Reduction of electric sensation during treatment of a subject with an alternating electric field using closed-loop technology

Abstract

A subject can be treated with an alternating electric field (e.g., TT field) by applying an alternating electric field to a target area and measuring neural or muscular activity generated in the subject's body in response to the alternating electric field. A treatment course is modified based on the measured neural or muscular activity to reduce or eliminate electric sensation. The neural or muscular activity can be, for example, neural activity measured based on an evoked compound action potential (ECAP). In some embodiments, the modification is performed by adjusting the amplitude or frequency of the alternating electric field. In other embodiments, the modification is performed by applying an electrical signal to the subject's body, and the electrical signal is configured to reduce electric sensation.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 355,871, filed on June 27, 2022, the entire content of which is incorporated herein by reference.

Background Art

[0002] Tumor treating electric fields (TTFields) therapy is a proven approach for treating tumors using alternating electric fields at frequencies of 50 kHz to 1 MHz (e.g., 150 - 200 kHz). In the conventional Optune® system, the TTFields are delivered to a patient via four transducer arrays 21 - 24 placed on the patient's skin in proximity to the tumor (e.g., in the case of a glioblastoma patient as shown in FIG. 1). The transducer arrays 21 - 24 are arranged in two sets, and each transducer array is connected to an AC signal generator via a multi - wire cable. The AC signal generator (a) sends an alternating current to the front / back pair of transducer arrays 21, 22 for one second to induce an electric field in a first direction in the tumor. Next, (b) it sends an alternating current to the left / right pair of arrays 23, 24 for one second to induce an electric field in a second direction in the tumor. Then, during the treatment period, steps (a) and (b) are repeated. Each of the transducer arrays 21 - 24 includes a plurality (e.g., 9 to 20) of capacitively coupled electrode elements, and each electrode element has a conductive substrate on which a dielectric layer is disposed.

[0003] Alternating electric fields are also useful for treating medical conditions other than tumors. For example, as described in U.S. Patent No. 10,967,167 (the entire content of which is incorporated herein by reference), alternating electric fields can be used to increase the permeability of the blood - brain barrier (BBB), such that, for example, chemotherapeutic agents can reach the brain.

Summary of the Invention

[0004] One aspect of the present application relates to a first method of treating a target region of a subject's body with an alternating electric field. The first method includes applying an alternating electric field to the target region during a treatment course, measuring neural or muscular activity generated in the subject's body in response to the application of the alternating electric field, and modifying the treatment course based on the measured neural or muscular activity. The frequency of the alternating electric field is between 50 kHz and 1 MHz.

[0005] In some examples of the first method, the neural or muscular activity includes neural activity, and the neural activity is measured using a passive array of ECAP electrodes. In some examples of the first method, the neural or muscular activity includes muscular activity, and the muscular activity is measured using electromyography. In some examples of the first method, the neural or muscular activity includes muscular activity, and the muscular activity is measured by mechanically sensing muscle twitches.

[0006] In some examples of the first method, the modification includes adjusting the amplitude of the alternating electric field applied to the target region based on the measured neural or muscular activity. In some examples of the first method, the modification includes decreasing the amplitude of the alternating electric field applied to the target region if the measured neural or muscular activity indicates that an electric sensation is expected. In some examples of the first method, the modification includes increasing the amplitude of the alternating electric field applied to the target region if the measured neural or muscular activity indicates that the amplitude can be increased without causing an electric sensation. In some examples of the first method, the modification includes adjusting the frequency of the alternating electric field applied to the target region based on the measured neural or muscular activity. In some examples of the first method, the modification includes increasing the frequency of the alternating electric field applied to the target region if the measured neural or muscular activity indicates that an electric sensation is expected.

[0007] In some examples of the first method, the modification includes applying an electrical signal to the subject's body during each of a plurality of time intervals during the treatment course. In these examples, the electrical signal is configured to reduce the electrical sensation when an alternating electric field is applied during the treatment course, and the timing for applying the electrical signal is determined based on the measured nerve or muscle activity. Optionally, in these examples, the timing for applying the electrical signal is performed based on whether the measured nerve or muscle activity indicates that an electrical sensation is expected. Optionally, in these examples, the electrical signal includes a train of at least 10 pulses.

