Vagus Nerve Stimulation System

Abstract

A system for treating at least one of the conditions depression and atrial fibrillation, the system comprising: a) a bracket configured to be attachable to a tragus of the subject, the bracket comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) a signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapy signal that can be applied to the vagus nerve within the tragus via the electrodes to thereby modulate the vagus nerve and treat depression and / or atrial fibrillation.

Description

[0001] The present invention relates to a nerve stimulation system and, more particularly, to a non-invasive vagus nerve stimulation system for stimulating the vagus nerve.

[0002] References in this description to prior publications (or information derived therefrom) or to known facts are not to be understood as an acknowledgment or admission or as an indication that the prior publications (or information derived therefrom) or known facts are part of the general technical knowledge in the field to which this description refers.

[0003] The vagus nerve consists of a complex neural network that maintains homeostasis and the balance of vital processes. Reciprocal neural connections with multiple brain areas serve as a control center, responding to new information (stimuli) with appropriate adaptive feedback for modulation. The vagus nerve has four vagal nuclei, which, with corresponding neurotransmitters, perform important control functions for the cardiovascular, respiratory, and digestive systems. It is the tenth of twelve cranial nerves and the main nerve connected to the parasympathetic branch of the autonomic nervous system. Recent clinical studies have shown that the vagus nerve is also involved in the regulation of inflammation, mood, and pain, all of which can be modulated by stimulating the vagus nerve with electrical micropulses, known as vagus nerve stimulation (VNS).

[0004] The development of vagus nerve stimulation (VNS) as a therapy began with the research of James Corning, who developed the first fundamentally functional VNS device. In the late 1990s, following the success of several clinical trials demonstrating the benefits of VNS in treatment-resistant epilepsy and depression, the FDA approved its use for these applications. This demonstrated the safe and effective use of this treatment method.

[0005] Vagus nerve stimulation leverages multiple modulatory effects in the nervous, immune, autonomic, endocrine, cardiorespiratory, and gastrointestinal systems. The precise mechanisms of action of vagal nerve stimulation are still being investigated, but this does not affect its safe and effective use in patients with disorders affecting the vagal pathways. For example, vagus nerve stimulation therapies have already been approved by regulatory authorities for applications such as mood elevation, pain relief, improved sleep, and anxiety reduction; studies are currently underway to evaluate cardiac and anti-inflammatory properties, as well as harnessing the effects of neuroplasticity.

[0006] In this context, the vagus nerve is the master nerve of the parasympathetic branch of the autonomic nervous system, which regulates unconscious processes in the body. The parasympathetic nervous system (PNS) is often referred to as the "rest and digest" system, while the sympathetic nervous system (SNS) is considered the "fight or flight" system. Stimulation of the vagus nerve has been shown to increase PNS activity and decrease SNS activity. Through this regulation of metabolic homeostasis, the vagus nerve also controls heart rate, with increased vagal activity being associated with a reduction in heart rate. This is important because autonomic dysfunction, characterized by an overactive SNS response, is thought to underlie several serious chronic diseases, highlighting the value of an intervention that can modulate it.

[0007] Neurotransmitters are chemical substances released by impulses from nerve fibers to the surrounding areas of this electrical activity. Examples of neurotransmitters include serotonin, noradrenaline / norepinephrine, and gamma-aminobutyric acid (GABA). Research in this area suggests that stimulation of the vagus nerve can influence the release of neurotransmitters in the brain. Clinical studies indicate that vagus nerve stimulation likely leads to changes in serotonin, noradrenaline, GABA, and glutamate, all neurotransmitters involved in the pathogenesis of major depression. This influence on neurotransmitters, along with several other theoretical mechanisms, likely explain the mood-enhancing effect of vagus nerve stimulation.

[0008] It is now known that the nervous system reflexively regulates the inflammatory response in real time, similar to how it controls heart rate and other vital functions. This is thought to occur via the vagus nerve through a neural reflex mechanism known as the "inflammatory reflex." The brain receives signals from the immune system to optimally control inflammation in the body. However, malfunctioning of these signals can lead to excessive inflammation. It has been observed that without vagus nerve activity (either due to vagotomy or neural lesions), the inflammatory reflex is absent, which can lead to excessive innate immune responses and cytokine toxicity (excessive inflammation). This led to clinical trials and evidence that vagus nerve stimulation can lead to a reduction in inflammatory cytokines.The anti-inflammatory properties of the vagus nerve's (stimulatory) action are mediated via the cholinergic anti-inflammatory pathway (CAP) and the hypothalamic-pituitary-adrenal (HPA) axis. These findings have led to new possibilities in the treatment of inflammation through these selective and reversible "hard-wired" neural systems.

[0009] Research towards the end of the 20th century showed that many aspects of the brain can be changed, or are "plastic," even in adulthood. Neuroplasticity is the brain's ability to restructure itself through the formation of new neural connections. It enables the neurons, or nerve cells, in the brain to compensate for injury or disease and adapt their processes in response to new situations or environmental changes. The promotion of neuroplastic effects by VNS through changes in neurotransmitter concentrations and / or processing in the central nervous system has led to a greater focus on the use of VNS as a therapy for tinnitus and stroke rehabilitation. It is now suspected that a significant number of cases of tinnitus arise from, or are disproportionately affected by, maladaptive plasticity in the auditory cortex.These applications utilize the mechanisms of "targeted plasticity" by stimulating the vagus nerve to promote neuroplasticity, combining this with a specific stimulus, such as sound therapy (for tinnitus) or rehabilitation exercises (for stroke rehabilitation), that target this plasticity effect in the specific region of the brain associated with the respective condition. This has led to results such as accelerated and improved recovery from stroke and a reduction in tinnitus symptoms.

[0010] Traditionally, VNS as a treatment modality was limited by the need for surgical implantation. This ultimately restricted access geographically (to centers specializing in the procedure), by the severity of the condition (warranting surgery), and financially (to those who can afford the procedure). More recently, a number of non-invasive stimulation devices have been proposed. Specifically, this can be achieved by harnessing the auricular branch of the vagus nerve, which runs along the outer ear, for transcutaneous vagus nerve stimulation (tVNS). This method has been shown to activate the vagal pathways in the same way as the surgical procedure (VNS), making it an easily accessible, low-risk, and cost-effective option for vagus nerve stimulation.

[0011] US20050165460 describes a self-contained, wearable headset carrying a waveform source and tissue interface circuitry in a self-positioning position to deliver treatment signals to a preselected area in the pinna of a human. An electronics housing supports a waveform source that communicates with right and left tissue interface circuits housed in right and left earbud housings, respectively. The headset supports each earbud housing at a backward and downward angle such that a projecting stem enters the pinna and contacts the pinna generally below and behind the ear canal. A speaker emits corresponding sounds during treatment. An end wall of the stem supports an array of electrodes that contact the preselected area in the pinna.

[0012] US10130809 describes an electrical stimulation device comprising a computer that generates an electrical stimulation generator control signal and outputs a music signal, a transcutaneous electrical stimulation generator, an electronic signal line, and an electrode coupler. The generator receives the generator control signal and the music signal, generates a neural electrical stimulation signal in response to the generator control signal, and outputs the neural electrical stimulation signal to the stimulation output and the music signal to an audio output.The coupler fits into an ear canal, has a speaker connected to the audio output to output the music signal into the ear canal when worn, and has electrical stimulation electrodes that are conductively connected to the stimulation output via the electronic signal line to receive the neural electrical stimulation signal. These electrodes are positioned to contact tissue in the ear canal for transcutaneous application of the neural electrical stimulation signal. The coupler delivers the neural electrical stimulation signal while music is output from the speaker.

[0013] US8457765 describes an ear clip electrode used to deliver a tiny amount of current from a stimulator to a patient's earlobes. The ear clip electrode is provided with an inner and an outer plastic part, onto which separate metal plates are attached. Both the metal plate and the plastic parts have a circular end on which a metal pole is attached. Electrode pads are placed on these metal pins, and the current is conducted from each of the plates to the electrode pad and then to the patient's earlobe. A plastic cover is placed over a substantial portion of the length of each of the metal plates. Plastic material also covers the end face of each of the metal pins. The ear clip electrode is connected to a source of tiny electrical energy.

[0014] US20070250145 describes a device (1) for the transcutaneous stimulation of a nerve of the human body, wherein the device (1) comprises at least one stimulation electrode (2) and at least one reference electrode (3) for transcutaneous nerve stimulation, wherein the at least one stimulation electrode (2) and the at least one reference electrode (3) are connected to a control unit (4) and can be supplied with electrical current by the latter, and wherein the at least one stimulation electrode (2) and the at least one reference electrode (3) are arranged in or on a housing (5) which is designed to be attached to or in the human ear.In order to make the nerve stimulation effective and easier to handle for the patient, it is proposed according to the invention that the housing (5) has an arcuate extension piece (6) which is designed to be inserted into the auditory canal, wherein the arcuate extension piece (6) corresponds to the shape of the auditory canal entrance or the external auditory canal, and with an electrode head (7) which is arranged at the end of the arcuate extension piece (6) and has two contact points (8, 9) for the two electrodes (2, 3).

[0015] US20180021564 describes a nerve stimulation system with a headset and an earpiece comprising two or more ear contact elements, such as an ear canal insert and a concha insert. Ear contact elements may be attached to an earphone housing and may include protruding attachment structures that establish a mechanical and electrical connection between the ear contact elements and the housing through various materials and configurations. In one embodiment, a nerve stimulation system includes a nerve stimulation subsystem with a nerve stimulation device control circuit for use in combination with a personal computing device to control a nerve stimulation device.

[0016] However, these typically require devices electrically connected to the inner and / or outer surfaces of the concha, which can be uncomfortable for the user and makes it difficult to create a device that stays in place during use. Furthermore, these systems present issues regarding safety, efficacy, and usability. For example, some electrode configurations and current densities can cause skin burns, while others fail to achieve effective neurostimulation.

[0017] In a general form, one aspect of the present invention aims to provide a vagus nerve stimulation system for stimulating a vagus nerve in a biological subject, the system comprising: a clamp configured to be attached to a tragus of the subject, the clamp comprising: opposing arms configured such that a distal end of the arms is biased toward each other; and electrodes positioned proximate a distal end of the arms on opposing surfaces such that the electrodes are urged into engagement with opposing surfaces of the tragus; and a signal generator electrically connected to the electrodes, the signal generator configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0018] In one embodiment, the system includes a hook extending over and behind an ear of the subject to at least partially support the bracket.

[0019] In one embodiment, the hook is configured to extend laterally from the clip so that the lead can be looped over and behind an ear of the subject.

[0020] In one embodiment, the system comprises a lead extending from the clamp, the lead comprising connections configured to electrically connect the electrodes to the signal generator.

[0021] In one embodiment, the lead is configured to extend laterally from the clamp so that the lead can be looped over and behind an ear of the subject.

[0022] In one embodiment, the conduit is configured to extend from a distal end of one of the arms.

[0023] In one embodiment, the lead comprises a sheath extending at least partially along a length of the lead, and wherein the sheath defines a hook shaped to be placed over and behind an ear of the subject.

[0024] In one embodiment, one of the arms is configured to be positionable within an auricle of the user.

[0025] In one embodiment, the arms are pivotally connected about a central section.

[0026] In one embodiment, the distal ends of the arms are biased together using a biasing mechanism.

[0027] In one embodiment, the biasing mechanism comprises at least one of the following elements: a pivot point; a spring; a rubber element; a malleable element connecting the arms to each other; at least partially malleable arms; an at least partially elastic element connecting the arms to each other; at least partially elastic arms; and / or magnets provided on the arms.

[0028] In one embodiment, a proximal outer surface of the arms includes a recess configured to allow a person to grasp and spread the arms apart.

[0029] In one embodiment, the arms have at least one of the following features: a length that has at least one of the following features: greater than 15 mm; greater than 16 mm; greater than 17 mm; greater than 18 mm; greater than 19 mm; greater than 20 mm; greater than 21 mm; less than 30 mm; less than 28 mm; less than 27 mm; less than 26 mm; less than 25 mm; less than 24 mm; less than 23 mm; about 22 mm; and a width that is at least one of the following: greater than 5 mm; greater than 6 mm; greater than 7 mm; greater than 8 mm; greater than 9 mm; greater than 10 mm; less than 16 mm; less than 15 mm; less than 14 mm; less than 13 mm; less than 12 mm; about 11 mm.

[0030] In one embodiment, the electrodes are: substantially circular; rounded rectangular; rounded square; at least partially dome-shaped; have a diameter of at least one of the following: greater than 4 mm; greater than 5 mm; greater than 6 mm; greater than 7 mm; less than 12 mm; less than 11 mm; less than 10 mm; less than 9 mm; and about 8 mm.

[0031] In one embodiment, a surface of the electrodes comprises at least one of the following features: roughened; grooved; ribbed; and / or coated.

[0032] In one embodiment, a surface of the electrodes is coated with at least one of the following materials: an inert metal; and / or gold.

[0033] In one embodiment, therapy signals are signals having a frequency that is at least one of the following: less than 20 kHz; less than 10 kHz; less than 1 kHz; less than 500 Hz; less than 200 Hz; less than 150 Hz; less than 100 Hz; less than 75 Hz; greater than 1 Hz; greater than 2 Hz; greater than 5 Hz; greater than 10 Hz; greater than 20 Hz; about 20 Hz; and about 50 Hz.

[0034] In one embodiment, therapy signals are signals having a pulse width of at least one of the following values: less than 5,000 µs; less than 2,500 µs; less than 1,000 µs; less than 500 µs; less than 200 µs; less than 100 µs; less than 75 µs; greater than 1 µs; greater than 2 µs; greater than 5 µs; greater than 10 µs; greater than 20 µs; and about 50 µs.

[0035] In one embodiment, the therapy signals are signals having a voltage that has at least one of the following characteristics: less than 50 V; less than 25 V; less than 10 V; less than 5 V; less than 2 V; less than 1 V; greater than 0.1 V; greater than 0.2 V; greater than 0.5 V; and greater than 1 V.

[0036] In one embodiment, the therapy signals are signals having a current that has at least one of the following values: less than 50 mA; greater than 0.1 mA; and between 0.1 mA and 36 mA.

