Reducing electrical sensations when treating subjects with alternating electric fields by increasing the number of steps in the ramp-up portion of the waveform

Abstract

When an AC 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. This electric sensation can be improved by increasing the number of steps as the voltage ramps up from zero to its peak when the AC voltage is first applied to any given transducer array and when switching the direction of the AC electric field.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 435967, filed December 29, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Tumor Treating Field (TT) 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, and then repeats steps (a) and (b) 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. 6,299,949 (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 and / or the frequency of the AC electric field decreases (e.g., to around 100 kHz), some subjects experience electrosensory effects. These electrosensations can include, for example, vibration sensations, paresthesia, and / or a sensation of muscle fiber twitching or contraction, or flickering lights in the eyes (phosphenes). These electrosensations may deter some subjects from continuing treatment with AC electric fields. Furthermore, electrosensations 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. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 10,967,167 Summary of the Invention [Means for solving the problem]

[0006] One aspect of the present invention relates to a first method for improving electrosensation while applying an electric field to a target region in a living organism, the first method comprising applying an alternating current electric field having a frequency between 50 kHz and 1 MHz to the target region during each of a plurality of time intervals, wherein the amplitude of the alternating current electric field is increased stepwise during a first portion of the time interval, and the stepwise increase during the first portion of the time interval includes at least 170 steps.

[0007] In some examples of the first method, each of the at least 170 steps has a height of less than 1 V. In some examples of the first method, during each of the time intervals, the step increase during the first portion of the time interval includes at least 200 steps.

[0008] In some examples of the first method, during each of the time intervals, the alternating electric field has an amplitude that remains substantially constant during a second portion of the time interval that follows the first portion of the time interval. Optionally, in these examples, during each of the time intervals, the alternating electric field has an amplitude that decreases in a stepwise manner during a third portion of the time interval that follows the second portion of the time interval.

[0009] In some examples of the first method, the plurality of time intervals includes at least 100 time intervals all occurring within one hour. In some examples of the first method, when the first portion of the time intervals ends during each of the time intervals, the alternating electric field has an amplitude of at least 1 V / cm in at least a portion of the target area. In some examples of the first method, the alternating electric field has a frequency of 100 kHz to 500 kHz.

[0010] In some examples of the first method, the alternating electric field is applied to the target region in a first direction during a first subset of the plurality of time intervals, and the alternating electric field is applied to the target region in a second direction during a second subset of the plurality of time intervals, the second direction being offset from the first direction by at least 45 degrees.

[0011] In some examples of the first method, the AC electric field is applied to the target area in a first direction during a first subset of the plurality of time intervals, and the AC electric field is applied to the target area in a second direction during a second subset of the plurality of time intervals. The second direction is offset from the first direction by at least 45°. The plurality of time intervals includes at least 100 time intervals that all occur within one hour. During each of the time intervals, the stepwise increase during the first portion of the time interval includes at least 200 steps. Also, when the first portion of the time interval ends during each of the time intervals, the AC electric field has an amplitude of at least 1 V / cm in at least a portion of the target area.

[0012] Another aspect of the present invention relates to a first apparatus comprising a signal generator and a controller. The signal generator has at least one control input and is configured to generate a first AC output at a frequency between 50 kHz and 1 MHz. The first AC output has an amplitude that depends on the state of the at least one control input. The controller is configured to send a first set of control signals to the at least one control input during each of a plurality of first time intervals per hour. The first set of control signals during each of the first time intervals is configured to increase the amplitude of the first AC output in steps during a first portion of the first time interval, the step increase during the first portion of the first time interval comprising at least 170 steps.

[0013] In some embodiments of the first apparatus, each of the at least 170 steps has a height of less than 1 V. In some examples of the first apparatus, during each of the first time intervals, the step increase during the first portion of the first time interval includes at least 200 steps.

[0014] In some embodiments of the first apparatus, during each of the first time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the first time interval that follows the first portion of the first time interval. Optionally, in these embodiments, during each of the first time intervals, the first AC output has an amplitude that decreases in a stepped manner during a third portion of the first time interval that follows the second portion of the first time interval.

[0015] In some embodiments of the first apparatus, the plurality of first time intervals includes at least 100 first time intervals that all occur within one hour. In some embodiments of the first apparatus, the first AC output has a frequency between 100 kHz and 500 kHz.

