Percutaneous ear vagus nerve stimulation

Abstract

A taVNS system (100) includes an electrode support (110), a conchae electrode and a conchae cavity electrode (120, 130) attached to and protruding from the electrode support (110) configured to contact skin in the conchae and the conchae cavity, respectively, of an ear of a human subject. A resilient headband (140) is attached to the electrode support (110) and is configured to, when attached to the head of the human subject, apply pressure on the electrode support (110) to press the conchae and conchae electrodes (120, 130) against the skin in the conchae and conchae of the ear of the human subject.

Description

Technical Field

[0001] This invention generally relates to transcutaneous ear vagus nerve stimulation (taVNS). Background Technology

[0002] The vagus nerve plays a crucial role in maintaining autonomic tone throughout the brain, chest, and abdomen. Electrical vagus nerve stimulation (VNS) is currently approved for the treatment of drug-resistant epilepsy, major depressive disorder, and morbid obesity. This VNS is implanted in the cervical spine. VNS implantation requires surgery to position the lead in the neck along the left vagus nerve trunk while a pulse generator is subcutaneously inserted into a pocket formed in the upper chest. The most common adverse reactions to VNS implantation are related to surgical intervention during implantation. Laryngeal and tracheal dysfunction associated with stimulation of the recurrent laryngeal nerve occurs in approximately two-thirds of epilepsy treatment cohorts and is usually transient. However, other surgical challenges exist under test stimulation, including electrode breakage, dislocation, generator malfunction, wound infection, recurrent laryngeal nerve palsy, and cardiac arrhythmias.

[0003] An attractive and promising approach to circumventing the risks of invasive VNS in humans is the use of VNS generated by an external pulse generator. Two types of percutaneous VNS have been developed: percutaneous cervical VNS (tcVNS) and percutaneous auricular VNS (taVNS). tcVNS is achieved by delivering electrical signals to the cervical vagus nerve, located within the carotid sheath posterolateral to the internal carotid and common carotid arteries and medial to the internal jugular vein, with electrodes placed on the skin covering the sternocleidomastoid muscle. Although the implanted electrodes of VNS are located in similar positions, the location of the vagus nerve beneath the skin, superficial fascia, and sternocleidomastoid muscle makes percutaneous electrical stimulation of the vagus nerve fibers difficult to achieve with current bioelectronic devices, potentially stimulating both afferent and efferent fibers within the vagal 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 fibers. NTS signals project to multiple areas of the forebrain, amygdala, hippocampus, limbic system, and brainstem structures, including the nucleus ambiguus, locus coeruleus, and dorsal motor nucleus, facilitating vagal motor output. Functional magnetic resonance imaging (fMRI) studies have confirmed that the central projection of the auricular branch of the vagus nerve coincides with the vagal projection activated after invasive vagal nerve stimulation (VNS), and taVNS can be performed non-invasively via the outer ear. taVNS is typically performed at home using a small, battery-powered handheld stimulation device that generates pulsed currents, which are transmitted via skin electrodes within the auricle.

[0005] The drawback of these handheld taVNS devices is that they cannot accurately deliver stimulation pulses to the correct location on the auricle, nor can they provide sufficient electrical contact between the stimulation electrodes and the skin throughout the stimulation process.

[0006] US2022 / 0143390 discloses a multi-electrode earmuff comprising an inner surface and an outer surface. The inner surface corresponds to the surface of the ear and is configured to overlap the cymba conchae and cavum conchae. The multi-electrode earmuff also includes multiple sockets for receiving stimulation electrodes that can contact various locations, including the cymba conchae, cavum conchae, crus of the helix, antihelix, tragus, and auricular acupoints. A conductive gel is applied to the skin of the ear to ensure adequate electrical contact between the stimulation electrodes and the skin.

[0007] A user-friendly taVNS system is still needed to provide efficient taVNS stimulation. Summary of the Invention

[0008] The overall goal is to provide a user-friendly transcutaneous ear vagus nerve stimulation (taVNS) system that delivers highly effective taVNS stimulation.

[0009] The embodiments disclosed in this application can achieve this and other purposes.

[0010] This invention is defined by the independent claims. Other embodiments of the invention are defined by the dependent claims.

[0011] One aspect of the invention relates to a taVNS system comprising an electrode support, an cymba conchae electrode attached to and protruding therefrom and configured to contact the skin in the cymba conchae of a human subject's ear, and an cavum conchae electrode attached to and protruding therefrom and configured to contact the skin in the cavum conchae of a human subject's ear. The taVNS system also includes an elastic headband attached to the electrode support and, when attached to the head of a human subject, configured to apply pressure to the electrode support to press the cymba conchae electrode against the skin in the cymba conchae of the human subject's ear and the cavum conchae electrode against the skin in the cavum conchae of the human subject's ear. According to the invention, the electrode support does not include any other electrodes besides the cymba conchae electrode and the cavum conchae electrode.

