Apparatus for inducing an alternating electric field in a target region within a subject's body

Abstract

By applying a series of pulses of alternating current between electrode elements located on or within the subject's body during each of a plurality of first time intervals, an alternating electric field (e.g., a TTField) can be induced in a target region within the subject's body. Following each first time interval, the electrode elements are allowed to cool. While the pulses of alternating current in any given first time interval have a magnitude that would cause overheating if the series of pulses were allowed to continue for an hour, each series of pulses does not actually continue for an hour. Rather, each series of pulses is short enough to avoid overheating. The interlacing of cooling periods between pulse periods enables the use of higher current pulses, and the use of these higher current pulses can advantageously increase treatment efficacy.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application 63 / 325,230, filed March 30, 2022, which is incorporated herein by reference in its entirety. Background Technology

[0003] A tumor therapeutic field, or TTField, is an alternating electric field in the mid-frequency range (e.g., 100-500 kHz) that inhibits the growth of cancer cells. This non-invasive treatment targets solid tumors and is described in U.S. Patent 7,565,205, which is incorporated herein by reference in its entirety. A 200 kHz TTField is FDA-approved for the treatment of glioblastoma (GBM). Alternating electric fields with frequencies between 50 kHz and 1 MHz can also be used to treat medical conditions other than cancer. For example, as described in U.S. Patent No. 10,967,167 (which is incorporated herein by reference in its entirety), an alternating electric field of, for example, 50-200 kHz can increase the permeability of the blood-brain barrier (BBB), allowing, for example, chemotherapy drugs to reach the brain. And as described in U.S. Patent No. 11,103,698 (which is incorporated herein by reference in its entirety), an alternating electric field of, for example, 50-500 kHz can increase the permeability of cell membranes, allowing macromolecules to cross cell membranes.

[0004] Optune ® This is the standard method for delivering TTFields to living organisms. (Option) ® It includes a field generator and two pairs of transducer arrays (i.e., electrode arrays) placed on the patient's shaved head. One pair of arrays (L / R) is located on the left and right sides of the tumor, and the other pair of arrays (A / P) is located on the anterior and posterior sides of the tumor. In a preclinical setting, TTField can also be applied in vitro, for example using Inovitro with existing technology. TM TTField laboratory bench system. In Optune ® and Inovitro TM In the process, the field generator (a) applies an AC voltage for 1 second between the L / R transducer array (or electrodes), which induces an electric field through the tumor in one direction; then (b) applies an AC voltage for 1 second between the A / P transducer array (or electrodes), which induces an electric field through the tumor in another direction; then the two-step sequence (a) and (b) is repeated during treatment. Summary of the Invention

[0005] One aspect of this application relates to a first method for inducing an alternating electric field in a target region within a subject's body. The first method includes applying a series of pulses of alternating current between at least one first electrode element and at least one second electrode element during each of a plurality of first time intervals, wherein the at least one first electrode element and the at least one second electrode element are located on or within the subject's body; and allowing the at least one first electrode element and the at least one second electrode element to cool during each of the plurality of second time intervals. Each of the plurality of second time intervals immediately follows a corresponding one of the plurality of first time intervals. The pulses of alternating current within any given first time interval have a level of magnitude that, if the series of pulses were allowed to continue for one hour, would cause at least one first electrode element to exceed a temperature threshold between 37°C and 43°C. However, the series of pulses within each first time interval is substantially short enough to prevent the at least one first electrode element from exceeding the temperature threshold and to prevent the at least one second electrode element from exceeding the temperature threshold.

[0006] In some instances of the first method, each of the plurality of second time intervals is at least as long as the immediately preceding first time interval. In some instances of the first method, each of the plurality of second time intervals is at least 5 minutes. In some instances of the first method, each second time interval is long enough that a subsequent series of pulses of alternating current can be applied without causing at least one first electrode element to exceed a temperature threshold and without causing at least one second electrode element to exceed a temperature threshold.

[0007] In some instances of the first method, the temperature threshold is between 38°C and 40°C. In some instances of the first method, all pulses of alternating current within any given time interval of the first time interval have the same magnitude. In some instances of the first method, during each first time interval, the magnitude of the pulses of alternating current ramps up from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0008] In some instances of the first method, the step of allowing at least one first electrode element and at least one second electrode element to cool during each of a plurality of second time intervals is achieved by not applying a pulse of alternating current between at least one first electrode element and at least one second electrode element during the second time interval.

[0009] In some instances of the first method, the step of allowing the at least one first electrode element and the at least one second electrode element to cool during each of a plurality of second time intervals is achieved by applying a series of second magnitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein each series of second magnitude pulses has an average magnitude less than half the average magnitude of a series of pulses in the immediately preceding first time interval.

[0010] In some instances of the first method, the plurality of first time intervals includes at least 100 first time intervals, and the plurality of second time intervals includes at least 100 second time intervals. Optionally, in these embodiments, each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, and each series of pulses includes at least 50 pulses.

[0011] Another aspect of this application relates to a second method for inducing an alternating electric field in a target region within a subject's body. The second method includes applying a series of pulses of alternating current between at least one first electrode element and at least one second electrode element during each of a plurality of first time intervals. The at least one first electrode element and the at least one second electrode element are located on or within the subject's body. The second method also includes allowing the at least one first electrode element and the at least one second electrode element to cool during each of a plurality of second time intervals, each of the plurality of second time intervals immediately following a corresponding one of the plurality of first time intervals. The second method also includes applying a series of pulses of alternating current between at least one third electrode element and at least one fourth electrode element during each of a plurality of third time intervals, wherein the at least one third electrode element and the at least one fourth electrode element are located on or within the subject's body. Furthermore, the second method also includes allowing the at least one third electrode element and the at least one fourth electrode element to cool during each of a plurality of fourth time intervals, each of the plurality of fourth time intervals immediately following a corresponding one of the plurality of third time intervals. The alternating current pulses within any given first time interval have a magnitude at a first level that, if allowed to continue for one hour, would cause at least one first electrode element to exceed a temperature threshold between 37°C and 43°C. However, the series of pulses within each first time interval is actually short enough to prevent the at least one first electrode element from exceeding the temperature threshold and to prevent the at least one second electrode element from exceeding the temperature threshold. Similarly, the alternating current pulses within any given third time interval have a magnitude at a second level that, if allowed to continue for one hour, would cause at least one third electrode element to exceed a temperature threshold. However, the series of pulses within each third time interval is actually short enough to prevent the at least one third electrode element from exceeding the temperature threshold and to prevent the at least one fourth electrode element from exceeding the temperature threshold.

