Reduction of electric sensation during application of alternating electric fields by ensuring a continuous increase in amplitude occurs between opposite phases of the AC waveform

Abstract

When an alternating current electric field is applied to a subject's body using a transducer array (i.e., an array of electrode elements), the subject may experience an electrical sensation, particularly during the portion of the waveform where the amplitude of the AC voltage rises. This electrical sensation may be improved by synchronizing the amplitude inter-step transitions with the AC signal so that when a given inter-step transition occurs while the AC signal has a given polarity, the next inter-step transition occurs while the AC signal has the opposite polarity.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Application No. 63 / 436,034, filed December 29, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Tumor Treating Field (TT) therapy is a proven approach to treating tumors using alternating current (AC) electric fields at frequencies between 50 kHz and 1 MHz (e.g., 150-250 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 one 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 one 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, the entire contents of which are incorporated herein by reference, 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] When treating a subject with an AC electric field, the greater the amplitude, the greater the therapeutic effect. However, as the amplitude of the AC electric field increases or the frequency of the AC electric field decreases (e.g., to around 100 kHz), some subjects experience an electrosensory effect. This electrosensation can be, for example, a vibratory sensation, paresthesia, and / or a sensation of muscle fiber twitching or contraction, or a flickering of lights in the eyes (phosphenes). These electrosensations may deter some subjects from continuing treatment with the AC electric field. Furthermore, the electrosensation may limit the amplitude of the AC electric field that can be comfortably applied to a given subject, thereby limiting the effectiveness of the treatment. [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 apparatus comprising a signal generator and a controller. The signal generator has at least one control input, and the signal generator 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 sequence of control signals to the at least one control input, the first sequence of control signals instructing the signal generator to increase the amplitude of the first AC output in steps. Each control signal in the first sequence of control signals corresponds to a single step of the amplitude increase, and the first sequence of control signals is a sequence of at least 10 control signals. The first sequence of control signals is synchronized with the first AC output such that when a given control signal in the first sequence of control signals instructs the signal generator to increase the amplitude of the first AC output while the first AC output has a given polarity, an immediately subsequent control signal in the first sequence of control signals instructs the signal generator to increase the amplitude of the first AC output while the first AC output has a polarity opposite to the given polarity.

[0007] In some embodiments of the first apparatus, the first sequence of control signals causes the first AC output to have a given instantaneous voltage V G and when a given control signal in the first sequence of control signals commands the signal generator to increase the amplitude of the first AC output, while the first AC output has a voltage G The first AC output is synchronized with the first control signal such that an immediately subsequent control signal in the first sequence of control signals instructs the signal generator to increase the amplitude of the first AC output while having an instantaneous voltage of ±20%.

[0008] In some embodiments of the first apparatus, the first sequence of control signals is configured to control the first AC output to have a given phase φ Gwhile operating at φ, when a given control signal in the first sequence of control signals commands the signal generator to increase the amplitude of the first AC output, G While operating at a phase of +180°±10°, the immediately following control signal in the first sequence of control signals is synchronized with the first AC output such that the signal generator increases the amplitude of the first AC output.

[0009] In some embodiments of the first apparatus, the first sequence of control signals is a sequence of at least 20 control signals. In some embodiments of the first apparatus, the first sequence of control signals is a sequence of at least 50 control signals.

[0010] In some embodiments of the first apparatus, the controller is further configured to, after sending the first sequence of control signals to the at least one control input, send at least one first control signal to the at least one control input, the at least one first control signal instructing the signal generator to hold the amplitude of the first AC output constant for at least 0.5 seconds. Optionally, in these embodiments, the first AC output has an amplitude greater than 150 V RMS while the amplitude of the first AC output is held constant.

[0011] In some embodiments of the first apparatus, at least half of the steps in the amplitude step increase have a step height greater than 2 V. In some embodiments of the first apparatus, the first AC output has a frequency between 75 kHz and 500 kHz.