[0012] Another aspect of the invention relates to a taVNS method for use in human subjects. The method includes attaching an elastic headband of the taVNS system according to the invention to the head of a human subject to position the cymba conchae electrode in contact with the skin in the cymba conchae of the human subject's ear, and positioning the cavum conchae electrode in contact with the skin in the cavum conchae of the human subject's ear. The method further includes generating electrical stimulation pulses via the stimulation device of the taVNS system to apply the electrical stimulation pulses to the cymba conchae electrode and the cavum conchae electrode.

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

[0014] The taVNS system of this invention is user-friendly and can be used at home without medical guidance. By correctly aligning the electrodes with the predetermined stimulation site in the outer ear, the taVNS system reliably and repeatedly provides effective vagus nerve stimulation in each stimulation session. Furthermore, effective vagus nerve stimulation can be achieved without any contact-facilitating media, such as conductive gel. Attached Figure Description

[0015] The embodiments and their further objects and advantages can be best understood by referring to the following description and accompanying drawings, wherein:

[0016] Figures 1A-1C The taVNS system according to an embodiment is shown;

[0017] Figure 2 A taVNS system according to another embodiment is shown;

[0018] Figure 3 A taVNS system according to another embodiment is shown;

[0019] Figure 4 A stimulation device applicable to the taVNS system according to an embodiment is shown;

[0020] Figure 5 This is a flowchart illustrating the taVNS method used on human subjects; and

[0021] Figures 6A-6E The study showed the cytokine levels in whole blood cultures of 12 healthy donors with lipopolysaccharide (LPS) activation before and after taVNS treatment. Detailed Implementation

[0022] This invention relates generally to transcutaneous ear vagus nerve stimulation (taVNS), and more particularly to systems for taVNS.

[0023] The taVNS system of this invention aims to facilitate effective and repeatable percutaneous vagus nerve stimulation in human subjects, for example, at home. This is achieved by placing the stimulating electrodes in the correct location on the outer ear of the human subject. Currently, it is difficult for human subjects to achieve this correct electrode placement in a repeatable manner using handheld taVNS stimulation devices. Therefore, with such handheld taVNS stimulation devices, it is not uncommon for human subjects to fail to correctly position one or both stimulating electrodes at the intended stimulation site on the outer ear, resulting in poor stimulation delivery and therapeutic efficacy.

[0024] Another drawback of existing taVNS stimulation devices, including the stimulation system disclosed in US2022 / 0143390, is that a conductive gel needs to be applied to the skin of the outer ear to provide sufficient electrical contact between the stimulation electrodes and the skin surface. This conductive gel is generally considered uncomfortable by human subjects, especially as it may cause skin irritation during prolonged use.

[0025] The stimulation system disclosed in US2022 / 0143390 is further compromised by the need to design subject-specific multi-electrode earmuffs for each individual human subject to be treated. First, clinicians need to take three-dimensional (3D) images of each human subject's outer ear and then generate the multi-electrode earmuff based on these 3D images. Although the multi-electrode earmuff is manufactured for a specific human subject, securing it firmly into the outer ear while minimizing movement relative to the outer ear during stimulation remains challenging. This is because the multi-electrode earmuff needs to include multiple protrusions and indentations to accommodate specific areas of the outer ear, such as the antihelix, inferior antihelix, superior antihelix, and antitragus. Human subjects often find it difficult to correctly align the protrusions and indentations with specific areas or structures of the outer ear during each percutaneous vagus nerve stimulation procedure.

[0026] This invention relates to the taVNS system 100, see [link / reference]. Figures 1A-1C , Figure 2 and Figure 3 The taVNS system 100 includes an electrode support 110, an cymba conchae electrode 120, an cavum conchae electrode 130, and an elastic headband 140. The cymba conchae electrode 120 and the cavum conchae electrode 130 are attached to and protrude from the electrode support 110. The cymba conchae electrode 120 is configured to contact the skin within the cymba conchae of a human subject's ear. Correspondingly, the cavum conchae electrode 130 is configured to contact the skin within the cavum conchae of a human subject's ear. The elastic headband 140 is attached to the electrode support 110 and, when attached to the head of a human subject, is configured to apply pressure to the electrode support 110 to press the cymba conchae electrode 120 against the skin within the cymba conchae of the human subject's ear and the cavum conchae electrode 130 against the skin within the cavum conchae of the human subject's ear.