[0008] Another aspect of the present application relates to a first apparatus for treating a target region of a subject's body with an alternating electric field. The first apparatus includes an alternating voltage generator having an alternating output operating at a frequency between 50 kHz and 1 MHz and at least one control input, and a controller. The controller is configured to (a) receive a signal from at least one sensor that measures nerve or muscle activity generated in the subject's body in response to the application of the alternating electric field, and (b) modify the treatment course based on the measured nerve or muscle activity.

[0009] In some embodiments of the first apparatus, the at least one sensor includes a set of ECAP electrodes, and the controller is configured to receive a signal representing nerve activity from the set of ECAP electrodes. In some embodiments of the first apparatus, the at least one sensor includes a set of electromyogram electrodes, and the controller is configured to receive a signal representing muscle activity from the set of electromyogram electrodes. In some embodiments of the first apparatus, the at least one sensor includes an accelerometer, and the controller is configured to receive a signal representing muscle activity from the accelerometer.

[0010] Some embodiments of the first device further include at least one first electrode element configured to be disposed on or within the subject's body and at least one second electrode element configured to be disposed on or within the subject's body. In these embodiments, an alternating current output is applied between the at least one first electrode element and the at least one second electrode element.

[0011] In some embodiments of the first device, the controller is programmed to send a signal to at least one control input to cause the alternating current voltage generator to adjust the amplitude of the alternating current output based on the measured nerve or muscle activity. In some embodiments of the first device, the controller is programmed to send a signal to at least one control input to cause the alternating current voltage generator to decrease the amplitude of the alternating current output if the measured nerve or muscle activity indicates that an electric sensation is expected. In some embodiments of the first device, the controller is programmed to send a signal to at least one control input to cause the alternating current voltage generator to increase the amplitude of the alternating current output if the measured nerve or muscle activity indicates that the amplitude can be increased without causing an electric sensation. In some embodiments of the first device, the controller is programmed to send a signal to at least one control input to cause the alternating current voltage generator to adjust the frequency of the alternating current output based on the measured nerve or muscle activity. In some embodiments of the first device, the controller is programmed to send a signal to at least one control input to cause the alternating current voltage generator to decrease the frequency of the alternating current output if the measured nerve or muscle activity indicates that an electric sensation is expected.

[0012] Some embodiments of the first device further include a signal generator configured to generate an electrical signal configured to reduce an electric sensation when an alternating current electric field is applied to the subject's body. In these embodiments, the controller is programmed to activate the signal generator based on the measured nerve or muscle activity.

[0013] Some embodiments of the first device further include a signal generator configured to generate an electrical signal that reduces the electrical sensation when an alternating current electric field is applied to the subject's body. In these embodiments, the controller is programmed to activate the signal generator based on the measured nerve or muscle activity, and the decision to activate the signal generator is made based on whether the measured nerve or muscle activity indicates that an electrical sensation is expected. Optionally, in these embodiments, the electrical signal includes a train of at least 10 pulses.

[0014] Some embodiments of the first device further include a signal generator configured to generate an electrical signal that reduces the electrical sensation when an alternating current electric field is applied to the subject's body, at least one first electrode element configured to be disposed on or in the subject's body, at least one second electrode element configured to be disposed on or in the subject's body, a third electrode element configured to be disposed on or in the subject's body, and a fourth electrode element configured to be disposed on or in the subject's body. In these embodiments, the controller is programmed to activate the signal generator based on the measured nerve or muscle activity. The alternating current output is applied between at least one first electrode element and at least one second electrode element. And the electrical signal is applied between the third electrode element and the fourth electrode element.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Best Mode for Carrying Out the Invention

[0016] When treating a subject with an alternating electric field, the greater the amplitude, the higher the therapeutic effect. However, when the amplitude of the alternating electric field increases or the frequency of the alternating electric field decreases (e.g., up to around 100 kHz), some subjects feel an electric sensation effect when the direction of the alternating electric field switches. This electric sensation is, for example, a vibrating sensation, a perceptual abnormality, a sensation of muscle fiber twitching or contraction, or a flickering of light in the eyes (flashes). And these sensations may cause some subjects to stop the treatment using the alternating electric field. The electric sensation is thought to be generated from the interaction between the alternating electric field and nerve cells or fibers (neurons or axons) arranged near or adjacent to the transducer array.

[0017] In the embodiments described below, based on the measured nerve or muscle activity generated in the subject's body in response to the application of the alternating electric field, it is determined when or how imminent the electric sensation is occurring. Thereafter, based on the measured nerve or muscle activity, the treatment course is modified to improve the electric sensation.