[0016] In some embodiments of the first apparatus, the signal generator is further configured to generate a second AC output at a frequency between 50 kHz and 1 MHz, the second AC output having an amplitude that depends on the state of the at least one control input. The controller is further configured to send a second set of control signals to the at least one control input during each of a plurality of second time intervals per hour. The second set of control signals during each of the second time intervals is configured to increase the amplitude of the second AC output in steps during a first portion of the second time interval, the step increase during the first portion of the second time interval comprising at least 170 steps.

[0017] Optionally, in the embodiment described in the previous paragraph, during each of the first time intervals, the incremental increase during the first portion of the first time interval comprises at least 200 steps, and during each of the second time intervals, the incremental increase during the first portion of the second time interval comprises at least 200 steps.

[0018] In some embodiments of the first device, the signal generator is further configured to generate a second AC output at a frequency between 50 kHz and 1 MHz, the second AC output having an amplitude that depends on the state of the at least one control input. The controller is further configured to send a second set of control signals to the at least one control input during each of a plurality of second time intervals per hour. The second set of control signals during each of the second time intervals is configured to increase the amplitude of the second AC output in steps during a first portion of the second time interval, the step increase during the first portion of the second time interval comprising at least 170 steps. During each of the first time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the first time interval that follows the first portion of the first time interval. During each of the second time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the second time interval that follows the first portion of the second time interval. The plurality of first time intervals includes at least 100 first time intervals that all occur within one hour, and the plurality of second time intervals includes at least 100 second time intervals that all occur within one hour. [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the amplitude of the AC output 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, the ramp-up of the amplitude of the AC output including at least 170 steps. [Figure 3] 1 is a schematic diagram of a signal applied to a set of transducer arrays with a peak amplitude of 100V, with 100 steps during the ramp-up period. [Figure 4] 1 is a schematic diagram of a signal applied to a set of transducer arrays having a peak amplitude of 200V with 100 steps during the ramp-up period. [Figure 5]1 is a schematic diagram of a signal applied to a set of transducer arrays with a peak amplitude of 200 V, with 200 steps during the ramp-up period. This signal can be used to improve electrosensation. DETAILED DESCRIPTION OF THE INVENTION

[0020] Various embodiments are described in detail below with reference to the accompanying drawings, in which like reference numerals represent like elements, and in which:

[0021] FIG. 1 shows the amplitude of the AC output of the L / R and A / P channels in 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 time window that is nominally 100 ms but never exceeds 160 ms. 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 another time window that is nominally 100 ms but never exceeds 160 ms.

[0022] In the prior art Optune® system, the ramping up and down of amplitude was accomplished by updating the control word in the AC signal generator at regular 1 ms intervals between the ramping up and ramping down portions of the waveform. Thus, while the main portion of Figure 1 shows the ramping up portion of the waveform as smooth, zooming in on the waveform reveals that the amplitude actually becomes stepped, as shown in inset A of Figure 1. Also, because the ramping up portion of the waveform in Optune® never exceeds 160 ms, the stepped ramp up in amplitude never exceeds 160 steps.

[0023] Without being bound by this theory, it is believed that electrosensation arises from the interaction of an alternating electric field with nerve cells or fibers (neurons or axons) positioned near or adjacent to the transducer array. In the prior art Optune® system, electrosensation was not a significant issue. However, when the inventors modified the Optune® system to operate at higher amplitudes or lower frequencies (while keeping all other relevant aspects unchanged), electrosensation became more of a problem.

[0024] This application describes an approach to improving electrical sensation in systems that generate alternating electric fields (eg, TT fields) by increasing the number of steps in the ramp-up portion of the waveform.

[0025] Figure 2 is a block diagram of a system for driving a pair of transducer arrays with an AC voltage signal whose amplitude can be controlled. 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-1 MHz, 50-500 kHz, 75-300 kHz, or 150-250 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.

[0026] When AC signal generator 20 applies a voltage between transducer array 10L and transducer array 10R, an alternating electric field is induced in the target area with electric field lines running generally from left to right. When AC signal generator 20 applies a voltage between transducer array 10A and transducer array 10P, an alternating electric field is induced in the target area with electric field lines running generally from front to back. The frequency of the alternating 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).