[0012] In some instances of the second method, each of the plurality of second time intervals is at least as long as the immediately preceding first time interval, and each of the plurality of fourth time intervals is at least as long as the immediately preceding third time interval.

[0013] In some instances of the second method, the pulses of the alternating current during the first time interval and the pulses of the alternating current during the third time interval have independently controllable magnitudes. In some instances of the second method, the magnitude of the pulses of the alternating current during the first time interval differs from the magnitude of the pulses of the alternating current during the third time interval.

[0014] In some instances of the second method, each of the plurality of second time intervals is at least 5 minutes, and each of the plurality of fourth time intervals is at least 5 minutes. In some instances of the second method, each of the plurality of first time intervals is at least 10 minutes, and each of the plurality of third time intervals is at least 10 minutes.

[0015] In some instances of the second method, each of these second time intervals is long enough to allow a subsequent series of alternating current pulses to be applied without causing the at least one first electrode element to exceed the temperature threshold and without causing the at least one second electrode element to exceed the temperature threshold, and each of the fourth time intervals is long enough to allow a subsequent series of alternating current pulses to be applied without causing the at least one third electrode element to exceed the temperature threshold and without causing the at least one fourth electrode element to exceed the temperature threshold.

[0016] In some instances of the second method, the temperature threshold is between 38°C and 40°C. In some instances of the second method, all pulses of alternating current within any given time interval of the first time interval have the same magnitude. In some instances of the second method, during each first time interval, the magnitude of the pulses of alternating current ramps up from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0017] In some instances of the second method, each third time interval overlaps with a corresponding first time interval. In some instances of the second method, each third time interval is mutually exclusive with all first time intervals, and each first time interval is mutually exclusive with all third time intervals.

[0018] In some instances of the second method, the step of allowing at least one first electrode element and at least one second electrode element to cool during each of a plurality of second time intervals is achieved by a pulse that does not apply alternating current between at least one first electrode element and at least one second electrode element during the second time interval. Similarly, the step of allowing at least one third electrode element and at least one fourth electrode element to cool during each of a plurality of fourth time intervals is achieved by a pulse that does not apply alternating current between at least one third electrode element and at least one fourth electrode element during the fourth time interval.

[0019] In some instances of the second method, the step of allowing the at least one first electrode element and the at least one second electrode element to cool during each of a plurality of second time intervals is achieved by applying a series of second magnitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein each series of second magnitude pulses has an average magnitude less than half the average magnitude of a series of pulses in the immediately preceding first time interval. Similarly, the step of allowing the at least one third electrode element and the at least one fourth electrode element to cool during each of a plurality of fourth time intervals is achieved by applying a series of fourth magnitude pulses of alternating current between the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals, wherein each series of fourth magnitude pulses has an average magnitude less than half the average magnitude of a series of pulses in the immediately preceding third time interval.

[0020] In some instances of the second method, the plurality of first time intervals includes at least 100 first time intervals, the plurality of second time intervals includes at least 100 second time intervals, the plurality of third time intervals includes at least 100 third time intervals, and the plurality of fourth time intervals includes at least 100 second and fourth time intervals. Optionally, in these embodiments, each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, each of the plurality of third time intervals is at least one minute long, each of the plurality of fourth time intervals is at least one minute long, and each series of pulses includes at least 50 pulses.

[0021] Another aspect of the invention relates to a first device for sensing an alternating electric field in a target region within a subject's body. The first device includes a pulse generator and a controller. The pulse generator is configured to generate a series of pulses of alternating current between a first output terminal and a second output terminal, the magnitude of which depends on the state of at least one control input. The controller is configured to send a signal to the at least one control input causing the pulse generator to output a pulse having a first magnitude between the first and second output terminals during each of a plurality of first time intervals. The controller is also configured to, during each of a plurality of second time intervals, each immediately following a corresponding one of the plurality of first time intervals, either (i) send a signal to the at least one control input causing the pulse generator not to output a pulse during each of the plurality of second time intervals, or (ii) send a signal to the at least one control input causing the pulse generator to output a pulse having a second magnitude between the first and second output terminals during each of the plurality of second time intervals, wherein the second magnitude is less than half the first magnitude. The controller is also configured to receive at least one first input signal from at least one first temperature sensor and at least one second input signal from at least one second temperature sensor. The plurality of first time intervals include at least 10 first time intervals, the plurality of second time intervals include at least 10 second time intervals, each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, and each pulse sequence includes at least 10 pulses.

[0022] In some embodiments of the first device, the controller is further configured to adjust a first magnitude value based on at least one first input signal and at least one second input signal during each of a plurality of first time intervals. In some embodiments of the first device, each of the plurality of second time intervals is at least 5 minutes long. In some embodiments of the first device, the controller is further configured to terminate a given first time interval based on at least one first input signal and at least one second input signal. In some embodiments of the first device, the controller is further configured to terminate a given second time interval based on at least one first input signal and at least one second input signal.

[0023] Another aspect of the invention relates to a second device for sensing an alternating electric field in a target region within a subject's body. The second device includes a pulse generator and a controller. The pulse generator is configured to generate a series of pulses of alternating current between a first output terminal and a second output terminal, the magnitude of which depends on the state of at least one control input. The controller is configured to send a signal to the at least one control input causing the pulse generator to output a pulse having a first magnitude between the first and second output terminals during each of a plurality of first time intervals. The controller is also configured to, during each of a plurality of second time intervals, each of the second time intervals immediately following a corresponding one of the plurality of first time intervals, either (i) send a signal to the at least one control input causing the pulse generator not to output a pulse during each of the plurality of second time intervals, or (ii) send a signal to the at least one control input causing the pulse generator to output a pulse having a second magnitude between the first and second output terminals during each of the plurality of second time intervals, wherein the second magnitude is less than half the first magnitude. The controller is also configured to receive at least one first input signal from at least one first temperature sensor and at least one second input signal from at least one second temperature sensor. The plurality of first time intervals include at least 10 first time intervals, the plurality of second time intervals include at least 10 second time intervals, each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, and each pulse sequence includes at least 10 pulses.

