Nerve modulation system

Abstract

The present invention attempts to provide a neuromodulation system for treating a disease, the system comprising: an electrode configured to be attached to a subject; and a signal generator electrically connected to the electrode, the signal generator configured to generate at least one treatment signal applied to the subject via the electrode to thereby modulate a nerve, and wherein the at least one treatment signal comprises at least one sequence of different types of waveforms.

Description

Technical Field

[0001] The present invention relates to a modulation system, and in a particular instance, to a neuromodulation system for modulating nerves. Background Technology

[0002] References to any prior disclosure (or information derived therefrom) or any known matter in this specification shall not and should not be construed as an endorsement or permission or any form of advice to any prior disclosure (or information derived therefrom) or known matter that forms part of the general knowledge in the field of this specification and its related efforts.

[0003] The vagus nerve is composed of a complex neural network that maintains homeostasis and balance in vital processes within the body. Its interconnected neural connections with several brain regions serve as a control center, responding to new information (stimuli) with appropriate adaptive feedback for modulation. The vagus nerve contains four vagal nuclei that provide crucial control over the cardiovascular, respiratory, and digestive systems using their respective neurotransmitters. The tenth of the twelve cranial nerves is the primary nerve that interfaces with the parasympathetic branches of the autonomic nervous system. Recent clinical studies have shown that the vagus nerve also participates in the regulation of inflammation, mood, and pain, all of which can be potentially modulated by micropulse stimulation or inhibition of neural activity using electrical currents calibrated to communicate with the brainstem via nerve fibers (a process known as neuromodulation).

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

[0005] Vagus nerve stimulation utilizes several regulatory mechanisms within the nervous, immune, autonomic, endocrine, cardiopulmonary, and gastrointestinal systems. The exact mechanisms of action within the VNS remain theoretical; however, this does not preclude its potential for safe and effective use in individuals with diseases involving the vagus nerve pathway. For example, vagus nerve stimulation therapy has been approved by regulatory agencies for applications such as mood enhancement, pain relief, sleep improvement, and anxiety reduction; current research is assessing its cardiac and inflammatory modulatory properties and its utilization of neuroplasticity effects.

[0006] In this respect, the vagus nerve is the main nerve of the parasympathetic branch of the autonomic nervous system, regulating the body's unconscious processes. The parasympathetic nervous system (PNS) is often referred to as the "rest and digest" system, while the sympathetic nervous system is considered the "fight or flight" system. Stimulation of the vagus nerve has been shown to increase PNS activity and decrease SNS activity. Further through this regulation of metabolic homeostasis, the vagus nerve also controls heart rate, with increased vagus nerve activity associated with a decrease in heart rate. This is significant because autonomic dysfunction characterized by an overactive SNS response is considered to be the basis of several high-impact chronic diseases, thus illustrating the value of interventions that can modulate this response.

[0007] Neurotransmitters are chemical substances released from nerve fiber impulses into the surrounding areas of this electrical activity. Examples of neurotransmitters include serotonin, norepinephrine / norepinephrine, and gamma-aminobutyric acid (GABA). Research in this field indicates that vagus nerve stimulation can affect the release of neurotransmitters in the brain. Clinical studies suggest that vagus nerve stimulation may lead to changes in serotonin, norepinephrine, GABA, and glutamate—all neurotransmitters associated with the pathogenesis of major depressive disorder. This effect on neurotransmitters, along with several other theoretical mechanisms, is considered to explain the mood-enhancing effects of vagus nerve stimulation.

[0008] It should now be understood that the nervous system reflexively modulates the inflammatory response in real time in much the same way it controls heart rate and other vital functions. This is thought to occur via the vagus nerve through a neuroreflex mechanism known as the "inflammatory reflex." The brain receives signals from the immune system for the purpose of optimally controlling inflammation in the body; however, dysfunction of these signals can lead to excessive inflammation. It has been observed that in the absence of vagal nerve activity (attributable to vagotomy or nerve damage), the inflammatory reflex is absent, which can lead to an excessive innate immune response and cytokine toxicity (excessive inflammation). This has led to clinical studies and confirmation that vagal nerve stimulation can reduce inflammatory cytokines. The anti-inflammatory properties of (vagal) nerve stimulation are thought to be mediated through the cholinergic anti-inflammatory pathway (CAP) and through the hypothalamic-pituitary-adrenal (HPA) axis. This profound understanding has opened up new opportunities for treating inflammation through these selective and reversible "hardwired" nervous systems.

[0009] Late 20th-century research demonstrated that many aspects of the brain remain modifiable, or "plastic," even in adulthood. Neuroplasticity is the brain's ability to reorganize itself by generating new neural connections. It allows neurons or nerve cells in the brain to compensate for damage or disease and to modify their processes in response to new situations or environmental changes. Promoting the neuroplasticity of the vagus nerve (VNS) by altering neurotransmitter levels and / or processing in the central nervous system has led to increased interest in its use as a stroke rehabilitation therapy. This application utilizes a "labeled plasticity" mechanism, stimulating the vagus nerve to promote neuroplasticity and pairing this with specific stimuli, such as rehabilitation exercises (for stroke recovery), that label this effect of plasticity in specific brain regions associated with various diseases. This results in outcomes such as accelerated and modified stroke recovery.

[0010] Traditionally, VNS as a treatment method has been limited by the need for surgical implantation. This has ultimately limited access due to geographical factors (specialized surgical centers), the severity of the condition (requiring surgery), and economic factors (those who can afford the surgery). Several non-invasive devices have recently been proposed. Specifically, this can be achieved using the auricular branch of the vagus nerve passing through the outer ear, thus allowing for the delivery of non-invasive vagus nerve neuromodulation (nVN). This approach has now been shown to activate the vagus nerve pathway in the same manner as surgery, making it an accessible, low-risk, and lower-cost route for vagus nerve neuromodulation.

[0011] US20050165460 describes a self-contained portable headset that carries a waveform source device and tissue interface circuitry in a self-positioning position for delivering therapeutic signals to a pre-selected region in the concha of a human subject. An electronic housing carries the waveform source device in communication with right and left tissue interface circuitry, respectively carried in the right and left earpiece housings. The headset carries each earpiece housing at a rearward and downward angle, such that it protrudes from the torso into the concha of the outer ear and typically contacts the concha below and behind the ear canal. An audio speaker delivers the associated tone during treatment. An endwall of the torso carries an electrode array that contacts the pre-selected region in the concha.

[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 conduit, and an electrode coupler. The generator receives the generator control signal and the music signal, generates a neural electrical stimulation signal depending on the generator control signal, and outputs the neural electrical stimulation signal at a stimulation output and the music signal at an audio output. The coupler fits into the 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 electrically connected to the stimulation output via the electronic signal conduit to receive the neural electrical stimulation signal and positioned to contact tissue within the ear canal to apply the neural electrical stimulation signal transcutaneously thereto. The coupler supplies the neural electrical stimulation signal while simultaneously outputting music from the speaker.

[0013] US8457765 describes an ear clip electrode for transmitting a micro-electro-stimulator to a patient's earlobe. The ear clip electrode comprises an inner and outer plastic part with separate metal plates disposed thereon. Both the metal plates and the plastic parts have circular ends with metal electrodes disposed thereon. Electrode pads are placed on these metal electrodes, and electricity is conducted from the plates to the electrode pads and then to the patient's earlobe. A plastic shield is placed along a considerable length of each metal plate. Plastic material also covers the end faces of each metal electrode. The ear clip electrode is connected to a small electrical energy source.

[0014] US20070250145 describes a device (1) for transcutaneous stimulation of a human nerve, the device (1) comprising at least one stimulating electrode (2) and at least one reference electrode (3) for transcutaneous nerve stimulation, the at least one stimulating electrode (2) and at least one reference electrode (3) being connected to a control unit (4) and capable of being supplied with current from the control unit (4), and the at least one stimulating electrode (2) and at least one reference electrode (3) being disposed in or on a housing (5) designed to fit into or in the ear. To make nerve stimulation effective and easier for patient management, according to the invention, the housing (5) is provided to have: an arcuate extension (6) designed to be inserted into the auditory canal, the arcuate extension (6) conforming to the shape of an entrance to the auditory canal or external auditory canal; and an electrode head (7) disposed at an end of the arcuate extension (6) and having two contact points (8, 9) for the two electrodes (2, 3).

[0015] US20180021564 describes a neurostimulation system including headphones and a handset, the handset including two or more ear contact elements, such as ear canal inserts and outer ear inserts. The ear contact elements can be mounted on a handset housing having a protruding mounting structure that provides mechanical and electrical connection between the ear contact elements and the housing through various materials and configurations. In one embodiment, the neurostimulation system includes a neurostimulation subsystem comprising a neurostimulation device control circuitry for use in conjunction with a personal computing device to control the neurostimulation device.

[0016] However, such devices, which typically require electrical contact with the inner and / or outer surfaces of the outer ear, can be uncomfortable for the user and make it difficult to maintain their position during use. Furthermore, the system suffers from issues related to safety, effectiveness, and usability. For example, some electrode configurations and current densities can cause skin burns, while others fail to achieve effective nerve stimulation. Summary of the Invention

[0017] In a broad form, this invention seeks to provide a neuromodulation system for treating a disease, the system comprising: an electrode configured to be attached to a subject; and a signal generator electrically connected to the electrode, the signal generator being configured to generate at least one therapeutic signal applied to the subject via the electrode to modulate nerves thereon, wherein the at least one therapeutic signal comprises at least one sequence of waveforms of different types.

[0018] In one embodiment, the at least one sequence of different types of waveforms includes: a single repeating sequence of different types of waveforms; multiple different sequences of waveforms; and multiple repeating different sequences of waveforms.

[0019] In one embodiment, the sequence of at least one different type of waveform is based on at least one of the following selections and / or adjustments: cardiovascular disease under treatment; autonomous dysfunction under treatment; responsiveness to treatment; biofeedback; and user input.

[0020] In one embodiment, the waveform of this type includes at least one of the following: rectangular pulse waveform; triangular pulse waveform; spike waveform; sine waveform; ramp waveform; exponential ramp waveform; exponential decay waveform; burst waveform; arbitrary waveform; pre-modulated waveform; linear waveform; increasing or decreasing ζ waveform; increasing or decreasing sawtooth waveform; DC waveform; damped sine waveform; double S-shaped waveform; composite waveform; pulse waveform; square waveform; random noise waveform; customized waveform; differential waveform; and rest.

[0021] In one embodiment, the at least one therapeutic signal is triggered by at least one of the following: user input; sensor input; electrical signal; bioelectrical signal; movement of the subject; audio signal; vibration; and the physiological state of the subject.

[0022] In one embodiment, the at least one treatment signal is at least one of the following: symmetrical; asymmetrical; monophasic; biphasic; triphasic; multiphasic; and includes multiple phases having at least one scattered dwell time.

[0023] In one embodiment, the different types of waveform sequences include at least the time intervals between the different types of waveforms.

[0024] In one embodiment, the time interval is at least one of the following: variable; fixed; 0µs; 0µs to 200,000µs; 200µs to 2,000µs; 100µs to 500µs; selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; the autonomous function being treated; responsiveness to treatment; biofeedback; and user input.

[0025] In one embodiment, different types of waveform sequences are repeated, with a dwell time between each repetition.

[0026] In one embodiment, the dwell time is at least one of the following: variable; fixed; 0 µs; 1 µs to 10,000 µs; 10,000 µs to 10,000,000 µs; approximately 50,000 µs; and selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; the autonomous function being treated; responsiveness to treatment; biofeedback; and user input.

[0027] In one embodiment, at least one of the following: the amplitude of at least one of the different types of waveforms is at least one of the following: variable; fixed; selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; the autonomous functioning being treated; responsiveness to treatment; biofeedback; and user input; and the relative amplitude of the waveform in the different types of waveform sequences is at least one of the following: variable; fixed; selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; the autonomous functioning being treated; responsiveness to treatment; biofeedback; and user input.

[0028] In one embodiment, at least one of the following is true: the duration of each waveform in the waveform sequence is at least one of the following: variable; fixed; 1µs to 20000µs; 200µs to 500µs; and selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; responsiveness to treatment; the autonomous function being treated; biofeedback; and user input; and the relative duration of the waveform in different types of waveform sequences is at least one of the following: variable; fixed; selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated; the autonomous function being treated; responsiveness to treatment; biofeedback; and user input.

[0029] In one embodiment, different types of waveform sequences include a first waveform followed by a second waveform.