[0027] 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. For example, in some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of at least 2 V / cm, at least 3 V / cm, or at least 5 V / cm in at least a portion of the cells. In some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of 1-10 V / cm, 2-10 V / cm, 5-10 V / cm, or 2-20 V / cm in at least a portion of the cells.

[0028] Similar to the prior art Optune® system, (a) a first AC output is applied to the L / R transducer array for a period of time, (b) a second AC output is applied to the A / P transducer array for a period of time, and the two-step sequence of (a) and (b) is repeated for the duration of treatment. However, in the embodiment of FIG. 2, the way in which the AC voltage ramps up from zero to its peak differs from the way in which the AC voltage ramps up from zero to its peak in Optune®. This difference also contributes to the improved electrical sensation experienced by the subject, as explained in more detail below.

[0029] AC signal generator 20 is configured to generate first and second AC outputs having controllable amplitudes depending on the state of at least one control input. Controller 30 rapidly sequentially sends control signals (e.g., at a rate of one control signal per ms) to the at least one control input to control the output amplitude of AC signal generator 20, as described below. Note that while controller 30 and AC signal generator 20 are shown as two separate blocks in FIG. 2, these two blocks may be integrated into a single hardware device.

[0030] The details of the structure of controller 30 and the characteristics 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.

[0031] Thus, controller 30 of FIG. 2 can achieve any desired rate of increase of the first and second outputs of AC signal generator 20 in any desired pattern by sequentially sending appropriate control words to the DACs within AC signal generator 20.

[0032] For example, assume that a given patient experiences no electrical sensation when an AC signal similar to that used in a prior art Optune® system is applied to the subject's body at a peak amplitude of 100 V using left and right transducer arrays 10L and 10R. Signal 35 shown in FIG. 3 is an example of a single instance of such a signal, which is generated repeatedly (e.g., once every 2 seconds). In signal 35, the amplitude ramps up from 0 VAC to 100 VAC for a 100 ms interval divided into 100 equally spaced steps (i.e., 1 ms per step), then remains at 100 VAC for 800 ms, and then ramps down from 100 VAC to 0 VAC for the next 100 ms interval. In this example, the height of each step in the ramp-up portion of the waveform is 1 V per step.

[0033] As noted above, when treating a subject with an AC electric field, the greater the amplitude, the greater the therapeutic effect. In prior art Optune® systems, the amplitude of the AC voltage that could be applied to a given subject's body was typically limited by thermal considerations. More specifically, Optune® transducer arrays heat up as the amplitude of the AC voltage applied to their transducers increases, eventually reaching a safe temperature threshold (e.g., 39°C). Furthermore, that temperature threshold has traditionally been a limiting factor for Optune® from operating at higher amplitudes.

[0034] We conduct a thought experiment to analyze what would happen if thermal considerations were overcome to the point where the amplitude of an AC signal applied to the same subject's body could be doubled without any other changes to the waveform. Signal 45 shown in Figure 4 is an example of such a signal. More specifically, in signal 45, the amplitude ramps up from 0 VAC to 200 VAC for a 100 ms interval divided into 100 equally spaced steps (i.e., 1 ms per step), then remains at 200 VAC for 800 ms, and then ramps down from 200 VAC to 0 VAC for the next 100 ms interval.

[0035] If a signal 45 of double the amplitude is applied to the subject's body, the subject is likely to experience an electrosensation. In this situation, the electrosensation would prevent the system from operating at a higher voltage (because we assume that thermal considerations are not a limiting factor in this thought experiment). This application describes an approach to improve the electrosensation so that the system can operate at a higher voltage, increasing the amplitude of the AC electric field and thus increasing the effectiveness of the treatment.

[0036] In particular, for double amplitude signal 45, the height of each step in the ramp-up portion of the waveform is 2 V per step, and the inventors have found that the increase in step height during the ramp-up portion of the waveform (i.e., from 1 V to 2 V) contributes much more to the electrical sensation than the increase in overall amplitude during the middle portion of the 800 ms period of the waveform (i.e., from 100 VAC to 200 VAC).

