Use of interleaved variations in amplitude and frequency to improve electrical sensation during treatment with alternating electric field

Abstract

When a transducer array (i.e., an array of electrode elements) is used to apply an alternating electric field (e.g., TTField) to a subject's body, the subject may experience an electrical sensation. The electrical sensation may be improved by (a) increasing the amplitude of the electric field at a series of steps and allowing the subject to accommodate each step over a period of time prior to increasing the amplitude to the next higher value, (b) starting at a frequency higher than the recommended frequency for each indication (e.g., higher than 200 kHz for the treatment of glioblastoma), and (c) increasing the amplitude of the electric field to the next higher value. The frequency is then reduced to the recommended frequency in a series of steps and a period of time is allowed to adapt to each step by the subject before the frequency is reduced to the next lower value, and (c) the situation that an increase in amplitude and a decrease in frequency occur at the same time is avoided (or at least maximally reduced).

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application 63 / 541,347, filed on September 29, 2023, the full text of which is incorporated herein by reference. Background Technology

[0002] Tumor therapeutic electric field (TTField) therapy is an effective method for treating tumors using alternating electric fields with frequencies between 50 kHz and 5 MHz (e.g., 150 kHz to 200 kHz). In the prior art Optune® system, the TTField is delivered to the patient via four transducer arrays placed on the patient's skin close to the tumor. These transducer arrays are arranged in two pairs, with one pair positioned on the left and right sides of the tumor and the other pair positioned on the front and back sides. Each transducer array is connected to an AC signal generator via a multi-wire cable. The AC signal generator (a) sends an AC current for 1 second through the front / back (A / P) transducer array pair, inducing an electric field with a first direction through the tumor; then (b) sends an AC current for 1 second through the left / right (L / R) array pair, inducing an electric field with a second direction through the tumor; steps (a) and (b) are then repeated over the treatment duration. Each transducer array includes multiple (e.g., 9 to 30) electrode elements.

[0003] Alternating electric fields can also be used to treat medical conditions other than cancer. For example, as described in U.S. Patent No. 10,967,167 (the entire contents of which are incorporated herein by reference), alternating 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] When using alternating electric fields to treat subjects, specific frequencies are generally recommended for each indication (e.g., 200 kHz for glioblastoma, 150 kHz for mesothelioma, 75 kHz to 100 kHz for improving BBB permeability, etc.). Furthermore, higher amplitudes are closely associated with higher therapeutic efficacy. However, as the amplitude of the alternating electric field increases, and / or as the frequency decreases, some subjects experience electrosensory effects. These electrosensory effects may include, for example, vibrational sensations, paresthesia and / or twitching or contraction of muscle fibers, or flashes of light in the eyes (photophanosis). Electrosensory effects may prevent some subjects from continuing their treatment with alternating electric fields. Furthermore, electrosensory effects may limit the amplitude of an alternating electric field that can be comfortably applied to a given subject at any given frequency, which in turn may limit therapeutic efficacy. Summary of the Invention

[0005] One aspect of the present invention relates to a first device for applying an electrical signal to at least one electrode element in a first group, a second group, a third group, and a fourth group. The first device includes an AC signal generator and a controller. The AC signal generator has a first output, a second output, and at least one control input. The AC signal generator is configured such that the at least one control input controls the amplitude of the first output, the frequency of the first output, the amplitude of the second output, and the frequency of the second output. The controller is configured to apply a sequence of control signals to the at least one control input of the AC signal generator, wherein the sequence of control signals controls the AC signal generator such that (a) when the first output is activated at a given time, the first output has an initial amplitude and an initial frequency; (b) after the given time and during a first set of time periods while the first output remains active, the amplitude of the first output increases while the frequency of the first output remains constant; and (c) after the given time and during a second set of time periods while the first output remains active, the frequency of the first output decreases while the amplitude of the first output remains constant, wherein the first set of time periods and the second set of time periods are mutually exclusive. The control signal sequence further controls the AC signal generator such that (a) when the second output is activated at a certain time, the second output has an initial amplitude and an initial frequency; (b) after the certain time and during a third set of time while the second output remains active, the amplitude of the second output increases while the frequency of the second output remains constant; and (c) after the certain time and during a fourth set of time while the second output remains active, the frequency of the second output decreases while the amplitude of the second output remains constant, wherein the third set of time and the fourth set of time are mutually exclusive. The control signal sequence causes the AC signal generator to: (i) activate the first output within a time interval, (ii) subsequently activate the second output within a time interval, and (iii) subsequently repeat (i) and (ii) at least 10 times in an alternating sequence.

[0006] In some embodiments of the first device, each first time group includes at least 10 time periods, each second time group includes at least 3 time periods, each third time group includes at least 10 time periods, and each fourth time group includes at least 3 time periods. In some embodiments of the first device, each first time group includes at least 50 time periods, each second time group includes at least 3 time periods, each third time group includes at least 50 time periods, and each fourth time group includes at least 3 time periods. In some embodiments of the first device, the duration of each time interval activating the first output is at least 800 ms, and the duration of each time interval activating the second output is at least 800 ms. In some embodiments of the first device, each first time group and corresponding second time group are interleaved, and each third time group and corresponding fourth time group are interleaved.

[0007] In some embodiments of the first device, the initial frequency of the first output is at least 50% higher than the final frequency of the first output, and the initial frequency of the second output is at least 50% higher than the final frequency of the second output. Optionally, in these embodiments, the final frequencies of both the first output and the second output are between 75 kHz and 300 kHz.