[0030] In one embodiment, at least one of the following is true: the first waveform has a duration longer than the second waveform; the first waveform has a duration shorter than the second waveform; the first waveform has the same duration as the second waveform; the first waveform has an amplitude greater than the second waveform; the first waveform has an amplitude less than the second waveform; and the first waveform has the same amplitude as the second waveform.

[0031] In one embodiment, different types of waveform sequences include rectangular pulse waveforms and exponential ramp waveforms.

[0032] In one embodiment, different types of waveform sequences include rectangular pulse waveforms, spike waveforms, and exponentially decaying waveforms at a first threshold.

[0033] In one embodiment, the rectangular pulse waveform is a pre-pulse at a first threshold value. In one embodiment, the first threshold value is at least one of the following: less than the threshold value; greater than 0% and less than 100% of the threshold value; between 50% and 70% of the threshold value; approximately 60% of the threshold value; and approximately 50% of the threshold value.

[0034] In one embodiment, the neuromodulation system is configured to stimulate the nerve to modulate at least one of the following: the presence, absence, or concentration of inflammatory biomarkers; electrocardiographic biomarkers; temperature; blood oxygen content; heart rate; heart rate variability; impedance; and skin current response.

[0035] In one embodiment, the disease includes at least one of the following: cardiovascular disease, including at least one of the following: cardiovascular disease with inflammatory manifestations; coronary artery disease; cerebrovascular disease; peripheral artery disease; rheumatic heart disease; congenital heart disease; ischemic heart disease; arrhythmia; atrial fibrillation; hypertension; heart failure with reduced ejection fraction; acute heart failure; heart failure with mildly reduced ejection fraction; heart failure with maintained ejection fraction; diastolic dysfunction; postural orthostatic tachycardia syndrome; myocardial infarction; and stroke; chronic fatigue; prolonged COVID; rheumatoid arthritis; autonomic nervous system dysfunction; autonomic nervous system dysfunction; mental health disorder; inflammatory disease; autoimmune disease; cognitive impairment; postviral syndrome, including prolonged COVID; pain disorder; stress, including acute and chronic stress; post-traumatic stress disorder; systemic lupus erythematosus; diabetes; and cancer.

[0036] In one embodiment, the system enhances at least one of the following: accompanying treatment delivery; cognition; memory; mobility; physical performance; recovery after physical activity; sleep quality; and divergent thinking.

[0037] In one embodiment, the nervous system includes at least one of the following: cranial nerves, including at least one of cranial nerves I to XII; vagus nerve, including at least one of the following: auricular branch; cervical branch; efferent branch; and afferent branch; central nerve; and peripheral nerves, including at least one of the following: median nerve; and radial nerve.

[0038] In one embodiment, the signal generator modulates the nerve, including modulating at least one target of the nerve.

[0039] In one embodiment, the at least one target of the nerve includes: the auricular branch of the nerve; the cervical branch of the nerve; the radial branch of the nerve; a specific nerve fiber; an efferent fiber; an afferent fiber; an A-α (Aα) fiber; an A-β (Aβ) fiber; an A-δ (Aδ) fiber; B fibers, which at least include myelinated B fibers; and C fibers.

[0040] In one embodiment, the electrode is configured to be attached to the subject in the form of at least one of the following: clip; collar; wristband; headband; earpiece; earpiece; fabric accessory; handheld accessory; ankle strap; ring; wearable piece; wearable jewelry; collar ornament; and invasively.

[0041] In one embodiment, the electrode is configured to be attached to the subject's ear via an accessory, wherein the accessory includes a shell that is biased against the ear and close to the subject's target nerve location.

[0042] In one embodiment, the electrode is configured to attach to the subject's tragus, the accessory or earpiece including: opposing arms configured such that the distal ends of the arms are biased toward each other; and the electrode, such that the distal ends of the arms are positioned on opposing surfaces such that the electrode is advanced to engage with the opposing surface of the tragus.

[0043] In one embodiment, the system includes hooks extending above and behind the subject's ear to at least partially support the accessory.

[0044] In one embodiment, the hook is configured to extend laterally from the earpiece such that the lead can wrap around the subject's ear above and behind.

[0045] In one embodiment, the system includes a lead extending from the earpiece, the lead including a connection configured to electrically connect the electrode to the signal generator.

[0046] In one embodiment, the lead is configured to extend laterally from the earpiece such that it can wrap around the subject's ear above and behind.

[0047] In one embodiment, the lead is configured to extend from the distal end of one of the arms.

[0048] In one embodiment, the lead includes a sheath that extends at least partially along the length of the lead, and wherein the sheath defines a hook shaped to surround above and behind the subject's ear.

[0049] In one embodiment, one of the arms is configured to be positioned within the user's auricle.

[0050] In one embodiment, the arm is pivotally connected about a central portion.

[0051] In one embodiment, the distal ends of the arms are biased together using a biasing mechanism.

[0052] In one embodiment, the biasing mechanism includes at least one of the following: a pivot; a spring; a rubber component; an extendable component that interconnects the arms; at least a portion of the extendable arms; at least a portion of the elastic component that interconnects the arms; at least a portion of the elastic arms; and a magnet, etc., provided on the arms.

[0053] In one embodiment, the proximal outer surface of the arm includes a recess configured to allow a subject to engage the arm and bias the arm apart.

[0054] In one embodiment, the arm has at least one of the following: a length, which is at least one of the following: 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 about 22 mm; and a width, which 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; and about 11 mm.

[0055] In one embodiment, the electrode is: substantially circular; rounded rectangle; rounded square; at least partially dome-shaped; and has 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.

[0056] In one embodiment, a surface of the electrode is at least one of the following: roughened; includes trenches; includes ridges; and coated.

[0057] In one embodiment, the surface of the electrode is coated with at least one of the following: an inert metal; and gold.

[0058] In one embodiment, the treatment signal is a signal having a frequency having at least one of the following: less than 20 kHz; less than 10 kHz; less than 1 Hz; 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.

[0059] In one embodiment, the treatment signal is a signal having a pulse width of at least one of the following: 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.

[0060] In one embodiment, the treatment signal is a signal having a voltage of at least one of the following: less than 50V; less than 25V; less than 10V; less than 5V; less than 2V; less than 1V; greater than 0.1V; greater than 0.2V; greater than 0.5V; and greater than 1V.

[0061] In one embodiment, the treatment signal is a current signal having at least one of the following: less than 50 mA; greater than 0.1 mA; and between 0.1 mA and 36 mA.

[0062] In one embodiment, the treatment signal is at least one of the following: symmetrical; asymmetrical; monophasic; biphasic; triphasic; multiphasic; and includes multiple phases having at least one scattered dwell time.

[0063] In one embodiment, each therapeutic signal is applied to the respective electrode.

[0064] In one embodiment, the respective treatment signals are at least one of the following: in-phase; and out-of-phase.

[0065] In one embodiment, the lead includes at least one of the following: a respective conductor for each electrode; at least one insulating layer; and a braided shield.

[0066] In one embodiment, the treatment signal is configured to perform at least one of the following: stimulating the activity of the vagus nerve; and inhibiting the activity of the vagus nerve.

[0067] In one embodiment, the signal generator is mounted on the earpiece.

[0068] In one embodiment, the system includes a control system with a housing containing at least one of the following: the signal generator; a power supply; and a controller.

[0069] In one embodiment, a lead extends from the earpiece to the housing.

[0070] In one embodiment, the system includes a controller configured to control the signal generator.

[0071] In one embodiment, the controller is configured to: determine treatment signal parameters; and control the signal generator according to the treatment signal parameters.

[0072] In one embodiment, the controller is configured to determine the treatment signal parameter based on at least one of the following: a defined treatment signal parameter stored in memory; a user input command; biofeedback; a signal from a sensor; and a selected treatment mode.

[0073] In one embodiment, the system includes a sensor configured to sense at least one subject parameter, and in another embodiment, the controller is configured to: determine at least one subject parameter using a signal from the sensor; and cause the signal generator to generate a treatment signal based on the at least one subject parameter.

[0074] In one embodiment, the sensor is at least one of the following: proximity to at least one electrode mounted on the earpiece; and electrically coupled to at least one of the electrodes.

[0075] 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 an impedance sensor.

[0076] In one embodiment, the at least one subject parameter includes at least one of the following: presence, absence, or concentration of inflammatory biomarkers; temperature; blood oxygen content; heart rate; heart rate variability; impedance; and skin current response.

[0077] In one embodiment, the controller is configured to: determine feedback using user input commands; and cause the signal generator to generate the treatment signal based on the feedback.

[0078] In one embodiment, the controller is configured to: cause the signal generator to generate a therapeutic signal with a progressively increasing amplitude; and select the amplitude of the therapeutic signal in response to a user input command.

[0079] In one embodiment, the controller is configured to progressively increase the treatment signal in steps of at least one of the following: 0.1mA; 0.2mA; 0.5mA; 0.8mA; 1mA; 1.5mA; and 2mA.

[0080] In one embodiment, the controller is configured to: determine the selection of a treatment mode based on a user input command; and control the signal generator according to the selected mode.

[0081] In one embodiment, the system includes several treatment modes stored in a storage device, each treatment mode defining a sequence of treatment signals, wherein the controller is configured to cause the signal generator to generate the sequence of treatment signals.

[0082] In one embodiment, in a study mode, the controller is configured to: select the amplitude of a treatment signal in response to a user input command; and gradually reduce the amplitude of the treatment signal to zero.

[0083] In one embodiment, the present invention seeks to provide a neuromodulation method for treating a disease, the method comprising: placing an electrode close to a subject; and using a signal generator electrically connected to the electrode to generate at least one therapeutic signal applied to a nerve via the electrode to modulate the nerve thereon, and in one embodiment, the at least one therapeutic signal comprising at least one sequence of waveforms of different types.

[0084] It will be understood that the broad forms of the invention and their respective features can be used in combination and / or independently, and references to the separate broad forms are not intended to be limiting. Furthermore, it will be understood that features of the method can be performed using a system or apparatus, and features of a system or apparatus can be implemented using the method. Attached Figure Description

[0085] Various examples and embodiments of the invention will now be described with reference to the accompanying drawings, in which: Figure 1A This is a schematic plan view of an example of the vagus nerve modulation system; Figure 1B yes Figure 1A A schematic side view of the neural modulation system; Figure 1C In use Figure 1A A schematic plan view of the earpiece; Figure 1D In use Figure 1A A schematic side view of the earpiece; Figure 2 It is used for Figure 1A A schematic diagram of an example of a control system for a neural modulation system; Figure 3 This is a flowchart of an instance of a neural modulation procedure; Figure 4A This is a schematic side view of a specific example of a stethoscope used in a vagus nerve modulation system; Figure 4B yes Figure 4A A schematic plan view of the earpiece; Figure 4C yes Figure 4B A schematic perspective view of the earpiece; Figure 4D yes Figure 4A A schematic front view of the earpiece; Figure 4E yes Figure 4A A schematic rear view of the earpiece; Figure 4F yes Figure 4A A schematic close-up view of the earpiece's pivot; Figure 4G In use Figure 4A A schematic plan view of the earpiece; Figure 5A This is a schematic perspective view of an example of a control system; Figure 5B yes Figure 5A A schematic side view of the control system; Figure 5C yes Figure 5A A schematic plan view of the control system; Figure 6 This is a schematic diagram of a second example of a control system used in a neural modulation system; Figure 7 This is a flowchart of a specific instance of a neural modulation procedure; Figure 8 This is a schematic diagram of a neural modulation system; Figure 9 This is a flowchart of an instance of a neural modulation procedure; Figure 10 The results illustrate an example of a neural modulation system and program; and Figures 11A to 11AE This is a schematic diagram of the signal waveform in a case study. Detailed Implementation

[0086] Reference Figure 8 Describe an example of a neural modulation system 800.

[0087] In this example, a neuromodulation system 800 is used to treat a disease. The system 800 includes electrodes 821, 822 configured to be attached to a subject, and a signal generator 830 electrically connected to the electrodes 821, 822, for example, via respective connections 831, 832. The signal generator 830 is configured to generate at least one therapeutic signal applied to the subject via the electrodes 821, 822 to modulate nerves thereon.

[0088] Therefore, in use, the system is configured to attach to a subject for nerve modulation. Therapeutic signals applied to electrodes 821, 822 are thus applied to the nerve, resulting in an electric field around the nerve. This field can induce or inhibit action potentials, thereby causing nerve modulation. The signal is typically applied to the subject at a location near the surface of the subject where a portion of the nerve (such as the vagus nerve) is located, thereby maximizing the modulation. Example locations for nerve modulation include the ear, tragus, cymba conchae, wrist, back, and neck for the vagus nerve, median nerve, radial nerve, or other target nerves. In one example, a location for vagus nerve modulation may include the tragus and / or neck, and a location for the median or radial nerve may include the wrist, and these locations may be used simultaneously.