[0018] Several approaches for determining whether an electric sensation is occurring or is imminent are based on the measured neural activity. During a specific type of electrical stimulation to biological tissue, an evoked compound action potential (ECAP) represents the nearly synchronous firing of a population of electrically stimulated nerve fibers. When an electrical signal with sufficient energy to activate nerve fibers is applied, fibers with different diameters and at different locations are activated almost simultaneously (e.g., within a few milliseconds), and their action potentials (APs) propagate at different speeds near the recording electrodes. Furthermore, different nerve fibers with different diameters have different activation thresholds and conduction velocities, and transmit different signals for different types of sensations (e.g., vibration, temperature, hair movement, muscle contraction, joint position, etc.).

[0019] It has been found that ECAPs related to electric sensation can be measured using a series of electrodes placed on the subject's skin. These electrodes detect the combined sum of individual APs arriving almost simultaneously, which is displayed as a curve with a predetermined amplitude and duration.

[0020] The embodiments described below in relation to FIGS. 2-5 rely on ECAP signals received using such electrodes to detect or predict whether a subject may be experiencing an electric sensation and / or whether the electric sensation is close to a predicted threshold, and to modify the treatment course to improve the electric sensation. One way to modify the treatment course is to adjust the amplitude of the alternating electric field to improve the electric sensation. Another way to modify the treatment course is to adjust the frequency of the alternating electric field.

[0021] Yet another way to modify the treatment course is to apply a signal designed to block the activation of the fibers that generate the electric sensation. For example, a signal that raises the threshold of the electric sensation signal nerve allows a higher amplitude treatment signal to be applied without causing an electric sensation. Blocking the propagation of the electric sensation signal before it reaches the brain also allows the use of a higher treatment amplitude.

[0022] In the embodiments described below in connection with FIGS. 2-5, ECAP is used as feedback to modify an alternating current electric field, for example, to enhance a treatment effect or reduce undesirable side effects, i.e., to “close the loop” of the treatment process. The closed-loop technique described here is also referred to as adaptive control technology or adaptive delivery technology.

[0023] FIG. 2 shows an apparatus for treating a target region of a subject's body with an alternating current electric field that avoids or alleviates electric sensation by using ECAP to measure neural activity and modifying a treatment course based on the measured neural activity. The embodiment of FIG. 2 includes an alternating voltage generator 40 that generates an alternating output at a frequency of 50 kHz to 1 MHz (e.g., 50 to 500 kHz, 75 to 300 kHz, or 150 to 250 kHz). The alternating voltage generator 40 has at least one control input that can be used, for example, to control the output amplitude of the alternating voltage generator 40. The frequency of the alternating voltage generator 40 varies depending on the type of treatment. For example, when treating a tumor using a TT field, the frequency is 150 to 200 kHz. Alternatively, the frequency can be 50 kHz to 200 kHz (e.g., 100 kHz) to enhance the permeability of the subject's blood-brain barrier.

[0024] In the example shown in FIG. 2, a set of first electrode elements 45L is disposed on the left side of a target region on the subject's body (e.g., shaved skin), and a set of second electrode elements 45R is disposed on the right side of the target region on the subject's body. In another embodiment, the first electrode element sets 45L / 45R and the second electrode element sets 45L / 45R can be implanted on the left and right sides, respectively, of the target region inside the subject's body (e.g., just under the skin). When the alternating voltage generator 40 applies a voltage between the electrode element 45L and the electrode element 45R, an alternating current electric field having electric field lines generally running from right to left is induced in the target region. The frequency of the alternating current electric field matches the frequency of the alternating voltage generator 40. The electrode elements 45L / 45R can be capacitive coupling electrode elements or conductive electrode elements.

[0025] In addition to the electrode elements 45L / 45R used to induce an alternating electric field in the target area, an independent electrode set 55 is also provided to determine whether the subject is likely to be experiencing electric sensation or whether electric sensation is imminent. More specifically, a first ECAP electrode set 55 configured to detect an ECAP signal is disposed near the first electrode set 45L, and a second ECAP electrode set 55 configured to detect an ECAP signal is disposed near the second electrode set 45R. The sets of first and second ECAP electrodes 55 disposed on the left and right sides, respectively, may each be a passive electrode array.