[0012] 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 the second sequence of control signals to the at least one control input, the second sequence of control signals instructing the signal generator to increase the amplitude of the second AC output in steps. Each control signal in the second sequence of control signals corresponds to a single step in the amplitude increase, and the second sequence of control signals is a sequence of at least 10 control signals. The second sequence of control signals is synchronized with the second AC output such that when a given control signal in the second sequence of control signals instructs the signal generator to increase the amplitude of the second AC output while the second AC output has a given polarity, an immediately subsequent control signal in the second sequence of control signals instructs the signal generator to increase the amplitude of the second AC output while the second AC output has a polarity opposite to the given polarity.

[0013] Optionally, in the embodiment described in the previous paragraph, the controller may be further configured to, after sending the second sequence of control signals to the at least one control input, send at least one second control signal to the at least one control input, the at least one second control signal instructing the signal generator to hold the amplitude of the second AC output constant for at least 0.5 seconds.

[0014] Another aspect of the present invention relates to a first method for increasing the amplitude of an AC voltage, the first method comprising generating an AC voltage and increasing the amplitude of the generated AC voltage in steps, the steps including at least 10 steps, each step of the amplitude increase being synchronized with the generated AC voltage such that when a given step increases the amplitude of the generated AC voltage while the generated AC voltage has a given polarity, the immediately following step increases the amplitude of the generated AC voltage while the generated AC voltage has an opposite polarity to the given polarity.

[0015] In some examples of the first method, each step of the amplitude increase is such that while the generated AC voltage has a given instantaneous value XG, as a given step increases the amplitude of the generated AC voltage, the generated AC voltage becomes -X G A subsequent step is synchronized with the generated AC voltage to increase the amplitude of the generated AC voltage while having an instantaneous value of ±20%.

[0016] In some examples of the first method, each step of the amplitude increase is performed by increasing the amplitude of the generated AC voltage by a given phase φ. G When a given stage increases the amplitude of the generated AC voltage while operating at φ G While operating at a phase of +180°±10°, the immediately following stage is synchronized with the generated AC voltage to increase the amplitude of the generated AC voltage.

[0017] In some examples of the first method, the stepwise increase in amplitude includes at least 20 steps. In some examples of the first method, the stepwise increase in amplitude includes at least 50 steps. In some examples of the first method, the generated AC voltage has a frequency between 50 kHz and 1 MHz. In some examples of the first method, the generated AC voltage has a frequency between 75 kHz and 500 kHz.

[0018] Another aspect of the present invention relates to a second method for improving electrosensation while applying an electric field to a target region in a living organism. The second method includes applying an AC electric field having a frequency of 50 kHz to 1 MHz to the target region and increasing the amplitude of the AC electric field in steps. The stepwise increase in amplitude includes at least 10 steps. Each step of the stepwise increase in amplitude is synchronized with the AC electric field such that when a given step increases the amplitude of the AC electric field while the AC electric field has a given polarity, the immediately following step increases the amplitude of the AC electric field while the AC electric field has the opposite polarity.

[0019] In some examples of the second method, each step of the amplitude increase is a step of increasing the amplitude of the AC electric field to a given instantaneous value X G When a given step increases the amplitude of the AC electric field, while the AC electric field has a magnitude of -X G A subsequent step is synchronized with the AC field to increase the amplitude of the AC field while having an instantaneous value of ±20%.

[0020] In some examples of the second method, each step of the amplitude increase is performed by increasing the amplitude of the AC electric field at a given phase φ G When a given stage increases the amplitude of the AC electric field while operating at φ G While operating at a phase of +180°±10°, the immediately following stage is synchronized with the AC field to increase the amplitude of the AC field.

[0021] In some examples of the second method, the stepwise increase in amplitude includes at least 20 steps. In some examples of the second method, the stepwise increase in amplitude includes at least 50 steps. In some examples of the second method, the AC electric field has a frequency of 75 kHz to 500 kHz.