[0008] In some embodiments of the first device, each first time group includes at least 50 time periods, each second time group includes at least 3 time periods, each third time group includes at least 50 time periods, and each fourth time group includes at least 3 time periods; the duration of each time interval activating the first output is at least 2 seconds; the duration of each time interval activating the second output is at least 2 seconds; each first time group and corresponding second time group are interleaved; each third time group and corresponding fourth time group are interleaved; the initial frequency of the first output is at least 50% higher than the final frequency of the first output; and the initial frequency of the second output is at least 50% higher than the final frequency of the second output. Optionally, in these embodiments, the final frequencies of both the first output and the second output are between 75 kHz and 300 kHz.

[0009] Another aspect of the invention relates to a second device for applying an electrical signal to at least one electrode element in a first group and a second group. The second device includes an AC signal generator and a controller. The AC signal generator has an output and at least one control input, and is configured such that the at least one control input controls the amplitude and frequency of the output. The controller is configured to apply a sequence of control signals to the at least one control input of the AC signal generator, wherein the sequence of control signals controls the AC signal generator such that (a) when the output is activated at a given time, the output has an initial amplitude and an initial frequency; (b) in a first group of time after the given time and while the output remains active, the amplitude of the output increases while the frequency of the output remains constant; and (c) in a second group of time after the given time and while the output remains active, the frequency of the output decreases while the amplitude of the output remains constant. The first group of time and the second group of time are mutually exclusive.

[0010] In some embodiments of the second device, the first set of times includes at least 10 times; the second set of times includes at least 3 times; the first set of times and the second set of times are interleaved; the initial frequency of the output is at least 50% higher than the final frequency of the output; and the final frequency of the output is between 75 kHz and 300 kHz.

[0011] Another aspect of the invention relates to a first method for applying an alternating electric field to a target region of a subject's body. The first method includes: (i) applying a first alternating electric field to the target region in a first orientation within a time interval, wherein the first alternating electric field has a frequency and average amplitude that vary over time, such that (a) when the first alternating electric field is activated at a given time, the first alternating electric field has an initial average amplitude and an initial frequency; (b) after the given time and during a first set of time periods while the first alternating electric field remains active, the average amplitude of the first alternating electric field increases while the frequency of the first alternating electric field remains constant; and (c) after the given time and during a second set of time periods while the first alternating electric field remains active, the frequency of the first alternating electric field decreases while the average amplitude of the first alternating electric field remains constant, wherein the first set of time periods and the second set of time periods are mutually exclusive; (ii) subsequently within the time interval... The target region is subjected to a second alternating electric field in a second orientation, wherein the second alternating electric field has a frequency and average amplitude that vary over time, such that (a) when the second alternating electric field is activated at a certain time, the second alternating electric field has an initial average amplitude and an initial frequency; (b) after the certain time and while the second alternating electric field remains active, in a third set of times, the average amplitude of the second alternating electric field increases while the frequency of the second alternating electric field remains constant; and (c) after the certain time and while the second alternating electric field remains active, in a fourth set of times, the frequency of the second alternating electric field decreases while the average amplitude of the second alternating electric field remains constant, wherein the third set of times and the fourth set of times are mutually exclusive; and (iii) steps (i) and (ii) are subsequently repeated at least 10 times in an alternating sequence.

[0012] In some instances of this first method, each first time group includes at least 10 times, each second time group includes at least 3 times, each third time group includes at least 10 times, and each fourth time group includes at least 3 times. In some instances of this first method, each first time group includes at least 50 times, each second time group includes at least 3 times, each third time group includes at least 50 times, and each fourth time group includes at least 3 times.

[0013] In some instances of the first method, the duration of each time interval for applying the first alternating electric field is at least 800 ms, and the duration of each time interval for applying the second alternating electric field is at least 800 ms. In some instances of the first method, each first set of times and the corresponding second set of times are interleaved, and each third set of times and the corresponding fourth set of times are interleaved.

[0014] In some instances of the first method, the initial frequency of the first alternating field is at least 50% higher than the final frequency of the first alternating field, and the initial frequency of the second alternating field is at least 50% higher than the final frequency of the second alternating field. Optionally, in these instances, the final frequencies of both the first and second alternating fields are between 75 kHz and 300 kHz.

[0015] In some instances of this first method, each first time group comprises at least 50 time periods, each second time group comprises at least 3 time periods, each third time group comprises at least 50 time periods, and each fourth time group comprises at least 3 time periods; the duration of each time interval for applying the first alternating electric field is at least 2 seconds; the duration of each time interval for applying the second alternating electric field is at least 2 seconds; each first time group and corresponding second time group are interleaved; each third time group and corresponding fourth time group are interleaved; the initial frequency of the first alternating electric field is at least 50% higher than the final frequency of the first alternating electric field; and the initial frequency of the second alternating electric field is at least 50% higher than the final frequency of the second alternating electric field. Optionally, in these instances, the final frequencies of both the first and second alternating fields are between 75 kHz and 300 kHz.

