Neuromodulation devices and methods

Abstract

In some aspects, a neuromodulation system is provided that is configured to be placed within an ear in which a pressure applicator biases electrodes, e.g., in a direction toward the ear, to provide facilitated conductivity to achieve ear nerve stimulation. There is also provided, in some aspects, a neuromodulation system that can include: one or more sensors that measure data from one or more biomarkers of a physiological state of a user; and an optional controller that utilizes the measured data to adjust the one or more stimulation parameters.

Description

[0001] Citation of Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 380,225, filed Oct. 19, 2022, the entire contents of which are hereby incorporated by reference. Field of the Invention

[0003] The present disclosure relates to devices, methods, and / or systems for neuromodulation (such as, for example, non-invasive nerve stimulation) for treating various conditions. Summary of the Invention

[0004] There is a need for wearable systems with a compact, ergonomic form factor to enhance efficacy, compliance, and comfort when using these systems. In several embodiments, a neuromodulation system is provided that includes a headset and an electrical stimulation pulse generator, where the electrical stimulation pulse generator is configured to deliver a plurality of electrical stimulation pulses to the headset, and the headset is configured to be at least partially or fully placed in, on, or near the ear. The headset includes a body having a protective cover in some embodiments. In several embodiments, the protective cover includes a housing having a material for placement on a portion of the skin. In several embodiments, the protective cover is configured to be placed on a portion of the ear (including but not limited to the concha of the ear (e.g., concha cymba and / or concha cavum), helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, or antitragus, or a combination thereof); a first electrode and a second electrode extending from the protective cover; a first pressure applicator including a first spring-loaded actuation surface connected to the first electrode; and a second pressure applicator including a second spring-loaded actuation surface connected to the second electrode. The protective cover can be at least partially made of silicone and is designed to be placed at the entrance of the ear canal. In some embodiments, the first electrode and the second electrode are configured to deliver a plurality of electrical stimulation pulses to stimulate one or more nerves in or around the ear such as the auricular nerve (e.g., the auricular branch of the vagus nerve, the greater auricular nerve, and / or other nerves innervating the ear such as the ear canal, tragus, and / or auricle). In one embodiment, the first pressure applicator is configured to bias the first electrode in a first direction toward the ear by increasing a first pressure level at the first electrode against the ear to reduce a first impedance between the first electrode and the ear, and the second pressure applicator is configured to bias the second electrode in a second direction toward the ear by increasing a second pressure level at the second electrode against the ear to reduce a second impedance between the second electrode and the ear. In one embodiment, there is only one pressure applicator and one electrode. In some embodiments, one pressure applicator is used for a single electrode or multiple electrodes. When two or more electrodes are used, they can be used to stimulate the same or different nerves. The electrical stimulation pulse generator can be separate from the headset or integrated into the headset. In certain embodiments using pressure applicators, a sensor may or may not be included.

[0005] In some embodiments, a neuromodulation system includes one or more sensors that measure, for example, biomarkers. Such sensors can be on a headset or other wearable device (such as on the wrist or leg), coupled to a headset or other wearable device (such as on the wrist or leg), or communicate therewith without being attached to a headset or other wearable device (such as on the wrist or leg). The sensors can be integrated into a stimulator device, a skin patch, or a strip. One sensor can measure one biomarker, or one sensor can measure two or more biomarkers. The biomarkers can indicate a user's condition, such as migraine, colitis, irritable bowel disease, rheumatoid arthritis, hypertension, or atrial fibrillation. If the biomarker is above or below a desired level, at least one electrode is configured to deliver electrical stimulation to treat the condition (e.g., the symptoms of the condition or the condition itself). In one embodiment, the sensor can detect a too-low, too-high, or variant heart rate and, based on that feedback, based on user control, physician control, or automatically, provide nerve stimulation. The nerve stimulation can then treat the biomarker (e.g., the undesired heart rate) and / or treat the underlying condition (arrhythmia). In another embodiment, since the sensor can detect altered skin electricity or EEG activity as a biomarker and, based on the sensed information, provide nerve stimulation to treat migraines. In other embodiments, body temperature is used as a biomarker, and based on the sensor determining that the temperature is below or above a desired range, nerve stimulation is provided to treat a condition (including but not limited to colitis, inflammation, arrhythmia, migraine, or rheumatoid arthritis). Nerve stimulation can be provided based on sensor information, based on user control, physician control, or automatically. A closed-loop feedback loop can be used in some embodiments.

[0006] In some embodiments, the method provides multiple treatment paths that rely at least in part on sensing user biomarkers (e.g., heart rate, heart rate variability, heart rhythm, cutaneous sympathetic activity, electrodermal activity, body temperature measured at the wrist, respiratory cycle, electroencephalogram activity, cytokine levels, physical activity, oxygen level, etc.). In some embodiments, the biomarkers can include patient demographics, prior medication use, prior device treatment use, and / or sleep cycle. In some embodiments, additional data such as the weather or other information at the patient's local address (e.g., air temperature, humidity, barometric pressure, altitude, etc.) can be monitored to influence the stimulation and / or treatment. In one embodiment, physical activity can be measured with a motion sensor. In one embodiment, oxygen level can be measured with a pulse oximeter (e.g., via pulse oximetry). For example, in certain embodiments, the method can provide not only an acute relief path but also a symptom reduction and / or preventive treatment path, depending on the values of the sensed biomarkers. Preventive treatment can be one of the following: reducing the onset, frequency, duration, or severity of symptoms by at least 25 - 75% or more. As an example, through the nerve stimulation described herein, the severity or duration of symptoms can be significantly reduced compared to not using such nerve stimulation. For example, depending on the level of one or more sensed biomarkers, a wearable device can determine whether the user is likely currently experiencing the condition or will experience the condition, and then apply a peripheral nerve stimulation effective for the treatment path the user is actually experiencing at that time via the wearable system disclosed herein (e.g., a wrist-worn device, an ear-worn device, or any combination of a wrist-worn device and an ear device).

[0007] In some embodiments, the wearable systems disclosed herein deliver electrical stimulation in or around the ear (e.g., to the auricular branch of the vagus nerve and / or other nerves innervating the ear), while also sensing one or more biomarkers of the user to enhance the efficacy of the electrical stimulation. For example, in some embodiments, the wearable system is configured as a headset that includes electrodes, a controller, and at least one sensor. The sensors on the headset can be configured to sense the levels of one or more biomarkers and provide those levels to the controller to adjust the parameters of the electrical stimulation. Stimulating the vagus nerve in this manner can provide various therapeutic benefits, including the treatment of atrial fibrillation or other arrhythmias, colitis, rheumatoid arthritis, migraine, irritable bowel disease, hypertension, etc. The headset can be used in series with other neuromodulation devices (e.g., a neuromodulation device worn on the wrist) to further enhance the therapeutic benefits.

[0008] In some embodiments, the wearable systems disclosed herein are capable of determining a user's current respiratory phase and / or when a respiratory phase begins or ends. The ability to accurately determine the respiratory phase can be beneficial for the timing and efficacy of electrical stimulation. For example, improving the timing correspondence between the application of electrical stimulation and the user's current respiratory phase when performing respiratory-gated peripheral nerve stimulation can enhance therapeutic efficacy. In some embodiments, the wearable system includes a sensor that senses a quantitative value related to the user's respiratory state, and this quantitative value alone may not be sufficient to accurately determine the user's current respiratory phase and / or when a respiratory phase begins or ends. Some embodiments of the wearable systems disclosed herein include an algorithm that takes the sensed quantitative value and then determines various user parameters (e.g., respiratory threshold, sample inspection count, respiratory slope threshold, and / or lockout length) that indicate whether the user is inhaling or exhaling.

[0009] Various embodiments of devices, systems, and methods for delivering electro-neuromodulation (e.g., stimulation of one or more nerves) to a user are disclosed herein. In some embodiments, electrical stimulation is delivered to an area at or near the user's ear. In some embodiments, alternatively or in addition to delivering stimulation to an area at or near the ear, electrical stimulation is also delivered to an area at or near the user's wrist. For example, in certain embodiments, an ear device and / or a wrist-worn device that is at least partially secured within the ear canal applies electrical stimulation to the user. When electrical stimulation is applied to two locations, the stimulation modality parameters (e.g., frequency, phase, timing, amplitude, offset, etc.) can be complementary to enhance the efficacy of the treatment condition and / or the symptoms of the condition.

[0010] In one embodiment, electrical neuromodulation is delivered via electrodes (e.g., 1, 2, 3, 4, 5, or 6 electrodes). In several embodiments, the electrodes include a substrate material and a filling material. In one embodiment, the electrodes are dry electrodes. Dry electrodes can be advantageous in some embodiments because they provide a dry skin interface between the electrode and the user's skin without the need to adhere a hydrogel at the skin interface. The advantages of using dry electrodes are particularly evident for body-worn stimulation devices intended for long-term and repeated use. In one embodiment, the electrode material conforms to the body, is flexible, couples well with the body, and is biocompatible. In one embodiment, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine using peripheral nerve stimulation includes one or two treatment paths: (a) an acute relief path, and / or (b) a symptom reduction and / or prophylactic treatment path. In one embodiment, the treatment framework and each treatment path can be implemented by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an ear neuromodulation device, or any combination of a wrist-worn device and an ear device. In one embodiment, an algorithm for detecting the inspiratory and expiratory phases of respiration is used in conjunction with the electrical neuromodulation described herein. In some embodiments, unlike wet electrodes, dry electrodes provide a dry skin interface between the electrode and the user's skin without the need to adhere a hydrogel at the skin interface. According to some embodiments, the advantages of using dry electrodes are particularly evident for body-worn stimulation devices intended for long-term and repeated use. In some embodiments, the electrode material is flexible, which allows the skin interface of the dry electrode to remain in contact with the surface of the body (e.g., arm, wrist, leg, ear, etc.) during repeated use. The electrode material is also harmless to living tissue (e.g., biocompatible).

[0011] In various embodiments, inflammatory bowel diseases (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory diseases (such as neuroinflammation) are treated. Heart conditions (such as atrial fibrillation, hypertension, and stroke) are treated in various embodiments. In one embodiment, epilepsy and other seizure disorders are treated. Headaches (such as migraines) are treated in other embodiments. Inflammatory skin conditions and immune dysfunction can also be treated in certain embodiments. In several embodiments, cytokine signaling proteins that help control inflammation are affected (e.g., reduced or balanced) by stimulation.

[0012] In various embodiments, such neuromodulation can be beneficial for treating inflammation (such as neuroinflammation), movement disorders, cardiac disorders, pain, mental disorders, and other conditions. Some of the disclosed devices, systems, and methods can advantageously stimulate a user's vagus nerve (also referred to as the vagal nerve), while accommodating wide variations in ear anatomy and / or other characteristics among different users. In some embodiments, the placement and / or stimulation of the earpiece is provided at, near, or within one or more of the following locations in the concha cymba and / or in or around the ear: such as the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, antitragus, and cymba concha, or combinations thereof. In some embodiments, there are provided devices that provide stimulation (e.g., vagus nerve stimulation, e.g., via the concha (e.g., concha cymba and / or cymba concha)) and that can accommodate large variations in ear anatomy among individuals. Progressive increases or other alternations in the form of burst pattern stimulation are provided in several embodiments and can, for example, contribute to patient comfort, compliance, habituation, and / or efficacy. The terms "vagal" and "vagus nerve" can be used interchangeably herein.

[0013] In several embodiments, neuromodulation (such as nerve stimulation), as used herein, is used in place of pharmaceuticals and thus reduces undesirable pharmaceutical side effects. In other embodiments, neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to, for example, reduce the dose or duration of pharmaceutical treatment, thereby reducing undesirable side effects. Undesirable pharmaceutical side effects include, for example, addiction, tolerance, dependence, gastrointestinal ("GI") problems, nausea, confusion, movement disorders, appetite changes, and the like. In various embodiments, neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat epilepsy, depression, anxiety, inflammatory conditions such as inflammatory bowel disease (e.g., Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory conditions (e.g., neuroinflammation and inflammatory skin conditions) which are treated in several embodiments. Neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat cardiac conditions (e.g., atrial fibrillation, hypertension, and stroke), which are treated in various embodiments. Neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat headaches (e.g., migraines), which are treated in other embodiments. Neuromodulation can be delivered at the same time of day as the pharmaceutical is used. Alternatively, neuromodulation can be delivered at a different time of day than the pharmaceutical is used, and neuromodulation can also be delivered on a different date than the pharmaceutical is used. When used in conjunction with the nerve stimulation embodiments described herein, the pharmaceutical can be used at lower doses, for shorter durations, and / or with fewer side effects. For example, when used in conjunction with the nerve stimulation described herein, the pharmaceutical time course or dose can be reduced by 10 - 90% (e.g., 10 - 30%, 30 - 60%, 60 - 90%, and overlapping ranges therein). When used in conjunction with the nerve stimulation described herein, the patient can also tolerate the pharmaceutical or other treatment for a longer period of time because the side effects are reduced.

[0014] In some embodiments, the devices described herein (such as ear, leg, or wrist devices) employ a progressive stimulus burst mode. In some embodiments, the ear device employs a progressive stimulus burst mode while performing respiratory gating. In some embodiments, the system can deliver a burst of stimulus pulses at a particular frequency that depends on the respiratory cycle (e.g., theta bursts in the range of, for example, 4 - 8 Hz). In some embodiments, the ear device employs a progressive stimulus burst mode without respiratory gating. In some embodiments, the system can deliver a burst of stimulus pulses at a particular frequency that does not depend on the respiratory cycle (e.g., theta bursts in the range of, for example, 4 - 8 Hz). For example, in certain embodiments, the system can apply a progressively increasing stimulus intensity at the start of each burst of stimulus pulses. The progressive stimulus burst mode can enhance patient comfort for certain patients (e.g., in cases where gating or other stimuli might be uncomfortable and unexpected for the user). For example, when the pulses applied to the ear are turned on at full power, there may be no ramping period of intensity to mask the sensation of the stimulus to the ear. The progressive stimulus burst mode can include a lower stimulus intensity that progressively increases to a higher intensity during the burst to provide a ramping metric for the stimulus intensity.

