Transcutaneous auricular vagus nerve stimulation

Abstract

A taVNS system (100) comprises a first electrode support (110), and first cymba and cavum concha electrodes (120, 130) attached to and protruding from the first electrode support (110) and configured to be in contact with skin in cymba concha and cavum concha of a first ear of a human subject, respectively The taVNS system (100) further comprises a second electrode support (210), and second cymba and cavum concha electrodes (220, 230) attached to and protruding from the second electrode support (210) and configured to be in contact with skin in cymba concha and cavum concha of a second ear of the human subject, respectively. An elastic headband (140) is attached to the first and second electrode supports (110, 220) and is configured, when attached to a head of the human subject, to exert a pressure onto the first and second electrode supports (110, 210) to press the cymba and cavum concha electrodes (120, 130, 220, 230) towards the skin in cymba concha and cavum concha of the ears of the human subject.

Description

[0001] TRANSCUTANEOUS AURICULAR VAGUS NERVE STIMULATION

[0002] TECHNICAL FIELD

[0003] The present invention generally relates to transcutaneous auricular vagus nerve stimulation (taVNS).

[0004] BACKGROUND

[0005] The vagus nerves play a major role in maintaining autonomic tone throughout the brain, thorax and abdomen. Electrical vagus nerve stimulation (VNS) is currently authorized for drug-resistant epilepsy, major depression and morbid obesity. Such VNS is conducted in the form of a cervical implantable device. VNS implantation requires a surgical procedure that positions the lead wire at the cervical portion of the trunk of the left vagus nerve while the pulse generator is inserted subcutaneously in a pocket created in the upper chest. The most common adverse effects of implanted VNS devices are related to the surgical intervention at implantation. Laryngo-tracheal dysfunction, which is related to the stimulation of the inferior recurrent laryngeal nerve, occurs in approximately two thirds of cohorts treated for epilepsy and is usually transient. But there are also other surgical challenges including electrode fracture, dislocation, generator malfunction, wound infection, recurrent laryngeal nerve palsy and cardiac arrhythmias under test stimulation.

[0006] An attractive and promising approach to circumvent the caveats of invasive VNS in humans is to use VNS engendered by an external pulse generator. Two types of transcutaneous VNS have been developed: transcutaneous cervical VNS (tcVNS) and transcutaneous auricular VNS (taVNS). tcVNS can be accomplished by delivering an electrical signal to the cervical vagus nerve, situated within the carotid sheath posterolateral to the internal and common carotid arteries and medial to the internal jugular vein, with electrodes placed on the skin covering the sternocleidomastoid muscle. Although implanted electrodes for VNS are positioned at a similar location, the position of the vagus nerve beneath the skin, superficial fascia and sternocleidomastoid muscle makes the transcutaneous electrical stimulation of the vagus fibers difficult to access with current bioelectronic devices most likely stimulating both afferent and efferent fibers in both the vagal and glossopharyngeal nerve bundles.

[0007] The auricular branch of the vagus nerve projects sensory input to the brain stem nucleus tractus solitarius (NTS), which receives approximately 95% of all vagal afferents. The NTS projects to numerous areas in forebrain, amygdala, hippocampal, limbic and brainstem structures including the nucleus ambiguus, the locus coeruleus and the dorsal motor nucleus, which promotes motor outflow of the vagus nerve. Functional magnetic resonance imaging (fMRI) studies in humans verify that the central projections of the auricular branch of the vagus nerve are consistent with the vagal projections activated after invasive VNS and can be accessed non-invasively via the external ear in taVNS. taVNS, generally performed at home, is accomplished using a small battery-powered hand-held stimulating device generating pulsed electrical currents, which are delivered via skin electrodes in the auricle.

[0008] Shortcomings of these handheld taVNS devices is to accurately deliver the stimulation pulses at correct positions in the auricle, and provide sufficient electrical contact between the stimulation electrodes and the skin during the complete stimulation session.

[0009] US 2022 / 0143390 discloses a multi-electrode ear shell including an inner surface and an outer surface. The inner surface corresponds to a surface of an ear and is configured to overlap a cymba and a cavum of the ear. The multi-electrode ear shell further includes multiple sockets configured to receive stimulation electrodes that can be in contact to various locations including the cymba, cavum, crus of helix, antihelix, tragus, auricular acupuncture points, and the like. A conductive gel is applied on the skin of the ear to provide sufficient electrical contact between the stimulation electrodes and the skin.

[0010] There is still a need for a user-friendly taVNS system that provides efficient taVNS stimulation.

[0011] SUMMARY

[0012] It is a general objective to provide a user-friendly transcutaneous auricular vagus nerve stimulation (taVNS) system that provides efficient taVNS stimulation.

[0013] This and other objectives are met by embodiments as disclosed herein.

[0014] The present invention is defined by the independent claims. Further embodiments of the invention are defined by the dependent claims.

[0015] An aspect of the invention relates to a taVNS system comprising a first electrode support, a first cymba concha electrode attached to and protruding from the first electrode support and configured to be in contact with skin in cymba concha of a first ear of a human subject, and a first cavum concha electrode attached to and protruding from the first electrode support and configured to be in contact with skin in cavum concha of the first ear of the human subject. The taVNS system also comprises a second electrode support, a second cymba concha electrode attached to and protruding from the second electrode support and configured to be in contact with skin in cymba concha of a second ear of the human subject, and a second cavum concha electrode attached to and protruding from the second electrode support and configured to be in contact with skin in cavum concha of the second ear of the human subject. The taVNS system further comprises an elastic headband attached to the first and second electrode supports and configured, when attached to a head of the human subject, to exert a pressure onto the first and second electrode supports to press the first and second cymba concha electrodes towards the skin in cymba concha of the respective ear of the human subject and the first and second cavum concha electrodes onto the skin in cavum concha of the respective ear of the human subject. According to the invention, the first and second electrode supports do not comprise any other electrodes than the cymba concha electrode and the cavum concha electrode.

[0016] Another aspect of the invention relates to a method for taVNS in a human subject. The method comprises attaching the elastic headband of the taVNS system according to the invention onto a head of the human subject to position the first and second cymba concha electrodes in contact with skin in cymba concha of a respective ear of the human subject, and the first and second cavum concha electrode in contact with skin in cavum concha of the respective ear of the human subject. The method also comprises generating electrical stimulation pulses by a stimulation device of the taVNS system to apply the electrical stimulation pulses over the first cymba concha electrode and the first cavum concha electrode, over the second cymba concha electrode and the second cavum concha electrode, or over the first cymba concha electrode and the first cavum concha electrode and over the second cymba concha electrode and the second cavum concha electrode.

[0017] A further aspect of the 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 headaches, 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 comprising performing taVNS in the human subject according to above.

