Transcutaneous auricular vagus nerve stimulation

Abstract

The taVNS system (100) comprises an electrode support (110) and upper and lower conchaecular electrodes (120, 130) attached to the electrode support (110), protruding from the electrode support (110) and configured to contact the skin of the upper and lower conchaecular ears of a human subject, respectively. An elastic headband (140) is attached to the electrode support (110) and is configured to apply pressure to the electrode support (110) so that, when attached to the head of a human subject, the upper and lower conchaecular electrodes (120, 130) are pressed against the skin of the upper and lower conchaecular ears of the human subject.

Description

[Technical Field]

[0001] The present invention generally relates to transcutaneous auricular vagus nerve stimulation (taVNS). [Background technology]

[0002] The vagus nerve plays a major role in maintaining autonomic nervous system tone throughout the brain, chest, and abdomen. Electrical vagal stimulation (VNS) is currently approved for drug-resistant epilepsy, major depressive disorder, and morbid obesity. Such VNS is performed in the form of a cervical implantable device. VNS implantation requires a surgical procedure, involving the placement of lead wires in the cervical region of the left vagus trunk and subcutaneous insertion of a pulse generator into a pocket formed in the upper chest. The most common side effects of implantable VNS devices are related to the surgical intervention during implantation. Laryngotracheal dysfunction associated with stimulation of the inferior recurrent laryngeal nerve occurs in about two-thirds of the population treated for epilepsy and is usually transient. However, there are other surgical challenges, including electrode breakage, dislocation, generator malfunction, wound infection, recurrent laryngeal nerve paralysis, and arrhythmias under test stimulation.

[0003] An attractive and promising approach to avoid the drawbacks of invasive VNSs in humans is to use VNSs generated by external pulse generators. Two types of percutaneous VNSs have been developed: percutaneous cervical VNS (tcVNS) and percutaneous auricular VNS (taVNS). tcVNS can be achieved by placing electrodes on the skin covering the sternocleidomastoid muscle and supplying electrical signals to the cervical vagus nerve located in the carotid sheath, posterolateral to the internal and common carotid arteries and medial to the internal jugular vein. While implanted electrodes for VNSs are placed in similar locations, the vagus nerve is located beneath the skin, superficial fascia, and sternocleidomastoid muscle, making it difficult to access percutaneous electrical stimulation of vagus nerve fibers with current bioelectronic devices that are likely to stimulate both afferent and efferent fibers of the vagus bundle.

[0004] The auricular branch of the vagus nerve projects sensory input to the nucleus tractus solitarius (NTS) in the brainstem, which receives approximately 95% of vagal afferent nerves. The NTS projects to many areas of the forebrain, amygdala, hippocampus, limbic system, and brainstem structures, including the nucleus ambiguus, locus coeruleus, and dorsal motor nucleus, which facilitate vagal motor output. Functional magnetic resonance imaging (fMRI) studies in humans have confirmed that the central projections of the auricular branch of the vagus nerve are consistent with vagal nerve projections activated after invasive vagus nerve stimuli (VNS), and that taVNS can be accessed non-invasively via the outer ear. taVNS is typically performed at home using a small, battery-powered, handheld stimulator that generates pulsed currents delivered via skin electrodes in the auricle.

[0005] The drawbacks of these handheld taVNS devices are their inability to deliver stimulation pulses to the correct location within the auricle and to provide sufficient electrical contact between the stimulation electrode and the skin during a complete stimulation session.

[0006] US2022 / 0143390 discloses a multi-electrode ear shell including an inner and outer surface. The inner surface corresponds to the surface of the ear and is configured to overlap the superior and inferior conchae of the ear. The multi-electrode ear shell further includes multiple sockets configured to receive stimulating electrodes that can contact various locations, including the superior conchae, inferior conchae, crus of the helix, antichrium, tragus, and acupuncture points of the auricle. A conductive gel is applied to the skin of the ear to provide sufficient electrical contact between the stimulating electrodes and the skin.

[0007] There is still a need for a user-friendly taVNS system that provides efficient taVNS stimulation. [Overview of the project]

[0008] The general objective is to provide a user-friendly transcutaneous auricular vagus nerve stimulation (taVNS) system that delivers efficient taVNS stimulation.

[0009] This and other objectives are achieved by the embodiments disclosed herein.

[0010] The present invention is defined in the independent claims. Further embodiments of the present invention are defined by the dependent claims.

[0011] One aspect of the present invention relates to a taVNS system comprising an electrode support, an upper conchae electrode attached to the electrode support and protruding from the electrode support and configured to contact the skin of the upper concha of the ear of a human subject, and an lower conchae electrode attached to the electrode support and protruding from the electrode support and configured to contact the skin of the lower concha of the ear of a human subject. The taVNS system also comprises an elastic headband attached to the electrode support and configured, when attached to the head of a human subject, to apply pressure to the electrode support, thereby pressing the upper conchae electrode toward the skin of the upper concha of the ear of the human subject and pressing the lower conchae electrode toward the skin of the lower concha of the ear of the human subject. According to the present invention, the electrode support does not include electrodes other than the upper conchae electrode and the lower conchae electrode.

