Reducing electrical sensations in subjects treated with alternating electric fields by controlling ramp-up characteristics

Abstract

When an alternating current electric field is applied to a subject's body using a transducer array (i.e., an array of electrode elements), the subject may experience an electric sensation. The electric sensation can be improved by modifying the way the voltage ramps up from zero to its peak when the alternating current voltage is initially applied to any given pair of transducer arrays and when the alternating current electric field switches direction.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 357,111, filed June 30, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Tumor Treating Field (TT Field) therapy is a proven technique for treating tumors using alternating current (AC) electric fields at frequencies between 50 kHz and 1 MHz (e.g., 150–200 kHz). In the prior art Optune® system, TT Fields are delivered to a patient via four transducer arrays placed on the patient's skin near the tumor. The transducer arrays are arranged in pairs, with one pair positioned on the left and right sides of the tumor and the other pair positioned in front and behind 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 to the anterior / posterior (A / P) pair of transducer arrays for 1 second to induce an electric field in the tumor in a first direction, and then (b) sends an AC current to the left / right (L / R) pair of arrays for 1 second to induce an electric field in the tumor in a second direction. Steps (a) and (b) are then repeated throughout the treatment. Each transducer array includes a plurality of (eg, between 9 and 30) electrode elements.

[0003] Alternating current electric fields can also be used to treat conditions other than tumors. For example, as described in U.S. Patent No. 10,967,167 (incorporated herein by reference in its entirety), alternating current electric fields can be used to increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapy drugs to reach the brain.

[0004] High amplitudes are strongly correlated with high therapeutic efficacy when treating subjects with AC electric fields. However, as the amplitude of the AC electric field increases or the frequency of the AC electric field decreases (e.g., to around 100 kHz), some subjects experience an electrosensory effect. This electrosensation can be, for example, a vibratory sensation, paresthesia, and / or a sensation of muscle fiber twitching or contraction, or a flickering of lights in the eyes. These electrosensations may deter some subjects from continuing treatment with AC electric fields. Furthermore, electrosensation may limit the amplitude of the AC electric field that can be comfortably applied to a given subject, thereby limiting the effectiveness of the treatment. Summary of the Invention

[0005] One aspect of the present invention relates to a first method for applying an alternating current electric field to a target region within a subject's body. The first method includes: (a) applying a first alternating current electric field having a first orientation to the target region for a first time interval. The first alternating current electric field has an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval. Each of the plurality of second subsections of the first time interval is at least 10 ms long and follows immediately after a respective one of the first subsections of the first time interval. The first alternating current electric field has an amplitude that remains constant during a third subsection of the first time interval. The third subsection of the first time interval follows the last of the first subsections of the first time interval.

[0006] 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 subsections 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 subsections 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 between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval.

[0007] Some examples of the first method further include (b) applying a second AC electric field having a second orientation to the target region during a second time interval. The second AC electric field has an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval. The second orientation and the first orientation are different. Each of the plurality of second subsections of the second time interval is at least 10 ms long and follows immediately after a respective one of the first subsections of the second time interval. The second AC electric field has an amplitude that remains constant during a third subsection of the second time interval. And, the third subsection of the second time interval follows the last of the first subsections of the second time interval. These examples also include alternatingly repeating steps (a) and (b) at least 1000 times.

[0008] Optionally, in the example of the first method described above, the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval, and the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval.

[0009] Optionally, in the example of the first method described above, the first AC electric field has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval coming after the third subsection of the first time interval, and the second AC electric field has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval coming after the third subsection of the second time interval.

[0010] Some examples of the first method further include (b) applying a second AC electric field having a second orientation to the target region during a second time interval. The second AC electric field has an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval. The second orientation and the first orientation are different. Each of the plurality of second subsections of the second time interval is at least 10 ms long and follows immediately after each of the first subsections of the second time interval. The second AC electric field has an amplitude that remains constant during a third subsection of the second time interval. And, the third subsection of the second time interval follows the last of the first subsections of the second time interval. These examples also include alternatingly repeating steps (a) and (b) at least 1000 times. In these examples, when the first time interval begins, the first AC electric field has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval. Then, when the second time interval begins, the second alternating electric field has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during a third subsection of the second time interval.

[0011] Another aspect of the present invention relates to a first apparatus for applying electrical signals to first, second, third, and fourth sets of at least one electrode element, the first apparatus comprising an AC signal generator and a controller, the AC signal generator having a first output, a second output, and at least one control input, and the controller configured to apply a series of control signals to the at least one control input of the AC signal generator. The series of control signals instruct the AC signal generator to perform the steps of: (a) applying a first AC output signal to the first output during a first time interval, the first AC output signal having an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval, each of the plurality of second subsections of the first time interval being at least 10 ms in length and coming immediately after a respective one of the first subsections of the first time interval; and the first AC output signal having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after the last one of the first subsections of the first time interval.