[0024] In the second device, the pulse generator is further configured to generate a series of alternating current pulses between a third output terminal and a fourth output terminal, the magnitude of which depends on the state of at least one control input. The controller is further configured to send a signal to the at least one control input causing the pulse generator to output a pulse with a third magnitude between the third output terminal and the fourth output terminal during each of a plurality of third time intervals. The controller is also configured to, during each of the plurality of fourth time intervals, each of the plurality of second time intervals immediately following a corresponding one of the plurality of third time intervals, either (i) send a signal to the at least one control input causing the pulse generator not to output a pulse during each of the plurality of fourth time intervals, or (ii) send a signal to the at least one control input causing the pulse generator to output a pulse with a fourth magnitude between the third output terminal and the fourth output terminal during each of the plurality of fourth time intervals, wherein the fourth magnitude is less than half of the third magnitude. The controller is also configured to accept at least one third input signal from at least one third temperature sensor and at least one fourth input signal from at least one fourth temperature sensor. The plurality of third time intervals includes at least 10 third time intervals. The plurality of fourth time intervals includes at least 10 fourth time intervals. Each of the plurality of third time intervals is at least one minute long, and each of the plurality of fourth time intervals is at least one minute long.

[0025] In some embodiments of the second device, the controller is further configured to adjust a first magnitude value based on at least one first input signal and at least one second input signal during each of a plurality of first time intervals, and to adjust a third magnitude value based on at least one third input signal and at least one fourth input signal during each of a plurality of third time intervals.

[0026] In some embodiments of the second device, the controller is further configured to terminate a given first time interval based on at least one first input signal and at least one second input signal, and is configured to terminate a given third time interval based on at least one third input signal and at least one fourth input signal.

[0027] In some embodiments of the second device, the controller is also configured to terminate a given second time interval based on at least one first input signal and at least one second input signal, and to terminate a given fourth time interval based on at least one third input signal and at least one fourth input signal.

[0028] Some embodiments of the second device also include at least one first electrode element wired to the first output terminal; at least one second electrode element wired to the second output terminal; at least one third electrode element wired to the third output terminal; and at least one fourth electrode element wired to the fourth output terminal.

[0029] Optionally, in the embodiments described in the preceding paragraphs, the first temperature sensor includes a first thermistor in thermal contact with at least one first electrode element, the second temperature sensor includes a second thermistor in thermal contact with at least one second electrode element, the third temperature sensor includes a third thermistor in thermal contact with at least one third electrode element, and the fourth temperature sensor includes a fourth thermistor in thermal contact with at least one fourth electrode element. Attached Figure Description

[0030] Figure 1 shows the existing technology Optune. ® A schematic diagram illustrating how the system keeps the temperature of the electrode array below a safe threshold.

[0031] FIG. 2A The experimental results of measuring the peak current of six different shapes of alternating current pulses are presented.

[0032] FIG. 2B Experimental results depicting the cytotoxicity of pulses of alternating current with six different shapes are presented.

[0033] FIG. 3 This is a block diagram of an embodiment that can drive a transducer array using pulses of AC current having the magnitude distribution described herein.

[0034] FIG. 4 An example depicting the magnitude distribution of the L / R and A / P channels can be used... FIG. 3 This is achieved through an embodiment that generates high-current pulses of alternating current that are interleaved with the cooling cycle.

[0035] FIG. 5 Is FIG. 4 A detailed view of what a single pulse of alternating current during the time interval i1 / i3 in the embodiment can look like.

[0036] FIG. 6 Another example depicting the magnitude distribution of the L / R and A / P channels can be used... FIG. 3 This is achieved through an embodiment that generates high-current pulses of alternating current that are interleaved with the cooling cycle.

[0037] FIG. 7 Is FIG. 6A detailed view of what the pulses of the individual AC current for the L / R channel can look like during the time interval i1 in the embodiment.

[0038] FIG. 8 This is yet another example depicting the magnitude distribution of the L / R and A / P channels, which can be used... FIG. 3 This is achieved through an embodiment that generates high-current pulses of alternating current that are interleaved with the cooling cycle.

[0039] FIG. 9 An example of a magnitude distribution that can be achieved using a single embodiment is depicted in order to generate high current pulses of alternating current that are interleaved with cooling cycles.

[0040] FIG. 10 Another example of a magnitude distribution that can be achieved using a single embodiment is depicted in order to generate high current pulses of alternating current that are interleaved with cooling cycles.

[0041] Various embodiments are described in detail below with reference to the accompanying drawings, wherein the same reference numerals denote the same elements. Detailed Implementation

[0042] When treating subjects with TTField, a higher electric field strength is strongly correlated with higher therapeutic efficacy; and increasing the electric field strength can be achieved by increasing the current applied to the electrode array. However, the current cannot simply be increased to any desired level. This is because increasing the current causes the electrode array to heat up. The temperature of the electrode array must not exceed a safe threshold.

[0043] Figure 1 shows the existing Optune technology. ® This diagram illustrates how the system maintains the temperature of the electrode arrays below a safe threshold by adjusting the pulsed current of the alternating current applied to the electrode arrays. More specifically, when the system is first turned on, it starts by outputting a pulse of alternating current with an initial current level (e.g., 0.5 amps). The system then ramps up the pulsed current of the alternating current from this initial level while continuously monitoring the temperature at all four electrode arrays (using multiple thermistors positioned at each of the four electrode arrays) until the hottest array approaches a predetermined temperature threshold (e.g., 39°C). In the example of Figure 1, the left / right electrode arrays operate hotter than the front / rear electrode arrays, therefore the temperature of the left / right arrays will be the limiting factor.

[0044] When the hottest array approaches the temperature threshold (i.e., at t=15 in the example of Figure 1, when the current per pulse is approximately 1.1 A), the system stops increasing the current of the AC current pulses (i.e., it remains at a constant level) and continues to monitor the temperature of all four electrode arrays. If at some point the temperature of the hottest array reaches the temperature threshold (e.g., at t=25 in the example of Figure 1), the system will decrease the current of the AC current pulses to keep the temperature of all electrode arrays below the temperature threshold.

[0045] With Optune ® Similarly, the Inovitro™ TTField laboratory bench automatically adjusts the AC current applied to the electrodes to keep the sample tray at 37°C. FIG. 2A and FIG. 2B Results of experiments performed using the Inovitro™ system were depicted, which was modified to apply pulses of alternating current with different shapes to sample culture dishes containing U87 cells to determine (1) the peak current used when the temperature stabilized at 37°C and (2) cytotoxicity for each pulse of alternating current with different shapes. TTField was applied in these experiments as follows: (a) AC current was applied to the L / R electrode for 1 second or a portion thereof; (b) AC current was applied to the A / P electrode for 1 second or a portion thereof; the two steps (a) and (b) were repeated sequentially during the 120-hour experiment.

[0046] FIG. 2A The peak current of each different shape of AC current pulse is depicted. Bar #1 represents a control not processed with TTField. Bar #2 represents the peak current when the AC current jumps from zero to peak immediately at the start of each 1-second interval and jumps from peak to zero immediately at the end of each 1-second interval. Bar #3 represents the peak current when the AC current rises from zero to peak within the first 50 ms of each 1-second interval and falls from peak to zero within the last 50 ms of each 1-second interval. This means the AC current remains at its peak for 900 ms within each 1-second interval. Bar #4 represents the peak current when the AC current rises from zero to peak within the first 100 ms of each 1-second interval and falls from peak to zero within the last 100 ms of each 1-second interval. This means the AC current remains at its peak for 800 ms within each 1-second interval.