[0027] The electrode support 110 of the taVNS system 100 does not include any other electrodes besides the concha cymba electrode 120 and the concha cavity electrode 130.

[0028] The electrode support 110 of the taVNS system 100 therefore contains only two electrodes: the cymba conchae electrode 120 and the cavum conchae electrode 130. The design of the taVNS system 100 of the present invention allows these electrodes 120 and 130 to be correctly positioned in contact with the skin at the cymba conchae and cavum conchae of the ear, respectively. This should be compared to the stimulation system of US 2022 / 0143390, in which a multi-electrode earmuff contains multiple electrodes, theoretically capable of stimulating multiple sites, such as the superior crus of the antihelix, helix, scaphoid fossa, antihelix trunk, concha, antitragus, lobe, intertragic notch, tragus, crus of the helix, inferior crus of the antihelix, and triangular fossa. Due to the aforementioned issues with correctly attaching the multi-electrode earmuff to the outer ear, the stimulation system of US2022 / 0143390 may require multiple potential stimulation sites in order to provide the desired electrical stimulation to the target site.

[0029] The experimental data presented in this paper demonstrate that the electrode support 110 with attached and protruding conchae cymba electrodes 120 and conchae cavity electrodes 130 achieves an effective taVNS, which can induce biological effects in treated human subjects with only two such electrodes 120, 130 attached to and protruding from the electrode support 110.

[0030] Furthermore, the positions of the two electrodes 120 and 130 on the electrode support 110 are preferably fixed, and they cannot be adjusted along the length L or width W of the electrode support 110, see [link to documentation]. Figure 1C However, one or two electrodes 120, 130 protruding from the electrode support 110 are preferably adjustable, as will be further described herein. Compared to the multi-electrode earmuffs of US2022 / 0143390, this makes the design of the electrode support 110 less complex and still achieves efficient taVNS. Another benefit is that the taVNS system 100 of the present invention does not need to be subject-specific; that is, the same taVNS system 100 can be used to provide taVNS to multiple different human subjects.

[0031] The cymba conchae electrode 120 and the cavum conchae electrode 130 are made of conductive material, preferably conductive metal or metal alloy. The conductive material, preferably a conductive metal or metal alloy, should not only have good conductivity but should also preferably be biocompatible. The resistivity of conductive metals and metal alloys at 20°C is typically in the range of 10⁻⁶. -8 The conductivity is on the order of Ωm, therefore the conductivity at 20°C is in the range of 10. 6 -10 7The conductivity is on the order of S / m. In a specific embodiment, the conductive material of electrodes 120 and 130 is preferably a conductive metal or metal alloy, with a conductivity of at least 10 at 20°C. 6 S / m, preferably at least 0.5 × 10 7 S / m, more preferably at least 10 at 20°C 7 S / m. More preferably, the conductive material, preferably a conductive metal or metal alloy, has a strength of at least 3 × 10⁻⁶ at 20°C. 7 S / m.

[0032] As used herein, "bioacceptable" or "biotolerant" means that during taVNS treatment, when electrodes 120 and 130 come into contact with the skin inside the concha and cavum, the conductive material, preferably a conductive metal or metal alloy, does not cause any significant harmful effects on the skin inside the ear. Specifically, during normal use of the taVNS system 100, the conductive material, preferably a conductive metal or metal alloy, does not cause any significant skin irritation.

[0033] Currently preferred conductive materials include aluminum and aluminum alloys. Aluminum has a resistivity of 2.65 × 10⁻⁶ at 20°C. -8 Ωm, conductivity 3.77×10 7 S / m.

[0034] In one embodiment, the cymba conchae electrode 120 is made of aluminum or an aluminum alloy, or includes an electrode surface 121 made of aluminum or an aluminum alloy. Alternatively, or preferably, the cavum conchae electrode 130 is also 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 cymba conchae electrode 120 and the cavum conchae electrode 130 are made of aluminum, or include corresponding electrode surfaces 121, 131 made of aluminum.

[0035] Other metals and metal alloys that may be used for electrodes 120, 130 or at least electrode surfaces 121, 131 include gold, silver and their alloys.

[0036] Electrodes 120 and 130 may be made of a single metal or metal alloy, preferably aluminum or an aluminum alloy. For example, electrodes 120 and 130 may be solid electrodes composed 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 then include electrode surfaces 121 and 131 made of another conductive material, preferably another conductive metal or metal alloy. Electrode surfaces 121 and 131 may then be in the form of a conductive coating or surface layer on the electrode core. For example, the electrode core may be made of copper or an alloy thereof.