[0037] In one embodiment, the therapy signals are at least one of the following: symmetric; asymmetric; monophasic; biphasic; triphasic; polyphasic; and / or comprise multiple phases with at least one pause therebetween.

[0038] In one embodiment, a respective therapy signal is applied to each of the electrodes.

[0039] In one embodiment, the respective therapy signals are at least one of the following: in phase; and / or out of phase.

[0040] In one embodiment, the lead comprises at least one of the following: a respective conductor for each electrode; at least one insulating layer; and / or a braided shield.

[0041] In one embodiment, the therapy signals are configured to perform at least one of the following functions: stimulating vagus nerve activity; and / or inhibiting vagus nerve activity.

[0042] In one embodiment, the signal generator is attached to the bracket.

[0043] In one embodiment, the system comprises a control system having a housing containing at least one of the following elements: the signal generator; a power supply; and / or a control unit.

[0044] In one embodiment, a conduit extends from the bracket to the housing.

[0045] In one embodiment, the system comprises a control unit configured to control the signal generator.

[0046] In one embodiment, the control unit is configured to: determine therapy signal parameters; and control the signal generator according to the therapy signal parameters.

[0047] In one embodiment, the control unit is configured to determine the therapy signal parameters according to at least one of the following: defined therapy signal parameters stored in a memory; user input commands; biofeedback; neurofeedback; signals from a sensor; and a selected therapy mode.

[0048] In one embodiment, the system comprises a sensor configured to detect at least one subject parameter, and wherein the controller is configured to determine at least one subject parameter using signals from the sensor and to cause the signal generator to generate therapy signals according to the at least one subject parameter.

[0049] In one embodiment, the sensor is at least one of the following: attached to the bracket proximate to at least one electrode; electrically coupled to at least one of the electrodes; a wearable sensor; provided on a wearable band; and provided on a wearable wristband.

[0050] In one embodiment, the sensor is at least one of the following: an inflammatory biomarker sensor; a temperature sensor; a blood oxygen sensor; a pulse oximeter; a heart rate sensor; and / or an impedance sensor.

[0051] In one embodiment, the at least one subject parameter comprises at least one of the following: presence, absence, or concentration of an inflammatory biomarker; a temperature; a blood oxygen level; a heart rate; a heart rate variability; an impedance; and / or a galvanic skin response.

[0052] In one embodiment, the control unit is configured to: monitor a heart rate of the subject based on signals from the sensor; and cause the signal generator to generate the therapy signals at least partially in accordance with the feedback.

[0053] In one embodiment, the control unit is configured to: cause the signal generator to progressively generate therapy signals with progressively changing parameters; monitor a heart rate of the subject based on signals from the sensor while the therapy signals change; detect changes in heart rate; set a therapy signal parameter threshold based on a parameter of the therapy signal when changes in heart rate are detected; and cause the signal generator to generate therapy signals based on the therapy signal parameter threshold.

[0054] In one embodiment, the therapy signal parameter threshold is a therapy signal strength and is 50% to 60% of the therapy signal strength applied when the change in heart rate is detected.

[0055] In one embodiment, the control unit is configured to: cause the signal generator to generate the therapy signals; monitor changes in the subject's heart rate based on signals from the sensor in response to the applied therapy signals; and perform at least one of the following functions: cause the signal generator to generate therapy signals based on the monitored changes in heart rate; and analyze the monitored changes in heart rate to determine cardiac variability in response to the applied therapy signals.

[0056] In one embodiment, the controller is configured to use heart rate variability to generate an inflammatory indicator that indicates the presence, absence, or degree of inflammatory markers within the subject.

[0057] In one embodiment, the inflammation indicator is inversely proportional to heart rate variability.

[0058] In one embodiment, the controller is configured to use heart rate variability to generate a predictive indicator indicating responsiveness to the therapy signals.

[0059] In one embodiment, the predictive indicator indicates responsiveness to atrial fibrillation therapy.

[0060] In one embodiment, the control unit is configured to: determine feedback based on user inputs; and cause the signal generator to generate the therapy signals according to the feedback.

[0061] In one embodiment, the control unit is configured to: cause the signal generator to generate therapy signals with progressively changing parameters; and select one or more therapy signal parameters in response to user inputs.

[0062] In one embodiment, the parameters include at least one of the following: a therapy signal pulse width; a therapy signal amplitude; and a therapy signal frequency; and a therapy signal waveform.

[0063] In one embodiment, the control unit is configured to increase the therapy signal incrementally by at least one of the following values: 0.1 mA; 0.2 mA; 0.5 mA; 0.8 mA; 1 mA; 1.5 mA; and 2 mA.

[0064] In one embodiment, the control unit is configured to determine the selection of a therapy mode according to user inputs and to control the signal generator according to the selected mode.

[0065] In one embodiment, the system comprises a number of therapy modes stored in a memory, wherein each therapy mode defines a sequence of therapy signals, and wherein the control unit is configured to cause the signal generator to generate the sequence of therapy signals.

[0066] In one embodiment, in a research mode, the control unit is configured to perform at least one of the following functions: selecting a therapy signal strength in response to user input and progressively decreasing the therapy signal strength to zero; and delivering a non-electrical stimulus.

[0067] In one embodiment, the control unit comprises at least one of the following elements: at least one processing device; a software application executed by a client device; and an external control unit wirelessly connected to at least one of the following elements: the signal generator; and at least one sensor.

[0068] In one embodiment, the system includes a stimulator configured to apply a stimulus to the patient.

[0069] In one embodiment, the stimulator comprises at least one of the following elements: an audio stimulator, a vibration stimulator, an optical stimulator, and a thermal stimulator.

[0070] In one embodiment, the stimulator is integrated into the clamp.

[0071] In one embodiment, the stimulator is controlled by a control unit to cause the stimulus to be delivered in conjunction with the therapy signals.

[0072] In one embodiment, the nerve stimulation system is configured to treat at least one of the following symptoms: depression, mental disorders, autonomic nervous system dysfunction, stress, heart failure, traumatic brain injury, altered consciousness, inflammatory diseases, autoimmune diseases, cognitive dysfunction, infections, infectious symptoms, respiratory dysfunction, post-viral syndromes, fatigue, post-traumatic stress disorder, cancer, fibromyalgia, postural orthostatic tachycardia syndrome, myocardial infarction, and atrial fibrillation.

[0073] In one embodiment, the neural stimulation system is configured to improve at least one of the following: physical performance and cognitive function.

[0074] In a general form, one aspect of the present invention aims to provide a method of stimulating the vagus nerve for stimulating a vagus nerve in a biological subject, the method comprising: applying a clamp to a tragus of the subject, the clamp comprising: opposing arms configured such that a distal end of the arms is biased toward each other; and electrodes positioned proximate a distal end of the arms on opposing surfaces such that the electrodes are urged into engagement with opposing surfaces of the tragus; and using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0075] In a general form, one aspect of the present invention aims to provide a system for treating at least one of the conditions depression and atrial fibrillation, the device comprising: a clamp configured to be attached to a tragus of the patient, the clamp comprising: opposing arms configured such that a distal end of the arms is biased toward each other; and electrodes positioned proximate a distal end of the arms on opposing surfaces such that the electrodes are urged into engagement with opposing surfaces of the tragus; and a signal generator electrically connected to the electrodes, the signal generator configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0076] In a general form, one aspect of the present invention aims to provide a method for treating at least one of the conditions depression and atrial fibrillation, the method comprising: applying a clamp to a tragus of the patient, the clamp comprising: opposing arms configured such that a distal end of the arms is biased toward each other; and electrodes positioned proximate a distal end of the arms on opposing surfaces such that the electrodes are urged into engagement with opposing surfaces of the tragus; and using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0077] In a general form, one aspect of the present invention aims to provide a vagus nerve stimulation system for stimulating a vagus nerve in a biological subject, the system comprising: a mounting member configured to be attached to a tragus of the subject such that the electrodes are pressed into engagement with opposing surfaces of the tragus; and a signal generator electrically connected to the electrodes, the signal generator configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0078] In a general form, one aspect of the present invention aims to provide a method for stimulating the vagus nerve in a biological subject, the method comprising: attaching a fastener to a tragus of the subject such that electrodes are pressed into engagement with opposing surfaces of the tragus; and using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve.

[0079] It is understood that the general forms of the invention and their respective features may be used in conjunction with one another and / or independently of one another, and that reference to separate general forms is not intended to be limiting. Furthermore, it is understood that features of the method may be performed using the system or apparatus, and that features of the system or apparatus may be implemented using the method.

[0080] Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings, in which:- Fig. 1A is a schematic plan view of an example of a vagus nerve stimulation system; Fig. 1B is a schematic side view of the nerve stimulation system Fig. 1A is; Fig. 1C a schematic plan view of the bracket from Fig. 1A in action; Fig. 1D a schematic side view of the bracket from Fig. 1A in action; Fig. 2 a schematic diagram of an example of a control system for the nerve stimulation system of Fig. 1A shows; Fig. 3 is a flowchart of an example of a nerve stimulation process; Fig. 4A is a schematic side view of a specific example of a clamp for a vagus nerve stimulation system; Fig. Figure 4B is a schematic plan view of the bracket of Fig. 4A; Fig. Figure 4C is a schematic perspective view of the bracket of Fig. 4B; Fig. Figure 4D is a schematic front view of the bracket from Fig. 4A; Fig. Figure 4E is a schematic rear view of the bracket from Fig. 4A; Fig. is a schematic close-up of a pivot point of the bracket from Fig. ; Fig. is a schematic plan view of the bracket from Fig. in use; Fig. is a schematic perspective view of an example of a control system; Fig. is a schematic side view of the control system from Fig. ; Fig. is a schematic plan view of the control system from Fig. ; Fig. is a schematic diagram of a second example of a control system for a nerve stimulation system; Fig. is a flowchart of a specific example of a nerve stimulation process; The Fig. are schematic representations of example therapy signal waveforms; Fig. is a diagram illustrating the effect of stimulation on atrial fibrillation burden; and Fig. is a diagram illustrating the effect of stimulation on the symptoms of myalgic encephalomyelitis.

[0081] An example of a vagus nerve stimulation system will now be described with reference to the Fig. described.

[0082] In this example, the nerve stimulation system 100 includes a fastener configured to be attached to a tragus of the subject such that electrodes are pressed into engagement with opposing surfaces of the tragus.

[0083] In one example, the fastening element takes the form of a clamp 110 with opposed arms 111, 112, with electrodes 121, 122 disposed near a distal end of the arms on opposing surfaces that are biased toward each other. In this example, the arms are pivotally connected via a connecting joint 113, while a resilient element, such as a spring, a rubber stopper, or the like, is provided and configured to bias the distal end of the arms toward each other. However, as described in more detail below, other configurations could be used.

[0084] In this context, it should therefore be noted that the term "fastener" includes any arrangement capable of securing the nerve stimulation system in position such that the electrodes are held in contact with the tragus. In a specific example, the fastener is in the form of a clip having spaced-apart arms that can be compressed at their distal ends; however, the example arrangements described herein are not intended to be limiting. While the following description focuses on a clip, it will be appreciated that the techniques described herein can also be applied to other fasteners that do not resemble clips.

[0085] A signal generator 130 is electrically connected to the electrodes 121, 122, for example via corresponding connections 131, 132, wherein the signal generator 130 is configured to generate at least one therapy signal which can then be applied to the patient via the electrodes 121, 122.

[0086] In use, the clip is configured to be attached to a person’s tragus, and an example of this will now be described with reference to the Fig. 1C and Fig. 1D described.

[0087] In this example, a person's ear 100 is depicted, including a tragus 101, an inferior crus 102, a superior crus 103, a helix 104, a scapha 105, an antihelix 106, a concha 107, an antitragus 108, and a lobule 109. As shown, the clamp 110 is positioned so that the tragus 101 is disposed between the electrodes 121, 122, with the electrodes 121, 122 being urged into engagement with the opposing surfaces of the tragus due to the bias of the arms 111, 112.

[0088] Through this configuration, the therapy signals applied to electrodes 121, 122 are applied to the tragus, which in turn results in the generation of an electrical field around the vagus nerve within the tragus 101. This field can generate or inhibit action potentials within the tragus, which in turn results in modulation of the vagus nerve.

[0089] Accordingly, the nerve stimulation system described above serves to stimulate the vagus nerve within the tragus (low-level tragus stimulation) using a clip 110 that, during use, is attached to the tragus 101 of a subject. The clip includes electrodes 121, 122 on opposing biased arms 111, 112 so that the tragus 101 can be positioned between the electrodes, with the electrodes 121, 122 being pressed into engagement with the tragus 101. In this way, the electrodes 121, 122 grip the tragus, ensuring good electrical contact with the tragus 101 and thus maximizing the effectiveness of vagus nerve modulation.In addition, gripping the electrodes at the tragus helps to secure the clip in place, allowing it to be worn for extended periods of time and ensuring that the stimulation signals are successfully transmitted to the vagus nerve during a stimulation session.

[0090] The arrangement of the electrodes on opposing arms also results in the electrodes being arranged in a substantially parallel, spaced-apart configuration, with the electrodes located on either side of the tragus. This configuration can allow for an increased electrode surface area, which, combined with the substantially parallel positioning, maximizes the field generated for a given current density at the electrode / tissue interface.

[0091] Accordingly, the above arrangement can help ensure that the applied therapy signals achieve a therapeutic effect while avoiding current densities that may be uncomfortable for the patient, for example, due to burns. Furthermore, the arrangement described above contributes to maintaining safety and efficacy. In this regard, optimizing the efficacy of signal delivery ensures that the correct pacing is achieved and avoids over- or under-stimulation, which can lead to undesirable consequences such as bradycardia.

[0092] Furthermore, the arrangement described above, in one example, allows the clip 110 to be positioned at least partially within the concha 107, which offers a number of advantages. For example, it guides the positioning of the clip 110 so that the electrodes are correctly positioned relative to the tragus and the vagus nerve, ensuring effective modulation of the nerve. In addition, this arrangement reduces the extent to which the clip protrudes from the ear, making the clip unobtrusive and comfortable to wear. This allows the clip to be worn, for example, while the user is lying on their side, while reducing the risk of the clip becoming dislodged, which in turn could impair the stimulation process.