[0012] 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 subsections 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 subsections 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 between 20% and 80% of the amplitude that remains constant during a third subsection of the first time interval.

[0013] In some embodiments of the first device, the series of control signals instruct the AC signal generator to perform the steps of: (b) applying a second AC output signal to the second output during a second time interval, the second AC output signal having an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval, each of the plurality of second subsections of the second time interval being at least 10 ms long and coming immediately after a respective one of the first subsections of the second time interval, the second AC output signal having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval; and (c) alternatingly repeating steps (a) and (b) 1000 times.

[0014] Optionally, in the first device embodiment described in the previous paragraph, the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval, and the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval.

[0015] Optionally, in an embodiment of the first device described in the previous paragraph, the first AC output signal has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval coming after the third subsection of the first time interval, and the second AC output signal has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval coming after the third subsection of the second time interval.

[0016] In some embodiments of the first device, the series of control signals instruct the AC signal generator to perform the steps of: (b) applying a second AC output signal to the second output during a second time interval, the second AC output signal having an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval, each of the plurality of second subsections of the second time interval being at least 10 ms long and coming immediately after a respective one of the first subsections of the second time interval, the second AC output signal having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval; and (c) alternatingly repeating steps (a) and (b) 1000 times. In these embodiments, when the first time interval begins, the first alternating current output signal has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval, and when the second time interval begins, the second alternating current output signal has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the second time interval.

[0017] Another aspect of the present invention relates to a second method for applying an alternating current electric field to a target region within a subject's body, the second method including: (a) applying a first alternating current electric field having a first orientation to the target region for a first time interval. The first alternating current electric field has an amplitude that increases at a first rate during a first subsection of the first time interval and at a second rate that is slower than the first rate during a second subsection of the first time interval. The second subsection of the first time interval follows immediately after the first subsection of the first time interval. The first alternating current electric field has an amplitude that remains constant during a third subsection of the first time interval. The third subsection of the first time interval follows after the second subsection of the first time interval.

[0018] In some examples of the second method, the amplitude of the first alternating electric field increases linearly during the first subsection of the first time interval, and the amplitude of the first alternating electric field increases linearly during the second subsection of the first time interval. In some examples of the second method, a first derivative of the first alternating electric field decreases continuously during the second subsection of the first time interval.

[0019] Some examples of the second method further include (b) applying a second AC electric field having a second orientation to the target region during a second time interval. The second orientation is different from the first orientation. The second AC electric field has an amplitude that increases at a third rate during a first subsection of the second time interval and increases at a fourth rate slower than the third rate during a second subsection of the second time interval. The second subsection of the second time interval follows immediately after the first subsection of the second time interval. The second AC electric field has an amplitude that remains constant during a third subsection of the second time interval. And, the third subsection of the second time interval follows after the second subsection of the second time interval. In these examples, steps (a) and (b) are alternately repeated at least 1000 times.

[0020] Optionally, in the example of the second method described above, the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval, and the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval.

[0021] Optionally, in the example of the second method described above, the first AC electric field has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval coming after the third subsection of the first time interval, and the second AC electric field has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval coming after the third subsection of the second time interval.

[0022] Another aspect of the present invention relates to a second device for applying electrical signals to first, second, third, and fourth sets of at least one electrode element. 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 series of control signals to the at least one control input of the AC signal generator, the series of control signals instructing the AC signal generator to (a) apply a first AC output signal to the first output during a first time interval. The first AC output signal has an amplitude that increases at a first rate during a first subsection of the first time interval and increases at a second rate, slower than the first rate, during a second subsection of the first time interval. The second subsection of the first time interval follows immediately after the first subsection of the first time interval. The first AC output signal has an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval following the second subsection of the first time interval.

[0023] In some embodiments of the second device, the amplitude of the first alternating current output signal increases linearly during a first subsection of the first time interval, and the amplitude of the first alternating current output signal increases linearly during a second subsection of the first time interval. In some embodiments of the second device, a first derivative of the amplitude of the first alternating current output signal decreases continuously during the second subsection of the first time interval.