[0022] Some examples of the second method further include holding the amplitude of the alternating electric field constant for at least 0.5 seconds after the stepwise increase in amplitude. [Brief explanation of the drawings]

[0023] [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 detailed diagram of the step-to-step transition of amplitude as an AC voltage ramps up from zero to a peak value. [Figure 3] Three examples of how the interphase transitions can be matched to the instantaneous voltage being output by the AC signal generator are shown. [Figure 4] An example is shown in which all successive steps in the ramp-up portion of the waveform occur when the output of the AC signal generator is positive. [Figure 5] An example of how synchronizing the inter-phase transitions with the output of an AC signal generator can improve the electrical sensation is shown. [Figure 6] FIG. 1 is a block diagram of a system for driving a set of transducer arrays with AC voltage signals in which amplitude transitions are synchronized to improve electrical sensation. [Figure 7] 7 is a schematic diagram of the first and second outputs of the AC signal generator shown in FIG. 6. DETAILED DESCRIPTION OF THE INVENTION

[0024] Various embodiments are described in detail below with reference to the accompanying drawings, in which like reference numerals represent like elements, and in which:

[0025] FIG. 1 shows the AC output amplitude in the L / R and A / P channels of a prior art Optune® system. In particular, when the signal to either the A / P or L / R transducer array is turned on during any given one-second interval, the amplitude of the AC voltage does not immediately jump to its peak value. Instead, the amplitude of the AC voltage ramps up from zero to its peak during a first time window (nominal 100 ms) and then holds its peak value during a second time window (nominal 800 ms). Similarly, when the signal is turned off during any given one-second interval, the amplitude of the AC voltage ramps down from its peak to zero during a third time window (nominal 100 ms).

[0026] In the prior art Optune® system, the ramping up and down of amplitude was accomplished by updating the control signal in the AC signal generator at regular 1 ms intervals during the ramp-up and ramp-down portions of the waveform. Thus, while the main portion of Figure 1 shows the smooth ramp-up portion of the waveform, zooming in on the waveform reveals that the amplitude actually increases in steps, as shown in inset A of Figure 1.

[0027] We found that increasing the height of each step during the ramp-up portion of the waveform (e.g., from 1 V to 2 V) contributed much more to the electrical sensation than increasing the overall amplitude during the 800 ms middle portion of the waveform (i.e., from 100 VAC RMS to 200 VAC RMS).

[0028] Without being bound by this theory, it is believed that electrosensation arises from the interaction of an AC electric field with neurons placed near or adjacent to the transducer array. More specifically, the inventors believe that one of the primary factors contributing to electrosensation is the accumulation or lack of ions (e.g., potassium or sodium ions) in neurons. One basis for this theory is that even when relatively high AC voltages (e.g., 150-200 V RMS at 100 kHz) are applied to electrodes placed on the subject's skin, electrosensation is typically not observed during steady-state application of the AC electric field. On the other hand, electrosensation is observed when the voltage applied to these same electrodes ramps up and then back down every 1-2 seconds.

[0029] If the accumulation or depletion of ions within neurons were indeed the cause of electrosensation, steady-state application of an alternating electric field should not result in electrosensation because the polarity of the AC signal applied to the transducer array reverses every half cycle. If a particular half-cycle of steady AC drives a given amount of ions into a neuron, the next half-cycle of steady AC will drive the same given amount of ions out of that same neuron. Also, under these circumstances, ions will not accumulate or deplete to a degree that triggers electrosensation, unless the AC voltage is too high (e.g., 400-600 V RMS).

[0030] Here, we analyze ion migration when a step height of 2 V is used during the ramp-up portion of the waveform. Figure 2 shows the first 10 steps of the ramp-up portion with a step height of 2 V and a step duration of 1 ms, and this same pattern continues for the duration of the ramp-up portion (e.g., 100 steps total).

[0031] FIG. 3 shows three examples of how the inter-phase transition can coincide with the instantaneous voltage being output by the AC signal generator. More specifically, if the output of the AC signal generator is between 0 and 180° at the moment the inter-phase transition occurs (as shown for the transition from phase A3 to A4), the output of the AC signal generator will be positive. If the output of the AC signal generator is between 180 and 360° at the moment the inter-phase transition occurs (as shown for the transition from phase A4 to A5), the output of the AC signal generator will be negative. Also, if the output of the AC signal generator is exactly 0 or 180° at the moment the inter-phase transition occurs (as shown for the transition from phase A5 to A6), the output of the AC signal generator will be zero. FIG. 3 shows only three examples; if the timing of the inter-phase transition is not synchronized to the AC signal generator output (as in the prior art Optune® system), the inter-phase transition can occur anywhere in the sine wave cycle (i.e., between 0 and 360°).