[0089] At least one therapeutic signal comprises at least one sequence of waveforms of different types. The nature of the different waveforms will vary depending on the implementation and type of modulation to be performed, and this example will be described in more detail below. It should be understood that different waveforms can be configured to provide different modulation effects, and therefore the use of sequences of different waveforms can enhance the effectiveness of modulation and allow for more effective labeling of different conditions.

[0090] Therefore, therapeutic signals consisting of a sequence of waveforms of various types are applied to the nerves of a subject to modulate the nerves and the subject's parameters, which can then be used to treat diseases such as cardiovascular disease and / or autonomic dysfunction.

[0091] The configuration described above helps maximize neural supplementation and / or modified parasympathetic activation while minimizing side effects such as discomfort or burns. Additionally, this configuration increases the "memory effect" of treatment and helps maintain safety and effectiveness. The "memory effect" can be described as the length of time after treatment has ceased to be experienced. A longer memory effect allows for shorter treatment durations or extended time intervals between treatment phases. In one example, treatment may be triggered for one minute, followed by a rest interval. The rest interval can range from one minute to 18 hours, typically 30 minutes. In this regard, by optimizing the effectiveness of signal application, this ensures proper modulation, thereby avoiding over- or under-activation of subject parameters that could lead to adverse outcomes.

[0092] Therefore, the above configuration provides a neuromodulation system that can be used to modulate nerves and treat cardiovascular diseases and / or autonomic dysfunction, which is comfortable and easy to use over extended periods of time, thereby allowing users to more easily take advantage of the benefits of neuromodulation while avoiding risks, safety and effectiveness issues, such as burns and / or unsafe or ineffective levels of electrical delivery.

[0093] Reference Figure 9 Describe an example of a program used to perform neural modulation.

[0094] In use, in step 900, electrodes 821 and 822 are placed close to the subject. A signal generator 830 is electrically connected to electrodes 821 and 822. In step 910, a therapeutic signal is generated using the signal generator 830, which is applied to the subject's nerves via electrodes 821 and 822. Therefore, the nerves are modulated by the therapeutic signal in step 920.

[0095] Several further features will now be described.

[0096] In one example, a sequence of different types of waveforms comprises a single, repeating sequence of different types of waveforms. In this example, the sequence could be a sequence of rectangular waveforms followed by ramp waveforms, with this particular sequence repeated. In another example, a sequence of different types of waveforms comprises multiple different sequences of waveforms, wherein different sequences of different types of waveforms are applied. Alternatively or additionally, the sequence could be multiple repeating different sequences of waveforms, wherein different sequences of different types of waveforms are repeatedly applied.

[0097] In one instance, sequences of different types of waveforms can be selected and / or adjusted, such as selecting specific waveforms to use and the order in which these waveforms are applied. Selection and / or adjustment can be performed in any suitable manner and can be based on at least one of a disease (such as a cardiovascular disease being treated, a voluntary dysfunction being treated), responsiveness to treatment, biofeedback, and / or user input. Thus, for example, an initial sequence of waveforms can be selected to treat a specific disease, and the sequence can then be adjusted, for example, by changing one or more waveforms based on biofeedback and / or user input, depending on how effective the modulation has proven.

[0098] In one example, the waveform type includes at least one of the following: rectangular pulse waveform; triangular pulse waveform; spike waveform; sine waveform; ramp waveform; exponential ramp waveform; exponentially decaying waveform; burst waveform; arbitrary waveform; pre-modulated waveform; linear waveform; increasing or decreasing ζ-wave; increasing or decreasing sawtooth waveform; DC waveform; damped sine waveform; double S-shaped waveform; composite waveform; pulse waveform; square waveform; random noise waveform; custom waveform; differential waveform. The example waveform will be described in more detail below, and it should be understood that a range of different waveforms may be used.

[0099] In one instance, the treatment signal is triggered by at least one of the following: user input, sensor input, electrical signal, bioelectrical signal, subject movement, audio signal, vibration, and the subject's physiological state (including respiratory cycle).

[0100] In one instance, the treatment signal is at least one of the following: symmetrical, asymmetrical, monophasic, biphasic, triphasic, and multiphasic. The treatment signal may also include multiple phases with scattered dwell times.

[0101] In one instance, the sequence of different types of waveforms includes at least the time intervals between the different types of waveforms. In one instance, the time intervals are variable or fixed and can be any suitable time, such as 0µs, 0µs to 200,000µs, 200µs to 2,000µs, or 100µs to 500µs. Furthermore, different time intervals can vary between different waveforms in the sequence; for example, the time interval between the first and second waveforms may be greater than or less than the time interval between the second and third waveforms. In one instance, the time intervals are selected and / or adjusted based on at least one of factors such as the cardiovascular disease being treated, the autonomic dysfunction being treated, responsiveness to treatment, biofeedback, and / or user input. In instances where the time intervals are adjusted based on biofeedback, the time intervals can be algorithmically adjusted to mimic, synchronize with, or complement physiological patterns, such as cardiac and respiratory cycles.

[0102] In one instance, a sequence of waveforms of different types is repeated, with a dwell time between each repetition. In one instance, the dwell time is at least one of the following: variable, fixed, and 0µs, 1µs to 10000µs; 10000µs to 10000000µs, or about 50000µs. In one instance, the dwell time is selected and / or adjusted based on at least one of the following conditions: cardiovascular disease being treated, voluntary dysfunction being treated, responsiveness to treatment, biofeedback, and / or user input. In instances where the dwell time is adjusted based on biofeedback, the dwell time can be algorithmically adjusted to mimic, synchronize, or complement physiological patterns, such as cardiac and respiratory cycles. In one instance, the dwell time is randomly determined, which has the benefit of preventing or minimizing neural habituation and / or prolonging and increasing therapeutic benefits.

[0103] In one instance, the amplitudes of different types of waveforms are variable and / or fixed. In one instance, the amplitudes are selected and / or adjusted based on at least one of the following: the cardiovascular disease being treated, the autonomic dysfunction being treated, responsiveness to treatment, biofeedback, and / or user input. In one instance, the amplitudes of waveforms in a sequence of different types of waveforms are controlled relative to each other. The relative amplitudes are variable and / or fixed. In one instance, the relative amplitudes are selected and adjusted based on at least one of the following: the cardiovascular disease being treated, the autonomic dysfunction being treated, responsiveness to treatment, biofeedback, and / or user input. For example, the first waveform in the sequence may have a lower amplitude than the second waveform, which may then have a larger amplitude than the third waveform. This can be used to provide greater control over modulation, for example, activating the nerve before applying modulation, or using trailing modulation to increase the effect of modulation. These relative amplitudes may initially be selected based on the disease being treated and then adjusted based on biofeedback to optimize the amplitudes for both the disease being treated and the subject.

[0104] In one instance, the duration of each waveform in the waveform sequence is at least one of variable or fixed, and may have suitable durations, such as 1 µs to 20,000 µs, or 200 µs to 500 µs. In one instance, the duration may depend on factors affecting overall charge delivery and tolerance, such as amplitude and frequency. In one instance, the duration is selected and / or adjusted based on at least one of the following conditions: the cardiovascular disease being treated, the autonomous functioning being treated, responsiveness to treatment, biofeedback, and / or user input. In one instance, the durations of waveforms in a sequence of different types of waveforms are relative to each other, and such relative durations may be variable and / or fixed. Again, relative durations may be selected and adjusted based on at least one of the following conditions: the cardiovascular disease being treated, the autonomous functioning being treated, responsiveness to treatment, biofeedback, and / or user input. For example, the first waveform in the sequence may have a shorter duration than the second waveform, which in turn may have a longer duration than the third waveform. These durations can initially be selected based on the disease being treated, and then adjusted based on biofeedback to optimize the treatment of the disease and the magnitude of the subject.

[0105] In one instance, the sequence of waveforms of different types includes a first waveform followed by a second waveform. In one instance, the first waveform has a duration longer than the second waveform, the first waveform has a duration shorter than the second waveform, the first waveform has the same duration as the second waveform, the first waveform has an amplitude greater than the second waveform, the first waveform has an amplitude less than the second waveform, and / or the first waveform has the same amplitude as the second waveform.

[0106] In one example, the sequence of different waveform types includes rectangular pulse waveforms and exponential ramp waveforms. In another example, the sequence of different waveform types includes rectangular pulse waveforms, spike waveforms, and exponentially decaying waveforms at a first threshold.

[0107] In one example, the rectangular pulse waveform is a pre-pulse at a primary threshold, where the secondary threshold is a percentage of the threshold. In one example, the threshold is the limit at which a larger percentage of nerve fibers or parenchyma are excited. The primary threshold is the amplitude below the threshold; specifically, the primary threshold can be an amplitude greater than 0% and less than 100% of the threshold. In one example, the primary threshold is 60% of the threshold. In one example, the rectangular pulse waveform at the primary threshold is used as a pre-pulse for depolarizing nerve fibers. The sequence includes a pre-pulse at the primary threshold, the purpose of which is to depolarize nerve fibers such that the nerve and / or fiber are modulated with a primary threshold current to inactivate voltage-dependent sodium channels and increase the excitation threshold of a particular fiber. This can also facilitate the selection of nerve fibers after the pre-pulse. The primary threshold pre-pulse can facilitate the selective activation or selection of specific nerve fibers. This may have limitations, including the potential for nerve habituation. To address this, the secondary threshold waveform can be randomly selected or delivered, such as selectively randomized or adaptively randomized. This allows for the prevention or minimization of neural habituation and the prolongation of therapeutic effects, also known as the "memory effect," in which the therapeutic benefits are experienced for a longer period. In one instance, parasympathetic activation can have a longer duration after signal delivery.

[0108] In one example, a neural modulation system is configured to stimulate a nerve and thereby modulate at least one of the following: the presence, absence, or concentration of an inflammatory biomarker; an electrocardiographic biomarker; temperature; blood oxygen saturation; heart rate; heart rate variability; impedance; and skin current response. In this example, it will be understood that sensing these parameters and how they respond to modulation can then be used to provide biofeedback and thereby control the modulation procedure, thereby refining the modulation to make it more effective.

[0109] In one instance, the disease includes at least one of the following: cardiovascular disease; chronic fatigue; prolonged COVID; rheumatoid arthritis; autonomic nervous system dysfunction; autonomic nervous system dysfunction; mental health disorder; inflammatory disease; autoimmune disease; cognitive impairment; post-viral syndrome, including prolonged COVID; pain disorder; stress (including acute and chronic stress); post-traumatic stress disorder; systemic lupus erythematosus; diabetes; and cancer. Additionally, cardiovascular disease includes at least one of the following: cardiovascular disease with inflammatory manifestations; coronary artery disease; cerebrovascular disease; peripheral artery disease; rheumatic heart disease; congenital heart disease; ischemic heart disease; arrhythmia; atrial fibrillation; hypertension; acute heart failure; heart failure with reduced ejection fraction; heart failure with mildly reduced ejection fraction; heart failure with maintained ejection fraction; diastolic dysfunction; postural orthostatic tachycardia syndrome; myocardial infarction; and stroke.

[0110] In one instance, the system enhances at least one of the following: accompanying treatment delivery; cognition; memory; mobility; physical performance; recovery after physical activity; sleep quality; and divergent thinking.

[0111] In one instance, the nerve is at least one of the following: the vagus nerve, the central nervous system, and a peripheral nerve. In one instance, the vagus nerve includes at least one of the following: the auricular branch, the cervical branch, and the afferent branch of the vagus nerve. In one instance, the peripheral nerve includes at least one of the following: the median nerve and the radial nerve.

[0112] In one instance, the signal generator modulates a nerve, including modulating at least one target of the nerve. In one instance, the nerve target or nerve target includes the auricular branch of the nerve, a specific nerve fiber, efferent fiber, afferent fiber, A-α (Aα) fiber, A-β (Aβ) fiber, A-δ (Aδ) fiber, B fiber including myelinated B fiber, and C fiber.

[0113] In one instance, the electrodes may have any non-invasive form configured to attach to the proximal end of a nerve in a subject. In one instance, the electrodes are configured to attach to the subject in the form of at least one of the following: clips, collars, wristbands, headbands, earpieces, auricular attachments, fabric attachments, handheld attachments, ankle straps, rings, wearable items, wearable jewelry, and collar ornaments. These can be used to pinpoint specific areas of the vagus nerve where external modulation applied to the subject's skin can be more effectively modulated. In one instance, the attachment is at least one of the following: directly attached to the subject, indirectly attached to the subject, in direct contact with the subject's skin, and indirect contact with the subject's skin.