[0026] Signals from these ECAP electrodes 55 (e.g., on the order of 0.2 to 2 mV) are received by the ECAP measurement system 50, which measures the ECAPs on the left and right sides of the subject's body based on the signals arriving from the ECAP electrodes 55 disposed on the left and right sides, respectively. The ECAP measurement system 50 processes these signals (e.g., using an amplifier and an analog-to-digital converter) and transfers the resulting data to the controller 30. In this way, the ECAPs generated on each side of the subject's body in response to the application of the alternating electric field are measured.

[0027] The ECAPs related to electric sensation are measured using the ECAP electrodes 55 and the ECAP measurement system 50, and their measured values are reported to the controller 30, so that the controller 30 can determine whether the subject may be experiencing electric sensation and / or whether the electric sensation is close to the expected threshold. The controller 30 can modify the treatment course based on the measured ECAP. The modification based on the measured ECAP can be, for example, adjusting the amplitude or frequency of the alternating electric field applied to the target area based on the measured ECAP.

[0028] Figure 3 shows an example of a method for treating a target area of a subject's body with an alternating electric field, and the controller 30 modifies the treatment course based on the measured ECAP. In S20, an alternating electric field is applied to the target area in the treatment course (for example, when the alternating voltage generator 40 applies an alternating output to the electrodes 45L / 45R). In S30, the evoked compound action potential (ECAP) generated in the subject's body in response to the application of the alternating electric field in S20 is measured. This measurement is performed using the ECAP electrode 55 and the ECAP measurement system 50 as described above, and the measured value is reported to the controller 30. In S40, the controller 30 checks whether electric sensation is expected based on the measured ECAP. If electric sensation is expected, the method proceeds to S45, where the controller 30 sends commands to the control inputs of the alternating voltage generator 40, and these commands cause the output amplitude of the alternating voltage generator 40 to decrease. The decrease in amplitude improves the electric sensation.

[0029] If electric sensation is not expected, the method proceeds to S50, where the controller 30 determines whether it is possible to increase the amplitude without causing electric sensation based on the measured ECAP. If the result is "yes", the method proceeds to S55, where the controller 30 issues a command to the alternating voltage generator 40 to increase the output amplitude of the alternating voltage generator (as long as this does not cause the electrodes 45 to overheat). This increase in amplitude improves the effectiveness of the alternating electric field treatment without causing discomfort to the subject. If the result of S50 is "no", the method of Figure 3 restarts from the beginning.

[0030] In many anatomical locations, it is desirable to use electric fields whose orientation alternates between different directions. At these locations, additional sets of electrode elements 45 (not shown in FIG. 2) can be placed on the other side of the target region (e.g., front and back). In these embodiments, the alternating voltage generator 40 is preferably configured to alternately and repeatedly perform (a) applying a voltage between the left electrode element 45L and the right electrode element 45R, and (b) applying a voltage between the front electrode element and the back electrode element. The alternating voltage generator 40 can switch between these two states every second or at different intervals (e.g., between 50 milliseconds and 10 seconds). Thus, the direction of the electric field in these embodiments will repeatedly alternate between the left / right direction and the front / back direction.

[0031] In these embodiments where additional sets of electrode elements 45 are placed on the other side of the target region, corresponding additional sets of ECAP electrodes 55 need to be placed near the additional electrode elements 45 in order to determine whether the subject is likely to experience or is about to experience an electric sensation. The controller 30 processes the signals from these additional sets of ECAP electrodes 55 as described above for the left and right sets of ECAP electrodes 55 (e.g., reducing the amplitude of the voltage applied to the additional sets of electrode elements 45 when an electric sensation is expected at the additional sets of electrode elements 45).

[0032] Adjusting the amplitude of the output of the alternating voltage generator 40 (as described above in connection with FIGS. 2 - 3) is not the only way to avoid or improve an electric sensation. On the contrary, since lower frequencies generally cause an electric sensation more commonly than higher frequencies, another way to avoid or improve an electric sensation is for the controller 30 to send a command to the alternating voltage generator 40 to increase the frequency of the alternating electric field each time the controller 30 determines that an electric sensation is occurring or is likely to occur.

[0033] Figures 4-5 show another approach for treating a target region of a subject's body with an alternating electric field that avoids or improves electric sensation by measuring neural activity using ECAP. In particular, these embodiments avoid or improve electric sensation by applying an additional electric signal to the subject's body. These additional electric signals are configured to reduce the subject's sensation when the alternating electric field is applied during a treatment course.

