Delivery of a tumor therapeutic electrical field to the brain of a subject using electrodes mounted in a through-hole in the skin

Abstract

When a tumor therapy electric field (TTField) is applied to the brain of a subject across the skull of the subject, the amplitude of the TTField is significantly attenuated by the skull. The attenuation effect of the skull may be overcome by making small through-holes in the skull, and mounting individual electrodes in each of the through-holes, with the inner ends of the individual electrodes positioned beneath the skull of the subject. Then, when an AC voltage is applied between the electrode on one side of the subject's skull and the electrode on the other side of the subject's skull, the generated electric field will not pass through the skull and thus will not attenuate.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application 63 / 541,344, filed on September 29, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Tumor therapeutic electric field (TTField) therapy is a proven method for treating tumors using alternating electric fields with frequencies between 100 and 500 kHz (e.g., 200 kHz). In the existing Optune® system, the TTField is delivered to the patient via an array of four transducers placed on the skin near the tumor. These transducer arrays are arranged in two pairs, with one pair positioned on the left and right sides of the tumor and the other pair positioned on the front and back sides. When an AC voltage is applied between opposing electrode assemblies, an AC current couples through the electrode assemblies and into the subject's body, inducing an electric field in the target area (e.g., the tumor). Higher field strength is closely associated with higher therapeutic efficacy.

[0003] Conventional electrode assemblies for applying TTFields to a subject's body are applied to the subject's skin on the opposite side of the head, and examples of such conventional electrode assemblies are described in U.S. Patent 8,715,203 and U.S. Publication No. 2021 / 0202179. However, when the electrodes are positioned on the subject's skin, the electric field must pass through the patient's scalp and skull twice to reach the tumor, which introduces two challenges. First, the skull is present between the transducer array and the tumor, making it more difficult to align the field with the desired location in the brain (i.e., the tumor bed). Second, due to the attenuation of the electric field introduced by the skull and scalp, the voltage and current applied to the transducer array must be relatively high to obtain an electric field with a therapeutically effective amplitude in the tumor bed. Summary of the Invention

[0004] One aspect of the present invention relates to a first device for delivering an alternating electric field to a target region in the brain of a subject. The first device includes a plurality of first electrode assemblies and a plurality of second electrode assemblies, the plurality of first electrode assemblies being configured for positioning through corresponding plurality of first holes in the skull of the subject on a first side of the target region, and the plurality of second electrode assemblies being configured for positioning through corresponding plurality of second holes in the skull of the subject on a second side of the target region. Each of the plurality of first electrode assemblies has a first shaft having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the first shaft are designed to traverse a corresponding first hole in the first hole; a first flange disposed at the outer end of the first shaft, wherein the first flange has an outer diameter larger than the first shaft, and the shape and size of the first flange are designed to prevent the first electrode assembly from passing through the corresponding first hole; a first conductive electrode element disposed at the inner end of the first shaft, wherein the first electrode element has an inner surface perpendicular to the longitudinal axis of the first shaft with a deviation within 10°, and wherein the inner surface of the first electrode element has an area of ​​at least 5 mm²; and a first wire having a first portion positioned for electrical contact with the first electrode element and a second portion configured to extend under the scalp of the subject. Each of the plurality of second electrode assemblies has a second shaft having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the second shaft are designed to traverse a corresponding second hole in the second hole; a second flange disposed at the outer end of the second shaft, wherein the second flange has an outer diameter larger than the second shaft, and the shape and size of the second flange are designed to prevent the second electrode assembly from passing through the corresponding second hole; a second conductive electrode element disposed at the inner end of the second shaft, wherein the second electrode element has an inner surface perpendicular to the longitudinal axis of the second shaft with a deviation within 10°, and wherein the inner surface of the second electrode element has an area of ​​at least 5 mm²; and a second wire having a first portion positioned for electrical contact with the second electrode element and a second portion configured to extend under the subject's scalp. The first device also includes at least one port configured for attachment to the subject's skull. The at least one port includes (a) at least one first terminal configured to be electrically connected to each of the first conductors such that an electrical signal can be applied to each of the first conductors via the at least one port, and (b) at least one second terminal configured to be electrically connected to each of the second conductors such that an electrical signal can be applied to each of the second conductors via the at least one port.