[0015] In one embodiment, a method of determining a user's respiratory phase includes using a sensor to detect and measure respiration. This sensor produces some quantitative metric related to the user's respiratory state. In some embodiments, mechanical, electrical, impedance, acoustic (e.g., microphone), ultrasound, infrared, or video-based measurements are used to measure the respiratory state. The controller then receives this value from the sensor and applies an algorithm that uses various parameters to determine whether the person is inhaling or exhaling. In one embodiment, one such parameter used by the algorithm is the respiration threshold. This threshold is the minimum magnitude difference between two sample values obtained from the sensor. In one embodiment, a second potential type of parameter can be the sample check count. This sample check count is the minimum number of consecutive samples that need to be checked to account for whether the user has switched from one respiratory phase to another (e.g., from inhalation to exhalation). In one embodiment, a third potential type of parameter might be the respiration slope threshold. The respiration slope threshold is the minimum slope value assigned to the change from one respiratory phase to another (e.g., from inhalation to exhalation). In one embodiment, a fourth potential parameter can be the lockout length. The lockout length is the minimum amount of time the algorithm pauses. The algorithm can also include a genetic evolution algorithm, a machine learning algorithm, or some other algorithm based on artificial intelligence. In these cases, the algorithm might rely on as few as zero parameters to determine the user's respiratory phase.

[0016] In some embodiments, the gradual burst mode is generated by one or more hardware processors of the system, such as ear, leg, or wrist devices. In some embodiments, the system is capable of sensing an increase or decrease in one or more parameters sensed by one or more sensors selected from the following: photoplethysmography sensors (PPG), galvanic skin response sensors (GSR), inertial measurement unit sensors (IMU), temperature sensors (e.g., for body / skin temperature or ambient temperature), respiration sensors, and electroencephalography sensors (EEG), and combinations thereof. Based on the sensed increase or decrease, the system is capable of tuning the stimulation pulse burst to one or more parameters. In some embodiments, the system is capable of tuning or changing one, two, or more stimulation modality parameters (e.g., frequency, phase, timing, amplitude, offset, etc.) of the stimulation pulse burst accordingly. Such tuning can be achieved for any of the modalities described herein (e.g., epilepsy, depression, migraine, vagus nerve stimulation (VNS), etc.).

[0017] In some embodiments, a first portion of the ear device is at least partially secured within a user's ear canal, while a second portion coupled to the first portion is positioned adjacent to (e.g., adjacent to, within, or in contact with) the concha of the user's ear. In several embodiments, contact is made with the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, incisura intertragica, lobule, antitragus, cymba conchae, and / or concha of the ear, or combinations thereof. In some embodiments, the ear device includes a third portion having a stem and a boss. In some embodiments, the first portion includes an ear canal element, where the stem is slidably connected to the boss and rotatably connected to the ear canal element via the boss. In several embodiments, a progressive stimulation burst pattern is applied by a neuroeffector of the second portion (such as one, two, four, or six electrodes) and gently ramps up in intensity. The progressive stimulation burst pattern can ramp up in different ways. For example, in some embodiments, within multiple pulses of the progressive stimulation burst pattern, a lower stimulation intensity progressively increases to a higher intensity. In some embodiments, within an initial pulse of the progressive stimulation burst pattern, a lower stimulation intensity progressively increases to a higher intensity. In some embodiments, the stimulation can ramp up from 0.05 - 5.0 mA (e.g., 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 mA and overlapping ranges therein) in 0.1 - 30 seconds or longer (e.g., 0.1 - 0.5, 0.5 - 2, 2 - 5, 5 - 10, 10 - 15, 15 - 30 seconds and overlapping ranges therein), or the ramp up can increase by approximately 10 - 50%, 50 - 100%, or double or triple increments each time. The difference between increments can be constant or different. For example, the progressive increase or ramp up can be 0.1 mA to 0.2 mA to 0.3 mA to 0.4 mA to 0.8 mA to 1.0 A to 1.6 A to 3.2 A (higher if desired). Alternatively, the progressive increase or ramp up starts at 0.5 mA and continuously increases by 0.2 mA to reach a set point (such as 2.5 A). The ramp up can occur each time the stimulation is initially turned on or when the user increases the stimulation during a treatment session. The user can adjust the ramp up or have it automated by the system. In some embodiments, a ramp down is included. In some embodiments, the progressive increase or ramp up can also be used for non-burst stimulation (such as tonic stimulation).

[0018] In some embodiments, there is provided a method of neuromodulation for treating a condition and / or its symptoms or the use of the systems described herein. Conditions include, but are not limited to, rheumatoid arthritis, atrial fibrillation, and migraine. The method can include positioning a first electrode against the patient's skin near a first peripheral nerve, positioning a second electrode against the patient's skin near the first peripheral nerve or a second peripheral nerve, and sensing a level of a biomarker associated with the condition. If the sensed level indicates that the user is experiencing the condition, a first electrical stimulation is delivered via the first and second electrodes to provide acute relief treatment. If the sensed level indicates that the user is in an episode of the condition, a second electrical stimulation is delivered via the first and second electrodes to provide prophylactic treatment. The prophylactic treatment can be one of the following: reducing the onset, frequency, duration, or severity of future symptoms or the condition itself by at least 25 - 75% or more (e.g., 25, 40, 50, 70, 90%, etc.). The values of the stimulation modality parameters of the first electrical stimulation are different from the values of the stimulation modality parameters of the second electrical stimulation. The stimulation can be provided to nerves within and around the ear, arm (e.g., wrist), and leg (e.g., thigh, knee, and ankle). In one embodiment, the biomarker is heart rate, and if the sensed level indicates that the user is experiencing the condition, an electrical stimulation is delivered via the first electrode and / or the second electrode to provide relief treatment. In one embodiment, the biomarker is heart rate variability, and if the sensed level indicates that the user is in an episode of or suffering from rheumatoid arthritis, atrial fibrillation, or migraine, an electrical stimulation is delivered via the first electrode and / or the second electrode to provide treatment (such as prophylactic treatment) to reduce the onset, frequency, duration, or severity of the symptoms by at least 25 - 75% or more (e.g., 25, 40, 50, 70, 90%, etc.). At least one of the one or more targeted first nerves or one or more targeted second nerves is not common to both the one or more targeted first nerves and the one or more targeted second nerves. Additional sensors and / or electrodes can also be used.

[0019] In some embodiments, the stimulation modality parameter can be amplitude, and the value of the stimulation modality parameter of the first electrical stimulation can be lower than the value of the stimulation modality parameter of the second electrical stimulation. The stimulation modality parameter can be frequency. The stimulation modality parameter can be pulse width. The first and second electrodes can be disposed on a neuromodulation device. The neuromodulation device can be configured as a wrist-worn device. The first and second electrodes can be disposed on a neuromodulation device. The neuromodulation device can be configured to be worn in or near the ear. One of the first electrode (or first set of electrodes) and the second electrode (or second set of electrodes) can be configured to be disposed on the user's wrist, and the other of the first and second electrodes can be configured to be worn in or near another location (such as the ear, other wrist, or leg).

[0020] In some embodiments, sensing of the level of a biomarker can occur during the detection phase, and acute relief treatment and prophylactic treatment can occur during the treatment delivery phase and after the detection phase. Sensing of the level of the biomarker can be performed by one or more sensors, and the first electrode, the second (or third, fourth, or additional) electrode, and the one or more sensors can be integrated into a neuromodulation device. The detection phase can be performed by patient self-reporting of symptoms.

[0021] In some embodiments, the treatment delivery phase can be initiated by instructing the user to initiate delivery of a first electrical stimulation to provide acute relief treatment or a second electrical stimulation to provide prophylactic treatment. In one embodiment, the treatment delivery phase can automatically begin after the sensed level indicates that the user has, for example, rheumatoid arthritis, atrial fibrillation, or migraine, or that the user is in an episode of having rheumatoid arthritis, atrial fibrillation, or migraine. In one embodiment, the prophylactic treatment reduces the onset, frequency, duration, or severity of future symptoms by at least 25 - 75% or more (e.g., 25, 40, 50, 70, 90%, etc.).

[0022] In some embodiments, the measured biomarker can be at least one of heart rate, heart rate variability, heart rhythm, cutaneous sympathetic nerve activity, skin electrical activity, body temperature measured on the wrist or ear, respiratory cycle, electroencephalogram activity, and / or cytokine level. The biomarker can be measured by sensors located on the body (such as the ear, forehead, scalp or other parts of the head, wrist or other parts of the arm, ankle or other parts of the leg, chest, etc.). Machine learning algorithms can be used to evaluate when to initiate the treatment delivery phase based at least on the level of the sensed biomarker. The predetermined threshold for heart rate can be greater than 90, 100, 110, or 120 beats per minute, and when the sensed level exceeds the predetermined threshold, an acute relief treatment can be applied. In some embodiments, the method provides multiple treatment paths that at least partially rely on the sensing of the user's biomarkers (such as heart rate, heart rate variability, heart rhythm, cutaneous sympathetic nerve activity, skin electrical activity, body temperature measured on the wrist, respiratory cycle, electroencephalogram activity, cytokine level, physical activity, oxygen level, etc.). In some embodiments, the biomarker can include patient demographics, prior drug use, prior device treatment use, and / or sleep cycle. In some embodiments, additional data such as weather information (e.g., air temperature, humidity, air pressure, altitude) at the patient's local address can be monitored to affect the stimulation and / or treatment. In one embodiment, physical activity can be measured with a motion sensor. In one embodiment, oxygen level can be measured with a pulse oximeter (e.g., via pulse oximetry). Biomarkers are sensed immediately before, during, and / or immediately after the therapeutic stimulation. In another embodiment, biomarkers are sensed hours or days before or after the stimulation. For example, a blood test can be used to determine elevated biomarkers such as cytokines or other inflammatory compounds, and stimulation is applied as a treatment to reduce such biomarkers. In some embodiments, other body fluids are used to determine biomarkers, such as urine, saliva, sweat, tears, nasal secretions, etc. These can be measured using sensors that are separate from (e.g., independent of) or communicate with the neuromodulation components described herein.

[0023] In some embodiments, the predetermined threshold for heart rate variability can be greater than 1, 2, 3, 4, or 5, and when the sensed level exceeds the predetermined threshold, nerve stimulation (e.g., prophylactic treatment) can be applied. The predetermined threshold can be determined on a case-by-case basis and varies from patient to patient.

[0024] In some embodiments, at least one of the first electrical stimulation or the second electrical stimulation can be delivered in the form of a burst of pulses. In some embodiments, the burst frequency of the stimulation can be any value between 0 Hz and 15 Hz or between 4 Hz and 12 Hz. In some embodiments, the pulse frequency of the stimulation can be any value between 0 Hz and 200 Hz or between 50 Hz and 150 Hz.

[0025] In some embodiments, the electrical stimulation is delivered in the form of a pulse burst. In some embodiments, the burst frequency of the stimulation can be any value between 0 Hz and 15 Hz or between 4 Hz and 12 Hz. In some embodiments, the pulse frequency of the stimulation can be any value between 0 Hz and 200 Hz or between 50 Hz and 150 Hz. In some embodiments, the burst frequency of the stimulation can be any value between 0 Hz and 15 Hz or between 1 Hz and 14 Hz. In some embodiments, the pulse frequency of the stimulation can be any value between 0 Hz and 150 Hz or between 1 Hz and 149 Hz.

[0026] In some embodiments, a neuromodulation system is provided. The system (e.g., including one or more devices and / or components) can include an electrical stimulation pulse generator that delivers electrical stimulation pulses to an earphone placed in the ear. The earphone can include: two electrodes that project from the top of the protective cover and are placed on the concha of the ear to stimulate the auricular branch of the vagus nerve and / or other nerves innervating the ear; one or more sensors that measure data of one or more biomarkers of the physiological state of the user; and a controller that receives and uses the measured data to adjust one or more stimulation parameters of the electrical stimulation pulses. In several embodiments, the protective cover includes a housing having a material for placement on a portion of the skin. The protective cover can be at least partially made of silicone and is designed to be placed at the entrance of the ear canal.

[0027] In some embodiments, electrical stimulation pulses can be delivered at a pulse frequency of 1 Hz to 100 Hz. In some embodiments, the electrical stimulation can be delivered continuously. In some embodiments, the electrical stimulation pulse generator can include a circular form factor and be attached to an article of clothing via a clip. In some embodiments, the electrical stimulation pulse generator can be integrated into an earphone to include a device that resembles a hearing aid in appearance.

[0028] In some embodiments, the neuromodulation device can further include a watch-like wrist-worn stimulation device that delivers electrical stimulation to a peripheral nerve located in the wrist. The stimulation device can include a band that contains two rows of three electrodes, where the center electrode in each row is the stimulation electrode and the electrodes on either side of the center electrode are charge-balancing electrodes. The stimulation device can further include: a second electrical stimulation pulse generator that is worn on the wrist and delivers electrical stimulation pulse bursts to the electrodes on the band; a user interface that includes a display on the surface of the watch-like device; and a base station that is configured to charge the watch-like device and house the watch-like device.

[0029] In some embodiments, one of the sensors is a photoplethysmography sensor and the measured biomarker is heart rate or heart rate variability. In some embodiments, one of the sensors is an electrocardiogram and the biomarker is heart rhythm. In some embodiments, the electrocardiogram is integrated into the stimulator of a watch-like device. In some embodiments, the electrocardiogram is integrated into the aforementioned base station. In some embodiments, the electrocardiogram is integrated into a patch to be worn on a user's body.