[0032] If ions are driven into a given neuron when an inter-stage transition occurs when the AC signal generator output is positive (as shown for the transition from stage A3 to A4), then ions are urged out of that same neuron when an inter-stage transition occurs when the AC signal generator output is negative (as shown for the transition from stage A4 to A5).

[0033] If the height of each step is small enough, a single step will not drive enough ions into the associated neurons to cause an electrical sensation. However, we consider herein what happens when successive steps in the ramp-up portion of the waveform all occur when the AC signal generator outputs all have the same polarity, as shown in FIG. 4. More specifically, in the example of FIG. 4, the transition from step A13 to A14 occurs when the AC signal generator output is positive, meaning that a first batch of ions is driven into each of the associated neurons during that transition. The transition from step A14 to A15 occurs when the AC signal generator output is positive, meaning that a second batch of ions is driven into each of the associated neurons during that transition. The transition from step A15 to A16 occurs when the AC signal generator output is positive, meaning that a third batch of ions is driven into each of the associated neurons during that transition.

[0034] If we assume that the number of ions in each of the associated neurons is at normal levels at time t13, then the transitions from stage A13 to A14, stage A14 to A15, and stage A14 to A15 will drive three separate batches of ions into each of the associated neurons (all within a 3 ms time window). Without being bound by this theory, we believe that while urging a single batch of ions into each of the associated neurons may not be sufficient to cause an electric sensation, pushing multiple batches of ions into those same neurons over short time intervals (e.g., less than 50 ms, less than 20 ms, less than 10 ms, or less than 5 ms) (as a result of successive transitions that all occur during the same polarity of the AC signal generator's output) will result in an electric sensation.

[0035] Figure 5 shows an example of how synchronizing inter-phase transitions with the output of an AC signal generator can prevent electrosensation by preventing multiple batches of ions from being driven into associated neurons in a short time interval. We begin by assuming that the number of ions in each associated neuron is at a normal level at time t23. In this example of Figure 5, the transition from phase A23 to phase A24 occurs when the output of the AC signal generator is positive, meaning that the first batch of ions is deployed into each associated neuron during that transition.

[0036] Specifically, however, the transition from stage A24 to stage A25 is synchronized with the output of the AC signal generator such that this transition occurs when the output of the AC signal generator is negative. As a result, a second batch of ions is driven "out of" each of the associated neurons during that transition. Also, the transition from stage A25 to stage A26 is synchronized with the output of the AC signal generator such that this transition occurs when the output of the AC signal generator is positive. As a result, a third batch of ions is deployed within each of the associated neurons during that transition.

[0037] In particular, the inter-phase transitions are synchronized with the AC output such that when a given inter-phase transition occurs while the AC output has a given polarity, the next inter-phase transition occurs while the AC output has the opposite polarity. This causes ion movement to alternate between (a) movement into neurons and (b) movement out of neurons. This also prevents, or at least improves, electrosensation by preventing large amounts of ions from entering (or leaving) each of the associated neurons within a given time window.

[0038] In addition to optionally synchronizing the inter-phase transitions with the alternating polarity of the AC output (to ensure that successive batches of ions travel in opposite directions), some embodiments also attempt to approximately match the volume of successive batches of ions. One way to accomplish this is to consider the instantaneous voltage of the AC output. More specifically, the inter-phase transitions occur when the first AC output has a given instantaneous voltage V G While having a phase-to-phase transition, when a given phase-to-phase transition increases the amplitude of the AC output, the AC output G The AC output can be synchronized so that the immediate inter-phase transition increases the amplitude of the AC output while having an instantaneous voltage of ±20%, which will ensure that the amount of ions entering a given neuron matches the amount of ions exiting that neuron within 20%.

[0039] Another way to approximately match the amounts of successive batches of ions is by considering the phase of the AC output. More specifically, the interphase transition occurs when the AC output has a given phase φ G While operating at φ, when a given inter-phase transition increases the amplitude of the AC output, the first AC output G While operating at a phase of +180° ±10°, it can be synchronized with the AC output so that the immediate inter-phase transition increases the amplitude of the AC output. This will also ensure that the amount of ions entering a given neuron closely matches the amount of ions exiting that neuron, since any two points on a sine curve separated by 170° to 190° will be relatively close in magnitude (but have opposite signs).