[0005] In some embodiments of the first device, each of the plurality of first electrode assemblies has a first insulating material layer disposed on the inner surface of the first electrode element. When the first axis is positioned in the corresponding first hole, the first insulating material layer is positioned to insulate the first electrode element from the dura mater of the subject. The first insulating material layer has a dielectric constant of at least 10. In these embodiments, each of the plurality of second electrode assemblies has a second insulating material layer disposed on the inner surface of the second electrode element. When the second axis is positioned in the corresponding second hole, the second insulating material layer is positioned to insulate the second electrode element from the dura mater of the subject. The second insulating material layer has a dielectric constant of at least 10.

[0006] Optionally, in the embodiments described in the preceding paragraphs, each of the first insulating material layers and each of the second insulating material layers comprises a polymer layer having a thickness of less than 50 µm. Optionally, in the embodiments described in the preceding paragraphs, each of the first insulating material layers and each of the second insulating material layers comprises a ceramic material having a dielectric constant of at least 1000.

[0007] In some embodiments of the first device, each of the first electrode elements is positioned to contact the dura mater of the subject when the corresponding first axis is positioned in the corresponding first aperture, and each of the second electrode elements is positioned to contact the dura mater of the subject when the corresponding second axis is positioned in the corresponding second aperture. Optionally, in these embodiments, each of the first electrode elements and each of the second electrode elements is made of metal.

[0008] In some embodiments of the first device, the inner surface of each of the first electrode elements and the inner surface of each of the second electrode elements have an area of ​​5-20 mm². In some embodiments of the first device, each of the first electrode elements and each of the second electrode elements has a bottom surface that is perpendicular to the longitudinal axis of the corresponding axis, with a deviation within 2°.

[0009] Another aspect of the invention relates to a first method for delivering an alternating electric field to a target region in the brain of a subject. The first method includes positioning a plurality of first electrode assemblies through corresponding plurality of first holes in the subject's skull on a first side of the target region, and positioning a plurality of second electrode assemblies through corresponding plurality of first holes in the subject's skull on a second side of the target region. Each of the plurality of first electrode assemblies has a first shaft having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the first shaft are designed to traverse a corresponding first hole in the first hole; a first flange disposed at the outer end of the first shaft, wherein the first flange has an outer diameter larger than the first shaft, and the shape and size of the first flange are designed to prevent the first electrode assembly from passing through the corresponding first hole; a first conductive electrode element disposed at the inner end of the first shaft, wherein the first electrode element has an inner surface perpendicular to the longitudinal axis of the first shaft with a deviation within 10°, and wherein the inner surface of the first electrode element has an area of ​​at least 5 mm²; and a first wire having a first portion positioned for electrical contact with the first electrode element and a second portion configured to extend under the scalp of the subject. Each of the plurality of second electrode assemblies has a second shaft having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the second shaft are designed to traverse a corresponding second hole in the second hole; a second flange disposed at the outer end of the second shaft, wherein the second flange has an outer diameter larger than the second shaft, and the shape and size of the second flange are designed to prevent the second electrode assembly from passing through the corresponding second hole; a second conductive electrode element disposed at the inner end of the second shaft, wherein the second electrode element has an inner surface perpendicular to the longitudinal axis of the second shaft with a deviation within 10°, and wherein the inner surface of the second electrode element has an area of ​​at least 5 mm²; and a second wire having a first portion positioned for electrical contact with the second electrode element and a second portion configured to extend under the scalp of the subject. The first method further includes applying an alternating voltage having a frequency between 50 kHz and 1 MHz between (a) the plurality of first electrode assemblies and (b) the plurality of second electrode assemblies.

[0010] In some instances of the first method, each of the plurality of first electrode assemblies has a first insulating material layer disposed on the inner surface of the first electrode element. When the first axis is positioned in the corresponding first hole, the first insulating material layer is positioned to insulate the first electrode element from the dura mater of the subject, and the first insulating material layer has a dielectric constant of at least 10. In these instances, each of the plurality of second electrode assemblies has a second insulating material layer disposed on the inner surface of the second electrode element. When the second axis is positioned in the corresponding second hole, the second insulating material layer is positioned to insulate the second electrode element from the dura mater of the subject, and the second insulating material layer has a dielectric constant of at least 10.