[0047] Item #5 represents the peak current when the AC current rises from zero to its peak value within the first 300 ms of each 1-second interval and falls from its peak value to zero within the last 300 ms of each 1-second interval. This means the AC current remains at its peak value for 400 ms within each 1-second interval. Item #6 represents the peak current when the AC current rises from zero to its peak value within the first 350 ms of each 1-second interval and falls from its peak value to zero within the last 350 ms of each 1-second interval. This means the AC current remains at its peak value for 300 ms within each 1-second interval. Item #7 represents the peak current when the AC current rises from zero to its peak value within the first 400 ms of each 1-second interval and falls from its peak value to zero within the last 400 ms of each 1-second interval. This means the AC current remains at its peak value for 200 ms within each 1-second interval.

[0048] FIG. 2B The cytotoxicity results obtained for each different shape of alternating current pulse are depicted. FIG. 2B Each numbered bar in the text corresponds to FIG. 2A The corresponding numbered bars are listed. Notably, bars #6 and #7 yielded the best cytotoxicity results.

[0049] Similar combinations were performed on U87 and 118 cell lines. FIG. 2A The additional experiments described in / 2B, totaling six experiments involving a total of 231 culture dishes, revealed a Pearson correlation coefficient of 0.78 between peak current and cytotoxicity, and a Pearson correlation coefficient of 0.25 between the rise / fall time of different shapes of alternating current pulses and cytotoxicity. From this data, it is reasonable to infer that a TTField with a higher peak current applied for a smaller percentage of the time is more effective than a TTField with a lower peak current applied for a larger percentage of the time.

[0050] As described above, the existing Optune ® A series of alternating current pulses are generated, and current levels that will not cause any electrode array to overheat (i.e., exceed a predetermined temperature threshold) are selected for those alternating current pulses, even if the series of alternating current pulses continues indefinitely.

[0051] Conversely, the embodiments described below utilize the conclusion that a TTField with a higher peak current applied for a smaller percentage of the time is more effective than a TTField with a lower peak current applied for a larger percentage of the time. More specifically, the embodiments described below set the pulses of alternating current to a level that, if allowed to continue for one hour, would cause at least one electrode element to exceed a temperature threshold. The reader may now wonder: if the current is set at this level, why don't these embodiments overheat? The answer is that the pulse series is not allowed to continue for one hour. Instead, each pulse of alternating current ends before any electrode element exceeds the temperature threshold, and is immediately followed by a cooling period (during which the temperature of the electrode element decreases). Subsequent high-current pulses of alternating current do not begin until the temperature has sufficiently decreased.

[0052] FIG. 3 This is a block diagram of an embodiment that can drive a transducer array 10 with pulses of AC current having the magnitude distribution described herein. The system includes an AC signal generator 20, which is designed to generate a first AC output and a second AC output with frequencies between 50 kHz and 1 MHz. When the system is used to apply a TTField to a part of the human body (e.g.... FIG. 3 As shown, the first AC output is applied to a first pair of electrodes 10L and 10R located to the left and right of the tumor; the second AC output is applied to a second pair of electrodes 10A and 10P located in front of and behind the tumor. The AC signal generator 20 can also be used to apply the TTField to the in vitro culture (not shown) by applying the first AC output to electrodes located on the left and right walls of the Inovitro™ culture dish and applying the second AC output to electrodes located on the front and rear walls of the Inovitro™ culture dish. In either case, the voltage generated by the AC signal generator 20 should be high enough to drive a current that induces an electric field of at least 1 V / cm in at least a portion of the cancer cells. In some embodiments, the voltage generated by the AC signal generator 20 drives a current to induce an electric field between 1 V / cm and 10 V / cm in at least a portion of the cancer cells. In some embodiments, the voltage generated by the AC signal generator 20 is at least 75 V RMS.

[0053] AC signal generator 20 is configured to generate a first AC output and a second AC output, such that the first AC output and the second AC output have independently controllable magnitudes depending on the state of at least one control input. Controller 30 continuously sends control signals to at least one control input, and these control signals are configured to cause the first AC output and the second AC output to generate signals having the magnitude distribution described herein. Note that although... FIG. 3The controller 30 and the AC signal generator 20 are described as two different blocks, but these two blocks can be integrated into a single hardware device.

[0054] The structural details of controller 30 and the nature of the control signals will depend on the design of AC signal generator 20. In one example, the design of AC signal generator 20 is similar to that described in U.S. Patent 9,910,453, which is incorporated herein by reference in its entirety. This particular AC signal generator has two output channels (i.e., a first channel for L / R and a second channel for A / P). The instantaneous AC output voltage on either channel depends on the instantaneous output voltage of the DC-DC converter, and the output voltage of the DC-DC converter is controlled, for example, by writing a control word to the digital-to-analog converter (DAC) at an update rate of 1 ms.

[0055] The controller 30 receives at least one first input signal from at least one first thermistor positioned in contact with at least one first electrode element, at least one second input signal from at least one second thermistor positioned in contact with at least one second electrode element, at least one third input signal from at least one third thermistor positioned in contact with at least one third electrode element, and at least one fourth input signal from at least one fourth thermistor positioned in contact with the at least one fourth electrode element. By processing the first to fourth input signals, the controller can monitor the temperature of each electrode element and control the current to prevent the electrode element from overheating. An example of a suitable method for implementing temperature measurement is in Optune. ® The conventional method used. Another example is described in U.S. Patent 11,097,101, which is incorporated herein by reference.

[0056] FIG. 4 An example depicting the magnitude distribution of the L / R and A / P channels can be used... FIG. 3 This is achieved through an embodiment that generates high-current pulses of alternating current that interleave with the cooling cycle, as well as the corresponding temperature profiles for the two channels.

[0057] exist FIG. 4 In the example, the L / R channel and A / P channel begin their operation between t=0 and t=25 minutes, as shown above in conjunction with Figure 1 for the prior art Optune. ® The system is described above. However, instead of stabilizing the current at a level to avoid overheating (e.g., about 1.1 A as described above in conjunction with Figure 1), the system at time intervals (e.g., at...) FIG. 4 No pulses of alternating current are applied during the period between 25 and 35 minutes, which allows the electrode array to cool (as seen in the two temperature graphs).