[0030] In some embodiments, one of the aforementioned sensors is a sensor for detecting biomarkers of skin sympathetic nerve activity. In some embodiments, one of the aforementioned sensors is a sensor for detecting skin electrical activity. In some embodiments, one of the aforementioned sensors is a sensor for detecting skin temperature. In some embodiments, one of the sensors is a mechanical sensor that is integrated into a strap worn around the chest to detect changes in the respiratory cycle.

[0031] In some embodiments, the electrical stimulation pulse generator communicates wirelessly with the strap respiratory sensor and delivers electrical stimulation to the earpiece via a catheter. The earpiece can be a silicone protector placed at the entrance of the ear canal. The earpiece can be a clamp attached to the helix of the ear and includes a reflective or transmissive photoplethysmography sensor.

[0032] In some embodiments, one of the sensors is a microphone worn in the ear to detect changes in the user's respiratory cycle. In some embodiments, one of the sensors measures the temperature in the ear. In some embodiments, one of the sensors is an infrared reflection light monitor integrated into the earpiece to detect changes in the user's respiratory cycle. In some embodiments, one of the sensors is an electroencephalogram integrated into the earpiece to measure brain activity. In some embodiments, one of the sensors measures the cytokine level in the body and is integrated into the stimulator device, skin patch, or strap.

[0033] In some embodiments, these systems and methods are used to provide acute treatment to users suffering from migraines, colitis, irritable bowel disease, rheumatoid arthritis, hypertension, atrial fibrillation attacks, or other arrhythmias or pathologies. In some embodiments, these systems and methods are used to prevent or reduce the severity or frequency of future atrial fibrillation attacks or other arrhythmia attacks.

[0034] In some embodiments, the headset can include a pressure applicator configured to bias two electrodes in a direction toward the ear. In one embodiment, the headset can include two electrodes that project or otherwise extend from the top of the protective cover. In several embodiments, the protective cover includes a housing having a material for placement on a portion of the skin. The protective cover can be made at least in part of silicone and is designed to be positioned at the entrance of the ear canal. The (one or more) pressure applicators can be configured to increase the pressure level applied by the two electrodes against the ear to reduce the impedance between the two electrodes and the ear. The pressure applicator can include, for example, the following structures and / or functional features: the (one or more) actuating surfaces, such as a spring-loaded actuating surface or other pressure application modalities (e.g., gas pressure, fluid pressure, foam pressure, magnetic or temperature-changing material pressure configurations). Although the pressure applicators are used to increase the contact between the electrodes and the skin on or near the ear, they can also be used for the same purpose as electrodes used on other parts of the body such as the arm (e.g., wrist) or leg. In some embodiments, a neuromodulation (e.g., nerve stimulation) device uses a device that applies pressure, makes the electrodes contact the skin more closely, increases conductivity, reduces impedance, or a combination of these functions.

[0035] In some embodiments, a system for determining a user's respiratory phase is provided. The system can include a sensor for detecting and measuring a quantitative value generally related to the user's respiratory phase. The quantitative value can be one or more of a respiratory threshold, a sample inspection count, a respiratory slope threshold, and a lock-in length. The system further includes a controller configured to apply an algorithm to the quantitative value and determine the user's respiratory phase based on the application of the algorithm to the quantitative value. The quantitative value can be a respiratory threshold, and the respiratory threshold can be the minimum magnitude difference between two sample values. The quantitative value can be a sample inspection count, and the sample inspection count can be the minimum number of consecutive samples that need to be inspected to consider whether the user has switched from one respiratory phase to another. The quantitative value can be a respiratory slope, and the respiratory slope threshold can be the minimum slope value for the assigned change from one respiratory phase to another. The quantitative value can be a lock-in length, and the lock-in length can be the minimum amount of time for which the algorithm pauses. The determined respiratory phase can be an inhalation phase or an exhalation phase. Then, in some embodiments, the respiratory phase or other respiratory data can be used as a biomarker to initiate or ramp up the stimulation of one or more nerves.

[0036] In some embodiments, the value of the stimulation modality parameter for the first electrical stimulation is different from the value of the stimulation modality parameter for the second electrical stimulation. In some embodiments, the value of the stimulation modality parameter for the first electrical stimulation is the same as the value of the stimulation modality parameter for the second electrical stimulation.

[0037] Any of the devices described herein can be used for preventing (e.g., alleviating symptoms and / or treating) depression (such as postpartum depression), inflammation (such as neuroinflammation), Lyme disease, neurological disorders (such as Parkinson's disease and Alzheimer's disease) and gastrointestinal problems (including those in Parkinson's disease), inflammatory bowel diseases (such as Crohn's disease, colitis and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome and other inflammatory diseases (such as neuroinflammation), cardiac conditions (such as atrial fibrillation, hypertension and stroke), epilepsy and / or seizures, headache (such as migraine) and inflammatory skin conditions and immune dysfunction.

[0038] In some embodiments, an ear device for non-invasive neuromodulation includes: a first portion configured to be at least partially secured within a user's ear canal; and a second portion coupled to the first portion and configured to be positioned adjacent to (e.g., adjacent to, within, or in contact with) the user's ear when the first portion is at least partially secured within the user's ear canal, wherein the second portion includes a nerve effector (such as one or more electrodes or a device for delivering electrical stimulation) configured to modulate one or more nerves within or around the ear. The nerve effector can include at least a first and / or a second electrode and the nerve effector can be configured to stimulate the vagus nerve. In one embodiment, the first electrode can include an active electrode and the second electrode can include a return electrode. The active electrode and the return electrode can be spaced apart from each other by a distance between about 10 mm and about 15 mm. In some embodiments, the distance is about 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, and 15 mm. In one embodiment, the range is 11 - 13 mm. In some embodiments, the nerve effector is configured to apply a normal force on the ear (e.g., on the cymba conchae, concha cymba, helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, incisura intertragica, lobule, and / or antitragus, or a combination thereof) when the first portion of the ear device is at least partially secured within the user's ear canal. In some embodiments, the normal force is between about 0.01 Newton (N) and about 1 Newton (N) (e.g., 0.01 to 0.05 N, 0.05 to 0.05 N, 0.01 to 0.1 N, 0.1 to 0.5 N, 0.5 to 1 N, and overlapping ranges therein). In some embodiments, the vagus nerve, trigeminal nerve, and / or great auricular nerve are neuromodulated. In some embodiments, only the vagus nerve (such as the auricular branch or non-auricular branch of the vagus nerve) is neuromodulated. In some embodiments, the vagus nerve (such as the auricular branch or non-auricular branch of the vagus nerve) and one, two, or more other nerves are neuromodulated (e.g., the trigeminal nerve, great auricular nerve, nerves of the auricular branch, auricular branch of the vagus nerve, facial nerve, auriculotemporal nerve, etc.). In some embodiments, the vagus nerve (such as the auricular branch or non-auricular branch of the vagus nerve) is not stimulated, but rather, for example, other nerves (e.g., the trigeminal nerve, great auricular nerve, facial nerve, auriculotemporal nerve, other nerves of the auricular branch, etc.) are stimulated. Neuromodulation according to several embodiments includes stimulation using, for example, the parameters disclosed herein. In one embodiment, a second treatment (such as vibration therapy) is provided in combination with the nerve stimulation.

[0039] In some embodiments, the first portion can include an ear canal element and the second portion includes at least one prong, and the ear device can further include a stem connecting the ear canal element to the at least one prong. In some embodiments, the nerve effector includes an active electrode and a return electrode. In some embodiments, the active electrode and the return electrode are positioned along the at least one prong. In some embodiments, the at least one prong includes a first prong and a second prong, each of the first prong and the second prong having a first end connected to the stem and a second end opposite the first end, wherein the active electrode is positioned at the second end of the first prong and the return electrode is positioned at the second end of the second prong. In some embodiments, the second ends of the first prong and the second prong are spaced apart from each other. In some embodiments, the second ends of the first prong and the second prong are spaced apart from each other by a distance between about 10 mm and about 15 mm. In some embodiments, the distance is about 11 - 13 mm (e.g., 11.5 mm). In some embodiments, the diameter of the electrode-skin contact surface area of each of the active electrode and the return electrode is between about 2 mm and about 8 mm (e.g., 2 - 4, 3 - 5, 4 - 6 mm, 6 - 8 mm, and overlapping ranges therein). In some embodiments, the diameter of the electrode-skin contact surface area of each of the active electrode and the return electrode is about 3 - 5 mm (e.g., 4 mm). In some embodiments, the first prong and the second prong are angled relative to each other at an angle between about 20° and about 90° (e.g., 20° - 30°, 30° - 40°, 40° - 50°, 50° - 60°, 60° - 70°, 70° - 80°, 80° - 90°, and overlapping ranges therein). In some embodiments, the length of the first prong is greater than the length of the second prong. In some embodiments, the length of the second prong is greater than the length of the first prong. In some embodiments, one or more of the prongs (e.g., relative to the stem) are non-rotatable and / or non-bendable. In one embodiment, the boss provides sufficient adjustability (e.g., allows a certain amount of rotation) without the need for prong rotation and / or bendability.

[0040] The ear device can further include a boss configured to couple the stem to the ear canal element. In some embodiments, the boss is configured to move relative to the stem when coupled to the stem and the ear canal element. In some embodiments, the boss is configured to allow the ear canal element to rotate relative to the stem while the boss is coupled to the stem and the ear canal element. In some embodiments, the boss includes a recess configured to receive the stem. In some embodiments, when the boss is coupled to the stem, the recess surrounds a portion of the perimeter of the cross-section of the stem. In some embodiments, the recess includes a protrusion and wherein the stem includes one or more notches recessed from the surface of the stem, the one or more notches being configured to receive at least a portion of the protrusion. In some embodiments, the one or more notches include a plurality of notches (e.g., 2, 3, 4, 5, 6 or more notches).

[0041] The ear device can further include a power source configured to provide power to the nerve effector. The power source can be, for example, one or more batteries (e.g., rechargeable batteries). In one embodiment, the power source is placed on the device coupled to the ear or in a location other than the ear, such as on the wrist or other locations on or in the body.

[0042] In some embodiments: The first portion includes an ear canal element; the second portion includes at least one fork; the ear device further includes a stem connecting the ear canal element to the at least one fork; the nerve effector includes an active electrode and a return electrode. In some embodiments, the at least one fork is flexible. In some embodiments, the at least one fork is elastic. In some embodiments, the at least one fork includes a first fork and a second fork, each of the first fork and the second fork having a first end connected to the stem and a second end opposite the first end, wherein the active electrode is positioned at the second end of the first fork and the return electrode is positioned at the second end of the second fork. In some embodiments, the first fork and the second fork are configured to allow each of the active electrode and the return electrode to simultaneously make independent contact with various parts of the ear (e.g., the cymba conchae). In some embodiments, the first fork and the second fork are configured to exert a normal force on the ear (e.g., the cymba conchae, the cavum conchae, the helix, the scaphoid fossa, the antihelix, the triangular fossa, the superior crus, the inferior crus, the helix crus, the tragus, the intertragic notch, the lobule, and / or the antitragus, or a combination thereof) when the ear canal element is at least partially fixed within the user's ear canal. In some embodiments, the normal force is between approximately 0.01 N and approximately 1 N. In some embodiments, at least one of the first fork and the second fork is flexible and / or elastic. In some embodiments, only one of the first fork and the second fork is flexible and / or elastic. In some embodiments, both the first fork and the second fork are flexible and / or elastic. In some embodiments, the stem is rigid. In some embodiments, the second ends of the first fork and the second fork are spaced apart from each other. Additional forks may also be used.

[0043] In some embodiments, an ear device for non-invasive vagus nerve modulation includes: an ear canal element configured to be at least partially fixed within a user's ear canal; a boss rotatably coupled to the ear canal element; a stem slidably coupled to the boss and capable of rotating relative to the ear canal element via the boss; at least one fork coupled to the stem; and a nerve effector coupled to one end of the at least one fork. When the ear canal element is at least partially fixed within or in the user's ear canal, the stem and the at least one fork can be configured to position the nerve effector within, on, or near the user's ear.

[0044] In some embodiments, an ear device that uses a burst stimulation mode for non-invasive vagus nerve neuromodulation includes: a first portion configured to be at least partially fixed within a user's ear canal; a second portion coupled to the first portion and configured to be placed within the concha of the user's ear when the first portion is at least partially fixed within the user's ear canal; and one or more hardware processors configured to generate a burst stimulation mode. The second portion can include a neuroeffector configured to apply the burst stimulation mode to modulate the user's vagus nerve.

[0045] In some embodiments, the ear device further includes one or more sensors (e.g., 2, 3, 4, 5, 6 or more sensors). In some embodiments, the one or more sensors are selected from the group consisting of a photoplethysmography sensor (PPG), a galvanic skin response sensor (GSR), an inertial measurement unit sensor (IMU), a temperature sensor (e.g., for body / skin temperature or ambient temperature), a respiration sensor, and an electroencephalography sensor (EEG). In some embodiments, respiration is measured using mechanical, electrical, impedance, acoustic (e.g., microphone), ultrasound, infrared, or video-based measurements. In some embodiments, the one or more sensors can be used to measure the response to treatment and calibrate the treatment. In some embodiments, the ear device is configured to be electrically connected to a power source separate from the ear device.

[0046] In some embodiments, the devices and methods described herein do not include or use one or more of the following features: (i) a hydrogel material adjacent to the active electrode and / or the return electrode; (ii) an adhesive material adjacent to the active electrode and / or the return electrode; (iii) any percutaneous component; and / or (iv) any implantable component. Some embodiments include a battery and / or a cable, while other embodiments do not.