[0011] Optionally, in the examples described in the preceding paragraphs, each of the first insulating material layers and each of the second insulating material layers comprises a polymer layer having a thickness of less than 50 µm. Optionally, in the examples described in the preceding paragraphs, each of the first insulating material layers and each of the second insulating material layers comprises a ceramic material having a dielectric constant of at least 1000.

[0012] In some instances of this first method, when the corresponding first axis is positioned in the corresponding first aperture, each of the first electrode elements is positioned to contact the dura mater of the subject, and when the corresponding second axis is positioned in the corresponding second aperture, each of the second electrode elements is positioned to contact the dura mater of the subject. Optionally, in these instances, each of the first electrode elements and each of the second electrode elements is made of metal.

[0013] In some embodiments of the first method, the inner surface of each of the first electrode elements and the inner surface of each of the second electrode elements have an area of ​​5-20 mm². In some embodiments of the first method, each of the first electrode elements and each of the second electrode elements has a bottom surface perpendicular to the longitudinal axis of the corresponding axis, with a deviation within 2°. In some embodiments of the first method, the alternating electric field has a frequency between 100 kHz and 300 kHz.

[0014] Another aspect of the invention relates to a second device for delivering an alternating electric field to a target region in the brain of a subject. The second device includes a shaft having a longitudinal axis, an upper end, and a lower end, wherein the shaft has a length of 4-10 mm and an outer diameter of 2-15 mm; a flange disposed at the upper end of the shaft, wherein the flange has a diameter at least 2 mm larger than the outer diameter of the shaft; a conductive electrode element disposed at the lower end of the shaft, wherein the electrode element has a lower surface perpendicular to the longitudinal axis of the shaft, with a deviation within 10°, and wherein the lower surface of the electrode element has an area of ​​at least 5 mm²; and an insulating material layer disposed on the lower surface of the electrode element. The insulating material layer covers the lower surface of the electrode element to prevent the lower surface of the electrode element from contacting tissue located below the device. The insulating material layer has a dielectric constant of at least 10.

[0015] Some embodiments of the second device also include a metal wire having a first segment configured to make electrical contact with the electrode element and extending through the shaft. In these embodiments, the electrode element is made of metal.

[0016] Optionally, in the embodiments described in the preceding paragraphs, the insulating material layer comprises a polymer layer having a thickness of less than 50 µm. Optionally, in the embodiments described in the preceding paragraphs, the insulating material layer comprises a ceramic material having a dielectric constant of at least 1000.

[0017] In some embodiments of the second device, the lower surface of the electrode element has an area of ​​5-20 mm². In some embodiments of the second device, the shaft has a cylindrical outer surface. In some embodiments of the second device, the lower surface of the electrode element is perpendicular to the longitudinal axis of the shaft, with a deviation within 2°. Attached Figure Description

[0018] Figure 1 A system was described that can be used to apply TTField to the brain of a subject without suffering the attenuation effect of the subject's skull.

[0019] Figure 2 A type of electrode assembly installed through the subject's skull is depicted.

[0020] Figure 3 Another type of electrode assembly installed through the subject's skull is depicted.

[0021] Various embodiments are described in detail below with reference to the accompanying drawings, wherein the same reference numerals denote the same elements. Detailed Implementation

[0022] U.S. Patent 11,654,279 addresses the two aforementioned challenges by integrating electrodes into the interior of a skull implant designed to replace a portion of the human skull. However, while this solution overcomes the problem of interference with electric fields in the skull, it introduces a different set of problems: (1) the solution is a highly invasive method because a large portion of the subject's skull must be sawed off from the head, and (2) the solution may make the head vulnerable to impact.

[0023] This application describes a different method for overcoming the attenuation effect of the skull on a TTField. More specifically, the attenuation effect of the skull is overcome by creating numerous small, less invasive perforations in the skull and installing multiple individual electrodes in each of these perforations, rather than by replacing an entire skull segment with a skull implant comprising a set of internal electrodes. It is noteworthy that because the inner ends of these individual electrodes are positioned beneath the subject's skull, AC current introduced using these electrodes will not be attenuated by the skull. Advantageously, introducing a set of perforations through the skull is easier and less risky (compared to replacing an entire skull segment with a skull implant). Furthermore, a set of perforations better preserves the original structural integrity of the skull compared to a skull implant.