[0037] The conductive material of the electrode core is not necessarily biologically acceptable because it will not come into direct contact with the skin of a human subject. Therefore, conductive materials, preferably conductive metals or metal alloys, which have high conductivity but are not necessarily biologically acceptable, can be used as electrode core materials.

[0038] In a preferred embodiment, the concha cymba electrode 120 and the concha cavity electrode 130 are made of the same or one or more conductive materials. Therefore, the two electrodes 120 and 130 are preferably solid electrodes made of a single conductive material, which is preferably a single conductive metal or metal alloy. Alternatively, both electrodes 120 and 130 may include a conductive core material, preferably a conductive metal or alloy, and the electrode surfaces 121 and 131 may be made of another conductive material, preferably another conductive metal or alloy.

[0039] In one embodiment, the cymba conchae electrode 120 is configured to make direct physical contact with the skin in the cymba conchae of a human subject's ear, while the cavum conchae electrode 130 is configured to make direct physical contact with the skin in the cavum conchae of a human subject's ear.

[0040] Therefore, the two electrodes 120, 130 of the electrode support 110 are configured to not only make electrical contact with the skin of the cymba conchae and the cavum conchae, respectively, but also to make direct physical contact. In particular, the corresponding electrode surfaces 121, 131 of the electrodes 120, 130 are configured to make direct physical and electrical contact with the skin in these areas of the human subject's ear (cymba conchae and cavum conchae, respectively).

[0041] The direct physical contact used in this paper refers to electrodes 120 and 130, or more precisely, electrode surfaces 121 and 131, which directly contact and touch the skin in the cymba conchae and cavum conchae, respectively. Therefore, no intermediate medium, including conductive gel, is used to mediate the electrical contact between electrodes 120 and 130 and the skin.

[0042] In one embodiment, the cymba conchae electrode 120 includes an electrode body 123 in electrical contact with a power line 150 and a hemispherical electrode head 122, the hemispherical electrode head 122 including an electrode surface 121 configured to contact the skin in the cymba conchae of a human subject's ear.

[0043] In one embodiment, the electrode body 123 may be cylindrical, with a hemispherical electrode tip 122 at one end and the other end facing the electrode support 110. This design of the cymba conchae electrode 120 provides a smooth hemispherical electrode surface 121 that contacts the skin at the cymba conchae, while the electrode body 123 allows the hemispherical electrode tip 122 to protrude into the cymba conchae, while avoiding surrounding structures or areas in the ear that should not be electrically stimulated, such as the crus of the helix, the antihelix, and the inferior antihelix.

[0044] In one embodiment, the electrode body 123 of the cymbidium electrode 120 is attached to an adjustable electrode shaft 124, see Figure 2 In this embodiment, the adjustable electrode shaft 124 is arranged to adjust the protrusion of the hemispherical electrode head 122 of the auricular electrode 120 relative to the electrode support 110.

[0045] In this embodiment, the protrusion of the concha electrode 120 relative to the electrode support 110 is adjustable, such as... Figure 2 As indicated by the shaded arrow in the diagram. This means that the distance between the end of the hemispherical electrode head 122 and the electrode surface 121 and the electrode support 110 can be adjusted so that when the elastic headband 140 is attached to the head of a human subject, the electrode surface 121 properly contacts the skin in the concha.

[0046] In a particular embodiment, the taVNS system 100 also includes an adjusting screw 111 disposed on the electrode support 110, the adjusting screw 111 contacting the adjustable electrode shaft 124. The adjusting screw 111 is then configured to attach the adjustable electrode shaft 124 to a selected position relative to the electrode support 110.

[0047] In a preferred embodiment, the adjusting screw 111 can be tightened clockwise or counterclockwise relative to the electrode support 110. In one manner, preferably clockwise, turning the adjusting screw 111 causes the cymbidium electrode 120 to move further away from the electrode support 110, while in another manner, preferably counterclockwise, turning the adjusting screw 111 causes the cymbidium electrode 120 to move towards the electrode support 100. Therefore, the adjusting screw 111 can thus be used to adjust the amount or level of protrusion of the cymbidium electrode 120, particularly the hemispherical electrode head 122, from the electrode support 110.

[0048] In one embodiment, the concha electrode 130 includes an electrode body 133 in electrical contact with a power line 152 and a hemispherical electrode head 132, the hemispherical electrode head 132 including an electrode surface 131 configured to contact the skin in the concha of a human subject's ear.

[0049] In one embodiment, the electrode body 133 may be cylindrical, with a hemispherical electrode tip 132 at one end and the other end facing the electrode support 110. This design of the concha electrode 130 provides a smooth hemispherical electrode surface 131 that contacts the skin at the concha cavity, while the electrode body 133 allows the hemispherical electrode tip 132 to protrude into the concha cavity 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.