[0016] Another aspect of the invention relates to a second method for applying an alternating electric field to a target region of a subject's body. The second method includes applying the alternating electric field to the target region at time intervals, wherein the alternating electric field has a frequency and average amplitude that vary over time, such that (a) when the alternating electric field is activated at a given time, the alternating electric field has an initial average amplitude and an initial frequency; (b) in a first set of time intervals after the given time interval and while the alternating electric field remains active, the average amplitude of the alternating electric field increases while the frequency of the alternating electric field remains constant; and (c) in a second set of time intervals after the given time interval and while the alternating electric field remains active, the frequency of the alternating electric field decreases while the average amplitude of the alternating electric field remains constant. The first set of time intervals and the second set of time intervals are mutually exclusive.

[0017] In some instances of the second method, one or more of the following are present: the first set of times includes at least 10 times; the second set of times includes at least 3 times; the first set of times and the second set of times are interleaved; the initial frequency of the alternating electric field is at least 50% higher than the final frequency of the alternating electric field; and the final frequency of the alternating electric field is between 75 kHz and 300 kHz.

[0018] Another aspect of the invention relates to a third method for applying an alternating electric field to a target region of a subject's body. The third method includes applying a first alternating electric field to the target region in a first orientation over time intervals, wherein the first alternating electric field has a frequency and average amplitude that vary over time, such that (a) when the first alternating electric field is activated at a given time, the first alternating electric field has an initial average amplitude and an initial frequency; (b) in a first set of time intervals after the given time interval and while the first alternating electric field remains active, the average amplitude of the first alternating electric field increases while the frequency of the first alternating electric field remains constant; and (c) in a second set of time intervals after the given time interval and while the first alternating electric field remains active, the frequency of the first alternating electric field decreases while the average amplitude of the first alternating electric field remains constant. The first set of time intervals and the second set of time intervals are mutually exclusive. Attached Figure Description

[0019] Figure 1 The AC output amplitude in two channels of the existing Optune® system is depicted.

[0020] Figure 2 It is a block diagram of a system for driving an array of transducers using an AC voltage signal, wherein the amplitude and frequency of the AC output can be controlled in a manner that allows for control.

[0021] Figure 3 An example depicting a pattern of amplitude and frequency variations over time can be used to improve the electrosensory effect of an AC signal generator's output.

[0022] Figure 4 Another example depicting a pattern of amplitude and frequency changes over time, which can impart an AC signal generator output over time to improve electrosensory perception.

[0023] Various embodiments are described in detail below with reference to the accompanying drawings, wherein the same reference numerals denote the same elements. Detailed Implementation

[0024] Figure 1 The AC output amplitudes of the L / R and A / P channels in a prior art Optune® system are depicted. It is noteworthy that when a signal destined for the A / P or L / R transducer array is turned on during any given one-second interval, the AC voltage amplitude does not immediately jump to its peak value. Instead, the AC voltage amplitude rises from zero to its peak value over a 50ms window. Similarly, when the signal is turned off during any given one-second interval, the AC voltage amplitude drops from its peak value to zero over a 50ms window.

[0025] The inventors have determined that electrosensory sensation is not a problem during the application of a steady-state AC voltage to a given pair of transducer arrays or when the AC voltage is off / ramped. Instead, electrosensory sensation appears to be a problem only when the AC voltage is on / ramped (this occurs when the system is first turned on and whenever the electric field reverses direction). Electrosensory sensation is thought to originate from the interaction between the alternating electric field and nerve cells or fibers (i.e., neurons or axons) located near or adjacent to the transducer array.

[0026] The inventors have also determined that electrosensory can be improved by using certain modes of amplitude and frequency variation when an AC voltage is first applied to any given pair of transducers and when the direction of the alternating electric field changes.

[0027] More specifically, the inventors have determined that electrosensory perception can be improved by modifying the ramp-up characteristics to increase the amplitude of the AC voltage in a series of steps and allowing a period of time (e.g., 10 ms to 50 ms) before increasing the voltage to the next higher value, allowing the subject to adapt to any AC voltage applied during any given step.

[0028] The inventors have also determined that electrosensory characteristics can be improved by starting at a frequency higher than the recommended frequency for each indication (e.g., higher than 200 kHz for the treatment of glioblastoma) and then decreasing that frequency in a series of steps. Each step should be long enough (e.g., 10 ms to 50 ms) for the subject to adapt to the frequency applied during any given step before decreasing to the next lower value. For example, if the desired final frequency is 200 kHz (e.g., for the treatment of glioblastoma), the frequency could start at 400 kHz, then gradually decrease to 350 kHz, 300 kHz, 250 kHz, and then again to the desired target frequency of 200 kHz.

[0029] Finally, the inventors have determined that inductance can be improved by avoiding (or at least minimizing) the simultaneous occurrence of an increase in AC voltage amplitude and a decrease in AC voltage frequency. This can be achieved by arranging the timing of amplitude and frequency steps such that the times of amplitude change and frequency change are always (or at least most of the time) mutually exclusive.

[0030] Figure 2This is a block diagram of a system for driving an array of transducers using an AC voltage signal, where amplitude and frequency variations can be controlled. The system includes an AC signal generator 20, designed to produce a first AC output and a second AC output with frequencies between 50 kHz and 5 MHz (e.g., 50 kHz to 1 MHz, 50 kHz to 500 kHz, 75 kHz to 300 kHz, or 150 kHz to 250 kHz). When this system is used to apply a TTField to a human body (… Figure 2 As shown, a first AC output is applied across the first pair of transducer arrays 10L and 10R located on the left and right sides of the tumor; and a second AC output is applied across the second pair of transducer arrays 10A and 10P located on the front and back sides of the tumor.

