AC electric field waveform to reduce electrical sensation

Abstract

An apparatus for treating a target area of ​​a subject's body with an alternating electric field, the apparatus being capable of applying an alternating electric field to a target area of ​​the subject's body at a first frequency while increasing a strength of the alternating electric field from zero to a target strength, and varying the frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target strength, the target frequency and the target strength having a known efficacy for treating the target area of ​​the subject's body with an alternating electric field, and the first frequency being higher than the target frequency.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 18 / 128,937, filed March 30, 2023, U.S. Provisional Application No. 63 / 326,098, filed March 31, 2022, and U.S. Provisional Application No. 63 / 410,481, filed September 27, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Tumor treatment fields (TT fields) are low intensity alternating electric fields in the mid-frequency range that can be used to treat tumors, as described in U.S. Patent No. 7,565,205. TT fields are non-invasively induced in target areas by placing transducers directly on the patient's body and applying an alternating voltage between the transducers. During a first time interval, an alternating voltage is applied across a first pair of transducers, creating an electric field with field lines running generally in a front-to-back direction. Then, during a second time interval, an alternating voltage of the same frequency is applied across a second pair of transducers, creating an electric field with field lines running generally in a side-to-side direction. The system repeats this two-step sequence throughout the treatment. [Brief description of the drawings]

[0003] [Figure 1A] 1 illustrates an example of a method for treating a target area of ​​a subject's body. [Figure 1B] 1 illustrates an example of a method for treating a target area of ​​a subject's body. [Diagram 2] An example of a system with four transducers is shown. [Diagram 3] 1 shows an example of a device for controlling an AC electric field. [Figure 4] 4 shows an example of the waveform of an AC electric field. [Diagram 5] 4 shows an example of the waveform of an AC electric field. [Figure 6] 4 shows an example of the waveform of an AC electric field. [Figure 7]10 illustrates another example method for treating a target area of ​​a subject's body. [Figure 8] 1 illustrates an example of a method for delivering an alternating electric field to the body of a subject. [Figure 9] 1 shows an example of a method for delivering an alternating electric field to a subject's body as the temperature increases. [Figure 10] An example of a cytotoxicity assay showing the effect of electric field strength is given. [Figure 11A] This shows an experiment in which the sciatic nerve bundle of a rat was stimulated with an alternating electric field. [Figure 11B] This shows an experiment in which the sciatic nerve bundle of a rat was stimulated with an alternating electric field. [Figure 11C] This shows an experiment in which the sciatic nerve bundle of a rat was stimulated with an alternating electric field. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] This application describes exemplary systems and methods for delivering an alternating electric field to a subject's body for treating the body. In particular, the present disclosure relates to systems and methods for applying an alternating electric field according to a waveform that reduces electrical sensations in a subject.

[0005] When treating subjects with an AC electric field, there are strong indications that a higher intensity (e.g., amplitude) will result in a more effective treatment. However, as the intensity (e.g., amplitude) of the AC electric field increases and / or the frequency of the AC electric field decreases (e.g., near 100 kHz), some subjects may experience an electrosensory effect, especially at the onset of the AC electric field.

[0006] Electrical sensations may arise from the interaction between the alternating electric field and neural cells placed near or adjacent to the transducer array inducing the alternating electric field. For example, an alternating current of a predetermined frequency may be coupled into the subject's body through a pair of identical electrodes placed on the subject's skin to apply the alternating electric field. If the current density (e.g., the current through any electrode divided by the area of ​​that electrode) falls below a threshold (which may vary from person to person), no electrical sensation may occur. However, if the current density exceeds that threshold, electrical sensations may begin to occur and may become more pronounced as the current density is further increased. This electrical sensation may be, for example, a vibration sensation, paresthesia, and / or a twitching or contraction sensation of muscle fibers. These sensations may deter some subjects from continuing treatment with the alternating electric field.

[0007] The present inventors have recognized these problems and have discovered a method and system for reducing or eliminating the electric sensation while a subject is being treated with an AC electric field. In particular, the inventors have recognized that the electric sensation occurs in response to the current density present at the beginning of the duty cycle of the AC electric field. The present invention relates to a system and method for completely avoiding the electric sensation at the beginning of the duty cycle by applying a high frequency AC electric field during the dimming-up period. An AC electric field is applied to the subject's body with a voltage generated according to an AC voltage waveform. For a given duty cycle, the AC voltage waveform has a higher frequency during the dimming-up period and then switches to an optimal frequency for treating the subject's body at or near the time when the field reaches its peak intensity. This hybrid frequency AC voltage waveform helps to avoid the electric sensation that may occur if the optimal frequency for treating the subject's body is used throughout the entire duty cycle.

[0008] The inventors have discovered a system and method that minimizes electrical sensations at the beginning of a duty cycle by applying an AC electric field at a low intensity and high frequency during a dimming-up period. The AC electric field may be applied to the subject's body with a voltage generated according to an AC voltage waveform. During the dimming-up period of the duty cycle, the AC voltage waveform initially has an intensity lower than a target intensity and a frequency higher than a target frequency. As the dimming-up period progresses, the intensity increases to the target intensity and the frequency decreases to the target frequency. This AC voltage waveform helps to avoid electrical sensations that may occur if the target intensity and target frequency for treating the subject's body are used throughout the entire duty cycle.

[0009] FIG. 1A illustrates an example of a method 100 for treating a target region of a subject's body with an alternating electric field. The method 100 may include, in step S102, determining a target frequency and a target intensity for applying the alternating electric field. In one example, the target region may include at least one of a cancer, a tumor, an endothelial or epithelial tight junction (e.g., a blood-brain barrier (BBB) ​​or a gut wall tight junction), or any tissue or cell of the subject. In one example, the target region may be determined by treating a viral infection, a bacterial infection, a neurodegenerative disease, and / or an autoimmune disease. In certain embodiments, when an alternating electric field of a target intensity and a target frequency is applied, the subject may experience an electric sensation.

[0010] The term "target frequency" as used herein may refer to a clinically approved frequency that can provide a known efficacy for a desired treatment of a subject with an alternating electric field applied to the subject at the target frequency. For example, the target frequency may be a clinically approved frequency that provides a proven efficacy for tumor cell proliferation or for opening endothelial or epithelial tight junctions. For example, the target frequency may be determined from an in vitro assay. The term "target frequency" may refer to a frequency that is more effective for an intended treatment than a first frequency. Generally, the target frequency will be lower than the first frequency. The target frequency may be within a target frequency range that corresponds to a particular target cell, tissue, and / or treatment.

[0011] In non-limiting embodiments, the target frequency may be about 50 kHz to about 10 MHz, about 50 kHz to about 1 MHz, about 50 kHz to about 500 kHz, or about 100 kHz to about 400 kHz. As an example, if the target area is a glioblastoma (GBM), the target frequency for treating the GBM may be about 100 kHz to about 300 kHz (e.g., 50 kHz to 350 kHz, or 150 kHz to 250 kHz, or 200 kHz). For example, if the purpose of treatment is to suppress tumor cell proliferation, the target frequency may be about 100 kHz to about 400 kHz (e.g., 150 kHz to 200 kHz, or 140 kHz to 220 kHz). As another example, if the target area is an epithelial or endothelial tight junction, the target frequency may be about 50 kHz to about 190 kHz (e.g., 75 kHz to 190 kHz, or 100 kHz, or 150 kHz) to open the epithelial or endothelial tight junction. As another example, if the treatment goal is to change the permeability of cancer cell membranes (e.g., to increase the permeability of cancer cell membranes), the target frequency may be about 100 kHz to about 500 kHz (e.g., 50 kHz to 550 kHz, or 150 kHz to 350 kHz, or 250 kHz to 400 kHz). For example, if the treatment goal is to treat non-small cell lung cancer (NSCLC), the target frequency may be about 100 kHz to about 200 kHz (e.g., 150 kHz). For example, if the target area / tissue is pancreatic tissue / cancer, the target frequency may be about 100 kHz to about 200 kHz (e.g., 150 kHz). For example, if the target area / tissue is ovarian tissue / cancer, the target frequency may be about 150 kHz to about 250 kHz (e.g., 200 kHz). For example, if the target area / tissue is gastric tissue / cancer, the target frequency may be about 100 kHz to about 200 kHz (e.g., 150 kHz). Although this disclosure describes and illustrates specific frequency ranges, this disclosure contemplates any target frequency range configured to produce proven efficacy for treating a subject.