[0058] After sufficient cooling has occurred, in response to a command from controller 30, AC pulses are restarted during time interval i1 / i3. During this time interval, controller 30 commands AC signal generator 20 to apply a series of AC current pulses between at least one first electrode element 10L and at least one second electrode element 10R, and also a series of AC current pulses between at least one third electrode element 10A and at least one fourth electrode element 10P. The AC current pulses applied to 10L / 10R during time interval i1 have a magnitude at a first level that, if this series of pulses were allowed to continue for one hour, would cause at least one of the first electrode elements 10L to exceed a temperature threshold*. (Note how the 1.5A magnitude of the L / R channel is higher than the 1.1A magnitude used between t=15 and t=25; and also note how the temperature of electrode elements 10L / 10R increases during time interval i1.) However, it is important that this series of pulses *is not* allowed to continue for one hour. Conversely, controller 30 ensures that the AC pulse train within time interval i1 is actually short enough to prevent electrode elements 10L and 10R from exceeding the temperature threshold.

[0059] The situation is similar for pulses of AC current applied within time interval i3, except that the magnitude of the A / P channel is 1.7 A in the example shown. Note that the current applied to the A / P channel is set by the current applied to the A / P channel, and *if* a series of pulses of AC current are allowed to last for one hour, each of these currents is set to a magnitude level that will cause overheating.

[0060] Because the series of pulses of alternating current within the time interval i1 / i3 must be short enough to prevent the electrode elements 10L / 10R / 10A / 10P from exceeding the temperature threshold, the controller 30 issues a command (in FIG. 4 In the example, at t=40, a series of high-current pulses are used to stop the AC current applied to electrode element 10L / 10R, and a series of high-current pulses are used to stop the AC current applied to electrode element 10A / 10P before overheating occurs. The decision to stop the series of high-current pulses may be based on the temperature reaching a threshold (e.g., 37°C, 38°C, 39°C, 40°C, 41°C) and optionally have a maximum time (e.g., after 2, 5, 7, or 10 minutes have elapsed).

[0061] i2 / i4 is the time interval immediately following i1 / i3 after a series of high-current pulses of alternating current has stopped, and during this time interval i2 / i4, the controller 30 allows the electrode elements 10L / 10R / 10A / 10P to cool down. (Note that...) FIG. 4In the example, the temperature drops from t=40 to t=50. The time interval i2 / i4 is long enough that a subsequent series of alternating current pulses can be applied without causing the electrode elements 10L / 10R / 10A / 10P to exceed the temperature threshold. The controller 30 can optionally determine to restart the next series of high-current pulses based on the temperature of the electrode elements 10L / 10R / 10A / 10P reaching a lower threshold (e.g., 34°C, 35°C, 36°C) with a minimum cooling time (e.g., after 2, 5, 6, 8, or 10 minutes have elapsed). Alternatively, the time interval i2 / i4 can be a fixed time interval (e.g., 5, 6, 8, or 10 minutes).

[0062] After time interval i2 / i4 ends, the system alternates between the aforementioned conditions associated with time interval i1 / i3 (where pulses of alternating current are applied to the electrode elements) and time interval i2 / i4 (where the electrode elements are allowed to cool down). Controller 30 coordinates this alternation by repeating the commands associated with these time intervals.

[0063] FIG. 3 / 4 Examples of Optune Compared to the Prior Art ® It has significant advantages because FIG. 3 In the / 4 embodiment, the peak current of the AC current pulse is higher than that of Optune. ® The peak current. And as mentioned above... FIG. 2A and FIG. 2B As explained, a TTField with a higher peak current has higher efficiency than a TTField with a lower peak current, even when the latter is applied for a larger percentage of the available time.

[0064] It is important to note that FIG. 4 The current trace in the diagram represents the magnitude of any pulse of alternating current generated during a given time interval. For example, in... FIG. 4 In the illustrated example, the magnitude of each AC current pulse in the L / R channel is 1.5 A during time interval i1, while the magnitude of each AC current pulse generated in the A / P channel is 1.7 A during time interval i3. Because... FIG. 4 The timescale is quite long (i.e., 60 minutes) and the duration of each individual pulse can be on the order of 1 second, so hundreds of pulses of alternating current can exist within any given interval such as i1 / i3.

[0065] FIG. 5 Is FIG. 3 A detailed view of what the magnitude of a single pulse of alternating current during the time interval i1 / i3 in embodiment / 4 looks like. FIG. 5In the example, the upper trace depicts the magnitude of the first two pulses of an alternating current from a series of pulses generated every 2 seconds in the L / R channel, with a peak current of 1.5 A and relatively slow rise and fall times. Similarly, the lower trace depicts the magnitude of the first two pulses of an alternating current from a series of pulses generated every 2 seconds in the A / P channel, with a peak current of 1.7 A and relatively slow rise and fall times. (Because the timescale of a 50 kHz–1 MHz sine wave is...) FIG. 5 The timescale is much smaller, so the sinusoidal waveform within a pulse of any given alternating current is not... FIG. 5 (As shown in the image.) In particular, in FIG. 5 In the example shown, the pulses for the L / R channel and the pulses for the A / P channel are out of phase. Note that... FIG. 5 Only a single illustrative example is depicted, and the parameters of these pulses, including pulse repetition time, pulse width, rise time, fall time, etc., can all be changed.

[0066] Return to FIG. 3 / 4, in some embodiments, multiple cooling intervals i2 / i4 (i.e., in FIG. 4 Each of the pulses in the example shown (10 minutes) is at least associated with the immediately preceding pulse generation interval i1 / i3 (i.e., in... FIG. 4 The duration is the same as 5 minutes in the example shown. In some embodiments, each of the plurality of cooling time intervals is 1-2 times the immediately preceding pulse generation time interval. In some embodiments, each of the plurality of cooling time intervals is 1.5-2.5 times the immediately preceding pulse generation time interval. In some embodiments, each of the plurality of cooling time intervals is 2-3 times the immediately preceding pulse generation time interval.

[0067] In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have independently controllable magnitudes. In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have different magnitudes. In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have the same magnitude.

[0068] In some embodiments, each cooling interval i2 / i4 is at least 5 minutes. In other embodiments, each cooling interval i2 / i4 is at least 2, 6, 8, or 10 minutes.

[0069] In some embodiments, within any given time interval i1, the pulses of all alternating current in the L / R channel have the same magnitude. In other embodiments, during each time interval i1, the magnitude of the alternating current pulses ramps up from an initial level (e.g., using a linear ramp, an exponential ramp, or a ramp of a different shape) to a final level, and then remains at the final level for the duration of the first time interval.