[0050] In one embodiment, the electrode body 133 of the concha electrode 130 is attached to an adjustable electrode shaft 134, see Figure 1B In this embodiment, the adjustable electrode shaft 134 is arranged to adjust the protrusion of the hemispherical electrode head 132 of the concha electrode 130 relative to the electrode support 110.

[0051] In this embodiment, the protrusion of the cymbidium electrode 130 relative to the electrode support 110 is adjustable, such as... Figure 1B As indicated by the shaded arrow in the diagram. This means that the distance between the end of the hemispherical electrode head 132 and the end of the electrode surface 131 and the electrode support 110 can be adjusted so that when the elastic headband 140 is attached to the head of a human subject, the electrode surface 131 properly contacts the skin in the concha cavity.

[0052] In a particular embodiment, the taVNS system 100 also includes an adjusting screw 112 disposed on the electrode support 110, the adjusting screw 112 contacting the adjustable electrode shaft 134. The adjusting screw 112 is then configured to attach the adjustable electrode shaft 134 to a selected position relative to the electrode support 110.

[0053] In a preferred embodiment, the adjusting screw 112 can be tightened clockwise or counterclockwise relative to the electrode support 110. In one manner, preferably clockwise, turning the adjusting screw 112 will move the concha electrode 130 further away from the electrode support 110, while in another manner, preferably counterclockwise, turning the adjusting screw 112 will move the concha electrode 130 toward the electrode support 110. Therefore, the adjusting screw 112 can be used to adjust the amount or level of protrusion of the concha electrode 130, particularly the hemispherical electrode tip 132, from the electrode support 110.

[0054] Figures 1A-1C The illustrated embodiment allows for adjustment of the protrusion of the concha electrode 130, while Figure 2 The embodiment shown allows for adjustment of the protrusions of the concha electrode 120. Figure 3 Another embodiment combining the adjustment of the protrusion of the concha 130 with the adjustment of the protrusion of the concha cymba electrode 120 is shown.

[0055] like Figure 3The embodiment of the taVNS system 100 shown provides maximum freedom by individually adjusting the protrusions of the two electrodes 120, 130 relative to the electrode support 110. However, in most cases, it is sufficient to achieve effective electrical and physical contact between the electrode surfaces 121, 131 and the skin in the concha and cavum conchae as long as the protrusion of only one of the electrodes 120, 130 is adjustable. In this case, one of the electrodes 120, 130 is fixedly, i.e., non-adjustably, attached to the electrode support 110, while the other of the electrodes 120, 130 is adjustablely attached to the electrode support 110. Figure 3 Compared to the embodiment of the taVNS system 100 shown, this embodiment results in Figures 1A-1C or Figure 2 The design of the taVNS system 100 is not very complex. In the currently preferred embodiment, the protrusion of the cymba conchae electrode 130 is adjustable, while the cymba conchae electrode 120 is fixed, as... Figures 1A-1C As shown.

[0056] The elastic headband 140 of the taVNS system 100 applies inward pressure or force to the electrode support 110, then presses against the fixed electrode, which is in physical contact with the skin at the target stimulation site in the outer ear of the human subject. The amount or level of protrusion of the adjustable electrode can then be used to fine-tune the pressure applied to the skin by the adjustable electrode to achieve direct physical contact between the adjustable electrode and the skin without causing discomfort to 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 the two electrodes 120, 130 and the skin at the cymba conchae and cavum conchae, without pressing the electrodes 120, 130 too tightly against the skin and causing discomfort to the human subject. This is possible even with only one fixed electrode and one adjustable electrode.

[0057] Therefore, in one embodiment, one of the cymba conchae electrode 120 and the conchae cavity 130 is fixedly attached to the electrode support 110 and protrudes from the electrode support 100 at a fixed distance. In this embodiment, the other of the cymba conchae electrode 120 and the conchae cavity 130 is adjustablely attached to the electrode support 110 and protrudes from the electrode support 100 at an adjustable distance.

[0058] In one embodiment, the distance between the cymba conchae electrode 120 and the cavum conchae electrode 130 in the electrode support 110 corresponds to the average distance between the cymba conchae and the cavum conchae in a group of multiple human subjects.

[0059] The inventors discovered that the distance between the cymba conchae and the cavum conchae does not vary significantly in the adult human population. This means that the electrode support 110, with a fixed, i.e., non-adjustable distance between the cymba conchae electrode 120 and the cavum conchae electrode 130, can be used to electrically stimulate multiple human subjects. Therefore, the taVNS system 100 can still be used to treat multiple different human (adult) subjects without needing to adjust the distance between the electrodes 120 and 130 in the electrode support 110.