[0024] In some embodiments of the second device, the series of control signals instruct the AC signal generator to (b) apply a second AC output signal to the second output during a second time interval. The second AC output signal has an amplitude that increases at a third rate during a first subsection of the second time interval and increases at a fourth rate slower than the third rate during a second subsection of the second time interval. The second subsection of the second time interval follows immediately after the first subsection of the second time interval. The second AC output signal has an amplitude that remains constant during a third subsection of the second time interval. And, the third subsection of the second time interval follows after the second subsection of the second time interval. Steps (a) and (b) are alternately repeated at least 1000 times.

[0025] Optionally, in the second device embodiment described in the previous paragraph, the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval, and the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval.

[0026] Optionally, in an embodiment of the second device described above, the first AC output signal has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval coming after the third subsection of the first time interval, and the second AC output signal has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval coming after the third subsection of the second time interval.

[0027] Another aspect of the present invention relates to a third method of applying an alternating current electric field to a target region within a subject's body, the third method comprising the step of: (a) applying a first alternating current electric field having a first orientation within the target region during a first time interval, the first alternating current electric field having an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval, each of the plurality of second subsections of the first time interval coming immediately after a respective one of the first subsections of the first time interval, the first alternating current electric field having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after the last one of the first subsections of the first time interval, and when the first time interval begins, the first alternating current electric field having an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval.

[0028] Some examples of the third method further include (b) applying a second AC electric field having a second orientation within the target region during a second time interval, the second AC electric field having an amplitude that increases during multiple first subsections of the second time interval and remains constant or decreases during multiple second subsections of the second time interval, each of the multiple second subsections of the second time interval coming immediately after a respective one of the first subsections of the second time interval, the second AC electric field having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval, and when the second time interval begins, the second AC electric field having an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the second time interval. These examples of the third method also further include alternatingly repeating steps (a) and (b) at least 1000 times. In these examples of the third method, the second orientation and the first orientation are different. [Brief explanation of the drawings]

[0029] [Figure 1] 1 shows the AC output amplitude in two channels of a prior art Optune® system. [Figure 2] FIG. 1 is a block diagram of a system for driving a set of transducer arrays with an AC voltage signal that can control the amplitude trajectory of the AC output. [Figure 3] 10 shows an example of an amplitude trajectory that can be applied to the output of an AC signal generator to improve electrical sensation. [Figure 4] 10 shows additional examples of amplitude trajectories that can be applied to the output of an AC signal generator to improve electrical sensation.

[0030] Various embodiments will now be described in detail with reference to the accompanying drawings, in which like reference numerals represent like elements. DETAILED DESCRIPTION OF THE INVENTION

[0031] FIG. 1 shows the AC output amplitude in the L / R and A / P channels of a prior art Optune® system. In particular, when the signal to either the A / P or L / R transducer array is turned on for 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 ramps up from zero to its peak over a 50-ms window. Similarly, when the signal is turned off for any given one-second interval, the amplitude of the AC voltage ramps down from its peak to zero over a 50-ms window.

[0032] The inventors have determined that electrosensation is not an issue during steady-state application of AC voltage to a given pair of transducer arrays or when the AC voltage is turned off / ramped down. Instead, electrosensation appears to be an issue only when the AC voltage is turned on / ramped up (occurring when the system is initially turned on and each time the electric field direction switches). Electrosensation is believed to result from the interaction between the AC electric field and nerve cells or fibers (i.e., neurons or axons) located near or adjacent to the transducer arrays.

[0033] The inventors have also determined that electrosensation can be improved by changing the trajectory of how the AC voltage increases from zero to its peak when the AC voltage is initially applied to any given pair of transducer arrays and as the AC field switches direction.

[0034] Figure 2 is a block diagram of a system for driving a pair of transducer arrays with an AC voltage signal that can control the trajectory of how the AC voltage increases from zero to its peak. The system includes an AC signal generator 20 designed to generate first and second AC outputs at frequencies between 50 kHz and 10 MHz (e.g., 50 kHz to 1 MHz, 50 to 500 kHz, 75 to 300 kHz, or 150 to 250 kHz). When using this system to apply TT fields to a portion of a human body (as shown in Figure 2), the first AC output is applied to a first pair of transducer arrays 10L and 10R positioned to the left and right of the tumor, and the second AC output is applied to a second pair of transducer arrays 10A and 10P positioned in front and behind the tumor.

[0035] When AC signal generator 20 applies a voltage between transducer array 10L and transducer array 10R, an AC electric field having electric field lines running generally from left to right is induced in the target region. When AC signal generator 20 applies a voltage between transducer array 10L and transducer array 10R, an AC electric field having electric field lines running generally from front to back is induced in the target region. The frequency of the AC electric field matches the frequency of AC signal generator 20. The electrode elements in transducer array 10 can be capacitively coupled electrode elements (i.e., electrode elements including a thin dielectric layer that contacts the subject's body) or conductive electrode elements (i.e., electrode elements including a conductive surface that contacts the subject's body).