[0037] The inventors have further determined that the electrical sensation introduced by doubling the amplitude of the waveform can be improved by increasing the number of steps used during the ramp-up portion of the waveform to a point where the step height is small enough so that the electrical sensation is no longer an issue. For example, as shown for signal 55 in FIG. 5, if the number of steps during the ramp-up from 0V to 200V is increased from 100 to 200 steps, the height of each step decreases from 2V per step to 1V per step, which is often sufficient to improve electrical sensation. If electrical sensation is not improved for a particular patient, the number of steps can be further increased (e.g., to 250 steps, where the height of each step decreases to 0.8V per step). In another example, if the increase in amplitude is smaller (e.g., from 100V to 170V), a smaller increase in the number of steps (e.g., to 170 steps) may be sufficient to improve electrical sensation.

[0038] In some embodiments, the duration and height of each individual step remain the same regardless of how many steps are included within a ramp-up period. In these embodiments, we assume that each step has a duration of 1 ms and a height of 1 V, so that ramping up from 0 V to 100 V takes 100 ms and ramping up from 0 V to 200 V takes 200 ms. Thus, in these embodiments, the overall duration of each ramp-up period depends on the number of steps. In these embodiments, the number of steps can be at least 170 steps, and can also be, but is not limited to, at least 200 steps, at least 250 steps, at least 300 steps, at least 350 steps, at least 400 steps, at least 450 steps, at least 500 steps, at least 750 steps, at least 1000 steps, or more than 1000 steps. Alternatively, for example, the number of stages may be 200 stages to 10,000 stages, 200 stages to 1,000 stages, 200 stages to 750 stages, or 200 stages to 500 stages.

[0039] In other embodiments, the number of steps within each ramp-up period is increased to a fixed number higher than in the prior art (e.g., 170 or 200 steps), while the duration of each step remains the same as in the prior art (e.g., 1 ms / step). For example, each ramp-up period can have a fixed number of steps, such as at least 170 steps, at least 200 steps, at least 250 steps, at least 300 steps, at least 350 steps, at least 400 steps, at least 450 steps, at least 500 steps, at least 750 steps, at least 1000 steps, or more than 1000 steps. Or, for example, each ramp-up period can have a fixed number of steps, such as 200 steps to 10,000 steps, 200 steps to 10000 steps, 200 steps to 750 steps, or 200 steps to 500 steps. In these embodiments, the height of each step depends on the overall height of the lamp. For example, if 200 steps are used to ramp up from 0V to 100V, each step is 0.5V high. However, if the same 200 steps are used to ramp up from 0V to 200V, each step is 1V high. Of course, if 200 steps are used, each with a 1ms duration, the overall duration of the ramp-up period will be longer than that of the prior art.

[0040] In still other embodiments, the number of steps within each ramp-up period may be increased to a fixed number greater than the prior art (e.g., 170 or 200 steps), and the duration of each step may be less (e.g., 0.5 ms) or greater (e.g., 2-10 ms) than the examples given above for signal 55. For example, each ramp-up period may have a fixed number of steps, such as at least 170 steps, at least 200 steps, at least 250 steps, at least 300 steps, at least 350 steps, at least 400 steps, at least 450 steps, at least 500 steps, at least 750 steps, at least 1000 steps, or more than 1000 steps. Or, for example, each ramp-up period may have a fixed number of steps, such as 200 steps to 10,000 steps, 200 steps to 10000 steps, 200 steps to 750 steps, or 200 steps to 500 steps. In any of such embodiments, the duration of each stage may be, for example, less than 1 ms, less than 0.8 ms, less than 0.6 ms, or less than 0.5 ms. Alternatively, the duration of each stage may be, for example, at least 2 ms, at least 3 ms, at least 4 ms, at least 5 ms, at least 10 ms, at least 15 ms, at least 20 ms, at least 25 ms, at least 30 ms, at least 40 ms, at least 50 ms, at least 100 ms, at least 1 s, at least 10 s, at least 30 s, at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, or at least 20 minutes. The duration of each stage may be, for example, between 2 ms and 30 minutes, between 2 ms and 20 minutes, between 2 ms and 10 minutes, between 2 ms and 5 minutes, between 1 ms and 2 minutes, between 2 ms and 1 minute, between 2 ms and 100 ms, between 2 ms and 50 ms, between 2 ms and 25 ms, or between 2 ms and 10 ms. Any such number or range of steps can be combined with any of the illustrated numbers or ranges of step durations in these embodiments. In this situation, the height of each step depends on the overall height of the lamp. Of course, the overall duration of the ramp-up period also depends on the duration of each step. For example, if the ramp-up period includes 200 steps, each with a duration of 0.5 ms, the overall duration of the ramp-up period will be 100 ms.However, if the ramp-up period includes 200 steps, each of which has a duration of 2 ms, then the overall duration of the ramp-up period will be 400 ms.