[0070] In some embodiments, including FIG. 4 In the example shown, no AC pulse is applied to the L / R channel or A / P channel during the cooling time interval i2 / i4. Alternatively, a low-current pulse (i.e., an AC current pulse with an average magnitude less than half the average magnitude of the pulses of AC current generated during the time interval i1 / i3) may be applied during the cooling time interval i2 / i4.

[0071] Note that in FIG. 4 In the example shown, time interval i3 (when an AC current pulse is generated in the A / P channel) overlaps with time interval i1 (when an AC current pulse is generated in the L / R channel).

[0072] In some embodiments, there are at least 10 first time intervals i1, at least 10 second time intervals i2, at least 10 third time intervals i3, and at least 10 fourth time intervals i4. In these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least one minute long, and each series of pulses includes at least 10 pulses. In some embodiments, there are at least 100 first time intervals i1, at least 100 second time intervals i2, at least 100 third time intervals i3, and at least 100 fourth time intervals i4. Optionally, in these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least one minute long, and each series of pulses includes at least 50 pulses. Optionally, in these embodiments, each of the first and third time intervals i1, i3 is independently at least 2, 3, 4, or 5 minutes long, and each series of pulses within these intervals includes at least 100, 150, 200, or 250 pulses. Optionally, in these embodiments, each of the second and fourth time intervals i2, i4 is independently at least two minutes, three minutes, four minutes, five minutes, six minutes, seven minutes, eight minutes, nine minutes, or ten minutes long, and each series of pulses within these intervals includes at least 100, 150, 200, 250, 300, 350, 400, 450, or 500 low-current pulses, or includes no pulses at all.

[0073] FIG. 6Another example depicting the magnitude distribution of the L / R and A / P channels can be used... FIG. 3 This is achieved through an embodiment that generates high-current pulses of alternating current interleaved with the cooling cycle, and corresponding temperature profiles for the two channels. This embodiment is similar to the one described above. FIG. 4 In one embodiment, the high-current pulse of the AC current in the A / P channel is shifted to a different time slot. FIG. 6 The first 35 minutes in the example are the same as those mentioned above. FIG. 4 Same as in the example.

[0074] After sufficient cooling has occurred, in response to a command from controller 30, an AC pulse is initiated again during time interval i1. During this time interval, AC signal generator 20 applies a series of AC current pulses between at least one first electrode element 10L and at least one second electrode element 10R. The AC current pulses applied to 10L / 10R during time interval i1 have a magnitude at a first level, which, *if* this series of pulses were allowed to continue for one hour, would cause at least one of the first electrode elements 10L to exceed a temperature threshold. However, it is important that this series of pulses *is not* allowed to continue for one hour. Instead, the AC pulse train within time interval i1 is actually short enough to prevent electrode elements 10L and 10R from exceeding the temperature threshold.

[0075] Because the series of pulses of alternating current within the time interval i1 must be short enough to prevent the electrode elements 10L / 10R from exceeding the temperature threshold, the controller 30 issues a command (in FIG. 6 In the example at t=40, a series of high-current pulses are used to stop the AC current applied to the electrode element by 10L / 10R before overheating occurs. The decision to stop the series of high-current pulses of AC current can be based on the temperature reaching a threshold (e.g., 37°C, 38°C, 39°C, 40°C, or 41°C) and optionally have a maximum time (e.g., after 2, 5, 7, or 10 minutes).

[0076] i2 is the time interval immediately following i1 after a series of high-current pulses of alternating current has stopped, and during this time interval i2, the controller 30 allows the electrode elements 10L / 10R to cool down. (Note that for...) FIG. 6In the example, the temperature of the L / R channel drops from t=40 to t=50. The time interval i2 is long enough that a subsequent series of alternating current pulses can be applied without causing the electrode element 10L / 10R to exceed its temperature threshold. The controller 30 can, based on the electrode element 10L / 10R reaching a lower threshold (e.g., 34°C, 35°C, or 36°C), optionally decide to restart the next series of high-current pulses of alternating current with a minimum cooling time (e.g., after 2, 5, 6, 8, or 10 minutes have elapsed).

[0077] After time interval i2 ends, the system alternates between the aforementioned states related to time interval i1 (in which a pulse of alternating current is applied to the electrode element) and time interval i2 (in which the electrode element is allowed to cool down). Controller 30 coordinates this alternation by repeating the commands associated with these time intervals.

[0078] FIG. 3 / 6 Examples of Optune Compared to the Prior Art ® It has significant advantages because FIG. 3 In embodiment / 6, the peak current of the AC current pulse is higher than that of Optune. ® The peak current. And as mentioned above... FIG. 2A and FIG. 2B As explained, a TTField with a higher peak current has higher efficiency than a TTField with a lower peak current, even when the latter is applied for a larger percentage of the available time.

[0079] Similar to the above combination FIG. 4 The situation described, FIG. 6 The current trace in the diagram represents the magnitude of any pulse of alternating current generated during a given time interval. FIG. 7 Is FIG. 3 A detailed view of what the magnitude of the pulses of the individual AC current for the L / R channel looks like during the time interval i1 in embodiment / 6. FIG. 7 In the example, the trajectory depicts the magnitude of the first two pulses of an alternating current from a series of pulses generated every 2 seconds in the L / R channel, with a peak current of 1.5 A and relatively slow rise and fall times. (Because the timescale of a 50kHz-1MHz sine wave is...) FIG. 7 The timescale is much smaller than that, so the sinusoidal waveform within any given pulse of alternating current is not... FIG. 7 (As shown in the image.) Note that... FIG. 7 Only a single illustrative example is depicted, and the parameters of these pulses, including pulse repetition time, pulse width, rise time, fall time, etc., can all be changed.

[0080] FIG. 6 The operation of the A / P channel in this embodiment is similar to that of the L / R channel, but with a time offset, so that the high current pulse of the AC current in the A / P channel is not generated simultaneously with the high current pulse of the AC current in the L / R channel, and there is a current of 1.7 A in the A / P channel.

[0081] Return to FIG. 3 / 6, in some embodiments, multiple cooling intervals i2, i4 (i.e., in...) FIG. 6 Each of the pulses in the example shown (10 minutes) is at least associated with the preceding pulse generation intervals i1, i3 (i.e., in... FIG. 6 The duration is the same as 5 minutes in the example shown. In some embodiments, each of the plurality of cooling time intervals is 1-2 times the immediately preceding pulse generation time interval. In some embodiments, each of the plurality of cooling time intervals is 1.5-2.5 times the immediately preceding pulse generation time interval. In some embodiments, each of the plurality of cooling time intervals is 2-3 times the immediately preceding pulse generation time interval.