[0018] The taVNS system of the invention is user friendly allowing it to be used at home without the guidance of any physician. The taVNS system is constructed to reliably and reproducibly provide efficient vagus nerve stimulation at each stimulation session by correctly aligning the electrodes at the intended stimulation sites in the external ear. An efficient vagus nerve stimulation is further achieved without the need for any contact promoting medium, such as electrically conductive gels. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The embodiments, together with further objects and advantages thereof, may best be understood by making reference to the following description taken together with the accompanying drawings, in which:

[0020] Figs. 1 A-1 B illustrate a taVNS system according to one or more embodiments;

[0021] Figs. 2A-2B illustrate details of a taVNS system according to one or more embodiments;

[0022] Figs. 3A-3C illustrate variations of a taVNS system according to one or more embodiments;

[0023] Figs. 4A-4B illustrate a stimulation device that can be used in a taVNS system according to the embodiments;

[0024] Fig. 5 is a flow chart illustrating a method for taVNS in a human subject; and

[0025] Figs. 6A-6F illustrate cytokine levels in lipopolysaccharide (LPS) activated whole blood cultures from 12 healthy donors before and after taVNS treatment.

[0026] Figs. 7A-7D illustrate cytokine levels in LPS activated whole blood cultures from 1 healthy donor before and after unilateral taVNS treatment (7A, 7C) and bilateral taVNS treatment (7B, 7D).

[0027] DETAILED DESCRIPTION

[0028] The present invention generally relates to transcutaneous auricular vagus nerve stimulation (taVNS), and in particular to a system for taVNS.

[0029] The taVNS system of the invention is designed to facilitate effective and reproducible transcutaneous auricular vagus nerve stimulation of a human subject, for instance, at home. This is achieved by placement of the stimulation electrodes at the correct positions in the external ears of the human subject. Such a correct electrode positioning is currently hard to achieve in a reproducible way by the human subject using handheld taVNS stimulating devices. Hence, it is not uncommon with such handheld taVNS stimulating devices that the human subject is not able to correctly position one or more of the stimulating electrodes at the intended stimulation sites in the external ears, with a consequence of less effective stimulation delivery and treatment. A further shortcoming with prior art taVNS stimulating devices, including the stimulation system as disclosed in US 2022 / 0143390, is that an electrically conductive gel needs to be applied to the skin of the external ear to provide sufficient electrical contact between the stimulation electrodes and the skin surface. Such electrically conductive gels are often perceived as uncomfortable by the human subjects, and may cause skin irritation in particular during prolonged use.

[0030] The stimulating system disclosed in US 2022 / 0143390 is further marred by requiring design of a subjectspecific multi-electrode ear shell for each individual human subject to be treated. Firstly, the clinician needs to take three-dimensional (3D) images of the external ear of each human subject and then generate the multi-electrode ear shell from such 3D images. Although, the multi-electrode ear shell is produced for a specific human subject, it is still cumbersome to securely insert in the external ear while minimizing movement of the multi-electrode ear shell relative the external ear during stimulation. The reason being that the multi-electrode ear shell needs to contain a plurality of protrusions and recesses to accommodate specific regions of the external ear, such the stem of antihelix, inferior crus of antihelix, superior crus of antihelix and antitragus. It is often hard for the human subject to correctly align the protrusions and recesses correctly with the specific regions or structures of the external ear each every time the transcutaneous auricular vagus nerve stimulation should take place.

[0031] The present invention relates to a taVNS system 100, see Figs. 1A-1 B, 2A-2B and 3A-3C. The taVNS system 100 comprises a first electrode support 110, a first cymba concha electrode 120, a first cavum concha electrode 130, a second electrode support 210, a second cymba concha electrode 220, a second cavum concha electrode 230, and an elastic headband 140. The first cymba concha electrode 120 and the first cavum concha electrode 130 are attached to and protrude from the first electrode support 110, and the second cymba concha electrode 220 and the second cavum concha electrode 230 are attached to and protrude from the second electrode support 210. The first and second cymba concha electrodes 120, 220 are configured to be in contact with skin in cymba concha of a first and second ear of a human subject. The first and second cavum concha electrodes 130, 230 are correspondingly configured to be in contact with skin in cavum concha of the first and second ear of the human subject. The elastic headband 140 is attached to the first and second electrode supports 110, 210 and is configured, when attached to a head of the human subject, to exert a pressure onto the first and second electrode supports 110, 210 to press the first and second cymba concha electrodes 120, 220 towards the skin in cymba concha of the respective ear of the human subject and the first and second cavum concha electrodes 130, 230 onto the skin in cavum concha of the respective ear of the human subject. The first and second electrode supports 110, 210 of the taVNS system 100 do not comprise any other electrodes than the first and second cymba concha electrode 120, 220 and the first and second cavum concha electrode 130, 230.

[0032] The first electrode support 110 of the taVNS system 100 thereby only contains two electrodes, i.e. , the first cymba concha electrode 120 and the first cavum concha electrode 130. Similarly, the second electrode support 120 of the taVNS system 100 only contains two electrodes, i.e., the second cymba concha electrode 220 and the second cavum concha electrode 230. The design of the taVNS system 100 of the invention enables a correct positioning of these electrodes 120, 130, 220, 230 in contact with the skin at the cymba concha and cavum concha, respectively, of the respective ear. This should be compared to the stimulating system of US 2022 / 0143390, in which the multi-electrode ear shell contains a plurality of electrodes to, in theory, be capable of stimulating a plurality of sites, such as the superior crus of antihelix, helix, scapha, the stem of antihelix, the concha, antitragus, the ear lobe, intertragal notch, tragus, crus of helix, inferior crus of antihelix and triangular fossa. Such a plurality of potential stimulation sites may be necessary for the stimulating system of US 2022 / 0143390 in order to provide the intended electrical stimulation to the target site due to above-mentioned problems of correctly attaching the multi-electrode ear shell to the external ear.

[0033] Experimental data presented herein shows that the first and second electrode support 110, 210 with attached and protruding first and second cymba concha electrode 120, 220 and first and second cavum concha electrode 130, 230 achieves an efficient taVNS capable of inducing a biological effect in the treated human subjects with merely two such electrodes 120, 130, 220, 230 attached to and protruding from each electrode support 110, 210.

[0034] Furthermore, the positions of the two electrodes 120, 130, 220, 230 at each electrode support 110, 210 is preferably fixed in terms of not being adjustable along the length L or width W of the electrode supports 110, 210 (see Fig. 1 B). However, the protrusion of one or both electrodes 120, 130, 220, 230 from the electrode supports 110, 210 is preferably adjustable as will be further described herein. This enables a less complex design of the electrode supports 110, 210 as compared to the multi-electrode ear shell of US 2022 / 0143390 and still achieving efficient taVNS. A further benefit is that the taVNS system 100 of the invention does not need to be subject-specific, i.e., one and the same taVNS system 100 could be used to provide taVNS to multiple different human subjects. The first and / or second cymba concha electrode 120, 220 and the first and / or second cavum concha electrode 130, 230 are made of an electrically conducting material, preferably an electrically conducting metal or metal alloy. The electrically conducting material, preferably electrically conducting metal or metal alloy, should not only have good electrical conductivity but should also preferably be biologically acceptable. Electrically conducting metals and metal alloys generally have a resistivity at 20°C in the order of 108Qm and thereby an electrical conductivity at 20°C in the order of 106-107S / m. In a particular embodiment, the electrically conducting material, preferably electrically conducting metal or metal alloy, of the electrodes 120, 130, 220, 230 has an electrical conductivity of at least 106S / m, preferably at least 0.5x107S / m, and more preferably at least 107S / m at 20°C. More preferably, the electrically conducting material, preferably electrically conducting metal or metal alloy, has an electrical conductivity at 20°C of at least 3*107S / m.