[0047] In some embodiments, a controller is provided. In some embodiments, the system includes one or more hardware processors configured to: generate a stimulation waveform for stimulation using one or more electrodes, wherein the stimulation waveform includes a progressive burst mode; and apply the stimulation waveform to the one or more electrodes. In some embodiments, the one or more hardware processors are further configured to modify the stimulation waveform based on one or more physiological parameters determined from a physiological sensor selected from the group consisting of: a photoplethysmography sensor (PPG), a galvanic skin response sensor (GSR), a temperature sensor, and an electroencephalography sensor (EEG). In some embodiments, the one or more hardware processors are further configured to modify the stimulation waveform based on data determined from an inertial measurement unit sensor (IMU).

[0048] In some embodiments, depression (including but not limited to postpartum depression, depression associated with neurological diseases, major depression, seasonal affective disorder, depressive disorders, etc.), inflammation (such as neuroinflammation), Lyme disease, neurological diseases (such as Parkinson's disease and Alzheimer's disease), and gastrointestinal problems (including those in Parkinson's disease. Inflammatory bowel diseases (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, and other inflammatory diseases are treated in several embodiments. Inflammatory skin diseases can also be treated.

[0049] In some embodiments, heart diseases (such as atrial fibrillation, hypertension, and stroke) are treated in one embodiment. Epilepsy and other seizures are treated in one embodiment. Headaches (such as migraines) are treated in other embodiments. The neuromodulation devices (e.g., nerve stimulation devices) described herein can be used to treat chronic fatigue syndrome. In one embodiment, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine with peripheral nerve stimulation includes multiple treatment paths: (a) an acute relief path, and / or (b) a prophylactic treatment path. In one embodiment, the treatment framework and each treatment path can be implemented by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an ear neuromodulation device, or any combination of a wrist-worn device and an ear device. Devices for stimulating nerves in the legs are also provided in some embodiments.

[0050] In some embodiments, the devices described herein can be used to treat chronic inflammatory symptoms and acute flare-ups. Bradykinesia, dyskinesia, gait dysfunction, dystonia, and / or rigidity can also be treated according to several embodiments. In several embodiments, rehabilitation resulting from certain events (e.g., recovery from a stroke or other cardiovascular event) is treated. In several embodiments, systems and methods are provided for reducing the habituation and / or tolerance to stimulation of the disorders and symptoms identified herein, for example, by introducing variability in the (one or more) stimulation parameters described herein.

[0051] In some embodiments, a system for applying neuromodulation to a subject includes a plurality of neuromodulation devices placed on different parts of the subject's body or placed adjacent to different parts of the subject's body. For example, such a system can include a first neuromodulation device (such as any ear device described herein) placed on or near the subject's ear and a second neuromodulation device placed on or near a different part of the subject's body (such as the wrist, palm, finger, part of the arm, leg, ankle, foot, sole of the foot, toes, etc.). The subject can wear one, two, three, or four neuromodulation devices. When two or more neuromodulation devices are used, they can be activated individually or together (e.g., synchronously). According to several embodiments, modulation of the vagus nerve is achieved using the devices described herein. In some embodiments, the devices described herein are used to stimulate the autonomic system. In some embodiments, the devices described herein are used to balance the sympathetic / parasympathetic nervous system. In some embodiments, improvement of the condition to be treated is an indicator that such balance has occurred. For example, in some embodiments, balance of the sympathetic / parasympathetic nervous system is indicated by a reduction in one or more of tremors, inflammation, cardiac aberration, imbalance, movement disruption, headache, pain, etc. (compared to before use) after using the neuromodulation devices described herein. Balance can also be shown by measuring neurotransmitters and showing improvement in neurotransmitter function, quantity, activity, uptake, etc.

[0052] In some embodiments, neuromodulation (e.g., neuromodulation of the vagus nerve) using the devices and methods described herein affects (increases, decreases, or maintains) neurotransmitter release, uptake, and / or metabolism. Certain neurotransmitters can be increased while other neurotransmitters can be decreased to achieve the desired effect. The dopaminergic and / or serotonergic systems are modulated according to several embodiments described herein. In some embodiments, the brain-gut axis is modulated using the devices and methods described herein.

[0053] Although nerve stimulation is disclosed in several embodiments herein, it should be understood that downregulation of various pathways can be achieved. For example, cytokine production and / or activity can be inhibited to treat inflammation (including disorders such as various arthritis conditions, gastrointestinal disorders, etc.). Certain neurotransmitter production and / or activity can be reduced. Neurotransmitter uptake and / or metabolism can be increased.

[0054] Methods of using the systems described herein are also provided. For example, in some embodiments, a method of modulating a subject's vagus nerve includes: generating, by one or more hardware processors, a stimulation waveform for use in stimulating with one or more electrodes, wherein the stimulation waveform includes a progressive burst pattern; and applying, by the one or more electrodes, the stimulation waveform to a portion of the subject's body. In some embodiments, the method further includes using a physiological sensor to determine one or more physiological parameters of the subject and modifying the stimulation waveform based on the one or more physiological parameters. In some embodiments, the method further includes using an inertial measurement unit sensor (IMU) to determine motion data of the subject and modifying the stimulation waveform based on the motion data. In some embodiments, the physiological sensor includes a photoplethysmography sensor (PPG). In some embodiments, the physiological sensor includes a galvanic skin response sensor (GSR). In some embodiments, the physiological sensor includes an electroencephalography sensor (EEG) or a sensor that measures temperature.

[0055] In some embodiments, a method of non-invasively modulating a subject's vagus nerve includes: positioning a neuromodulation device proximate to the subject's ear; and modulating the subject's vagus nerve with a neuroeffector of the neuromodulation device. In some embodiments, the neuroeffector includes at least one electrode and modulating the subject's vagus nerve includes stimulating the vagus nerve with the at least one electrode. In some embodiments, the neuroeffector includes at least a first electrode and a second electrode. In some embodiments, the first electrode includes an active electrode and the second electrode includes a return electrode. In some embodiments, the neuromodulation device includes a first portion and a second portion coupled to the first portion, wherein the second portion includes the neuroeffector, and wherein the method further includes at least partially securing the first portion within the subject's ear canal. Additional electrodes may also be used.

[0056] In some embodiments: the first portion includes an ear canal element; the second portion includes at least one prong configured to operably position a nerve effector adjacent to (e.g., adjacent to, within, or in contact with) a portion of the ear of an object; the nerve modulation device further includes a stem connecting the ear canal element to the at least one prong; and the method further includes adjusting the position of the ear canal element relative to the stem. In some embodiments, adjusting the position of the ear canal element relative to the stem includes moving the ear canal element along a portion of the length of the stem. In some embodiments, the nerve modulation device further includes a boss configured to couple the ear canal element to the stem and to allow the ear canal element to move along this portion of the length of the stem. In some embodiments, the ear canal element is rotatably coupled to the stem and wherein adjusting the position of the ear canal element relative to the stem includes rotating the ear canal element. In some embodiments, the nerve modulation device further includes a boss configured to rotatably couple the ear canal element to the stem and to allow the ear canal element to rotate while being coupled to the stem.

[0057] In some embodiments, the method further includes positioning a nerve effector adjacent to (e.g., adjacent to, within, or in contact with) the cymba conchae or other portions of the ear of an object, such as the cymba cavity, helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, and / or antitragus, or a combination thereof. In some embodiments, a first nerve effector and a second nerve effector (e.g., electrodes or other devices that deliver electrical pulses or energy) are spaced apart from each other by a certain distance. In some embodiments, the distance is between approximately 10 mm and approximately 15 mm. In some embodiments, the distance is approximately 11.5 mm. In some embodiments, the method further includes applying a normal (e.g., perpendicular) force in or around the ear using the nerve effector. In some embodiments, the normal force is between approximately 0.01 N and approximately 1 N.

[0058] In some embodiments, the devices described herein are used to downregulate, upregulate, or both (e.g., balance) vagal nerve activity. In various embodiments, the devices described herein can be used to apply neuromodulation to the vagus nerve to increase neurotransmitter release, uptake, and / or metabolism. In some embodiments, the neuromodulation is used to affect (e.g., decrease or increase) neurotransmitter release, uptake, and / or metabolism. Several embodiments are used to apply neuromodulation to the vagus nerve to balance neurotransmitter release, uptake, and / or metabolism by increasing and decreasing neurotransmitter activity. Several embodiments are used to apply neuromodulation to the vagus nerve to initiate or downregulate the dopaminergic system and / or the serotonergic system. Several embodiments are used to apply neuromodulation to the vagus nerve to regulate the brain-gut axis. Several embodiments are used to treat depression (including but not limited to postpartum depression, depression associated with neurological diseases, major depression, seasonal affective disorder, depressive disorders, etc.), inflammation (such as neuroinflammation), Lyme disease, neurological diseases (such as Parkinson's disease and Alzheimer's disease), and gastrointestinal problems (including those in Parkinson's disease). Several embodiments are used to treat inflammatory bowel diseases (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, osteoarthritis, psoriasis, and other inflammatory diseases. In several embodiments, the devices described herein can be used to treat inflammatory skin conditions; chronic fatigue syndrome; and / or chronic inflammatory symptoms and flare-ups. In some embodiments, the devices and methods described herein (e.g., by nerve stimulation) provide regulation (dilation or constriction) of blood vessels. Such treatment can in turn reduce inflammation (including but not limited to inflammation after microbial infection). The devices and methods described herein can, in various embodiments, increase, decrease, or otherwise balance vasodilation and vasoconstriction by neuromodulation (such as modulation of the vagus nerve, trigeminal nerve, and / or other nerves in or around the ear). For example, in several embodiments, a reduction in vasodilation is provided to treat or prevent migraine or other conditions exacerbated by vasodilation. In other embodiments, vasoconstriction is reduced in conditions where dilation is beneficial (such as in hypertension and pain). In one embodiment, reduction of inflammation treats tinnitus. In some embodiments, regulation (dilation or constriction) of blood vessels is used to treat tinnitus. Tinnitus can be treated, according to several embodiments, by modulating (e.g., stimulating) the vagus nerve (such as the non-auricular portion of the vagus nerve) alone or in combination with one, two, or more other nerves (including, for example, the trigeminal nerve, great auricular nerve, nerves of the auricular branch, auricular branch of the vagus nerve, facial nerve, auriculotemporal nerve, etc.). In one embodiment, nerves other than the vagus nerve are modulated to treat tinnitus. In some embodiments, the cranial / auditory nerves can be modulated to treat tinnitus and / or ear inflammation.

[0059] Neuromodulation (such as nerve stimulation) as described in several embodiments herein can provide therapeutic benefits for a variety of diseases, including but not limited to movement disorders (including but not limited to essential tremor, Parkinsonian tremor, orthostatic tremor, and multiple sclerosis), urological disorders, gastrointestinal disorders, heart diseases, inflammatory diseases (such as neuroinflammation), mood disorders (including but not limited to depression, bipolar disorder, dysthymia, and anxiety disorders), pain syndromes (including but not limited to migraine and other headaches, trigeminal neuralgia, fibromyalgia, complex regional pain syndrome), Lyme disease, stroke, etc. Inflammatory bowel diseases (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory diseases are treated in several embodiments. Heart conditions (such as atrial fibrillation, hypertension, and stroke) are treated in one embodiment. Epilepsy and other seizure disorders are treated in one embodiment. Inflammatory skin conditions and immune dysfunction are also treated in some embodiments.

[0060] In some embodiments, disorders and symptoms caused or exacerbated by microbial infections (e.g., bacteria, viruses, fungi, and parasites) are treated. Symptoms include but are not limited to sympathetic / parasympathetic imbalance, autonomic dysfunction, inflammation (including but not limited to neuroinflammation and other inflammation), movement and balance dysfunction, pain, and other neurological symptoms. Disorders include but are not limited to tetanus, meningitis, Lyme disease, urinary tract infections, mononucleosis, chronic fatigue syndrome, autoimmune disorders, etc. In some embodiments, autoimmune disorders and / or pain unrelated to microbial infections are treated, including for example inflammation (e.g., neuroinflammation, etc.), headache, back pain, joint pain and stiffness, muscle pain and tension, etc.

[0061] In several embodiments, the devices described herein can be used to treat cardiac conditions such as atrial fibrillation, hypertension, and stroke. Epilepsy and other seizure disorders are treated in one embodiment. In several embodiments, the devices described herein can be used to treat immune dysfunction. Several embodiments are used to stimulate or otherwise modulate the autonomic nervous system, and more particularly to treat diseases or disease symptoms exacerbated by autonomic dysfunction, including but not limited to depression, anxiety, insomnia, hypertension, arrhythmia, overactive bladder, inflammatory bowel disease (e.g., Crohn's disease, colitis, and functional dyspepsia), fecal incontinence, headache and migraine, chronic pain, vasovagal syncope, inflammatory diseases (e.g., rheumatoid arthritis, lupus, and other autoimmune diseases), and tinnitus. Several embodiments are used to balance the sympathetic / parasympathetic nervous system, and more particularly to treat diseases associated with an imbalance of the autonomic nervous system using a wearable device, including but not limited to tremors, cardiac disorders, mental health disorders, or other diseases or conditions such as those disclosed elsewhere herein.

[0062] Other disorders can also be treated using the various embodiments described herein. For example, stimulation of the vagus nerve has been shown to improve the symptoms of hypertension, agility, and cardiac arrhythmias.

[0063] To provide an overview of the present disclosure, certain aspects, advantages, and novel features are discussed herein. It should be understood that not all of these aspects, advantages, or features will be present in any particular embodiment of the present disclosure. The disclosure herein supports numerous combinations of these aspects, advantages, or features. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Certain features of the present disclosure are described below with reference to the drawings. The illustrated embodiments are intended to illustrate and not to limit these embodiments. The various features of different disclosed embodiments can be combined to form further embodiments that are part of the present disclosure.