[0024] Figure 1 A system is described that can be used to apply TTFields to a subject's brain without suffering attenuation effects from the subject's skull. For use with this system, four sets of small holes are made on the left, right, front, and back sides of the subject's skull, and individual electrode assemblies 10 are installed in each of these holes. Note that, although... Figure 1 Fourteen individual electrode assemblies 10 are shown mounted on each of the four sides of the subject's head, but the number of individual electrode assemblies 10 on any one side may differ (e.g., 1-50, 2-25, 4-20, 4-15, etc.). Furthermore, although... Figure 1 Four sets of electrode assemblies 10 are shown, but the number of sets of electrode assemblies 10 may vary, for example, 2-10. When only two sets of electrode assemblies 10 are installed, they should be positioned on opposite sides of the subject's skull (e.g., one set on the left and one set on the right, or one set on the front and one set on the back).

[0025] After the electrode assemblies 10 have been mounted on the corresponding sides of the subject's head, the AC voltage generator 30 can apply AC current between opposing sets of electrodes (i.e., between the left and right sets of electrode assemblies, or between the front and rear sets of electrode assemblies). The operation of the AC voltage generator 30 is controlled by the controller 20. Various methods for implementing the AC voltage generator 30 can be used, including but not limited to the method described in U.S. Patent 11,601,067, the entire contents of which are incorporated herein by reference. In some embodiments, the AC voltage generator 30 and the controller 20 may be combined into a single device.

[0026] In some embodiments, the electrode assembly 10 is mounted to Figure 2 The depicted anatomical location places the inner tip of electrode element 13 in contact with the outer layer of the dura mater within the epidural space. Notably, the inner tip of electrode assembly 10 does not penetrate the dura mater.

[0027] A suitable method for mounting the electrode assembly 10 at this anatomical location is similar to the mounting method for PEG epidural electrodes. More specifically, each electrode assembly 10 can be mounted by making a small (e.g., 1 cm) puncture incision, drilling a guide hole, and inserting the electrode assembly 10 into the guide hole. Figure 2 The depicted anatomical location places the inner tip of electrode element 13 in contact with the outer layer of the dura mater within the epidural space. However, various alternative methods can also be used to mount electrode assembly 10. Figure 2 The anatomical locations depicted.

[0028] exist Figure 2 In the depicted embodiments, each electrode assembly in the electrode assembly 10 has a shaft 11 having a longitudinal axis, an inner end, and an outer end. The shape and size of the shaft are designed to pass through a corresponding hole in a hole in the skull. In some preferred embodiments, the shaft has a length of 4-10 mm and an outer diameter of 2-15 mm.

[0029] Each electrode assembly in the electrode assembly 10 also has a flange 12 disposed at the outer end of the shaft, and the flange has an outer diameter larger than that of the shaft, and the shape and size of the flange are designed to prevent the electrode assembly from passing through the corresponding hole. In some preferred embodiments, the flange 12 has a diameter at least 2 mm larger than the outer diameter of the shaft 11.

[0030] Each electrode assembly in electrode assembly 10 further includes a conductive electrode element 13 disposed at the inner end of the shaft. The electrode element has an inner surface perpendicular to the longitudinal axis of the shaft, with a deviation within 10° (or within 2° in some preferred embodiments), and the inner surface of the electrode element has an area of ​​at least 5 mm². Each electrode assembly in electrode assembly 10 also includes a conductor 14 having a first portion positioned for electrical contact with the electrode element 13 and a second portion configured to extend beneath the subject's scalp. In some preferred embodiments, the inner surface of each electrode element 13 has an area of ​​5-20 mm².

[0031] exist Figure 2 In this embodiment, each electrode element in electrode element 13 is positioned to electrically contact the subject's dura mater when the corresponding axis is positioned in its corresponding hole through the skull. Each electrode element in electrode element 13 is made of a conductive material, such as a biocompatible metal, like stainless steel. Thus, when the first set of electrode assemblies 10 is mounted on one side of the subject's head and the second set of electrode assemblies 10 is mounted on the opposite side of the subject's head, and an AC voltage (via wire 14) is applied between the electrode elements 13 in these two sets of electrode assemblies 10, an AC current will be conductively coupled into the subject's brain through the electrode assembly 10.