[0012] Another aspect of the present invention relates to a method of taVNS in a human subject. The method includes attaching an elastic headband of the taVNS system according to the present invention to the head of a human subject in order to position the superior conchae electrode in contact with the skin of the superior conchae of the human subject's ear and the inferior conchae electrode in contact with the skin of the inferior conchae of the human subject's ear. The method also includes generating electrical stimulation pulses by the stimulator of the taVNS system in order to apply the electrical stimulation pulses through the superior and inferior conchae electrodes.

[0013] A further aspect of the present invention relates to a method for treating a medical condition in a human subject. The medical condition is selected from the group consisting of epilepsy, depression, obesity, migraine, cluster headache, insomnia, neuropathic pain, back pain, chronic pain, cognitive decline, inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis, and Alzheimer's disease. The method comprises administering taVNS in the above human subject.

[0014] The taVNS system of the present invention is user-friendly and can be used at home without medical supervision. The taVNS system is designed to reliably and consistently provide efficient vagus nerve stimulation in each stimulation session by correctly aligning electrodes to the intended stimulation site in the outer ear. Efficient vagus nerve stimulation is further achieved without the need for any contact-facilitating medium such as conductive gels.

[0015] Embodiments, along with their further objectives and advantages, can be best understood by referring to the following description in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0016] [Figure 1A-C] This shows a taVNS system according to one embodiment. [Figure 2] Another embodiment of the taVNS system is shown. [Figure 3] Further embodiments of the taVNS system are shown. [Figure 4] This shows a stimulation device that can be used in the taVNS system according to the embodiment. [Figure 5] This flowchart shows the taVNS method in human subjects. [Figure 6A-E] This shows cytokine levels in lipopolysaccharide (LPS)-activated whole blood cultures from 12 healthy donors before and after taVNS treatment. [Modes for carrying out the invention]

[0017] The present invention generally relates to transcutaneous auricular vagus nerve stimulation (taVNS), and more particularly to a system for taVNS.

[0018] The taVNS system of the present invention is designed to effectively and reproducibly promote transcutaneous auricular vagus nerve stimulation in a human subject, for example, in a home environment. This is achieved by placing a stimulation electrode at the correct position on the outer ear of the human subject. Such correct electrode positioning is currently difficult for a human subject to achieve in a reproducible manner using a handheld taVNS stimulation device. Therefore, in such a handheld taVNS stimulation device, it is not uncommon for a human subject to be unable to correctly place one or both of the stimulation electrodes at the intended stimulation site within the outer ear, resulting in reduced stimulation transmission and treatment effectiveness.

[0019] A further drawback of conventional taVNS stimulation devices, including the stimulation system disclosed in US2022 / 0143390, is that it is necessary to apply a conductive gel to the skin of the outer ear in order to provide sufficient electrical contact between the stimulation electrode and the skin surface. Such a conductive gel is often felt uncomfortably by the human subject and may cause skin irritation, especially during long-term use.

[0020] The stimulation system disclosed in US2022 / 0143390 is further disadvantaged by the need to design a subject-specific multi-electrode ear shell for each individual human subject to be treated. First, a clinician needs to take a three-dimensional (3D) image of the outer ear of each human subject and generate a multi-electrode ear shell from that 3D image. Although the multi-electrode ear shell is manufactured for a specific human subject, it is still cumbersome to securely insert it into the outer ear while minimizing the movement of the multi-electrode ear shell relative to the outer ear during stimulation. The reason is that the multi-electrode ear shell needs to include a plurality of protrusions and recesses in order to fit specific regions of the outer ear, such as the anthelix, inferior crus of the anthelix, superior crus of the anthelix, and antitragus. Each time transcutaneous auricular vagus nerve stimulation is performed, it is often difficult for a human subject to accurately align the protrusions and recesses with specific regions or structures of the outer ear.

[0021] The present invention relates to a taVNS system 100. Refer to FIGS. 1A - 1C, FIG. 2, and FIG. 3. The taVNS system 100 includes an electrode support 110, a superior concha electrode 120, an inferior concha electrode 130, and an elastic headband 140. The superior concha electrode 120 and the inferior concha electrode 130 are attached to the electrode support 110 and protrude from the electrode support 110. The superior concha electrode 120 is configured to contact the skin in the superior concha of a human subject's ear. The inferior concha electrode 130 is correspondingly configured to contact the skin in the inferior concha of a human subject's ear. The elastic headband 140 is attached to the electrode support 110 and is configured to apply pressure to the electrode support 110 when attached to a human subject's head, pressing the superior concha electrode 120 against the skin of the superior concha of the human subject's ear and pressing the inferior concha electrode 130 against the skin of the inferior concha of the human subject's ear.

[0022] The electrode support 110 of the taVNS system 100 does not include electrodes other than the superior concha electrode 120 and the inferior concha electrode 130.