[0093] Accordingly, the arrangement described above provides a non-invasive vagus nerve stimulation system that can be used to modulate the vagus nerve, but is comfortable and easy to use for extended periods of time, allowing users to more easily reap the benefits of vagus nerve stimulation while avoiding risks, safety and efficacy issues such as burns and / or unsafe or ineffective neurostimulation levels.

[0094] A number of additional features are described below.

[0095] In one example, the system includes a hook that extends over and behind a subject's ear to at least partially support the clip. The hook may have any suitable shape, but is typically made of an at least partially elastic material that retains its shape while being comfortable to wear. The hook may be attached to any part of the clip, but in one example is configured to extend laterally from the clip so that the hook can reach over and behind the subject's ear. The hook can help distribute the weight of the clip across the ear so that the weight is not solely borne by the tragus.Additionally, this provides a secondary attachment mechanism that reduces the likelihood of the clamp becoming loose and prevents the clamp from falling to the floor if it does become loose, which in turn helps reduce the risk of damage to the clamp. Furthermore, it also aids in correct clamp positioning, ensuring the electrodes are aligned with the vagus nerve, which in turn optimizes the effect of the applied therapy signals.

[0096] In one example, the system includes a lead extending from the clamp, the lead including the connections configured to electrically connect the electrodes to the signal generator. This allows the signal generator to be deployed remotely from the clamp and connected to it via the connections. This may reduce the weight of the clamp, but is not essential, and alternative embodiments could be provided, as described in more detail below.

[0097] In one particular example, the lead is configured to extend laterally from the bracket, allowing the lead to be looped over and behind a patient's ear, allowing the lead to help secure the bracket in place. It can be seen that in this case, the lead can perform the hooking function described above, reducing the weight load on the tragus and minimizing the likelihood and adverse effects of bracket slippage.

[0098] In one example, the lead may be configured to extend from a distal end of an outer arm. This helps secure the clip in place while leaving a proximal end of the arms unobstructed, which can facilitate clip placement on the tragus. Additionally, this further aligns the lead with the tragus and guides it to extend more easily behind the helix, making the clip more comfortable to wear and ensuring proper clip positioning.

[0099] In a particular example, the lead includes a sheath extending at least partially along the lead, the sheath defining the hook shape to loop over and behind an ear of the patient. In this example, the sheath may have greater elasticity than the unsheathed portions of the lead, which may help maintain the shape of the lead in the area of ​​the ear while allowing the lead to be freely flexible in other areas, making it more comfortable to use. This also helps protect the lead where it connects to the clip, reducing, for example, the chance of forces disengaging the lead from the clip or damaging the electrical connections between the clip and the lead.

[0100] As mentioned above, in one example, at least one of the arms, particularly an inner arm 111, is positioned within a concha of the user. This allows the clip to grip the tragus while remaining in a substantially natural position, making the clip comfortable to wear. This also reduces the amount of the clip extending outward from the ear, which in turn reduces the likelihood of the clip being bumped and displaced, while at the same time making the clip comfortable to wear when the ear is resting on a pillow or other surface, making the arrangement particularly suitable for long-term use. Furthermore, this also aids in the correct positioning of the clip, ensuring that the electrodes are correctly positioned on the tragus and thus aligned with the vagus nerve, which in turn optimizes the effect of the applied therapy signals.

[0101] In one example, the arms are pivotally connected about a central portion, although this is not required and other arrangements could be used. For example, the arms could be made of a malleable material or connected together so that the arms can be deformed into a desired shape, such that the distal ends of the arms are biased into engagement with the tragus.

[0102] The clip typically also includes a biasing mechanism to bias the distal ends of the arms into engagement. The type of biasing mechanism may vary depending on the preferred design and may include the use of a spring or rubber element disposed between the arms. The biasing could be achieved by a malleable element connecting the arms together, or by at least partially malleable arms, an at least partially elastic element connecting the arms together, or at least partially elastic arms.

[0103] In another example, the preload could be achieved by magnets provided in the arms. For example, magnets of opposite polarities could be provided in the distal ends of the arms to pull the distal ends of the arms together. It can be seen that this arrangement induces a magnetic field around the tragus, which can be used to amplify or modulate the applied therapy signals, thereby improving safety and / or efficacy. Alternatively, magnets of the same polarities could be provided at the proximal ends of the arms to push the proximal ends apart.

[0104] In a preferred example, the arms are pivotally connected and optionally biased about a central portion so that a proximal end of the arms can be biased together to urge the distal ends, and thus the electrodes, apart, allowing easy application of the clamp. This arrangement can also help ensure that the arms are approximately parallel when the tragus is positioned between the arms, facilitating electrode positioning and ensuring maximum surface contact between the electrodes and the tragus, in turn reducing the current density required to achieve effective stimulation, thus improving efficacy and reducing burns.

[0105] In one example, a proximal outer surface of the arms includes a recess configured to guide the positioning of a person to grasp and spread the arms, for example, by grasping the proximal ends of the arms between the thumb and index finger.

[0106] In one example, the arms have a length that is greater than 15 mm, greater than 16 mm, greater than 17 mm, greater than 18 mm, greater than 19 mm, greater than 20 mm, greater than 21 mm, less than 30 mm, less than 28 mm, less than 27 mm, less than 26 mm, less than 25 mm, less than 24 mm, less than 23 mm, and typically about 22 mm. Similarly, the arms typically have a width that is greater than 5 mm, greater than 6 mm, greater than 7 mm, greater than 8 mm, greater than 9 mm, greater than 10 mm, less than 16 mm, less than 15 mm, less than 14 mm, less than 13 mm, less than 12 mm, and typically about 11 mm. These dimensions facilitate the handling of the arms while allowing the brace to be positioned within the concha, making the brace comfortable to wear.

[0107] Furthermore, the aforementioned dimensions of the arms provide a sufficiently large surface area to accommodate the electrodes. In this regard, the electrodes are typically substantially circular, although rounded rectangular or rounded square shapes could also be used. The electrodes are also optionally at least partially domed, which can help ensure that the electrodes make good electrical contact with the tragus regardless of the relative angle of the arms. Furthermore, the use of domed and substantially circular electrodes ensures that the electrodes do not have sharp edges that could cause discomfort.

[0108] Typically, the electrodes have a diameter greater than 4 mm, greater than 5 mm, greater than 6 mm, greater than 7 mm, less than 12 mm, less than 11 mm, less than 10 mm, less than 9 mm, and typically around 8 mm. These dimensions provide a surface area that allows a sufficiently large current to be applied to induce a field that can effectively stimulate the vagus nerve without causing excessive charge or current density on the surface of the tragus, which in turn can cause discomfort or burns and / or ineffective treatment. The electrodes also serve as a contact surface with the tragus, and a sufficiently large electrode surface can help ensure that the staple adheres effectively to the tragus and stays in place even when subjected to external forces.

[0109] Additionally and / or alternatively, a surface of the electrodes may be roughened or have grooves or ridges. The use of roughened or profiled electrode surfaces can initially increase the friction between the electrode and the tragus, which in turn helps maintain the position of the clip. Furthermore, roughening or providing grooves or ridges on the electrode surface can help ensure good electrical contact between the electrode and the tragus. This can, for example, help minimize interference from uneven surfaces, such as bumps on the tragus or similar.Another advantage is that the surface roughness leads to an increase in the total area of ​​the electrodes, which in turn helps to reduce the current density required to generate a given field within the tragus, which in turn ensures effectiveness while avoiding excessive current densities that can lead to burns.

[0110] In one example, the electrodes could also be coated, for example, to improve electrical conductivity, increase surface friction, and ensure biocompatibility. Any form of conductive coating could be used, and in one example, the electrodes are formed from copper electrodes coated with an inert metal, such as gold or another similar highly conductive material.

[0111] The signal generator is typically configured to generate therapy signals at a frequency that has at least one of the following characteristics: less than 20 kHz, less than 10 kHz, less than 1 kHz, less than 500 Hz, less than 200 Hz, less than 150 Hz, less than 100 Hz, less than 75 Hz, greater than 1 Hz, greater than 2 Hz, greater than 5 Hz, greater than 10 Hz, greater than 20 Hz, about 20 Hz, and typically about 50 Hz. The therapy signals typically have a pulse width of less than 5,000 µs, less than 2,500 µs, less than 1,000 µs, less than 500 µs, less than 200 µs, less than 100 µs, less than 75 µs, greater than 1 µs, greater than 2 µs, greater than 5 µs, greater than 10 µs, greater than 20 µs and typically about 50 µs.The therapy signals typically have a voltage that is less than 50 V, less than 25 V, less than 10 V, less than 5 V, less than 2 V, less than 1 V, greater than 0.1 V, greater than 0.2 V, greater than 0.5 V, and typically greater than 1 V. The therapy signals typically have a current of less than 50 mA, more than 1 mA, more than 0.1 mA, and between 0.1 mA and 36 mA.

[0112] The therapy signals can be symmetric, asymmetric, monophasic, or biphasic. In this regard, the use of symmetric biphasic signals can help reduce charge buildup on a surface of the tragus, which in turn maximizes the electrical fields generated in the tragus by the applied therapy signal while preventing charges from building up to a level that can cause discomfort. This, in turn, contributes to optimizing vagus nerve stimulation. Nevertheless, under certain circumstances, for example, depending on the intended application, asymmetric and / or monophasic therapy signals could be used. Additionally and / or alternatively, triphasic or, more generally, polyphasic signals could be used.In one example, asymmetric three-phase signals can be used with negative pulses that have a lower amplitude and duration than an intervening positive pulse, which can help reduce charge buildup. The signals could also include multiple phases with a dwell time between them, allowing a charge to remain in place for a short time before being discharged.

[0113] The therapy signals are typically configured to at least stimulate or inhibit activity within the vagus nerve, and it is evident that the signal parameters used, such as voltage, current, frequency, and waveform, can be selected depending on the intended application and the desired effect of the modulation on the vagus nerve.

[0114] In one example, one of the electrodes 121, 122 acts as ground, with the therapy signals applied via the other electrode. However, this is not strictly required, and in one example, therapy signals may be applied to either electrode. The therapy signals could be in-phase, but are typically out of phase to achieve a maximum overall field gradient across the vagus nerve, which in turn contributes to the generation of action potentials within the nerve. Furthermore, this helps minimize the strength of the current applied across each electrode to create a specific electrical field, which in turn contributes to reducing discomfort while ensuring the clinical efficacy of the system.

[0115] Generally, a lead, if used, includes a separate conductor for each electrode, with the conductors contained within an insulating layer and optionally surrounded by a braided shield. This helps ensure electrical insulation between the connections while providing a strong and lightweight interconnecting lead.

[0116] In one example, the system typically includes a control system having a housing containing the signal generator along with other associated electronics, such as a power supply and / or a controller. The controller is configured to control the signal generator, thereby enabling a variety of desired therapy signals to be generated. The control unit may take any suitable form, but typically includes one or more electronic processing devices, such as a microprocessor, a microchip processor, a logic gate configuration, firmware optionally coupled to implementation logic such as a field programmable gate array (FPGA), or any other electronic device, system, or arrangement.For ease of illustration, the further description generally refers to a control unit formed from one processing device, but it should be noted that multiple processing devices may be used, with processing distributed among the devices as needed, and that reference to the singular form includes the plural form and vice versa.

[0117] In one example, the lead extends from the clip to the housing so that the therapy signals generated by the signal generator can be applied to the electrodes. However, as previously mentioned, this is not essential, and in alternative embodiments, the signal generator may be mounted on the clip. In this example, the control unit could be integrated into a housing forming part of the clip, or alternatively, the control unit could communicate with the signal generator via wireless connections, such as Bluetooth, allowing the signal generator to be remotely controlled using a suitable device, such as a smartphone or other client device, which then acts as the control unit.

[0118] In one example, the control unit is configured to determine therapy signal parameters and control the signal generator according to the therapy signal parameters. The therapy signal parameters could be determined in a variety of ways, including retrieving defined therapy signal parameters stored in memory based on signals from a sensor, based on biofeedback, neurofeedback, based on user input, and / or a selected therapy mode. For example, several different operating modes could be defined, with the user selecting a therapy mode depending on the application, and the control unit retrieving therapy signal parameters depending on the selected mode. This allows the system to be used to achieve a range of different outcomes depending on the user's requirements, such as stimulation and / or inhibition of the vagus nerve.Furthermore, the control unit can thus determine feedback, for example, based on signals from a sensor, and adjust the therapy signals based on the feedback, so that the therapy signals can be optimized for the patient and, in particular, the patient's response to the signals. Thus, a software-based control system can be implemented in conjunction with feedback from a sensor to dynamically adjust the applied stimulation and thereby optimize it for the intended application.

[0119] In one example, the system includes a sensor configured to sense at least one subject parameter. The sensor may take any suitable form, depending on the preferred implementation, and may include one or more of the following sensors: an inflammatory biomarker sensor, a temperature sensor, a blood oxygen sensor, a pulse oximeter, a heart rate sensor, or an impedance sensor. The sensor may be formed at least partially from the electrodes. For example, a heart rate sensor could utilize a voltage sensor coupled to the electrodes to sense electrical signals, such as electrocardiogram (ECG) signals, while an impedance sensor could include a voltage sensor coupled to the electrodes to measure voltages across the tragus resulting from current signals applied by the signal generator.Alternatively, a separate sensor could be used, which could be attached to the bracket near the electrodes. For example, a pulse oximeter typically includes an infrared sensor, such as a photodiode, and infrared light-emitting diodes (LEDs). The LEDs could be positioned on one arm and the photodiode on the other arm to detect infrared radiation transmitted through the tragus. In one example, the electrodes could be transparent electrodes made of indium tin oxide (ITO) or other similar materials, with the LEDs and photodiodes positioned behind the electrodes.

[0120] A sensor separate from the bracket could also be provided. The sensor could be a wearable sensor, for example, integrated into a wearable band, such as an armband or chest band, but this is not intended to be limiting, and any suitable sensor could be used, including sensors integrated into fitness monitors, smartwatches, mobile phones, medical devices, photoplethysmogram sensors, electroencephalogram sensors, electrocardiogram sensors, or the like. In this case, sensor signals can be transmitted via suitable wired or wireless connections, such as Bluetooth, to a control unit (explained in more detail below), so that signals from the sensor can be used to monitor the subject and / or provide biofeedback to control the stimulation system.

