there is provided an AC electric field for selectively destroying or inhibiting the growth of rapidly dividing cells located within a target region of a subject's body. The AC electric field has an electric field orientation that rotates with respect to the target region. The electric field has a frequency of 50 kHz to 1 MHz. The electric field has an amplitude that increases from an initial level to a final level over at least 0.1 seconds.

Brief Description of the Drawings

[0023] [Figure 1] It is a block diagram of a system for applying a TT field to a target region within a subject's body. [Figure 2] An example of an amplitude trajectory that may result in a significant electric sensation is shown. [Figure 3] An example of an amplitude trajectory that can be used to improve the electric sensation is shown. [Figure 4] Another example of an amplitude trajectory that can be used to improve the electric sensation is shown. [Figure 5] Four examples of non-linear amplitude increase trajectories that can be used to improve the electric sensation are shown. [Figure 6] [[ID= 27]]It is a block diagram of another system for applying a TT field to a target region within a subject's body.

Modes for Carrying Out the Invention

[0024] Hereinafter, various embodiments will be described in detail with reference to the accompanying drawings. In the drawings, like reference numerals represent like elements.

[0025] Figure 1 is a block diagram of a system for applying an AC field to a target area within a subject's body. The system includes an AC signal generator 20 designed to produce a first AC output and a second AC output at frequencies between 50 kHz and 10 MHz (e.g., 50 kHz to 1 MHz, 50 kHz to 500 kHz, 80 kHz to 300 kHz, or 150 kHz to 250 kHz). The AC signal generator 20 applies a first sine wave to an A / P pair of electrode elements 10A / 10P and a second sine wave of the same frequency to an L / R electrode element 10L / 10R. The surfaces of each of these electrode elements are configured to be positioned relative to the subject's body. When an AC voltage is applied to the electrode elements 10A / 10P / 10L / 10R, an AC electric field is applied to the target area. Electrode elements 10A / 10L / 10P / 10R are positioned at 90° intervals around the target body part, and when the first and second sine waves alternately shift in phase by 90°, the orientation of the electric field within the target region rotates continuously and repeatedly 360° during the course of treatment.

[0026] Since the first sine wave is applied between the 10A output and the 10P output, the signal at 10P is 180° out of phase with respect to the signal at 10A. Similarly, since the second sine wave is applied between the 10L output and the 10R output, the signal at 10L is 180° out of phase with respect to the signal at 10R. Furthermore, because the second sine wave is 90° out of phase with respect to the first sine wave, the signal at 10L is 90° out of phase with respect to the signal at 10A, and the signal at 10R is 270° out of phase with respect to the signal at 10A.

[0027] In some embodiments, each electrode element includes a conductive substrate, and each surface configured to be positioned relative to the subject's body includes an insulating material having a dielectric constant of at least 20, disposed on a separate conductive substrate.

[0028] Electrical sensation is thought to arise from the interaction between an alternating electric field and nerve cells or fibers (neurons or axons) located near or adjacent to electrode elements. The inventors determined that electrical sensation is not a problem while an alternating voltage is applied in a steady state to a given pair of electrode elements, or when the alternating voltage is turned off or ramped down. Instead, electrical sensation appears to be a problem that only occurs when the AC voltage is turned on or increased. The inventors also identified that electrical sensation is strongly dependent on the trajectory of how the AC voltage increases from zero to its peak when the AC voltage is switched on.

[0029] More specifically, if the amplitude of the AC voltage applied to the subject's body rises immediately from zero to its peak level when the system is turned on at t=0, as shown in Figure 2, the electrical sensation can be very pronounced. However, if the amplitude of the AC voltage applied to the subject's body rises more gradually to its peak level, the electrical sensation does not occur (or is at least dramatically reduced).

[0030] Embodiments described herein utilize this phenomenon to eliminate or reduce electrosensory sensation by avoiding the rapid increase shown in Figure 2 and configuring the system so that the amplitude of the AC voltage applied to the subject's body does not increase too rapidly. More specifically, the trajectory of how the AC voltage increases from zero to its peak in the embodiment of Figure 1 differs from the instantaneous on trajectory shown in Figure 2 in that it prevents the occurrence of electrosensory sensation or at least reduces the level of electrosensory sensation.

[0031] The AC signal generator 20 is configured to produce two out-of-phase sinusoidal outputs having amplitudes dependent on the state of at least one control input. The controller 30 sequentially transmits control signals to at least one control input, and these control signals cause the AC signal generator 20 to adjust its output amplitude as appropriate. Thus, using the combination of the controller 30 and the AC generator 20, any of the amplitude trajectories described herein can be generated. Note that although the controller 30 and the AC signal generator 20 are shown as two separate blocks in Figure 1, these two blocks may be integrated into a single hardware device.