[0032] Figure 3 The embodiments are similar to Figure 2 In addition to the embodiments, Figure 3 The embodiment has an electrode element 13 disposed on its inner surface (i.e., Figure 3 Outside the additional insulating material layer 15 on the lower part of the skull. When the shaft is positioned in the corresponding hole through the skull, the insulating material layer 15 is positioned to insulate the electrode element 13 from the subject's dura mater. Therefore, when the first set of electrode assemblies 10' is mounted on one side of the subject's head and the second set of electrode assemblies 10' is mounted on the opposite side of the subject's head, and an AC voltage is applied between the two sets of electrode assemblies 10, an AC current will be capacitively coupled into the subject's brain through the electrode assembly 10'.

[0033] The insulating material layer has a dielectric constant of at least 10. In some embodiments, the insulating material layer 15 comprises a polymer layer having a thickness of less than 50 µm. In some embodiments, the insulating material layer 15 comprises a ceramic material having a dielectric constant of at least 1000.

[0034] Back Figure 1A first set of electrode assemblies 10 is installed on a first side (e.g., the left side) of a target region in the subject's brain through corresponding first plurality of holes in the subject's skull, and a second set of electrode assemblies 10 is installed on the opposite side (e.g., the right side) of the target region through corresponding second plurality of holes in the subject's skull. The installation of the electrode assemblies 10 can be achieved using the combination described above. Figure 2 The method described may be used to achieve this, or any suitable alternative method may be used to position the internal tip of each electrode assembly 10 against the subject's dura mater.

[0035] Port 40 is attached to the subject's skull. Port 40 includes (a) at least one first terminal configured to be electrically connected on one side of the head (e.g., the left side) to each of the wires 14 in a first set of electrode assemblies 10, such that an electrical signal can be applied to each of these wires; and (b) at least one second terminal configured to be electrically connected on the opposite side of the head (e.g., the right side) to each of the wires 14 in a second set of electrode assemblies 10, such that an electrical signal can be applied to each of these wires. When two or more sets of electrode assemblies 10 are present, port 40 further includes at least one additional terminal configured to be electrically connected to each of the wires 14 in each set of electrode assemblies in an additional set of electrode assemblies 10, such that an electrical signal can be applied to each of these wires.

[0036] In an alternative embodiment, instead of relying on a single port 40 to drive all groups of electrode assemblies (such as...), Figure 1 As depicted, dedicated ports can be used to drive each group of electrode assemblies 10 separately. Therefore, in these alternative embodiments, the number of dedicated ports will match the number of groups of electrode assemblies 10.

[0037] AC voltage generator 30 operates at a frequency between 50 kHz and 1 MHz (e.g., between 100 kHz and 300 kHz). The output of AC voltage generator 30 is connected to port 40, and port 40 routes the output of AC voltage generator across opposite groups of electrode assemblies 10. For example, if AC voltage generator 30 is generating a 200 kHz AC signal, port 40 will route the 200 kHz output of AC voltage generator 30 such that the output appears across (a) the left and right groups of electrode assemblies 10, or (b) the front and rear groups of electrode assemblies 10.

[0038] When the AC voltage generator 30 applies its output signal across the electrode assembly 10 of the opposite group, an alternating electric field is induced between the inner tip of the electrode assembly 10 on one side of the target region and the inner tip of the electrode assembly 10 on the other side of the target region (via conductive coupling or capacitive coupling, as described above respectively). Figure 2 and Figure 3 (As described). It is also noteworthy that because the inner tip of each electrode assembly in electrode assembly 10 is located within the skull, the electric field does not need to traverse the subject's skull. Therefore, a much lower voltage than that used in prior art Optune® systems can be used to apply an electric field much stronger than that generated by prior art Optune® systems. This improvement enhances therapeutic efficacy.

[0039] While the invention has been disclosed with reference to certain embodiments, various modifications, alterations, and changes can be made to the described embodiments without departing from the scope and domain of the invention as defined by the appended claims. Therefore, the invention is intended to be limited to the described embodiments, but rather to have the full scope defined by the language of the appended claims and their equivalents.