[0012] In some embodiments, the term "target intensity" may refer to a clinically approved intensity that provides a known efficacy for a desired treatment of a subject with an alternating electric field applied to the subject at the target intensity. For example, the target intensity may be a clinically approved intensity that provides a proven efficacy against tumor cell proliferation or for opening epithelial or endothelial tight junctions. For example, the target intensity may be determined from an in vitro assay.

[0013] In some embodiments, the term "target intensity" may refer to an intensity that is more effective for an intended treatment than a first intensity applied to a subject. Generally, the target intensity is higher than the first intensity. In certain embodiments, the target intensity may be within a target intensity range that corresponds to a particular target cell, tissue, and / or treatment.

[0014] In some embodiments, the term "target intensity" may refer to an intensity based on a temperature associated with an alternating electric field applied to a subject's body. For example, the target intensity may be based on the temperature of the subject's body measured at a location on the subject's body that receives the alternating electric field. For example, the target intensity may be based on the temperature of the electrodes providing the alternating electric field to the subject's body. For example, the target intensity may be the maximum intensity that the subject's body and / or the electrodes applying the alternating electric field can achieve without exceeding a temperature threshold in a range (e.g., between about 37°C and about 43°C).

[0015] In some embodiments, the term "target intensity" may refer collectively and / or alternatively to a combination of two or more of the above example target intensity.

[0016] In non-limiting embodiments, the target intensity may be about 0.5 V / cm to about 10 V / cm, or about 0.1 V / cm to about 20 V / cm. For example, if the target area is a GBM, the target intensity may be about 1 V / cm to about 5 V / cm (e.g., 1 V / cm to 3 V / cm) to treat the GBM. For example, if the treatment goal is to suppress tumor cell proliferation, the target intensity may be about 1 V / cm to about 5 V / cm (e.g., 1 V / cm to 3 V / cm). For example, if the target area is the BBB, the target intensity to open the BBB may be about 1 V / cm to about 5 V / cm (e.g., 1 V / cm to 3 V / cm). For example, if the treatment goal is to change cell membrane permeability (e.g., to increase cell membrane permeability), the target intensity may be about 1 V / cm to about 5 V / cm (e.g., 1 V / cm-3 V / cm).

[0017] Although this disclosure describes and illustrates specific frequency and intensity ranges, this disclosure contemplates any target frequency range and any target intensity range having known efficacy for treating a subject. In non-limiting embodiments, the target frequency and / or target intensity can vary depending on the target region.

[0018] In step S104, the method 100 may select a first frequency to reduce electrical sensations in the subject's body. An alternating electric field beginning with the first frequency may reduce electrical sensations in the subject as compared to an alternating electric field applied at the target frequency while the intensity ramps up to the target intensity. In one example, the first frequency may be selected by incrementally decreasing the frequency level of the alternating electric field from the initial frequency until the subject experiences electrical sensations as indicated by the subject's response. In one example, the first frequency may be selected by incrementally decreasing the frequency level of the alternating electric field from the initial frequency until the subject experiences electrical sensations as indicated by an objective measure such as detection of nerve stimulation.

[0019] The first frequency is higher than the target frequency. For example, the first frequency may be at least about 10% (e.g., at least about 20%, 30%, 50%, 75%, 100%, 150%, 200%, or 300%) higher than the target frequency. As another example, the first frequency may be at least about 10 kHz (e.g., at least about 20 kHz, 30 kHz, 50 kHz, 75 kHz, 100 kHz, 150 kHz, 200 kHz, or 300 kHz) higher than the target frequency. In one example, the first frequency may be between about 100 kHz and about 400 kHz, between about 200 kHz and about 600 kHz, between about 300 kHz and about 800 kHz, or between about 50 kHz and about 350 kHz. In one example, the first frequency may be as high as 900 kHz, 1 MHz, 10 MHz, or higher. The first frequency may vary depending on the current applied to the transducer pair. Generally, the higher the intensity, the greater the electrical sensation felt by the subject. Thus, in some embodiments, when a higher intensity (e.g., a higher current) is applied, a higher first frequency may be used to compensate for the greater degree of electrical sensation at the higher intensity. For example, in an embodiment where a current of 2 amps is applied, the first frequency may be between about 300 kHz and 400 kHz. As another example, in an embodiment where a current of 4 amps is applied, the first frequency may be between about 500 kHz and 600 kHz. In certain embodiments, the first frequency may be predetermined based on certain criteria, such as the type of treatment, the part of the body where the transducer is applied to the subject, and / or other information about the subject.

[0020] In step S106, the method 100 includes applying an AC electric field to the target area of ​​the subject's body at a first frequency while increasing the strength of the AC electric field from zero to a target strength. This indicates the beginning of a duty cycle of the AC electric field. The duty cycle of the AC electric field may begin with applying an AC electric field at the first frequency while ramping up (or "dimming up") the strength of the AC field.

[0021] In step S108, the method 100 includes changing the frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target strength. In particular, the frequency of the alternating electric field is decreased from the first frequency to the target frequency optimal for treating the recipient's body. In one example, the change in frequency may occur immediately or may take less than about 200 milliseconds, less than about 100 milliseconds, less than about 50 milliseconds, less than about 25 milliseconds, less than about 10 milliseconds, less than about 5 milliseconds, less than about 1 millisecond, or less than about 0.1 milliseconds to occur. In another example, the change in frequency may be gradual (e.g., takes at least about 0.1 milliseconds, at least about 1 millisecond, at least about 5 milliseconds, at least about 10 milliseconds, at least about 25 milliseconds, at least about 50 milliseconds, at least about 100 milliseconds, or at least about 200 milliseconds to occur and / or occurs in a gradual manner). The change in frequency may occur immediately after the alternating electric field reaches the target strength or some time after the alternating electric field reaches the target strength.

[0022] The alternating electric field may continue at the target frequency until a first time period has elapsed in step S110. The first time period may be less than about 3 seconds (eg, less than about 2 seconds, or less than about 1 second).

[0023] After the first period (S110), the method 100 may include ceasing application of the alternating electric field to complete a first duty cycle of the alternating electric field in step S112. The alternating electric field may be configured to reduce electrical sensations in the subject compared to when the alternating electric field is applied at the target frequency for the entire duty cycle.

[0024] In step S114, method 100 may include determining whether a second period of time has elapsed. The second period of time may be from about 12 hours to about 4 weeks (e.g., from about 48 hours to about 3 weeks, or from about 1 week to about 2 weeks). If the second period of time has not elapsed, method 100 may repeat steps S106-S114. That is, method 100 may include applying one or more subsequent duty cycles of the alternating electric field of steps S106-S112. In certain embodiments, method 100 may include alternately applying the duty cycles of the alternating electric field via the first transducer array pair and via the second transducer array pair.

[0025] Once the second period (S114) has elapsed, the method 100 may include switching in step S116 from applying the AC electric field to the target area of ​​the subject's body to applying a second AC electric field to the target area of ​​the subject's body at a second frequency lower than the first frequency and close to or at the target frequency throughout each duty cycle. After the second period (S114), the subject's body may become insensitive to the current density at the electrode / skin interface and the subject may no longer feel electrical sensations during the dimming-up period. In this manner, the second AC electric field having a lower (or target) frequency throughout the duty cycle may be used to provide a greater therapeutic effect that is well tolerated by the subject.

[0026] In some embodiments, the alternating electric field can be applied periodically to the target area. Cycling therapy involves applying an alternating electric field for a period of time, followed by a period of rest, and repeating this sequential administration. Cycling therapy may reduce or avoid the electric sensation or improve the efficacy of the treatment. In non-limiting embodiments, the number of cycles can be from about 1 to about 50, or from about 1 to about 24. In one example, the rest period can be from about 10 seconds to about 1 week. In certain embodiments, the treatment is stopped if the subject experiences electric sensations and / or cannot tolerate side effects associated with the alternating electric field.

[0027] When the second alternating electric field is applied, the subject's body may not feel an electrical sensation. In one example, the second alternating electric field may have a second frequency that is closer to the target frequency than the first frequency or the same as the target frequency. In one example, the second alternating electric field may have a second intensity that is closer to the target intensity than the first intensity or the same as the target intensity. In one example, the second alternating electric field may have a second frequency and a second intensity, which are the target frequency and the target intensity. In a non-limiting embodiment, the first alternating electric field may be continuously switched to the second alternating electric field without turning off the system / transducer for a waiting period. In one example, the alternating electric field may be applied with or without a pause while the parameters of the alternating electric field are changed between the first and second sets. In one example, the alternating electric field having the first frequency and the first intensity may be discontinued and the second alternating electric field may be applied to the target area of ​​the subject's body. "Discontinued" may refer to the alternating electric field being stopped so that the alternating electric field is no longer applied, or the parameters of the alternating electric field being changed to, in effect, apply a different alternating electric field.