[0060] In another embodiment, the distance between the cymba conchae electrode 120 and the cavum conchae electrode 130 in the electrode support 110 corresponds to the distance between the cymba conchae and the cavum conchae of a human subject.

[0061] In this embodiment, a subject-specific taVNS system 100 may be used, wherein the distance between the cymba conchae electrode 120 and the cavum conchae electrode 130 in the electrode support 110 is defined to match the corresponding distance between the cymba conchae and the cavum conchae of a specific human subject.

[0062] In one particular embodiment, the distance between the cymba conchae electrode 120 and the cavum conchae electrode 130 in the electrode support 110 corresponds to the distance along the length (L) or length axis of the electrode support 110, see [link to relevant documentation]. Figure 1C .

[0063] The electrode support 110 of the taVNS system 100 is designed to be located outside the outer ear of a human subject when the electrodes 120 and 130 are in contact with the skin of the cymba conchae and cavum 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 earmuff attached inside the outer ear.

[0064] In one embodiment, electrodes 120 and 130 are attached to and protrude from the inner surface 113 of electrode support 110, see... Figure 1C Therefore, when the elastic headband 140 is attached to the head of a human subject, the 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., a surface that does not correspond to the ear.

[0065] The taVNS system 100 includes a resilient headband 140 attached to an electrode support 110. The resilient headband 140 is designed to attach to the head of a human subject. In this position, the electrode support 110 will be aligned with the outer ear of one of the human subject's ears, i.e., the right or left ear, preferably the left ear. Furthermore, in this position, the cymba conchae electrode 120 will be aligned with the cymba conchae, while the cavum conchae electrode 130 will be aligned with the cavum conchae of the ear. The headband 140 is resilient to allow it to attach to the head of the human subject, but is preferably made of or includes a rigid material capable of applying inward pressure or force against the human subject's ear on the electrode support 110.

[0066] The headband 140 includes a top band or top piece 142, which is designed to extend over at least a portion of the head of a human subject. The headband 140 may optionally be held in place against the head of the human subject by a retaining device 144. In this case, the retaining device 144 is preferably disposed at one end of the top band 142, and the electrode support 110 is disposed at the other end of the top band 142. The retaining device 144 not only provides comfortable contact with the side of the head (preferably located above the unstimulated ear), but also helps balance the position of the headband 140 on the human subject's head. Therefore, the retaining device 144 can provide a counterweight to at least partially balance the weight of the electrode support 110.

[0067] The elastic headband 140 can be attached to the electrode support 110 or integrally formed with the electrode support 110. In the latter case, the elastic headband 140, or at least its top band 142, forms an integral unit with the electrode support 110.

[0068] The headband 140 may optionally include an adjustment mechanism for fitting the headband 140 to the head of a human subject. This adjustment mechanism can be used to adjust the size of the headband 140 according to different head sizes. Furthermore, the adjustment mechanism can also be used to adjust the pressure exerted by the headband 140 on the electrode support 110 to allow the electrodes 120, 130 attached to and protruding from the electrode support 110 to make physical contact with the skin within the cymba conchae and canal of the ear. An exemplary, but non-limiting, example of such an adjustment mechanism includes a telescopic section to extend or retract the end of the elastic headband 140. This telescopic section can then be locked using well-known solutions, such as friction or ratchet brakes.

[0069] In one embodiment, the taVNS system 100 further includes a stimulation device 200, see Figure 4 In this configuration, the stimulation device 200 is in electrical contact with the cymba conchae electrode 120 and the cavum conchae electrode 130. The stimulation device 200 is configured to generate electrical stimulation pulses.

[0070] The stimulation device 200 typically includes connection ports 210 and 212, to which the power lines 150 and 152 can be connected to electrically connect the stimulation device 200 to the electrodes 120 and 130.

[0071] The stimulation device 200 can be any stimulation device capable of generating electrical stimulation pulses suitable for taVNS. Such stimulation devices 200, sometimes referred to as transcutaneous electrical nerve stimulation (TENS) devices or machines, are available from a variety of vendors, including but not limited to TENS. Omron, Axion, Body Clock, Saneo, Health Technologies, RoscoeMedical, Auri Stim Medical, tVNS Technology GmbH, Cerbomed, Parasym, SoterixMedical, Xana Stim, NESOS, etc.