[0082] In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have independently controllable magnitudes. In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have different magnitudes. In some embodiments, the pulses of the AC current in the L / R channel within time interval i1 and the pulses of the AC current in the A / P channel within time interval i3 have the same magnitude.

[0083] In some embodiments, each cooling interval i2, i4 is at least 5 minutes. In other embodiments, each cooling interval i2 / i4 is at least 2, 6, 8, or 10 minutes.

[0084] In some embodiments, within any given time interval i1, the pulses of all alternating current in the L / R channel have the same magnitude. In other embodiments, during each time interval i1, the magnitude of the alternating current pulses rises from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0085] In some embodiments, including FIG. 6 In the example shown, no AC pulses are applied to the L / R channel or A / P channel during cooling time intervals i2 and i4. Alternatively, low-current pulses (i.e., pulses of AC current with an average magnitude less than half the average magnitude of the pulses of AC current generated during time intervals i1 and i3) may be applied during cooling time intervals i2 and i4.

[0086] As mentioned above, in FIG. 6 In the embodiments (and) FIG. 4 Compared to other embodiments, the high-current pulses of the AC current in the A / P channel are shifted to different time slots. In some embodiments (including...) FIG. 6 (as shown in the example), each third time interval i3 is mutually exclusive with all first time intervals i1, and each first time interval i1 is mutually exclusive with all third time intervals i3.

[0087] In some embodiments, there are at least 10 first time intervals i1, at least 10 second time intervals i2, at least 10 third time intervals i3, and at least 10 fourth time intervals i4. In these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least one minute long, and each series of pulses includes at least 10 pulses. In some embodiments, there are at least 100 first time intervals i1, at least 100 second time intervals i2, at least 100 third time intervals i3, and at least 100 fourth time intervals i4. Optionally, in these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least one minute long, and each series of pulses includes at least 50 pulses. Optionally, in these embodiments, each of the first and third time intervals i1, i3 is independently at least 2, 3, 4, or 5 minutes long, and each series of pulses within these intervals includes at least 100, 150, 200, or 250 pulses. Optionally, in these embodiments, each of the second and fourth time intervals i2, i4 is independently at least two minutes, three minutes, four minutes, five minutes, six minutes, seven minutes, eight minutes, nine minutes, or ten minutes long, and each series of pulses within these intervals includes at least 100, 150, 200, 250, 300, 350, 400, 450, or 500 pulses, or includes no pulses at all.

[0088] Note that in FIG. 4 and FIG. 6 In the example shown, each second time interval i2 (i.e., cooling interval) is depicted as longer than the immediately preceding first time interval i1 (where a series of alternating current pulses are applied between the first electrode elements and at the second electrode elements); and each fourth time interval i4 (i.e., cooling interval) is depicted as longer than the immediately preceding third time interval i3 (where a series of alternating current pulses are applied between the third electrode elements and at the fourth electrode elements). However, this is not necessarily the case in all embodiments. Instead, each second time interval i2 may be shorter than the immediately preceding first time interval i1; and each fourth time interval i4 may be shorter than the immediately preceding third time interval i3.

[0089] existFIG. 8 An example of this situation is depicted, where each first time interval i1 and each third time interval i3 is 10 minutes long, and each second time interval i2 and each fourth time interval i4 is 5 minutes long. Specifically, utilizing this timing relationship, at least one channel (i.e., L / R or A / P) will always operate at its peak current (e.g., FIG. 8 (As shown). Note that, FIG. 8 Only a single illustrative example of the potential durations of the first to fourth time intervals i1-i4 is depicted, and these durations can vary. FIG. 8 In a preferred variation of the illustrated scenario, each first time interval i1 and each third time interval i3 is 15 minutes long, and each second time interval i2 and each fourth time interval i4 is 10 minutes long. FIG. 8 In the second preferred variation of the illustrated case, each first time interval i1 and each third time interval i3 is 30 minutes long, and each second time interval i2 and each fourth time interval i4 is 15 minutes long. Using any of these preferred timing relationships, at least one channel (i.e., L / R or A / P) will always operate at its peak current.

[0090] In vivo experimental data revealed that FIG. 8 The second preferred variation shown provides more than Optune simultaneously in both channels. ® The second preferred method uses a higher current. More specifically, at least one channel operated at a current above 90 mA for 80.2% of the time in mice using the second preferred method. In contrast, at least one channel operated at a current above 90 mA for 55.5% of the time in mice using the prior art method. Furthermore, the average current using the second preferred method was 17.45% higher than the prior art method in one in vivo experiment in mice and 20.9% higher than in another in vivo experiment in mice.

[0091] When the first and third time intervals i1, i3 are longer than the second and fourth time intervals i2, i4, the visualization of the magnitude of the individual pulses of alternating current will vary depending on whether one or both channels are active at any given moment. For example, because... FIG. 8 Only the L / R channel is valid between t=35 and t=40, so the magnitude of a single pulse of AC current during this time interval will be similar to... FIG. 7 The situation shown. On the other hand, because... FIG. 8 Both channels are active between t=40 and t=45, so the magnitude of a single pulse of alternating current during this time interval will be similar to... FIG. 5 The situation is shown below. Note that... FIG. 5 and FIG. 7Each example is only described as a single illustrative example, and the parameters of these pulses, including pulse repetition time, pulse width, rise time, fall time, etc., can all be changed.

[0092] In combination with the above FIG. 3 to FIG. 8 In the described embodiments, an alternating electric field is applied to the subject's body (or to an in vitro culture dish) using two pairs of electrode elements—one pair positioned on the left and right sides of the target region, and a second pair positioned on the front and back of the target region. This configuration is advantageous in many cases, particularly where the alternating electric field has a directional effect (as in the case of TTField). However, in other cases, an alternating electric field applied in only a single direction is sufficient. These cases include, for example, using an alternating electric field to increase the permeability of the subject's blood-brain barrier. The hardware of these individual embodiments is similar to... FIG. 3 The hardware shown, except for the omitted FIG. 3 One of the L / R and A / P channels shown.

[0093] FIG. 9 An example of a magnitude distribution that can be achieved using this single embodiment is depicted to generate high-current pulses of alternating current interleaved with cooling cycles, and the corresponding temperature profile for a single channel. Single-channel operation is similar to the combination described above. FIG. 4 The operation of the L / R channel is described. Compared with the existing Optune technology... ® In comparison, this FIG. 9 A significant advantage of this embodiment is that the peak current of the alternating current pulse is higher than that of Optune. ® The peak current. And as mentioned above... FIG. 2A and FIG. 2B As explained, a TTField with a higher peak current has higher efficiency than a TTField with a lower peak current, even when the latter is applied for a larger percentage of the available time.