[0028] It should be noted that the target frequency, target intensity, first frequency, first duration, and second duration may be tailored to the individual subject receiving treatment based on the target area and / or the presence or amount of electrical sensations felt by the subject.

[0029] In one example, the alternating electric field can be applied to the target area one or more times, for example, the alternating electric field can be applied to the target area once a day, twice a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every two weeks, once a month, twice a month, once every two months, or once every three months.

[0030] During the treatment period, the patient may take breaks in the middle of the treatment but still be considered to be continuing the treatment. For example, the patient may take breaks about 80% of the time undergoing AC electric field treatment. In one example, to open the BBB, the patient may wear or wear the disclosed system / device for about 3 days (e.g., about 72 hours) to open the BBB, but may take breaks during the treatment time. For tumors, the device may be used for an extended period (indefinitely) with breaks for showering, swimming, changing the array, etc., but with a goal of 80% of the treatment time with the array on. For example, for BBB applications, once a month may be useful, as long as "once a month" is at least 72 hours, but for tumors, the device may need to be used for a longer period.

[0031] As an example, an alternating electric field can be applied to a target region for a predetermined time interval. For example, the time interval may be determined based on the time for a typical subject to experience an electric sensation at a target frequency and / or intensity. For example, the time interval may be determined based on the length of time for a subject to experience an electric sensation at a target frequency and / or intensity. Such time intervals may be subjective based on the subject.

[0032] In one example, the predetermined time interval (e.g., duration of the AC electric field treatment) can be between about 1 second and about 1 month. For example, the interval may be between about 1 hour and about 12 hours, between about 12 hours and about 24 hours, between about 1 day and about 3 days, between about 3 days and about 7 days, between about 1 week and about 2 weeks, or between about 1 week and about 3 weeks.

[0033] FIG 1B illustrates an example of a method 150 for treating a target area of ​​a subject's body with an alternating electric field. The target area may be a target area similar to that described above with respect to FIG 1A. Method 150 may include step 102, similar to FIG 1A.

[0034] In step S124, the method 150 may include selecting a first frequency and a first intensity to reduce electrical sensations in the subject's body. During the dimming-up period, the first frequency and first intensity of the alternating electric field are adjusted to a target frequency and target intensity, which may reduce electrical sensations in the subject compared to initially applying the alternating electric field at the target frequency and / or target intensity. The first frequency is higher than the target frequency, as described above in step S104 of FIG. 1A.

[0035] The first intensity is lower than the target intensity. For example, the first intensity may be at least about 10% (e.g., at least about 20%, 30%, 50%, 75%, 100%, 150%, 200%, or 300%) lower than the target intensity. For example, the first intensity may be at least 0.1 V / cm (e.g., at least about 0.2 V / cm, 0.3 V / cm, 0.4 V / cm, 0.5 V / cm, 0.6 V / cm, 0.7 V / cm, 0.8 V / cm, 0.9 V / cm, 1 V / cm, 1.5 V / cm, 2 V / cm, 2.5 V / cm, 3.0 V / cm, 3.5 V / cm, or 4.5 V / cm) lower than the target intensity. In one example, the first intensity may be between about 0.1 V / cm and about 4.5 V / cm, between about 0.5 V / cm and about 3.0 V / cm, between about 0.1 V / cm and about 2.5 V / cm, In one example, the first intensity may be 0 V / cm, slightly higher than 0 V / cm, or about 0 V / cm.

[0036] In step S126, the method 150 includes applying an alternating electric field to the target region of the subject's body while increasing the strength of the alternating electric field from a first strength to a target strength and decreasing the frequency of the field from the first frequency to the target frequency. This indicates the beginning of a duty cycle of the alternating electric field. The duty cycle of the alternating electric field may begin by ramping up (or "dimming up") the strength of the alternating electric field and simultaneously decreasing the frequency of the alternating electric field while applying the alternating electric field at the first strength and first frequency.

[0037] In one example, the change in frequency may be instantaneous or may take less than about 200 milliseconds, less than about 100 milliseconds, less than about 50 milliseconds, less than about 25 milliseconds, less than about 10 milliseconds, less than about 5 milliseconds, less than about 1 millisecond, or less than about 0.1 milliseconds to occur, hi another example, the change in frequency may be gradual (e.g., takes at least about 0.1 milliseconds, at least about 1 millisecond, at least about 5 milliseconds, at least about 10 milliseconds, at least about 25 milliseconds, at least about 50 milliseconds, at least about 100 milliseconds, or at least about 200 milliseconds to occur and / or occurs in a gradual manner).

[0038] The change in frequency may correspond to an equivalent change in intensity. Alternatively, the rate of increase in intensity and the rate of decrease in frequency may be different. The rate of increase in intensity and the rate of decrease in frequency need not start and stop at the same time. In some embodiments, an overlap of the increase in intensity and decrease in frequency may occur at the beginning of the treatment (e.g., the overlap may occur at least within, e.g., the first 0.1 seconds of the treatment).

[0039] In one example, the change in intensity may be instantaneous or may take less than about 200 milliseconds, less than about 100 milliseconds, less than about 50 milliseconds, less than about 25 milliseconds, less than about 10 milliseconds, less than about 5 milliseconds, less than about 1 millisecond, or less than about 0.1 milliseconds to occur, hi another example, the change in intensity may be gradual (e.g., taking at least about 0.1 milliseconds, at least about 1 millisecond, at least about 5 milliseconds, at least about 10 milliseconds, at least about 25 milliseconds, at least about 50 milliseconds, at least about 100 milliseconds, or at least about 200 milliseconds to occur and / or occurring in a gradual manner).

[0040] After step S126, method 150 proceeds to steps S110, S112, S114, and S116 as in Figure 1A, except that the "no" branch from step S114 proceeds to step S126 in Figure 1B. Thus, in Figure 1B, method 150 may include applying one or more subsequent duty cycles of the alternating electric field in steps S126, S110, and S112.

[0041] FIG. 2 shows an example of a system with four transducers (or "transducer arrays") 200A-D. The system may be used to treat a target region of a subject's body with an alternating electric field. In one example, the target region is in the subject's brain, and the alternating electric field is provided to the subject's body via a transducer array pair positioned on the subject's head. In another example, the target region is in the subject's torso, and the alternating electric field is provided to the subject's body via a transducer array pair positioned on at least one of the chest, abdomen, or one or both thighs of the subject's body. Other transducer array placements on the subject's body are possible.

[0042] Each transducer 200A-D may include a substantially planar electrode element 202A-D disposed on and electrically and physically connected (e.g., via conductive traces 206A-D) to a substrate 204A-D. The substrate 204A-D may include, for example, fabric, foam, flexible plastic, and / or conductive medical gel. Two of the transducers (e.g., 200A and 200D) may be a first transducer pair configured to apply an alternating electric field to a target area of ​​the subject's body. The other two transducers (e.g., 200B and 200C) may be a second transducer pair similarly configured to apply an alternating electric field to a target area.

[0043] The transducers 200A-D are coupled to a voltage generator 208 (i.e., an AC voltage generator), and the system further includes a controller 210 communicatively coupled to the AC voltage generator 208. The controller 210 may include a computer including one or more processors 212 and a memory 214 accessible by the one or more processors. The memory 214 may store instructions that, when executed by the one or more processors, control the voltage generator 208 to induce an AC electric field between the transducer pairs 200A-D according to one or more voltage waveforms and / or cause the computer to perform one or more methods disclosed herein. The controller 210 may monitor operations performed by the AC voltage generator 208 (e.g., via the processor 212). One or more sensors 216 are coupled to the controller 210 and can provide measurements or other information to the controller 210.

[0044] The voltage generator 208 may provide one or more voltages to different transducer pairs (e.g., 200A / D, 200B / C) to apply an alternating electric field to the subject's body. The controller 210 may direct the voltage generator 208 to generate one or more voltages according to one or more waveforms. For example, the method described below with reference to FIG. 7 may be implemented using the voltage generator 208 and the controller 210.