[0036] 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 between 1 V / cm and 10 V / cm in at least a portion of the cells.

[0037] Similar to the prior art Optune® system, (a) a first AC output is applied to the L / R transducer array for 1 second, (b) a second AC output is applied to the A / P transducer array for 1 second, and the two-step sequence (a) and (b) is repeated for the duration of the treatment. However, the trajectory of how the AC voltage increases from zero to its peak in the embodiment of Figure 2 differs from the ramp-up trajectory used in Optune® in a way that helps improve the electrical sensation felt by the subject.

[0038] The AC signal generator 20 is configured to generate first and second AC outputs having amplitudes that depend on the state of at least one control input. The controller 30 rapidly sends a series of control signals (e.g., at a rate of one control signal per ms) to the at least one control input to generate the amplitude trajectories described herein. Note that while the controller 30 and the AC signal generator 20 are shown as two separate blocks in FIG. 2, these two blocks may be integrated into a single hardware device.

[0039] The details of the construction of controller 30 and the nature of its control signals depend on the design of AC signal generator 20. In one example, the design of 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. This particular AC signal generator includes two output channels (i.e., a first channel for L / R and a second channel for A / P). The instantaneous AC output voltage of either channel depends on the instantaneous output voltage of a DC-DC converter, which is controlled by writing control words to a digital-to-analog converter (DAC) at a rate of, for example, one control signal per ms.

[0040] This AC C signal generator can therefore be used to increase the AC output voltage at any desired rate and with any trajectory by sequentially sending appropriate control words to the DAC.

[0041] 3 shows an example of amplitude trajectories that can be applied to the L / R and A / P output channels of AC signal generator 20 (shown in FIG. 2) to improve electrical sensation. More specifically, trace 51 shows how the amplitude of the AC voltage in the L / R channel changes over time, and trace 52 shows how the amplitude of the AC voltage in the A / P channel changes over time. Panel A is an enlarged version of the ramp-up portion 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', then increases further during interval 1". To generate this amplitude trajectory, controller 30 sequentially sends control words (e.g., once per ms) to AC signal generator 20. Upon receiving these control words, AC signal generator 20 generates an output having an amplitude similar to the waveform shown in panel A of FIG. 3. A similar sequence of control words is used to control the A / P channel. Note that if controller 30 sends control words to AC signal generator at a rate of one control word per ms, intervals 1, 1', and 1" will not be a true ramp (as shown in FIG. 3). Instead, these intervals are steps with very small step heights, and in a zoomed-out view, resemble the slope shown in FIG. 3.

[0042] When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, a first AC electric field having a first orientation is applied to the target region for a first time interval. The first AC electric field has an amplitude that increases during a plurality of first subsections 1, 1', 1'' of the first time interval and remains constant for at least 10 ms during a plurality of second subsections 2, 2' of the first time interval. Each of the plurality of second subsections 2, 2' of the first time interval immediately follows a respective one of the first subsections 1, 1' of the first time interval. The rationale for including the second subsections 2, 2' of the first time interval (each at least 10 ms long) in the trajectory is to allow the subject to become accustomed to a given voltage setting before the voltage is further increased. In some embodiments, each of these intervals is at least 20 ms or 40 ms long.

[0043] Note that while the first subsections 1, 1', 1" of the first time interval in the example shown in Panel A occupy more than half of the first time interval as a whole, the first subsections 1, 1', 1" (during which the amplitude rises) can be significantly shorter. For example, in some embodiments, these subsections can be 1 ms, 1 μs, or even shorter than 1 μs. And, in these embodiments, each of the second subsections 2, 2' is much longer (10 ms or longer), so the resulting waveform during the first time interval resembles 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 jumps to the next step in the staircase as quickly as possible, limited only by the response time of the AC signal generator 20. This response time can be as short as 1 μs or even shorter than 1 μs. In these embodiments, the duration of each first subsection 1, 1', 1" is correspondingly shorter.

[0044] After the ramp-up period (which includes subsections 1, 2, 1', 2', and 1" of the first time interval), the output of the AC signal generator 20 remains constant for interval 3. Interval 3 comes after the last of the first subsection 1". After interval 3, the output of the AC signal generator 20 ramps down for interval 4. When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, the first AC electric field has an amplitude that remains constant for the third subsection 3 of the first time interval. The third subsection 3 of the first time interval comes after (but not "immediately after" in this example) the last of the first subsection 1" of the first time interval.