[0035] Biologically acceptable or biologically tolerant as used herein indicates that the electrically conducting material, preferably electrically conducting metal or metal alloy, does not cause any significant deleterious effects to the skin in the ear when the electrodes 120, 130, 220, 230 are in contact with the skin in cymba concha and cavum concha during the duration of a taVNS session. In particular, the electrically conducting material, preferably electrically conducting metal or metal alloy, should not cause any significant skin irritation during such normal use of the taVNS system 100.

[0036] Currently preferred electrically conducting materials include aluminum and aluminum alloys. Aluminum has a resistivity of 2.65x108Qm and an electrical conductivity of 3.77x107S / m at 20°C.

[0037] In an embodiment, the first and / or second cymba concha electrode 120, 220 is made of aluminum or an aluminum alloy or comprises an electrode surface 121 , 221 made of aluminum or the aluminum alloy. Alternatively, or preferably in addition, the first and / or second cavum concha electrode 130, 230 is made of aluminum or an aluminum alloy or comprises an electrode surface 131 , 231 made of aluminum of the aluminum alloy. In a preferred embodiment, the first and / or second cymba concha electrode 120, 220 and the first and / or second cavum concha electrode 130, 230 are made of aluminum or comprise a respective electrode surface 121 , 131 , 221 , 231 made of aluminum.

[0038] Other metals and metal alloys that could be used for the electrodes 120, 130, 210, 230 or at least the electrode surfaces 121 , 131 , 221 , 231 include gold and silver and alloys thereof. The electrodes 120, 130, 210, 230 may be made of a single metal or metal alloy, preferably aluminum or an aluminum alloy. For instance, the electrodes 120, 130, 210, 230 could be solid electrodes consisting of the single metal or metal alloy. Alternatively, the electrodes 120, 130, 210, 230 could comprise an electrically conducting core material, preferably an electrically conducting metal or metal alloy, and then comprising an electrode surface 121 , 131 , 221 , 231 made of another electrically conducting material, preferably another electrically conducting metal or metal alloy. The electrode surface 121, 131 , 221 , 231 could then be in the form an electrically conducting coating or surface layer on the electrode core. As an example, the electrode core could be made of copper or an alloy thereof.

[0039] The electrically conducting material of the electrode core does then not necessarily have to be biologically acceptable since it will not be in direct contact with the skin of the human subject. Thus, electrically conducting material, preferably electrically conducting metals or metal alloys, having a high electrically conductivity but not necessary biologically acceptable could be used as electrode core material.

[0040] In a preferred embodiment, the first and / or second cymba concha electrode 120, 220 and the first and / or second cavum concha electrode 130, 230 are made of the same electrically conducting material or materials. Hence, all electrodes 120, 130, 210, 230 are preferably solid electrodes made of a single electrically conducting material, preferably a single electrically conducting metal or metal alloy, or all electrodes 120, 130, 210, 230 comprise an electrically conducting core material, preferably an electrically conducting metal or metal alloy, and an electrode surface 121 , 131 , 221 , 231 made of another electrically conducting material, preferably another electrically conducting metal or metal alloy.

[0041] In an embodiment, the first and second cymba concha electrodes 120, 220 are configured to be in direct physical contact with the skin in the cymba concha of the ears of the human subject and the first and / or second cavum concha electrode 130, 230 is configured to be in direct physical contact with the skin in the cavum concha of the ears of the human subject.

[0042] Hence, the electrodes 120, 130, 210, 230 of the electrode supports 110, 220 are configured to be not only in electrical contact with but also direct physical contact with the skin in the cymba concha and cavum concha, respectively. In particular, the respective electrode surface 121 , 131 , 221 , 231 of the electrodes 120, 130, 210, 230 is configured to be in direct physical contact and electrical contact with the skin in these regions (cymba concha and cavum concha, respectively) of the ears of the human subject. Direct physical contact as used herein means that the electrodes 120, 130, 210, 230, or rather the electrode surface 121 , 131 , 221 , 231 , directly contacts and touches the skin in cymba concha and cavum concha, respectively. Accordingly, no intermediate medium, including an electrically conducting gel, is used to mediate the electrical contact between the electrodes 120, 130, 210, 230 and the skin.

[0043] In an embodiment, the first and / or second cymba concha electrode 120, 220 comprises an electrode body 123, 223 in electrical contact with a power cord 150, 250 and a hemispherical electrode head 122, 222 comprising an electrode surface 121 , 221 configured to be in contact with the skin the cymba concha of the ear of the human subject. There may be a first power cord 150 for the first electrode support 110 (as illustrated in Fig. 2B) and a second power cord 250 for the second electrode support 210 (as illustrated in Fig. 2A). Alternatively, there may be just one power cord 150, 250 for both electrode supports 110, 210 (as illustrated in Fig. 1A). In this case, the power cord 150, 250 may connect to either the first electrode support 110 or the second electrode support 210 but is electrically connected to the electrodes 120, 130, 220, 230 of both electrode supports 110, 210. For instance, a power cord (not shown) may be running from one of the electrode supports 110, 210 to the other electrode support along the elastic headband 140.

[0044] In an embodiment, the electrode body 123, 223 could be in the form of a cylinder having the hemispherical electrode head 122, 222 at one of its ends and the other, opposite end facing the electrode support 110, 210. Such a design of the first and / or second cymba concha electrode 120, 220 provides a smooth hemispherical electrode surface 121 , 221 touching the skin at cymba concha while the electrode body 123, 223 enables the hemispherical electrode head 122, 222 to protrude into cymba concha while avoiding surrounding structures or regions in the ear that should not be electrically stimulated, such as the crus of helix, antihelix and inferior crus of antihelix.

[0045] In an embodiment, the electrode body 123, 223 of the first and / or second cymba concha electrode 120, 220 is attached to an adjustable electrode shaft 124, 224, see Fig. 3B. In such an embodiment, the adjustable electrode shaft 124, 224 is arranged to adjust a protrusion of the hemispherical electrode head 122, 222 of the first and / or second cymba concha electrode 120, 220 relative the electrode support 110, 210.

[0046] In this embodiment, the protrusion of the first and / or second cymba concha electrode 120, 220 relative the electrode support 110, 210 is adjustable as indicated by the dashed arrows in Figs. 3B. This means that the distance between the end of the hemispherical electrode head 122, 222 and thereby of the electrode surface 121 , 221 and the electrode support 110, 210 could be adjusted so that electrode surface 121 , 221 correctly touches the skin in cymba concha when the elastic headband 140 is attached to the head of the human subject.