[0040] Figure 6 is a block diagram of a system for driving a set of transducer arrays with AC voltage signals whose amplitude transitions are synchronized in the manner shown in Figure 5. The system includes an AC signal generator 20 that generates first and second AC outputs at frequencies between 50 kHz and 1 MHz (e.g., 75-500 kHz, 50-300 kHz, or 150-250 kHz). When using this system to apply a TT field to a portion of a human body, the first AC output is applied to a first pair of transducer arrays 10L, 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, 10P positioned in front and behind the tumor.

[0041] 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 region 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 region 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).

[0042] In some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of at least 1 V / cm in at least a portion of the cells. In some embodiments, the voltage generated by AC signal generator 20 is sufficient to induce an electric field of 1-10 V / cm, 1-20 V / cm, 2-20 V / cm, or 4-20 V / cm in at least a portion of the cells.

[0043] As best seen in FIG. 7 , (a) a first AC output of AC signal generator 20 is applied to L / R transducer arrays 10L, 10R for a period of time, (b) a second AC output of AC signal generator 20 is applied to A / P transducer arrays 10A, 10P for a period of time, and the two-step sequence of (a) and (b) is repeated for the duration of the treatment. Notably, the manner in which AC signal generator 20 ramps up its output voltages from zero to their peak in the embodiments of FIGS. 6 and 7 differs from prior art Optune® systems. More specifically, the inter-step transitions in the amplitude ramp-up are synchronized with the output of AC signal generator 20 (e.g., as described above in connection with FIG. 5 ), which can advantageously prevent electrical sensations even when higher voltages (e.g., >150 VAC or >200 VAC RMS) are output.

[0044] AC signal generator 20 is configured to generate first and second AC outputs at a frequency between 50 kHz and 10 MHz (e.g., 50 kHz and 1 MHz, 75 to 500 kHz, 50 to 300 kHz, or 150 to 250 kHz) and having amplitudes that depend 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 at least one control input to control the output amplitude of AC signal generator 20 to incrementally increase the amplitude of the first and second AC outputs. Each control signal corresponds to a single step in the incremental increase in amplitude, and each sequence of control signals is a sequence of at least 10 control signals. In some embodiments, there may be at least 20 control signals, or at least 50 control signals.

[0045] 6 shows the controller 30 and the AC signal generator 20 as two separate blocks, these two blocks may be integrated into a single hardware device. In some embodiments, at least half of the amplitude step increases have a step height greater than 2 V. In other embodiments, at least half of the amplitude step increases have a step height of >1.5 V, >1.75 V, >2.5 V, >3 V, >4 V, or >5 V.

[0046] In particular, the sequence of control signals generated by controller 30 is synchronized with the output of AC signal generator 20 such that when a given control signal in the sequence of control signals commands AC signal generator 20 to increase its output amplitude while the AC output has a given polarity, the immediately following control signal commands AC signal generator 20 to increase its output amplitude while the AC output has the opposite polarity (as described above in connection with FIG. 5). This feature also improves electrical sensation, as described above in connection with FIG. 5.

[0047] After any output is increased stepwise as described above, controller 30 sends at least one control signal to a control input of AC signal generator 20. These control signal(s) instruct AC signal generator 20 to hold the amplitude of the AC output constant for at least 0.5 seconds (best seen in FIG. 7). In some embodiments, the AC output has an amplitude greater than 150V RMS while the amplitude of the AC output is held constant. In some embodiments, this amplitude can be >150V, >175V, >200V, >225V, or >250V RMS.

[0048] The details of the structure of controller 30 and the characteristics of the control signal vary depending 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 in turn is controlled by writing control signals to a digital-to-analog converter (DAC) at a rate of, for example, one control signal per ms.

[0049] 6 can implement any desired rate of increase of the first and sixth outputs of AC signal generator 20 in any desired pattern by sequentially sending appropriate control signals to the DACs within AC signal generator 20. Also, the necessary synchronization can be achieved, for example, by precisely timing the exact moment at which controller 30 issues each control signal. Alternatively, signal generator 20 can be configured not to act on an incoming command until a particular phase of the AC signal is reached.