[0023] Therefore, the electrode support 110 of the taVNS system 100 includes only two electrodes, namely, the superior concha electrode 120 and the inferior concha electrode 130. With the design of the taVNS system 100 of the present invention, it is possible to correctly position these electrodes 120, 130 in contact with the skin of the superior concha and inferior concha of the ear respectively. This should be compared with the stimulation system of US2022 / 0143390. The multi - electrode ear shell theoretically includes multiple electrodes so that it can stimulate multiple sites such as the superior antihelix, helix, scaphoid fossa, antihelical trunk, concha, antitragus, earlobe, intertragal notch, tragus, helix crus, inferior antihelical crus, and triangular fossa. Such multiple potential stimulation sites may be necessary for the stimulation system of US2022 / 0143390 to provide the intended electrical stimulation to the target site due to the above - mentioned problems in correctly attaching the multi - electrode ear shell to the outer ear.

[0024] The experimental data presented herein demonstrate that an electrode support 110 to which superior conchae electrode 120 and inferior conchae electrode 130 are attached and protruding achieves an efficient taVNS capable of inducing biological effects in human subjects using only the two electrodes 120 and 130 attached to and protruding from the electrode support 110.

[0025] Furthermore, the positions of the two electrodes 120 and 130 on the electrode support 110 are preferably fixed so as not to be adjustable along the length L or width W of the electrode support 110, as shown in Figure 1C. However, the amount of protrusion of one or both electrodes 120 and 130 from the electrode support 110 is preferably adjustable, as will be further described herein. This makes it possible to achieve an efficient taVNS while simplifying the design of the electrode support 110 compared to the multi-electrode ear shell of US2022 / 0143390. A further advantage is that the taVNS system 100 of the present invention does not need to be subject-specific, i.e., one identical taVNS system 100 can be used to provide taVNS to multiple different human subjects.

[0026] The superior conchae electrode 120 and the inferior conchae electrode 130 are made of a conductive material, preferably a conductive metal or metal alloy. The conductive material, preferably a conductive metal or metal alloy, shall not only have good conductivity but also preferably be bioacceptable. Conductive metals and metal alloys generally have a resistivity of 10 at 20°C. -8 It is approximately Ωm, and the conductivity at 20°C is 10 6 ~10 7 It is approximately S / m. In certain embodiments, the conductive material of electrodes 120 and 130, preferably a conductive metal or metal alloy, is at least 10°C at 20°C. 6 S / m, preferably at least 0.5 × 10 7 S / m, more preferably at least 10 7 It has an electrical conductivity of S / m. More preferably, the conductive material, preferably a conductive metal or metal alloy, has at least 3 × 10 at 20°C. 7It has a conductivity of S / m.

[0027] As used herein, biologically acceptable or biologically tolerable means that the conductive material, preferably a conductive metal or metal alloy, does not have a significant adverse effect on the skin of the ear when electrodes 120 and 130 are in contact with the skin of the upper and lower conchae during a taVNS session. In particular, the conductive material, preferably a conductive metal or metal alloy, shall not cause any significant skin irritation during normal use of such a taVNS system 100.

[0028] Currently preferred conductive materials include aluminum and aluminum alloys. Aluminum has a resistivity of 2.65×10 -8 Ωm and an electrical conductivity of 3.77×10 7 S / m at 20°C.

[0029] In one embodiment, the upper concha electrode 120 is made of aluminum or an aluminum alloy, or includes an electrode surface 121 made of aluminum or an aluminum alloy. Alternatively, preferably in addition to this, the lower concha electrode 130 is made of aluminum or an aluminum alloy, or includes an electrode surface 131 made of aluminum or an aluminum alloy. In a preferred embodiment, the upper concha electrode 120 and the lower concha electrode 130 are made of aluminum, or include respective electrode surfaces 121 and 131 made of aluminum.

[0030] Other metals and metal alloys that can be used for electrodes 120, 130, or at least electrode surfaces 121, 131 include gold and silver and their alloys.

[0031] Electrodes 120 and 130 may be manufactured from a single metal or metal alloy, preferably aluminum or an aluminum alloy. For example, electrodes 120 and 130 may be solid electrodes made of a single metal or metal alloy. Alternatively, electrodes 120 and 130 may include a conductive core material, preferably a conductive metal or metal alloy, and further include electrode surfaces 121 and 131 manufactured from another conductive material, preferably another conductive metal or metal alloy. The electrode surfaces 121 and 131 may be in the form of a conductive coating or surface layer on the electrode core. As an example, the electrode core may be manufactured from copper or an alloy thereof.

[0032] Since the conductive material of the electrode core does not come into direct contact with the skin of the human subject, it does not necessarily need to be biologically acceptable. Therefore, a conductive material, preferably a conductive metal or metal alloy, that has high conductivity but does not need to be biologically acceptable can be used as the electrode core material.

[0033] In a preferred embodiment, the superior concha electrode 120 and the inferior concha electrode 130 are manufactured from the same conductive material or group of conductive materials. Therefore, both electrodes 120, 130 are preferably solid electrodes manufactured from a single conductive material, preferably a single conductive metal or metal alloy, or both electrodes 120, 130 comprise a conductive core material, preferably a conductive metal or metal alloy, and electrode surfaces 121, 131 manufactured from another conductive material, preferably another conductive metal or metal alloy.