Claims

1. A device for delivering an alternating electric field to a target region in the brain of a subject, the device comprising: A plurality of first electrode assemblies, the plurality of first electrode assemblies being configured for positioning through corresponding plurality of first holes in the subject's skull on a first side of the target region, wherein each of the plurality of first electrode assemblies has A first shaft, having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the first shaft are designed to traverse a corresponding first hole in the first aperture. A first flange is disposed at the outer end of the first shaft, wherein the first flange has a larger outer diameter than the first shaft, and the shape and size of the first flange are designed to prevent the first electrode assembly from passing through the corresponding first hole. A first conductive electrode element is disposed at the inner end of the first shaft. The first electrode element has an inner surface perpendicular to the longitudinal axis of the first shaft, with a deviation within 10°. The inner surface of the first electrode element has an area of ​​at least 5 mm². A first lead wire, the first lead wire having a first portion positioned to make electrical contact with the first electrode element and a second portion configured to extend under the subject's scalp; Multiple second electrode assemblies, configured for positioning through corresponding multiple second holes on a second side of the target region in the subject's skull, wherein each of the multiple second electrode assemblies has A second shaft, having a longitudinal axis, an inner end, and an outer end, wherein the shape and dimensions of the second shaft are designed to traverse a corresponding second hole in the second aperture. A second flange is disposed at the outer end of the second shaft, wherein the second flange has a larger outer diameter than the second shaft, and the shape and size of the second flange are designed to prevent the second electrode assembly from passing through the corresponding second hole. A second conductive electrode element is disposed at the inner end of the second shaft. The second electrode element has an inner surface perpendicular to the longitudinal axis of the second shaft, with a deviation within 10°. The inner surface of the second electrode element has an area of ​​at least 5 mm². The second wire has a first portion positioned to make electrical contact with the second electrode element and a second portion configured to extend under the subject's scalp; as well as At least one port configured for attachment to the subject's skull, wherein the at least one port includes (a) at least one first terminal configured to be electrically connected to each of the first wires in the first conductors such that an electrical signal can be applied to each of the first wires via the at least one port, and (b) at least one second terminal configured to be electrically connected to each of the second wires in the second conductors such that an electrical signal can be applied to each of the second wires via the at least one port.

2. The device of claim 1, wherein each of the plurality of first electrode assemblies has a first insulating material layer disposed on the inner surface of the first electrode element, wherein when the first shaft is positioned in the corresponding first hole, the first insulating material layer is positioned to insulate the first electrode element from the dura mater of the subject, wherein the first insulating material layer has a dielectric constant of at least 10, and Each of the plurality of second electrode assemblies has a second insulating material layer disposed on the inner surface of the second electrode element, wherein when the second axis is positioned in the corresponding second hole, the second insulating material layer is positioned to insulate the second electrode element from the dura mater of the subject, wherein the second insulating material layer has a dielectric constant of at least 10.

3. The device according to claim 2, wherein each of the first insulating material layers and each of the second insulating material layers comprises a polymer layer having a thickness of less than 50 µm.

4. The device according to claim 2, wherein each of the first insulating material layers and each of the second insulating material layers comprises a ceramic material having a dielectric constant of at least 1000.

5. The device of claim 1, wherein when the respective first axis is positioned in the respective first hole, each of the first electrode elements is positioned to contact the dura mater of the subject, and When the corresponding second axis is positioned in the corresponding second hole, each of the second electrode elements is positioned to contact the dura mater of the subject.

6. The device according to claim 1, wherein the inner surface of each of the first electrode elements and the inner surface of each of the second electrode elements have an area of ​​5-20 mm².