[0047] In a particular embodiment, the taVNS system 100 also comprises an adjustment screw 111 , 211 arranged at the electrode support 110, 210 in contact with the adjustable electrode shaft 124, 224. The adjustment screw 111 , 211 is then configured to attach the adjustable electrode shaft 124, 224 at a selected position relative the electrode support 110, 210.

[0048] In a preferred embodiment, the adjustment screw 111 , 211 can be screwed clockwise or counterclockwise relative the electrode support 110, 210. Turning the adjustment screw 111 , 211 one way, preferably clockwise, causes movement of the cymba concha electrode 120, 220 further away from the electrode support 110, 220, whereas turning the adjustment screw 111 , 211 the other way, preferably counter-clockwise, causes movement of the cymba concha electrode 120, 220 towards the electrode support 110, 210. Accordingly, the adjustment screw 111 , 211 can thereby be used to adjust the amount or level of protrusion of the cymba concha electrode 120, 220, and in particular of the hemispherical electrode head 122, 222, from the electrode support 110, 210.

[0049] In an embodiment, the first and / or second cavum concha electrode 130, 230 comprises an electrode body 133, 233 in electrical contact with a power cord 152, 252 and a hemispherical electrode head 132, 232 comprising an electrode surface 131 , 231 configured to be in contact with the skin the cavum concha of the ear of the human subject. There may be a first power cord 152 for the first electrode support 110 (as illustrated in Fig. 2B) and a second power cord 252 for the second electrode support 210 (as illustrated in Fig. 2A). Alternatively, there may be just one power cord 152, 252 for both electrode supports 110, 210 (as illustrated in Fig. 1A). In this case, the power cord 152, 252 may connect to either the first electrode support 110 or the second electrode support 210 but is electrically connected to the electrodes 120, 130, 220, 230 of both electrode supports 110, 210. For instance, a power cord (not shown) may be running from one of the electrode supports 110, 210 to the other electrode support along the elastic headband 140.

[0050] In an embodiment, the electrode body 133, 233 could be in the form of a cylinder having the hemispherical electrode head 132, 232 at one of its ends and the other, opposite end facing the electrode support 110, 210. Such a design of the cymba concha electrode 130, 230 provides a smooth hemispherical electrode surface 131 , 231 touching the skin at cavum concha while the electrode body 133, 233 enables the hemispherical electrode head 132, 232 to protrude into cavum concha while avoiding surrounding structures or regions in the ear that should not be electrically stimulated, such as the crus of helix, tragus, and antitragus.

[0051] In an embodiment, the electrode body 133, 233 of the cavum concha electrode 130, 230 is attached to an adjustable electrode shaft 134, 234, see Figs. 1 A, 1 B, 2A, 2B, 3A. In such an embodiment, the adjustable electrode shaft 134, 234 is arranged to adjust a protrusion of the hemispherical electrode head 132, 232 of the cavum concha electrode 130, 230 relative the electrode support 110, 210.

[0052] In this embodiment, the protrusion of the cymba concha electrode 130, 230 relative the electrode support 110, 210 is adjustable as indicated by the dashed arrows in Fig. 3A. This means that the distance between the end of the hemispherical electrode head 132, 232 and thereby of the electrode surface 131 , 231 and the electrode support 110, 210 could be adjusted so that electrode surface 131 , 231 correctly touches the skin in cavum concha when the elastic headband 140 is attached to the head of the human subject.

[0053] In a particular embodiment, the taVNS system 100 also comprises an adjustment screw 112, 212 arranged at the electrode support 110, 210 in contact with the adjustable electrode shaft 134, 234. The adjustment screw 112, 212 is then configured to attach the adjustable electrode shaft 134, 234 at a selected position relative the electrode support 110, 210.

[0054] In a preferred embodiment, the adjustment screw 112, 212 can be screwed clockwise or counterclockwise relative the electrode support 110, 210. Turning the adjustment screw 112, 212 one way, preferably clockwise, causes movement of the cavum concha electrode 130, 230 further away from the electrode support 110, 210, whereas turning the adjustment screw 112, 212 the other way, preferably counter-clockwise, causes movement of the cavum concha electrode 130 towards the electrode support 110, 210. Accordingly, the adjustment screw 112, 212 can thereby be used to adjust the amount or level of protrusion of the cavum concha electrode 130, 230, and in particular of the hemispherical electrode head 132, 232, from the electrode support 110, 210.

[0055] The embodiment shown in Figs. 1 A-1 B, 2A-2B and 3A enables adjustment of the protrusion of the cavum concha electrodes 130, 230, whereas the embodiment shown in Fig. 3B enables adjustment of the protrusion of the cymba concha electrodes 120, 220. Fig. 3C illustrates another embodiment combining adjustment of the protrusion of the cavum concha electrodes 130, 230 with adjustment of the protrusion of the cymba concha electrodes 120, 220. The embodiment of the taVNS system 100 as shown in Fig. 3C provides the largest degree of freedom by individually adjusting the protrusion of the two electrodes 120, 130, 220, 230 relative the electrode support 110, 210. However, it is in most cases sufficient if the protrusion of merely one of the electrodes 120, 130, 220, 230 is adjustable to still achieve efficient electrical and physical contact between the electrode surfaces 121 , 131 , 221 , 231 and the skin in the cymba concha and cavum concha. In such a case, one of the electrodes 120, 130, 220, 230 is fixedly, i.e., non-adjustably, attached to the electrode support 110, 210, whereas the other electrode 120, 130, 220, 230 is adjustably attached to the electrode support 110, 210. Such an embodiment leads to a less complex design of the taVNS system 100 shown in Figs. 1 A-1 B, 2A-2B, 3A-3B as compared to the embodiment of the taVNS system 100 as shown in Fig. 3C.

[0056] In an alternative embodiment, the first cymba concha electrode 120 and the first cavum concha electrode 130 are adjustable as shown in the right part of Fig. 3C whereas the second cymba concha electrode 220 and the second cavum concha electrode 230 are fixed, i.e., not adjustable, relative to the second electrode support 210. In another alternative embodiment, the second cymba concha electrode 220 and the second cavum concha electrode 230 are adjustable as shown in the left part of Fig. 3C whereas the first cymba concha electrode 120 and the first cavum concha electrode 130 are fixed, i.e., not adjustable, relative to the first electrode support 110. In these alternative embodiments, the protrusions of the electrodes 120, 130 or 220, 230 at one of the electrode supports 110 or 210 but not both electrode supports 110, 210 are adjustable.

[0057] In a currently preferred embodiment, the protrusion of the cavum concha electrode 130, 230 is adjustable whereas the cymba concha electrode 120, 220 is fixed as shown in Figs. 1A-1 BC, 2A-2B, 3A-3B.