[0045] In one example, the controller 210 provides signals to a first transducer pair (200A, 200D) to control a first alternating electric field according to a first waveform, such that the first alternating electric field starts at a first frequency, increases from zero intensity to a target intensity while the first alternating electric field remains at the first frequency, and after reaching the target intensity, the first alternating electric field changes from the first frequency to the target frequency, where the target frequency is lower than the first frequency. Similarly, the controller 210 may provide signals to a second transducer pair (200B, 200C) to control a second alternating electric field according to the same or a similar waveform.

[0046] FIG. 3 illustrates an example of an apparatus for use in the embodiments of the present disclosure. As an example, the apparatus 300 may be a computer for implementing certain techniques disclosed herein. As an example, the apparatus 300 may be a controller apparatus for applying an AC electric field for the embodiments of the present disclosure. For example, the apparatus 300 may be used as the controller 210 of FIG. 2. The apparatus 300 may include one or more processors 302, a memory 304, and one or more output devices 306. The memory 304 is accessible by the one or more processors 302, and the one or more processors 302 can read information from the memory 304. The memory 304 may store instructions that, when executed by the one or more processors 302, implement one or more embodiments of the present disclosure. For example, the apparatus 300 includes one or more processors and a memory accessible by the one or more processors, and the memory stores instructions that, when executed by the one or more processors, cause the apparatus 300 to perform operations for implementing one or more embodiments of the present disclosure.

[0047] In one example, based on the input 308, the one or more processors 302 may control a voltage generator to generate control signals to implement an embodiment of the invention. The input 308 may be a user input, a sensor input, or an input from another computer in communication with the apparatus 300. The output device 306 can provide an operational status of the invention, such as transducer selection, voltage generated, and other operational information. The output device 306 may provide visualization data.

[0048] 4-6 show example waveforms (400, 500, 600) that may be used to control an AC electric field and / or that are in accordance with the present disclosure. The waveforms (400, 500, 600) show patterns of an AC electric field during one or more duty cycles according to the method of FIG. 1. In one example, the waveforms (400, 500, 600) may represent the amplitude (402, 502, 602) of the strength of the AC electric field versus time (404, 504, 604) or the amplitude (402, 502, 602) of the voltage applied to a transducer pair versus time (404, 504, 604).

[0049] 4 and 5, the waveforms (400, 500) may include an initial ramp-up period (406, 506) during which the amplitude (402, 502) of the waveforms (400, 500) increases from zero (408, 508) to a target amplitude (410, 510) while the frequency of the waveforms (400, 500) is at a first frequency. The waveforms (400, 500) also include a sustained intensity period (412, 512) during which the frequency of the waveforms (400, 500) changes to a target frequency that is lower than the first frequency while the amplitude (402, 502) of the waveforms (400, 500) remains at the target amplitude (410, 510).

[0050] 4, changing the frequency of the waveform 400 (e.g., the AC electric field) from a first frequency to a target frequency may be performed instantaneously (or nearly instantaneously) at one time during application of the AC electric field. In one example, changing the frequency of the waveform 400 from the first frequency to the target frequency may be performed in a period of less than 200 milliseconds. Thus, the waveform 400 starts at a high frequency during an initial ramp-up period 406 and immediately (or nearly immediately) switches to a lower optimal treatment frequency once a sufficiently high amplitude 402 is reached.

[0051] As shown in FIG. 5, changing the frequency of the waveform 500 (e.g., the AC electric field) from a first frequency to a target frequency may be performed gradually over a period of time during application of the AC electric field (e.g., during the sustained intensity period 512). Thus, the waveform 500 may start at a high frequency during the initial ramp-up period 506 and then gradually switch to a lower optimal treatment frequency once a sufficiently high amplitude 502 is reached. As shown in FIG. 5, during the sustained intensity period 512, the frequency is gradually changed from the first frequency to the target frequency. In some embodiments, the frequency is gradually changed from the first frequency to the target frequency during the initial ramp-up period 506 or during both the initial ramp-up period 506 and the sustained intensity period 512.

[0052] An alternating electric field according to the present disclosure may be applied using a voltage generated according to an alternating voltage waveform (e.g., 400, 500). As shown in Figures 4 and 5, the change in frequency from the first frequency to the target frequency may be performed at one or more time points corresponding to zero crossings of the alternating voltage waveform (e.g., 400, 500), respectively. A "zero crossing" may be any time point (404, 504) where the amplitude (402, 502) is zero (408, 508). In one example, as shown in Figure 4, the change in frequency may be performed at a single time point corresponding to a zero crossing of the waveform 400. In another example, as shown in Figure 5, the change in frequency may be performed in stages with each shift occurring at a different zero crossing of the waveform 500. Changing the frequency at one or more zero crossings provides a smooth transition in the electric field applied to the subject's body and does not cause a shock or electric sensation to the subject's body.

[0053] 4 and 5 each show a single duty cycle of an AC electric field applied according to a waveform (e.g., the "first waveform" described above with reference to FIG. 2). FIG. 6 shows two duty cycles 620A and 620B of an AC electric field. The duty cycles 620A and 620B may be for the same transducer or for different transducers. As shown, the second duty cycle 620B follows a similar pattern of intensity (e.g., amplitude 602) and frequency as the first duty cycle 620A. The term "similar pattern" may refer to a general pattern of frequency changing to a lower frequency after an initial ramp-up period (i.e., after the amplitude 602 reaches a target level). Thus, the frequency and amplitude need not be exactly the same between the first duty cycle 620A and the second duty cycle 620B, as long as they follow the same general pattern. In some embodiments, as shown in FIG. 6, duty cycles 620A, 620B may be applied according to the same waveform 600 (i.e., the first frequency, the target frequency, and the time over which the frequency is changed are the same for both duty cycles).

[0054] FIG. 7 illustrates an example method 700 for treating a target region of a subject's body with an alternating electric field. Method 700 may be implemented using voltage generator 208 and controller 210 of FIG. 2. Method 700 may include, at step S702, generating and providing a first voltage to a first transducer pair, the first voltage being generated according to a first waveform (e.g., an alternating voltage waveform). The first waveform may be similar to the waveforms shown in FIGS. 4-6. That is, the first waveform includes an initial ramp-up period in which the amplitude increases from zero to a target amplitude while the frequency is at the first frequency, and then the frequency changes to a target frequency that is lower than the first frequency while the amplitude remains at the target amplitude.

[0055] In step S704, the method 700 may include generating and supplying a second voltage to the second transducer pair, the second voltage being generated according to a first waveform (e.g., an alternating voltage waveform). In step S706, the method 700 may include alternating between supplying the first voltage to the first transducer pair and supplying the second voltage to the second transducer pair. Step S706 may be repeated until a second period of time has elapsed in step S708. After the second period of time has elapsed, the method 700 proceeds to step S710. The second period of time (S708) in FIG. 7 may be the same as the second period of time (S114) in FIG. 1.

[0056] In step S710, the method 700 may include generating and providing a third voltage to the first transducer pair, the third voltage being generated according to a second waveform (e.g., an alternating voltage waveform). The second waveform may include an initial ramp-up period during which the amplitude of the second waveform increases from zero to a target amplitude while the frequency of the second waveform is at a frequency lower than the first frequency. The frequency lower than the first frequency may be equal to the target frequency. The second waveform may include a sustained intensity period during which the frequency of the second waveform is at the target frequency and the amplitude remains at the target amplitude.

[0057] FIG. 8 illustrates an example of a method 800 for delivering an alternating electric field to a subject's body. In the method 800, step S802 includes applying a target alternating electric field to the subject's body to treat the subject's body. The target alternating electric field has a target frequency and a target intensity, the target frequency and the target intensity having a known efficacy for treating the subject's body. In step S804, the method 800 includes receiving a response from the subject regarding the electric sensation. The response from the subject may include feedback 806 from the subject, a subject measurement 808 (e.g., a sensor measurement), or both. In step S810, the method 800 includes determining whether the response indicates that the subject's body is experiencing an electric sensation from the target alternating electric field. In step S810, if the response indicates that the subject's body is not experiencing an electric sensation, the method 800 proceeds to step S812 and continues applying the target alternating electric field to the subject's body to treat the subject's body.

[0058] In step S810, if the response indicates that the subject's body is experiencing electrical sensations, the method 800 proceeds to step S814, where a first frequency of the alternating electric field is selected to reduce the electrical sensations experienced by the subject's body. The first frequency is higher than the target frequency. In step S816, the method 800 includes applying an alternating electric field to the subject's body, the alternating electric field having a first frequency and ramping up in intensity from zero to a target intensity and changing to the target frequency upon reaching the target intensity. In the method 800 of FIG. 8, the process of reducing or eliminating electrical sensations for individual subjects can be tailored, since not all subjects will experience electrical sensations from the target alternating electric field.