[0031] When the AC signal generator 20 applies a voltage between transducer arrays 10L and 10R, an alternating electric field with field lines extending approximately from left to right is induced through the target region. Similarly, when the AC signal generator 20 applies a voltage between transducer arrays 10A and 10P, an alternating electric field with field lines extending approximately from front to back is induced through the target region. The frequency of the alternating electric field is matched to the frequency of the output of the AC signal generator 20. The electrode elements in the transducer array 10 can be capacitively coupled electrode elements (i.e., electrode elements including a thin dielectric layer in contact with the subject's body) or conductive electrode elements (i.e., electrode elements including a conductive surface in contact with the subject's body).

[0032] In some embodiments, the voltage generated by the 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 the AC signal generator 20 is sufficient to induce an electric field of 1 V / cm to 10 V / cm in at least a portion of the cells. In some embodiments, the output current of the AC signal generator 20 is > 0.1A, > 0.5A, > 0.7A, or > 1A (e.g., 0.1A to 10A, 0.5A to 2A, 0.5A to 5A, 0.7A to 2A, or 0.7A to 5A).

[0033] As in the existing Optune® system, (a) a first AC output is applied to the L / R transducer array during the time interval; (b) a second AC output is applied to the A / P transducer array during the time interval; and the two-step sequence (a) and (b) are repeated during the treatment duration. However... Figure 2 The amplitude and frequency characteristics during the ramp cycle in this embodiment differ from those used in Optune® in a way that helps improve the electrical sensation experienced by the subject.

[0034] AC signal generator 20 is configured to generate a first AC output and a second AC output, the amplitude and frequency of which depend on the state of at least one control input. AC signal generator 20 is configured such that the at least one control input controls the amplitude, frequency, amplitude, and frequency of the first output, the second output, and the second output. Controller 30 (e.g., at a rate of one control signal per ms) sends sequential control signals to the at least one control input to generate the amplitude and frequency variation pattern described herein. It should be noted that although... Figure 2 The controller 30 and the AC signal generator 20 are depicted as two separate blocks, but these two blocks can be integrated into a single hardware device, as described below.

[0035] The construction details of controller 30 and the nature of the control signals will depend on the design of AC signal generator 20. In one example, the design of AC signal generator 20 is similar to that described in U.S. Patent 9,910,453 (the entire contents of which are incorporated herein by reference), but includes additional hardware that enables it to operate at different frequencies. This particular AC signal generator has two output channels (i.e., a first channel for the L / R array and a second channel for the A / P array). The instantaneous AC output voltage on either channel depends on the instantaneous output voltage of the DC-DC converter, and the output voltage of the DC-DC converter is controlled, for example, by writing a control word to a digital-to-analog converter (DAC) at a rate of one control signal per ms. Frequency selection can be achieved, for example, by adjusting the timing of various signals within the AC signal generator and using a switch group to switch appropriate passive components (e.g., inductors and capacitors) to filter out harmonics from the signal. For example, the ability to operate at five different frequencies (e.g., 400 kHz, 350 kHz, 300 kHz, 250 kHz, and 200 kHz) can be achieved by using a switch group to switch different groups of passive components, thereby operating at each of these frequencies.

[0036] Therefore, this AC signal generator can be used to switch desired passive components by sequentially sending appropriate control words to the DAC and by sending appropriate control words to the switch group, thereby setting the AC output voltage and frequency to any desired level (within its operating range) in any desired time mode.

[0037] Figure 3 An example depicting a pattern of amplitude and frequency variations occurring over time, which can be applied to an AC signal generator 20 ( Figure 2The L / R output channel and A / P output channel (shown) are designed to improve inductance. More specifically, track 51 (along with the accompanying frequency markings f1 to f5) depicts the amplitude and frequency of the AC voltage of the L / R or first output channel as a function of time, and this is similar to that of track 52 and the A / P or second output channel. Illustration 51m is an enlarged version of the ramp segment of track 51 for the L / R channel during interval 1. During the remaining intervals 2, 3, etc., the ramp segments (not shown) of tracks 51 and 52 are similar to the ramp segment of the depicted first interval 1.

[0038] exist Figure 3 In the example, the L / R channel is activated during odd-numbered intervals (i.e., intervals 1, 3, 5, etc.), and the A / P channel is activated during even-numbered intervals (i.e., intervals 2, 4, 6, etc.). At the beginning of each interval, there is a ramp-up segment between t0 and t5, during which the amplitude of the corresponding output (i.e., L / R or A / P) of the AC signal generator gradually increases from an initial level of 0V to a final level of Vf. And during this ramp-up segment, the frequency of the corresponding output of the AC signal generator also decreases from an initial frequency f1 to a final frequency f5. After this ramp-up segment, the amplitude remains constant at the final level Vf, and the frequency remains constant at the final level f5 until a short period before the end of the interval (e.g., 50ms), at which point the amplitude ramps down or drops to 0V (while the frequency remains at the final frequency f5, or alternatively, the frequency ramps up to the initial frequency f1).

[0039] To generate these modes of amplitude and frequency variation, controller 30 sends control words sequentially to AC signal generator 20 (e.g., once every ms). When AC signal generator 20 receives these control words, it generates an output that has the same amplitude and frequency variation as the AC signal generator 20. Figure 3 The depicted waveforms exhibit similar amplitude and frequency patterns. Similar control word sequences are used to control the A / P channels.