[0034] In one embodiment, the superior concha electrode (120) is configured to be in direct physical contact with the skin of the superior concha of the ear of a human subject, and the inferior concha electrode 130 is configured to be in direct physical contact with the skin of the inferior concha of the ear of a human subject.

[0035] Therefore, the two electrodes 120 and 130 of the electrode support 110 are configured to not only electrically contact the skin in the superior and inferior conchae, but also to directly physically contact it. In particular, the electrode surfaces 121 and 131 of electrodes 120 and 130 are configured to directly physically and electrically contact the skin in these areas of the ear of a human subject (superior and inferior conchae, respectively).

[0036] As used herein, direct physical contact means that electrodes 120, 130, or electrode surfaces 121, 131, directly contact and touch the skin of the superior and inferior conchae, respectively. Therefore, no intermediate medium, including conductive gels, is used to mediate the electrical contact between electrodes 120, 130 and the skin.

[0037] In one embodiment, the superior concha electrode 120 comprises an electrode body 123 that is electrically in contact with a power cord 150, and a hemispherical electrode head 122 having an electrode surface 121 configured to contact the skin of the superior concha of a human subject's ear.

[0038] In one embodiment, the electrode body 123 may be cylindrical in shape, having a hemispherical electrode head 122 at one end and the other end, i.e., the opposite end, facing the electrode support 110. Such a design of the superior conchae electrode 120 provides a smooth hemispherical electrode surface 121 that contacts the skin in the superior conchae, while the electrode body 123 allows the hemispherical electrode head 122 to protrude into the superior conchae while avoiding surrounding structures or areas in the ear that should not be electrically stimulated, such as the crus of the helix, the antichrium, and the inferior crus of the antichrium.

[0039] In one embodiment, the electrode body 123 of the superior conchae electrode 120 is attached to an adjustable electrode shaft 124, as shown in Figure 2. In this embodiment, the adjustable electrode shaft 124 is positioned to adjust the amount of protrusion of the hemispherical electrode head 122 of the superior conchae electrode 120 relative to the electrode support 110.

[0040] In this embodiment, the amount of protrusion of the superior conchae electrode 120 relative to the electrode support 110 is adjustable, as indicated by the diagonal arrows in Figure 2. This means that the distance between the end of the hemispherical electrode head 122, and thus the end of the electrode surface 121, and the electrode support 110 can be adjusted so that the electrode surface 121 makes proper contact with the skin of the superior conchae when the elastic headband 140 is attached to the head of a human subject.

[0041] In certain embodiments, the taVNS system 100 also includes an adjustment screw 111 positioned on the electrode support 110 in contact with the adjustable electrode shaft 124. The adjustment screw 111 is then configured to mount the adjustable electrode shaft 124 to a selected position relative to the electrode support 110.

[0042] In a preferred embodiment, the adjustment screw 111 can be screwed clockwise or counterclockwise relative to the electrode support 110. Rotating the adjustment screw 111 in one direction, preferably clockwise, moves the superior concha electrode 120 further away from the electrode support 110, while rotating the adjustment screw 111 in the other direction, preferably counterclockwise, moves the superior concha electrode 120 toward the electrode support 110. Thus, the adjustment screw 111 can be used to adjust the amount or level of protrusion of the superior concha electrode 120, particularly the hemispherical electrode head 122, from the electrode support 110.

[0043] In one embodiment, the inferior conchae electrode 130 comprises an electrode body 133 that is electrically in contact with a power cord 152, and a hemispherical electrode head 132 having an electrode surface 131 configured to contact the skin of the inferior conchae of a human subject's ear.

[0044] In one embodiment, the electrode body 133 may be cylindrical in shape, having a hemispherical electrode head 132 at one end and the other end, i.e., the opposite end, facing the electrode support 110. Such a design of the superior conchae electrode 130 provides a smooth hemispherical electrode surface 131 that contacts the skin in the inferior conchae, while the electrode body 133 allows the hemispherical electrode head 132 to protrude into the inferior conchae while avoiding surrounding structures or areas in the ear that should not be electrically stimulated, such as the crus of the helix, tragus, and antitragus.

[0045] In one embodiment, the electrode body 133 of the inferior conchae electrode 130 is attached to an adjustable electrode shaft 134, as shown in Figure 1B. In this embodiment, the adjustable electrode shaft 134 is positioned to adjust the amount of protrusion of the hemispherical electrode head 132 of the inferior conchae electrode 130 relative to the electrode support 110.

[0046] In this embodiment, the amount of protrusion of the superior conchae electrode 130 relative to the electrode support 110 is adjustable, as indicated by the diagonal arrows in Figure 1B. This means that the distance between the end of the hemispherical electrode head 132, and thus the end of the electrode surface 131, and the electrode support 110 can be adjusted so that the electrode surface 131 makes proper contact with the skin of the inferior conchae when the elastic headband 140 is attached to the head of a human subject.

[0047] In certain embodiments, the taVNS system 100 also includes an adjustment screw 112 positioned on the electrode support 110 in contact with the adjustable electrode shaft 134. The adjustment screw 112 is then configured to mount the adjustable electrode shaft 134 to a selected position relative to the electrode support 110.