[0045] The operation of the front / rear channels (and second AC electric field) is similar to that of the left / right channels (and first AC electric field) described above, except that the two channels are activated in an alternating sequence (e.g., at least 1000 times) and are out of phase. When one channel is active, the other channel is off. As a result, during the time interval immediately following the first time interval, the first AC electric field is not applied to the target region, and during the time interval immediately following the second time interval, the second AC electric field is not applied to the target region.

[0046] A wide variety of alternative designs for the AC signal generator 20 and controller 30 can be substituted for the above example, so long as the controller 30 is capable of controlling the AC signal generator 20. For example, if the AC signal generator is designed to respond to analog control signals, the controller 30 must generate the sequence of analog control signals necessary to cause the AC signal generator 20 to output the desired waveform. In this situation, the controller 30 can be implemented using a microprocessor or microcontroller programmed to write appropriate control words to a digital-to-analog converter, the output of which generates the analog control signals that cause the AC signal generator 20 to generate the desired waveform. Alternatively, the controller 30 can be implemented using analog circuitry that automatically generates the appropriate sequence of control signals (which are then applied to the control inputs of the AC signal generator).

[0047] The trajectory of how the AC voltage increases from zero to its peak shown in panel A of FIG. 3 is not the only trajectory that can be used to improve electrical sensation. Conversely, various alternative trajectories can be used. One example of an alternative trajectory that can be used to improve electrical sensation is shown in panel B of FIG. 3. This example is similar to the embodiment described above in connection with panel A of FIG. 3, except that instead of remaining constant for at least 10 ms between intervals 2 and 2', the amplitude of the AC signal generator 20 decreases for at least 10 ms between intervals 2 and 2'. To generate this amplitude trajectory, the controller 30 sequentially transmits control words (e.g., once every 1 ms) to the AC signal generator 20. Upon receiving these control words, the AC signal generator 20 generates an output having an amplitude similar to the waveform shown in panel A of FIG. 3. A similar sequence of control words is used to control the A / P channel.

[0048] When the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, a first AC electric field having a first orientation is applied to the target region for a first time interval. The first AC electric field has an amplitude that increases during a plurality of first subsections 1, 1', 1'' of the first time interval and decreases during a plurality of second subsections 2, 2' of the first time interval for at least 10 ms. Each of the plurality of second subsections 2, 2' of the first time interval immediately follows a respective one of the first subsections 1, 1' of the first time interval. A similar sequence occurs in the A / P channel. The rationale for including the second subsections 2, 2' of the first time interval (each at least 10 ms long) in the trajectory is to allow the subject to become accustomed to a given voltage setting before the voltage is further increased. In some embodiments, each of these intervals is at least 20 ms or 40 ms long.

[0049] Panel C of FIG. 3 shows another example of the trajectory of how an AC voltage increases from zero to its peak, which can be used to improve the electrical sensation felt by a subject. This example is similar to the embodiment described above in connection with Panel A of FIG. 3, except that the amplitude of AC signal generator 20 increases at a first rate during a first subsection 1 of a first time interval and increases at a second rate, slower than the first rate, during a second subsection 2 of the first time interval. The increase during the first subsection of the first time interval can be a linear increase (as shown in Panel C) or a nonlinear increase. Similarly, the increase during the second subsection of the first time interval can be a linear increase (as shown in Panel C) or a nonlinear increase (as shown in Panel D).

[0050] The second subsection of the first time interval immediately follows the first subsection of the first time interval. The third and fourth subsections of the first time interval in this embodiment are similar to the corresponding subsections in the embodiment of Panel A above. To generate this amplitude trajectory, controller 30 sequentially transmits control words (e.g., once per ms) to AC signal generator 20. Upon receiving these control words, AC signal generator 20 generates an output having an amplitude similar to the waveform shown in Panel A of FIG. 3. A similar sequence of control words is used to control the A / P channel.

[0051] In these embodiments, when the output of the AC signal generator 20 is applied to the transducer arrays 10L, 10R, a first AC electric field having a first orientation is applied to the target region during a first time interval. The first AC electric field has an amplitude that increases at a first rate during a first subsection 1 of the first time interval and increases at a second rate, slower than the first rate, during a second subsection 2 of the first time interval. A similar sequence occurs in the A / P channel.