[0114] In one instance, the electrodes are configured to be attached to the subject's ear via an accessory. The accessory includes a shell that is biased against the ear and close to the subject's target nerve localization.

[0115] Reference Figures 1A to 1D Describe an example of the vagus nerve modulation system.

[0116] In this example, the neuromodulation system 100 includes a handset 110 having opposing arms 111, 112, wherein electrodes 121, 122 are positioned on opposing surfaces near the distal ends of the arms, the opposing surfaces being biased toward each other. In this example, the arms are pivotally connected via a connecting hinge 113, while providing resilient components, such as springs, rubber stops, or the like, configured to bias the distal ends of the arms toward each other. However, other configurations may be used, as will be described in more detail below. Therefore, in this respect, it will be understood that the term handset is intended to cover any configuration in which spaced arms that can be biased together at their distal ends are provided, and the example configurations described herein are not intended to be limiting.

[0117] Signal generator 130 is electrically connected, for example, to electrodes 121, 122 via respective connections 131, 132, wherein signal generator 130 is configured to generate at least one therapeutic signal that can be applied to a subject via electrodes 121, 122.

[0118] In use, the earpiece is configured to attach to the subject's tragus, and the following reference is provided. Figure 1C and Figure 1D An example describing this.

[0119] In this example, the subject's ear 100 is shown, which includes a tragus 101, a lower crura 102, a superior crura 103, a helix 104, a scaphoid 105, an antihelix 106, a concha 107, an antitragus 108, and an earlobe 109. As shown, the earpiece 110 is positioned such that the tragus 101 is positioned between electrodes 121 and 122, wherein electrodes 121 and 122 are advanced to engage with the opposite surfaces of arms 111 and 112 by means of the bias of arms 111 and 112.

[0120] Due to this configuration, the therapeutic signals applied to electrodes 121 and 122 are applied to the tragus, which in turn causes an electric field to be generated around the vagus nerve within the tragus 101. This field can generate or inhibit action potentials within the tragus, thereby causing modulation of the vagus nerve.

[0121] Therefore, in use, the aforementioned neuromodulation system operates to stimulate the vagus nerve within the tragus using a receiver 110 attached to the tragus 101 of the subject. The receiver includes electrodes 121 and 122 positioned relative to each other via bias arms 111 and 112, allowing the tragus 101 to be positioned between the electrodes, wherein the electrodes 121 and 122 are advanced to engage with the tragus 101. In this manner, the electrodes 121 and 122 clamp the tragus, which helps ensure good electrical contact with the tragus 101, thereby maximizing the effectiveness of vagus nerve modulation. Furthermore, clamping the tragus with the electrodes also helps to secure the receiver in the appropriate position, allowing for extended receiver wear time, thereby ensuring that the stimulation signal is successfully applied to the vagus nerve throughout the stimulation phase.

[0122] The configuration of the electrodes on opposite arms also results in the electrodes being provided at substantially parallel intervals, with the electrodes on either side of the tragus. This configuration allows for an increase in electrode surface area, which, combined with substantially parallel positioning, maximizes the electric field generated at the electrode / tissue interface for a given current density.

[0123] Therefore, the above configuration helps ensure that the applied therapeutic signal produces a therapeutic effect while avoiding current densities that could cause discomfort to the subject, such as burns. Furthermore, this configuration helps maintain safety and effectiveness. In this respect, by optimizing the effectiveness of signal application, this ensures that the correct stimulation is achieved, thereby avoiding excessive or insufficient stimulation that could lead to adverse outcomes such as bradycardia.

[0124] Furthermore, in one example, the above configuration allows the earpiece 110 to be at least partially positioned within the concha 107, which provides several benefits. For example, this positioning of the guiding earpiece 110 ensures that the electrodes are correctly positioned relative to the tragus and vagus nerve, thereby ensuring effective modulation of the nerves. Additionally, this configuration reduces the extent to which the earpiece protrudes outward from the ear, making the earpiece inconspicuous and comfortable to wear. For example, this allows the earpiece to be worn when the user is lying on their side, while also reducing the risk of earpiece dislocation, which could subsequently affect the stimulation procedure.

[0125] Therefore, the above configuration provides a non-invasive vagus nerve stimulation system that can be used to modulate vagus nerve and / or modify parasympathetic nerve activation, but is comfortable and easy to use over extended periods, thereby allowing users to more easily take advantage of the benefits of vagus nerve stimulation while avoiding risks, safety and effectiveness issues such as burns and / or unsafe or ineffective levels of electrical delivery.

[0126] Several further features will now be described.

[0127] In one example, the system includes hooks extending above and behind the subject's ear to at least partially support the earpiece. The hooks can have any suitable form, but are typically made of at least partially elastic material that maintains its shape while providing comfortable wear. The hooks can be attached to any part of the earpiece, but in one example, they are configured to extend laterally from the earpiece so that the hooks can wrap around above and behind the subject's ear. The hooks help distribute the weight of the earpiece across the ear, so that the weight is not supported solely by the tragus. Additionally, this provides an auxiliary attachment mechanism, thereby helping to reduce the likelihood of earpiece dislocation and, in the event of dislocation, preventing the earpiece from falling to the ground, thus helping to reduce the probability of damage to the earpiece. Furthermore, this also helps guide the correct positioning of the earpiece, thereby ensuring that the electrodes are aligned with the vagus nerve, and thus optimizing the effect of the applied therapeutic signal.

[0128] In one example, the system includes a lead extending from the earpiece, wherein the lead includes a connection configured to electrically connect electrodes to a signal generator. This allows the signal generator to be disposed at the distal end of the earpiece and connected thereto via the connection. This can reduce the weight of the earpiece, although this is not critical and alternative embodiments are available, as will be described in more detail below.

[0129] In one particular instance, the lead wire may be configured to extend laterally from the earpiece, allowing it to wrap around the subject's ear above and behind it, thereby enabling the lead wire to help secure the earpiece in place. It will be understood that in this example, the lead wire can be used to provide the hook functionality outlined above, thereby helping to reduce weight load on the tragus and minimize the possibility and adverse effects of earpiece dislocation.

[0130] In one example, the lead wire can be configured to extend from the distal end of the outer arm. This helps to secure the earpiece in place while leaving the proximal end of the arm unobstructed, which facilitates application of the earpiece to the tragus. Additionally, this further aligns the lead wire with the tragus and guides it to extend more easily behind the helix, resulting in a more comfortable earpiece fit and helping to ensure proper earpiece positioning.

[0131] In one particular example, the lead includes a sheath that extends at least partially along the lead, wherein the sheath defines a hook shape to wrap around the subject above and behind the ear. In this example, the sheath may have greater elasticity than the unsheathed portion of the lead, which helps maintain the shape of the lead in the area of ​​the ear while allowing the lead to remain flexible freely in other areas, thus making this use easier. This also helps protect the lead where it engages with the earpiece and, for example, reduces the probability of forces causing the lead to decouple from the earpiece or damage the electrical connection between the earpiece and the lead.

[0132] As mentioned above, in one instance, at least one of the arms, specifically the inner arm 111, is positioned within the user's concha. This allows the earpiece to hold the tragus while maintaining it in a substantially natural position, thus ensuring comfortable earpiece wear. It also reduces the extent to which the earpiece extends outward from the ear, thereby reducing the likelihood of impact and dislocation, and making the earpiece comfortable to wear when the ear rests on a pillow or other surface, making the configuration particularly suitable for long-term use. Furthermore, this helps guide the correct positioning of the earpiece, ensuring that the electrodes are correctly positioned on the tragus and thus aligned with the vagus nerve, thereby optimizing the effect of the applied therapeutic signal.

[0133] In one example, the arms are pivotally connected about the middle section, although this is not critical and other configurations can be used. For example, the arms may be made of or interconnected from a stretchable material, allowing the arms to be deformed into desired shapes such that the distal ends of the arms are biased to engage with the tragus.

[0134] The handset also typically includes a biasing mechanism to bias the distal end of the arm into engagement. The nature of the biasing mechanism may vary depending on a preferred embodiment and may include the use of a spring or rubber component positioned between the arms. Biasing may be achieved using an extendable component interconnected with the arm or at least a portion of the extendable arm, or at least a partially resilient component interconnected with the arm or at least a portion of the resilient arm.

[0135] In a further example, biasing can be achieved using magnets provided in the arm. For example, magnets of opposite polarity can be provided in the distal end of the arm to attract the distal ends of the arm together. It will be understood that this configuration generates a magnetic field around the tragus, which can be used to amplify or modulate the applied therapeutic signal, thereby improving safety and / or effectiveness. Alternatively, magnets of the same polarity can be provided in the proximal end of the arm to promote proximal separation.

[0136] In a preferred embodiment, the arms are pivotally connected and, where appropriate, biased around a central portion, allowing the proximal ends of the arms to be biased together to advance the distal ends and thus separate the electrodes, thereby facilitating the application of the earpiece. This configuration also ensures that the arms are approximately parallel when positioned between the arms, which helps in electrode positioning and ensures maximum surface contact between the electrodes and the tragus, thereby reducing the current density required to achieve effective stimulation and thus improving effectiveness and reducing burns.

[0137] In one instance, to further facilitate this procedure, the proximal outer surface of the arm includes a recess configured to guide the subject's positioning such that the subject can engage the arm and deflect the arm apart, for example, by grasping the proximal end of the arm between the thumb and forefinger.

[0138] In one example, the arm has a length greater than 15mm, greater than 16mm, greater than 17mm, greater than 18mm, greater than 19mm, greater than 20mm, greater than 21mm, less than 30mm, less than 28mm, less than 27mm, less than 26mm, less than 25mm, less than 24mm, less than 23mm, and more typically about 22mm. Similarly, the arm typically has a width greater than 5mm, greater than 6mm, greater than 7mm, greater than 8mm, greater than 9mm, greater than 10mm, less than 16mm, less than 15mm, less than 14mm, less than 13mm, less than 12mm, and more typically about 11mm. These dimensions make the arm easy to manipulate while allowing the earpiece to be positioned within the concha, thus ensuring comfortable earpiece wear.

[0139] Additionally, the arms, as defined above, provide a sufficiently large surface area to accommodate the electrodes. In this regard, the electrodes are typically substantially circular, although rounded rectangles or rounded squares may be used. The electrodes may also be at least partially dome-shaped, which helps ensure good electrical contact between the electrodes and the tragus, regardless of the relative angle of the arm. Furthermore, the use of dome-shaped and substantially circular electrodes ensures that they do not contain any sharp edges that could cause discomfort.

[0140] Typically, 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 more typically about 8 mm. These dimensions provide a surface area that allows for the application of a sufficiently large current to induce a field that effectively stimulates the vagus nerve without causing excessive charge or current density on the surface of the tragus (which could subsequently cause discomfort or burns and / or result in ineffective treatment). The electrode also serves as the contact surface with the tragus, and including a sufficiently large electrode surface area helps ensure that the earpiece is effectively coupled to the tragus and remains in the proper position, even under external forces.

[0141] Additionally and / or alternatively, the electrode surface may be roughened, or may include grooves or ridges. The use of roughened or contoured electrode surfaces can first increase friction between the electrode and the tragus, which in turn helps maintain the position of the earpiece. Additionally, roughening the electrode surface or including grooves or ridges on the electrode surface can help ensure good electrical contact between the electrode and the tragus. For example, this can help minimize damage caused by uneven surfaces, such as bumps or similar features on the tragus. A further benefit is that surface roughness results in an increase in the overall surface area of ​​the electrode, which in turn helps reduce the current density required to generate a given field within the tragus, thus helping to ensure effectiveness while avoiding excessive current density that could lead to burns.

[0142] In one instance, the electrode may be coated, for example, to improve conductivity, increase surface friction, and ensure biocompatibility. Any form of conductive coating may be used, and in one instance, the electrode is formed from a copper electrode coated with an inert metal (such as gold or other similar highly conductive material).

[0143] The signal generator is typically configured to generate a therapeutic signal having a frequency having at least one of the following: less than 20 kHz, less than 10 kHz, less than 1 Hz, 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 more typically about 50 Hz. The therapeutic signal typically has a pulse width that is 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 more typically about 50 µs. Therapeutic signals typically have a voltage that is less than 50V, less than 25V, less than 10V, less than 5V, less than 2V, less than 1V, greater than 0.1V, greater than 0.2V, greater than 0.5V, and more usually greater than 1V. Therapeutic signals typically have a current amplitude that is less than 50mA, greater than 1mA, greater than 0.1mA, and between 0.1mA and 36mA.