[0059] FIG. 9 illustrates an example of a method 900 for delivering an alternating electric field to a subject's body as the temperature increases. In the method 900, the strength and / or frequency of the alternating electric field may be modified in response to changes in temperature. In step S902, after applying an alternating electric field of a first frequency while increasing the strength of the alternating electric field from zero to a target strength in step S106, the temperature at which the alternating electric field is applied may be monitored. For example, the temperature of the transducer applying the alternating electric field, the temperature of the target area, and / or the temperature of the subject's skin at or near where the alternating electric field is applied may be monitored. The sensor for monitoring the temperature may be part of the transducer or may be separate from the transducer.

[0060] In step S904, if the measured temperature is equal to or less than the predetermined threshold, the flow proceeds to step S902 and the loop is repeated. The alternating electric field of the first frequency and first intensity may be continuously applied to the subject's body. In one example, the predetermined threshold temperature of the transducer may be from about 37°C to about 39°C, or from about 38.5°C to about 39°C, or from about 37°C to about 41.5°C. On the other hand, if the measured temperature is higher than the predetermined threshold, the flow proceeds to step S906.

[0061] In step S906, a second intensity can be selected. In a non-limiting embodiment, the second intensity can be lower than the first intensity. For example, the second intensity can be at least 10% lower than the target intensity than the first intensity (e.g., at least about 20%, 30%, 40%, 50%, or 60%). For example, the second intensity can be at least 0.1 V / cm lower than the target intensity than the first intensity (e.g., at least about 0.2 V / cm, 0.3 V / cm, 0.4 V / cm, 0.5 V / cm, 0.6 V / cm, 0.7 V / cm, 0.8 V / cm, 0.9 V / cm, 1 V / cm, or 2 V / cm lower). For example, the second intensity can be in the range of about 0.1 V / cm to about 20 V / cm, such as about 0.5 V / cm to about 10 V / cm.

[0062] In step S908, after selecting the second intensity, a second frequency can be selected. In one example, the second frequency can be lower than the first frequency and closer to or equal to the target frequency to compensate for the reduced efficacy caused by reducing the intensity. For example, the second frequency can be at least 10% (e.g., at least about 20%, 30%, 40%, 50%, or 60%) lower than the first frequency without falling below the target frequency. In one example, the second frequency can be at least about 10 kHz (e.g., at least about 20 kHz, 30 kHz, 50 kHz, 75 kHz, 100 kHz, 150 kHz, 200 kHz, or 300 kHz) lower than the target frequency without falling below the target frequency. In one example, the second frequency can be based on the range of the first frequency.

[0063] In step S910, applying an alternating electric field of a first frequency and a first intensity to the subject's body may be switched to applying a second alternating electric field of a second frequency and a second intensity to the subject's body. In one example, the second alternating electric field may provide similar efficacy to the alternating electric field of the first frequency and the first intensity. In another example, the second alternating electric field may provide better efficacy than the alternating electric field of the first frequency and the first intensity. In a non-limiting embodiment, the alternating electric fields may be generated from the same transducer or different transducers. In a non-limiting embodiment, the first alternating electric field may be switched to the second alternating electric field continuously without turning off the system / transducer or having a waiting period. Experimental Results

[0064] Figure 10 shows an example of a cytotoxicity analysis showing the effect of magnetic field strength on the survival of different types of cancer. Cytotoxicity analysis was performed by counting the number of cells (% of control) after applying TT fields of the disclosed frequencies for 72 hours to cell lines of different types of cancer: glioblastoma (U373, U87-MG, and A172; 200 kHz), lung (NCI-H520 and A549; 150 kHz), mesothelioma (MSTO-211 and H2052; 150 kHz), gastric (KATOIII and AGS; 150 kHz), ovarian (OVCAR-3, Caov-3, and A2780; 200 kHz), and cervical (HeLa and Ca-Ski; 150 kHz).

[0065] Figures 11A-11C show an experiment in which a rat's sciatic nerve bundle was stimulated with an alternating electric field. Figure 11A shows five graphs showing the nerve response after treatment with increasing voltages (4,000 mV, 6,000 mV, 8,000 mV, 10,000 mV, 12,500 mV). As the voltage increased, the nerve response increased. Figure 11B shows a graph plotting the stimulation amplitude (mVp-p) versus the response amplitude (mV) (blue circle, "A") and response width (msec) (red circle, "B"). The response width is a proxy for a measure of velocity along the nerve bundle. As the response amplitude increased, more nerves in the nerve bundle were activated.

[0066] FIG. 11C shows graphs illustrating experiments in which amplitude, frequency, and both amplitude and frequency were dimmed for 100 ms. Human testing was performed with an OPTUNE® field generator using a 100 ms dimming up cycle. At this time, the frequency was reduced from 300 Hz to 100 Hz. When the amplitude was increased in 1 ms increments, the electrosensory threshold was 0.8 A. When both amplitude and frequency were dimmed up, the electrosensory threshold was approximately 1.4-1.5 A.

[0067] The AM graph shows the neural response to a stimulus whose amplitude was increased from 500mV to 12.5 volts for 100 microseconds. The FM graph shows a similar response to a stimulus whose frequency was decreased from 400Hz to 200Hz for 100 microseconds. The AM+FM graph shows that there was no response to a stimulus whose amplitude was increased and whose frequency was simultaneously decreased. The bottom three graphs show repeats of the experiment shown in the top three graphs, which produced fairly similar results. The graph on the right shows the measured response to each treatment. Increasing both amplitude and frequency does not produce any action potentials.

[0068] The present invention includes other exemplary embodiments ("embodiments"), such as:

[0069] Embodiment 1. A method of treating a target area of ​​a subject's body with an alternating electric field, comprising the steps of applying an alternating electric field to a target area of ​​the subject's body at a first frequency while increasing the intensity of the alternating electric field from zero to a target intensity, and changing the frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target intensity, wherein the target frequency and target intensity have known efficacy for treating the target area of ​​the subject's body with an alternating electric field, and wherein the first frequency is higher than the target frequency.

[0070] Embodiment 2. The method according to embodiment 1, wherein the change in frequency of the AC electric field is performed instantaneously at one time during application of the AC electric field.

[0071] Embodiment 3. The method of embodiment 2, wherein an alternating electric field is applied using a voltage generated according to an alternating voltage waveform, and the change in frequency of the alternating electric field is performed at a time corresponding to a zero crossing of the alternating voltage waveform.

[0072] Embodiment 4. The method of embodiment 1, wherein the change in frequency of the alternating electric field is performed within a period of less than 200 ms.

[0073] Embodiment 5. The method of embodiment 4, wherein an alternating electric field is applied using a voltage generated according to an alternating voltage waveform, and a change in frequency of the alternating electric field is performed at a time corresponding to a zero crossing of the alternating voltage waveform.

[0074] Embodiment 6. The method of embodiment 1, wherein the change in frequency of the alternating electric field is performed gradually over a period of time during application of the alternating electric field.

[0075] Embodiment 7. A method as described in embodiment 6, wherein the AC electric field is applied using a voltage generated according to an AC voltage waveform, and the change in frequency of the AC electric field is performed in steps, with each shift occurring at a different zero crossing of the AC voltage waveform.

[0076] Embodiment 8. The method of claim 1, further comprising the steps of ceasing application of the alternating electric field after the first period of time to complete a first duty cycle of the alternating electric field, and applying one or more subsequent duty cycles of the alternating electric field, each subsequent duty cycle following the same pattern of intensity and frequency as the first duty cycle.

[0077] Embodiment 9. The method of embodiment 8, wherein the alternating electric field is applied using a voltage generated according to an alternating voltage waveform, and each duty cycle of the alternating electric field is applied according to the same alternating voltage waveform.

[0078] Embodiment 10. The method of embodiment 8, further comprising the step of switching from applying an alternating electric field to the target area of ​​the subject's body at a second frequency that is lower than the first frequency and close to or at the target frequency to applying a second alternating electric field to the target area of ​​the subject's body throughout each duty cycle after a second period of time has elapsed.

[0079] Embodiment 11. The method of embodiment 10, wherein the second period of time is from about 12 hours to about 4 weeks.