[0048] In a preferred embodiment, the adjustment screw 112 can be screwed clockwise or counterclockwise relative to the electrode support 110. Rotating the adjustment screw 112 in one direction, preferably clockwise, moves the inferior concha electrode 130 further away from the electrode support 110, while rotating the adjustment screw 112 in the other direction, preferably counterclockwise, moves the inferior concha electrode 130 toward the electrode support 110. Thus, the adjustment screw 112 can be used to adjust the amount or level of protrusion of the inferior concha electrode 130, particularly the hemispherical electrode head 132, from the electrode support 110.

[0049] In the embodiments shown in Figures 1A to 1C, the protrusion of the inferior conchae electrode 130 can be adjusted, whereas in the embodiment shown in Figure 2, the protrusion of the superior conchae electrode 120 can be adjusted. Figure 3 shows another embodiment that combines the adjustment of the protrusion of the inferior conchae electrode 130 and the adjustment of the protrusion of the superior conchae electrode 120.

[0050] The embodiment of the taVNS system 100 shown in Figure 3 provides maximum freedom by individually adjusting the protrusions of the two electrodes 120 and 130 relative to the electrode support 110. However, in most cases, it is still sufficient to achieve efficient electrical and physical contact between the skin and the electrode surfaces 121 and 131 in the superior and inferior conchae if only the protrusion of one of the electrodes 120 and 130 is adjustable. In such cases, one of the electrodes 120 and 130 is fixed, i.e., non-adjustable, to the electrode support 110, while the other electrode 120 and 130 is adjustable. Such an embodiment simplifies the design of the taVNS system 100 in Figures 1A-1C or Figure 2 compared to the embodiment of the taVNS system 100 shown in Figure 3. In the currently preferred embodiment, as shown in Figures 1A-1C, the superior concha electrode 120 is fixed, while the protrusion of the inferior concha electrode 130 is adjustable.

[0051] The elastic headband 140 of the taVNS system 100 applies inward pressure or force to the electrode support 110, thereby bringing the fixed electrode into physical contact with the skin of the target stimulation site in the outer ear of a human subject. The protrusion amount or level of the adjustable electrode can be used to fine-tune the pressure the adjustable electrode applies to the skin, achieving direct physical contact between the adjustable electrode and the skin while ensuring it is not uncomfortable for the human subject. In other words, the design of the taVNS system 100 with the elastic headband 140 attached to the electrode support 110 allows for sufficient electrical and physical contact between both electrodes 120, 130 and the skin in the superior and inferior conchae, while ensuring that the electrodes 120, 130 are not pressed too hard against the skin, thus not causing discomfort to the human subject. This is possible even with just one fixed electrode and one adjustable electrode.

[0052] Therefore, in one embodiment, one of the superior conchae electrode 120 and the inferior conchae electrode 130 is fixedly attached to the electrode support 110 and protrudes from the electrode support 110 at a fixed distance. In this embodiment, the other of the superior conchae electrode 120 and the inferior conchae electrode 130 is adjustablely attached to the electrode support 110 and protrudes from the electrode support 110 at an adjustable distance.

[0053] In one embodiment, the distance between the superior conchae electrode 120 and the inferior conchae electrode 130 on the electrode support 110 corresponds to the average distance between the superior and inferior conchae in a group of multiple human subjects.

[0054] The inventors have found that the distance between the superior and inferior conchae is not significantly different in a population of adult humans. This means that multiple human subjects can be electrically stimulated using an electrode support 110 in which the distance between the superior conchae electrode 120 and the inferior conchae electrode 130 is fixed, i.e., not adjustable. Therefore, the taVNS system 100 can be used to treat multiple different human (adult) subjects without the need to adjust the distance between electrodes 120 and 130 in the electrode support 110.

[0055] In another embodiment, the distance between the superior conchae electrode 120 and the inferior conchae electrode 130 in the electrode support 110 corresponds to the distance between the superior and inferior conchae of a human subject.

[0056] In this embodiment, a subject-specific taVNS system 100 can be used, in which the distance between the superior conchae electrode 120 and the inferior conchae electrode 130 on the electrode support 110 is defined to match the corresponding distance between the superior and inferior conchae of a particular human subject.

[0057] In certain embodiments, the distance between the superior concha electrode 120 and the inferior concha electrode 130 in the electrode support 110 corresponds to the length (L) of the electrode support 110 or the distance along the length axis, as shown in Figure 1C.

[0058] The electrode support 110 of the taVNS system 100 is designed to be located outside the outer ear of a human subject when electrodes 120 and 130 are in contact with the skin of the superior and inferior conchae, respectively. In a typical embodiment, when the elastic headband 140 is attached to the head of a human subject, the electrode support 110 is configured to align with at least a portion of the human subject's outer ear. However, the electrode support 110 is preferably located outside the outer ear, i.e., not in the form of an ear shell attached inside the outer ear.

[0059] In one embodiment, referring to Figure 1C, electrodes 120 and 130 are attached to the inner surface 113 of the electrode support 110 and protrude from there. This ensures that when the elastic headband 140 is attached to the head of a human subject, this inner surface 113 of the electrode support 110 faces the outer ear of the human subject. The inner surface 113 is preferably a flat surface, i.e., it does not correspond to the surface of the ear.