[0094] FIG. 10 An example of a magnitude distribution that can be achieved using this single embodiment is depicted to generate high-current pulses of alternating current interleaved with cooling cycles, and the corresponding temperature profile for a single channel. This example is similar to... FIG. 9 For example, except that the pulses of all AC currents in the L / R channel do not have the same magnitude within any given time interval i1. Instead, during each time interval i1, the magnitude of the AC current pulses slopes up from an initial level (e.g., using a depicted linear slope, or different slopes including but not limited to logarithmic or exponential slopes) to a final level, and then remains at the final level for the duration of time interval i1. Alternatively, the magnitude of the AC pulses may also slope down before the end of any given time interval i1 / i3.

[0095] Note that although the combination FIG. 10 The first description depicts the ramp ascent within each time interval i1, but similar ramp ascent characteristics can be combined with the above. FIG. 3 to FIG. 8 In any of the time intervals i1, i3 in any of the embodiments discussed.

[0096] The above is in conjunction with Figure 2 to... FIG. 10 The described concepts can be applied to both in vivo and in vitro settings. In the in vitro experiments described above, the electric field is capacitively coupled to the culture because the modified Inovitro™ system uses conductive electrodes positioned on the outer surface of the sidewall of the culture dish, with the ceramic material of the sidewall serving as the dielectric. However, in alternative embodiments, the electric field can be applied directly to the cells without capacitive coupling (e.g., by modifying the Inovitro™ system configuration so that the conductive electrodes are positioned on the inner surface of the sidewall instead of the outer surface).

[0097] The concepts described herein can be applied in vivo in an in vivo environment by applying an alternating electric field to a target area within the body of a living subject. This can be achieved, for example, by positioning electrodes on or under the skin of the subject such that applying an AC voltage between a selected subset of these electrodes will create an alternating electric field in the target area within the subject's body. For instance, in the case where the relevant cells are located in the subject's lungs, one pair of electrodes could be located in front of and behind the subject's chest cavity, and a second pair of electrodes could be located on the right and left sides of the subject's chest cavity.

[0098] In some in vivo embodiments, the electrode is capacitively coupled to the subject's body (e.g., by using an electrode that includes a conductive plate and also has a dielectric layer disposed between the conductive plate and the subject's body). However, in alternative embodiments, the dielectric layer may be omitted, in which case the conductive plate will be in direct contact with the subject's body.

[0099] Although the above discussion focuses on applying alternating electric fields to cancer cells in vitro and / or in vivo, the same concept can be used when applying alternating electric fields to a subject's body for other purposes, including but not limited to increasing the permeability of the blood-brain barrier and increasing the permeability of cell membranes, as described in U.S. Patents 10,967,167 and 11,103,698.

[0100] While the invention has been disclosed with reference to certain embodiments, various modifications, alterations, and variations can be made to the described embodiments without departing from the scope and meaning of the invention as defined by the appended claims. Therefore, the invention is not limited to the described embodiments, but has the full scope defined by the language of the appended claims and their equivalents.

Claims

1. A device for sensing an alternating electric field in a target region within a subject's body, the device comprising: A pulse generator is configured to generate a series of alternating current pulses between a first output terminal and a second output terminal, the magnitude of which depends on the state of at least one control input. as well as The controller is configured to send a signal to the at least one control input, the signal causing the pulse generator to output a pulse having a first magnitude between the first output terminal and the second output terminal during each of a plurality of first time intervals. The controller is further configured to, during each of a plurality of second time intervals, each of the plurality of second time intervals immediately following a corresponding one of the plurality of first time intervals, either (i) send a signal to the at least one control input such that the pulse generator does not output a pulse during each of the plurality of second time intervals, or (ii) send a signal to the at least one control input such that the pulse generator outputs a pulse having a second magnitude between the first output terminal and the second output terminal during each of the plurality of second time intervals, wherein the second magnitude is less than half of the first magnitude. The controller is further configured to accept at least one first input signal from at least one first temperature sensor and at least one second input signal from at least one second temperature sensor. The plurality of first time intervals includes at least 10 first time intervals. The plurality of second time intervals includes at least 10 second time intervals. Each of the plurality of first time intervals is at least one minute long. Each of the plurality of second time intervals is at least one minute long, and Each series of pulses includes at least 10 pulses.

2. The device according to claim 1, wherein, Each of the plurality of second time intervals is at least 5 minutes long.

3. The device according to claim 1, in, The pulse generator is also configured to generate a series of alternating current pulses between the third output terminal and the fourth output terminal, the alternating current pulses having magnitudes that depend on the state of the at least one control input. as well as The controller is further configured to send a signal to the at least one control input, the signal causing the pulse generator to output a pulse having a third magnitude between the third output terminal and the fourth output terminal during each of a plurality of third time intervals. The controller is further configured to, during each of a plurality of fourth time intervals, each of the plurality of fourth time intervals immediately following a corresponding one of the plurality of third time intervals, either (i) send a signal to the at least one control input such that the pulse generator does not output a pulse during each of the plurality of fourth time intervals, or (ii) send a signal to the at least one control input such that the pulse generator outputs a pulse having a fourth magnitude between the third output terminal and the fourth output terminal during each of the plurality of fourth time intervals, wherein the fourth magnitude is less than half of the third magnitude. The controller is further configured to accept at least one third input signal from at least one third temperature sensor and at least one fourth input signal from at least one fourth temperature sensor. The plurality of third time intervals includes at least 10 third time intervals. The plurality of fourth time intervals includes at least 10 fourth time intervals. Each of the plurality of third time intervals is at least one minute long, and Each of the plurality of fourth time intervals is at least one minute long.

4. The device according to claim 3, wherein, The controller is also configured to adjust a first value based on at least one first input signal and at least one second input signal during each of the plurality of first time intervals, and to adjust a third value based on at least one third input signal and at least one fourth input signal during each of the plurality of third time intervals.

5. The device according to claim 3, wherein, The controller is also configured to terminate a given first time interval based on the at least one first input signal and the at least one second input signal, and is configured to terminate a given third time interval based on the at least one third input signal and the at least one fourth input signal.

6. The device according to claim 3, wherein, The controller is also configured to terminate a given second time interval based on the at least one first input signal and the at least one second input signal, and to terminate a given fourth time interval based on the at least one third input signal and the at least one fourth input signal.

7. The device according to claim 3, further comprising: At least one first electrode element connected to the first output terminal; At least one second electrode element is wired to the second output terminal; At least one third electrode element is wired to the third output terminal; as well as At least one fourth electrode element is wired to the fourth output terminal.

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