[0034] As described above, electric sensation is thought to arise from the interaction of an alternating electric field with nerve cells or fibers (neurons or axons) located near or adjacent to the transducer array. Without being bound by this theory, the additional electric signals applied in the embodiments of Figures 4-5 are thought to reduce the subject's sensation by blocking their activation, such as by raising the action potential threshold of the associated nerve cells, or interfering with the operation of ion channel gates, or inhibiting AP propagation by having a similar effect on the axonal region near the AP generation point.

[0035] The electrical signal that reduces the subject's sensation may include a train of at least 10 pulses. In some embodiments, experimentally, different nerve fibers have been shown to respond to different blocking signal designs, so each such electrical signal may include a train of at least 12 pulses, at least 15 pulses, or at least 20 pulses. For example, it has been shown that the activation thresholds of the median nerve and the peroneal nerve increase significantly in response to a train of 10 or more pulses, but do not respond to a single pulse. In some embodiments, each electrical signal may include a train of 10 - 15 pulses, or a train of 10 - 20 pulses. In some embodiments, each of these pulses has a width of at least 100 μs. In some embodiments, each of these pulses has a width of at least 150 μs, 200 μs, 250 μs, 300 μs, or 400 μs. In some embodiments, each of these pulses has a width of 100 μs - 500 μs, 100 μs - 250 μs, or 100 μs - 200 μs. In some embodiments, each of these pulses has a width of at least 20 ms, 50 ms, or 100 ms. In some embodiments, each of these pulses has a width of 20 - 50 ms, 50 - 100 ms, or 100 - 200 ms.

[0036] In some embodiments, the train of pulses continues for at least 100 ms. In some embodiments, the train of pulses continues for at least 150 ms, 200 ms, 250 ms, 300 ms, or 400 ms. In some embodiments, the train of pulses continues from 100 ms to 500 ms, from 100 ms to 250 ms, or from 100 ms to 200 ms. In some embodiments, the pulses are configured to provide a charge - balanced waveform.

[0037] Increases in the thresholds of the median and peroneal nerves have been shown to last longer when the applied blocking train lasts for hundreds of milliseconds, and in some blocking protocols, the increase in threshold can last for several minutes or tens of minutes. A longer increase period of the threshold is desirable because it allows for a lower application frequency of the blocking signal, simplifies treatment, and reduces energy requirements.

[0038] The frequency of the electrical signal that reduces the subject's sensation can also be in the range of 4 kHz to 30 kHz. Alternatively, the frequency of the electrical signal can be in the range of 0.1 Hz to 30 Hz (for example, 0.1 Hz to 1 Hz, or 1 Hz to 10 Hz). In some embodiments, the frequency of the electrical signal is between 1 Hz and 2 Hz. In some embodiments, the amplitude of the electrical signal is 0.5 to 10 mA. In some embodiments, the amplitude is 0.5 to 1 mA, 1 to 2 mA, or 2 to 10 mA. In some embodiments, the duration of the electrical signal is 1 to 60 seconds. In some embodiments, the duration of the electrical signal is less than 10 seconds (for example, 1 to 10 seconds, 1 to 2 seconds, 2 to 5 seconds, or 5 to 10 seconds).

[0039] The frequency of the electrical signal that alleviates the subject's sensation can also be 0.25 to 10 Hz (for example, 0.5 to 5 Hz, or 1 to 2 Hz). In these embodiments, the electrical signal may optionally be offset from zero amplitude. In these embodiments, the duration of each electrical signal may be 100 milliseconds to 30 seconds, 200 milliseconds to 20 seconds, 500 milliseconds to 20 seconds, or 500 milliseconds to 10 seconds.

[0040] The electrical signal that reduces the subject's sensation may be below or above the threshold of the nerve fibers that produce the unwanted sensation. In some embodiments, the electrical signal is first applied below the threshold of the nerve fibers that produce the unwanted sensation, and after the first electrical signal causes an increase in the action potential threshold of the associated nerve cells, its amplitude is then increased until it exceeds that threshold. The applied electrical signal may be below or above the threshold of the 7-15 μm Abeta nerve fibers that produce at least one of vibration and paresthesia. In some embodiments, the electrical signal is first applied below the threshold of the 7-15 μm Aβ nerve fibers that produce at least one of vibration and paresthesia, and after the first electrical signal causes an increase in the action potential threshold of the associated nerve cells, their amplitudes are then increased until they exceed the original threshold. The electrical signal preferably always remains below the threshold of the nerve fibers that cause at least one of muscle twitching and contraction.