[0144] The therapeutic signal can be symmetrical, asymmetrical, monophasic, or biphasic. In this regard, the use of a symmetrical biphasic signal can help reduce charge buildup on the surface of the tragus, thereby maximizing the electric field generated within the tragus by the applied therapeutic signal, while preventing charge buildup to levels that could cause discomfort. This, in turn, helps optimize vagal nerve stimulation. However, depending on the intended application, asymmetrical and / or monophasic therapeutic signals may be used in some situations. Additionally and / or alternatively, triphasic or more broadly, polyphasic signals may be used. In one instance, an asymmetrical triphasic signal may be used in conjunction with a negative pulse having a smaller amplitude and duration than the intermediate positive pulse, which can help reduce charge buildup. The signal may also include multiple phases with intermediate dwell times, allowing the charge to remain in place for a short duration before being discharged.

[0145] Therapeutic signals are typically configured to perform at least one of the following: stimulate or inhibit activity within the vagus nerve, and it will be understood that the signal parameters used, such as voltage, current, frequency, and waveform, may be selected depending on the intended application and the desired effect on the vagus nerve.

[0146] In one instance, one of electrodes 121 and 122 serves as ground, with the therapeutic signal applied via the other electrode. However, this is not critical, and in one instance, the therapeutic signal may be applied to each of the electrodes. The therapeutic signal may be in phase and more typically out of phase to maximize the overall field gradient across the vagus nerve, which in turn helps generate action potentials within the nerve. Additionally, this helps minimize the amplitude of the current applied via each electrode to generate a given electric field, which in turn helps reduce discomfort while ensuring the system remains clinically effective.

[0147] Generally speaking, when using leads, the leads consist of individual conductors for each electrode, wherein the conductors are contained within an insulating layer and, where applicable, surrounded by a braided shield. This helps ensure electrical isolation between connections while providing robust and lightweight connection leads.

[0148] In one instance, the system typically includes a control system with a housing containing a signal generator and other associated electronics, such as a power supply and / or a controller. The controller is configured to control the signal generator, thereby allowing the generation of a series of different desired therapeutic signals. The controller can take any suitable form but typically includes one or more electronic processing devices, such as microprocessors, microchip processors, logic gate configurations, firmware associated with the implemented logic (such as an FPGA (Field Programmable Gate Array)), or any other electronic device, system, or configuration. For ease of illustration, the remaining description will generally refer to the controller formed by the processing devices, but it will be understood that multiple processing devices may be used, with processing distributed among the devices as needed, and references to the singular cover plural configurations and vice versa.

[0149] In one example, leads extend from the earpiece to the housing so that therapeutic signals generated by the signal generator can be applied to the electrodes. However, as previously discussed, this is not critical, and in alternative embodiments, the signal generator may be mounted on the earpiece. In this example, the controller may be integrated into the housing forming part of the earpiece, or alternatively, the controller may communicate with the signal generator via a wireless connection, thereby allowing the signal generator to be remotely controlled using a suitable device (such as a smartphone or other user terminal device), which then functions as the controller.

[0150] In one example, the controller is configured to determine treatment signal parameters and control a signal generator based on these parameters. The treatment signal parameters can be determined in any of a variety of ways, including retrieving defined treatment signal parameters stored in memory, based on signals from sensors, based on biofeedback, based on user input commands, and / or a selected treatment mode. For example, several different operating modes can be defined, where the user selects a treatment mode depending on the application being used, and the controller retrieves treatment signal parameters depending on the selected mode. This allows the system to be used according to the user's requirements to achieve a range of different results, such as stimulation and / or inhibition of the vagus nerve. Furthermore, this allows the controller to determine feedback, for example, using signals from sensors, and adjust the treatment signal based on the feedback, so that the treatment signal can be optimized for the subject and, specifically, the subject's response to the signal.

[0151] In one example, the system includes a sensor configured to sense at least one subject parameter. The sensor may have any suitable form depending on the preferred embodiment and may include any one or more of the following: 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 at least partially formed of electrodes. For example, a heart rate sensor may utilize a voltage sensor coupled to the electrodes to detect electrical signals (such as electrocardiogram (ECG) signals), while an impedance sensor may include a voltage sensor coupled to the electrodes to measure the voltage across a target of a current signal applied by a source-free signal generator. Alternatively, separate sensors may be used, with their proximity to the electrodes mounted on the earpiece. For example, a pulse oximeter typically includes an infrared sensor, such as a photodiode and an infrared light-emitting diode (LED), in which case the LED may be positioned on one arm, with the photodiode on the other arm to detect infrared radiation transmitted through the tragus. In one example, the electrodes may be transparent electrodes made of indium tin oxide (ITO) or other similar materials, with the LED and photodiode positioned behind the electrodes.

[0152] Regardless of the sensors used, the controller can be configured to determine at least one subject parameter using signals from the sensors and cause a signal generator to generate a treatment signal based on the at least one subject parameter. Thus, for example, the controller can determine subject parameters (such as the presence, absence, or concentration of inflammatory biomarkers, temperature, blood oxygen saturation, heart rate, heart rate variability, impedance or skin current response, arrhythmia) and use this as biofeedback to aid in the effectiveness of the applied treatment. This can then be used to adjust the applied treatment signal, for example, by increasing the amplitude of the treatment signal or changing the frequency of the treatment signal to optimize the treatment signal for the responsiveness of the respective subject. In this regard, it will be understood that the manner in which the signal can be adjusted can be defined in memory and may include a scaled signal based on the measured subject parameters.

[0153] In another example, the controller can be configured to use user input commands to determine feedback and cause a signal generator to produce a therapeutic signal based on the feedback. Thus, the user can indicate via input whether they perceive any improvement, such as a reduction in anxiety or stress, where this input is used to adjust the applied therapeutic signal.

[0154] In one example, the controller is configured to cause a signal generator to produce a therapeutic signal with progressively increasing amplitude, and then select the amplitude of the therapeutic signal in response to a user input command. This can be used to progressively increase the amplitude of the therapeutic signal current until the subject notices it, where this level is then used to select the desired therapeutic signal amplitude. This can be used to maximize the amplitude of the therapeutic signal while preventing it from causing discomfort to the user. In one example, the therapeutic signal increases from 1 mA to a maximum value of 36 mA in 1 mA increments, although other amplitudes such as 0.1 mA, 0.2 mA, 0.5 mA, 1.5 mA, 2 mA, or similar can be used.

[0155] In another example, the controller may be configured to determine the selection of a mode based on a user-input command, and then control the signal generator according to the selected mode. In this regard, the system typically includes several treatment modes stored in a memory, each defining a sequence of treatment signals that can be customized to, for example, provide different interventions for treating different diseases or similar conditions. Therefore, depending on a preferred embodiment, the selected mode can be used to control the nature of the treatment signals and can be used to stimulate or inhibit the vagus nerve, or to switch between symmetrical, asymmetrical, monophasic, and / or biphasic signals. In this example, the controller is configured to cause the signal generator to produce a sequence of treatment signals, thereby applying the selected intervention.

[0156] In another instance, a research paradigm can be provided to investigate the effectiveness of vagus nerve stimulation. In this regard, the research paradigm typically operates by selecting the amplitude of the therapeutic signal, as described above, and then progressively reducing the amplitude to zero, thereby effectively applying zero stimulation while still allowing subjects to continue calibration to ensure they believe stimulation is occurring. This allows for the assessment of the placebo effect and allows the use of a zero-stimulation procedure as a control in experiments evaluating the effectiveness of the stimulation protocol.

[0157] While the system can be used to treat a wide range of different diseases, the neurostimulation system is particularly well-suited for treating heart failure or atrial fibrillation.

[0158] Reference Figure 2 A specific instance that describes the functionality of the controller.

[0159] In this example, the control system 250 includes a signal generator 230, a controller 251, a memory 252, and input / output devices 253 (such as input buttons and a display) interconnected via a bus 255. The signal generator 230 is connected to electrodes 221 and 222 via leads 240 containing first connections and second connections 231 and 232.

[0160] An external interface 254 may also be provided, which can be a wired or wireless interface, such as Wi-Fi, Bluetooth, or another short-range wireless communication interface. The external interface 254 can be used to allow external devices (such as computer systems, smartphones, or tablets) to interface with the control system, for example, to allow updates to treatment signal parameters or operating modes, or to allow remote control of the control system. Additionally and / or alternatively, the external interface 254 may be connected to a sensor 223 (such as a pulse oximeter or the like). In one example, the sensor 223 may be integrated into the earpiece 110, in which case the connection to the sensor may be integrated into the lead wire 240. It will also be appreciated that in other examples, a signal sensor (such as a voltage sensor (not shown)) may be connected to electrodes 221, 222, thereby allowing the sensing of signals within the body, such as ECG or impedance signals.

[0161] In use, the controller 251 executes instructions in the form of application software stored in the memory 252 to allow the execution of the required program, and specifically, to allow the control signal generator 230 to generate a treatment signal, which is then applied to the electrodes 221, 222.

[0162] Application software may include one or more software modules and may execute in a suitable execution environment, such as an operating system environment or the like. The controller may be a microprocessor, microchip processor, logic gate configuration, firmware associated with the implementation logic (such as an FPGA (Field Programmable Gate Array)) or any other electronic device, system or configuration.

[0163] The memory 252 will also typically store information required to generate the treatment signal (such as details of the treatment signal parameters, operating mode, or the like), as well as instructions for interpreting any feedback (such as signals from sensor 223 or user input commands), thereby allowing this feedback to be used to control the generation of the treatment signal.

[0164] Reference Figure 3 Describe an example of a program used to perform neural modulation.

[0165] In this example, the earpiece is attached to the tragus in step 300. Typically, this involves biasing arms 111, 112 apart by applying pressure between the thumb and forefinger to the proximal ends of each arm. The tragus is then positioned between the distal ends of arms 111, 112 before the earpiece is released, thereby allowing electrodes 121, 122 to be advanced into contact with the tragus, as... Figure 1D It is displayed in the middle.

[0166] Next, in step 310, the amplitude of the therapeutic signal is calibrated. This procedure typically involves generating the therapeutic signal at an increased amplitude until it is perceptible to the user. In this example, the user can indicate when the signal is perceived and / or becomes uncomfortable, where this is used to set the maximum amplitude of the therapeutic signal.

[0167] Following this, in step 320, stimulation is performed by applying a therapeutic signal. In this regard, the controller 251 typically retrieves therapeutic signal parameters from memory as needed, based on the operating mode and / or user input commands, and uses these to control the signal generator 230 to generate the desired therapeutic signal.

[0168] Reference Figures 4A to 4G A more detailed description of specific instances of neural modulation systems.

[0169] In this example, the neuromodulation system includes a receiver 410 having a first arm 411 and a second arm 412. The first arm 411 and the second arm 412 are interconnected via a pivot mount 413, which is formed by spaced parallel upright members 413.1 and 413.2 extending upward from the inner surfaces of each of the first arm 411 and the second arm 412. A pin is provided to extend through the upright members to allow pivotal movement of the arms, and a spring 413.3 is mounted on the pin to deflect the distal ends of the arms together.

[0170] Grooves 411.1 and 412.1 are provided on the outer surface of the proximal end of each of the first arm 411 and the second arm 412, wherein groove 412.1 is configured to align with the user's thumb and forefinger, such that applying pressure between the thumb and forefinger deflects the distal ends of 411.1 and 412.1 apart.

[0171] Electrodes 421 and 422 are disposed on the inner surfaces of the distal ends of 411.1 and 412.1. The electrodes are circular and dome-shaped, such that when the tragus is positioned between electrodes 421 and 422, electrodes 421 and 422 can contact the surface of the tragus. In this respect, the upright members 413.1 and 413.2 are generally sized based on the approximate thickness of the tragus, such that when the earpiece is positioned on the tragus, arms 411 and 412, and therefore electrodes, are substantially parallel.

[0172] A lead 440 is provided, comprising a lead body 441 and a sheath 442 extending partially along the distal end of the lead body 441. Specifically, the sheath 442 is formed by a covered molding area extending from the distal end of the outer arm 412 and has a hook shape, thereby allowing it to be positioned behind the ear, as... Figure 4GAs shown in the image. The covered molding section is typically about 100 mm long and is stretchable, allowing it to be shaped to fit the user's ear. As previously described, this helps support the earpiece 410, thereby preventing excessive strain from being applied to the tragus and preventing the earpiece 410 from falling out if it becomes dislodged.