7. A method for delivering an alternating electric field to a target region in the brain of a subject, the method comprising: A plurality of first electrode assemblies are positioned through corresponding plurality of first holes in the subject's skull on a first side of the target region, wherein each of the plurality of first electrode assemblies has A first shaft, having a longitudinal axis, an inner end, and an outer end, wherein the shape and size of the first shaft are designed to traverse a corresponding first hole in the first aperture. A first flange is disposed at the outer end of the first shaft, wherein the first flange has a larger outer diameter than the first shaft, and the shape and size of the first flange are designed to prevent the first electrode assembly from passing through the corresponding first hole. A first conductive electrode element is disposed at the inner end of the first shaft. The first electrode element has an inner surface perpendicular to the longitudinal axis of the first shaft, with a deviation within 10°. The inner surface of the first electrode element has an area of ​​at least 5 mm². A first lead wire, the first lead wire having a first portion positioned to make electrical contact with the first electrode element and a second portion configured to extend under the subject's scalp; A plurality of second electrode assemblies are positioned through corresponding plurality of second holes on a second side of the target region in the subject's skull, wherein each of the plurality of second electrode assemblies has A second shaft, having a longitudinal axis, an inner end, and an outer end, wherein the shape and dimensions of the second shaft are designed to traverse a corresponding second hole in the second aperture. A second flange is disposed at the outer end of the second shaft, wherein the second flange has a larger outer diameter than the second shaft, and the shape and size of the second flange are designed to prevent the second electrode assembly from passing through the corresponding second hole. A second conductive electrode element is disposed at the inner end of the second shaft. The second electrode element has an inner surface perpendicular to the longitudinal axis of the second shaft, with a deviation within 10°. The inner surface of the second electrode element has an area of ​​at least 5 mm². The second wire has a first portion positioned to make electrical contact with the second electrode element and a second portion configured to extend under the subject's scalp; as well as An alternating voltage is applied between (a) the plurality of first electrode assemblies and (b) the plurality of second electrode assemblies, wherein the alternating voltage has a frequency between 50 kHz and 1 MHz.

8. The method of claim 7, wherein each of the plurality of first electrode assemblies has a first insulating material layer disposed on the inner surface of the first electrode element, wherein when the first shaft is positioned in the corresponding first hole, the first insulating material layer is positioned to insulate the first electrode element from the dura mater of the subject, wherein the first insulating material layer has a dielectric constant of at least 10, and Each of the plurality of second electrode assemblies has a second insulating material layer disposed on the inner surface of the second electrode element, wherein when the second axis is positioned in the corresponding second hole, the second insulating material layer is positioned to insulate the second electrode element from the dura mater of the subject, wherein the second insulating material layer has a dielectric constant of at least 10.

9. The method of claim 8, wherein each of the first insulating material layers and each of the second insulating material layers comprises a polymer layer having a thickness of less than 50 µm.

10. The method of claim 8, wherein each of the first insulating material layers and each of the second insulating material layers comprises a ceramic material having a dielectric constant of at least 1000.

11. The method of claim 7, wherein when the respective first axis is positioned in the respective first hole, each of the first electrode elements is positioned to contact the dura mater of the subject, and When the corresponding second axis is positioned in the corresponding second hole, each of the second electrode elements is positioned to contact the dura mater of the subject.

12. The method of claim 7, wherein the inner surface of each of the first electrode elements and the inner surface of each of the second electrode elements have an area of ​​5-20 mm².

13. The method of claim 7, wherein the AC voltage has a frequency between 100 kHz and 300 kHz.

14. A device for delivering an alternating electric field to a target region in the brain of a subject, the device comprising: A shaft having a longitudinal axis, an upper end, and a lower end, wherein the shaft has a length of 4-10 mm and an outer diameter of 2-15 mm; A flange is disposed at the upper end of the shaft, wherein the flange has a diameter at least 2 mm larger than the outer diameter of the shaft; A conductive electrode element is disposed at the lower end of the shaft, wherein the electrode element has a lower surface perpendicular to the longitudinal axis of the shaft, with a deviation within 10°, and wherein the lower surface of the electrode element has an area of ​​at least 5 mm². An insulating material layer is disposed on the underside of the electrode element, wherein the insulating material layer covers the underside of the electrode element to prevent the underside of the electrode element from contacting tissue located below the device, and wherein the insulating material layer has a dielectric constant of at least 10.

15. The device of claim 14, further comprising a metal wire having a first segment configured to be in electrical contact with the electrode element and extending through the shaft. The electrode element is made of metal.

16. The device of claim 15, wherein the insulating material layer comprises a polymer layer having a thickness of less than 50 µm.

17. The device of claim 15, wherein the insulating material layer comprises a ceramic material having a dielectric constant of at least 1000.

18. The device of claim 14, wherein the lower part of the electrode element has an area of ​​5-20 mm².

19. The device of claim 14, wherein the shaft has a cylindrical outer surface.

20. The device of claim 14, wherein the lower surface of the electrode element is perpendicular to the longitudinal axis of the shaft, with a deviation of less than 2°.

Images