[0060] The taVNS system 100 comprises an elastic headband 140 attached to an electrode support 110. The elastic headband 140 is designed to be attached to the head of a human subject. In such a position on the head, the electrode support 110 aligns with one of the human subject's outer ears, i.e., the right or left ear, preferably the left ear. Furthermore, in such a position, the superior concha electrode 120 aligns with the superior concha, and the inferior concha electrode 130 aligns with the inferior concha of the ear. The headband 140 is elastic so as to be attached to the head of a human subject, but preferably it is made of or includes a rigid material that can apply inward pressure or force to the electrode support 110 against the ear of the human subject.

[0061] The headband 140 comprises an overhead band or portion 142 designed to pass over at least a portion of the top of the head of a human subject. The headband 140 may optionally be held in place on the head of a human subject by a retaining device 144. In such a case, the retaining device 144 is preferably located at one end of the overhead band 142, and the electrode support 110 is located at the other end of the overhead band 142. The retaining device 144 not only provides comfortable contact with the temporal region, preferably in a position above the non-irritating ear, but can also help balance the headband 140 on the head of a human subject. Thus, the retaining device 144 can provide a counterweight to balance the weight of the electrode support 110, at least partially.

[0062] The elastic headband 140 may be attached to the electrode support 110, or it may be formed integrally with the electrode support 110. In the latter case, the elastic headband 140, or at least its overhead band 142, and the electrode support 110 form a monolithic unit.

[0063] The headband 140 may optionally include an adjustment mechanism for fitting the headband 140 to the head of a human subject. The size of the headband 140 can then be adjusted to different head sizes using such an adjustment mechanism. Furthermore, the adjustment mechanism may be used to adjust the pressure exerted by the headband 140 on the electrode support 110, thereby pressing the electrodes 120, 130, which are attached to and protruding from the electrode support 110, into physical contact with the skin at the superior and inferior conchae of the ear. An exemplary, but non-limiting, example of such an adjustment mechanism is the inclusion of a telescoping section for extending or retracting the ends of the elastic headband 140. Such a telescoping section can then be locked using a well-known solution, such as a friction brake or ratchet brake.

[0064] In one embodiment, the taVNS system 100 also includes a stimulating device 200, referring to Figure 4. In such a case, the stimulating device 200 is in electrical contact with the superior concha electrode 120 and the inferior concha electrode 130. The stimulating device 200 is configured to generate electrical stimulation pulses.

[0065] The stimulator 200 typically includes connection ports 210 and 212, and the aforementioned power cords 150 and 152 may be attached to electrically connect the stimulator 200 to the electrodes 120 and 130.

[0066] The stimulating device 200 may be any stimulating device capable of generating electrical stimulation pulses suitable for taVNS. Such stimulating devices 200 may also be called transcutaneous electrical nerve stimulation (TENS) devices or machines and are available on the market from a variety of vendors, including but not limited to TENS7000®, Omron, Axion, Body Clock, Saneo, Health Technologies, Roscoe Medical, Auri Stim Medical, tVNS Technology GmbH, Cerbomed, Parasym, Soterix Medical, Xana Stim, and NESOS.

[0067] Figure 5 is a flowchart of a method for transcutaneous auricular vagus nerve stimulation (taVNS) in a human subject according to one embodiment. This method includes, in step S1, attaching the elastic headband 140 of the taVNS system 100 described in the present invention to the head of a human subject in order to position the superior conchae electrode 120 in contact with the skin of the superior conchae of the human subject's ear and the inferior conchae electrode 130 in contact with the skin of the inferior conchae of the human subject's ear. This method also includes, in step S2, generating electrical stimulation pulses by a stimulation device 200 to apply electrical stimulation pulses through the superior conchae electrode 120 and the inferior conchae electrode 130.

[0068] An advantage of the taVNS system 100 of the present invention is that even with relatively short stimulation sessions, biological effects on human subjects can be achieved, as shown in the Examples section. Thus, in one embodiment, step S2 in Figure 5 includes generating electrical stimulation pulses by the stimulation device 200 once or twice a day, preferably twice, for each stimulation period or session ranging from 2 to 10 minutes, preferably from 3 to 7 minutes, and more preferably about 5 minutes.

[0069] The taVNS system 100 of the present invention and its use as shown in Figure 5 can be applied to the treatment of various medical conditions for which taVNS can be beneficial. Exemplary, but non-limiting, examples of such medical conditions include epilepsy, depression, obesity, migraine, cluster headache, insomnia, neuropathic pain, back pain, chronic pain, cognitive decline, inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis, and Alzheimer's disease. Examples

[0070] In this study, the effect of taVNS on cytokine levels in LPS-activated whole blood cultures from healthy donors was investigated before and after taVNS administration. material and method Research design