[0040] exist Figure 3 In the depicted example, controller 30 is configured to apply a sequence of control signals to at least one control input of AC signal generator 20 during each odd-numbered time interval (e.g., intervals 1, 3, 5, etc.). This sequence of control signals controls AC signal generator 20 such that when a first output is activated at a given time t0, the first output has an initial amplitude and an initial frequency f1. The sequence of control signals also controls AC signal generator 20 such that after the given time and during a first set of time intervals while the first output remains active, the amplitude of the first output increases while the frequency of the first output remains constant. Figure 3In this first set of times, the following 15 items are included: (a) three increases in amplitude between t0 and t1, (b) three increases in amplitude between t1 and t2, (c) three increases in amplitude between t2 and t3, (d) three increases in amplitude between t3 and t4, and (e) three increases in amplitude between t4 and t5. Figure 3 In the illustration 51m, each of the 15 increases in amplitude is clearly visible. Each increase in amplitude can be instantaneous or can occur over a period of time (e.g., < 50ms, < 20ms, < 10ms, < 5ms, < 2ms, or < 1ms).

[0041] The control signal sequence also controls the AC signal generator 20 such that, after the given time and during a second set of time periods while the first output remains active, the frequency of the first output decreases while the amplitude of the first output remains constant. Figure 3 In illustration 51m, the second set of times includes the following four terms: t1 (i.e., when the frequency decreases from f1 to f2), t2 (i.e., when the frequency decreases from f2 to f3), t3 (i.e., when the frequency decreases from f3 to f4), and t4 (i.e., when the frequency decreases from f4 to f5). Each decrease in frequency can be instantaneous or can occur over a period of time (e.g., < 50ms, < 20ms, < 10ms, < 5ms, < 2ms, or < 1ms).

[0042] Note that in the example depicted in Illustration 51m, both frequency and amplitude never change at the same time, which helps to avoid electrointuitive effects. Therefore, within interval 1, the first set of times (i.e., the 15 times when amplitude changes) and the second set of times (i.e., the 4 times when frequency changes) are mutually exclusive. After t4, the frequency remains at f5 until the end of that interval. The situation is similar for intervals 3, 5, and subsequent odd-numbered intervals.

[0043] continue Figure 3 In the depicted example, controller 30 is also configured to apply a sequence of control signals to at least one control input of AC signal generator 20 during each even-numbered time interval (e.g., intervals 2, 4, etc.). This sequence of control signals further controls the AC signal generator such that (a) when the second output is activated at a certain time, the second output has an initial amplitude and an initial frequency f1; (b) in a third set of times after the certain time and while the second output remains active, the amplitude of the second output increases while the frequency of the second output remains constant; and (c) in a fourth set of times after the certain time and while the second output remains active, the frequency of the second output decreases while the amplitude of the second output remains constant. (Note that although...) Figure 3Excluding the enlarged illustration of the ramp segment of trajectory 52 for the second output (i.e., the A / P channel) of AC signal generator 20, the pattern of amplitude and frequency changes of the second output is similar to that described above for the first output of AC signal generator 20 and depicted in illustration 51m. And to reiterate here, both frequency and amplitude never change at the same time, which helps to avoid electroinduction. Therefore, within interval 2, the third set of times (i.e., the 15 times when amplitude changes) and the fourth set of times (i.e., the 4 times when frequency changes) are mutually exclusive. The situation is similar for interval 4 and subsequent even-numbered intervals.

[0044] The control signal sequence generated by controller 30 causes AC signal generator 20 to: (i) activate the first output during a time interval, (ii) subsequently activate the second output during a time interval, and (iii) subsequently repeat (i) and (ii) at least 10 times in an alternating sequence (although...). Figure 3 Only the first 2.25 of these repetitions are depicted.

[0045] Despite Figure 3 In the depicted example, the first and third time groups within a given time interval each include 15 time periods with increasing amplitude, and the second and fourth time groups within a given time interval each include 4 time periods with decreasing frequency (i.e., t1, t2, t3, and t4), the number of items in each of these groups may vary. In some embodiments, each first time group includes at least 10 time periods, each second time group includes at least 3 time periods, each third time group includes at least 10 time periods, and each fourth time group includes at least 3 time periods. In other embodiments, each first time group includes at least 50 time periods, each second time group includes at least 3 time periods, each third time group includes at least 50 time periods, and each fourth time group includes at least 3 time periods.

[0046] exist Figure 3 In the depicted example, each time interval activating the first output (interval 1, 3, 5, etc.) is 5 seconds long, and each time interval activating the second output (interval 2, 4, etc.) is 5 seconds long. However, in alternative embodiments, the duration of these intervals may differ (e.g., between 5 and 60 seconds, between 1 and 5 seconds, or at least 2 seconds). For example, the duration of each time interval activating the first output may be at least 800 ms, and the duration of each time interval activating the second output may be at least 800 ms.

[0047] exist Figure 3In the depicted example, each first group of times and the corresponding second group of times are interleaved using the following pattern: aaafaaafaaafaaafaaa (where "a" represents amplitude variation and "f" represents frequency variation). And each third group of times and the corresponding fourth group of times are interleaved using the same pattern. However, in an alternative embodiment, these groups of times do not need to be interleaved. For example, the amplitude may change 15 times until it reaches Vf, while the frequency remains constant at f1, and then the frequency may change 4 times until it reaches f5 (in this case, the pattern would be aaaaaaaaaaaaaaaaffff). Various alternative patterns may also be used, including but not limited to ffffaaaaaaaaaaaaaaaa, afafafafafafa, affaffaffaffa, etc.