[0032] Figure 3 shows an example of an amplitude trajectory that can be used to improve electrosensory perception. In this example, the controller 30 transmits a first set of control signals to the AC generator 20. This first set of control signals instructs the AC generator 20 to linearly increase its output amplitude over a period of 2 seconds until it reaches a final voltage. In some embodiments, the final voltage is at least 50V RMS (e.g., at least 100V RMS or 100-200V RMS), which induces an electric field with an electric field strength of at least 1V / cm (e.g., at least 5V / cm, 1V / cm-10V / cm, or 5V / cm-10V / cm) in at least a portion of the target area. Also, because the AC voltage applied to the subject's body rises slowly to its final level in this embodiment, electrosensory perception does not occur (or is at least dramatically reduced). After the ramp-up period, the output of the AC signal generator 20 remains constant for a long period of time (e.g., at least 30 seconds, at least 60 seconds, at least 100 seconds, etc.).

[0033] Figure 4 shows another example of an amplitude trajectory that can be used to improve electrosensory perception. In this example, the controller 30 transmits a second set of control signals to the AC generator 20. This second set of control signals instructs the AC generator 20 to set its output amplitude to a relatively low initial level at t=0, and then to linearly ramp up its output amplitude over 2 seconds until it reaches a final voltage. The initial level is selected to be below the threshold that causes electrosensory perception (e.g., below 20V RMS). In some embodiments, the final voltage is at least 50V RMS (e.g., at least 100V RMS or 100V RMS~200V RMS), which induces an electric field with an electric field strength of at least 1V / cm (e.g., at least 5V / cm, 1V / cm~10V / cm, or 5V / cm~10V / cm) in at least a portion of the target area. Here, as the AC voltage applied to the subject's body also rises slowly to its final level, electrosensory perception does not occur (or is at least dramatically reduced). After the ramp-up period, the output of the AC signal generator 20 remains constant for a long period of time, as described above in relation to Figure 3.

[0034] It should be noted that while both examples shown in Figures 3 and 4 have a 2-second ramp-up period, the ramp-up period can vary (e.g., at least 0.1 seconds, at least 0.3 seconds, at least 1 second, at least 3 seconds, at least 10 seconds, etc.). Furthermore, the linear ramps shown in Figures 3 and 4 are not the only amplitude trajectories that can be used to prevent or improve electrosensory effects. On the contrary, any of the wide variety of amplitude trajectories can be used, as long as the AC voltage applied to the subject's body increases slowly enough to avoid or at least minimize electrosensory effects.

[0035] Figure 5 shows four examples of nonlinear amplitude increasing trajectories that can be used to improve electrical sensation. In the first example 51, the amplitude increases during interval 1, then remains constant during interval 2, then increases further during interval 1', then remains constant during interval 2', and then increases further during interval 1''. To generate this amplitude trajectory, the controller 30 sequentially transmits control signals (e.g., once every 1 millisecond, 2 milliseconds, 5 milliseconds, 10 milliseconds, 20 milliseconds, 50 milliseconds, or 100 milliseconds) to the AC signal generator 20. When the AC signal generator 20 receives these control signals, it produces an output with an amplitude trajectory similar to trace 51. Each of the intervals 1, 1', 1', 2, and 2' can be, for example, 10 milliseconds to 10 seconds in length. The rationale for including intervals 2 and 2' in the trajectory is to allow the subject to become accustomed to the given voltage setting before the voltage rises further. In some embodiments, each of these intervals is at least 20 milliseconds, at least 50 milliseconds, or at least 100 milliseconds in length. After the amplitude-increasing trajectory has occurred, the output of the AC signal generator 20 remains constant over a long period of time at its final value (e.g., at least 50V RMS, at least 100V RMS, etc.), as described above in relation to Figure 3.

[0036] The second example 52 is similar to the first example 51, except that the amplitude of the AC signal generator 20 decreases during intervals 2 and 2' instead of remaining constant during intervals 2 and 2'. To generate this amplitude trajectory, the controller 30 sequentially transmits control signals to the AC signal generator 20 (e.g., once every 1 millisecond, 2 milliseconds, 5 milliseconds, 10 milliseconds, 20 milliseconds, 50 milliseconds, or 100 milliseconds). When the AC signal generator 20 receives these control signals, it produces an output with an amplitude trajectory similar to trace 52. Each of the intervals 1, 1', 1'', 2, and 2' can be, for example, 10 milliseconds to 10 seconds in length. After the amplitude increasing trajectory has occurred, the output of the AC signal generator 20 remains constant at its final value over a long period of time, as described above in relation to trace 51.