[0041] A signal such as signal 55 (having at least 170 steps within the ramp-up period) may be generated using a system such as that shown in FIG. 2 , including signal generator 20 and controller 30. Signal generator 20 has at least one control input and is configured to generate a first AC output at a frequency between 50 kHz and 1 MHz (e.g., 100-500 kHz). The amplitude of the first AC output depends on the state of the at least one control input. Controller 30 sends a first set of control signals to the at least one control input during each of a plurality of first time intervals per hour. In some embodiments, there are 1800 first time intervals per hour (i.e., 30 per minute), with each first time interval lasting on the order of one second. However, in other embodiments, the number of first intervals in a given time period may be greater or less (e.g., 10-60 per minute), and the duration of each first time interval may be adjusted accordingly. The first set of control signals during each of the first time intervals is configured to increase the amplitude of the first AC output in steps during a first portion of the first time interval (i.e., the left ramp-up portion of signal 55). The step-up during the ramp-up portion includes at least 170 steps.

[0042] In some embodiments, each of the at least 170 steps has a height of less than 1 V. For example, the step height can be less than 0.9 V, less than 0.8 V, less than 0.7 V, less than 0.5 V, less than 0.3 V, or less than 0.1 V. The step height can be between 0.1 V and 0.5 V, between 0.1 V and 0.7 V, between 0.1 V and 0.9 V, between 0.2 V and 0.8 V, or between 0.5 V and 0.9 V. In some embodiments, the step increase during the ramp-up portion during each first time interval includes at least 200 steps (e.g., at least 250 steps, at least 300 steps, at least 350 steps, at least 400 steps, at least 450 steps, at least 500 steps, at least 750 steps, at least 1000 steps, or more than 1000 steps). In some embodiments, during each first time interval, the ramp-up portion includes between 200 steps and 10,000 steps, between 200 steps and 1,000 steps, between 200 steps and 750 steps, or between 200 steps and 500 steps.

[0043] In some embodiments, during each first time interval, the first AC output has an amplitude that remains substantially constant (e.g., ±5%) during a second portion of the first time interval that follows a first portion of the first time interval. This second portion corresponds to an upper plateau of signal 55. Optionally, in these embodiments, during each first time interval, the first AC output has an amplitude that decreases in a stepped manner during a third portion of the first time interval that follows the second portion of the first time interval. This third portion corresponds to a right ramp-down period of signal 55.

[0044] In some embodiments, the plurality of first time intervals includes at least 100 first time intervals that all occur within one hour.

[0045] In some embodiments (including the embodiment shown in FIG. 2 ), the AC electric field is applied to the subject from two directions in an alternating and repeating sequence (e.g., 1 second in the L / R direction, followed by 1 second in the A / P direction, repeated for at least 1 hour). In these embodiments, signal generator 20 is further configured to generate a second AC output at a frequency between 50 kHz and 1 MHz, the second AC output having an amplitude that depends on the state of at least one control input. Controller 30 is also further configured to send a second set of control signals to the at least one control input during each of a plurality of second time intervals per hour. The second set of control signals during each second time interval is configured to increase the amplitude of the second AC output in steps during a first portion (i.e., ramp-up portion) of the second time interval. These step-up increases during the ramp-up portions also include at least 170 steps.

[0046] Optionally, in these bidirectional embodiments, the ramp-up portion includes at least 170 steps (e.g., 200 steps) during each first time interval, and the ramp-up portion includes at least 170 steps (e.g., at least 200 steps) during each second time interval.

[0047] Methods for improving electrosensation can use a signal such as signal 55 shown in FIG. 5, which can be generated using the system shown in FIG. 2. In these methods, electrosensation can be improved while applying an electric field to a target region in vivo by applying an alternating current electric field having a frequency of 50 kHz to 1 MHz (e.g., 100 to 500 kHz) to the target region during each of a plurality of time intervals. During each of the time intervals, the amplitude of the alternating current electric field is increased in steps during a first portion of the interval (e.g., the ramp-up portion on the left of signal 55), and the step increase during the first portion of the interval includes at least 170 steps.