[0048] In some embodiments, the initial frequency f1 of the first output is at least 50% higher than the final frequency f5 of the first output, and the initial frequency of the second output is at least 50% higher than the final frequency of the second output. For example, in the context of treating glioblastoma, the initial frequency f1 may be 400 kHz, and the final frequency f5 may be 200 kHz. However, in another embodiment, the initial frequencies of both the first and second outputs may be at least 25% higher than the final frequencies of these outputs.

[0049] In some embodiments, the final frequencies of the first and second outputs are between 75 kHz and 300 kHz. These embodiments include, for example, using a final frequency of 200 kHz to treat glioblastoma or ovarian cancer, using a final frequency of 150 kHz to treat mesothelioma, non-small cell lung cancer, or liver cancer, and using a final frequency between 75 kHz and 190 kHz (or between 75 kHz and 220 kHz) to improve the permeability of the blood-brain barrier in a subject.

[0050] As long as controller 30 can control AC signal generator 20, various alternative designs for AC signal generator 20 and controller 30 can replace the examples provided above. For example, if the AC signal generator is designed to respond to analog control signals, controller 30 must generate any sequence of analog control signals required for AC signal generator 20 to output the desired waveform. In this case, controller 30 can be implemented using a microprocessor or microcontroller programmed to write appropriate control words to a digital-to-analog converter whose output generates analog control signals that cause AC signal generator 20 to produce the desired waveform. Alternatively, controller 30 can be implemented using analog circuitry that automatically generates appropriate control signal sequences (and then applies these control signals to the control inputs of the AC signal generator).

[0051] Figure 3 The pattern of increasing amplitude and decreasing frequency of AC voltage depicted in Illustration 51m is not the only pattern that can be used to improve electrosensory perception. Instead, various alternative patterns can be used. For example, although trajectory 51 shows that each amplitude change in the amplitude variation has the same magnitude, the magnitude of the amplitude change within the first set of time (or the third set of time) can vary. Similarly, the timing between successive amplitude steps within the first set of time (or the third set of time) can be consistent or inconsistent. The magnitude of each frequency step within the second set of time (or the fourth set of time) can be consistent or inconsistent, and the timing between successive frequency steps within the second set of time (or the fourth set of time) can be consistent or inconsistent.

[0052] In conjunction with the above Figure 3 In the described example, at the start of the first and second time intervals, the amplitudes of both the first and second outputs of the AC signal generator are very small (e.g., less than 1% of Vf). Similarly, at the start of the first and second time intervals, the corresponding first and second alternating electric fields are both very small (e.g., less than 1% of the final field strength). However, in alternative embodiments (e.g., as...), Figure 4 In the depicted scenario, the amplitudes of the first and second outputs of the AC signal generator can immediately jump to an initial level Vi, which is 20% to 80% of the final level Vf.

[0053] These embodiments are advantageous because inductance occurs relatively less when the voltage is below a threshold level (e.g., 40V). Therefore, the voltage jumps immediately from 0V to the initial voltage Vi (e.g., 40V) at the start of the first and second time intervals. Figure 4 The described voltage does not induce electrosensory sensation in the vast majority of patients. Since there is no wasted time ramping from 0V to Vi, more time is available to ramp from Vi to the final voltage Vf (e.g., the final voltage Vf may exceed 100V). This will advantageously (a) increase the average field strength applied to the subject, (b) provide the subject with more time to adapt to each new voltage level before increasing to the next level, and (c) provide the subject with more time to adapt to each new frequency level before decreasing to the next level, thereby further improving electrosensory sensation.

[0054] In some embodiments, the initial level Vi will be the same for all patients (e.g., 40V). In other embodiments, the initial level Vi may be patient-specific and can be set via a suitable user interface communicating with controller 30. In a later embodiment, controller 30 may be programmed to apply different voltage levels to the subject to determine a threshold voltage Vth at which the electrosensory response of a particular subject to be treated begins. Then, during the treatment of that particular subject, the initial level Vi is set below the threshold Vth.

[0055] In the example described above, the direction of the alternating electric field switches between two directions. However, in an alternative embodiment, the direction of the alternating electric field may switch between three or more directions (assuming additional transducer array pairs are provided). For example, the direction of the alternating electric field may switch between three directions, each of which is determined by the placement of its own pair of transducer arrays. In other alternative embodiments, the transducer arrays do not need to be arranged in pairs. See, for example, the transducer array positioning described in U.S. Patent 7,565,205, which is incorporated herein by reference. However, regardless of the arrangement of the transducer arrays, whenever a given transducer array is activated, one of the modes of amplitude and frequency variation described herein is used.

[0056] In some anatomical locations, the transducer array is not positioned on the subject's skin. Instead, the transducer array is implanted into the subject's body (e.g., just under the subject's skin) such that applying an AC voltage between the transducer arrays will create an alternating electric field in the target region of the subject's body.