[0041] Figure 4 shows another apparatus for treating a target region of a subject's body with an alternating electric field that utilizes ECAP to reduce or eliminate electrical sensation. The embodiment of Figure 4 includes an alternating voltage generator 40 similar to the alternating voltage generator 40 described above in connection with Figure 2. The frequency of the alternating voltage generator 40 varies depending on the type of treatment, as described above in connection with Figure 2.

[0042] The embodiment of Figure 4 includes a set of first electrode elements 45L and a set of second electrode elements 45R, which are used to induce an alternating electric field in the target region and are similar to the correspondingly numbered electrode elements described above in connection with Figure 2. Further, the embodiment of Figure 4 has multiple sets of ECAP electrodes 55 similar to the ECAP electrodes 55 described above in connection with Figure 2. Signals from these ECAP electrodes 55 are received, processed by an ECAP measurement system 50 (e.g., as described above in connection with Figure 2), and the resulting data is transferred to the controller 30.

[0043] ECAP related to electroesthesia is measured using the ECAP electrode 55 and the ECAP measurement system 50, and the measured values are reported to the controller 30. Therefore, the controller 30 can determine whether the subject may be experiencing electroesthesia and / or whether the electroesthesia is close to the predicted threshold. The controller 30 can change the treatment course based on the measured ECAP.

[0044] In the embodiment of FIG. 4, during each of a plurality of time intervals in the treatment course, the treatment course is modified by applying an electrical signal to the subject's body using the signal generator 60 via yet another set of electrode elements 65. The electrical signal generated by the signal generator 60 is configured to reduce electroesthesia when an alternating electric field is applied to the subject's body in the treatment course (e.g., as described above).

[0045] In the example shown in FIG. 4, the electrode elements 65 are arranged in pairs and are arranged on the opposite side adjacent to each set of electrode elements 45L / 45R. As a result, when an electrical signal is applied between the electrode elements 65, the electrical signal will pass through the skin area under the electrode elements 45L / 45R. The electrical signal interacts with the nerve fibers in these areas, and this interaction reduces electroesthesia while the electrode elements 45L / 45R are active. Here, "adjacent" as used herein means "nearby", and the term "adjacent" does not require contact or an adjacency relationship.

[0046] The controller 30 determines the timing at which the signal generator 60 applies an electrical signal to the electrode elements 65 based on the measured ECAP and executes this determination by sending an appropriate command to the signal generator 60. For example, the determination of the timing for applying the electrical signal can be made based on whether the measured ECAP (measured using the ECAP electrode 55 and the ECAP system 50) indicates that electroesthesia is expected.

[0047] FIG. 5 shows an example of a method of treating a target region of a subject's body with an alternating electric field, in which the controller 30 of FIG. 4 modifies the treatment course based on the measured ECAP. In S120, an alternating electric field is applied to the target region in the treatment course (for example, when the alternating voltage generator 40 applies an alternating output to the electrodes 45L / 45R). In S130, the ECAP generated by the subject's body in response to the application of the alternating electric field in S120 is measured. This measurement is performed using the ECAP electrode 55 and the ECAP measurement system 50 as described above, and the measured value is reported to the controller 30. In S140, the controller 30 checks whether electric sensation is expected based on the measured ECAP. If electric sensation is expected, the method proceeds to S160, where the controller 30 sends commands to the control inputs of the signal generator 60, and the signal generator 60 generates electrical signals configured to reduce the electric sensation (for example, as described above). If electric sensation is not expected in S140, the method of FIG. 5 restarts from the beginning.

[0048] As described above in connection with FIG. 3, it is preferable to use additional sets of electrode elements 45 (not shown in FIG. 4) to use electric fields with alternating orientations between different directions at many anatomical locations. In such a situation, each set of electrode elements 45 preferably has its own associated set of ECAP electrodes 55 and its own associated set of electrodes 65, which operate in the same manner as the corresponding electrodes 55 / 65 shown in FIG. 4 and described above.

[0049] In the example shown in FIG. 4, the electrode element 65 is adjacent to the electrode element 45 and is separate from the electrode element 45. However, in an alternative embodiment, a single physical electrode element can also perform multiple functions of these electrode elements 45, 65 simultaneously (for example, using superposition to combine two signals and applying the superimposed signal to a single electrode element), or a single physical electrode element can perform multiple functions of these electrode elements 45, 65 at different times (for example, using time-division multiplexing).