[0048] Optionally, each of the at least 170 steps has a height of less than 1 V. For example, each of the at least 170 steps can have a height of less than 0.9 V, less than 0.8 V, less than 0.75 V, less than 0.7 V, less than 0.6 V, or less than 0.5 V. For example, each of the at least 170 steps can have a height of about 0.9 V, about 0.8 V, about 0.7 V, about 0.6 V, about 0.5 V, about 0.4 V, about 0.3 V, about 0.2 V, or about 0.1 V. Optionally, the stepwise increments during the first portion of the intervals include at least 200 steps during each time interval. For example, the stepwise increments during the first portion of the intervals can include at least 200 steps, at least 250 steps, at least 300 steps, at least 350 steps, at least 400 steps, at least 450 steps, or at least 500 steps.

[0049] Optionally, during each of the time intervals, the AC electric field has an amplitude that remains substantially constant (e.g., ±5%) during a second portion of the interval (e.g., the upper plateau of signal 55) following a first portion of the interval (e.g., the ramp-up portion). Optionally, in these embodiments, during each of the time intervals, the AC electric field has an amplitude that decreases in a stepwise manner during a third portion of the interval (e.g., the right ramp-down portion of signal 55) following a second portion of the interval (e.g., the plateau).

[0050] Optionally, the plurality of time intervals includes at least 100 time intervals, all occurring within one hour. Optionally, when the first portion of the intervals ends during each of the time intervals, the alternating electric field has an amplitude of at least 1 V / cm, at least 2 V / cm, at least 3 V / cm, or at least 5 V / cm in at least a portion of the target region. For example, when the first portion of the intervals ends during each of the time intervals, the alternating electric field can have an amplitude of 1 V / cm to 10 V / cm, 2 V / cm to 10 V / cm, 5 V / cm to 10 V / cm, 2 V / cm to 20 V / cm, or 1 V / cm to 20 V / cm. In other words, in some embodiments, the alternating electric field has an amplitude of at least 1 V / cm (e.g., 1 V / cm to 10 V / cm, 2 V / cm to 10 V / cm, 5 V / cm to 10 V / cm, 2 V / cm to 20 V / cm, or 1 V / cm to 20 V / cm) during each second portion of the time interval.

[0051] Optionally, the alternating electric field is applied to the target region in a first direction during a first subset of the plurality of time intervals, and the alternating electric field is applied to the target region in a second direction during a second subset of the plurality of time intervals, the second direction being offset from the first direction by at least 45°.

[0052] Returning to Figure 2, the operation of the front / rear channels is similar to that of the left / right channels described above in connection with Figure 5, 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.

[0053] A wide variety of alternative designs for AC signal generator 20 and controller 30 can be substituted for the above example, so long as controller 30 is capable of controlling AC signal generator 20. For example, if the AC signal generator is designed to respond to analog control signals, controller 30 must generate the sequence of analog control signals necessary to cause AC signal generator 20 to output the desired waveform. In this situation, controller 30 may 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 AC signal generator 20 to generate the desired waveform. Alternatively, controller 30 may 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).

[0054] 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 may 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 arrangement of its own paired transducer array. In other alternative embodiments, the transducer arrays need not be arranged 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 arrangement of the transducer arrays, a ramp-up portion comprising at least 170 steps is initiated each time a given transducer array is activated.

[0055] 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 applying an AC voltage across the transducer array generates an AC voltage at a target area within the subject's body.

[0056] Finally, in some anatomical locations, a constant-direction AC electric field may be used instead of switching the field back and forth between two or more different directions. 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 gradually increase the voltage when first switched on, as described above in connection with FIG. 5, and then maintain the output voltage at a constant level for the duration of treatment, or to repeatedly switch a single output on and off (e.g., on for 0.1-10 seconds, off for 0.1-10 seconds). In the latter situation, each time the AC voltage generator is switched on again, its voltage is increased, as described above in connection with FIG. 5.