[0050] In some embodiments (including the embodiment shown in FIG. 6 ), the AC electric field is applied to the subject in 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 10 MHz (e.g., 50 kHz and 1 MHz, 75-500 kHz, 50-300 kHz, or 150-250 kHz), the second AC output having an amplitude that depends on the state of at least one control input. In these embodiments, controller 30 is further configured to send a second sequence of control signals to at least one control input of signal generator 20. The sequence of control signals instructs signal generator 20 to increase the amplitude of the second AC output in steps. Each control signal in the second sequence of control signals corresponds to a single step in the stepwise increase in amplitude. The second sequence of control signals is a sequence of at least 10 control signals. The necessary synchronization may also be achieved, for example, by precisely timing the exact moment at which controller 30 issues each control signal. Alternatively, signal generator 20 may be configured not to act on an arriving command until a particular phase of the AC signal is reached.

[0051] The second sequence of control signals generated by controller 30 is synchronized with the second AC output such that when a given control signal in the second sequence of control signals instructs signal generator 20 to increase the amplitude of the second AC output while the second AC output has a given polarity, the immediately following control signal in the second sequence of control signals instructs signal generator 20 to increase the amplitude of the second AC output while the second AC output has the opposite polarity to the given polarity. This is similar to the situation described above in connection with FIG. 5 for the first AC output.

[0052] Returning to Figure 6, 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 can be implemented using a microprocessor or microcontroller programmed to write the appropriate control signals 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 can be implemented using analog circuitry that automatically generates the appropriate sequence of control signals (which are then applied to the control inputs of the AC signal generator at the appropriate times).

[0054] In many of the examples described above, the direction of the AC electric field was switched between two directions. However, in alternative embodiments, the direction of the AC electric field can be switched between three or more directions (assuming additional paired transducer arrays are provided). For example, the direction of the AC electric field is switched between three directions, each determined by the placement of its own paired transducer array. In other alternative embodiments, the transducer arrays need not be placed in pairs. See, for example, the positioning of the transducer arrays described in U.S. Pat. No. 7,565,205, which is incorporated herein by reference. However, regardless of the placement of the transducer arrays, the increase in amplitude during the ramp-up portion is synchronized with the AC output of AC signal generator 20, for example, as described above in connection with FIG. 5.

[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. 6, 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 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. 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 sequence of control signals to the at least one control input, the first sequence of control signals instructing the signal generator to increase an amplitude of the first AC output in steps, each control signal in the first sequence of control signals corresponding to a single step of the increase in amplitude, the first sequence of control signals being a sequence of at least 10 control signals; the first sequence of control signals is synchronized with the first AC output such that when a given control signal in the first sequence of control signals instructs the signal generator to increase an amplitude of the first AC output while the first AC output has a given polarity, an immediately subsequent control signal in the first sequence of control signals instructs the signal generator to increase an amplitude of the first AC output while the first AC output has a polarity opposite to the given polarity.

2. The first AC output has a given instantaneous voltage V Ｇ and when a given control signal in the first sequence of control signals commands the signal generator to increase the amplitude of the first AC output, while the first AC output has a voltage of −V Ｇ 2. The apparatus of claim 1, wherein the first sequence of control signals is synchronized with the first AC output such that an immediately succeeding control signal in the first sequence of control signals instructs the signal generator to increase the amplitude of the first AC output while having an instantaneous voltage of ±20%.

3. The first sequence of control signals controls the first AC output to have a given phase φ Ｇ while operating at φ, when a given control signal in the first sequence of control signals commands the signal generator to increase the amplitude of the first AC output, Ｇ 2. The apparatus of claim 1, wherein while operating at a phase of +180°±10°, the signal generator is synchronized with the first AC output such that an immediately subsequent control signal in the first sequence of control signals instructs the signal generator to increase the amplitude of the first AC output.

4. The apparatus of claim 1 , wherein the first sequence of control signals is a sequence of at least 50 control signals.

5. the controller is further configured to send at least one first control signal to the at least one control input after sending the first sequence of control signals to the at least one control input; 2. The apparatus of claim 1, wherein the at least one first control signal instructs the signal generator to hold the amplitude of the first AC output constant for at least 0.5 seconds.