[0071] This study enrolled 13 healthy individuals aged 21 to 75 years. Participants were required to have not taken any nonsteroidal anti-inflammatory drugs (NSAIDs) within the past 48 hours and to have not consumed any food or drink (other than water) for at least 8 hours prior to the study. Each participant's study schedule consisted of a baseline pre-stimulation blood sample, a 30-minute waiting period, 5 minutes of stimulation with the taVNS device of the present invention (settings: frequency 20 Hz, pulse width 200 μs, current intensity individually adjusted to below the pain threshold <3 mA), and a blood sample taken 2 hours after stimulation. The study was conducted over 3 consecutive days, with baseline pre-stimulation blood samples taken before 10:00 AM for all patients. All blood samples were collected in 10 mL heparin sodium-containing tubes and analyzed using a custom-made in vitro whole blood endotoxin assay. One participant did not complete the study due to a failure in post-stimulation blood sampling. In vitro endotoxin whole blood assay

[0072] Blood collected in heparinized tubes was immediately dispensed and stimulated (retention time did not exceed 1 hour). All preparations were performed in a biosafety level 2 (BSL-2) laboratory environment. In summary, endotoxin (lipopolysaccharide (LPS), Escherichia coli 0111:B4, Sigma Aldrich, USA) was resuspended at 5 mg / mL, sonicated for 30 minutes, vortex mixed, and diluted with phosphate-buffered saline (PBS) to produce a 1 mg / mL working stock to be stored at -20°C. On each study day, a new LPS dilution was prepared from this working stock. The working stock was sonicated for 30 minutes and serially diluted 10-fold with saline to concentrations ranging from 50 μg / mL to 5 ng / mL. Heparinized blood was dispensed into 15 round-bottom 2 mL tubes, and 10 μL of LPS diluent was added to the blood samples in three replicates until the final concentrations in 500 μL of blood separatory reached 0 ng / mL and 10 ng / mL. These tubes were incubated on an orbital shaking platform at 37°C for 4 hours. After 4 hours, plasma was collected from all samples by centrifugation at 2000 × g for 10 minutes using a refrigerated centrifuge and frozen at -20°C for future analysis. Cytokine assay

[0073] Plasma tumor necrosis factor (TNF) levels were quantified using a commercially available enzyme immunosorbent assay (ELISA) (R&D Systems #DY210), and all samples were duplicated. Further cytokine analysis was performed using blood stimulated with 0 ng / mL and 10 ng / mL LPS. These samples were duplicated using a custom MesoScale Discovery U-Plex cytokine panel, targeting interleukin-1 receptor antagonist (IL-1RA), IL-1α, IL-1β, IL-6, and IL-8. Plates were imaged using a MESO QuickPlex SQ 120 instrument (MSD, Gaithersburg, MD) and analyzed using MSD Discovery Workbench software. All data were analyzed and graphed using GraphPad Prism 9. statistics [Table 1] result

[0074] The results are shown in Figures 6A-6F, illustrating the effect of taVNS on cytokine levels in LPS-activated (10 ng / mL) whole blood cultures from healthy donors. Quantitative evaluations were performed for the pro-inflammatory cytokines IL-1α (Figure 6A), IL-1β (Figure 6B), IL-6 (Figure 6C), IL-8 (Figure 6D), TNF (Figure 6E), and the anti-inflammatory cytokine IL-1RA (Figure 6F). As shown in the figures, taVNS stimulation reduced the pro-inflammatory cytokines investigated, but did not significantly affect the anti-inflammatory cytokine IL-1RA. Therefore, this example demonstrates that the taVNS system of the present invention can achieve effective taVNS stimulation that reduces inflammatory cytokines. Accordingly, the taVNS system of the present invention is considered suitable for the treatment of various inflammatory diseases and conditions that can benefit from taVNS stimulation.

[0075] The embodiments described above should be understood as some descriptive examples of the present invention. Those skilled in the art will understand that various modifications, combinations, and changes can be made to the embodiments without departing from the scope of the present invention. In particular, different partial solutions in different embodiments can be combined in other configurations where technically possible.

Claims

1. Electrode support (110) and An upper concha electrode (120) is attached to the electrode support (110), protrudes from the electrode support (110), and is configured to contact the skin of the upper concha of the ear of a human subject, An inferior concha electrode (130) is attached to the electrode support (110), protrudes from the electrode support (110), and is configured to contact the skin of the inferior concha of the ear of the human subject, An elastic headband (140) is attached to the electrode support (110) and, when attached to the head of the human subject, is configured to apply pressure to the electrode support (110) to press the superior concha electrode (120) toward the skin of the superior concha of the human subject's ear, and the inferior concha electrode (130) toward the skin of the inferior concha of the human subject's ear, wherein the electrode support (110) does not include electrodes other than the superior concha electrode (120) and the inferior concha electrode (130), and the elastic headband (140) A transcutaneous auricular vagus nerve stimulation (taVNS) system (100) comprising the above.

2. The taVNS system according to claim 1, wherein the superior concha electrode (120) is made of aluminum or an aluminum alloy, preferably aluminum, or comprises an electrode surface (121) made of aluminum or an aluminum alloy, preferably aluminum.

3. The taVNS system according to claim 1 or 2, wherein the inferior concha electrode (130) is made of aluminum or an aluminum alloy, preferably aluminum, or comprises an electrode surface (131) made of aluminum or an aluminum alloy, preferably aluminum.