[0058] The elastic headband 140 of the taVNS system 100 exerts an inwards pressure or force on the electrode supports 110, 210 that then presses the fixed electrodes in physical contact with the skin at the target stimulation site in the external ear of the human subject. The amount or level of protrusion of the adjustable electrodes can then be used to fine tune the pressure exerted by the adjustable electrodes on the skin to achieve a direct physical contact between the adjustable electrodes and the skin but not being uncomfortable for the human subject. In other words, the design of the taVNS system 100 with the elastic headband 140 attached to the electrode supports 110, 210 enables sufficient electrical and physical contact between the electrodes 120, 130, 220, 230 and the skin at cymba concha and cavum concha and still not pressing the electrodes 120, 130, 220, 230 too tightly against the skin to be uncomfortable for the human subject. This is possible even with one fixed electrode and one adjustable electrode per electrode support 110, 120, or indeed one electrode support with fixed electrodes and another electrode support with adjustable electrodes.

[0059] Hence, in an embodiment, one of the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 is fixedly attached to the electrode support 110, 210 and protrudes at a fixed distance from the electrode support 110, 210. In this embodiment, the other of the cymba concha electrode 120, 220 and the cavum concha 130, 230 is adjustably attached to the electrode support 110 and protrudes at an adjustable distance from the electrode support 110, 220.

[0060] In an embodiment, the distance between the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 in the electrode support 110, 210 corresponds to an average distance between the cymba concha and the cavum concha in a population of a plurality of human subjects.

[0061] The inventors have found that the distance between the cymba concha and the cavum concha does not differ much in a population of human adults. This means that an electrode support 110, 210 with a fixed, i.e., non-adjustable, distance between the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 in the electrode support 110, 210 could be used to electrically stimulate a plurality of human subjects. Hence, taVNS system 100 can still be used to treat a plurality of different human (adult) subjects without the need for adjusting the distance between the electrodes 120, 130, 220, 230 in the electrode support 110, 210.

[0062] In another embodiment, the distance between the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 in the electrode support 110, 210 corresponds to a distance between the cymba concha and the cavum concha of a human subject.

[0063] In this embodiment, a subject-specific taVNS system 100 could be used, in which the distance between the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 in the electrode support 110, 210 is defined to match the corresponding distance between the cymba concha and the cavum concha of the particular human subject.

[0064] In a particular embodiment, distance between the cymba concha electrode 120, 220 and the cavum concha electrode 130, 230 in the electrode support 110, 210 corresponds to a distance along the length (L) or length axis of the electrode support 110, 210, see Fig. 1 B. The electrode supports 110, 210 of the taVNS system 100 are designed to be positioned external of the outer ears of the human subject when the electrodes 120, 130, 220, 230 are in contact with the skin of the cymba concha and cavum concha, respectively. In a typical embodiment, each electrode support 110, 210 is configured to be aligned with at least a portion of the external ear of the human subject when the elastic headband 140 is attached to the head of the human subject. However, the electrode supports 110, 210 are preferably present outside of the external ears, i.e., not in the form of ear shells to be attached inside the external ears.

[0065] In an embodiment, the electrodes 120, 130, 220, 230 are attached to and protrude from inner surfaces 113, 213 of the electrode supports 110, 210, see Fig. 1A. The inner surfaces 113, 213 of the electrode supports 110, 210 are thereby facing the external ears of the human subject when the elastic headband 140 is attached to the head of the human subject. The inner surfaces 113, 213 are preferably flat surfaces, i.e., does not correspond to a surface of the ear.

[0066] This design has the advantage of minimizing any irritation between the electrode supports 110, 210 and the external or outer ears of the human subject when wearing the taVNS system 100. Thus, in a preferred embodiment, the only portion of the taVNS system 100 in physical contact with the skin of the external or outer ears of the human subject is the electrode surface 121 , 221 , 131 , 231 of the electrodes 120, 130, 220, 230.

[0067] The taVNS system 100 comprises an elastic headband 140 attached to the electrode supports 110, 210. The elastic headband 140 is designed to be attached to the head of the human subject. At such a position on the head, the electrode supports 110, 210 will be aligned with external or outer ears of the human subject. Furthermore, at such a position the cymba concha electrodes 120, 220 will be aligned with the cymba concha and the cavum concha electrodes 130, 230 will be aligned with cavum concha of the ears. The headband 140 is elastic to enable it to be attached to the head of the human subject but is preferably made of or comprises a rigid material that is capable of exerting an inward pressure or force on the electrode supports 110, 210 against the ears of the human subject. The headband 140 comprises an over-head band or piece 142 designed to run over and on top of a least a portion of the head of the human subject.

[0068] The headband 140 may be attached to the electrode supports 110, 210 or may be integrally formed with the first and / or second electrode support 110, 210. In the latter case, the elastic headband 140, or at least the over-head band 142 thereof, and the first and / or second electrode support 110, 210 forms a monolithic unit.

[0069] The headband 140 may optionally include an adjustment mechanism for fitting the headband 140 to the head of the human subject. Such an adjustment mechanism can then be used to adjust the size of the headband 140 to different head sizes. Furthermore, the adjustment mechanism could be used to adjust the pressure exerted by the headband 140 onto the electrode supports 110, 210 to press the electrodes 120, 130, 220, 230 attached to and protruding from the electrode supports 110, 210 in physical contact with the skin in the cymba concha and cavum concha of the ears. An illustrative, but non-limiting, example of such an adjustment mechanism is to include telescoping sections to extend or retract the ends of the elastic headband 140. Such telescoping sections could then be lockable using well-known solutions, such as friction or rachet brakes.

[0070] In an embodiment, the taVNS system 100 also comprises a stimulation device 300, see Figs. 4A-4B. In such a case, the stimulation device 300 is in electrical contact with the first and / or second cymba concha electrode 120, 220 and the first and / or second cavum concha electrode 130, 230. The stimulation device 300 is configured to generate electrical stimulation pulses.

[0071] The stimulation device 300 typically contains connection ports 310, 315, 320, 325, to which the above- mentioned power cords 150, 152, 250, 252 could be attached to electrically connect the stimulation device 300 with the electrodes 120, 130, 220, 230. The stimulation device 300 may contain two connection ports 310, 320, as illustrated in Fig. 4A, or four connection ports 310, 315, 320, 325, as illustrated in Fig. 4B.

[0072] In an embodiment, a single stimulation device 300 with two or four connection ports 310, 315, 320, 325 is connected to power cords 150, 152, 250, 252 to provide stimulation pulses to the electrodes 120, 130, 220, 230. It could, however, be possible to use two stimulation devices 300, were a first stimulation device 300 is connected, by power cord(s) 150, 152, to the electrodes 120, 130 of the first electrode support 110 and a second stimulation device connected, by power cord(s) 250, 252, to the electrodes 220, 230 of the second electrode support 210.