[0052] In the above-described example, AC voltage generator 20 is configured to increase the output voltage using the same trajectory each time (e.g., (a) always use the trajectory described above in connection with panel A of FIG. 3 , (b) always use the trajectory described above in connection with panel B, (c) always use the trajectory described above in connection with panel C, or (d) always use the trajectory described above in connection with panel D). However, in alternative embodiments, AC voltage generator 20 can be configured to control the trajectory of how the AC voltage increases from zero to its peak in different ways at different times. For example, using the trajectories of Panel A and Panel B at different times, using the trajectories of Panel A and Panel C at different times, using the trajectories of Panel A, Panel B, and Panel C at different times, or using the trajectories of Panel A, Panel B, Panel C, and Panel D at different times.

[0053] 3, the amplitudes of the first and second outputs of the AC signal generator are both very small (e.g., less than 1% of the constant level applied during the third subsection of each time interval) when the first and second time intervals begin. Similarly, the first and second AC electric fields are both very small (e.g., less than 1% of the level applied during the third subsection of each time interval) when the first and second time intervals begin.

[0054] However, in alternative embodiments (e.g., as shown in FIG. 4 ), the amplitudes of the first and second outputs of the AC signal generator can immediately jump to an initial level Vi that is 20-80% of the constant level Vf applied during the third subsection of their respective time intervals. Similarly, the amplitudes of the first and second AC electric fields can immediately jump to an initial level Vi that is 20-80% of the constant level Vf applied during the third subsection of their respective time intervals. After the initial jump to the initial level Vi, the amplitudes increase from Vi to Vf, for example, using the trajectory shown in Panel A of FIG. 4 (which is similar to the trajectory in Panel A of FIG. 3 but offset by Vi). Furthermore, these embodiments are not limited to the single amplitude trajectory shown in Panel A. Conversely, various other trajectories for varying the amplitude after the initial jump to Vi can be used in place of the trajectory shown in Panel A, including, but not limited to, the amplitude trajectories shown in Panels B, C, and D of FIG. 3 (but with an added offset of Vi).

[0055] These embodiments are advantageous because there is relatively little electrical sensation when the voltage is below a threshold level (e.g., 40 V). Thus, jumping immediately (e.g., in less than 200 μs) from 0 V to an initial voltage V (e.g., 40 V) when the first and second time intervals begin (as shown in FIG. 4 ) will not result in an electrical sensation in the majority of patients. And, because no time is wasted ramping up from 0 V to V, more time is available to ramp up from V to the final voltage V (which can, for example, exceed 100 V). This (a) increases the average electric field strength applied to the subject and (b) provides the subject with more time to acclimate to each new voltage level before the voltage is increased to the next level, thereby further improving electrical sensation.

[0056] In some implementations, the value of the initial level Vi is the same for all patients (e.g., 40 V). In other embodiments, the value of the initial level Vi is patient-specific and can be set via an appropriate user interface in communication with the controller 30. In the latter embodiment, the controller 30 can be programmed to apply different voltage levels to the subject to determine the threshold voltage Vth at which electrical sensations begin for the particular subject being treated. The initial level Vi is then set below that threshold Vth during the course of treatment for that particular subject.

[0057] These embodiments in which the amplitude jumps to an initial level of Vi are similar to the embodiments described above in connection with Figures 2 and 3, with two exceptions. First, at the beginning of each first interval and each second interval, the amplitude immediately jumps to the initial level Vi and then follows a subsequent trajectory until it reaches a final level Vf. Second, the duration of (a) each of the plurality of second subsections of the first time interval and (b) each of the plurality of second subsections of the second time interval can be either (i) at least 10 ms (as described above in connection with Figures 2 and 3) or less than 10 ms (e.g., 5 to 10 ms, or less than 5 ms).

[0058] In the example described above, the direction of the AC field was switched between the L / R and A / P channels every second, so each time interval was 1 second long. However, in alternative embodiments, the direction of the AC field could be switched at a faster rate (e.g., every 1-1000 ms) or a slower rate (e.g., every 1-360 seconds), with each interval lasting less or more than 1 second. Optionally, the overall duration of the treatment could be interrupted by a break.

[0059] In the above example, the direction of the AC electric field was switched between two directions. However, in alternative embodiments, the direction of the AC electric field can be switched between three or more directions (assuming additional paired transducer arrays are provided). For example, the direction of the AC electric field is switched between three directions, each determined by the placement of its own paired transducer array. In other alternative embodiments, the transducer arrays need not be placed in pairs. See, for example, the transducer array positioning described in U.S. Pat. No. 7,565,205, which is incorporated herein by reference. However, regardless of the placement of the transducer array, one of the correction trajectories described herein is used each time a given transducer array is activated.