[0057] While the present invention has been disclosed with reference to particular embodiments, numerous variations, substitutions, and alterations of the above embodiments are possible without departing from the scope and spirit 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 improving electrosensation while applying an electric field to a target region in a living body, the method comprising: applying an alternating electric field having a frequency between 50 kHz and 1 MHz to the target region during each of a plurality of time intervals; During each of the time intervals, the amplitude of the alternating electric field is increased in steps during a first portion of the time interval, the step increase during the first portion of the time interval comprising at least 170 steps.

2. The method of claim 1 , wherein each of the at least 170 steps has a height of less than 1 V.

3. The method of claim 1 , wherein during each of the time intervals, the step increase during the first portion of the time interval includes at least 200 steps.

4. 2. The method of claim 1, wherein during each of the time intervals, the alternating electric field has an amplitude that remains substantially constant during a second portion of the time interval following the first portion of the time interval.

5. 5. The method of claim 4, wherein during each of the time intervals, the alternating electric field has a stepped decreasing amplitude during a third portion of the time interval following the second portion of the time interval.

6. 2. The method of claim 1, wherein the plurality of time intervals comprises at least 100 time intervals that all occur within one hour.

7. 10. The method of claim 1, wherein the alternating electric field has an amplitude of at least 1 V / cm in at least a portion of the target area when the first portion of the time interval ends during each of the time intervals.

8. The method of claim 1 , wherein the alternating electric field has a frequency between 100 kHz and 500 kHz.

9. the alternating electric field is applied to the target region in a first direction during a first subset of the plurality of time intervals; the alternating electric field is applied to the target region in a second direction during a second subset of the plurality of time intervals; The method of claim 1 , wherein the second direction is offset from the first direction by at least 45°.

10. the plurality of time intervals includes at least 100 time intervals that all occur within one hour; during each of the time intervals, the step increase during the first portion of the time interval includes at least 200 steps; 10. The method of claim 9, wherein the alternating electric field has an amplitude of at least 1 V / cm in at least a portion of the target area when the first portion of the time interval ends during each of the time intervals.

11. 1. An apparatus comprising: a signal generator having at least one control input configured to generate a first AC output at a frequency between 50 kHz and 1 MHz, the first AC output having an amplitude that depends on a state of the at least one control input; a controller configured to send a first set of control signals to the at least one control input during each of a plurality of first time intervals per hour, the first set of control signals during each of the first time intervals configured to increase an amplitude of the first AC output in steps during a first portion of the first time interval, the step increase during the first portion of the first time interval comprising at least 170 steps; An apparatus comprising:

12. 12. The apparatus of claim 11, wherein each of the at least 170 steps has a height of less than 1V.

13. 12. The apparatus of claim 11, wherein during each of the first time intervals, the step increase during the first portion of the first time interval comprises at least 200 steps.

14. 12. The apparatus of claim 11, wherein during each of the first time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the first time interval following the first portion of the first time interval.

15. 15. The apparatus of claim 14, wherein during each of the first time intervals, the first AC output has a stepped decreasing amplitude during a third portion of the first time interval following the second portion of the first time interval.

16. 12. The apparatus of claim 11, wherein the plurality of first time intervals comprises at least 100 first time intervals that all occur within one hour.

17. 12. The apparatus of claim 11, wherein the first AC output has a frequency between 100 kHz and 500 kHz.

18. the signal generator is further configured to generate a second AC output at a frequency between 50 kHz and 1 MHz, the second AC output having an amplitude that depends on the state of the at least one control input; 12. The apparatus of claim 11, wherein the controller is further configured to send a second set of control signals to the at least one control input during each of a plurality of second time intervals per hour, the second set of control signals during each of the second time intervals being configured to increase an amplitude of the second AC output in steps during a first portion of the second time interval, the step increase during the first portion of the second time interval comprising at least 170 steps.

19. during each of the first time intervals, the step increase during the first portion of the first time interval includes at least 200 steps; 20. The apparatus of claim 18, wherein during each of the second time intervals, the step increase during the first portion of the second time interval comprises at least 200 steps.

20. during each of the first time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the first time interval following the first portion of the first time interval; during each of the second time intervals, the first AC output has an amplitude that remains substantially constant during a second portion of the second time interval following the first portion of the second time interval; the plurality of first time intervals includes at least 100 first time intervals that all occur within one hour; 20. The apparatus of claim 18, wherein the plurality of second time intervals comprises at least 100 second time intervals that all occur within one hour.

Images