[0065] Figure 1A The ear of a user in accordance with aspects of the present disclosure is shown.

[0066] Figure 1B An example contact location of an electrode for delivering nerve stimulation in the ear in accordance with aspects of the present disclosure is schematically shown.

[0067] Figures 1C - 1F An embodiment of an electrode annular interface in accordance with aspects of the present disclosure is shown.

[0068] Figures 1G - 1K An experimental setup for measuring the applied force or pressure and its relationship to impedance in accordance with various embodiments of the present disclosure is shown.

[0069] Figures 1L - 1M An electrode with a pressure applicator according to various embodiments of the present disclosure is shown.

[0070] Figure 2A A perspective view of an embodiment of an ear device for delivering nerve stimulation according to aspects of the present disclosure is shown.

[0071] Figures 2B - 2C Shown according to aspects of the present disclosure Figure 2A An enlarged perspective view of the ear device.

[0072] Figures 2D - 2E Shown according to aspects of the present disclosure Figure 2A A side view of the ear device.

[0073] Figures 2F - 2G Shown according to aspects of the present disclosure Figure 2A A top view and a bottom view of the ear device.

[0074] Figures 2H - 2J Shown according to aspects of the present disclosure Figure 2A A part of the ear device.

[0075] Figures 2K - 2M Shown according to aspects of the present disclosure Figure 2A A part of the ear device.

[0076] Figures 2N - 2O Shown according to aspects of the present disclosure Figure 2A A rear view and a front view of the ear device.

[0077] Figure 3 Another embodiment of an ear device for delivering nerve stimulation according to aspects of the present disclosure is shown.

[0078] Figure 4 An embodiment of a boss that can be incorporated into any ear device disclosed herein is shown.

[0079] Figures 5A - 5B Another embodiment of an ear device for delivering nerve stimulation according to aspects of the present disclosure is shown.

[0080] Figures 5C - 5D Shows how the Figures 5A - 5B ear device can be adjusted to be compatible with different ear anatomies.

[0081] Figures 6A - 6B Another embodiment of an ear device for delivering nerve stimulation according to aspects of the present disclosure is shown.

[0082] Figure 7 Another embodiment of an ear device for delivering nerve stimulation according to aspects of the present disclosure is shown.

[0083] Figure 8A FIG. shows a block diagram of an exemplary neuromodulation (e.g., nerve stimulation) device.

[0084] Figure 8B FIG. shows a user interface device capable of connecting to a Figure 8A nerve stimulation device.

[0085] Figure 8C FIG. shows an embodiment of a controller that can be implemented with some or all of the hardware components described with respect to Figure 8A or Figure 8B a block diagram.

[0086] Figures 9A - 9C FIG. shows an exemplary stimulation pattern applicable to a Figure 8A neuromodulation device.

[0087] Figure 10 FIG. shows a framework for cardiac measurement tasks, acute relief treatment, and prophylactic treatment according to embodiments of the present disclosure.

[0088] Figures 11 - 12 FIG. shows a neuromodulation device for delivering electrical stimulation to the auricular branch of the vagus nerve according to various embodiments of the present disclosure.

[0089] Figure 13 FIG. shows a device for delivering electrical stimulation to the auricular branch of the vagus nerve with an additional stimulation device according to various embodiments of the present disclosure.

[0090] Figures 14A - 14B FIG. shows a neuromodulation device for delivering electrical stimulation to the auricular branch of the vagus nerve according to various embodiments of the present disclosure.

[0091] Figures 15A - 15C FIG. shows a neuromodulation device for delivering electrical stimulation to the auricular branch of the vagus nerve according to various embodiments of the present disclosure.

[0092] Figure 16 and Figure 17 FIG. shows an algorithm for determining a person's current respiratory phase and when the respiratory phase begins or ends according to various embodiments of the present disclosure. SPECIFIC EMBODIMENTS

[0093] Various features and advantages of the present disclosure will now be described with reference to the accompanying drawings. The following description is merely illustrative in nature and is in no way intended to limit the present disclosure, its application, or uses. The present disclosure is not limited to the specifically disclosed embodiments and / or uses and their obvious modifications and equivalents. Accordingly, it is intended that the scope of the present disclosure not be limited by any particular embodiment described below. The features of the illustrated embodiments can be modified, combined, removed, and / or substituted.

[0094] Vagus nerve stimulation can treat a variety of diseases and conditions, including but not limited to postpartum depression and gastrointestinal problems in Parkinson's disease. Figure 1A An example ear is shown, with its various parts indicated by text, including one or more of the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, antitragus, and concha (e.g., concha cavity and / or cymba concha). Due to the termination location of the vagus nerve, in one embodiment, the appropriate area of the ear for stimulation is within the cymba concha. Other locations on the ear, such as the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, antitragus, and / or concha cavity and combinations thereof are also used in various embodiments. According to several embodiments, regulation of the vagus nerve is achieved with the devices described herein. In some embodiments, the devices described herein are used to stimulate the autonomic system. In some embodiments, the devices described herein are used to balance the sympathetic / parasympathetic nervous system (e.g., by upregulating / downregulating / maintaining nerve activity to achieve balance). Several embodiments of the system utilize multiple elements to alter the treatment to prevent habituation and / or adjust the amplitude to manage discomfort. In one embodiment, changing the frequency or other parameters reduces tolerance or habituation and / or increases patient comfort / compliance.

[0095] Figure 1B Two example locations are shown where a neuroeffector (e.g., an electrode) can be placed within the cymba concha for delivering stimulation. In several embodiments, placement at the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, antitragus, concha cavity, and / or cymba concha of the ear, or combinations thereof, is provided. Some embodiments of the ear devices discussed herein include electrodes (e.g., active electrodes and return electrodes) positioned in the locations as Figure 1B shown. In one embodiment, the electrode comprises stainless steel, which has low impedance but requires a gel to electrically couple to the skin / tissue. In one embodiment, the electrode comprises a base material (e.g., silicone) and a conductive filler or filling (e.g., carbon nanotubes (CNT)). In some embodiments, the conductive filling material can comprise a powder or fine particulate material. The conductive filling material can comprise a metal, carbon, or a mixture thereof. In some embodiments, the conductive filling material can comprise single-walled carbon nanotubes (SWCN). In some embodiments, the conductive filling material can comprise double-walled carbon nanotubes (DWCN). In certain embodiments, the filler in the form of CNT does not require a coupling gel but has a high baseline impedance and its performance degrades rapidly with wear and use.

[0096] In one embodiment, at Figures 1C - 1D and Figures 1E - 1FAs shown, the ear device 100 includes an electrode 122, and the electrode 122 includes an annular interface. In one embodiment, the width and thickness vary. In one embodiment, a nub less design is used.

[0097] In one embodiment, the impedance decreases as the pressure on the interface between the electrode and the skin / tissue increases. In one embodiment, the optimal pressure impedance is achieved at a pressure of about 2 - 3 Newtons (N). In various embodiments, from 0.01 Newton (N) to about 1 Newton (N) (e.g., 0.01 to 0.05 N, 0.05 to 0.05 N, 0.01 to 0.1 N, 0.1 to 0.5 N, 0.5 to 1 N, and overlapping ranges therein). In various embodiments, the pressure impedance is achieved with a pressure of about 0.01 - 5 Newtons (e.g., 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.5, 3.6, 4.0, 4.3, 4.5, 4.7, 5.0, and any values and ranges therein). In one embodiment, the pressure is measured by using an Arduino Nano equipped with an FSR and an HC - 05 Bluetooth module (in conjunction with an Android application for viewing on a terminal), and an exponential regression calibration curve is revealed to give a reading in Newtons, as Figure 1G 、 Figure 1H 、 Figure 1I 、 Figure 1J 、 Figure 1K shown. In various embodiments, as Figures 1L - 1MAs shown, the earphone includes a pressure applicator 160 (e.g., a spring-loaded actuating surface, and other pressure application surfaces such as gas pressure, fluid pressure, foam pressure, magnetic or temperature-varying material pressure configurations) and various angles to reduce the impedance between the electrodes and the tissue. In some embodiments, the ear device 100 can include a pressure applicator 160 configured to bias one or more electrodes in a direction towards the ear. The pressure applicator 160 can be configured to increase the pressure level applied by the one or more electrodes to the ear, thereby reducing the impedance between the one or more electrodes and the ear. The pressure applicator 160 can be a spring-loaded actuating surface. In various embodiments, the pressure applicator 160 involves gas pressure, fluid pressure, foam pressure, magnetic or temperature-varying material pressure configurations. In some embodiments, a neuromodulation system (which includes devices and components) is provided. The system can include an electrical stimulation pulse generator that delivers electrical stimulation pulses to an earphone placed within the ear. The earphone can include two electrodes and a pressure applicator, the two electrodes extending from the top of a protective cover 165 and positioned on the concha of the ear to stimulate the auricular branch of the vagus nerve; the pressure applicator is configured to bias at least one of the two electrodes in a direction towards the ear. In several embodiments, the protective cover 165 includes a housing having a material for placement on a portion of the skin. The protective cover 165 can be at least partially made of silicone and designed to be positioned at the entrance of the ear canal. In some embodiments, the pressure applicator can be configured to increase the pressure level applied by at least one of the two electrodes to the ear, thereby reducing the impedance between at least one or more of the two electrodes and the ear. The pressure applicator 160 can be a spring-loaded actuating surface. In various embodiments, the pressure applicator 160 involves gas pressure, fluid pressure, foam pressure, magnetic or temperature-varying material pressure configurations.

[0098] In one embodiment, the loaded dry electrode includes a base material and a filler. The base material can be composed of silicone or a silicone-like material (such as fluorosilicone), but any other elastomer can also be used. The filler can be composed of carbon nanotubes or any other conductive metal nanowires. Other filler materials can be used in place of these nanowires, or other filler materials can be used in addition to the nanowires. Such filler can be loaded such that the percentage loaded into the material matrix can be any value between 0 - 25% (e.g., 1%, 2%, 5%, 8%, 10%, 12%, 15%, 17%, 19%, 20%, 22%, 24%, and / or 25%, and any value or range therein). The electrode can be in the range of 0.25 - 5 millimeters (e.g., 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, and any value or range therein). In one embodiment, the electrode is self-wetting.

[0099] In one embodiment, the electrode is configured as a non-invasive neuromodulation device. In one embodiment, the electrode includes an elastomeric substrate that forms a matrix, and the elastomeric substrate can be loaded with a filler material. In one embodiment, the dry electrode allows for long-term use to achieve non-invasive peripheral nerve stimulation. In various embodiments, such material can be implemented as an electrode for a wrist-worn device and / or an ear device.

[0100] In one embodiment, the dry electrode includes a base material and a filler. In one embodiment, the base material can be one or more of silicone, fluorosilicone, or some other elastomer. In one embodiment, the filler can be one or more of carbon nanotubes (CNT), metal nanowires, or other filler materials. In one embodiment, the electrode thickness is at least 0.25 millimeters and at most 5 millimeters. In one embodiment, the electrode is self-wetting. In one embodiment, the loading percentage of the filler is between 0% and 25%.

[0101] Each embodiment of the ear device discussed herein can include an active electrode and a return electrode, which are positioned such that (e.g., center-to-center relative to each other) they are approximately between 5 mm and 20 mm apart from each other, such as between approximately 6 mm and 19 mm, between approximately 7 mm and 18 mm, between approximately 8 mm and 17 mm, between approximately 9 mm and 16 mm, between approximately 10 mm and 15 mm, between approximately 11 mm and 14 mm, between approximately 12 mm and 13 mm, or between approximately 11 mm and 12 mm, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in certain cases. As another example, each embodiment of the ear device discussed herein can include an active electrode and a return electrode positioned approximately 11.5 mm apart from each other. Such a configuration can advantageously maximize vagus nerve stimulation and can accommodate large variations in ear anatomy and / or characteristics.

[0102] Each embodiment of the ear device discussed herein can include electrodes (e.g., an active electrode and a return electrode) and the diameter of the electrode-skin contact surface area of each electrode is between approximately 1 mm and 10 mm, such as between approximately 2 mm and 9 mm, between approximately 3 mm and 8 mm, between approximately 4 mm and 7 mm, between approximately 5 mm and 6 mm, between approximately 3 mm and 5 mm, or between approximately 2 mm and 6 mm, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in certain cases. As another example, each embodiment of the ear device discussed herein includes electrodes and the diameter of the electrode-skin contact surface area of each electrode is approximately 4 mm. Such a configuration can advantageously maximize vagus nerve stimulation and can accommodate large variations in ear anatomy and / or characteristics.

[0103] Each embodiment of the ear device discussed herein includes a first portion configured to be securable to and / or within a user's ear canal (e.g., at least partially within the ear canal) and a second portion coupled to the first portion, the second portion being placeable and / or positionable adjacent to and / or proximate to the concha of the user's ear (e.g., adjacent to, within, or in contact therewith) when the first portion is secured to the ear canal and / or within the ear canal. Such a second portion can include a neuroeffector capable of providing electro-neuromodulation (e.g., stimulation). As discussed elsewhere herein, a neuroeffector can be and / or include one or more, a plurality, and / or at least one or at least two electrodes (e.g., an active electrode and a return electrode). Such a configuration that "couples" the first and second portions of the ear device (e.g., with reference points of the ear canal) advantageously provides a heightened spatial understanding and proper placement of the neuroeffector adjacent to and / or proximate to the concha of the ear (e.g., adjacent to, within, or in contact therewith) as the first portion can be used as a positioning and / or confirmation feature for placement of the ear device. In several embodiments, placement is provided adjacent to the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, intertragic notch, lobule, antitragus, cymba conchae, and / or concha of the ear, or a combination thereof.