[0060] In some anatomical locations, the transducer array is not placed on the subject's skin, but instead is implanted in the subject's body (e.g., just beneath the subject's skin) such that application of an AC voltage across the transducer array generates an AC voltage at a target area within the subject's body.

[0061] Finally, in some anatomical locations, instead of switching the AC field back and forth between two or more different directions, a constant-direction electric field may be used. Embodiments for use in these locations are similar to the embodiment of FIG. 2, except that the AC signal generator 20 has a single output (e.g., only an L / R output). In these embodiments, the AC voltage generator is configured to increase its output voltage using one of the trajectories described above (e.g., in conjunction with panels A, B, C, or D of FIG. 3) when first switched on, and then either maintain its output voltage at a constant level for the duration of treatment, or repeatedly switch a single output on and off (e.g., on for 1-10 seconds, off for 0.1-10 seconds). In the latter situation, each time the AC voltage generator is switched on again, it increases its output voltage using one of the trajectories described above (e.g., in conjunction with panels A, B, C, or D of FIG. 3).

[0062] While the present invention has been disclosed with reference to particular embodiments, numerous modifications, corrections, and variations can be made to the described embodiments without departing from the field and scope of the invention, as defined in the appended claims. Accordingly, it is intended that the present invention not be limited to the described embodiments, but rather have the full scope defined by the language of the following claims and their equivalents.

Claims

1. 1. A method of applying an alternating electric field to a target region within a subject's body, comprising:

12. A method comprising: (a) applying a first alternating electric field having a first orientation within the target region during a first time interval, the first alternating electric field having an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval, each of the plurality of second subsections of the first time interval being at least 10 ms in length and coming immediately after a respective one of the first subsections of the first time interval; the first alternating electric field having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after a last one of the first subsections 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 subsections of the first time interval.

3. The method of claim 1 , wherein the first alternating electric field has a decreasing amplitude during the plurality of second subsections of the first time interval.

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

5. (b) applying a second alternating electric field having a second orientation within the target region during a second time interval, the second alternating electric field having an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval, each of the plurality of second subsections of the second time interval being at least 10 ms in length and coming immediately after a respective one of the first subsections of the second time interval, the second alternating electric field having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval; repeating steps (a) and (b) alternately at least 1000 times; further comprising the second orientation and the first orientation are different; The method of claim 1.

6. the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval; the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval. The method of claim 5.

7. the first alternating electric field has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval occurring after the third subsection of the first time interval; the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval; the second alternating electric field has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval occurring after the third subsection of the second time interval; the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval. The method of claim 5.

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

9. 1. An apparatus for applying electrical signals to first, second, third, and fourth sets of at least one electrode element, comprising: an AC signal generator having a first output, a second output, and at least one control input; a controller configured to apply a series of control signals to the at least one control input of the AC signal generator; The series of control signals are transmitted to the AC signal generator: (a) instructing an apparatus to apply a first AC output signal to the first output during a first time interval, the first AC output signal having an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval, each of the plurality of second subsections of the first time interval being at least 10 ms in length and coming immediately after a respective one of the first subsections of the first time interval, the first AC output signal having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after a last one of the first subsections of the first time interval.

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

11. 10. The apparatus of claim 9, wherein the first alternating output signal has a decreasing amplitude during each of the plurality of second subsections of the first time interval.

12. 10. The apparatus of claim 9, wherein when a first time interval begins, the first alternating current output signal has an initial amplitude that is between 20% and 80% of an amplitude that remains constant during the third subsection of the first time interval.

13. The series of control signals are transmitted to the AC signal generator: (b) applying a second AC output signal to the second output during a second time interval, the second AC output signal having an amplitude that increases during a plurality of second subsections of the second time interval and remains constant or decreases during a plurality of subsections of the second time interval, each of the plurality of second subsections of the second time interval being at least 10 ms in length and coming immediately after a respective one of the first subsections of the second time interval, the second AC output signal having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval; (a) and (b) are alternately repeated at least 1000 times; 10. The apparatus of claim 9, further comprising:

14. the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval; the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval; 14. The apparatus of claim 13.

15. the first AC force signal has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval occurring after the third subsection of the first time interval; the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval; the second AC output signal has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval occurring after the third subsection of the second time interval; the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval; 14. The apparatus of claim 13.

16. when a first time interval begins, the first AC output signal has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval; When the second time interval begins, the second AC output signal has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the second time interval.