[0073] In yet another embodiment, a single stimulation device 300 could be connected to the electrodes 120, 130 of the first electrode support 110, whereas the electrodes 220, 230 of the second electrode support 210 are then not electrically connected to any stimulation device 300. In such an embodiment, the stimulation device 300 could then be disconnected from the electrodes 120, 130 of the first electrode support 110 and instead be connected to the electrodes 220, 230 of the second electrode support 210 to provide stimulation pulses to those electrodes 220, 230. In this embodiment, the stimulation device 300 could thereby be alternating between being connecting to the electrodes 120, 130, 220, 230 in either electrode support 110, 210.

[0074] The stimulation device 300 could be any stimulation device capable of generating electrical stimulation pulses suitable for taVNS. Such stimulation devices 300, sometimes referred to as transcutaneous electrical nerve stimulation (TENS) devices or machines, are available on the marked from various vendors including, but not limited to, TENS 7000®, Omron, Axion, Body Clock, Saneo, Health Technologies, Roscoe Medical, Auri Stim Medical, tVNS Technology GmbH, Cerbomed, Parasym, Soterix Medical, Xana Stim, NESOS, etc.

[0075] Fig. 5 is a flow chart of a method for transcutaneous auricular vagus nerve stimulation (taVNS) in a human subject according to an embodiment. The method comprises attaching, in step S1 , the elastic headband 140 of the taVNS system 100 according to the invention onto a head of the human subject to position the cymba concha electrodes 120, 220 in contact with skin in cymba concha of the ears of the human subject, and the cavum concha electrodes 130, 230 in contact with skin in cavum concha of the ears of the human subject. The method also comprises generating, in step S2, electrical stimulation pulses by the stimulation device 300 to apply the electrical stimulation pulses over the first cymba concha electrode 120 and the first cavum concha electrode 130, over the second cymba concha electrode 220 and the second cavum concha electrode 230, or over the first cymba concha electrode 120 and the first cavum concha electrode 130 and over the second cymba concha electrode 220 and the second cavum concha electrode 230.

[0076] Thus, the electrical stimulation pulses may, during a treatment session, be applied to stimulate only the vagus nerve at the left ear or at the right ear. Alternatively, a treatment session may involve alternate between stimulating the vagus nerve at the left ear and the vagus nerve at the right ear. Yet, another alternative is to apply the electrical stimulation pulses simultaneously to both the vaugs nerve at the right side and the vagus nerve at the left side.

[0077] An advantage of the present taVNS system 100 is that enables flexibility in the application of electrical stimulation pulses. Thus, the taVNS system 100 can be used to stimulate only the vagus nerve at the left or right ear, stimulate the vagus nerve at both ears or switch between stimulation of the vagus nerve at the left and right ears during a single stimulation session without the need for repositioning the taVNS system 100 or the electrodes 120, 130, 220, 230 on the human subject.

[0078] Another advantage of the present taVNS system 100 is that comparatively short stimulation sessions can be used and still achieving biological effects on the human subject as shown in the Example section. Hence, in an embodiment, step S2 in Fig. 5 comprises generating the electrical stimulation pulses by the stimulation device 300 once or twice, preferably twice, a day for a respective stimulation period or session of from 2 minutes up to 10 minutes, preferably from 3 minutes up to 7 minutes, and more preferably for about 5 minutes.

[0079] The taVNS system 100 of the invention and the use thereof as shown in Fig. 5 could be applied to treat various medical conditions, which would benefit from taVNS. Illustrative, but non-limiting, examples of such medical conditions include epilepsy, depression, obesity, migraine, cluster headaches, 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.

[0080] First and second as referred to herein relate to left and right, or vice versa, when the taVNS system 100 is worn by human subject. For instance, in such a case, the first cymba and cavum concha electrodes 120, 130 could then be regarded as left cymba and cavum concha electrodes 120, 130 or right cymba and cavum concha electrodes 120, 130, whereas the second cymba and cavum concha electrodes 220, 230 are then regarded as right cymba and cavum concha electrodes 220, 230 or left cymba and cavum concha electrodes 220, 230.

[0081] EXAMPLES

[0082] EXAMPLE 1

[0083] The present Example investigated the effects of taVNS on cytokine levels in LPS-activated whole blood cultures from healthy donors before and after taVNS.

[0084] Materials & Methods

[0085] Study design

[0086] The study enrolled 13 healthy individuals between 21 and 75 years of age. Participants confirmed no non-steroidal anti-inflammatory drug (NSAID) medications within 48 hours and no food or drink (besides water) for at least 8 hours prior to the study. The study schedule for each participant was a baseline pre- stimulation blood draw, a 30-minute wait period, 5 minutes of stimulation with the taVNS system of the invention (with the following settings: frequency 20 Hz, pulse width 200 ps, current intensity individually adjusted below pain threshold denoting < 3 mA, stimulation at only one side) and 2 hours post stimulation blood draw. The study was arranged over three consecutive days with the baseline pre-stimulation blood draw for all patients taken before 10 am. All blood draws were collected into 10 mL sodium heparin tubes and assayed with the custom ex vivo whole blood endotoxin assay. One participant did not finish the study due to a failed post stimulation blood draw.

[0087] Ex vivo endotoxin whole blood assay

[0088] Blood drawn in heparin tubes was immediately aliquoted and stimulated (hold time did not exceed 1 hour). All preparations were done in a biosafety level 2 (BSL-2) lab setting. In brief, endotoxin (lipopolysaccharide (LPS), Escherichia coli 0111 :B4, Sigma Aldrich, USA) was re-suspended to 5 mg / ml, sonicated for 30 min, vortexed, and diluted with phosphate buffered saline (PBS) to generate a working 1 mg / ml stock stored at -20 °C. For each day of the study, fresh dilutions of LPS were made from this working stock. Working stock was sonicate for 30 minutes and serially diluted 10-fold with saline to concentrations of 50 pg / mL to 5 ng / mL. Heparinized blood was aliquoted into 15 round bottom 2 mL tubes and 10 pL of LPS dilutions were added to blood samples in triplicate to achieve final concentrations of 0 ng / mL and 10 ng / mL in 500 pL blood aliquots. These tubes were then incubated on an orbital rocking platform at 37 °C for 4 h. After 4 hours, plasma was collected from all samples by centrifugation for 10 minutes at 2000 x g in a refrigerated centrifuge and frozen at -20 °C for future analysis.

[0089] Cytokine assays

[0090] Tumor necrosis factor (TNF) levels in the plasma were quantitated using a commercial enzyme-linked immunosorbent assay (ELISA) (R&D Systems #DY210) with all samples assayed in duplicate. Further cytokine analysis was performed on the blood stimulated with 0 ng / mL and 10 ng / mL LPS and these samples were assayed in duplicate on a custom MesoScale Discovery U-Plex cytokine panel for interleukin-1 receptor antagonist (IL-1 RA), IL-1 a, IL-10, IL-6 and IL-8. Plate was imaged using MESO QuickPlex SQ 120 instrument (MSD, Gaithersburg, MD) and analyzed using MSD Discovery Workbench Software. All data was analyzed and graphed using GraphPad Prism 9.