[0104] Each embodiment of the ear device discussed herein can be configured to not interfere with a user's ability to hear external sounds or with a user's ability to connect to personalized audio.

[0105] Figures 2A - 2GShows various views of an example embodiment of an ear device 100. The ear device 100 can include a first part that can be fixed to and / or within a user's ear canal (e.g., at least partially fixed within the ear canal) and a second part coupled to the first part. When the first part is fixed to the ear canal and / or within the ear canal, the second part can be placed and / or positioned near and / or adjacent to the concha of the user's ear (e.g., adjacent to it, within it, or in contact with it). Such a first part of the ear device 100 can be, for example, the ear canal element 110. The ear canal element 110 can be sized and / or shaped to fit within the user's ear canal (or at least partially fit within the ear canal). For example, the ear canal element 110 can include a constricted and / or tapered tip that can facilitate insertion and / or fixation within a portion of the ear canal. For example, in some embodiments, the ear canal element 110 can be similar to those elements suitable for use with an audio microphone (e.g., an earbud). In some embodiments, the ear canal element 110 is a custom 3D printed component to allow for a better fit within the user's ear canal. In some embodiments, the ear device 100 is configured to allow for the exchange and / or interchange of various ear canal elements to provide sizing flexibility. Such a second part of the ear device 100 can be and / or include one or more fork-shaped members, such as one or both of the fork-shaped members 120a, 120b. The fork-shaped members 120a, 120b can include and / or be operatively positioned with one or more electrodes. For example, the ear device 100 can include a first electrode 122a coupled to and / or positioned along the fork-shaped member 120a and / or can include a second electrode 122b coupled to and / or positioned along the fork-shaped member 120b (see Figure 2C ). The first electrode 122a can be an active electrode and the second electrode 122b can be a return electrode, and vice versa. The first electrode 122a can be coupled to one end of the fork-shaped member 120a and / or the second electrode 122b can be coupled to one end of the fork-shaped member 120b. In some embodiments, the ear device 100 does not include a hydrogel material adjacent to and / or on the first electrode 122a and / or does not include a hydrogel material adjacent to and / or on the second electrode 122b. Additionally or alternatively, in some embodiments, the ear device 100 does not include an adhesive material adjacent to and / or on the first electrode 122a and / or does not include an adhesive material adjacent to and / or on the second electrode 122b.

[0106] The first and second portions of the ear device 100 discussed above can be coupled to each other. For example, the ear device 100 can include a third portion that can couple the first and second portions together. Such a third portion can be, for example, the rod 130 and / or the boss 140 (discussed below). The rod 130 can be an elongated element (e.g., the rod 130 can have a length or height greater than one or more dimensions of the cross-section of the rod 130). In some embodiments, the ear device 100 includes a boss 140 (which can also be referred to herein as a "coupler" or "adapter"), and the boss 140 can couple the first and / or second portions of the ear device 100 to each other, for example, together with the rod 130. For example, the ear device 100 can include a boss 140 that can couple (e.g., directly or indirectly couple) the ear canal element 110 to the rod 130 and can thus couple the ear canal element 110 to the fork(s) 120a, 120b. In some embodiments, the boss 140 can be removably coupled to the rod 130. For example, in some embodiments, the boss 140 can be configured to be fixed to the rod 130 by a snap-fit arrangement.

[0107] In some embodiments, the ear device 100 includes a cable 150 that can facilitate an electrical connection between electrical components of the ear device 100 (e.g., the electrodes 122a, 122b of the ear device 100) and a power source. Such a power source can be spaced and / or separated from the ear device 100. For example, the ear device 100 can include a cable 150 that is connected to a power source integrated into a housing or casing attached to a portion of the user (e.g., fixed behind the ear, fixed above the ear, fixed in a headband fixed around the user's head, fixed around the user's neck, and / or fixed around the user's arm). As another example, the ear device 100 can include a cable 150 that is connected to a power source integrated into a housing or casing attached to the upper arm of the user (e.g., a patient), and the upper arm can also include a blood pressure cuff that can be used as a therapeutic sensor. In some embodiments, the ear device 100 is configured to receive power via the cable 150, and the cable 150 can also be configured to facilitate the delivery of audio via the ear canal element 110. In some embodiments, the cable 150 is a 2.5 mm cable.

[0108] In some embodiments, the ear device 100 does not include a cable (such as the cable 150). For example, in some embodiments, the ear device 100 includes a power source to provide power to the electrical components of the ear device 100 (e.g., the electrodes 122a, 122b of the ear device 100). For example, any one of the ear canal element 110, the rod 130, the boss 140, and / or the fork(s) 120a, 120b can include a power source (e.g., a battery) that can provide power to the electrical components of the ear device 100 (e.g., the electrodes 122a, 122b of the ear device 100).

[0109] In some embodiments, the ear device 100 includes one or more sensors for calibration or for therapeutic delivery (e.g., closed-loop therapeutic delivery) purposes, including but not limited to a photoplethysmography sensor (PPG), a galvanic skin response sensor (GSR), an inertial measurement unit sensor (IMU), a temperature sensor, a respiration sensor, and an electroencephalography sensor (EEG). In some embodiments, respiration is measured using mechanical, electrical, impedance, acoustic (e.g., microphone), ultrasound, infrared, or video-based measurements. Alternatively or additionally, any such above-mentioned sensors can be incorporated into a housing or enclosure that is separate from and / or spaced apart from the ear device 100 such as discussed above.

[0110] As discussed above and continuing to refer Figures 2A - 2G , the rod 130 can have a generally elongated shape. The rod 130 can include a shape such as a cylindrical shape. The rod 130 can include, for example, a circular cross-section. The rod 130 can include a first end that is connected to and / or receives a portion of the cable 150 (e.g., in the case where the ear device 100 includes such a cable 150) and the rod 130 can include a second end that is connected to the fork members 120a, 120b. In some embodiments, the rod 130 includes a hollow interior that is sized and / or shaped to receive the cable 150.

[0111] As discussed above, the ear device 100 can include one or more fork members, such as fork members 120a, 120b. In some embodiments, the ear device 100 includes both fork members 120a, 120b. Alternatively, in some embodiments, the ear device 100 includes only one of fork member 120a or fork member 120b. The fork member 120a and / or the fork member 120b can extend from a portion of the rod 130. For example, the fork member 120a and / or the fork member 120b can extend from one end of the rod 130. The fork member 120a and / or the fork member 120b can extend away from each other from the rod 130. For example, each fork member 120a, 120b can have a first end connected to the rod 130 and a second end (which can be referred to as a "free" end) opposite the first end. The fork members 120a, 120b can extend from the rod 130 such that the second ends or free ends of the fork members 120a, 120b are spaced apart from each other. The fork members 120a, 120b can include a shape such as a cylindrical shape. The fork members 120a, 120b can include a hollow interior that is sized and / or shaped to receive the cable 150, a portion thereof, or a cable coupled to the cable 150 - e.g., in the case where the cable 150 electrically connects the electrodes 122a, 122b to a power source. The fork members 120a, 120b can have a cross-section such as a circular cross-section, for example.

[0112] The ear device 100 can include one or more electrodes positioned at or near the free ends of the fork members 120a, 120b. For example, the ear device 100 can include an active electrode 122a located at the free end of the fork member 120a and a return electrode 122b located at the free end of the fork member 120b. In some embodiments, the free ends of the fork members 120a, 120b and thus the electrodes 122a, 122b are positioned a certain distance apart from each other, for example, about 5 mm to about 20 mm apart from each other. For example, the free ends of the fork members 120a, 120b and thus the electrodes 122a, 122b can be positioned between about 6 mm and about 19 mm, between about 7 mm and about 18 mm, between about 8 mm and about 17 mm, between about 9 mm and about 16 mm, between about 10 mm and about 15 mm, between about 11 mm and about 14 mm, between about 12 mm and about 13 mm, or between about 11 mm and about 12 mm, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in certain cases. As another example, in some embodiments, the free ends of the fork members 120a, 120b and thus the electrodes 122a, 122b are positioned about 11.5 mm apart from each other. This configuration can advantageously maximize vagus nerve stimulation and can accommodate large variations in ear anatomy and / or characteristics.

[0113] At least refer to Figures 2B - 2C and Figure 2F , the fork members 120a, 120b can be angled relative to each other at an angle between about 5° and about 120°. For example, the fork members 120a, 120b can be angled relative to each other at the following angles: between about 10° and about 110°, between about 20° and about 100°, between about 30° and about 90°, between about 40° and about 80°, between about 50° and about 70°, between about 30° and about 90°, between about 40° and about 80°, between about 40° and about 70°, between about 40° and about 60°, or between about 40° and about 50°, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in certain cases.

[0114] In some embodiments, the diameter of the electrode-skin contact surface area of each of the electrodes 122a, 122b is between about 1 mm and about 10 mm, e.g., between about 2 mm and about 9 mm, between about 3 mm and about 8 mm, between about 4 mm and about 7 mm, between about 5 mm and about 6 mm, between about 3 mm and about 5 mm, or between about 2 mm and about 6 mm, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in some cases. As another example, in some embodiments, the diameter of the electrode-skin contact surface area of each of the electrodes 122a, 122b is about 4 mm. This configuration can advantageously maximize vagus nerve stimulation and can accommodate large variations in ear anatomy and / or characteristics.

[0115] In some embodiments, when the ear device 100 is used (e.g., when the ear canal element 110 is at least partially secured within the user's ear canal), the (one or more) fork members 120a, 120b are configured to apply a normal force between about 0.1 N and about 1 N to the concha and / or on the concha. For example, such an applied normal force can be between about 0.2 mm and about 0.9 mm, between about 0.3 mm and about 0.8 mm, between about 0.4 mm and about 0.7 mm, or between about 0.5 mm and about 0.6 mm, or any value therebetween, or any range defined by any combination of these values, but values outside of these values or ranges can be used in some cases. In several embodiments, a normal force is applied at the helix, scaphoid fossa, antihelix, triangular fossa, superior crus, inferior crus, crus of helix, tragus, incisura intertragica, lobule, antitragus, cymba conchae, and / or concha, or a combination thereof.

[0116] In some embodiments, the ear device 100 can be configured to allow the ear canal element 110 to move relative to the stem 130, and thus can allow the ear canal element 110 and the fork members 120a, 120b (and / or the electrodes 122a, 122b) to move relative to each other. Additionally or alternatively, in some embodiments, the ear device 100 can be configured to allow the ear canal element 110 to rotate relative to the stem 130 and / or the fork members 120a, 120b, and / or the electrodes 122a, 122b. For example, the ear device 100 can include a boss 140 that can facilitate such movement and / or rotation.

[0117] Figures 2H - 2JShows various views of the boss 140 and the ear canal element 110, with other components of the ear device 100 not shown. As shown, the boss 140 can be coupled to the ear canal element 110. The boss 140 can be rotatably coupled to the ear canal element 110 to allow the boss 140 and the ear canal element 110 to rotate relative to each other. For example, the boss 140 and / or the ear canal element 110 can be coupled to each other to facilitate a 360° rotation relative to each other, or a rotation amount or range less than 360°. The boss 140 can include a cavity 142 sized and / or shaped to receive and / or secure the rod 130 or a portion thereof. The cavity 142 can have, for example, a circular or partially circular cross-section (see Figure 2I ). The cavity 142 can be sized and / or shaped to surround all or a portion of the perimeter of the cross-section of the rod 130. For example, the cavity 142 can be sized and / or shaped to surround no more than the entire perimeter of the cross-section of the rod 130. This configuration can allow the rod 130 to be inserted into the cavity 142 transversely (e.g., perpendicular to) the axis extending through the cavity 142 and / or parallel to the axis. The cavity 142 can allow the boss 140 and the rod 130 to move relative to each other (e.g., linearly or longitudinally) while the boss 140 and the rod 130 are coupled to each other. Because the boss 140 and the rod 130 can be coupled to the ear canal element 110 and the fork members 120a, 120b, this relative movement between the boss 140 and the rod 130 can allow the fork members 120a, 120b and the ear canal element 110 to move relative to each other. This configuration advantageously allows the ear device 100 to be adjusted to accommodate the user's anatomy, such as the variable distance between the user's ear canal and the concha.

[0118] In some embodiments, the ear device 100 includes a mechanism that allows the boss 140 and the stem 130 to be held or removably fixed in certain positions. For example, the boss 140 can include a protrusion 144 that can interact with one or more notches 132 of the stem 130 to facilitate adjustment of the boss 140 and the stem 130 in various positions. In some embodiments, the protrusion 144 can be positioned within a recess 142. For example, in some embodiments, the protrusion 144 is located at or near the center of the recess 142 and / or extends outward from the surface of the recess 142. The protrusion 144 can be rounded, for example, can have a semi-circular shape or an arched shape. The notch 132 can be recessed from the outer surface of the stem 130 and can be sized and / or shaped to receive all or a portion of the protrusion 144. The stem 130 can include one, two, three, four, five, six, seven, or eight, or more notches 132, and such notches 132 can be equally or unequally spaced from each other along the length of the stem 130. The fixation (e.g., removable fixation) of the protrusion 144 within one or more notches 132 can be, for example, a snap fit or other type of fixation. The protrusion 144 can have a rounded and / or curved structure and / or shape to facilitate a smooth transition into and / or out of the notch 132. In some embodiments, the ear canal element 110 and / or the boss 140 (discussed elsewhere herein) can be disposable, and the stem 130, fork members 120a, 120b, and / or cable 150 are reusable.

[0119] In some embodiments, the stem 130 is straight (e.g., not curved). However, in alternative embodiments, the stem 130 is curved. In some embodiments, the stem 130 is rigid. Alternatively, in some embodiments, the stem 130 is flexible.