[0080] Embodiment 12 The method of embodiment 8, wherein the first period of time is less than 3 seconds.

[0081] Embodiment 13. The method according to embodiment 1, wherein the target frequency is between about 50 kHz and about 1 MHz.

[0082] Embodiment 14. The method of embodiment 1, wherein the target frequency is between about 50 kHz and about 500 kHz.

[0083] Embodiment 15. The method of embodiment 1, wherein the first frequency is at least about 10% higher than the target frequency.

[0084] Embodiment 16. The method of embodiment 1, wherein the first frequency is at least about 10 kHz higher than the target frequency.

[0085] Embodiment 17. The method of embodiment 1, wherein the target intensity is between about 0.1 V / cm and about 10.0 V / cm.

[0086] Embodiment 18. The method of embodiment 1, wherein the alternating electric field is configured to reduce electrical sensation in the subject compared to when the alternating electric field is applied at the target frequency over its entire duty cycle.

[0087] Embodiment 19. The method of embodiment 1, wherein the target region is a glioblastoma (GBM) and the target frequency is from about 100 kHz to about 300 kHz.

[0088] Embodiment 20. The method of embodiment 1, wherein the target area is an endothelial or epithelial tight junction and the target frequency is from about 50 kHz to about 190 kHz.

[0089] Embodiment 21. The method of embodiment 1, wherein an alternating electric field is delivered to the subject's body to change the permeability of cancer cell membranes, and the target frequency is between about 100 kHz and about 500 kHz.

[0090] Embodiment 22. A method as described in embodiment 1, wherein the alternating electric field is delivered to the subject's body via a transducer array pair positioned on the head of the subject's body, and the target region is within the subject's brain.

[0091] Embodiment 23. A method as described in embodiment 1, wherein the alternating electric field is delivered to the subject's body via a transducer array pair positioned in at least one of the chest, abdomen, or one or both thighs of the subject's body, and the target area is in the subject's torso.

[0092] Embodiment 24. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to the target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and capable of supplying a first voltage to the first transducer pair to apply the first alternating electric field; and a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory storing instructions that, when executed by the one or more processors, cause the controller to direct the voltage generator to generate a first voltage according to a first waveform, the first waveform having an initial ramp-up period during which an amplitude of the first waveform increases from zero to a target amplitude while the frequency of the first waveform is at a first frequency, and a sustained intensity period during which the frequency of the first waveform changes to a target frequency lower than the first frequency while the frequency of the first waveform remains at the target amplitude.

[0093] Embodiment 25. The apparatus of embodiment 24, wherein the frequency of the first waveform is changed instantaneously from the first frequency to the target frequency.

[0094] Embodiment 26. The apparatus of embodiment 25, wherein the frequency of the first waveform is varied at the zero crossings of the first waveform.

[0095] Embodiment 27. The device of embodiment 24, wherein the frequency of the first waveform is changed from the first frequency to the target frequency in less than 200 milliseconds.

[0096] Embodiment 28. The apparatus of embodiment 27, wherein the frequency of the first waveform is varied at the zero crossings of the first waveform.

[0097] Embodiment 29. The device of embodiment 24, wherein the frequency of the first waveform is gradually changed from the first frequency to the target frequency.

[0098] Embodiment 30. The apparatus of embodiment 29, wherein the frequency of the first waveform is changed in steps, with each shift occurring at a different zero crossing of the first waveform.

[0099] Embodiment 31. The device of embodiment 24, wherein the voltage generator is coupled to the first transducer pair and is capable of supplying a third voltage to the first transducer pair to apply a third alternating electric field to a target area of ​​the subject's body, and when the instructions are executed by the one or more processors, the controller instructs the voltage generator to generate the third voltage according to a second waveform, the second waveform having an initial ramp-up period during which the amplitude of the second waveform increases from zero to a target amplitude while the frequency of the second waveform is a lower frequency than the first frequency, and a sustained intensity period during which the frequency of the second waveform is at the target frequency while the amplitude of the second waveform remains at the target frequency.

[0100] Embodiment 32. The apparatus of embodiment 31, wherein the second waveform is a target frequency during the initial ramp-up period.

[0101] Embodiment 33. The device of embodiment 24, further comprising a second transducer pair configured to apply a second alternating electric field to a target area of ​​the subject's body, wherein the voltage generator is coupled to the second transducer pair and is capable of supplying a second voltage to the second transducer pair to apply the second alternating electric field, and when the instructions are executed by the one or more processors, the controller instructs the voltage generator to generate the second voltage according to the first waveform.

[0102] Embodiment 34. The apparatus described in embodiment 33, wherein when the instructions are executed by one or more processors, the controller instructs the voltage generator to alternate at regular intervals between supplying a first voltage to a first transducer pair and supplying a second voltage to a second transducer pair.

[0103] Embodiment 35. A method of delivering an alternating electric field to a subject's body, comprising the steps of: applying a target alternating electric field to the subject's body to treat the subject's body, the target alternating electric field having a target frequency and a target intensity, the target frequency and target intensity having a known efficacy for treating the subject's body; receiving a response from the subject regarding electrical sensations, the response from the subject including at least one of subject feedback or subject measurements; if the response indicates that the subject's body experiences electrical sensations from the target alternating electric field, selecting an alternating electric field of a first frequency higher than the target frequency to reduce the electrical sensations experienced by the subject's body from the target alternating electric field; applying an alternating electric field to the subject's body, the alternating electric field of the first frequency ramping up from zero intensity to a target intensity and changing to the target frequency once the target intensity is reached.

[0104] Embodiment 36. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a transducer pair configured to apply a first alternating electric field to the target area of ​​the subject's body; and a controller implemented with at least one processor that provides signals to the transducer pair to control the first alternating electric field, whereby the first alternating electric field begins at a first frequency, the first alternating electric field increases from zero intensity to a target intensity while remaining at the first frequency, and upon reaching the target intensity, the first alternating electric field changes from the first frequency to the target frequency, the target frequency being lower than the first frequency.

[0105] Embodiment 37. A method of treating a target area of ​​a subject's body with an alternating electric field, comprising the steps of applying an alternating electric field to a target area of ​​the subject's body at a first frequency while increasing a current of the alternating electric field from zero to a target current, and changing the frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target current, wherein the target frequency and target current have known efficacy for treating the target area of ​​the subject's body with an alternating electric field, and the first frequency is higher than the target frequency.

[0106] Exemplary embodiment 38. A method of delivering an alternating current electric field to a subject's body, the method comprising: applying a target alternating current electric field to the subject's body to treat the subject's body, the target alternating current electric field having a target frequency and a target intensity, the target frequency and the target intensity having a known efficacy for treating the subject's body; receiving feedback regarding an electrical sensation experienced by the subject's body from applying the target alternating current electric field; and if the subject's body experiences an electrical sensation from the target alternating current electric field at the target frequency and target intensity, selecting at least one of a first frequency or a first intensity of the alternating current electric field to reduce the electrical sensation experienced by the subject's body from the target alternating current electric field, the first frequency being higher than the target frequency and the first intensity being lower than the target intensity; and applying a first alternating current electric field to the subject's body to treat the subject's body, the first alternating current electric field having at least one of a first frequency or a first intensity.

[0107] Exemplary embodiment 39. The method of exemplary embodiment 38, wherein the first frequency is at least about 10% higher than the target frequency and the first intensity is at least about 10% lower than the target intensity.

[0108] Exemplary embodiment 40. The method of embodiment 39, further comprising the step of ceasing application of the first alternating electric field to the subject's body after a certain time interval, and applying a second alternating electric field to the subject's body at at least one of a second frequency close to the target frequency, or a second intensity close to the target intensity, or a second intensity close to the target intensity.

[0109] Exemplary embodiment 41. A method of delivering an alternating electric field to a subject's body, comprising applying an alternating electric field to a target area of ​​the subject's body, the alternating electric field having a first frequency and a first intensity, and for a target frequency and target intensity of the alternating electric field, the subject experiences an electric sensation, the first intensity being a target intensity, and the first frequency being greater than the target frequency.

[0110] Exemplary embodiment 42. The method of exemplary embodiment 41, wherein the alternating electric field is configured to reduce electrical sensation in the subject compared to when the alternating electric field is applied at a target frequency and a target strength.

[0111] Exemplary embodiment 43. The method of embodiment 41, further comprising the steps of determining a first intensity of the alternating electric field prior to applying the alternating electric field, and identifying a first frequency of the alternating electric field based on a response from the subject regarding the electrical sensation experienced by the subject after the first intensity has been determined, the first frequency being a frequency of the alternating electric field that reduces the electrical sensation of the subject at the first intensity.