6. 6. The apparatus of claim 5, wherein the first AC output has an amplitude greater than 150V RMS while the amplitude of the first AC output is held constant.

7. 2. The apparatus of claim 1, wherein at least half of the amplitude increasing steps have a step height greater than 2V.

8. 10. The apparatus of claim 1, wherein the first AC output has a frequency between 75 kHz and 500 kHz.

9. 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 a state of the at least one control input; the controller is further configured to send a second sequence of control signals to the at least one control input, the second sequence of control signals instructing the signal generator to increase an amplitude of the second AC output in steps, each control signal in the second sequence of control signals corresponding to a single step of the step increase in amplitude, the second sequence of control signals being a sequence of at least 10 control signals; 2. The apparatus of claim 1, wherein the second sequence of control signals is synchronized with the second AC output such that when a given control signal in the second sequence of control signals instructs the signal generator to increase the amplitude of the second AC output while the second AC output has a given polarity, an immediately subsequent control signal in the second sequence of control signals instructs the signal generator to increase the amplitude of the second AC output while the second AC output has a polarity opposite to the given polarity.

10. the controller is further configured to send at least one second control signal to the at least one control input after sending the second sequence of control signals to the at least one control input; 10. The apparatus of claim 9, wherein the at least one second control signal instructs the signal generator to hold the amplitude of the second AC output constant for at least 0.5 seconds.

11. 1. A method for increasing the amplitude of an AC voltage, comprising: generating an AC voltage; and increasing the amplitude of the generated AC voltage in steps; the stepwise increase in amplitude includes at least 10 steps; wherein each step of the amplitude increase is synchronized with the generated AC voltage such that when a given step increases the amplitude of the generated AC voltage while the generated AC voltage has a given polarity, an immediately following step increases the amplitude of the generated AC voltage while the generated AC voltage has a polarity opposite to the given polarity.

12. The generated AC voltage has a given instantaneous value X Ｇ When a given step increases the amplitude of the generated AC voltage, while having Ｇ 12. The method of claim 11, wherein each step of the amplitude increase is synchronized with the generated AC voltage such that the immediately following step increases the amplitude of the generated AC voltage while having an instantaneous value of ±20%.

13. The generated AC voltage has a given phase φ Ｇ When a given stage increases the amplitude of the generated AC voltage while operating at φ Ｇ 12. The method of claim 11, wherein each step of the amplitude increase is synchronized with the generated AC voltage such that an immediately subsequent step increases the amplitude of the generated AC voltage while operating at a phase of +180°±10°.

14. The method of claim 11 , wherein the amplitude step increase comprises at least 50 steps.

15. The method of claim 11, wherein the generated AC voltage has a frequency between 50 kHz and 1 MHz.

16. The method of claim 11, wherein the generated AC voltage has a frequency between 75 kHz and 500 kHz.

17. 1. A method of improving electrosensation while applying an electric field to a target region in a living body, comprising: applying an alternating electric field having a frequency between 50 kHz and 1 MHz to the target area; increasing the amplitude of the AC electric field in steps, the stepwise increase in amplitude including at least 10 steps; wherein each step of the amplitude increase is synchronized with the AC electric field such that when a given step increases the amplitude of the AC electric field while the AC field has a given polarity, an immediately following step increases the amplitude of the AC electric field while the AC field has a polarity opposite to the given polarity.

18. The AC electric field has a given instantaneous value X Ｇ When a given step increases the amplitude of the AC electric field, while the AC electric field has a magnitude of -X Ｇ 18. The method of claim 17, wherein each step of the incremental increase in amplitude is synchronized with the alternating electric field such that the immediately following step increases the amplitude of the alternating electric field while having an instantaneous value of ±20%.

19. The AC electric field has a given phase φ Ｇ When a given stage increases the amplitude of the AC electric field while operating at φ Ｇ 18. The method of claim 17, wherein each step of the incremental increase in amplitude is synchronized with the AC electric field such that an immediately subsequent step increases the amplitude of the AC electric field while operating at a phase of +180°±10°.

20. 18. The method of claim 17, wherein the alternating electric field has a frequency between 75 kHz and 500 kHz.

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