[0120] The above-described features that allow the boss 140 and the stem 130 (and thus the ear canal element 110 and fork members 120a, 120b, electrodes 122a, 122b) to move and / or rotate relative to each other advantageously allow the ear device 100 to provide a "universal" solution to accommodate large variations in ear anatomy or characteristics when providing electro-neural modulation (e.g., stimulation) to the vagus nerve via the cymba concha.

[0121] The stem 130, boss 140, fork members 120a, 120b, and / or ear canal element 110 can partially or entirely include plastic. Alternatively or additionally, the stem 130, boss 140, fork members 120a, 120b, and / or ear canal element 110 can partially or entirely include silicone, silicone-like materials such as fluorosilicone, or other elastomers.

[0122] As discussed elsewhere herein, the ear device 100 can include forks 120a, 120b, each of which can include an electrode and / or operably position the electrode at or near the cymba conchae of the ear of an object. In some embodiments, one or both of such forks 120a, 120b are flexible and / or elastic. One or both of such forks 120a, 120b can be independently flexible, e.g., with respect to each other and / or other parts of the ear device 100 (such as the ear canal element 110 and / or the stem 130). One or both of such forks 120a, 120b can be configured to allow each of the active electrode 122a and the return electrode 122b (discussed herein) to simultaneously make independent contact with respective portions of the cymba conchae. One or both of such forks 120a, 120b can be configured to allow each of the active electrode 122a and the return electrode 122b (discussed herein) to simultaneously apply a force (such as a normal force) of, for example, from about 0.01 N to about 1 N—or any other force value discussed elsewhere herein—onto respective portions of the cymba conchae. For example, such (one or more) normal forces can be applied when the ear canal element 110 is fixed within the ear canal of a user. Such a configuration can advantageously allow the forks 120a, 120b to provide independent suspension (e.g., when engaged with the ear of an object together with the ear canal element 110), which can allow each electrode coupled to the forks 120a, 120b to independently contact the cymba conchae in a comfortable manner without applying too much force and / or pressure. Thus, such a configuration can reduce or eliminate the possibility that contact between the electrode coupled to the fork 120a and the cymba conchae breaks the contact between the cymba conchae and the electrode coupled to the fork 120b. Any fork of any other ear device discussed herein can be flexible and / or elastic, as discussed above with respect to the forks 120a, 120b.

[0123] Figure 3 Another embodiment of an ear device 200 is shown. The ear device 200 can be the same as the ear device 100 in some or more aspects. For example, the ear device 200 can include an ear canal element 210, a stem 230, a boss 240, one or more forks 220a, 220b, and / or a cable 250, each of which can be similar or identical to the ear canal element 110, the stem 130, the boss 140, one or more forks 120a, 120b, and / or the cable 150 discussed above with reference to the ear device 100. The forks 220a, 220b can include electrodes similar or identical to the electrodes 122a, 122b discussed above—such as located at the free ends of the forks 220a, 220b.

[0124] As Figure 3As shown, the stem 230 can include one or more indicators 235, each of which can be aligned with and / or associated with one or more notches that can be located on other portions of the stem 230 (e.g., on opposite sides or portions of the stem 230). Such notches can be the same as the notches 132 discussed above with respect to the stem 130. The indicator 235 can advantageously indicate to the user where the corresponding notch of the stem 230 is located to assist the user in adjusting the distance and / or position of the boss 240 and / or the ear canal element 210 relative to the stem 230, the fork members 220a, 220b, and / or the electrodes coupled to the fork members 220a, 220b. The stem 230 can include one, two, three, four, five, six, seven, or eight, or more indicators 235, and such indicators 235 can be spaced equidistantly or non-equidistantly from each other along the length of the stem 230. Such an indicator 235 can be, for example, a line extending across the surface of the stem 230.

[0125] As Figure 3 As shown, the stem 230 can be curved, e.g., curved between opposite ends of the stem 230. However, in an alternative embodiment, the stem 230 is straight (e.g., not curved). In some embodiments, the stem 230 is rigid. Alternatively, in some embodiments, the stem 230 is flexible. The stem 230, the boss 240, the fork members 220a, 220b, and / or the ear canal element 210 can partially or entirely include plastic. Alternatively or additionally, the stem 230, the boss 240, the fork members 220a, 220b, and / or the ear canal element 210 can partially or entirely include silicone. In some embodiments, the stem 230 includes silicone and the boss 240 includes plastic (e.g., hard plastic).

[0126] Figure 4 Shown are bosses 240', 240", 240''' that can be associated with three different sizing and / or settings of the ear device 200 (or any ear device discussed herein), where each sizing includes a locking position of the stem 230 such that rotation and axial / linear movement of the stem 230 are fixed. For example, each of these three sizings can be associated with a fixed rotational and axial / linear position of the stem 230. Such a configuration can ensure, for example, that the stem of the ear device rotates and / or extends to the correct or optimal angle relative to the ear canal element.

[0127] Figures 5A - 5BAnother embodiment of the ear device 300 is shown. The ear device 300 can be the same as the ear device 100 (and / or other ear devices discussed herein) in some or more aspects. For example, the ear device 300 can include an ear canal element 310, a stem 330, and (one or more) forks 320a, 320b, each of which can be similar or identical to the ear canal element 110, the stem 130, and / or (one or more) forks 120a, 120b discussed above with reference to the ear device 100. Similar to the stem 230, the stem 330 can be curved, for example, curved along all or a part of its length (e.g., less than half of its length). The forks 320a, 320b can extend from the stem 330 and can be angled, for example, at any angle such as the angles discussed above with respect to the forks 120a, 120b. In one embodiment, the forks 320a, 320b are at an angle of approximately 90° relative to each other (e.g., 70° - 80°, 80° - 90°, 90° - 100°, and the overlapping ranges therein). The fork 320a can form and / or be part of an extension of the stem 330, for example, can extend along the same path as the stem 330.

[0128] Reference Figure 5C and Figure 5D , the stem 330 can be a curved flexible element that can move linearly and / or longitudinally relative to the ear canal element 310 to move or position the forks 320a, 320b in a position close to the cymba conchae, upward and / or forward. In some embodiments, the ear canal element 310 can be manufactured separately from the stem 330 and / or the forks 320a, 320b.

[0129] Figures 6A - 6BAnother embodiment of the ear device 400 is shown. The ear device 400 can include an ear canal element 410 that can be fixed to and / or within the user's ear canal (e.g., at least partially fixed within the user's ear canal), a wire element 430, and a boss 440 that can couple the ear canal element 410 to the wire element 430. The boss 440 can include one or more openings (e.g., holes) that are sized and / or shaped to receive the wire element 430 and are configured to allow the boss 440 to move relative to the wire element 430, e.g., along the length of the wire element 430. This configuration can in turn allow the ear canal element 410 to move relative to the wire element 430 when the boss 440 is coupled to the ear canal element 410. The wire element 430 can include one or more electrodes, such as electrodes 422a, 422b. Electrodes 422a, 422b can be active electrodes and return electrodes. Electrodes 422a, 422b can be positioned along a portion of the wire element 430 that is defined and / or separated by the boss 440 and / or the coupling portion of the opening (e.g., hole) in the boss 440 that receives the wire element 440. The length and / or size of the defined and / or separated portion of the wire element 430 that includes electrodes 422a, 422b can be adjusted, e.g., by movement of the boss 440 along the wire element 430. This configuration can advantageously allow the defined and / or separated portion of the wire element 430 to be adjusted to the size and / or shape of the concha of a given user. In some embodiments, one or more clamps or other attachment mechanisms / coupling devices are used to couple the neuromodulation device to the ear. In some embodiments, earbuds are used. In some embodiments, vibration therapy is included.

[0130] Electrodes 422a, 422b can be pre-mounted or overmolded onto the wire element 430. Electrodes 422a, 422b can be fixed to the wire element 430 and can also be configured to move along the wire element 430. Electrodes 422a, 422b can be spaced from each other along the wire element 430 at a distance 425 that can be the same distance as discussed above for electrodes 122a, 122b (e.g., at a distance of about 10 - 14 mm, such as 11.5 mm).

[0131] Figure 7Another embodiment of an ear device 400', which can be the same as the ear device 400, is shown. The difference is that the ear device 400' includes a placement indicator 480' and a separate component 470' including electrodes 422a, 422b, which have a predetermined spacing (e.g., the distance discussed above regarding electrodes 122a, 122b), and the electrodes 422a, 422b can be coupled to the wire element 430 according to the indicator 480'. For example, the indicator 480' can be printed on the wire element 430. Alignment of a portion of the separate component 470' with one or more of the placement indicators 480' can facilitate a user to perform a small, medium, or large "sizing". Such a separate component 470' can be adjusted by the user or locked in place and / or can be pre-threaded onto the wire element 430 or configured to clip onto the wire element 430.

[0132] Neuromodulation device

[0133] Figure 8A A block diagram of an example neuromodulation (e.g., nerve stimulation) device 800 is shown. In several embodiments, the features discussed with reference to the neuromodulation device 800 can form part of and / or can be incorporated into any ear device described herein that can be placed in or near a user's ear. However, the features discussed with reference to the neuromodulation device 800 are not limited thereto and can be incorporated into other types of neuromodulation devices. The device 800 includes a plurality of hardware components that can or are programmed to provide therapy through a user's skin. As Figure 8A shown, some of these hardware components can be optional, as indicated by the dashed boxes. In some cases, the device 800 can include only the hardware components required for stimulation therapy. The hardware components will be described in more detail below.

[0134] The device 800 can include two or more effectors, e.g., electrodes 802 for providing nerve stimulation signals. In some cases, the device 800 is configured for transdermal use only and does not include any percutaneous or implantable components. In some embodiments, the electrodes can be dry electrodes. In some embodiments, water or gel can be applied to the dry electrodes or the skin to improve conductivity. In some embodiments, the electrodes do not include any hydrogel materials, adhesives, or similar materials. In one embodiment, one or more implantable components are provided.

[0135] The device 800 can further include a stimulation circuit 804 for generating signals applied through the electrode(s) 802. The frequency, phase, timing, amplitude, or bias of the signals can be changed. The device 800 can also include power electronics 806 for providing power to the hardware components. For example, the power electronics 806 can include a battery.

[0136] Device 800 can include one or more hardware processors 808. The hardware processor 108 can include a microcontroller, a digital signal processor, an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. In one embodiment, all processing discussed herein is performed by the (one or more) hardware processors 808. The memory 810 can store patient-specific data and operating rules discussed below.

[0137] In the illustrated figure, device 800 can include one or more sensors 812. As shown, the (one or more) sensors 812 can be optional. The sensors can include, for example, biomechanical sensors configured to measure, for example, movement, respiration, and / or bioelectric sensors (e.g., EMG, EEG, and / or nerve conduction sensors). The sensors can include, for example, cardiac activity sensors (e.g., ECG, PPG), skin conductance sensors (e.g., galvanic skin response, skin electrical activity), respiration sensors (e.g., respiratory effort belt, acoustic device, microphone), and movement sensors (e.g., accelerometer, gyroscope) and combinations thereof. One or more sensors 102 can include an inertial measurement unit (IMU).

[0138] In some embodiments, the IMU can include one or more of a gyroscope, an accelerometer, and a magnetometer. The IMU can be attached or integrated with a neuromodulation (e.g., nerve stimulation) device 800. In one embodiment, the IMU is an off-the-shelf component. In addition to its ordinary meaning, the IMU can also include specific components discussed below. For example, the IMU can include one or more sensors capable of collecting motion data. In one embodiment, the IMU includes an accelerometer. In some embodiments, the IMU can include multiple accelerometers to determine motion along multiple axes. Additionally, in additional embodiments, the IMU can also include one or more gyroscopes and / or magnetometers. Since the IMU can be integrated with the nerve stimulation device 800, the IMU can generate data from its sensors in response to motion, movement, or vibration sensed by the device 800. Additionally, when a user wears a device 800 with an integrated IMU, the IMU can enable detection of the user's voluntary and / or involuntary movements.

[0139] The device 800 can optionally include user interface components such as a feedback generator 814 and a display 816. The display 816 can provide instructions or information related to calibration or treatment to the user. The display 816 can also provide alerts, such as an indication of the response to treatment. The feedback generator 814 can also be used to provide alerts. The feedback generator 814 can provide tactile feedback to the user, such as at the beginning or termination of the stimulation, to achieve a reminder alert, thereby alerting the user to troubleshoot conditions, etc. Therefore, user interface components such as the feedback generator 814 and the display 816 can provide auditory, visual, and tactile feedback to the user.

[0140] In addition, the device 800 can also include communication hardware 818 to enable wireless or wired communication between the device 800 and an external system (such as the user interface device discussed below). The communication hardware 818 can include an antenna. The communication hardware 818 can also include an Ethernet or data bus interface to enable wired communication.

[0141] Although the illustrated figure shows several components of the device 800, some of these components are optional and not necessary in all embodiments of the device 800. In some embodiments, the system can include a diagnostic device or component that does not include a neuromodulation function. The diagnostic device can be a companion wearable device wirelessly connected through a connected cloud server and includes, for example, sensors such as the heart activity, skin conductance, respiration, and / or motion sensors described elsewhere herein.

[0142] In some embodiments, the device 800 can also be configured to deliver one, two, or more of the following: magnetic stimulation, vibration stimulation, mechanical stimulation, thermal stimulation, ultrasonic stimulation, or other forms of stimulation instead of or in addition to electrical stimulation. Such stimulation can be delivered through one, two, or more effectors in contact with or close to the patient's skin surface. However, in some embodiments, the device is configured to deliver only electrical stimulation and is not configured to deliver one or more of magnetic stimulation, vibration stimulation, mechanical stimulation, thermal stimulation, ultrasonic stimulation, or other forms of stimulation.