[0112] Exemplary embodiment 44. The method of exemplary embodiment 43, wherein the step of identifying a first frequency of the alternating electric field includes incrementally decreasing a frequency level of the alternating electric field from an initial frequency until a response from the subject indicates that the subject has experienced an electrical sensation.

[0113] Exemplary embodiment 45. The method of exemplary embodiment 43, wherein the response from the subject includes at least one of feedback from the subject or a measurement of the subject.

[0114] Exemplary Embodiment 46 The method of exemplary embodiment 41, wherein the target frequency is between about 100 kHz and about 400 kHz and the target strength is between about 0.5 V / cm and about 10.0 V / cm.

[0115] Exemplary embodiment 47. The method of embodiment 41, further comprising the steps of: determining a second strength of the alternating electric field when a temperature to which the alternating electric field is applied reaches a threshold temperature, the second strength being lower than the first strength; identifying a second frequency of the alternating electric field, the second frequency being lower than the first frequency; and switching from applying the alternating electric field to applying another alternating electric field having a second strength and a second frequency.

[0116] Exemplary embodiment 48. The method of exemplary embodiment 41, further comprising the step of switching, after a period of time, from applying an alternating electric field to the target area of ​​the subject's body to applying a second alternating electric field to the target area of ​​the subject's body at a lower frequency that is close to or the same as the target frequency.

[0117] Exemplary embodiment 49. A method as described in exemplary embodiment 48, wherein the interval between application of an AC electric field of a first frequency and application of a second AC electric field of a lower frequency is from about 12 hours to about 4 weeks (e.g., from about 12 hours to about 2 weeks).

[0118] Exemplary Embodiment 50 The method of exemplary embodiment 41, wherein the first frequency is at least about 10% higher than the target frequency.

[0119] Exemplary Embodiment 51 The method of exemplary embodiment 41, wherein the first frequency is at least about 10 kHz higher than the target frequency.

[0120] Exemplary embodiment 52. The method of exemplary embodiment 41, wherein the target area is a glioblastoma (GBM), the target frequency is between about 50 kHz and about 350 kHz, and the target intensity is between about 1 V / cm and about 5 V / cm.

[0121] Exemplary embodiment 53. The method of exemplary embodiment 41, wherein the target region is the blood-brain barrier (BBB), the target frequency is between about 50 kHz and about 190 kHz, and the target intensity is between about 1 V / cm and about 5 V / cm.

[0122] Exemplary embodiment 54. A method according to exemplary embodiment 41, wherein an alternating electric field is delivered to the subject's body to alter cell membrane permeability, the target frequency being between about 50 kHz and about 550 kHz, and the target strength being between about 0.5 V / cm and about 20 V / cm.

[0123] Exemplary embodiment 55. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a transducer configured to apply an alternating electric field to a target area of ​​the subject's body; and a controller implemented with at least one processor and providing a signal for the alternating electric field to the transducer, wherein the alternating electric field has a first frequency and a target intensity, and for the frequency and intensity having a known efficacy for treating the target area of ​​the subject's body with the alternating electric field, the subject experiences an electric sensation, the first intensity is an intensity having a known efficacy, and the first frequency is higher than the frequency having the known efficacy.

[0124] Exemplary embodiment 56. The apparatus of exemplary embodiment 55, wherein the controller comprises one or more processors and a memory storing processor-executable instructions that, when executed by the one or more processors, cause the controller to determine a first intensity of the alternating electric field prior to applying the alternating electric field, and to identify a first frequency of the alternating electric field based on a response from the subject regarding the electrical sensation experienced by the subject after the first intensity has been determined, the first frequency being a frequency of the alternating electric field that reduces the electrical sensation of the subject at the first intensity.

[0125] Exemplary embodiment 57. The apparatus of exemplary embodiment 56, wherein the response from the subject includes at least one of feedback from the subject or a measurement of the subject.

[0126] Exemplary embodiment 58. The device of exemplary embodiment 56, wherein the memory further stores processor-executable instructions that, when executed by the one or more processors, cause the device to incrementally decrease the frequency level of the alternating electric field from an initial frequency until feedback from the subject indicates that the subject is experiencing an electrical sensation.

[0127] Exemplary embodiment 59. The device of exemplary embodiment 56, wherein the memory stores processor-executable instructions that, when executed by the one or more processors, cause the device to reduce the frequency level of the alternating electric field in stages from an initial frequency until a measurement of the subject's nerve stimulation indicates that the subject is experiencing an electrical sensation.

[0128] Exemplary Embodiment 60. The apparatus of exemplary embodiment 55, wherein the controller includes one or more processors and a memory storing processor-executable instructions, which when executed by the one or more processors, cause the controller to determine a second strength of the alternating electric field that is lower than the first strength, identify a second frequency of the alternating electric field that is lower than the first frequency, and apply the alternating electric field at the second strength and second frequency when a temperature to which the alternating electric field is applied reaches a threshold temperature.

[0129] Exemplary embodiment 61. The device of exemplary embodiment 55, wherein the alternating electric field applies a tumor treatment electric field to open the subject's blood-brain barrier, disrupt the subject's cell membranes, or change the permeability of the subject's cell membranes.

[0130] Exemplary embodiment 62. An apparatus for calibrating delivery of an alternating electric field to a subject's body, comprising: one or more processors; and a memory storing processor-executable instructions, wherein when the instructions are executed by the one or more processors, the apparatus determines a target frequency and a target strength for applying the alternating electric field to treat a target area of ​​the subject's body, the target frequency and the target strength having known efficacy for treating the subject's body; selects a first frequency for applying the alternating electric field to treat the target area of ​​the subject's body, the first frequency selected to reduce electrical sensations experienced by the subject's body at the target strength, the first frequency being higher than the target frequency.

[0131] Exemplary embodiment 63. The apparatus of exemplary embodiment 62, wherein the target frequency and target intensity have known efficacy for treating tumors, opening the blood-brain barrier of a subject, disrupting cell membranes of a subject, or altering the permeability of cell membranes of a subject.

[0132] Exemplary embodiment 64. A method of delivering an alternating current electric field to a subject's body, comprising the steps of: applying a target alternating current electric field to the subject's body to treat the subject's body, the target alternating current electric field having a target frequency and a target intensity, the target frequency and target intensity having a known efficacy for treating the subject's body; receiving a response from the subject regarding electrical sensations, the response from the subject including at least one of subject feedback or subject measurements; if the response indicates that the subject's body experiences electrical sensations from the target alternating current electric field at the target frequency and target intensity, selecting a first frequency of the alternating current electric field to reduce the electrical sensations experienced by the subject's body from the target alternating current electric field, the first frequency being higher than the target frequency; and applying a first alternating current electric field to the subject's body to treat the subject's body, the first alternating current electric field having a first frequency and a target intensity.

[0133] Exemplary Embodiment 65 The method of exemplary embodiment 64, wherein the first frequency is at least about 10% higher than the target frequency.

[0134] Exemplary embodiment 66. The method of exemplary embodiment 64, further comprising the step of switching from applying a first alternating electric field to the subject's body after a period of time to applying a second alternating electric field to the subject's body at a second frequency that is close to or the same as the target frequency.

[0135] Exemplary embodiment 67. A method of treating a target area of ​​a subject's body with an alternating electric field, comprising the steps of applying an alternating electric field to a target area of ​​the subject's body at a frequency and an intensity, where the frequency is a first frequency and the intensity is a first intensity, and increasing the intensity from the first intensity to a target intensity while decreasing the frequency from the first frequency to a target frequency, where the target frequency and the target intensity have a known efficacy for treating the target area of ​​the subject's body with an alternating electric field, where the first frequency is higher than the target frequency and the first intensity is lower than the target intensity.

[0136] Exemplary embodiment 68. The method of embodiment 67, wherein during application of the alternating electric field, the frequency is decreased instantaneously from the first frequency to the target frequency in one go.

[0137] Exemplary Embodiment 69 The method of embodiment 67, wherein increasing the strength while decreasing the first frequency of the alternating electric field is performed for a period of less than 200 milliseconds.

[0138] Exemplary embodiment 70. The method of embodiment 67, wherein increasing the strength while decreasing the first frequency of the alternating electric field is performed gradually over a period of time during application of the alternating electric field.