[0057] In some anatomical locations, an electric field with a constant orientation can be used instead of alternating the orientation of the electric field back and forth between two or more different directions. The embodiments used in these locations are similar, except that the AC signal generator 20 has only a single output (e.g., only an L / R output). Figure 2 Examples of these embodiments. In these embodiments, the AC voltage generator is configured to: upon initial switching on, use the above (e.g., in conjunction with...) Figure 3 In the mode described in Illustration 51m, any mode increases its output voltage and then maintains its output voltage and frequency at a fixed level during the treatment duration, or repeatedly switches a single output on and off (e.g., on for 1 to 60 seconds and off for 0.1 to 10 seconds), or occasionally switches a single output on and off (e.g., on for 6 hours or more and off for 1 to 4 hours, for example, to take a shower break or change the array). In the latter case, whenever the AC voltage generator is switched back on, it uses the above (e.g., in combination with...) Figure 3The illustration in Figure 51m describes any of the modes to increase its output voltage and decrease its frequency from the initial level to the final level.

[0058] Finally, the above (for example, in combination) Figures 2 to 3 or Figure 2 and Figure 4 The device described herein can be used to perform the steps (i) to (iii): (i) applying a first alternating electric field in a first orientation to the target region within a time interval, wherein the first alternating electric field has a frequency and average amplitude that vary with time, such that (a) when the first alternating electric field is activated at a given time, the first alternating electric field has an initial average amplitude and an initial frequency; (b) after the given time and during a first set of time periods while the first alternating electric field remains active, the average amplitude of the first alternating electric field increases while the frequency of the first alternating electric field remains constant; and (c) after the given time and during a second set of time periods while the first alternating electric field remains active, the frequency of the first alternating electric field decreases while the average amplitude of the first alternating electric field remains constant, wherein the first set of time periods and the second set of time periods are mutually exclusive; (ii) Subsequently, a second alternating electric field is applied to the target region in a second orientation during the time interval, wherein the second alternating electric field has a frequency and average amplitude that vary with time, such that (a) when the second alternating electric field is activated at a certain time, the second alternating electric field has an initial average amplitude and an initial frequency; (b) after the certain time and during a third set of time while the second alternating electric field remains active, the average amplitude of the second alternating electric field increases while the frequency of the second alternating electric field remains constant; and (c) after the certain time and during a fourth set of time while the second alternating electric field remains active, the frequency of the second alternating electric field decreases while the average amplitude of the second alternating electric field remains constant, wherein the third set of time and the fourth set of time are mutually exclusive; and (iii) steps (i) and (ii) are then repeated at least 10 times in an alternating sequence.

[0059] The embodiments and methods described herein can be advantageously used to improve electrosensory sensation when subjects are treated with alternating electric fields. This improvement in electrosensory sensation is highly beneficial because it allows subjects to tolerate higher amplitudes and / or lower frequencies compared to amplitudes and frequencies that subjects could tolerate without relying on the embodiments and methods described herein.

[0060] While the invention has been disclosed with reference to certain embodiments, various modifications, alterations, and changes can be made to the described embodiments without departing from the scope and domain of the invention as defined by the appended claims. Therefore, the invention is intended to be limited to the described embodiments, but rather to have the full scope defined by the language of the appended claims and their equivalents.

Claims

1. An apparatus for applying an electrical signal to at least one electrode element in a first group, a second group, a third group, and a fourth group, said apparatus comprising: An AC signal generator having a first output, a second output, and at least one control input, wherein the AC signal generator is configured such that the at least one control input controls the amplitude of the first output, the frequency of the first output, the amplitude of the second output, and the frequency of the second output. and A controller configured to apply a sequence of control signals to at least one control input of the AC signal generator, wherein the sequence of control signals controls the AC signal generator such that (a) when the first output is activated at a given time, the first output has an initial amplitude and an initial frequency; (b) after the given time and while the first output remains active, for a first set of time periods, the amplitude of the first output increases while the frequency of the first output remains constant; and (c) after the given time and while the first output remains active, for a second set of time periods, the frequency of the first output decreases while the amplitude of the first output remains constant, wherein the first set of time periods and the second set of time periods are mutually exclusive. The control signal sequence further controls the AC signal generator such that (a) when the second output is activated at a certain time, the second output has an initial amplitude and an initial frequency; (b) after the certain time and while the second output remains active, in a third set of times, the amplitude of the second output increases while the frequency of the second output remains constant; and (c) after the certain time and while the second output remains active, in a fourth set of times, the frequency of the second output decreases while the amplitude of the second output remains constant, wherein the third set of times and the fourth set of times are mutually exclusive. The control signal sequence causes the AC signal generator to: (i) activate the first output during a time interval, (ii) subsequently activate the second output during a time interval, and (iii) subsequently repeat (i) and (ii) at least 10 times in an alternating sequence.

2. The device according to claim 1, wherein each first group of time comprises at least 10 times, each second group of time comprises at least 3 times, each third group of time comprises at least 10 times, and each fourth group of time comprises at least 3 times.

3. The device according to claim 1, wherein each first group of time comprises at least 50 times, each second group of time comprises at least 3 times, each third group of time comprises at least 50 times, and each fourth group of time comprises at least 3 times.

4. The device of claim 1, wherein the duration of each time interval activating the first output is at least 800 ms, and The duration of each time interval that activates the second output is at least 800ms.

5. The device according to claim 1, wherein each first set of times and the corresponding second set of times are interleaved, and The times of each third group and the corresponding fourth group are interleaved.

6. The device of claim 1, wherein the initial frequency of the first output is at least 50% higher than the final frequency of the first output, and The initial frequency of the second output is at least 50% higher than the final frequency of the second output.