4. The superior concha electrode (120) is configured to be in direct physical contact with the skin on the superior concha of the ear of the human subject. The inferior concha electrode (130) is configured to be in direct physical contact with the skin on the inferior concha of the ear of the human subject. The taVNS system according to any one of claims 1 to 3.

5. The aforementioned superior conchae electrode (120) The power cord (150) and the electrode body (123) which are in electrical contact, A hemispherical electrode head (122) having an electrode surface (121) configured to contact the skin on the superior concha of the ear of the human subject, and The taVNS system according to any one of claims 1 to 4, comprising:

6. The taVNS system according to claim 5, wherein the electrode body (123) of the superior conchae electrode (120) is attached to an adjustable electrode shaft (124) arranged to adjust the amount of protrusion of the hemispherical electrode head (122) of the superior conchae electrode (120) relative to the electrode support (110).

7. The taVNS system according to claim 6, further comprising an adjustment screw (111) positioned on the electrode support (110) in contact with the adjustable electrode shaft (124), and configured to attach the adjustable electrode shaft (124) to a selected position relative to the electrode support (110).

8. The taVNS system according to any one of claims 5 to 7, wherein the electrode surface (121) of the hemispherical electrode head (122) of the superior concha electrode (120) is configured to be in direct physical and electrical contact with the skin of the superior concha of the ear of the human subject.

9. The aforementioned inferior concha electrode 130) The power cord (152) and the electrode body (133) which are in electrical contact, A hemispherical electrode head (132) having an electrode surface (131) configured to contact the skin of the inferior concha of the ear of the human subject, and The taVNS system according to any one of claims 1 to 8, comprising:

10. The taVNS system according to claim 9, wherein the electrode body (133) of the inferior conchae electrode (130) is attached to an adjustable electrode shaft (134) arranged to adjust the amount of protrusion of the hemispherical electrode head (132) of the superior conchae electrode (130) relative to the electrode support (110).

11. The taVNS system according to claim 10, further comprising an adjustment screw (112) positioned on the electrode support (110) in contact with the adjustable electrode shaft (134) and configured to attach the adjustable electrode shaft (134) to a selected position relative to the electrode support (110).

12. The taVNS system according to any one of claims 9 to 11, wherein the electrode surface (131) of the hemispherical electrode head (132) of the inferior concha electrode (130) is configured to be in direct physical and electrical contact with the skin of the inferior concha of the ear of the human subject.

13. The taVNS system according to any one of claims 1 to 12, wherein the distance between the superior concha electrode (120) and the inferior concha electrode (130) on the electrode support (110) corresponds to the average distance between the superior concha and the inferior concha in a group of multiple human subjects.

14. One of the superior conchae electrode (120) and the inferior conchae electrode (130) is fixedly attached to the electrode support (110) and protrudes from the electrode support (110) at a fixed distance. The other of the superior conchae electrode (120) and the inferior conchae electrode (130) is adjustablely attached to the electrode support (110) and protrudes from the electrode support (110) at an adjustable distance. The taVNS system according to any one of claims 1 to 13.

15. The taVNS system according to any one of claims 1 to 14, wherein the superior concha electrode (120) and the inferior concha (130) are attached to the inner surface (113) of the electrode support (110) and protrude from the inner surface (113) of the electrode support (110), and the inner surface (113) is a flat surface.

16. The taVNS system according to any one of claims 1 to 15, further comprising a stimulating device (200) configured to electrically contact the superior concha electrode (120) and the inferior concha electrode (130) and generate electrical stimulation pulses.

17. A method for transcutaneous auricular vagus nerve stimulation (taVNS) in human subjects, To position the upper concha electrode (120) in contact with the skin of the upper concha of the human subject's ear, and the lower concha electrode (130) in contact with the skin of the lower concha of the human subject's ear, the elastic headband (140) of the taVNS system (100) according to claim 16 is attached to the head of the human subject (S1), In order to apply the electrical stimulation pulses via the upper concha electrode (120) and the lower concha electrode (130), the stimulating device (200) generates the electrical stimulation pulses (S2) A method that includes this.

18. The method according to claim 17, wherein generating an electrical stimulation pulse (S2) is performed by the stimulating device (200) to apply the electrical stimulation pulse via the superior conchae electrode (120) and the inferior conchae electrode (130) for a stimulating period of 2 to 10 minutes, preferably 3 to 7 minutes, and more preferably about 5 minutes.

19. The method according to claim 17 or 18, wherein generating an electrical stimulation pulse (S2) is performed by the stimulating device (200) to apply the electrical stimulation pulse once or twice a day, preferably twice a day, via the superior conchae electrode (120) and the inferior conchae electrode (130).

20. A method for treating a medical condition in a human subject, wherein the medical condition is selected from the group consisting of epilepsy, depression, obesity, migraine, cluster headache, insomnia, neuropathic pain, back pain, chronic pain, cognitive impairment, inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis, and Alzheimer's disease, and the method comprises performing percutaneous auricular vagus nerve stimulation (taVNS) as described in any one of claims 17 to 19 in the human subject.

Images