[0173] exist Figures 5A to 5C The image shows a specific example of the external dimensions of the control system.

[0174] In this example, the control system includes a body 561, input buttons 562, and a display 563. In this example, four input buttons 562 are provided, including a power button 562.1, a mode button 562.2, and up and down buttons 562.3 and 562.4, allowing the user to select different modes and indicating when the desired stimulation current has been reached. The display can be of any form and may include an LED or LCD display or the like. These can be used to display operational information, such as details of the selected operating mode, treatment signal parameters, information about the current therapy phase (such as duration), or the like.

[0175] The housing typically includes a connector socket that receives a plug 543 attached to a lead 441 extending to a handset 410, as previously described. The plug and socket can be of any form, and in one system, are USB or other similar connectors.

[0176] It will become clear that, in one instance, the internal components of a control system are typically similar to Figure 2 The components shown in the image. References will follow. Figure 6 Describe alternative instances of internal component configurations.

[0177] In this example, the control system 650 includes a remote device 650.1, which includes a controller 651, a memory 652, an input / output device 653, and an external interface 654 interconnected via a bus 655. In this example, a second external interface 656 is provided, providing short-range wireless connectivity (such as Bluetooth™ or similar) to provide connectivity to an on-earpiece device 650.2 mounted on the earpiece 410. In this example, the second control system portion 650.2 includes an interface system-on-a-chip (SoC) 657 coupled to a power supply 658 and a signal generator 650. The signal generator is again connected to electrodes 621 and 622 via respective connections 651 and 652.

[0178] This configuration allows control signals to be provided from the remote device 650.1 to the handset-mounted device 650.2 and thus the signal generator 650, enabling remote control of the signal generator. In one example, the remote device 650.1 may have a similar... Figures 5A to 5CThe form shown in the diagram. However, it will be understood that since the remote device only needs to generate control signals, this can be achieved using any suitable processing system and can be executed using a user-end device (such as a tablet computer, smartphone, or similar).

[0179] Further examples of stimulation procedures will now be described.

[0180] In this example, in step 700, the earpiece 410 is attached to the tragus by having the user separate their arms, positioning the arms on both sides of the tragus, and releasing the arms, as previously described.

[0181] In step 710, the user uses the mode input button 522.2 to select an operating mode, thereby allowing the controller 251 to retrieve from the memory 252 the treatment signal parameters defined in step 720 for the respective selected operating mode. The treatment signal parameters are used to control the waveform of the generated treatment signal and include parameters such as pulse waveform shape, pulse duration, signal amplitude, signal frequency, or similar parameters.

[0182] Specific examples of neural modulation methods for treating cardiovascular diseases using waveform sequences will now be described.

[0183] In this example, a neuromodulation system and method for treating or preventing cardiovascular disease are provided. The neurostimulation system non-invasively applies therapeutic signals via a pair of electrodes and calibrates the auricular branch of the vagus nerve in the subject. Treatment may include auricular vagus nerve neuromodulation therapy (AVNT), in which the auricular branch of the vagus nerve is modulated and / or simulated. In one example, AVNT can be used to treat heart rate variability. The therapeutic signals comprise sequences of different types of waveforms in this order of pre-pulse and exponential ramp. It should be understood that the system and method provided herein can also treat autonomic dysfunction.

[0184] In one instance, a pre-pulse is applied to a depolarizing nerve fiber (which may be a vagus nerve fiber), and a subsequent waveform is calibrated to initiate efferent B fibers, thereby initiating efferent vagal nerve communication in the brainstem and thereby stimulating and / or modulating the efferent B fibers of the vagus nerve.

[0185] Current scientific evidence indicates that heart rate variability (HRV) is a robust, non-invasive, and quantifiable marker of autonomic nervous activity. The fluctuations observed in HRV originate from the homeostatic regulation between two branches of the autonomic nervous system: the sympathetic and parasympathetic components, whose separate interactions directly affect cardiac automaticity. Parasympathetic effects are mediated via the vagus nerve and the neurotransmitter acetylcholine, while sympathetic effects are mediated by adrenaline and noradrenaline. Clearly, autonomic dysfunction plays a crucial role in the presentation of cardiovascular disease. For example, abnormalities in autonomic input reflected by changes in the HRV index are associated with a higher risk of heart failure, atrial fibrillation, and coronary artery disease. The advent of non-invasive techniques for HRV testing provides clinicians with an excellent opportunity to examine autonomic tone in greater detail and is a useful complement to cardiovascular disease management and existing treatments.

[0186] refer to Figure 10 This demonstrates the results of the above configuration. In this example, a heart failure patient was positioned at rest and their resting HRV was measured. Specifically, their isohigh frequency (HF) and low frequency (LF) parameters were measured, where HF indicates parasympathetic activity and LF is associated with sympathetic activity. The patient then participated in the above configuration for approximately 5 minutes of treatment / therapy. In this example, a sequence of treatment signals consisting of a rectangular waveform used as a pre-pulse followed by an exponential ramp waveform was used. The time interval between the pre-pulse rectangular waveform and the exponential ramp waveform was 1000 µs, and the sequence dwell time was 50,000 µs. At the end of the treatment, HRV (both HF and LF) was recorded. It should be further noted that the LF / HF ratio is a low-frequency to high-frequency ratio, and a lower ratio indicates better autonomic balance / tonality and cardiac function.

[0187] As described above, the device can deliver or receive neural modulation signals including at least one of the following: electrical signals; sound signals; ultrasound signals; and optical signals. In one example, the sound signal includes PPG signals that can be applied to or generated from the subject's ears, head, chest, and / or limbs.

[0188] Neural modulation signals can include different types of waveforms. In one example, the signal includes a sequence of high-frequency pulses followed by low-frequency pulses. In one example, the HF frequency can be from 1 Hz to 1000 Hz, or between 5 Hz and 50 Hz, and the low frequency can be from 0.2 Hz to 100 Hz, or between 0.5 Hz and 5 Hz. Alternatively, the signal can have alternating waveforms to manage charge. In one example, alternating waveforms include alternating sequences, alternating polarities, alternating shapes, and alternating intensities. As described, alternation can help initiate action potentials with limited excess residual charge, thereby extending electrode material lifespan and reducing user discomfort. The above configuration can help maximize neural supplementation and / or modify parasympathetic activation while minimizing side effects such as discomfort or burns. In addition, the above configuration increases the "memory effect" of treatment, helping to maintain safety and effectiveness. In this regard, by optimizing the effectiveness of signal application, this ensures that correct stimulation is achieved, thereby avoiding overstimulation or understimulation that could lead to adverse outcomes.

[0189] Therefore, the above configuration provides a neurostimulation system that can be used to stimulate nerves and treat cardiovascular diseases and / or autonomic dysfunction, which is comfortable and easy to use over extended periods of time, thereby allowing users to more easily take advantage of the benefits of neurostimulation while avoiding risks, safety and effectiveness issues, such as burns and / or unsafe or ineffective levels of nerve stimulation.

[0190] Reference Figures 11A to 11R Provide a more detailed description of the example waveform.

[0191] exist Figure 11A and Figure 11B In the examples, the waveform is usually rectangular, where Figure 8 The signal A includes a ramp attenuation, which can result from the charge on the capacitor used to generate the pulse waveform. The waveform is typically biphasic, comprising both positive and negative components, and is symmetrical, so that the amplitudes of the positive and negative components are equal. This ensures that the surface of the tragus carries a neutral charge at the end of each pulse in the pulse sequence, helping to prevent charge buildup. This, in turn, can mask the electric field generated by the applied therapeutic signal and thus reduce signal and overall effectiveness. Furthermore, charge buildup can increase the risk of thermal burns or other discomfort.

[0192] You will learn that different shapes can be used, however, as Figure 11C and Figure 11D The diagrams show a gradual increase in signal amplitude in both rectangular pulse and sinusoidal waveforms. The use of this type of gradually increasing waveform helps avoid sudden application of current to the subject, thus preventing some of the discomfort associated with electrical stimulation.

[0193] exist Figure 11E and Figure 11F The following example waveform is shown. In this example, the signal is again biphasic, but asymmetrical, meaning that the amplitude of the waveform is not equal in the positive and negative phases. In this example, this could lead to the generation of a net charge in the subject. However, this can be mitigated by including unequal durations in the positive and negative phases of the waveform, thereby ensuring equal discharge and charge occur even though the signal amplitudes are different.

[0194] Figure 11G This demonstrates a three-phase waveform consisting of two negative pulses and an intermediate positive pulse. In this example, the sum of the negative phases equals the positive phase to minimize charge accumulation. Furthermore, the preceding negative phase introduces negative charge into the tissue before the positive phase is applied, allowing the positive phase to have a greater amplitude without the risk of thermal burns.

[0195] Figure 11H One configuration is shown in which a residence time in the form of an interphase gap is introduced between phases. This allows some charge to remain in place before being actively discharged, which can contribute to efficiency. This can also be implemented using single-phase pulses, such as... Figure 11I It is displayed in the middle.

[0196] Figure 11J The diagram illustrates an asymmetric biphase signal, where each pulse has a different waveform shape. Figure 11K Displays a sawtooth waveform. Figure 11L Draw a rectangular waveform with a slope, and Figure 11M The display is similar to Figure 11L A waveform with unequal durations in the positive and negative phases. Figure 11N Draw a biphasic rectangular waveform with exponential decay.

[0197] Figure 110 to Figure 11Q Draw diagrams with alternating polarities and / or shapes Figure 11N The sequence of waveforms shown in the image. Figure 11R This displays a sequence of high-frequency pulses followed by low-frequency pulses.

[0198] Figures 11S to 11AE Each waveform or a combination of waveform sequences is plotted.

[0199] As will be understood from the above, a wide range of different signal waveforms can be used, and the above is for illustrative purposes only and is not necessarily intended to be limiting.

[0200] Therefore, signals can include single-phase, single-phase, unidirectional pulses from the baseline to either positive or negative. This should not be confused with direct current (DC), where one electrode is always positive and the other is always negative, but pulsed single-phase waves have interruptions and use shorter pulse durations and lower intensities than DC. Therefore, single-phase waveforms do not cause the same magnitude of chemical changes as DC and are less likely to cause discomfort or thermal burns.

[0201] The signal can be biphase, consisting of two phases, one positive and one negative, causing the electrodes to change polarity. The phases can be symmetrical, causing identical phases to cancel each other out, or asymmetrical, where dissimilar phases are balanced with no net charge or unbalanced, thus generating a net charge.

[0202] Finally, and more broadly, multiphase signals, such as three-phase signals, can be used, having three or more phases in the cluster. Again, the phases can be symmetrical or asymmetrical, and can be separated by interphase gaps.

[0203] It will also be understood that the therapeutic signal parameters can vary throughout the stimulation sequence, for example, causing the amplitude, frequency and / or waveform to vary during a single stimulation phase, which can last for several minutes or up to or more than an hour.

[0204] Given the determined signal parameters, controller 251 uses the treatment signal parameters to generate a control signal, which is supplied to signal generator 230 to control signal generator 230 in step 730. Initially, this will cause signal generator 230 to generate a low-amplitude treatment signal, which is applied to the subject via electrodes 221, 222, thereby allowing the subject to assess whether they can perceive the signal and / or whether the signal causes discomfort.

[0205] If no response is detected in step 740, the current is increased in increments of 1mA in step 750, and the procedure is repeated until a response is detected (or until the threshold signal amplitude is reached), which is initiated by the user via one of the input buttons 562.

[0206] Once a response is detected (or a threshold amplitude is reached) in step 740, the therapeutic signal amplitude is set and the stimulation sequence is executed in step 760. As previously described, the stimulation sequence is typically defined by a selected operating mode and may involve applying a varying therapeutic signal over a period of time. One example is when the device is operating in study mode, in which case the stimulation signal gradually slopes down so that no significant active stimulation is applied during the stimulation working phase, thereby allowing this to be used as a control to assess the effectiveness of the stimulation sequence applied to other subjects.

[0207] Once stimulation has begun, the system may, as appropriate, monitor feedback in step 770 by, for example, by having controller 251 monitor signals from one or more sensors 223 and use this to determine a value or change in one of the subject's parameters, or by monitoring user input commands received via input button 562. In step 780, feedback may then be used to determine the effectiveness of the treatment signal and, if necessary, further modify the signal by, for example, by modifying treatment signal parameters to change amplitude, waveform shape, intensity, or the like. The procedure may then return to step 760, allowing the application of the modified treatment signal, repeating this procedure until treatment is complete. This allows the system to provide closed-loop control and thus become a closed-loop system.