7. The device of claim 6, wherein the final frequency of the first output is between 75 kHz and 300 kHz, and The final frequency of the second output is between 75 kHz and 300 kHz.

8. The device of claim 1, wherein each first group of time comprises at least 50 times, each second group of time comprises at least 3 times, each third group of time comprises at least 50 times, and each fourth group of time comprises at least 3 times. The duration of each time interval activating the first output is at least 2 seconds. The duration of each time interval that activates the second output is at least 2 seconds. The times in each first group are interleaved with the corresponding times in the second group. The times for each third group are interleaved with the corresponding times for the fourth group. Wherein the initial frequency of the first output is at least 50% higher than the final frequency of the first output, and The initial frequency of the second output is at least 50% higher than the final frequency of the second output.

9. The device of claim 8, wherein the final frequency of the first output is between 75 kHz and 300 kHz, and The final frequency of the second output is between 75 kHz and 300 kHz.

10. An apparatus for applying an electrical signal to at least one electrode element in a first group and a second group, the apparatus comprising: An AC signal generator having an output and at least one control input, wherein the AC signal generator is configured such that the at least one control input controls the amplitude and frequency of the output; and A controller configured to apply a sequence of control signals to at least one control input of the AC signal generator, wherein the sequence of control signals controls the AC signal generator such that (a) when the output is activated at a given time, the output has an initial amplitude and an initial frequency; (b) in a first set of time intervals after the given time interval and while the output remains active, the amplitude of the output increases while the frequency of the output remains constant; and (c) in a second set of time intervals after the given time interval and while the output remains active, the frequency of the output decreases while the amplitude of the output remains constant, wherein the first set of time intervals and the second set of time intervals are mutually exclusive. The first set of times includes at least 10 times. The second set of times includes at least three times. The first set of times and the second set of times are interleaved. The initial frequency of the output is at least 50% higher than the final frequency of the output, and The final frequency of the output is between 75 kHz and 300 kHz.

11. A method for applying an alternating electric field to a target region of a subject's body, the method comprising: (i) A first alternating electric field is applied in a first orientation to the target region during a time interval, wherein the first alternating electric field has a frequency and average amplitude that vary with time, such that (a) when the first alternating electric field is activated at a given time, the first alternating electric field has an initial average amplitude and an initial frequency; (b) in a first set of time after the given time and while the first alternating electric field remains active, the average amplitude of the first alternating electric field increases while the frequency of the first alternating electric field remains constant; and (c) in a second set of time after the given time and while the first alternating electric field remains active, the frequency of the first alternating electric field decreases while the average amplitude of the first alternating electric field remains constant, wherein the first set of time and the second set of time are mutually exclusive.

12. The method according to claim 11, further comprising: (ii) Subsequently, within a time interval, a second alternating electric field is applied to the target region in a second orientation, wherein the second alternating electric field has a frequency and average amplitude that vary with time, such that (a) when the second alternating electric field is activated at a certain time, the second alternating electric field has an initial average amplitude and an initial frequency; (b) after the certain time and during a third set of time while the second alternating electric field remains active, the average amplitude of the second alternating electric field increases while the frequency of the second alternating electric field remains constant; and (c) after the certain time and during a fourth set of time while the second alternating electric field remains active, the frequency of the second alternating electric field decreases while the average amplitude of the second alternating electric field remains constant, wherein the third set of time and the fourth set of time are mutually exclusive. (iii) Then repeat steps (i) and (ii) at least 10 times in an alternating sequence.

13. The method of claim 12, wherein each first group of time comprises at least 10 times, each second group of time comprises at least 3 times, each third group of time comprises at least 10 times, and each fourth group of time comprises at least 3 times.

14. The method of claim 12, wherein each first group of time comprises at least 50 times, each second group of time comprises at least 3 times, each third group of time comprises at least 50 times, and each fourth group of time comprises at least 3 times.

15. The method of claim 12, wherein the duration of each time interval for applying the first alternating electric field is at least 800 ms, and The duration of each time interval in which the second alternating electric field is applied is at least 800 ms.

16. The method of claim 12, wherein each first set of times and the corresponding second set of times are interleaved, and The times of each third group and the corresponding fourth group are interleaved.

17. The method of claim 12, wherein the initial frequency of the first alternating electric field is at least 50% higher than the final frequency of the first alternating electric field, and The initial frequency of the second alternating electric field is at least 50% higher than the final frequency of the second alternating electric field.

18. The method of claim 17, wherein the final frequency of the first alternating electric field is between 75 kHz and 300 kHz, and The final frequency of the second alternating electric field is between 75 kHz and 300 kHz.

19. The method of claim 12, wherein each first group of times comprises at least 50 times, each second group of times comprises at least 3 times, each third group of times comprises at least 50 times, and each fourth group of times comprises at least 3 times. The duration of each time interval in which the first alternating electric field is applied is at least 2 seconds. The duration of each time interval in which the second alternating electric field is applied is at least 2 seconds. The times in each first group are interleaved with the corresponding times in the second group. The times for each third group are interleaved with the corresponding times for the fourth group. The initial frequency of the first alternating electric field is at least 50% higher than the final frequency of the first alternating electric field, and The initial frequency of the second alternating electric field is at least 50% higher than the final frequency of the second alternating electric field.

20. The method of claim 19, wherein the final frequency of the first alternating electric field is between 75 kHz and 300 kHz, and The final frequency of the second alternating electric field is between 75 kHz and 300 kHz.

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