[0121] Regardless of the sensor used, the control unit can be configured to determine at least one subject parameter based on the signals from the sensor and cause the signal generator to generate therapy signals corresponding to the at least one subject parameter. For example, the control unit can determine a subject parameter such as the presence, absence, or concentration of an inflammatory biomarker, temperature, blood oxygen level, heart rate, heart rate variability (HRV), impedance, or galvanic skin response and use this as biofeedback to evaluate the effectiveness of an applied therapy. This can then be used to adjust the applied therapy signals, for example, by increasing a magnitude or changing a frequency of the therapy signals, in order to optimize the therapy signals for the responsiveness of the respective patient.In this context, it is understood that the manner in which signals are to be adjusted may be defined in a memory and may include scaling signals based on measured patient parameters.

[0122] In a particular example, the control unit is configured to utilize biofeedback from heart rate sensors by monitoring a subject's heart rate based on signals from the sensor and then causing the signal generator to generate the therapy signals at least partially in accordance with the feedback. Thus, in this case, the control unit can respond to changes in heart rate to control the applied therapy signals, for example, by adjusting the applied signals to maximize the effectiveness of the therapy signals.

[0123] In one particular example, this can be used to define thresholds for various signal parameters, such as a frequency, pulse width, or amplitude of the therapy signals, to ensure both the safety and effectiveness of the signals. This can be done using signals from any of the sensors, but is generally done based on signals from a heart rate sensor, as heart rate is particularly sensitive to the applied therapy signals. In one example, the control unit is configured to cause the signal generator to progressively generate therapy signals with progressively changing parameters, such as progressively increasing or decreasing amplitudes, frequencies, or the like.While the therapy signals are applied, the control unit monitors the subject's heart rate based on signals from the sensor and uses the signals to detect changes in heart rate. Changes in heart rate can then be used to set a therapy signal parameter threshold based on a parameter of the therapy signal when changes in heart rate are detected, allowing therapy signals to be generated based on the therapy signal parameter threshold. Accordingly, it is understood that feedback from sensors, such as an indication of HRV, can be used to determine an optimal treatment threshold.

[0124] In a particular example, the process described above is performed to gradually increase a therapy signal strength, thereby detecting a bradycardia threshold that triggers a reduction in heart rate. In this case, an initial safety threshold may be set at the bradycardia threshold to ensure that the therapy signal does not exceed this value in the future, so that the system can be safely used with that individual. Additionally and / or alternatively, this may be used to set a threshold to optimize therapeutic efficacy. This is typically achieved by setting a threshold that is at least 20%, and typically between 50 and 60%, of the bradycardia safety threshold, resulting in optimal therapeutic pacing for the patient.

[0125] In another example, the control unit may be configured to cause the signal generator to generate the therapy signals and then, in response to the applied therapy signals, to monitor changes in the patient's heart rate using signals from the sensor. This may be used to generate therapy signals based on the monitored changes in heart rate, such that the signals are continuously or periodically adjusted to changes in heart rate, again to ensure safety and / or efficacy. Additionally and / or alternatively, the control unit may be configured to analyze monitored changes in heart rate to determine heart rate variability in response to the applied therapy signals. Heart rate variability can provide useful feedback for a number of reasons.

[0126] For example, the control unit may be configured to use heart rate variability to generate an inflammatory indicator indicating the presence, absence, or degree of inflammatory markers within the patient. In one example, this may be used to create a baseline inflammatory index score for patients based on their HRV. In this context, it has been shown that HRV can be a reliable index of cardiac vagal regulation and is inversely related to inflammatory markers (see: "Heart Rate Variability Predicts Levels of Inflammatory Markers: Evidence for the Vagal Anti-Inflammatory Pathway" by Timothy M. Cooper, Paula S. McKinley, Teresa E. Seeman, Tse-Hwei Choo, Seonjoo Lee, and Richard P. Sloan, Brain Behav Immun. 2015 Oct; 49: 94-100). In one example, HRV is used to generate an inflammation indicator that is inversely proportional to HRV.

[0127] In another example, HRV can be used to generate a predictive indicator indicating responsiveness to therapy signals, for example, to determine potential responsiveness to atrial fibrillation therapy. In this context, studies (see: Stavrakis, S., Stoner, J.A., Humphrey, M.B., Morris, L., Filiberti, A., Reynolds, J.C., ... & Varahan, S. (2020). TREAT AF (transcutaneous electrical vagus nerve stimulation for the suppression of atrial fibrillation): a randomized clinical trial. JACC: Clinical Electrophysiology, Volume 6, Issue 3, March 2020, pages 282-291) have shown that an initial response to stimulation (the magnitude of change in HRV) can be used to predict whether a person will respond to therapy (a "responder"). In this study, patients whose AF burden decreased by >75% at follow-up were classified as responders.Thus, feedback can also be used to determine whether a person is responding to treatment based on a scoring system derived from HRV values. For example, higher fluctuations in the LF / HF HRV ratio may indicate a better response.

[0128] It is also apparent that signals from the sensors could be used independently of stimulation, for example to derive indicators, monitor heart rate variability, or the like, so that such monitoring can be performed regardless of whether the subject is currently undergoing stimulation.

[0129] In another example, the control unit may be configured to determine feedback based on user input and cause the signal generator to generate the therapy signals according to the feedback. For example, the user could provide an input indicating whether they perceive an improvement, such as a reduction in anxiety or stress, and this input would be used to adjust the applied therapy signals.

[0130] In one example, the control unit is configured to cause the signal generator to generate therapy signals with progressively changing parameters, such as increasing or decreasing amplitudes, frequencies, or pulse widths, or different waveforms, and then select one or more therapy signal parameters in response to user inputs. This, in turn, can be used, for example, to gradually increase the amplitude of a stream of therapy signals to a point where they are perceptible to the patient, with this level then being used to select a desired therapy signal amplitude. This can be used to maximize the amplitude of the therapy signals while preventing them from being unpleasant to the user.In one example, the therapy signals are increased in 1 mA increments from 1 mA to a maximum of 36 mA, although other values ​​could also be used, such as 0.1 mA, 0.2 mA, 0.5 mA, 1.5 mA, 2 mA, or the like.

[0131] In another example, the control unit may be configured to determine the selection of a mode according to the user's input commands and then control the signal generator according to the selected mode. In this regard, the system typically includes a number of therapy modes stored in memory, with each therapy mode defining a sequence of therapy signals that can be customized, for example, to provide a different intervention, treat a different condition, or the like. Thus, the selected mode could be used to control the type of therapy signals and could be used to stimulate or inhibit the vagus nerve, or could be used to switch between symmetric, asymmetric, monophasic, and / or biphasic signals, depending on the preferred implementation.In this case, the control unit is configured to cause the signal generator to generate the sequence of therapy signals, thereby applying the selected intervention.

[0132] Thus, it is apparent from the above that feedback can be obtained objectively using sensor signals or subjectively using subject inputs, with the feedback being used to control the operation of the stimulation system to ensure safety and / or efficacy.

[0133] In another example, a research mode may be provided that is used to investigate the effectiveness of vagus nerve stimulation. In this context, the research mode typically operates by selecting the strength of the therapy signal as described above and then gradually decreasing it to zero, effectively applying null stimulation while allowing the subject to continue calibration, believing stimulation is occurring. In this way, a placebo effect can be assessed, and a null stimulation process can be used as a control in experiments evaluating the effectiveness of the stimulation process.

[0134] In another example, the neural stimulation system could include a stimulator configured to deliver a stimulus to the subject. The stimulator and the delivered stimulus can take any suitable form depending on the preferred implementation and / or the condition being treated. Examples of stimulators include an audio stimulator, such as a speaker; a vibration stimulator, such as an offset motor; an optical stimulator, such as an LED; or a thermal stimulator, such as a Peltier cooler or a heating element.

[0135] The stimulator could be integrated into the bracket, allowing stimulation to be applied to the ear and, in some examples, the tragus, depending on the type of stimulation. However, this is not strictly necessary, and in other examples, the stimulator could be provided separately from the bracket. For example, the stimulator could be integrated into a wearable arrangement such as a bracelet or similar, which could optionally also include one or more sensors as previously described. Alternatively, the stimulator could be a separate and optionally non-wearable device.

[0136] Stimulation could be used to complement vagus nerve stimulation, with complementary therapy in some cases enhancing treatment efficacy. In this case, the control unit can be configured to deliver a stimulus in conjunction with the therapy signals. Typically, however, stimulation is used in research mode, for example, as a decoy, essentially for a sham control study, so that the subject believes some form of stimulation is being applied, allowing the degree of effectiveness of vagus nerve stimulation to be determined.

[0137] While the system can be used to treat a wide variety of different conditions, the nerve stimulation system is particularly suitable for the treatment of depression or atrial fibrillation, as well as mental disorders, dysfunction of the autonomic nervous system, stress, heart failure, traumatic brain injury, impaired consciousness, inflammatory diseases, autoimmune diseases, cognitive dysfunction, infections, infectious symptoms, respiratory dysfunction, post-viral syndromes, fatigue, post-traumatic stress disorder, cancer, fibromyalgia, postural orthostatic tachycardia or myocardial infarction, or it can be used to enhance physical, particularly athletic, performance and / or cognitive functions.

[0138] A concrete example of the functionality of the control unit will now be given with reference to Fig. described.

[0139] In this example, the control system 250 includes a signal generator 230, a control unit 251, a memory 252, and an input / output device 253, such as input keys and a display, interconnected via a bus 255. The signal generator 250 is connected to the electrodes 221, 222 via a line 240 containing first and second connections 231, 232.

[0140] An external interface 254 may also be provided, which may be a wired or wireless interface, such as Wi-Fi, Bluetooth, or another short-range wireless communication interface. The external interface 254 may be used to connect an external device, such as a computer system, a smartphone, or a tablet, to the control system, for example, to update therapy signal parameters or operating modes or to remotely control the control system. Additionally and / or alternatively, the external interface 254 could be connected via a wired and / or wireless connection to a sensor 223, such as a pulse oximeter, a heart rate sensor, and / or a stimulator 224, or the like.In one example, the sensor 223 and / or a stimulator 224 may be integrated into the bracket 110, in which case the connection to the sensor 223 and / or a stimulator 224 could be integrated into the lead 240. It will also be appreciated that in other examples, a signal sensor, such as a voltage sensor (not shown), could be connected to the electrodes 221, 222, whereby signals within the body, such as ECG or impedance signals, could be detected. However, this is not strictly necessary, and in other examples, the sensor 223 and / or a stimulator 224 could be separate from the bracket 110 and optionally integrated into a wearable device, such as a wristband or the like, in which case separate wired or wireless connections could be used.

[0141] In operation, the control unit 251 executes instructions in the form of application software stored in the memory 252 to perform the necessary processes and, in particular, to control the signal generator 230 to generate therapy signals which are then applied to the electrodes 221, 222.

[0142] The application software may comprise one or more software modules and may be executed in a suitable execution environment, such as an operating system environment or the like. The control unit may be a microprocessor, a microchip processor, a logic gate configuration, firmware optionally coupled to implementation logic such as a Field Programmable Gate Array (FPGA), or any other electronic device, system, or arrangement.

[0143] The memory 252 also typically stores information necessary to generate therapy signals, such as details of therapy signal parameters, operating modes, or the like, as well as instructions for interpreting feedback, such as signals from sensors 223 or user inputs, whereby this feedback can be used to control the generation of therapy signals.

[0144] It can be seen that the control unit typically comprises at least one processing device and can optionally be distributed across multiple processing devices, with different tasks, such as the analysis of sensor signals and / or the generation of control signals, being distributed among the processing devices as required. In one example, the control unit comprises a software application executed by a client device, such as a computer system, a tablet, or a smartphone, which can communicate directly with the signal generator and / or the sensor via wired or wireless connections or can communicate with other processing devices that are in turn connected to the signal generator and / or the sensor. Thus, the control unit could be an external control unit that is wirelessly connected to the signal generator and / or the sensor(s).

[0145] An example of a process for performing nerve stimulation will now be described with reference to Fig. described.

[0146] In this example, the clamp is attached to the tragus in step 300. Typically, this is done by pushing the arms 111, 112 apart by applying pressure with the thumb and index finger to a proximal end of each arm 111, 112. The tragus is then positioned between the distal ends of the arms 111, 112 before the clamp is released so that the electrodes 121, 122 can be pressed into contact with the tragus, as shown in Fig. shown.

[0147] Next, in step 310, the strength of the therapy signal is calibrated. This process typically involves generating therapy signals of increasing strength until they are perceptible to the user. In this case, the user can indicate when the signals are perceptible and / or become unpleasant, after which a maximum strength for the therapy signals is determined.

[0148] Subsequently, in step 320, stimulation is performed by applying therapy signals. In this context, the control unit 251 typically retrieves therapy signal parameters from memory, optionally in accordance with an operating mode and / or user inputs, and uses them to control the signal generator 230 to generate the desired therapy signals.

[0149] A concrete example of a nerve stimulation system will now be shown using the Fig. 4A to 4G are described in more detail.

[0150] In this example, the nerve stimulation system comprises a clamp 410 having first and second arms 411, 412. The first and second arms 411, 412 are connected to each other via a pivotable support 413 formed from spaced parallel upright members 413.1, 413.2 extending upwardly from the inner surfaces of the first and second arms 411, 412. A pin is provided extending through the upright members to allow pivotal movement of the arms, while a spring 413.3 is mounted on the pin to compress the distal ends of the arms.

[0151] Recesses 411.1, 412.1 are provided on the outer surfaces of the proximal ends of each of the first and second arms 411, 412, wherein the recesses 412.1 are configured to align with the thumb and index finger of a user such that by applying pressure between the thumb and index finger, the distal ends of the 411.1, 412.1 are biased apart.

[0152] Electrodes 421, 422 are provided on the inner surfaces of the distal ends of 411.1, 412.1. The electrodes are circular and curved so that the electrodes 421, 422 can contact a surface of the tragus when the tragus is positioned between the electrodes 421, 422. In this regard, the upstanding elements 413.1, 413.2 are typically dimensioned based on an approximate thickness of the tragus, so that the arms 411, 412, and thus the electrodes, are substantially parallel when the clamp is positioned on the tragus.