[0208] In one instance, the system can also be used to treat autonomic dysfunction.

[0209] In another instance, the system was used to treat atrial fibrillation. A case study evaluating the effectiveness of the tVNS was conducted using the aforementioned configuration for non-invasive activation of the cholinergic anti-inflammatory pathway. In this study, compared to patients assigned to sham surgery, the median atrial fibrillation burden was reduced by 85% in patients assigned the device (median ratio, 0.15; 95% CI, 0.03 to 0.65; P = .011). The stimulated group also showed a significant alteration in the frequency domain index of heart rate variability (P = .003) and a 23% decrease in TNF-α (P = .0093) compared to the sham surgery group, thus confirming the effectiveness of the device.

[0210] Therefore, the above configuration provides a system suitable for performing non-invasive vagus nerve stimulation using a stethoscope configured to be positioned on the tragus of a subject.

[0211] The above configuration offers several benefits, such as avoiding the risk of nerve damage that may occur in the neck VNS, avoiding the risk of irritation of the carotid artery in the neck VNS and neck nVNS, avoiding the uncomfortable side effect of "lip pulling" in the neck nVNS, and avoiding the probability of thermal burns.

[0212] In one instance, the system employs electrodes arranged in a substantially parallel configuration to target nerve stimulation, thereby providing easier nerve activation by allowing for the generation of a larger overall electric field while avoiding excessive current density on the tissue surface.

[0213] Compared to several other non-invasive techniques, the current system operates by stimulating the vagus nerve in the tragus, specifically the inner and outer traguss, which contain longer vagus nerve fibers, thereby increasing the probability of generating action potentials within the nerve. This improves the effectiveness of stimulation while minimizing the amount of current required to achieve action potentials, thus avoiding undesirable electrical currents.

[0214] The above configuration uses an earpiece to advance the electrodes against the tissue surface. This allows for optimized pressure against the tragus to advance the electrodes, which helps overcome skin resistance without causing pain or skin penetration. Furthermore, this helps ensure consistent current delivery, ensuring consistent nerve stimulation, which is important for ensuring the effectiveness of some treatments.

[0215] The above configuration can use various therapeutic signal waveforms, which ensures optimal nerve stimulation and maximizes the generation of action potentials, while avoiding the need to apply signals that cause pain to the user.

[0216] In one instance, the system is configured to apply an asymmetric balanced biphasic square waveform, which is more tolerable to the user, has a lower probability of evoking a pain response, and can more effectively focus on specific nerve fibers. Additionally and / or alternatively, a symmetric balanced biphasic square waveform can be used to reduce charge buildup, thereby resulting in less skin irritation for the user.

[0217] In one instance, the aforementioned device can be used to record physiological measurements of biofeedback, such as heart rate, heart rate variability, skin current response, ECG, inflammatory biomarkers, or the like. This can be achieved by employing measurement devices at or around the electrode in skin contact.

[0218] This biofeedback can then be used to deliver optimal stimulation, where therapeutic signal parameters (such as stimulation intensity, waveform, and frequency) are adjusted in real time to achieve the best results in physiological and / or immune balance.

[0219] In one instance, with proper configuration, the above setup can overcome skin resistance while avoiding pain. The system can effectively pinpoint vagus nerve fibers and maintain the electric field around the target nerve fibers. The use of the stethoscope allows the electrodes to be held in place during use, ensuring stable pressure and consistent electrical contact between the skin and the electrodes, resulting in more stable contact impedance and thus, the applied current and the resulting stimulation.

[0220] In one example, the system employs a lead wire comprising a molded overlay having a soft plastic outer layer with a fine wire center layer for maintaining the shape of the ear. This section covers standard insulated cables containing an anode / cathode core that aids in load distribution and helps hold the earpiece in place, thereby allowing for more consistent application of the therapeutic signal.

[0221] It will be understood that the above method contrasts with traditional invasive VNS (vaginal nerve endings), which require surgical implantation by a physician and are irreversible. Specifically, the device can be non-invasively implanted without surgery and can be applied directly to the external skin. The device can be operated by the individual without physician assistance and can be applied or removed by the individual at any time without any additional risks.

[0222] Other non-invasive devices for locating the vagus nerve typically require manual holding in place to deliver the stimulus and use methods that cannot effectively penetrate the skin for stimulation.

[0223] Conversely, the current configuration is designed to attach to the ear to deliver effective stimulation, and in addition, the skin on both sides of the tragus is stimulated to deliver a more concentrated current to the target nerve.

[0224] Other devices typically require manual guidance to the appropriate stimulation site, while the system described above guides the electrode plates to a location where stimulation will be delivered to the skin directly above the vagus nerve innervation, while avoiding stimulation at sites very close to the carotid artery (which can lead to adverse results).

[0225] The above configuration avoids the high risk of skin irritation caused by the small surface area of ​​electrodes that generate higher relative current densities. In contrast, the above configuration uses a larger surface area of ​​electrodes, which disperses the current, thus resulting in a lower risk of skin irritation or thermal burns.

[0226] Throughout this specification and the claims below, unless the background context requires otherwise, the word "comprise" and variations such as "comprises" or "comprising" shall be construed as implying inclusion of the stated integers or groups of integers or steps but excluding any other integers or groups of integers. As used herein and unless otherwise stated, the term "about" means ±20%.

[0227] Those skilled in the art will understand and become aware of numerous variations and modifications. All such variations and modifications that will become apparent to those skilled in the art should be considered to fall within the broad spirit and scope of the invention as described above.

Claims

1. A neuromodulation system for treating diseases, the system comprising: a) Electrodes configured to be attached to the subject; and b) A signal generator electrically connected to the electrodes, the signal generator being configured to generate at least one therapeutic signal applied to the subject via the electrodes to modulate nerves, wherein the at least one therapeutic signal comprises at least one sequence of waveforms of different types.

2. The neural modulation system of claim 1, wherein at least one sequence of different types of waveforms comprises: a) A single repeating sequence of waveforms of different types; b) Multiple different sequences of waveforms; and c) Multiple repeating different sequences of waveforms.

3. The neural modulation system of claim 1 or 2, wherein at least one sequence of different types of waveforms is selected and / or adjusted based on at least one of the following: a) Cardiovascular disease currently under treatment; b) Active functional impairment currently under treatment; c) Responsiveness to treatment; d) Biofeedback; and e) User input.

4. The neural modulation system as described in any one of claims 1 to 3, wherein the waveform of this type includes at least one of the following: a) Rectangular pulse waveform; b) Triangular pulse waveform; c) Spike waveform; d) Sine wave; e) Slope waveform; f) Exponential ramp waveform; g) Exponentially decaying waveform; h) Burst waveform; i) Arbitrary waveform; j) Pre-modulated waveform; k) Linear waveform; l) An increasing or decreasing ζ waveform; m) Increasing or decreasing sawtooth waveform; n) DC waveform; o) Damped sinusoidal waveform; p) Double S-shaped waveform; q) Composite waveform; r) Pulse waveform; s) Square waveform; t) Random noise waveform; u) Custom waveform; v) Differential waveform; and w) rest.

5. The neuromodulation system as described in any one of claims 1 to 4, wherein the at least one therapeutic signal is triggered by at least one of the following: a) User input; b) Sensor input; c) Electrical signals; d) Bioelectrical signals; e) The subject's movement; f) Audio signals; g) Vibration; and h) The subject's physiological state.

6. The neuromodulation system according to any one of claims 1 to 5, wherein the at least one therapeutic signal is at least one of the following: a) Symmetrical; b) Asymmetrical; c) Single-phase; d) Biphasic; e) Three-phase; f) Multiphase; and g) includes multiple phases having at least one scattered dwell.

7. The neural modulation system according to any one of claims 1 to 6, wherein different types of waveform sequences include at least the time interval between different types of waveforms.

8. The neural modulation system of claim 7, wherein the time interval is at least one of the following: a) Variable; b) Fixed; c) 0µs; d) 0µs to 200,000µs; e) 200µs to 2000µs; f) 100µs to 500µs; g) Based on at least one of the following selections and / or adjustments: i) Cardiovascular disease currently under treatment; ii) Active dysfunction currently under treatment; iii) Responsiveness to treatment; iv) Biofeedback; and v) User input.

9. The neural modulation system according to any one of claims 1 to 8, wherein different types of waveform sequences are repeated, with a dwell time between each repetition.

10. The neural modulation system of claim 9, wherein the dwell time is at least one of the following: a) Variable; b) Fixed; c) 0µs; d) 1µs to 10000µs; e) 10000µs to 10000000µs; f) Approximately 50,000 µs; and g) Based on at least one of the following selections and / or adjustments: i) Cardiovascular disease currently under treatment; ii) Active dysfunction currently under treatment; iii) Responsiveness to treatment; iv) Biofeedback; and v) User input.

11. The neural modulation system according to any one of claims 1 to 10, wherein at least one of the following: a) The amplitude of at least one of the waveforms of this different type is at least one of the following: i) Variable; ii) Fixed; iii) Based on at least one of the following selections and / or adjustments: (1) Cardiovascular disease currently under treatment; (2) Undergoing treatment for autonomic dysfunction; (3) Responsiveness to treatment; (4) Biofeedback; and (5) User input; and b) The relative amplitude of the waveform in different types of waveform sequences is at least one of the following: i) Variable; ii) Fixed; iii) Based on at least one of the following selections and / or adjustments: (1) Cardiovascular disease currently under treatment; (2) Undergoing treatment for autonomic dysfunction; (3) Responsiveness to treatment; (4) Biofeedback; and (5) User input.

12. The neural modulation system according to any one of claims 1 to 11, wherein at least one of the following: a) The duration of each waveform in the waveform sequence is at least one of the following: i) Variable; ii) Fixed; iii) 1µs to 20000µs; iv) 200µs to 500µs; and v) Based on at least one of the following selections and / or adjustments: (1) Cardiovascular disease currently under treatment; (2) Undergoing treatment for autonomic dysfunction; (3) Responsiveness to treatment; (4) Biofeedback; and (5) User input; and b) The relative duration of the waveform in different types of waveform sequences is at least one of the following: i) Variable; ii) Fixed; iii) Based on at least one of the following selections and / or adjustments: (1) Cardiovascular disease currently under treatment; (2) Undergoing treatment for autonomic dysfunction; (3) Responsiveness to treatment; (4) Biofeedback; and (5) User input.

13. The neural modulation system according to any one of claims 1 to 12, wherein different types of waveform sequences include a first waveform followed by a second waveform.

14. The neural modulation system of claim 13, wherein at least one of the following: a) The first waveform has a longer duration than the second waveform; b) The first waveform has a shorter duration than the second waveform; c) The first waveform has the same duration as the second waveform; d) The first waveform has a greater amplitude than the second waveform; e) The first waveform has a smaller amplitude than the second waveform; and f) The first waveform has the same amplitude as the second waveform.

15. The neural modulation system according to any one of claims 1 to 14, wherein different types of waveform sequences include rectangular pulse waveforms and exponential ramp waveforms.

16. The neural modulation system according to any one of claims 1 to 15, wherein different types of waveform sequences include rectangular pulse waveforms, spike waveforms, and exponentially decaying waveforms at a first threshold.

17. The neural modulation system of claim 15 or 16, wherein the rectangular pulse waveform is a pre-pulse at a first threshold value, wherein the first threshold value is at least one of the following: a) Less than the critical limit; b) Greater than 0% of the threshold value and less than 100% of the threshold value; c) Between 50% and 70% of the critical limit; d) Approximately 60% of the critical limit; and e) Approximately 50% of the critical limit value.

18. The neuromodulation system according to any one of claims 1 to 17, wherein the neuromodulation system is configured to stimulate the nerve to modulate at least one of the following: a) The presence, absence, or concentration of inflammatory biomarkers; b) Electrocardiographic biomarkers; c) Temperature; d) Blood oxygen content; e) Heart rate; f) Heart rate variability; g) Impedance; and h) Skin current response.

19. The neuromodulation system as described in any one of claims 1 to 18, wherein the disease comprises at least one of the following: a) Cardiovascular disease, including at least one of the following: i) Cardiovascular diseases exhibiting inflammatory manifestations; ii) Coronary heart disease; iii) Cerebrovascular diseases; iv) Peripheral artery disease; v) Rheumatic heart disease; vi) Congenital heart disease; vii) Ischemic heart disease; viii) Cardiac arrhythmia; ix) Atrial fibrillation; x) Hypertension; xi) Heart failure with decreased ejection fraction; xii) Acute heart failure; xiii) Heart failure with a mild decrease in ejection fraction; xiv) Heart failure requiring sustained ejection fraction; xv) Diastolic dysfunction; xvi) Postural orthostatic tachycardia syndrome; xvii) Myocardial infarction; and (xviii) Stroke; b) Chronic fatigue; c) Long COVID; d) Rheumatoid arthritis; e) Autonomic nervous system dysfunction; f) Autonomic nervous system dysfunction; g) Mental health disorders; h) Inflammatory diseases; i) Autoimmune diseases; j) Cognitive impairment; k) Post-viral syndrome, including prolonged COVID; l) Pain disorders; m) Stress, including acute stress and chronic stress; n) Post-traumatic stress disorder; o) Systemic lupus erythematosus; p) Diabetes; and q) Cancer.