[0091] Statistics

[0092] Table 1 - Statistics

[0093] Results

[0094] The results are presented in Figs. 6A-6F demonstrating the effects of taVNS on cytokine levels in LPS- activated (10 ng / mL) whole blood cultures from healthy donors before and after taVNS. Quantitative assessments were performed of the pro-inflammatory cytokines IL-1 a (Fig. 6A), IL-10 (Fig. 6B), IL-6 (Fig. 6C), IL-8 (Fig. 6D), and TNF (Fig. 6E) and the anti-inflammatory cytokine IL-1 RA (Fig. 6F). As is shown in the figures, taVNS stimulation induced a reduction in the investigated pro-inflammatory cytokines but had no significant effect on the anti-inflammatory cytokine IL-1 RA. This Example thereby showed that the taVNS system of the invention was capable of effective taVNS stimulation, which reduced inflammatory cytokines. Hence, the taVNS system of the invention would be suitable for treatment of various inflammatory diseases and conditions that would benefit from taVNS stimulation.

[0095] EXAMPLE 2

[0096] The present Example investigated the effects mediated by unilateral or bilateral taVNS on ex vivo LPS-induced whole blood sample production of TNF.

[0097] Materials & Methods

[0098] Study design

[0099] This study enrolled a healthy 76-year-old individual. The study person confirmed no non-steroidal antiinflammatory drug (NSAID) medications within 48 hours and no food or drink (besides water) for at least 8 hours prior to the study. The study schedule was a baseline pre-stimulation blood draw followed by 5 minutes of electrical stimulation with the taVNS system of the invention programmed with the following settings: frequency 20 Hz, pulse width 200 ps, current intensity adjusted below pain threshold denoting < 5 mA. A second blood draw was performed 2 hours after the taVNS. The study was arranged over two separate days, 48 hours apart, with the baseline pre-stimulation blood draw taken before 10 am. External auricular vagus nerve stimulation was performed, on the first study day, unilaterally in the left ear with a taVNS systema as disclosed in WO 2024 / 228655 A1 equipped with two aluminum electrodes of the same design as the ones in the taVNS system of the invention. The electrodes contacted the skin in the cymba concha area and in the cavum concha. External auricular vagus nerve stimulation was once more performed 48 hours later, bilaterally in both ears simultaneously using the invention taVNS device. Blood draws were collected into 10 mL sodium heparin tubes and assayed with the custom ex vivo whole blood endotoxin assay.

[0100] Ex vivo endotoxin whole blood assay

[0101] Blood drawn in heparin tubes was immediately aliquoted and stimulated (hold time did not exceed 1 hour). All preparations were done in a biosafety level 2 (BSL-2) lab setting. In brief, endotoxin (lipopolysaccharide (LPS), Escherichia coli 0111 :B4, Sigma Aldrich, USA) was re-suspended to 5 mg / ml, sonicated for 30 min, vortexed, and diluted with phosphate buffered saline (PBS) to generate a working 1 mg / ml stock stored at -20 °C. For each day of the study, fresh dilutions of LPS were made from this working stock. Working stock was sonicated for 30 minutes and serially diluted 10-fold with saline to concentrations of 50 pg / mL to 5 ng / mL. Heparinized blood was aliquoted into round bottomed 2 mL tubes and 10 pL of LPS dilutions were added to blood samples in triplicate to achieve final concentrations of 0 ng / mL, 0.1 ng / mL, 1 ng / mL, 10 ng / mL, and 100 ng / mL in 500 pL blood aliquots. These tubes were then incubated on an orbital rocking platform at 37 °C for 4 h. After 4 hours, plasma was collected from all samples by centrifugation for 10 minutes at 2000 x g in a refrigerated centrifuge and frozen at -20 °C for future analysis.

[0102] Cytokine assay

[0103] Tumor necrosis factor (TNF) levels in the plasma were quantitated using a commercial enzyme-linked immunosorbent assay (ELISA) (R&D Systems #DY210) with all samples assayed in triplicate. The assay was performed on Jan 29thof 2025 (a week after the initial blood drawings, Figs. 7A and 7B) and was repeated on Feb 14thof 2025 (Figs. 7C and 7D).

[0104] Table 2 - Statistics

[0105] Results The results are presented in Figs. 7A to 7D demonstrating the effects of taVNS on TNF levels in LPS- activated and non-LPS-activated whole blood cultures from the donor after unilateral taVNS (Figs. 7A, 7C) and bilateral taVNS (Figs. 7B, 7D), respectively. As is shown in the figures, bilateral taVNS stimulation induced a significant TNF reduction in the blood cultures (Figs. 7B, 7D). The inhibition was more pronounced than observed after left-sided unilateral taVNS. No inhibition occurred after ex vivo stimulation with 100 ng / mL LPS (Figs. 7B, 7D). These results are in line with historical controls, using the same culture system, since neither invasive nor external VNS have managed to downregulate the production of TNF after high-dose LPS stimulation (100 ng / mL).

[0106] The present results thereby showed that the bilateral taVNS system of the invention was capable of effective taVNS stimulation, which reduced the release of the potent inflammatory cytokine TNF. Hence, the taVNS system of the invention would be suitable for treatment of various inflammatory diseases and conditions that would benefit from reduced TNF production.

[0107] The embodiments described above are to be understood as a few illustrative examples of the present invention. It will be understood by those skilled in the art that various modifications, combinations and changes may be made to the embodiments without departing from the scope of the present invention. In particular, different part solutions in the different embodiments can be combined in other configurations, where technically possible.

Claims

CLAIMS1 . A transcutaneous auricular vagus nerve stimulation, taVNS, system (100) comprising: a first electrode support (110); a first cymba concha electrode (120) attached to and protruding from the first electrode support (110) and configured to be in contact with skin in cymba concha of a first ear of a human subject; a first cavum concha electrode (130) attached to and protruding from the first electrode support (110) and configured to be in contact with skin in cavum concha of the first ear of the human subject; a second electrode support (210); a second cymba concha electrode (220) attached to and protruding from the second electrode support (210) and configured to be in contact with skin in cymba concha of a second ear of the human subject; a second cavum concha electrode (230) attached to and protruding from the second electrode support (210) and configured to be in contact with skin in cavum concha of the second ear of the human subject; and an elastic headband (140) attached to the first and second electrode supports (110, 210) and configured, when attached to a head of the human subject, to exert a pressure onto the first and second electrode supports (110, 210) to press the first and second cymba concha electrodes (120, 220) towards the skin in cymba concha of the respective ear of the human subject, and the first and second cavum concha electrodes (130, 230) onto the skin in cavum concha of the respective ear of the human subject, wherein the first and second electrode supports (110, 210) do not comprise any other electrodes than the cymba concha electrode (120, 220) and the cavum concha electrode (130, 230).

2. The taVNS system according to claim 1 , wherein the first and / or second cymba concha electrode (120, 220) is made of aluminum or an aluminum alloy, preferably aluminum, or comprises an electrode surface (121 , 221) made of aluminum or the aluminum alloy, preferably aluminum.