[0153] A lead 440 is provided, which includes a lead body 441 and a sheath 442 extending partially along a distal end of the lead body 441. In particular, the sheath 442 is formed from an overmolded portion extending from a distal end of the outer arm 412 and having a hook shape, whereby it can be positioned behind the ear, as shown in Fig. 4G. The overmolded portion is typically approximately 100 mm long and is moldable, allowing it to be adjusted to the user's ear. As previously described, this helps support the clip 410, avoid excessive stress on the tragus, and prevent the clip 410 from falling out if it becomes loose.

[0154] A concrete example of a form factor of a control system can be found in the Fig. shown.

[0155] In this example, the control system comprises a body 561, input buttons 562, and a display 563. In this example, four input buttons 562 are provided, including an on / off button 562.1, a mode button 562.2, and an up and down button 562.3, 562.4, which allow users to select different modes and also indicate when a desired stimulation current is reached. The display can take any form and include, for example, LED or LCD displays or the like. These can be used to show operational information, such as details about selected operating modes, therapy signal parameters, information about a current therapy session, such as a duration, or the like.

[0156] The housing typically includes a receptacle that receives a plug 543 attached to the lead 441, which extends to the bracket 410 as previously described. The plug and receptacle may have any shape, but in one example are USB or similar connectors.

[0157] It is understood that in an example, the internal components of the control system generally correspond to those in Fig. 2. An alternative example of an arrangement of the internal components will now be described with reference to Fig. 6 described.

[0158] In this example, the control system 650 comprises a remote control device 650.1, which includes a control unit 651, a memory 652, an input / output unit 653, and an external interface 654, which are interconnected via a bus 656. In this example, a second external interface 656 is provided, which provides a short-range wireless connection, for example, Bluetooth™ or similar, to establish a connection to a device 650.2 attached to the clip 410. In this example, the second control system part 650.2 comprises an interface system on a chip (SoC) 657 and a signal generator 650 coupled to a power supply 658. The signal generator, in turn, is connected to the electrodes 621, 622 via corresponding connections 651, 652.

[0159] This arrangement allows control signals to be delivered from the remote device 650.1 to the device 650.2 on the clip and thus to the signal generator 650, so that the signal generator can be remotely controlled. In one example, the remote device 650.1 could have a shape similar to that shown in the Fig. 5A to 5C. However, it is understood that the remote device only needs to generate control signals and this could therefore be achieved with any suitable processing system, for example, a client device such as a tablet, a smartphone, or the like. It is also understood that control with a device such as a tablet, a smartphone, or the like could be used in conjunction with other physical embodiments of the clip. This could, for example, consist of enclosing the signal generator in a clip without a hook portion in order to minimize the size of the clip device, which has a shape similar to an earphone, and furthermore being able to control it remotely via a smartphone in order to minimize the shape of the wearable component of the system.

[0160] Another example of a stimulation process is now described.

[0161] In this example, in step 700, the clip 410 is attached to the tragus by the user pushing the arms apart, positioning the arms on either side of the tragus, and releasing the arms as previously described.

[0162] In step 710, the user selects an operating mode using the mode entry key 522.2, allowing the control unit 251 to retrieve the therapy signal parameters defined for the selected operating mode from the memory 252 in step 720. The therapy signal parameters are used to control the waveform of the generated therapy signals and include parameters such as the pulse waveform, pulse duration, signal amplitude, signal frequency, or the like.

[0163] Example waveforms are now shown using the Fig. 8A to 8F are described in more detail.

[0164] In the examples of Fig. 8A and Fig. 8B, the waveforms are generally rectangular, with the signal in Fig. 8A exhibits a sloping slope, which can result from the discharge of capacitors used to generate the pulse waveform. The waveform is generally biphasic, includes positive and negative components, and is symmetrical, so the amplitude of the positive and negative components is equal, ensuring that the surface of the tragus is neutrally charged at the end of each pulse in the pulse sequence. This helps prevent charge buildup, which in turn can mask the field created by the applied therapy signals and thus reduce signal efficacy and overall effectiveness. In addition, charge buildup can also increase the risk of thermal burns or other discomfort.

[0165] However, it is understood that other forms may also be used, as in the Fig. , which demonstrate a ramped increase in signal amplitude in a rectangular pulse waveform and a sine waveform, respectively. The use of gradually increasing waveforms of this type can help avoid a sudden current delivery to the patient, thereby avoiding some of the discomfort associated with electrical stimulation.

[0166] Alternative example waveforms are shown in the Fig. shown. In this example, the signals are again biphasic, but not symmetrical, meaning that the amplitude of the waveform is unequal in the positive and negative phases. In this case, this can lead to the generation of a net charge in the subject. However, this can be mitigated by having the waveform of unequal duration in the positive and negative phases, ensuring equal discharge and charge even if the signal amplitude is different.

[0167] Fig. shows a three-phase waveform with two negative pulses and an intervening positive pulse. In this example, the sum of the negative phases is equal to the positive phase, thus minimizing charge buildup. Furthermore, the preceding negative phase introduces a negative charge into the tissue before the positive phase is applied, allowing the positive phase to have a larger amplitude without the risk of thermal burns.

[0168] Fig. shows an arrangement in which a pause in the form of an interphase gap is inserted between the phases, allowing part of the charge to remain in place before the active discharge, which can improve efficiency. This can also be achieved with single-phase pulses, as in Fig. shown.

[0169] Fig. shows asymmetric biphasic signals where each phase has a different waveform, while Fig. shows a sawtooth waveform.

[0170] The Fig. show variations of the waveforms from the Fig. , but with a ramp-like increase in signal strength during the initial phase of the waveform.

[0171] From the above, it will be appreciated that a variety of different signal waveforms may be used and the above examples are for illustrative purposes only and are not necessarily limiting.

[0172] Thus, signals can include monophasic, unidirectional pulses from the baseline to either positive or negative. This is not to be confused with direct current (DC), where one electrode is always positive and one electrode is always negative, as pulsed monophasic waves have interruptions, use shorter pulses, and are less powerful than direct current. As a result, monophasic waveforms do not cause the same chemical changes as direct current and are less likely to cause discomfort or thermal burns.

[0173] Signals can be biphasic, meaning they have two phases, a positive and a negative phase, so the electrodes reverse their polarity. The phases can be symmetrical, so that identical phases cancel each other out, or asymmetrical, where non-identical phases are either balanced with no net charge or unbalanced, resulting in a net charge.

[0174] Finally, in a broader sense, multiphase signals, such as three-phase signals, with three or more phases in bursts could also be used. Here, too, the phases can be symmetrical or asymmetrical and separated by interphase gaps.

[0175] It will also be appreciated that the parameters of the therapy signal may vary during a stimulation sequence, for example, the amplitude, frequency, pulse width, and / or waveform may change during a single stimulation session, which may last several minutes or up to an hour or more.

[0176] After determining the signal parameters, the control unit 251 uses the therapy signal parameters to generate control signals that are delivered to the signal generator 230 to thereby control the signal generator 230 in step 730. This initially causes the signal generator 230 to generate a low-strength therapy signal that is applied to the subject via the electrodes 221, 222 so that the subject can assess whether they can perceive the signal and / or whether the signal causes discomfort.

[0177] If no response is detected in step 740, the current is increased in 1 mA increments in step 750 and the process is repeated until a response is detected (or until a threshold signal strength is reached), which is indicated by the user pressing one of the input keys 562.

[0178] Once a response is detected in step 740 (or a threshold level is reached), the therapy signal level is adjusted, and the stimulation sequence is performed in step 760. As previously described, the stimulation sequence is typically defined by the selected operating mode and may involve the application of different therapy signals over a specific period of time. An example of this is operating the device in research mode, where the stimulation signals are gradually ramped down so that the stimulation session does not provide significant active stimulation, allowing it to serve as a control for evaluating the effectiveness of a stimulation sequence applied to other subjects.

[0179] After stimulation begins, the system may optionally monitor feedback at step 770, for example, by the control unit 251 monitoring signals from one or more sensors 223 and using them to determine a value or changes in a subject parameter, or by monitoring user inputs received via an input key 562. The feedback may then be used to determine the effectiveness of the therapy signals and to further modify the signals if necessary, for example, by modifying the therapy signal parameters to change a magnitude, waveform, intensity, or the like at step 780. The process may then return to step 760, allowing the modified therapy signals to be applied, with this process being repeated until therapy is complete.

[0180] In one example, the system can also be used to treat depression. In this context, inflammation has been shown to cause depressive symptoms, and reducing inflammation can have antidepressant effects. Stimulation of the vagus nerve can influence the cholinergic anti-inflammatory pathway, and a study (Stavrakis, S., Stoner, J.A., Humphrey, M.B., Morris, L., Filiberti, A., Reynolds, J.C., ... & Varahan, S. (2020). TREAT AF (transcutaneous electrical vagus nerve stimulation for the suppression of atrial fibrillation): a randomized clinical trial. JACC: Clinical Electrophysiology, Volume 6, Issue 3, March 2020, pages 282-291) using the above-described setup to perform tragus-based vagus nerve stimulation showed a significant reduction in the inflammatory biomarker TNF-alpha.Furthermore, the study showed that vagus nerve stimulation activates the parasympathetic nervous system, which has antiadrenergic effects that may be stress-relieving, so the vagus nerve stimulation approach can be used to treat stress, depression, and other related mental disorders.

[0181] In another example, the system is used to treat atrial fibrillation (AF). An example study (Stavrakis, S., Stoner, J.A., Humphrey, M.B., Morris, L., Filiberti, A., Reynolds, J.C., ... & Varahan, S. (2020). TREAT AF (transcutaneous electrical vagus nerve stimulation for the suppression of atrial fibrillation): a randomized clinical trial. JACC: Clinical Electrophysiology Volume 6, Issue 3, March 2020, pages 282-291) evaluating the efficacy of tVNS was conducted using the above-described setup to non-invasively stimulate vagal fibers, for example, to activate antiadrenergic or anti-inflammatory pathways, to perform autonomic modulation, for example, to reduce sympathetic nervous system activity, or the like.

[0182] In this study, the primary endpoint of median atrial fibrillation burden was reduced, as in Fig. shown, a graph showing the effects of tragus-based stimulation on AF 901 compared to sham stimulation 902. Data are presented as median and interquartile range. The p-value is based on a comparison of median AF burden values ​​6 months after adjustment to baseline. The total duration of AF at 6 months was 83% lower in the active group than in the control group. Including patients with non-zero AF burden at baseline, 47% of patients in the active group experienced a >75% reduction in AF burden during the follow-up period compared to 5% in the control group (p = 0.003).

[0183] Cytokine levels, particularly serum TNF-alpha, were also significantly reduced by 23% in the active group compared to the control group. There was no significant effect of active stimulation compared to sham stimulation on heart rate, confirming the low-risk profile of this device in the target population.

[055] The results of the clinical study demonstrate a significant improvement in the primary endpoint (reduction in AF burden) and thus a statistically significant clinical improvement in the patient population, with no device-related adverse events reported.

[0184] Another important point is that vagus nerve stimulation (VNS) was originally used to induce atrial fibrillation, but this low-level stimulation with the device described above has been shown to suppress atrial fibrillation. Stimulation at the tragus preferentially activates afferent rather than efferent vagal fibers, leading to parasympathetic activation. This is an advantage over cervical and invasive VNS and results in antiadrenergic effects that reduce the burden of atrial fibrillation.

[0185] Thus, the study met its primary endpoints and demonstrated that chronic, intermittent, transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus using the above-described setup suppressed atrial fibrillation in patients with paroxysmal atrial fibrillation over a period of 6 months. The significance of the study results is underscored by recent findings that lower AF burden over a two-week monitoring period is associated with a lower risk of ischemic stroke, independent of known stroke risk factors, in patients with paroxysmal atrial fibrillation. Thus, the results support other findings that stimulation of either the cervical vagus nerve or the tragus is capable of suppressing atrial fibrillation and reversing electrical and autonomic remodeling of the atria.

[0186] Further studies on the use of tVNS in the treatment of atrial fibrillation have demonstrated additional benefits, including the suppression of atrial fibrillation (Stavrakis, S., Humphrey, M.B., Scherlag, B.J., Hu, Y., Jackman, W.M., Nakagawa, H., ... & Po, S.S. (2015). Low-dose transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. Journal of the American College of Cardiology, 65(9), 867-875) and the improvement of left ventricular strain in humans (Tran, N., Asad, Z., Elkholey, K., Scherlag, B.J., Po, S.S., & Stavrakis, S. (2019). Autonomic neuromodulation acutely improves left ventricular strain in humans. Journal of cardiovascular translational research, 12(3), 221-230) and the suppression of postoperative atrial fibrillation and inflammation (Stavrakis, S., Humphrey, MB, Scherlag, B., Iftikhar, O., Parwani, P., Abbas, M., ... & McUnu, A. (2017).Low-frequency vagus nerve stimulation suppresses postoperative atrial fibrillation and inflammation: a randomized trial. JACC: Clinical Electrophysiology, 3(9), 929–938.

[0187] Furthermore, research has shown that in people with atrial fibrillation, the discomfort threshold is approximately 60% of the bradycardia threshold, whereas pacing at 50% of the bradycardia threshold resulted in a significant reduction in inflammatory cytokines and atrial fibrillation duration. In particular, low-frequency cervical VNS has demonstrated antiarrhythmic effects attributable to its antiadrenergic effects. Specifically, tVNS has been shown to activate central vagal projections in the human brain, leading to a reduction in sympathetic activity. Transcutaneous VNS may offer clinical advantages over cervical VNS because tVNS preferentially activates afferent rather than efferent vagal fibers. Cervical VNS may inadvertently lead to stimulation of sympathetic fibers, which are colocalized with vagal fibers in the vagus nerve.However, tVNS can elicit minimal or no accompanying sympathetic stimulation by preferentially activating afferent vagal fibers, thus reducing sympathetic activity. This may help achieve the "neural pivot point" where afferent and efferent branches of the vagus nerve are activated to achieve a neutral heart rate response (HRR) (which still produces beneficial changes in HRV).