[0072] Figure 5 This is a flowchart of a method for percutaneous vagus nerve stimulation (taVNS) in a human subject according to an embodiment. The method includes step S1, wherein an elastic headband 140 of the taVNS system 100 according to the invention is attached to the head of a human subject to position an cymba conchae electrode 120 in contact with the skin in the cymba conchae of the human subject's ear, and a caudal conchae electrode 130 in contact with the skin in the caudal conchae of the human subject's ear. The method further includes step S2, wherein an electrical stimulation pulse is generated by a stimulation device 200 to apply the electrical stimulation pulse to the cymba conchae electrode 120 and the caudal conchae electrode 130.

[0073] The advantage of this taVNS system 100 is that it can use a relatively short stimulation course while still producing biological effects on human subjects, as shown in the "Examples" section. Therefore, in one embodiment, Figure 5 Step S2 includes generating one or two electrical stimulation pulses per day by the stimulation device 200 during a corresponding stimulation period or treatment course of 2 to 10 minutes, preferably 3 to 7 minutes, more preferably about 5 minutes.

[0074] like Figure 5 As shown, the taVNS system 100 of the present invention and its uses can be used to treat a variety of health conditions that will benefit from taVNS. Exemplary but non-limiting examples of such health 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.

[0075] Example

[0076] This example study investigated the effects of taVNS treatment on cytokine levels in LPS-activated whole blood cultures from healthy donors.

[0077] Materials and Methods

[0078] Research Design

[0079] This study recruited 13 healthy individuals aged 21 to 75 years. Participants confirmed that they had not taken any nonsteroidal anti-inflammatory drugs (NSAIDs) within 48 hours prior to the study and had not consumed any food or fluids (except water) for at least 8 hours prior to the study. The study plan for each participant consisted of a pre-baseline stimulation blood draw, a 30-minute waiting period, stimulation for 5 minutes using the taVNS device of this invention (with the following settings: frequency 20 Hz, pulse width 200 μs, current intensity individually adjusted below the pain threshold, expressed as <3 mA), and a blood draw 2 hours after stimulation. The study was scheduled over three consecutive days, with all patients undergoing pre-baseline stimulation blood draws before 10:00 AM. All blood draws were collected in 10 mL heparin sodium tubes and analyzed using a custom-designed in vitro whole blood endotoxin assay. One participant did not complete the study due to a failed post-stimulation blood draw.

[0080] In vitro whole blood endotoxin test

[0081] Blood drawn from heparinized tubes was immediately aliquoted and stimulated (holding time not exceeding 1 hour). All preparations were performed in a biosafety level 2 (BSL-2) laboratory environment. In brief, endotoxin (lipopolysaccharide (LPS), *E. coli* O111:B4, Sigma-Aldrich, USA) was resuspended to 5 mg / mL, sonicated for 30 minutes, vortexed, and diluted with phosphate-buffered saline (PBS) to prepare a 1 mg / mL working solution, stored at -20°C. Fresh LPS dilutions were prepared using this working solution each day of the study. The working solution was sonicated for 30 minutes and serially diluted 10-fold with physiological saline until a concentration of 50 μg / mL to 5 ng / mL was achieved. Heparinized blood was aliquoted into 15 2 mL round-bottom centrifuge tubes, and 10 μL of LPS dilution was added to each blood sample in three fractions to achieve final concentrations of 0 ng / mL and 10 ng / mL in each 500 μL aliquot. These tubes were then incubated on a 37°C track shaker for 4 hours. Four hours later, plasma was collected from all samples by centrifugation at 2000×g for 10 minutes in a refrigerated centrifuge and frozen at -20°C for future analysis.

[0082] Cytokine detection

[0083] Plasma tumor necrosis factor (TNF) levels were quantified using a commercial enzyme-linked immunosorbent assay (ELISA) (R&D Systems #DY210), with all samples tested twice. Further cytokine analysis was performed on blood stimulated with 0 ng / mL and 10 ng / mL LPS, and these samples were tested twice for interleukin-1 receptor antagonists (IL-1RA), IL-1α, IL-1β, IL-6, and IL-8 using a custom MesoScale Discovery U-Plex cytokine assay plate. The culture 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.

[0084] statistics

[0085] Table 1 - Statistics

[0086]

[0087] result

[0088] The results are as follows Figures 6A-6F The image shows the effect of taVNS stimulation on cytokine levels in LPS-activated (10 ng / mL) whole blood cultures from healthy donors before and after stimulation. This also illustrates the effect on pro-inflammatory cytokine IL-1α (…). Figure 6A ), IL-1β Figure 6B ), IL-6 Figure 6C ), IL-8 Figure 6D ) and TNF Figure 6E ) and the anti-inflammatory cytokine IL-1RA ( Figure 6F Quantitative evaluation was performed. As shown in the figure, taVNS stimulation led to a reduction in the studied pro-inflammatory cytokines, but had no significant effect on the anti-inflammatory cytokine IL-1RA. This example demonstrates that the taVNS system of the present invention can effectively perform taVNS stimulation, thereby reducing inflammatory cytokines. Therefore, the taVNS system of the present invention is suitable for treating a variety of inflammatory diseases and conditions that can benefit from taVNS stimulation.