14. The apparatus of claim 13.

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

18. the amplitude of the first alternating electric field increases linearly during the first subsection of the first time interval; the amplitude of the first alternating electric field increases linearly during the second subsection of the first time interval.

18. The method of claim 17.

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

20. (b) applying a second alternating electric field having a second orientation within the target region during a second time interval, the second alternating electric field having an amplitude that increases at a third rate during a first subsection of the second time interval and that increases at a fourth rate that is slower than the third rate during a second subsection of the second time interval, the second subsection of the second time interval coming immediately after the first subsection of the second time interval, the second alternating electric field having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the second subsection of the second time interval; repeating steps (a) and (b) alternately at least 1000 times; further comprising the second orientation and the first orientation are different; 18. The method of claim 17.

21. the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval; the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval.

21. The method of claim 20.

22. the first alternating electric field has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval occurring after the third subsection of the first time interval; the first alternating electric field is not applied to the target region during a time interval that immediately follows the first time interval; the second alternating electric field has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval occurring after the third subsection of the second time interval; the second alternating electric field is not applied to the target region during a time interval that immediately follows the second time interval.

21. The method of claim 20.

23. 1. An apparatus for applying electrical signals to first, second, third, and fourth sets of at least one electrode element, comprising: an AC signal generator having a first output, a second output, and at least one control input; a controller configured to apply a series of control signals to the at least one control input of the AC signal generator; The series of control signals are transmitted to the AC signal generator: (a) instructing an apparatus to apply a first alternating current output signal to the first output during a first time interval, the first alternating current output signal having an amplitude that increases at a first rate during a first subsection of the first time interval and that increases at a second rate slower than the first rate during a second subsection of the first time interval, the second subsection of the first time interval coming immediately after the first subsection of the first time interval, the first alternating current output signal having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after the second subsection of the first time interval.

24. the amplitude of the first AC output signal increases linearly during the first subsection of the first time interval; the amplitude of the first AC output signal increases linearly during the second subsection of the first time interval.

24. The apparatus of claim 23.

25. 24. The apparatus of claim 23, wherein a first derivative of the amplitude of the first alternating output signal decreases continuously during the second subsection of the first time interval.

26. The series of control signals are transmitted to the AC signal generator: (b) applying a second AC output signal to the second output during a second time interval, the second AC output signal having an amplitude that increases at a third rate during a first subsection of the second time interval and that increases at a fourth rate slower than the third rate during a second subsection of the second time interval, the second subsection of the second time interval occurring immediately after the first subsection of the second time interval, the second AC output signal having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval occurring after the second subsection of the second time interval; (a) and (b) are alternately repeated at least 1000 times; 24. The apparatus of claim 23, further comprising:

27. the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval; the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval; 27. The apparatus of claim 26.

28. the first AC force signal has a decreasing amplitude during a fourth subsection of the first time interval, the fourth subsection of the first time interval occurring after the third subsection of the first time interval; the first AC output signal is not applied to the first output during a time interval that immediately follows the first time interval; the second AC output signal has a decreasing amplitude during a fourth subsection of the second time interval, the fourth subsection of the second time interval occurring after the third subsection of the second time interval; the second AC output signal is not applied to the second output during a time interval that immediately follows the second time interval; 27. The apparatus of claim 26.

29. 1. A method of applying an alternating electric field to a target region within a subject's body, comprising:

11. A method according to claim 10, wherein the first alternating electric field has an amplitude that increases during a plurality of first subsections of the first time interval and remains constant or decreases during a plurality of second subsections of the first time interval, each of the plurality of second subsections of the first time interval coming immediately after a respective one of the first subsections of the first time interval, the first alternating electric field having an amplitude that remains constant during a third subsection of the first time interval, the third subsection of the first time interval coming after a last one of the first subsections of the first time interval, and when the first time interval begins, the first alternating electric field has an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the first time interval.

30. (b) applying a second AC electric field having a second orientation within the target region during a second time interval, the second AC electric field having an amplitude that increases during a plurality of first subsections of the second time interval and remains constant or decreases during a plurality of second subsections of the second time interval, each of the plurality of second subsections of the second time interval coming immediately after a respective one of the first subsections of the second time interval, the second AC electric field having an amplitude that remains constant during a third subsection of the second time interval, the third subsection of the second time interval coming after the last one of the first subsections of the second time interval, and when the second time interval begins, the second AC electric field having an initial amplitude that is between 20% and 80% of the amplitude that remains constant during the third subsection of the second time interval; repeating steps (a) and (b) alternately at least 1000 times; further comprising the second orientation and the first orientation are different; 30. The method of claim 29.

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