[0188] The system can also be used to treat heart failure. In particular, stimulation at the tragus has been shown to preferentially improve endothelial function in patients with heart failure and reduced ejection fraction, acutely alleviate diastolic dysfunction in humans, and acutely improve left ventricular strain in humans. Thus, tragus-based tVNS has cardioprotective mechanisms and also reduces global longitudinal strain (GLS). Studies have also demonstrated other benefits, including improved endothelial function (Dasari, TW, Gabor, F., Csipo, T., Palacios, FS, Yabluchanskiy, A., Samannan, R., & Po, S. (2018). Non-invasive neuromodulation of vagal activity improves endothelial function in patients with heart failure and reduced ejection fraction: A randomized trial. Journal of Cardiac Failure, 24(8), pp. 59-60) and improved diastolic function (Stavrakis, S., Tran, N., Asad, Z., & Po, SS(2017). P2437 Low-intensity transcutaneous vagus nerve stimulation acutely improves diastolic function in humans. European Heart Journal , 38 (suppl_1)).

[0189] Furthermore, the improvement in cardiac mechanics by tVNS is proportional to the improvement in autonomic function, which in turn can be measured by the LF / HF HRV ratio, thus allowing improvements in cardiac function to be quantified.

[0190] Traumatic brain injuries (TBI) cause neuroinflammation and, consequently, many negative side effects associated with brain inflammation. tVNS has neurorehabilitative effects, likely due to its effects on cortical plasticity. A recent study using the above-mentioned setup (Noé, E., Ferri, J., Colomer, C., Moliner, B., O'Valle, M., Ugart, P., ... & Llorens, R. (2020). Feasibility, safety, and efficacy of transauricular vagus nerve stimulation in a cohort of patients with impaired consciousness. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 13(2), 427-429) showed slight improvement in some patients. Thus, the device described above can be used to treat TBI, impaired consciousness, and other neurological disorders.

[0191] Inflammatory and other autoimmune diseases may benefit from novel nonpharmacological anti-inflammatory interventions. Conventional pharmacological anti-inflammatory options have many adverse side effects, whereas tVNS is low-risk with few side effects and no drug interactions. The aforementioned studies have demonstrated a significant reduction in inflammatory biomarkers, confirming the activation of the cholinergic anti-inflammatory pathway (CAP).

[0192] There is also significant evidence that tVNS can improve learning and memory, so the arrangement described above can also be used for cognitive enhancement (see: "Vagus Nerve Stimulation Improves Working Memory Performance" Lihua Sun, Jari Peräkylä, Katri Holm, Joonas Haapasalo, Kai Lehtimäki, Keith H. Ogawa, pages 954-964 | Submitted September 9, 2016, accepted January 16, 2017, published online February 19, 2017). A study (Effect of Transcutaneous Vagus Nerve Stimulation on Sports Performance by Kyle Lindley, ARIZONA STATE UNIVERSITY, May 2019) has also shown that it can improve athlete performance and support neurophysiological recovery. Accordingly, it is considered advantageous that the system described above can be used to improve cognitive and athletic performance.

[0193] Neuromodulation, and therefore the above-mentioned system, can also be used to treat disease states, particularly those associated with systemic inflammatory shock caused by the body's response to a virus or other infection (also known as a cytokine storm), such as coronavirus and other similar diseases (Implications for Neuromodulation Therapy to Control Inflammation and Related Organ Dysfunction in COVID-19 by Marat Fudim & Yawar J. Qadri & Kamrouz Ghadimi & David B. MacLeod & Jeroen Molinger & Jonathan P. Piccini & John Whittle & Paul E. Wischmeyer & Manesh R. Patel & Luis Ulloa, Journal of Cardiovascular Translational Research, May 26, 2020).In this context, anti-inflammatory drugs have been shown to be helpful in the treatment of Covid, and another study has shown positive results (The Use of Non-invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated With COVID -19: A Theoretical Hypothesis and Early Clinical Experience by Peter Staats, Georgios Giannakopoulos, Justyna Blake, Eric Liebler and Robert M. Levv).

[0194] Analogously, the system can be used to treat other post-viral illnesses, including ME / CFS "post-viral syndrome." One suspected cause of such illnesses is a small, localized infection of the vagus nerve, which causes an enhanced infection response without any actual risk of infection and leads to fatigue and depressive symptoms (Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis by Michael B. VanElzakker, Medical Hypotheses, Volume 81, Issue 3, September 2013, pages 414-423). Further studies with tVNS have also shown a reduction in fatigue scores using the modified Fatigue Impact Scale (MFIS), as described in Fig. shown.

[0195] An early-stage clinical trial investigating the effects of VNS on radiation-induced inflammation shows promising results: Patients exhibit a reduction in immunosuppressive and tumor-promoting MDSC cells and an increase in cancer-fighting immune cells.

[0196] tVNS has also been shown to reduce the effects of PTSD-related fear extinction learning in patients (Transcutaneous cervical vagus nerve stimulation blocks sympathetic responses to stress in posttraumatic stress disorder by Nil Z. Gurel, MS, Matthew T. Wittbrodt, Hewon Jung, Mobashir H. Shandhi, Emily G. Driggers, Stacy L. Ladd, Minxuan Huang, Yi-An Ko, Lucy Shallenberger, Joy Beckwith, Jonathon A. Nye, Bradley D. Pearce, Viola Vaccarino, Amit J. Shah, Omer T. Inan, J. Douglas Bremner).

[0197] Research is also underway into the effects of tVNS on fibromyalgia, while a study is underway into the effectiveness of vagus nerve stimulation in the treatment of postural orthostatic tachycardia syndrome (POTS).

[0198] Finally, the technology is also used to reduce the extent of myocardial damage caused by ischemia (Yu, L., Huang, B., Po, SS, Tan, T., Wang, M., Zhou, L., ... & Wang, Z. (2017). Low-level tragus stimulation for the treatment of ischemia and reperfusion injury in patients with ST-segment elevation myocardial infarction: a proof-of-concept study. JACC: Cardiovascular Interventions, 10(15), 1511-1520).

[0199] Accordingly, the arrangements described above provide a system suitable for performing non-invasive vagus nerve stimulation using a clamp configured to be positioned on a subject's tragus.

[0200] The arrangement described above can offer a number of advantages, such as avoiding the risk of nerve damage that can occur with cervical VNS, avoiding the risk of carotid artery stimulation that can occur with cervical VNS and cervical nVNS, or avoiding unpleasant side effects such as "lip pulling" that can occur with cervical nVNS, as well as avoiding burns.

[0201] In one example, the system uses targeted stimulation of the nerve via electrodes arranged in a substantially parallel, spaced-apart array, which allows for easier nerve excitation by generating a larger overall electric field while avoiding excessive current densities at a tissue surface.

[0202] Unlike several other non-invasive techniques, the present system stimulates the vagus nerve in the tragus, specifically the inner and outer tragus, which contain longer vagus nerve fibers, to increase the likelihood of triggering action potentials within the nerve. This improves the efficacy of stimulation while minimizing the currents required to achieve an action potential, thus avoiding discomfort.

[0203] The arrangement described above uses a clamp to press the electrodes against the tissue surface. This allows the electrodes to be pressed against the tragus with optimized pressure, which can help overcome skin impedance without causing pain or penetrating the skin. Furthermore, this helps ensure a consistent delivery of the electrical current, ensuring consistent nerve excitation, which is important for the effectiveness of some therapies.

[0204] The arrangements described above can use a variety of different therapy signal waveforms that ensure optimal nerve stimulation and maximize the generation of action potentials without the need to apply signals that cause pain to the user.

[0205] In one example, the system is configured to apply asymmetric, symmetric biphasic square waveforms that are better tolerated by users, cause less pain, and can be more effectively focused on specific nerve fibers. Additionally and / or alternatively, symmetric biphasic square waveforms can be used to reduce charge buildup, resulting in less skin irritation for the user.

[0206] In one example, the device described above can be used to record physiological measurements for biofeedback, such as heart rate, heart rate variability, galvanic skin response, ECG, inflammatory biomarkers, or the like. This can be achieved by using measuring devices at skin contact points on or around the electrode.

[0207] Such biofeedback can then be used to deliver optimal stimulation, adjusting therapy signal parameters such as stimulation intensity, waveform, and frequency in real time to achieve the optimal outcome of physiological autonomic balance and / or immunological balance.

[0208] In one example, the arrangement described above, with appropriate configuration, can overcome skin resistance while avoiding the development of pain. The system can effectively target the fibers of the vagus nerve and maintain an electric field around the target nerve fiber. The use of the clamp allows the electrodes to be held in place during use, ensuring stable pressure and consistent electrical contact between the skin and the electrode. This in turn leads to a more stable contact impedance and thus a more stable current delivery and consistent stimulation.

[0209] In one example, the system uses an overmolded lead with a soft plastic outer layer and a thin wire center layer to maintain the shape of the ear. This section includes a standard insulated cable with anode / cathode cores and can contribute to load distribution and help hold the clamp in place, allowing for a more consistent application of therapy signals.

[0210] It should be noted that the approach described above contrasts with conventional invasive VNS, which requires surgical implantation, must be administered by a physician, and is irreversible. In particular, the device can be administered non-invasively, without surgical intervention, and applied directly to the outer skin. The device can be operated by the patient themselves without physician assistance and can be inserted or removed at any time without additional risks.

[0211] Other devices that aim to non-invasively stimulate the vagus nerve typically require manual positioning to deliver stimulation and use methods of stimulation across the skin that do not penetrate effectively.

[0212] In contrast, the present device is designed to be attached to the ear to provide effective stimulation and, in addition, stimulates both sides of the skin of the tragus to deliver a more concentrated current to the target nerve.

[0213] Other devices also typically require manual guidance to the correct stimulation site, whereas the system described above guides the electrode plates to the location where stimulation is delivered to the skin directly over the vagal innervation, avoiding stimulation at a site close to the carotid artery, which may produce undesirable results.

[0214] The above-mentioned arrangements avoid the high risk of skin irritation caused by small electrode areas with a higher relative current density. In contrast, the above-mentioned arrangements use a larger electrode area that spreads the current, resulting in a lower risk of skin irritation or thermal burns.

[0215] In the above examples, the nerve stimulation system is described as being provided with a fastener in the form of a clamp having spaced arms that can be compressed at distal ends. However, it is understood that other fasteners capable of securing electrodes to the tragus may also be used, and the term "fastener" should be understood to include arrangements without clamps.

[0216] Throughout this specification and the following claims, unless the context otherwise requires, the word "comprise" and variations such as "comprises" or "comprising" are intended to imply the inclusion of a specified integer or group of integers or increments, but not the exclusion of other integers or groups of integers. Unless otherwise specified herein, the term "about" means ±20%.