[0037] In the third example 53, the controller 30 sequentially transmits control signals to the AC signal generator 20 such that the amplitude of the AC signal generator 20 increases linearly at a first rate during interval 1 (which can be, for example, 100 milliseconds to 10 seconds in length) and linearly at a second rate during interval 2 (which can also be, for example, 100 milliseconds to 10 milliseconds in length). After the amplitude increase trajectory has occurred, the output of the AC signal generator 20 remains constant at its final value over a long period of time, as described above in relation to trace 51.

[0038] In the fourth example 54, the controller 30 sequentially transmits control signals to the AC signal generator 20 such that the amplitude of the AC signal generator 20 increases at a first linear rate during interval 1 (which can be, for example, 100 milliseconds to 10 seconds in length) and at a second nonlinear rate during interval 2 (which can also be, for example, 100 milliseconds to 10 seconds in length). Here, after the amplitude increase trajectory has occurred, the output of the AC signal generator 20 remains constant at its final value over a long period of time, as described above in relation to trace 51.

[0039] The four examples 51-54 above are not exhaustive. Conversely, a wide variety of alternative amplitude increase trajectories can be easily envisioned to prevent the amplitude from increasing too rapidly in order to improve electrical sensation.

[0040] Figure 6 is a block diagram of another system for applying a TT field to a target area within a subject's body. This system is similar to the system in Figure 1 described above, except that the embodiment in Figure 6 uses a three-phase approach to perform electric field rotation instead of the sine-cos approach described above in relation to Figure 1. The embodiment in Figure 6 uses an AC signal generator 20 designed to produce three AC outputs at frequencies of 50 kHz to 10 MHz (e.g., 50 kHz to 1 MHz, 50 kHz to 500 kHz, 80 kHz to 300 kHz, or 150 kHz to 250 kHz). The three outputs are applied to three sets of electrode elements 10X / 10Y / 10Z configured to be 120° out of phase with each other and positioned relative to the subject's body. When the electrode elements 10X / 10Y / 10Z are positioned at 120° intervals around the target body part, applying the three-phase signals to these electrode elements improves the alternating electric field within the target area with a continuous and repeated 360° rotation orientation during the course of treatment.

[0041] Except for the distinction that this embodiment in Figure 6 uses three-phase electric field rotation instead of the sine / cosine-based electric field rotation described above in relation to Figure 1, the operation of this embodiment in Figure 6 is the same as the operation of the embodiment in Figure 1 described above.

[0042] Finally, in some anatomical locations, the electrode elements are not placed on the subject's skin. Instead, the electrode elements are implanted in the subject's body (for example, just beneath the subject's skin) so that the application of an alternating voltage between the electrode elements applies an alternating electric field to a target area of ​​the subject's body.

[0043] While the present invention is disclosed with reference to specific embodiments, numerous modifications, changes, and variations are possible with respect to the embodiments described, without departing from the scope and scope of the invention, as defined in the appended claims. Therefore, the present invention is not limited to the embodiments described, but is intended to encompass the entire scope defined by the following claims and their equivalents. [Explanation of Symbols]

[0044] 10A, 10L, 10P, 10R, 10X, 10Y, 10Z electrode elements, 20 AC signal generators, 30 controllers

Claims

1. A device for selectively destroying or inhibiting the proliferation of rapidly dividing cells located within a target area of ​​a subject's body, At least three electrodes, each having a surface configured to be positioned relative to the subject's body, The AC voltage source includes at least three outputs, each electrically connected to one of the individual electrodes, Each of the three outputs has a frequency of 50 kHz to 1 MHz. The apparatus wherein each of the at least three outputs has an amplitude that increases from at least an initial level to a final level of 50 V RMS over a period of at least 0.1 s.

2. The apparatus according to claim 1, wherein each of the at least three outputs has an amplitude that is maintained at the final level for at least 30 seconds.

3. The apparatus according to claim 1 or 2, wherein each of the at least three electrodes includes a conductive substrate, and each of the surfaces configured to be positioned relative to the subject's body includes an insulating material having a dielectric constant of at least 20 disposed on the individual conductive substrate.

4. The apparatus according to any one of claims 1 to 3, wherein each of the at least three outputs has an amplitude that increases from the initial level to the final level over a period of at least 0.3 seconds, and the final level is at least 100 V RMS, and optionally has an amplitude that increases from the initial level to the final level over a period of at least 1 second, and the final level is at least 100 V RMS.

5. The apparatus according to any one of claims 1 to 4, wherein each of the at least three outputs has a frequency of 80 kHz to 300 kHz.