[0139] Exemplary embodiment 71. The method of claim 67, further comprising ceasing application of the alternating electric field after the first period of time to complete a first duty cycle of the alternating electric field, and applying one or more subsequent duty cycles of the alternating electric field, each subsequent duty cycle following the same pattern of intensity and frequency as the first duty cycle.

[0140] Exemplary embodiment 72. The method of embodiment 71, wherein the alternating electric field is applied using a voltage generated according to an alternating voltage waveform, and each duty cycle of the alternating electric field is applied according to the same alternating voltage waveform.

[0141] Exemplary embodiment 73. The method of embodiment 71, further comprising the step of switching from applying an alternating electric field to the target area of ​​the subject's body at each duty cycle after the second period of time has elapsed to applying a second alternating electric field to the target area of ​​the subject's body at a second frequency that is lower than the first frequency and close to or at the target frequency.

[0142] Exemplary Embodiment 74 The method of embodiment 73, wherein the second period of time is from about 12 hours to about 4 weeks.

[0143] Exemplary embodiment 75 The method of embodiment 71, wherein the first period of time is less than 3 seconds.

[0144] Exemplary Embodiment 76 The method of embodiment 67, wherein the target frequency is between about 50 kHz and about 1 MHz.

[0145] Exemplary Embodiment 77 The method of embodiment 67, wherein the target frequency is between about 50 kHz and about 500 kHz.

[0146] Exemplary Embodiment 78 The method of embodiment 67, wherein the first frequency is at least about 10% higher than the target frequency.

[0147] Exemplary Embodiment 79 The method of embodiment 67, wherein the first frequency is at least about 10 kHz higher than the target frequency.

[0148] Exemplary Embodiment 80 The method of embodiment 67, wherein the target intensity is between about 0.1 V / cm and about 10.0 V / cm.

[0149] Exemplary embodiment 81. The method of embodiment 67, wherein the alternating electric field is configured to reduce electrical sensation in the subject compared to when the alternating electric field is applied at the target frequency over its entire duty cycle.

[0150] Exemplary embodiment 82. The method of embodiment 67, wherein the target region is a glioblastoma (GBM) and the target frequency is between about 100 kHz and about 300 kHz.

[0151] Exemplary embodiment 83. The method of embodiment 67, wherein the target area is an endothelial or epithelial tight junction and the target frequency is between about 50 kHz and about 190 kHz.

[0152] Exemplary embodiment 84. The method of embodiment 67, wherein an alternating electric field is delivered to the subject's body to alter the permeability of cancer cell membranes, and the target frequency is between about 100 kHz and about 500 kHz.

[0153] Exemplary embodiment 85. A method according to embodiment 67, wherein the alternating electric field is delivered to the subject's body via a pair of transducer arrays positioned on the head of the subject's body, and the target region is within the subject's brain.

[0154] Exemplary embodiment 86. A method according to embodiment 67, wherein the alternating electric field is delivered to the subject's body via a transducer array pair positioned in at least one of the chest, abdomen, or one or both thighs of the subject's body, and the target area is within the subject's torso.

[0155] Exemplary embodiment 87. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to the target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and capable of supplying a first voltage to the first transducer pair to apply the first alternating electric field; and a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory storing instructions that, when executed by the one or more processors, cause the controller to perform operations including: applying an alternating electric field at a first frequency to the target area of ​​the subject's body while increasing a strength of the alternating electric field from zero to a target strength; and varying a frequency of the alternating electric field from the first frequency to the target frequency while maintaining the alternating electric field at the target strength, wherein the target frequency and the target strength have a known efficacy for treating the target area of ​​the subject's body with the alternating electric field, and the first frequency is higher than the target frequency.

[0156] Exemplary embodiment 88. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to the target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and capable of supplying a first voltage to the first transducer pair to apply the first alternating electric field; and a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory storing instructions that, when executed by the one or more processors, cause the controller to perform operations including: applying an alternating electric field to the target area of ​​the subject's body at a frequency and an intensity, the frequency being a first frequency and the intensity being a first intensity; and increasing the intensity from the first intensity to the target intensity while decreasing the frequency from the first frequency to a target frequency, the target frequency and the target intensity having a known efficacy for treating the target area of ​​the subject's body with the alternating electric field, the first frequency being higher than the target frequency and the first intensity being lower than the target intensity.

[0157] Embodiments shown under any heading or in any portion of the disclosure may be combined with embodiments shown under the same or any other heading or in any other portion of the disclosure, unless otherwise indicated herein or clearly contradicted by context.

[0158] Numerous modifications, variations, and variations can be made to the described embodiments without departing from the scope of the invention as defined in the claims. It is intended that the present invention not be limited to the described embodiments, but rather have its full scope as defined by the language of the following claims and equivalents thereof.

Claims

1. 1. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to a target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and operable to supply a first voltage to the first transducer pair to apply the first alternating electric field; a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory, when executed by the one or more processors, applying an alternating electric field to a target area of ​​the subject's body at a first frequency while increasing the intensity of the alternating electric field from zero to a target intensity; changing a frequency of the AC electric field from a first frequency to a target frequency while maintaining the AC electric field at a target strength; the target frequency and the target intensity have a known efficacy for treating a target area of ​​the subject's body with the alternating electric field; The first frequency is greater than the target frequency.

2. The AC electric field is a voltage generated according to an alternating voltage waveform; The apparatus of claim 1 , wherein the variation in frequency of the alternating electric field is performed at times corresponding to zero crossings of the alternating voltage waveform.

3. The apparatus of claim 1 , wherein the change in frequency of the alternating electric field is performed gradually over a period of time during application of the alternating electric field.

4. The AC electric field is a voltage generated according to an alternating voltage waveform; The apparatus of claim 3 , wherein the change in frequency of the AC electric field is performed in steps, with each shift occurring at a different zero crossing of the AC voltage waveform.

5. moreover, ceasing application of the alternating electric field after a first period of time to complete a first duty cycle of the alternating electric field; applying one or more subsequent duty cycles of the alternating electric field, each subsequent duty cycle following a similar pattern of intensity and frequency as a first duty cycle.

6. 1. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to a target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and operable to supply a first voltage to the first transducer pair to apply the first alternating electric field; a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory storing instructions that, when executed by the one or more processors, cause the controller to direct the voltage generator to generate a first voltage according to a first waveform; the first waveform includes an initial ramp-up period during which the amplitude of the first waveform increases from zero to a target amplitude while the frequency of the first waveform is at a first frequency; and a sustained intensity period during which the frequency of the first waveform is changed to a target frequency that is lower than the first frequency while the amplitude of the first waveform remains at the target amplitude.

7. 7. The apparatus of claim 6, wherein the frequency of the first waveform changes instantaneously from the first frequency to the target frequency.

8. The apparatus of claim 7 , wherein the frequency of the first waveform changes at zero crossings of the first waveform.

9. 7. The apparatus of claim 6, wherein the frequency of the first waveform changes from the first frequency to the target frequency in less than 200 milliseconds.

10. 10. The apparatus of claim 9, wherein the frequency of the first waveform changes at zero crossings of the first waveform.

11. 7. The apparatus of claim 6, wherein the frequency of the first waveform is gradually changed from the first frequency to a target frequency.

12. 12. The apparatus of claim 11, wherein the frequency of the first waveform is changed in steps, each shift occurring at a different zero crossing of the first waveform.

13. 7. The apparatus of claim 6, wherein the target frequency is from about 50 kHz to about 500 kHz and the target intensity is from about 0.1 V / cm to about 10.0 V / cm.

14. The apparatus of claim 6 , wherein the first frequency is at least about 10 kHz higher than the target frequency.

15. 1. An apparatus for treating a target area of ​​a subject's body with an alternating electric field, comprising: a first transducer pair configured to apply a first alternating electric field to a target area of ​​the subject's body; a voltage generator coupled to the first transducer pair and operable to supply a first voltage to the first transducer pair to apply the first alternating electric field; a controller coupled to the voltage generator, the controller including one or more processors and a memory accessible by the one or more processors, the memory, when executed by the one or more processors, applying an alternating electric field at a frequency and an intensity to a target area of ​​the subject's body, the frequency being a first frequency and the intensity being a first intensity; decreasing the intensity from a first intensity to a target intensity while increasing the frequency from a first frequency to a target frequency; the target frequency and the target intensity have a known efficacy for treating a target area of ​​the subject's body with an alternating electric field; the first frequency is higher than the target frequency; The first intensity is less than a target intensity.

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