[0217] Those skilled in the art will recognize that numerous variations and modifications are possible. All variations and modifications obvious to those skilled in the art should be considered within the spirit and scope of the invention described above. 1) A vagus nerve stimulation system for stimulating a vagus nerve in a biological subject, the system comprising: a) a bracket configured to be attached to a tragus of the subject, the bracket comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) a signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. 2) The nerve stimulation system of embodiment 1, wherein the system includes a hook extending over and behind an ear of the subject to at least partially support the clamp. 3) A nerve stimulation system according to embodiment 2, wherein the hook is configured to extend laterally from the clamp so that the lead can be looped over and behind an ear of the subject. 4) The nerve stimulation system of any one of embodiments 1 to 3, wherein the system comprises a lead extending from the clamp, the lead comprising connections configured to electrically connect the electrodes to the signal generator. 5) The nerve stimulation system of embodiment 4, wherein the lead is configured to extend laterally from the clamp so that the lead can be looped over and behind an ear of the subject. 6) The nerve stimulation system of embodiment 4 or embodiment 5, wherein the lead is configured to extend from a distal end of one of the arms. 7) A nerve stimulation system according to any one of embodiments 4 to 6, wherein the lead comprises a sheath extending at least partially along a length of the lead, and wherein the sheath defines a hook shaped to loop over and behind an ear of the subject. 8) A nerve stimulation system according to any one of embodiments 1 to 7, wherein one of the arms is configured to be positioned within an auricle of the user. 9) Nerve stimulation system according to one of embodiments 1 to 8, wherein the arms are pivotally connected about a central portion. 10) Nerve stimulation system according to one of embodiments 1 to 9, wherein the distal ends of the arms are pre-tensioned together by means of a pre-tensioning mechanism. 11) Nerve stimulation system according to embodiment 10, wherein the biasing mechanism comprises at least one of the following elements: a) a pivot point; b) a spring; c) a rubber element; d) a malleable element connecting the arms; (e) arms that are at least partially malleable; f) an at least partially elastic element connecting the arms to each other; g) at least partially elastic arms; and h) Magnets provided on the arms. 12) The nerve stimulation system according to any one of embodiments 1 to 11, wherein a proximal outer surface of the arms has a recess configured to allow a subject to grasp and spread the arms apart. 13) Nerve stimulation system according to one of the embodiments 1 to 12, wherein the arms have at least one of the following features: (a) a length which has at least one of the following characteristics: (i) larger than 15 mm; (ii) larger than 16 mm; iii) larger than 17 mm; (iv) larger than 18 mm; (v) larger than 19 mm; (vi) larger than 20 mm; vii) greater than 21 mm; (viii) less than 30 mm; (ix) less than 28 mm; x) less than 27 mm; (xi) less than 26 mm; xii) less than 25 mm; (xiii) less than 24 mm; xiv) less than 23 mm; xv) about 22 mm; and b) a width which has at least one of the following values: (i) larger than 5 mm; (ii) larger than 6 mm; iii) larger than 7 mm; (iv) larger than 8 mm; (v) larger than 9 mm; (vi) larger than 10 mm; vii) less than 16 mm; (viii) less than 15 mm; (ix) less than 14 mm; x) less than 13 mm; (xi) less than 12 mm; xii) about 11 mm. 14) Nerve stimulation system according to one of the embodiments 1 to 13, wherein the electrodes: (a) are substantially circular; b) are rounded rectangular; c) are rounded and square; (d) at least partly dome-shaped; e) have a diameter of at least one of the following values: (i) larger than 4 mm; (ii) larger than 5 mm; iii) larger than 6 mm; (iv) larger than 7 mm; (v) less than 12 mm; (vi) less than 11 mm; vii) less than 10 mm; (viii) less than 9 mm; and ix) about 8 mm. 15) Nerve stimulation system according to one of the embodiments 1 to 14, wherein a surface of the electrodes has at least one of the following features: a) is roughened; b) includes grooves; c) includes ribs; and d) is coated. 16) Nerve stimulation system according to one of the embodiments 1 to 15, wherein a surface of the electrodes is coated with at least one of the following materials: a) an inert metal; and, b) Gold. 17) Nerve stimulation system according to one of embodiments 1 to 16, wherein therapy signals are signals having a frequency which is at least one of the following: (a) less than 20 kHz; b) less than 10 kHz; c) less than 1 kHz; d) less than 500 Hz; e) less than 200 Hz; f) less than 150 Hz; g) less than 100 Hz; h) less than 75 Hz; (i) more than 1 Hz; j) more than 2 Hz; k) more than 5 Hz; l) more than 10 Hz; m) more than 20 Hz; n) about 20 Hz; and o) about 50 Hz. 18) Nerve stimulation system according to one of the embodiments 1 to 17, wherein therapy signals are signals with a pulse width of at least one of the following values: a) less than 5,000 µs; b) less than 2,500 µs; c) less than 1,000 µs; d) less than 500 µs; (e) less than 200 µs; f) less than 100 µs; g) less than 75 µs; h) greater than 1 µs; i) greater than 2 µs; j) greater than 5 µs; k) greater than 10 µs; l) greater than 20 µs; and m) about 50 µs. 19) Nerve stimulation system according to one of the embodiments 1 to 18, wherein the therapy signals are signals with a voltage having at least one of the following properties: a) less than 50 V; b) less than 25 V; c) less than 10 V; d) less than 5 V; e) less than 2 V; f) less than 1 V; g) greater than 0,1 V; h) greater than 0.2 V; i) greater than 0.5 V; and j) greater than 1 V. 20) Nerve stimulation system according to one of the embodiments 1 to 19, wherein the therapy signals are signals with a current having at least one of the following properties: a) less than 50 mA; b) greater than 0.1 mA; and c) between 0.1 mA and 36 mA. 21) Nerve stimulation system according to one of the embodiments 1 to 20, wherein the therapy signals have at least one of the following features: a) are symmetrical; b) are asymmetrical; c) are monophasic; d) are biphasic; e) are triphasic; f) are polyphasic; and g) comprise several phases with at least one break in between. 22) Nerve stimulation system according to one of embodiments 1 to 21, wherein a respective therapy signal is applied to each of the electrodes. 23) Nerve stimulation system according to embodiment 22, wherein the respective therapy signals have at least one of the following features: a) in phase; and b) phase-shifted. 24) Nerve stimulation system according to one of embodiments 1 to 23, wherein the lead comprises at least one of the following elements: a) a respective conductor for each electrode; b) at least one insulating layer; and c) a braided shield. 25) Nerve stimulation system according to one of embodiments 1 to 24, wherein the therapy signals are configured to perform at least one of the following functions: a) to stimulate the activity of the vagus nerve; and b) to inhibit the activity of the vagus nerve. 26) Nerve stimulation system according to one of embodiments 1 to 25, wherein the signal generator is attached to the clamp. 27) Nerve stimulation system according to any one of embodiments 1 to 26, wherein the system comprises a control system with a housing containing at least one of the following elements: a) the signal generator; b) a power supply; and c) a control unit. 28) A nerve stimulation system according to embodiment 27, wherein a lead extends from the clamp to the housing. 29) Nerve stimulation system according to one of embodiments 1 to 28, wherein the system comprises a control unit configured to control the signal generator. 30) Nerve stimulation system according to embodiment 29, wherein the control unit is configured to: a) to determine therapy signal parameters; and b) to control the signal generator according to the therapy signal parameters. 31) Nerve stimulation system according to embodiment 30, wherein the control unit is configured to determine the therapy signal parameters according to at least one of the following elements: a) defined therapy signal parameters stored in a memory; b) user input; c) biofeedback; d) neurofeedback; e) signals from a sensor; and f) a selected therapy mode. 32) A nerve stimulation system according to any one of embodiments 29 to 31, wherein the system comprises a sensor configured to detect at least one patient parameter, and wherein the control unit is configured to: a) determining at least one subject parameter using signals from the sensor; and b) causing the signal generator to generate therapy signals according to the at least one subject parameter. 33) Nerve stimulation system according to embodiment 32, wherein the sensor is at least one of the following: (a) attached to the clamp near at least one electrode; b) electrically coupled to at least one of the electrodes; c) a wearable sensor; (d) provided on a portable tape; and (e) provided on a wearable wristband. 34) Nerve stimulation system according to embodiment 32 or embodiment 33, wherein the sensor is at least one of the following: a) an inflammatory biomarker sensor; b) a temperature sensor; c) a blood oxygen sensor; d) a pulse oximeter; e) a heart rate sensor; and f) an impedance sensor. 35) Nerve stimulation system according to one of embodiments 32 to 34, wherein the at least one subject parameter comprises at least one of the following elements: a) the presence, absence or concentration of an inflammatory biomarker; b) a temperature; c) a blood oxygen level; d) a heart rate; e) heart rate variability; f) an impedance; and g) a galvanic skin reaction. 36) A nerve stimulation system according to any one of embodiments 32 to 35, wherein the control unit is configured to: a) monitoring a heart rate of the subject based on signals from the sensor; and b) causing the signal generator to generate the therapy signals at least partially in accordance with the feedback. 37) A nerve stimulation system according to any one of embodiments 32 to 36, wherein the control unit is configured to: a) causes the signal generator to progressively generate therapy signals with progressively changing parameters; 38) The nerve stimulation system of embodiment 37, wherein the therapy signal parameter threshold is a therapy signal strength and is 50% to 60% of the therapy signal strength applied when the change in heart rate is detected. 39) A nerve stimulation system according to any one of embodiments 32 to 38, wherein the control unit is configured to: a) causes the signal generator to generate the therapy signals; b) monitoring changes in a heart rate of the subject based on signals from the sensor in response to the applied therapy signals; and c) at least one of the following: i) causing the signal generator to generate therapy signals based on the monitored changes in heart rate; and ii) Analyzing the monitored changes in heart rate to determine cardiac variability in response to the applied therapy signals. 40) The nerve stimulation system of embodiment 39, wherein the controller is configured to use heart rate variability to generate an inflammatory indicator indicating the presence, absence, or degree of inflammatory markers within the patient. 41) Nerve stimulation system according to embodiment 40, wherein the inflammation indicator is inversely proportional to heart rate variability. 42) The nerve stimulation system of any one of embodiments 39 to 41, wherein the control unit is configured to use heart rate variability to generate a predictive indicator indicative of responsiveness to the therapy signals. 43) A nerve stimulation system according to embodiment 42, wherein the predictive indicator indicates responsiveness to atrial fibrillation therapy. 44) A nerve stimulation system according to any one of embodiments 29 to 43, wherein the control unit is configured to: a) determines feedback based on user input; and b) causes the signal generator to generate the therapy signals according to the feedback. 45) A nerve stimulation system according to any one of embodiments 29 to 44, wherein the control unit is configured to: a) causes the signal generator to generate therapy signals with progressively changing parameters; and b) selects one or more therapy signal parameters in response to user input. 46) Nerve stimulation system according to one of embodiments 29 to 45, wherein the parameters comprise at least one of the following elements: a) a therapy signal pulse width; b) a therapy signal amplitude; and c) a therapy signal frequency; and d) a therapy signal waveform. 47) Nerve stimulation system according to embodiment 46, wherein the control unit is configured to gradually increase the therapy signal by at least one of the following values: a) 0.1 mA; b) 0.2 mA; c) 0.5 mA; d) 0.8 mA; e) 1 mA; f) 1.5 mA; and g) 2 mA. 48) A nerve stimulation system according to any one of embodiments 29 to 47, wherein the control unit is configured to: a) determines the selection of a therapy mode according to user input; and b) controls the signal generator according to the selected mode. 49) A nerve stimulation system according to embodiment 48, wherein the system comprises a number of therapy modes stored in a memory, each therapy mode defining a sequence of therapy signals, and wherein the control unit is configured to cause the signal generator to generate the sequence of therapy signals. 50) Nerve stimulation system according to any one of embodiments 29 to 49, wherein in a research mode the control unit is configured to perform at least one of the following functions: a) selecting a therapy signal strength in response to user inputs and progressively decreasing the therapy signal strength to zero; and b) . c) Delivering a non-electrical stimulus. 51) Nerve stimulation system according to one of the embodiments 29 to 50, wherein the control unit comprises at least one of the following elements: (a) at least one processing facility; b) a software application executed by a client device; and c) an external control unit wirelessly connected to at least one of the following: i) the signal generator; and ii) at least one sensor. 52) A nerve stimulation system according to any one of embodiments 29 to 51, wherein the system comprises a stimulator configured to deliver a stimulus to the patient. 53) Nerve stimulation system according to embodiment 51, wherein the stimulator comprises at least one of the following elements: a) an audio stimulator; b) a vibration stimulator; c) an optical stimulator; and d) a thermal stimulator. 54) Nerve stimulation system according to embodiment 51 or embodiment 52, wherein the stimulator is integrated into the clamp. 55) Nerve stimulation system according to one of embodiments 51 to 54, wherein the stimulator is controlled by a control unit to cause the stimulus to be applied in conjunction with the therapy signals. 56) Nerve stimulation system according to any one of embodiments 1 to 55, wherein the nerve stimulation system is configured to treat at least one of the following: a) depression; b) mental disorders; c) disorders of the autonomic nervous system; d) stress; e) heart failure; f) traumatic brain injuries; g) disturbances of consciousness; h) inflammatory diseases; i) autoimmune diseases; j) cognitive dysfunction; k) infections; l) symptoms of infections; m) respiratory disorders; n) Postviral syndrome; o) tiredness; p) Post-traumatic stress disorder; q) cancer; r) Fibromyalgia; s) Postural orthostatic tachycardia syndrome; t) myocardial infarction; and u) Atrial fibrillation. 57) A nerve stimulation system according to any one of embodiments 1 to 56, wherein the nerve stimulation system is configured to improve at least one of the following features: a) physical performance; and b) cognitive functions. 58) A method of vagus nerve stimulation for stimulating a vagus nerve in a biological subject, the method comprising: a) Applying a bracket to a tragus of the subject, the bracket comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) Using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. 59) A system for treating at least one of the conditions depression and atrial fibrillation, the device comprising: a) a bracket configured to be attached to a tragus of the patient, the bracket comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) a signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. 60) A method for treating at least one of the conditions depression and atrial fibrillation, the method comprising: a) Applying a clamp to a tragus of the patient, the clamp comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) Using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. 61) A vagus nerve stimulation system for stimulating a vagus nerve in a biological subject, the system comprising: a) a fastener configured to be attached to a tragus of the subject such that the electrodes are pressed into engagement with opposing surfaces of the tragus; and b) a signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. 62) A method for stimulating a vagus nerve in a biological subject, the method comprising: a) attaching a fastener to a tragus of the subject such that electrodes are pressed into engagement with opposing surfaces of the tragus; and b) Using a signal generator electrically connected to the electrodes to generate at least one therapy signal applied via the electrodes to the vagus nerve within the tragus to thereby modulate the vagus nerve. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] US 20050165460

[0011] US 10130809

[0012] US 8457765

[0013] US 20070250145

[0014] US 20180021564

[0015] Cited non-patent literature

[0000] Heart Rate Variability Predicts Levels of Inflammatory Markers: Evidence for the Vagal Anti-Inflammatory Pathway" by Timothy M. Cooper, Paula S. McKinley, Teresa E. Seeman, Tse-Hwei Choo, Seonjoo Lee and Richard P. Sloan, Brain Behav Immun. 2015 Oct; 49: 94-100

[0126] Stavrakis, S., Stoner, JA, Humphrey, MB, Morris, L., Filiberti, A., Reynolds, JC, ... & Varahan, S. (2020

[0127] JACC: Clinical Electrophysiology Volume 6, Issue 3, March 2020, pages 282-291 [0127, 0181] Stavrakis, S., Stoner, J.A., Humphrey, M.B., Morris, L., Filiberti, A., Reynolds, J.C., ... & Varahan, S. (2020). TREAT AF (transcutaneous electrical vagus nerve stimulation for the suppression of atrial fibrillation): a randomized clinical trial. JACC: Clinical Electrophysiology, Volume 6, Issue 3, March 2020, pages 282–291

[0180] Stavrakis, S., Stoner, J.A., Humphrey, M.B., Morris, L., Filiberti, A., Reynolds, J.C., ... & Varahan, S. (2020). TREAT AF (transcutaneous electrical vagus nerve stimulation for the suppression of atrial fibrillation): a randomized clinical trial

[0181] Stavrakis, S., Humphrey, MB, Scherlag, BJ, Hu, Y., Jackman, WM, Nakagawa, H., ... & Po, SS (2015). Low-dose transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. Journal of the American College of Cardiology, 65(9), 867-875

[0186] Tran, N., Asad, Z., Elkholey, K., Scherlag, B.J., Po, S.S., & Stavrakis, S. (2019). Autonomic neuromodulation acutely improves left ventricular strain in humans. Journal of cardiovascular translational research, 12(3), 221-230

[0186] Stavrakis, S., Humphrey, MB, Scherlag, B., Iftikhar, O., Parwani, P., Abbas, M., ... & McUnu, A. (2017). Low-frequency vagus nerve stimulation suppresses postoperative atrial fibrillation and inflammation: a randomized trial. JACC: Clinical Electrophysiology, 3(9), 929-938

[0186] Dasari, TW, Gabor, F., Csipo, T., Palacios, FS, Yabluchanskiy, A., Samannan, R., & Po, S. (2018

[0188] A randomized trial. Journal of Cardiac Failure, 24(8), pp. 59-60

[0188] Stavrakis, S., Tran, N., Asad, Z., & Po, SS (2017). P2437 Low-intensity transcutaneous vagus nerve stimulation acutely improves diastolic function in humans. European Heart Journal , 38 (suppl_1