6. The apparatus according to any one of claims 1 to 5, wherein the AC voltage source comprises a first output of a given frequency, a second output of a given frequency offset by 120° with respect to the first output, and a third output of a given frequency offset by 240° with respect to the first output.

7. The apparatus according to any one of claims 1 to 5, wherein the AC voltage source comprises a first output of a given frequency, a second output of a given frequency offset by 90° with respect to the first output, a third output of a given frequency offset by 180° with respect to the first output, and a fourth output of a given frequency offset by 270° with respect to the first output.

8. The apparatus according to any one of claims 1 to 7, wherein the AC voltage source simultaneously applies a sinusoidal signal of a first frequency to each of the at least three outputs, the signal applied to each of the at least three outputs is modulated by a sinusoidal wave of a second frequency at least 10 times lower than the first frequency, and the modulated sinusoidal wave is phase-shifted.

9. The apparatus according to any one of claims 1 to 8, wherein the increase in amplitude from the initial level to the final level is linear.

10. An AC electric field for use in a method for selectively destroying or inhibiting the proliferation of rapidly dividing cells located within a target area of ​​a subject's body, wherein the method is: A step of rotating the AC electric field within the target region, wherein the electric field orientation rotates relative to the target region, The electric field has a frequency of 50 kHz to 1 MHz. The electric field is an AC electric field having an amplitude that increases from an initial level to a final level over a period of at least 0.1 seconds.

11. An AC electric field for selectively destroying or inhibiting the proliferation of rapidly dividing cells located within a target area of ​​a subject's body, The AC electric field has an electric field orientation that rotates with respect to the target region, has a frequency of 50 kHz to 1 MHz, and has an amplitude that increases from an initial level to a final level over a period of at least 0.1 seconds.

12. The AC electric field for use according to claim 10 or the AC electric field according to claim 11, wherein the electric field in at least a portion of the target region is induced by an applied voltage, and when the amplitude of the electric field is at the final level, the applied voltage is at least 50 V RMS, and optionally, the applied voltage is at least 100 V RMS.

13. The electric field is an AC electric field for use according to claim 10 or claim 12, or an AC electric field according to claim 11 or claim 12, which is applied to the target region via an insulating electrode.

14. The AC electric field for use according to claim 10, claim 12, or claim 13, or the AC electric field according to claim 11, claim 12, or claim 13, wherein the electric field has an amplitude that increases from the initial level to the final level for at least 0.3 seconds and optionally for at least 1 second.

15. When the amplitude of the electric field is at its final level, the electric field has an electric field intensity of at least 1 V / cm, and optionally at least 5 V / cm, in at least a portion of the target region, an AC electric field for use according to claim 10 or any one of claims 12 to 14 or an AC electric field according to any one of claims 11 to 14.

16. The frequency of the electric field is 80 kHz to 300 kHz, an AC electric field for use according to claim 10 or any one of claims 12 to 15, or an AC electric field according to any one of claims 11 to 15.

17. The rotation of the AC electric field is achieved by simultaneously applying AC voltages having different phases to at least three electrodes, the AC electric field for use according to claim 10 or any one of claims 12 to 16 or the AC electric field according to any one of claims 11 to 16.

18. The increase in amplitude from the initial level to the final level is linear, an AC electric field for use according to claim 10 or any one of claims 12 to 17 or an AC electric field according to any one of claims 11 to 17.

19. The increase in amplitude from the initial level to the final level is nonlinear. a) A first interval in which the amplitude increases by a constant ratio, followed by a second interval in which the amplitude remains constant, followed by a third interval in which the amplitude increases by the constant ratio, b) A first interval in which the amplitude increases by a first constant ratio, followed by a second interval in which the amplitude decreases by a second constant ratio, followed by a third interval in which the amplitude increases by the first constant ratio, c) A first interval in which the amplitude increases by a first constant ratio, followed by a second interval in which the amplitude increases by a second constant ratio, wherein the second constant ratio is different from the first constant ratio, and the first and second intervals are such that d) The apparatus according to one of claims 1 to 8, comprising one or more of the following: a first interval in which the amplitude increases by a constant ratio, followed by a second interval in which the amplitude increases by a non-constant ratio; an AC electric field for use according to claim 10 or one of claims 12 to 17; or an AC electric field according to one of claims 11 to 17.

20. The increase in amplitude from the initial level to the final level is, a) Setting the amplitude to an intermediate level between the initial level and the final level, wherein the intermediate level is set below the threshold that causes electrical sensation. b) Thereafter, the amplitude is increased from the intermediate level to the final level, The apparatus according to one of claims 1 to 8, the AC electric field for use according to claim 10 or one of claims 12 to 17, or the AC electric field according to one of claims 11 to 17, wherein the intermediate level is optionally 20 V RMS.

Images