[0089] The above embodiments should be understood as exemplary examples of the present invention. Those skilled in the art should understand that various modifications, combinations, and changes can be made to these embodiments without departing from the scope of the invention. Specifically, where technically feasible, different parts of the solutions in different embodiments can be combined into other configurations.

Claims

1. A transcutaneous ear vagus nerve stimulation (taVNS) system (100), comprising: Electrode support (110); An auricular cymba electrode (120) is attached to and protrudes from the electrode support (110) and is configured to contact the skin in the auricular cymba of a human subject's ear; An auricular electrode (130) is attached to and protrudes from the electrode support (110) and is configured to contact the skin within the auricular cavity of the human subject's ear; and An elastic headband (140) is attached to the electrode support (110) and configured to apply pressure on the electrode support (110) when attached to the head of the human subject to press the cymba conchae electrode (120) against the skin in the cymba conchae of the human subject's ear and the cavum conchae electrode (130) against the skin in the cavum conchae of the human subject's ear, wherein the electrode support (110) does not include any other electrodes besides the cymba conchae electrode (120) and the cavum conchae electrode (130).

2. The taVNS system according to claim 1, wherein, The ear capsule electrode (120) is made of aluminum or an aluminum alloy, preferably aluminum, or includes 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 concha electrode (130) is made of aluminum or an aluminum alloy, preferably aluminum, or includes an electrode surface (131) made of aluminum or an aluminum alloy, preferably aluminum.

4. The taVNS system according to any one of claims 1 to 3, wherein, The cymba conchae electrode (120) is configured to make direct physical contact with the skin in the cymba conchae of the human subject's ear; and The concha electrode (130) is configured to make direct physical contact with the skin in the concha of the human subject's ear.

5. The taVNS system according to any one of claims 1 to 4, wherein, The auricular electrode (120) includes: Electrode body (123), which is in electrical contact with power line (150); and A hemispherical electrode head (122) includes an electrode surface (121) configured to contact the skin in the concha of the ear of the human subject.

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

7. The taVNS system of claim 6 further includes an adjusting screw (111) disposed at 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 concha electrode (120) is configured to make direct physical and electrical contact with the skin in the concha of the human subject's ear.

9. The taVNS system according to any one of claims 1 to 8, wherein, The concha electrode (130) includes: Electrode body (133), which is in electrical contact with power line (152); and A hemispherical electrode head (132) includes an electrode surface (131) configured to contact the skin in the concha cavity of the ear of the human subject.

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

11. The taVNS system of claim 10 further includes an adjusting screw (112) disposed at 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 concha electrode (130) is configured to make direct physical and electrical contact with the skin in the concha of the human subject's ear.

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

14. The taVNS system according to any one of claims 1 to 13, wherein, One of the conchae cymbidium electrode (120) and the conchae cavity (130) is fixedly attached to the electrode support (110) and protrudes from the electrode support (110) at a fixed distance; as well as The other of the conchae sac electrode (120) and the conchae cavity (130) is adjustablely attached to the electrode support (110) and protrudes from the electrode support (110) at an adjustable distance.

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

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

17. A method for transcutaneous vagus nerve stimulation (taVNS) in a human subject, the method comprising: The elastic headband (140) of the taVNS system (100) according to claim 16 is attached (S1) to the head of the human subject to position the cymba conchae electrode (120) in contact with the skin in the cymba conchae of the human subject's ear and the cavum conchae electrode (130) in contact with the skin in the cavum conchae of the human subject's ear. as well as The stimulation device (200) generates (S2) electrical stimulation pulses to apply the electrical stimulation pulses to the conchae cymba electrode (120) and the conchae cavity electrode (130).

18. The method according to claim 17, wherein, Generating (S2) electrical stimulation pulses includes generating (S2) the electrical stimulation pulses by the stimulation device (200) to apply the electrical stimulation pulses to the conchae cymba electrode (120) and the conchae cavity electrode (130) for a stimulation period of 2 to 10 minutes, preferably 3 to 7 minutes, more preferably about 5 minutes.

19. The method according to claim 17 or 18, wherein, Generating (S2) electrical stimulation pulses includes generating (S2) the electrical stimulation pulses by the stimulation device (200) to apply the electrical stimulation pulses once or twice a day, preferably twice a day, to the conchae cymba electrode (120) and the conchae cavity electrode (130).

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

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