[0188] Noé, E., Ferri, J., Colomer, C., Moliner, B., O'Valle, M., Ugart, P., ... & Llorens, R. (2020

[0190] Brain Stimulation: Basic, Translational and Clinical Research in Neuromodulation, 13(2), 427-429

[0190] Vagus nerve stimulation improves working memory performance” Lihua Sun, Jari Peräkylä, Katri Holm, Joonas Haapasalo, Kai Lehtimäki, Keith H. Ogawa, pages 954-964 | Submitted on 9 September 2016, accepted on 16 January 2017, published online on 19 February 2017

[0192] Effect of Transcutaneous Vagus Nerve Stimulation on Sports Performance by Kyle Lindley, ARIZONA STATE UNIVERSITY, May 2019

[0192] Implications for Neuromodulation Therapy to Control Inflammation and Related Organ Dysfunction in COVID-19 by Marat Fudim & Yawar J. Qadri & Kamrouz Ghadimi & David B. MacLeod & Jeroen Molinger & Jonathan P. Piccini & John Whittle & Paul E. Wischmeyer & Manesh R. Patel & Luis Ulloa, Journal of Cardiovascular Translational Research, May 26, 2020

[0193] The Use of Non-Invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated with COVID-19: A Theoretical Hypothesis and Early Clinical Experience by Peter Staats, Georgios Giannakopoulos, Justyna Blake, Eric Liebler and Robert M. Levv

[0193] Chronic Fatigue Syndrome from Vagus Nerve Infection: A Psychoneuroimmunologic Hypothesis by Michael B. VanElzakker, Medical Hypotheses, Band 81, Issue 3, September 2013, Pages 414-423

[0194] Nil Z. Gurel, MS, Matthew T. Wittbrodt, Hewon Jung, Mobashir H. Shandhi, Emily G. Driggers, Stacy L. Ladd, Minxuan Huang, Yi-An Ko, Lucy Shallenberger, Joy Beckwith, Jonathon A. Nye, Bradley D. Pearce, Viola Vaccarino, Amit J. Shah, Omer T. Inan, J. Douglas Bremner

[0196] Yu, L., Huang, B., Po, S. S., Tan, T., Wang, M., Zhou, L., ... & Wang, Z. (2017). Low-level tragus stimulation for the treatment of ischemia and reperfusion injury in patients with ST-segment elevation myocardial infarction: a proof-of-concept study. JACC: Cardiovascular Interventions, 10(15), 1511-1520

[0198]

Claims

[1] A system for treating at least one of the conditions depression and atrial fibrillation, the system comprising: a) a bracket configured to be attachable to a tragus of the subject, the bracket comprising: i) opposing arms configured such that a distal end of the arms is biased towards each other; and ii) electrodes positioned near a distal end of the arms on opposite surfaces so that the electrodes are pressed into engagement with opposite surfaces of the tragus; and b) a signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapy signal that can be applied to the vagus nerve within the tragus via the electrodes to thereby modulate the vagus nerve and treat depression and / or atrial fibrillation. [2] The system of claim 1, wherein the system comprises a bracket extending over and behind an ear of the subject to at least partially support the bracket; optionally wherein the bracket is configured to extend laterally from the bracket such that the lead is loopable over and behind an ear of the subject. [3] The system of claim 1 or 2, wherein the system comprises a lead extending from the clamp, the lead comprising connections configured to electrically connect the electrodes to the signal generator; optionally comprising at least one of the following features: a) the lead is configured to extend laterally from the clamp so that the lead can be looped over and behind one ear of the subject; b) the lead is configured to extend from a distal end of one of the arms; and / or c) the lead comprises a sheath extending at least partially along a length of the lead, the sheath defining a holder shaped to be placed over and behind an ear of the subject. [4] System according to one of claims 1 to 3, wherein one of the arms is at least one of the following: a) configured to be positionable within an auricle of the user; and b) is optionally pivotally connected around a central section. [5] The system of any one of claims 1 to 4, wherein a distal end of the arms is biased toward each other using a biasing mechanism; the biasing mechanism optionally comprising at least one of the following elements: a) a pivot point; b) a spring; c) a rubber element; d) a malleable element connecting the arms; (e) arms that are at least partially malleable; (f) an at least partially elastic element connecting the arms together; g) arms that are at least partially elastic; and h) Magnets provided on the arms. [6] System according to one of claims 1 to 5, wherein at least one of the following features is present: (a) a proximal outer surface of the arms has a recess configured to allow a person to grasp and spread the arms; b) the arms have at least one of the following features: (i) a length which has at least one of the following characteristics: (1) larger than 15 mm; (2) larger than 16 mm; (3) larger than 17 mm; (4) larger than 18 mm; (5) larger than 19 mm; (6) larger than 20 mm; (7) larger than 21 mm; (8) less than 30 mm; (9) less than 28 mm; (10) less than 27 mm; (11) less than 26 mm; (12) less than 25 mm; (13) less than 24 mm; (14) less than 23 mm; (15) about 22 mm; and (ii) a width corresponding to at least one of the following: (1) larger than 5 mm; (2) larger than 6 mm; (3) larger than 7 mm; (4) larger than 8 mm; (5) larger than 9 mm; (6) larger than 10 mm; (7) less than 16 mm; (8) less than 15 mm; (9) less than 14 mm; (10) less than 13 mm; (11) less than 12 mm; (12) about 11 mm; c) the electrodes are: (i) substantially circular; (ii) rounded rectangular; iii) rounded square; (iv) at least partially curved; (v) have a diameter of at least one of the following values: (1) larger than 4 mm; (2) larger than 5 mm; (3) larger than 6 mm; (4) larger than 7 mm; (5) less than 12 mm; (6) less than 11 mm; (7) less than 10 mm; (8) less than 9 mm; and (9) about 8 mm; d) the surface of the electrodes has at least one of the following features: i) is roughened; ii) has grooves; iii) has ribs; and iv) is coated; e) the surface of the electrodes is coated with at least one of the following materials: i) an inert metal; and, ii) gold; f) the line comprises at least one of the following elements: i) a respective conductor for each electrode; (ii) at least one insulating layer; and, iii) a braided shield; and g) the signal generator is mounted on the bracket; h) the nerve stimulation system is configured for at least one of: i) Treatment of at least one of: (1) depression; (2) mental disorders; (3) dysfunction of the autonomic nervous system; (4) stress; (5) heart failure; (6) traumatic brain injuries; (7) disturbances of consciousness; (8) inflammatory diseases; (9) Autoimmune diseases; (10) cognitive dysfunction; (11) infections; (12) symptoms of infections; (13) respiratory dysfunction; (14) post-viral syndrome; (15) Fatigue; (16) post-traumatic stress disorder; (17) cancer; (18) Fibromyalgia; (19) postural orthostatic tachycardia syndrome; (20) myocardial infarction; and (21) atrial fibrillation; (ii) improve at least one of the following characteristics: (1) physical performance; and (2) cognitive function. [7] A system according to any one of claims 1 to 6, wherein therapy signals are signals having at least one of the following features: (a) a frequency having at least one of the following characteristics: (i) less than 20 kHz; (ii) less than 10 kHz; (iii) less than 1 kHz; (iv) less than 500 Hz; (v) less than 200 Hz; (vi) less than 150 Hz; vii) less than 100 Hz; (viii) less than 75 Hz; ix) greater than 1 Hz; x) greater than 2 Hz; (xi) greater than 5 Hz; xii) greater than 10 Hz; xiii) greater than 20 Hz; xiv) about 20 Hz; and xv) about 50 Hz; b) with a pulse width of at least one of the following values: (i) less than 5 000 µs; (ii) less than 2,500 µs; (iii) less than 1,000 µs; (iv) less than 500 µs; (v) less than 200 µs; (vi) less than 100 µs; vii) less than 75 µs; viii) greater than 1 µs; ix) greater than 2 µs; x) greater than 5 µs; (xi) greater than 10 µs; xii) greater than 20 µs; and xiii) about 50 µs; c) with a voltage which is at least one of the following: (i) less than 50 V; (ii) less than 25 V; iii) less than 10 V; (iv) less than 5 V; (v) less than 2 V; (vi) less than 1 V; vii) greater than 0,1 V; viii) greater than 0,2 V; ix) greater than 0.5 V; and x) greater than 1 V; and d) with a current having at least one of the following values: (i) less than 50 mA; (ii) more than 0.1 mA; and iii) between 0.1 mA and 36 mA; e) which have at least one of the following characteristics: i) are symmetrical; ii) are asymmetric; iii) are monophasic; iv) are biphasic; v) are three-phase; (vi) are multiphasic; and (vii) comprise several phases with at least one break in between; f) configured to perform at least one of the following functions: i) to stimulate the activity of the vagus nerve; and ii) inhibit the activity of the vagus nerve. [8] A system according to any one of claims 1 to 7, wherein a respective therapy signal is applied to each of the electrodes; optionally wherein the respective therapy signals comprise at least one of the following features: a) in phase; and, b) phase-shifted. [9] A system according to any one of claims 1 to 8, wherein the system comprises a control system having a housing containing at least one of the following elements: a) the signal generator; b) a power supply; and c) a control unit; optionally a cable runs from the clamp to the housing. [10] The system of any one of claims 1 to 9, wherein the system comprises a control unit configured to control the signal generator; optionally wherein the control unit is configured to: a) determining therapy signal parameters; and b) to control the signal generator according to the therapy signal parameters; optionally, the control unit is configured to determine the therapy signal parameters according to at least one of the following elements: a) defined therapy signal parameters stored in a memory; b) user input; c) biofeedback; d) neurofeedback; e) signals from a sensor; and f) a selected therapy mode; [11] The system of claim 10, wherein the system comprises a sensor configured to detect at least one subject parameter, and wherein the control unit is configured to: a) determines at least one subject parameter using signals from the sensor; and b) causing the signal generator to generate therapy signals according to the at least one subject parameter; where optionally the sensor is at least one of the following: (a) is attached to the clamp near at least one electrode; b) is electrically coupled to at least one of the electrodes; c) is a wearable sensor; d) is provided on a portable band; and (e) is provided on a wearable wristband; where optionally the sensor is at least one of the following: a) an inflammatory biomarker sensor; b) a temperature sensor; c) a blood oxygen sensor; d) a pulse oximeter; e) a heart rate sensor; and f) an impedance sensor; wherein optionally the at least one subject parameter comprises at least one of the following elements: a) the presence, absence or concentration of an inflammatory biomarker; b) a temperature; c) a blood oxygen level; d) a heart rate; e) heart rate variability; f) an impedance; and g) a galvanic skin reaction; [12] The system of claim 11, wherein the control unit is configured to: a) monitors a heart rate of the subject based on signals from the sensor; and b) cause the signal generator to generate the therapy signals at least partly in accordance with the feedback; [13] A system according to claim 11 or 12, wherein the control unit is configured to: a) causes the signal generator to progressively generate therapy signals with progressively changing parameters; b) monitors a person's heart rate based on signals from the sensor while the therapy signals change; c) detecting changes in heart rate; d) setting a therapy signal parameter threshold based on a parameter of the therapy signal when changes in heart rate are detected; and e) causing the signal generator to generate therapy signals based on the therapy signal parameter threshold; optionally wherein the therapy signal parameter threshold is a therapy signal strength and is 50% to 60% of the therapy signal strength applied when the change in heart rate is detected; where optionally the control unit is configured to: a) to cause the signal generator to generate the therapy signals; b) monitor changes in the subject’s heart rate based on signals from the sensor in response to the applied therapy signals; and c) at least one of the following elements: i) causing the signal generator to generate therapy signals based on the monitored changes in heart rate; and ii) analyzing the monitored changes in heart rate to determine cardiac variability in response to the applied therapy signals; optionally wherein the control unit is configured to use the heart rate variability to generate an inflammatory indicator indicative of the presence, absence, or degree of inflammatory markers within the subject; optionally wherein the inflammatory indicator is inversely proportional to heart rate variability; optionally wherein the control unit is configured to use the heart rate variability to generate a predictive indicator indicative of responsiveness to the therapy signals; optionally wherein the predictive indicator indicates responsiveness to atrial fibrillation therapy. [14] System according to one of claims 10 to 13, wherein the control unit performs at least one of the following functions: a) is configured to perform at least one of the following functions: i) determining feedback using user input commands; ii) causing the signal generator to generate the therapy signals in accordance with the feedback; iii) causing the signal generator to generate therapy signals with progressively changing parameters; and iv) selecting one or more therapy signal parameters in response to user input commands; and b) includes at least one of the following elements: (i) at least one processing device; ii) a software application executed by a client device; and iii) an external control unit wirelessly connected to at least one of the following: (1) the signal generator; and (2) at least one sensor. [15] System according to one of claims 10 to 14, wherein at least one of the following elements is present: (a) the parameters include at least one of the following elements: i) a therapy signal pulse width; ii) a therapy signal amplitude; and iii) a therapy signal frequency; and iv) a therapy signal waveform; wherein the control unit is optionally configured to gradually increase the therapy signal by at least one of the following values: i) 0.1 mA; (ii) 0.2 mA; (iii) 0.5 mA; (iv) 0.8 mA; v) 1 mA; vi) 1.5 mA; and vii) 2 mA; b) the control unit is configured to: i) determine the selection of a therapy mode according to user input; and ii) to control the signal generator according to the selected mode; wherein optionally the system comprises a number of therapy modes stored in a memory, each therapy mode defining a sequence of therapy signals, and wherein the control unit is configured to cause the signal generator to generate the sequence of therapy signals; c) in a research mode, the control unit is configured to perform at least one of the following functions: i) selecting a therapy signal strength in response to user inputs and progressively decreasing the therapy signal strength to zero; and ii) delivering a non-electrical stimulus; and (d) the system comprises a stimulator configured to apply a stimulus to the subject; wherein optionally the stimulator comprises at least one of the following elements: i) an audio stimulator; ii) a vibration stimulator; iii) an optical stimulator; and, (iv) a thermal stimulator; The stimulator is optionally integrated into the clamp; wherein the stimulator is optionally controlled by a control unit to ensure that the stimulus can be applied in conjunction with the therapy signals.

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