20. The neural modulation system according to any one of claims 1 to 19, wherein the system enhances at least one of the following: a) Delivery of accompanying treatments; b) Cognition; c) Memory; d) Action-oriented; e) Physical performance; f) Recovery after physical activity; g) Sleep quality; and h) Divergent thinking.

21. The neural modulation system according to any one of claims 1 to 20, wherein the nerve is at least one of the following: a) Cranial nerves, including at least one of cranial nerves I through XII; b) The vagus nerve, which includes at least one of the following: i) ear branch; ii) Cervical branch; iii) Outgoing branches; and iv) Incoming branches; c) Central nervous system; and d) Peripheral nerves, including at least one of the following: i) median nerve; and ii) Radial nerve.

22. The neural modulation system according to any one of claims 1 to 21, wherein the signal generator modulates the nerve, including modulating at least one target of the nerve.

23. The neural modulation system according to any one of claims 1 to 22, wherein at least one target of the nerve includes: a) The auricular branch of this nerve; b) The cervical branch of this nerve; c) The radial branch of this nerve; d) Specific nerve fibers; e) Outgoing fibers; f) Afferent fibers; g)A-α(Aα) fiber; h)A-β(Aβ) fiber; i) A-δ (Aδ) fiber; j) B fibers, which include at least myelinated B fibers; and k)C fiber.

24. The neuromodulation system of any one of claims 1 to 23, wherein the electrodes are configured to be attached to the subject in at least one of the following forms: a) Clip; b) Collar; c) Wristband; d) Headband; e) Handpiece; f) Auricular appendages; g) Fabric accessories; h) Handheld attachments; i) Ankle strap; j) Ring; k) Wearable components; l) Wearable jewelry is permitted; m) Collar ornaments; and n) Invasively.

25. The neuromodulation system of any one of claims 1 to 24, wherein the electrode is configured to be attached to the subject's ear via an accessory, wherein the accessory includes a shell biased against the ear and close to the subject's target nerve localization.

26. The neuromodulation system of claim 24 or 25, wherein the electrodes are configured to be attached to the tragus of the subject, and the accessory or earpiece includes: a) Opposite arms, configured such that the distal ends of the arms are offset toward each other; and b) The electrode, located near the distal end of the arm on the opposing surface, is advanced to engage with the opposing surface of the tragus.

27. The neuromodulation system of claim 24 or 25, wherein the system includes hooks extending above and behind the subject's ear to at least partially support the accessory.

28. The neuromodulation system of claim 27, wherein the hook is configured to extend laterally from the earpiece such that the lead can be wrapped around the subject's ear above and behind.

29. The neuromodulation system of any one of claims 24 to 28, wherein the system includes a lead extending from the earpiece, the lead including a connection configured to electrically connect the electrodes to the signal generator.

30. The neuromodulation system of claim 29, wherein the lead is configured to extend laterally from the earpiece such that the lead can wrap around the subject above and behind the ear.

31. The neural modulation system of claim 29 or 30, wherein the lead is configured to extend from the distal end of one of the arms.

32. The neuromodulation system of any one of claims 29 to 31, wherein the lead includes a sheath extending at least partially along the length of the lead, and wherein the sheath defines a hook shaped to surround above and behind the subject's ear.

33. The neuromodulation system as claimed in any one of claims 24 to 32, wherein one of the arms is configured to be positioned within the concha of the user's ear.

34. The neuromodulation system as claimed in any one of claims 24 to 33, wherein the arm is pivotally connected about a central portion.

35. The neuromodulation system as claimed in any one of claims 24 to 34, wherein the distal ends of the arms are biased together using a biasing mechanism.

36. The neural modulation system of claim 35, wherein the biasing mechanism comprises at least one of the following: a) Pivot; b) Spring; c) Rubber components; d) An extendable component that interconnects the arms; e) At least partially extendable arm; f) At least some of the elastic components that interconnect the arms; g) at least a partially flexible arm; and h) Magnets, etc., are provided on the arm.

37. The neuromodulation system of any one of claims 24 to 36, wherein the proximal outer surface of the arm includes a recess configured to allow a subject to engage the arm and to bias the arm apart.

38. The neural modulation system according to any one of claims 24 to 37, wherein the arm has at least one of the following: a) Length, which is at least one of the following: i) Greater than 15mm; ii) Greater than 16mm; iii) Greater than 17mm; iv) Greater than 18mm; v) greater than 19mm; vi) Greater than 20mm; vii) greater than 21 mm; viii) Less than 30mm; ix) less than 28mm; x) less than 27mm; xi) less than 26mm; xii) Less than 25mm; xiii) Less than 24mm; xiv) less than 23mm; and xv) approximately 22mm; and b) Width, which is at least one of the following: i) Greater than 5mm; ii) Greater than 6mm; iii) Greater than 7mm; iv) Greater than 8mm; v) greater than 9mm; vi) Greater than 10mm; vii) Less than 16mm; viii) Less than 15mm; ix) less than 14mm; x) less than 13mm; xi) less than 12mm; and xii) Approximately 11mm.

39. The neuromodulation system according to any one of claims 24 to 38, wherein the electrodes are: a) Essentially circular; b) Round the rectangle; c) Round out the square; d) At least partially dome-shaped; and e) Having at least one of the following diameters: i) Greater than 4mm; ii) Greater than 5mm; iii) Greater than 6mm; iv) Greater than 7mm; v) less than 12mm; vi) Less than 11mm; vii) Less than 10mm; viii) Less than 9mm; and (ix) Approximately 8mm.

40. The neuromodulation system according to any one of claims 24 to 39, wherein the surface of said electrode is at least one of the following: a) Roughened; b) Includes trenches; c) Includes the spine; and d) Coated.

41. The neuromodulation system according to any one of claims 24 to 40, wherein the surface of said electrodes is coated with at least one of the following: a) Inert metals; and b) Gold.

42. The neuromodulation system according to any one of claims 24 to 41, wherein the therapeutic signal is a signal having a frequency having at least one of the following: a) Less than 20kHz; b) Less than 10kHz; c) Less than 1Hz; d) Less than 500Hz; e) Less than 200Hz; f) Less than 150Hz; g) Less than 100Hz; h) less than 75Hz; i) Greater than 1Hz; j) greater than 2Hz; k) greater than 5Hz; l) Greater than 10Hz; (m) greater than 20Hz; n) Approximately 20Hz; and (o) Approximately 50Hz.

43. The neuromodulation system according to any one of claims 24 to 42, wherein the therapeutic signal is a signal having a pulse width having at least one of the following: a) Less than 5,000 µs; b) Less than 2,500 µs; c) Less than 1,000 µs; d) Less than 500µs; e) Less than 200µs; f) Less than 100µs; g) less than 75µs; h) greater than 1µs; i) greater than 2µs; j) greater than 5µs; k) greater than 10µs; l) greater than 20µs; and (m) Approximately 50µs.

44. The neuromodulation system according to any one of claims 24 to 43, wherein the therapeutic signal is a voltage having at least one of the following: a) Less than 50V; b) Less than 25V; c) Less than 10V; d) Less than 5V; e) Less than 2V; f) Less than 1V; g) greater than 0.1V; h) greater than 0.2V; i) greater than 0.5V; and j) is greater than 1V.

45. The neuromodulation system according to any one of claims 24 to 44, wherein the therapeutic signal is a signal of an electrical current having at least one of the following: a) Less than 50mA; b) Greater than 0.1 mA; and c) Between 0.1mA and 36mA.

46. ​​The neuromodulation system as claimed in any one of claims 24 to 45, wherein the therapeutic signal is at least one of the following: a) Symmetrical; b) Asymmetrical; c) Single-phase; d) Biphasic; e) Three-phase; f) Multiphase; and g) includes multiple phases having at least one scattered dwell.

47. The neuromodulation system according to any one of claims 24 to 46, wherein the respective therapeutic signals are applied to each of the electrodes.

48. The neuromodulation system of claim 47, wherein the respective therapeutic signal is at least one of the following: a) In phase; and b) Different phase.

49. The neuromodulation system according to any one of claims 24 to 48, wherein the lead comprises at least one of the following: a) For each electrode's respective conductor; b) at least one insulating layer; and c) Braided shielding components.

50. The neuromodulation system according to any one of claims 24 to 49, wherein the therapeutic signal is configured to perform at least one of the following: a) Stimulation of the vagus nerve; and b) Inhibit the activity of the vagus nerve.

51. The neural modulation system as claimed in any one of claims 24 to 50, wherein the signal generator is mounted on the earpiece.

52. The neuromodulation system of any one of claims 24 to 51, wherein the system includes a control system having a housing, the housing comprising at least one of the following: a) The signal generator; b) Power supply; and c) Controller.

53. The neuromodulation system of claim 52, wherein the lead extends from the earpiece to the housing.

54. The neural modulation system of any one of claims 24 to 53, wherein the system includes a controller configured to control the signal generator.

55. The neural modulation system of claim 54, wherein the controller is configured to: a) Determine the treatment signal parameters; and b) Control the signal generator according to the treatment signal parameters.

56. The neuromodulation system of claim 55, wherein the controller is configured to determine the therapeutic signal parameter based on at least one of the following: a) Defined treatment signal parameters stored in memory; b) User inputs commands; c) Biofeedback; d) Signals from sensors; and e) Select a treatment modality.

57. The neuromodulation system of any one of claims 54 to 56, wherein the system includes a sensor configured to sense at least one subject parameter and wherein the controller is configured to: a) Use the signal from the sensor to determine at least one subject parameter; and b) This causes the signal generator to generate a treatment signal based on the at least one subject parameter.

58. The neural modulation system of claim 57, wherein the sensor is at least one of the following: a) Nearly one electrode is mounted on the earpiece; and b) Electrically coupled to at least one of the electrodes.

59. The neural modulation system of claim 57 or 58, wherein the sensor is at least one of the following: a) Inflammatory biomarker sensor; b) Temperature sensor; c) Blood oxygen sensor; d) Pulse oximeter; e) Heart rate sensor; and f) Impedance sensor.

60. The neuromodulation system of any one of claims 57 to 59, wherein the at least one subject parameter includes at least one of the following: a) The presence, absence, or concentration of inflammatory biomarkers; b) Temperature; c) Blood oxygen content; d) Heart rate; e) Heart rate variability; f) Impedance; and g) Skin current response.

61. The neural modulation system of any one of claims 54 to 60, wherein the controller is configured to: a) Use user input commands to determine feedback; and b) This causes the signal generator to produce the treatment signal based on the feedback.

62. The neural modulation system of claim 54, wherein the controller is configured to: a) This causes the signal generator to produce a therapeutic signal with a progressively increasing amplitude; and b) Select the therapeutic signal amplitude in response to user input commands.

63. The neuromodulation system of claim 62, wherein the controller is configured to progressively increase the therapeutic signal in steps of at least one of the following: a) 0.1mA; b) 0.2mA; c) 0.5mA; d) 0.8mA; e)1mA; f) 1.5mA; and g)2mA.

64. The neural modulation system of any one of claims 54 to 63, wherein the controller is configured to: a) Determine the selected treatment mode based on the user's input command; and b) Control the signal generator according to the selected mode.

65. The neuromodulation system of claim 64, wherein the system includes a plurality of treatment modes stored in a storage memory, each treatment mode defining a sequence of treatment signals and wherein the controller is configured to cause the signal generator to generate the sequence of treatment signals.

66. The neural modulation system as described in any one of claims 54 to 65, wherein in the study mode, the controller is configured as follows: a) Responding to user input commands to select the amplitude of the treatment signal; and b) Gradually reduce the amplitude of the treatment signal to zero.

67. A method for treating a disease by modulating neural pathways, the method comprising: a) Position the electrodes close to the subject; and b) Using a signal generator electrically connected to the electrode to generate at least one therapeutic signal applied to the nerve via the electrode to modulate the nerve, wherein the at least one therapeutic signal comprises at least one sequence of waveforms of different types.

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