[0050] The embodiments described above in connection with FIG. 2-5 rely on a passive array of ECAP electrodes to measure neural activity based on the theory that it is possible to determine whether or not electrical sensation is occurring or is imminent using neural activity. However, instead of the ECAP-based technology described above, various alternative approaches can be used to determine whether or not electrical sensation is occurring or is imminent.

[0051] As an example of an alternative approach, there are those that use electromyogram signals to measure muscle activity based on the theory that muscle activity (such as twitching) may indicate the occurrence of electrical sensation. In these embodiments, the electromyogram (EMG) signals are acquired using a set of EMG electrodes, preprocessed by an EMG system, and transferred to a controller (similar to the above-described controller 30 but programmed to interpret EMG signals rather than ECAP signals). As another example of an alternative approach, there are those that use a mechanical sensor (such as an accelerometer) to measure muscle activity based on the theory that muscle activity (for example, twitching) is a sign that electrical sensation is occurring. In these embodiments, vibration or acceleration signals are captured using a mechanical sensor, preprocessed by an appropriate front end, and transferred to a controller (similar to the above-described controller 30 but programmed to interpret mechanical events rather than ECAP signals). Other approaches based on measured neural or muscle activity can also be used.

[0052] In the embodiments described above in connection with FIGS. 2 and 4, the alternating voltage generator 40 generates an alternating output at a frequency of 50 kHz to 1 MHz. Then, when the output signal from the alternating voltage generator 40 drives the electrode elements 45L, 45R, an alternating electric field is applied to the target area at a frequency of 50 kHz to 1 MHz. However, this is not the only way to apply an alternating electric field in the frequency range of 50 kHz to 1 MHz to the target area. Conversely, an alternative approach to applying an alternating electric field in the frequency range of 50 kHz to 1 MHz to the target area can also be adopted.

[0053] An example of such an alternative approach relies on the concept of amplitude modulation (AM). Specifically, when a carrier signal at frequency f1 is amplitude modulated by a tone signal at frequency f2, the output of the modulator contains frequency components of f1, f1 + f2, and f1 - f2 (i.e., the original carrier, the sum, and the difference). Thus, when a 10 MHz carrier is amplitude modulated by a 9.8 MHz tone signal, the output of the modulator contains frequency components of 200 kHz, 10 MHz, and 19.8 MHz. Therefore, when using the output of the AM modulator to drive the electrode elements 45L, 45R, the 200 kHz component present in the output of the AM modulator induces an alternating electric field of 200 kHz frequency (and additional frequency components in the MHz range) in the target area.

[0054] In this AM modulation-based embodiment, based on the measured neural or muscular activity, the frequency of the alternating electric field applied to the target area can be increased by increasing the carrier frequency or decreasing the tone frequency. Or, based on the measured neural or muscular activity, the frequency of the alternating electric field applied to the target area can be decreased by decreasing the carrier frequency or increasing the tone frequency.

[0055] The present invention has been disclosed with reference to specific embodiments, but numerous modifications, alterations, and changes of the above embodiments are possible without departing from the scope or scope of the invention as described in the claims. Accordingly, the present invention is not intended to be limited to the above embodiments, but is intended to have all of the scope defined by the expressions of the following claims and the equivalents thereof.

Claims

1. A method to assist in the treatment of a target area of ​​a subject's body with an alternating electric field, The steps include measuring nerve or muscle activity generated in the subject's body in response to the application of an alternating electric field to a target area during a treatment course, with a frequency between 50 kHz and 1 MHz, A method comprising the step of assisting a course of treatment by modifying the course of treatment based on the measured nerve or muscle activity.

2. The method according to claim 1, wherein the nerve or muscle activity includes nerve activity, and the nerve activity is measured using a passive array of ECAP electrodes.

3. The method according to claim 1, wherein the nerve or muscle activity includes muscle activity, and the muscle activity is measured using electromyography.

4. The method according to claim 1, wherein the nerve or muscle activity includes muscle activity, and the muscle activity is measured by mechanically sensing muscle spasms.

5. The method according to claim 1, wherein the modification includes adjusting the amplitude of the alternating electric field applied to the target region based on the measured nerve or muscle activity.