3. The taVNS system according to claim 1 or 2, wherein the first and / or second cavum concha electrode (130, 230) is made of aluminum or an aluminum alloy, preferably aluminum, or comprises an electrode surface (131 , 231) made of aluminum or the aluminum alloy, preferably aluminum.

4. The taVNS system according to any one of claim 1 to 3, wherein the first and second cymba concha electrode (120, 220) are configured to be in direct physical contact with the skin in the cymba concha of the respective ear of the human subject; andthe first and second cavum concha electrode (130, 230) are configured to be in direct physical contact with the skin in the cavum concha of the respective ear of the human subject.

5. The taVNS system according to any one of claims 1 to 4, wherein the first and / or second cymba concha electrode (120, 220) comprises: an electrode body (123, 223) in electrical contact with a power cord (150, 250); and a hemispherical electrode head (122, 222) comprising an electrode surface (121 , 221) configured to be in contact with the skin in the cymba concha of the respective ear of the human subject.

6. The taVNS system according to claim 5, wherein the electrode body (123, 223) of the first and / or second cymba concha electrode (120, 220) is attached to an adjustable electrode shaft (124, 224) arranged to adjust a protrusion of the hemispherical electrode head (122, 222) of the respective cymba concha electrode (120, 220) relative the first and / or second electrode support (110, 210).

7. The taVNS system according to claim 6, further comprising at least one adjustment screw (111 , 211) arranged at the first and / or second electrode support (110, 220) in contact with the respective adjustable electrode shaft (124, 224) and configured to attach the adjustable electrode shaft (124, 224) at a selected position relative the electrode support (110, 210).

8. The taVNS system according to any one of claims 5 to 7, wherein the electrode surface (121 , 221 ) of the hemispherical electrode head (122, 222) of the first and / or second cymba concha electrode (120, 220) is configured to be in direct physical contact and electrical contact with skin in the cymba concha of the respective ear of the human subject.

9. The taVNS system according to any one of claims 1 to 8, wherein the first and / or second cavum concha electrode (130, 230) comprises: an electrode body (133, 233) in electrical contact with a power cord (152, 252); and a hemispherical electrode head (132, 232) comprising an electrode surface (131 , 231) configured to be in contact with the skin in the cavum concha of the respective ear of the human subject.

10. The taVNS system according to claim 9, wherein the electrode body (133, 233) of the first and / or second cavum concha electrode (130, 230) is attached to an adjustable electrode shaft (134, 234) arranged to adjust a protrusion of the hemispherical electrode head (132, 232) of the first and / or second cavum concha electrode (130, 230) relative the electrode support (110, 210).11 . The taVNS system according to claim 10, further comprising at least one adjustment screw (112, 212) arranged at the first and / or second electrode support (110, 210) in contact with the respective adjustable electrode shaft (134, 234) and configured to attach the respective adjustable electrode shaft (134, 234) at a selected position relative the electrode support (110, 210).

12. The taVNS system according to any one of claims 9 to 11 , wherein the electrode surface (131 , 231) of the hemispherical electrode head (132, 232) of the first and / or second cavum concha electrode (130, 230) is configured to be in direct physical contact and electrical contact with skin in the cavum concha of the respective ear of the human subject.

13. The taVNS system according to any one of claims 1 to 12, wherein a distance between the first and / or second cymba concha electrode (120, 220) and the respective cavum concha electrode (130, 230) in the electrode support (110, 210) corresponds to an average distance between the cymba concha and the cavum concha in a population of a plurality of human subjects.

14. The taVNS system according to any one of claims 1 to 13, wherein one of the first and / or second cymba concha electrode (120, 220) and the first and / or second cavum concha electrode (130, 230) is fixedly attached to the respective electrode support (110, 210) and protrudes at a fixed distance from the respective electrode support (110, 210); and the other of the first and / or second cymba concha electrode (120, 220) and the first and / or second cavum concha electrode (130, 230) is adjustably attached to the respective electrode support (110, 210) and protrudes at an adjustable distance from the respective electrode support (110, 210).

15. The taVNS system according to any one of claims 1 to 14, wherein the first and / or second cymba concha electrode (120, 220) and the first and / or second cavum concha (130, 230) are attached to and protrude from an inner surface (113, 213) of the respective electrode support (110, 210), wherein the inner surface (113, 213) is a flat surface.

16. The taVNS system according to any one of claims 1 to 15, further comprising a stimulation device (300) in electrical contact with the first and / or second cymba concha electrode (120, 220) and the first and / or second cavum concha electrode (130, 230) and configured to generate electrical stimulation pulses.

17. A method for transcutaneous auricular vagus nerve stimulation, taVNS, in a human subject, the method comprises: attaching (S1) the elastic headband (140) of the taVNS system (100) according to claim 16 onto a head of the human subject to position the first and second cymba concha electrodes (120, 220) in contact with skin in cymba concha of a first and second ear of the human subject, and the first and second cavum concha electrodes (130, 230) in contact with skin in cavum concha of the first and second ear of the human subject; and generating (S2) electrical stimulation pulses by the stimulation device (300) to apply the electrical stimulation pulses over the first cymba concha electrode (120) and the first cavum concha electrode (130), over the second cymba concha electrode (220) and the second cavum concha electrode (230), or over the first cymba concha electrode (120) and the first cavum concha electrode (130) and over the second cymba concha electrode (220) and the second cavum concha electrode (230).

18. The method according to claim 17, wherein generating (S2) electrical stimulation pulses comprises generating (S2) the electrical stimulation pulses by the stimulation device (300) to apply the electrical stimulation pulses over the first cymba concha electrode (120) and the first cavum concha electrode (130), over the second cymba concha electrode (220) and the second cavum concha electrode (230), or over the first cymba concha electrode (120) and the first cavum concha electrode (130) and over the second cymba concha electrode (220) and the second cavum concha electrode (230), for a stimulation period of from 2 minutes up to 10 minutes, preferably from 3 minutes up to 7 minutes, and more preferably for about 5 minutes.

19. The method according to claim 17 or 18, wherein generating (S2) electrical stimulation pulses comprises generating (S2) the electrical stimulation pulses by the stimulation device (300) to apply the electrical stimulation pulses once or twice, preferably twice, a day over the first cymba concha electrode (120) and the first cavum concha electrode (130), over the second cymba concha electrode (220) and the second cavum concha electrode (230), or over the first cymba concha electrode (120) and the first cavum concha electrode (130) and over the second cymba concha electrode (220) and the second cavum concha electrode (230).

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 headaches, insomnia, neuropathic pain, back pain, chronic pain, cognitive decline, inflammatory diseases, such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, systemic lupus erythematosus (SLE) multiplesclerosis and Alzheimer’s disease, the method comprising performing transcutaneous auricular vagus nerve stimulation, taVNS, in the human subject according to any one of claims 17 to 19.

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