6. The method according to claim 1, wherein the modification includes reducing the amplitude of the alternating electric field applied to the target region when the measured nerve or muscle activity indicates that electrosensation is expected.

7. The method according to claim 1, wherein the modification includes increasing the amplitude of the alternating electric field applied to the target region if the measured nerve or muscle activity can increase in amplitude without causing electrosensation.

8. The method according to claim 1, wherein the modification includes adjusting the frequency of the alternating electric field applied to the target region based on the measured nerve or muscle activity.

9. The method according to claim 1, wherein the modification includes increasing the frequency of the alternating electric field applied to the target region if the measured nerve or muscle activity indicates that electrosensation is expected.

10. The modification comprises applying an electrical signal to the subject's body during each of a plurality of time intervals in the course of treatment, The aforementioned electrical signal is configured to reduce electrical sensation when an alternating electric field is applied during the treatment course. The method according to claim 1, wherein the timing for applying the electrical signal is determined based on the measured nerve or muscle activity.

11. The method according to claim 10, wherein the timing for applying the electrical signal is determined based on the timing at which the measured nerve or muscle activity indicates that electrosensation is expected.

12. The method according to claim 11, wherein the electrical signal comprises a sequence of at least 10 pulses.

13. A device for treating a target area of ​​a subject's body with an alternating electric field, An AC voltage generator having an AC output operating at a frequency of 50 kHz to 1 MHz and at least one control input, An apparatus comprising: (a) receiving a signal from at least one sensor that measures nerve or muscle activity generated in a subject's body in response to the application of an alternating electric field; and (b) a controller configured to modify a course of treatment based on the measured nerve or muscle activity.

14. The apparatus according to claim 13, wherein the at least one sensor includes a set of ECAP electrodes, and the controller is configured to receive signals representing the activity of the nerve from the set of ECAP electrodes.

15. The apparatus according to claim 13, wherein the at least one sensor includes a set of electromyographic electrodes, and the controller is configured to receive signals representing muscle activity from the set of electromyographic electrodes.

16. The apparatus according to claim 13, wherein the at least one sensor comprises an accelerometer, and the controller is configured to receive a signal from the accelerometer representing the activity of the muscle.

17. The apparatus according to claim 13, further comprising at least one first electrode element configured to be positioned on or inside the body of the subject, and at least one second electrode element configured to be positioned on or inside the body of the subject, wherein the AC output is applied between the at least one first electrode element and the at least one second electrode element.

18. The apparatus according to claim 13, wherein the controller is programmed to transmit a signal to at least one control input causing an AC voltage generator to adjust the amplitude of its AC output based on measured nerve or muscle activity.

19. The apparatus according to claim 13, wherein, if the measured nerve or muscle activity indicates that electrosensation is expected, the controller is programmed to send a signal to the AC voltage generator to at least one control input that reduces the amplitude of the AC output.

20. The apparatus according to claim 13, wherein the controller is programmed to send a signal to the AC voltage generator to increase the amplitude of the AC output if the measured nerve or muscle activity can be increased without causing electrosensation.

21. The apparatus according to claim 13, wherein the controller is programmed to transmit a signal to at least one control input causing the AC voltage generator to adjust the frequency of the AC output based on the measured nerve or muscle activity.

22. The apparatus according to claim 13, wherein, if the measured nerve or muscle activity indicates that electrosensation is expected, the controller is programmed to send a signal to the AC voltage generator to at least one control input that reduces the frequency of the AC output.

23. The present invention further includes a signal generator that generates an electrical signal configured to reduce electrosensory sensation when the alternating electric field is applied to the body of the subject, The apparatus according to claim 13, wherein the controller is programmed to activate the signal generator based on the measured nerve or muscle activity.

24. The apparatus according to claim 23, wherein the decision to activate the signal generator is made based on the time at which the measured nerve or muscle activity indicates that electrosensation is expected.

25. The apparatus according to claim 24, wherein the electrical signal comprises a sequence of at least 10 pulses.

26. comprising at least one first electrode element configured to be positioned on or inside the body of the subject, and at least one second electrode element configured to be positioned on or inside the body of the subject, wherein the AC output is applied between the at least one first electrode element and the at least one second electrode element. The apparatus according to claim 23, comprising a third electrode element configured to be positioned on or inside the body of the subject, and a fourth electrode element configured to be positioned on or inside the body of the subject, wherein an electrical signal is applied between the third electrode element and the fourth electrode element.

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