[0143] Although several nerve stimulation devices are described herein, in some embodiments, the nerves are non-invasively regulated to achieve nerve inhibition. Nerve inhibition can occur in a variety of ways, including but not limited to hyperpolarizing neurons to inhibit action potentials and / or depleting neuronal ion stores to inhibit firing action potentials. In some embodiments, this can occur by generating nerve excitation or nerve inhibition. For example, anodic or cathodic stimulation, low-frequency stimulation (e.g., below about 5 Hz in certain cases), or continuous or intermittent burst stimulation (e.g., theta burst stimulation) can be implemented. In some embodiments, the wearable device has at least one implantable portion, which can be temporary or more long-term. In many embodiments, these devices are fully wearable and non-implantable. In some embodiments, the frequency does not exceed 1 kHz, 5 kHz, or 15 kHz. In some embodiments, theta burst stimulation at 1 Hz to 10 Hz (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Hz and the overlapping ranges therein (e.g., 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-6, 4-7, 4-8, 4-9, 4-10, 5-7, 5-8, 5-9, 5-10, 6-8, 6-9, 6-10, 7-9, 7-10, and 8-10 Hz)) is applied.

[0144] Any ear device discussed herein can be used to treat a variety of diseases and conditions, including but not limited to: depression, such as depression associated with Parkinson's disease and / or post-partum; gastrointestinal problems, such as gastrointestinal problems associated with Parkinson's disease and / or post-partum; inflammation, such as inflammation associated with Crohn's disease, rheumatoid arthritis (RA), multiple sclerosis (MS), psoriatic arthritis, osteoarthritis, and / or psoriasis; Lyme disease; Alzheimer's disease; atrial fibrillation; migraine; addiction; stress; tinnitus, etc. In several embodiments, immune dysfunction is treated. In several embodiments, the ear devices described herein can be unilateral or bilateral (e.g., placed in both ears) and can be used alone or in combination with other types of nerve modulation devices.

[0145] In several embodiments, neuromodulation (such as nerve stimulation) can provide therapeutic benefits for a variety of diseases, including but not limited to movement disorders (including but not limited to essential tremor, Parkinson's tremor, orthostatic tremor, and multiple sclerosis), urological disorders, gastrointestinal disorders, heart diseases, inflammatory diseases (e.g., neuroinflammation), mood disorders (including but not limited to depression, bipolar disorder, dysthymia, and anxiety disorders), pain syndromes (including but not limited to migraine and other headaches, trigeminal neuralgia, fibromyalgia, complex regional pain syndrome), Lyme disease, stroke, etc. Inflammatory bowel diseases (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory diseases are treated in several embodiments. In one embodiment, heart conditions (such as atrial fibrillation, hypertension, and stroke) are treated. In one embodiment, epilepsy and other seizure disorders are treated. In some embodiments, inflammatory skin conditions and immune dysfunction are also treated. Other disorders can also be treated. For example, stimulation of the vagus nerve has been shown to improve symptoms of hypertension, agility, and cardiac rhythm disorders.

[0146] In one embodiment, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine with peripheral nerve stimulation includes multiple treatment paths: (a) an acute relief path, and / or (b) a prophylactic treatment path. In one embodiment, the treatment framework and each treatment path can be executed by applying peripheral nerve stimulation via a wrist-worn nerve modulation device, an ear nerve modulation device, or any combination of a wrist-worn device and an ear device. One or both ears and / or the wrist can be stimulated.

[0147] As used herein, "prophylactic treatment path" or "prevention" shall include a reduction in the overall symptoms associated with a particular disease or condition. For example, a user can initiate nerve stimulation during the onset of mild symptoms, thereby preventing (or stopping or reducing) the occurrence of additional symptoms. As a non-limiting example, as soon as a prodromal (pre-headache) symptom is experienced, the nerve stimulation described herein is used to prevent other more severe symptoms from occurring. For example, in some embodiments, the nerve stimulation applied to a user as part of prophylactic treatment reduces the likelihood that the user will develop symptoms that would change the treatment regimen to an acute relief path. In one embodiment, the prophylactic treatment path stops or reduces more severe symptoms by 50 - 95% (e.g., stops or reduces by more than 70%, 80%, 90%, etc.).

[0148] In some embodiments, disorders and symptoms caused or exacerbated by microbial infections (e.g., bacteria, viruses, fungi, and parasites) are treated. Symptoms include, but are not limited to, sympathetic / parasympathetic imbalance, autonomic dysfunction, inflammation (e.g., neuroinflammation), motor and balance dysfunction, pain, and other neurological symptoms. Disorders include, but are not limited to, tetanus, meningitis, Lyme disease, urinary tract infections, mononucleosis, chronic fatigue syndrome, autoimmune disorders, etc. In some embodiments, autoimmune disorders and / or pain unrelated to microbial infections, including, for example, inflammation, headache, back pain, joint pain and stiffness, muscle pain and tension, etc. are treated.

[0149] Bradykinesia, dyskinesia, gait dysfunction, dystonia, and / or rigidity can also be treated according to several embodiments.

[0150] In some embodiments, the devices, systems, and methods described herein are used to treat Lyme disease (e.g., its related symptoms). In one embodiment, inflammation associated with Lyme disease (including, for example, long-term or chronic inflammation and / or acute flare-ups) is reduced. In some embodiments, the resulting neurological conditions, including, but not limited to, weakness, numbness, nerve damage, and facial muscle paralysis are treated. In addition to Lyme disease, chronic fatigue syndrome and its related symptoms, such as chronic inflammation, acute flare-ups, etc. are also treated according to several embodiments. Treatment can be accomplished, for example, by vagus nerve stimulation and / or sympathetic / parasympathetic balance. In some embodiments, the vagus nerve, trigeminal nerve, and / or great auricular nerve are neuromodulated. In some embodiments, only the vagus nerve (e.g., the auricular branch and / or non-auricular branch) is neuromodulated. In some embodiments, the vagus nerve (e.g., the auricular branch and / or non-auricular branch) and one, two, or more other nerves are neuromodulated (e.g., the trigeminal nerve, great auricular nerve, nerves of the auricular branch, etc.). In some embodiments, the vagus nerve (e.g., the auricular branch and / or non-auricular branch) is not stimulated, and instead, for example, one or more other nerves (e.g., the trigeminal nerve, great auricular nerve, other nerves of the auricular branch, etc.) are stimulated. For example, the auricular branch of the vagus nerve can be stimulated while other parts of the vagus nerve are not stimulated. In another embodiment, the auricular branch of the vagus nerve is stimulated before, after, or during the stimulation of the non-auricular part of the vagus nerve (or non-vagus nerve). Neuromodulation according to several embodiments includes stimulation using, for example, the parameters disclosed herein.

[0151] In some embodiments, a second therapy (such as vibration therapy) is provided in combination with the nerve stimulation disclosed herein. The frequency used for the second therapy can be lower or higher than that of the first stimulator and can include, for example, one or more ultrasound nerve effectors, such as piezoelectric elements. In some embodiments, the effector can be a phased array ultrasound (e.g., focused ultrasound) effector. For example, a phased array ultrasound effector can include a plurality of ultrasound transducer elements. Each of these elements can have a width and a thickness. The thickness can be related to the width (e.g., the thickness is a fraction of the width (e.g., 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, a range between such values, etc.) or a multiple (e.g., 2×, 3×, 4×, 5×, 10×, a range between such values, etc.)). Each of these elements can have a width, and the spacing between these elements can be related to the width (e.g., the same as the width, half of the width, twice the width). The spacing between these elements can be adjustable. In some embodiments, the width of these elements is between about 0.5 mm and about 2 mm and the spacing is between about 0.1 mm and about 2 mm. These elements can be arranged in a one-dimensional array or a two-dimensional array. These elements can be cuboid, rectangular, cylindrical, prismatic, pyramidal, or any suitable shape. The ultrasound signal can be, for example, between about 20 kHz and about 2 GHz or higher (e.g., about 20 kHz, about 50 kHz, about 100 kHz, about 500 kHz, about 1 MHz, about 1.5 MHz, about 2 MHz, a range between such values, etc.). At least one of these elements can transmit different frequencies. Each of these elements can transmit different frequencies. Each of these elements can transmit the same frequency. In some embodiments, the dose level applied by the ultrasound effector is between about 0 W / cm 2 and about 2 W / cm 2 (e.g., about 0 W / cm 2 , about 0.1 W / cm 2 , about 0.25 W / cm 2 , about 0.5 W / cm 2 , about 1 W / cm 2 , about 1.5 W / cm 2 , about 2 W / cm 2 , a range between such values, etc.). One, some, or all of the ultrasound transducer elements can be divergent, focused, scattered, flat, etc. In some embodiments, the transducer elements can be arranged in a manner that focuses energy (e.g., energy from different elements results in constructive interference) at a location beneath the skin surface near the target nerve or tissue region. In one embodiment, ear therapy is performed using only ultrasound therapy.

[0152] Neuromodulation (e.g., nerve stimulation), according to some embodiments, is used in place of pharmaceuticals and thus reduces unwanted drug side effects. In other embodiments, neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to, for example, reduce the dose or duration of drug therapy and thus reduce unwanted side effects. Unwanted drug side effects include, for example, addiction, tolerance, dependence, GI problems, nausea, confusion, movement disorders, appetite changes, and the like. In various embodiments, neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat epilepsy, depression, anxiety, inflammatory conditions such as inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory conditions (such as neuroinflammation and inflammatory skin conditions) which are treated in several embodiments. Neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat cardiac conditions (such as atrial fibrillation, hypertension, and stroke), which are treated in various embodiments. In one embodiment, seizure disorders are treated. Neuromodulation (such as nerve stimulation) is used in combination with (e.g., synergistically with) pharmaceuticals to treat headaches (such as migraines), which are treated in other embodiments.

[0153] User interface device

[0154] Figure 8B Communication between a nerve stimulation device 800 and a user interface device 850 via a communication link 830 is shown. The communication link 830 can be wired or wireless. The neuromodulation (e.g., nerve stimulation) device 800 is capable of communicating with the user interface device 850 and receiving instructions from the user interface device 850. The user interface device 850 can include a computing device. In some embodiments, the user interface device 850 is a mobile computing device, such as a mobile phone, smart watch, tablet computer, or wearable computer. The user interface device 850 can also include a server computing system remote from the nerve stimulation device. The user interface device 850 can include one or more hardware processors 852, a memory 854, a display 856, and power electronics 858. In some embodiments, the user interface device 850 can also include one or more sensors, such as the sensors described elsewhere herein. Additionally, in certain cases, the user interface device 850 can also generate an alert in response to a device problem or a response to treatment. The alert can be received from the nerve stimulation device 800.

[0155] In additional embodiments, data obtained from one or more sensors 802 is processed by a combination of (one or more) hardware processors 808 and (one or more) hardware processors 852. In further embodiments, data collected from one or more sensors 802 is transmitted to a user interface device 850 with little processing performed by the hardware processor 808. In some embodiments, the user interface device 850 can include a remote server that processes the data and transmits a signal back to the device 800 (e.g., via the cloud).

[0156] In some cases, the user interface device can be replaced or work with a base station. The base station can be configured to periodically (e.g., daily) stream motion sensor and usage data and charge the device.

[0157] Various embodiments of the devices and / or systems discussed herein can stimulate nerves in a user's outer ear, including but not limited to the auricular branch of the vagus nerve, the great auricular nerve, the auriculotemporal nerve, and / or the lesser occipital nerve, among others. In some embodiments, the stimulation can alternate between each nerve such that the nerves are not stimulated simultaneously. In some embodiments, all the nerves (e.g., the target nerves) are stimulated simultaneously. In some embodiments, the stimulation is delivered to each nerve in one of a plurality of burst patterns. The stimulation parameters can include one, two, three, or more of the following: on / off, duration, intensity, pulse rate, pulse width, waveform shape, and the ramp of the pulse on and off. In one embodiment, the pulse rate can be from about 1 Hz to about 100 Hz, from about 1 Hz to about 5000 Hz, from about 1 Hz to about 500 Hz, from about 5 Hz to about 50 Hz, from about 50 Hz to about 300 Hz, or about 150 Hz. In some embodiments, the pulse rate can be from 1 kHz to 20 kHz. The range of the pulse width can be 50 to 500 μs (microseconds) in some cases, such as about 300 μs. The intensity of the electrical stimulation can vary between 0 mA and 500 mA, and in some cases, the current can be about 1 to 11 mA. As another example, the current can be between about 1 mA and about 5 mA. The electrical stimulation can be adjusted according to different patients and different electrical stimulation methods. The increment of intensity adjustment can be, for example, from 0.1 mA to 1.0 mA. In one embodiment, the stimulation can last for about 10 minutes to 1 hour, such as about 10, 20, 30, 40, 50, or 60 minutes, or a range including any two of the foregoing values. In some embodiments, multiple electrical stimulations can be offset from each other in time by a predetermined fraction of a multiple of the period of a measured rhythmic biosignal (such as hand tremor) - such as, for example, 1 / 4, 1 / 2 or 3 / 4 - to deliver. In some embodiments, multiple electrical stimulations can be delivered with a predetermined fractional temporal offset from each other during the measured exhalation or during the measured inhalation (e.g., only during the measured exhalation or only during the measured inhalation). Other possible stimulation parameters are described, for example, in U.S. Patent No. 9,452,287 to Rosenbluth et al., U.S. Patent No. 9,802,041 to Wong et al., PCT Publication No. WO 2016 / 201366 to Wong et al., PCT Publication No. WO2017 / 132067 to Wong et al., PCT Publication No. WO 2017 / 023864 to Hamner et al., PCT Publication No. WO 2017 / 053847 to Hamner et al., PCT Publication No. WO 2018 / 009680 to Wong et al., and PCT Publication No. WO 2018 / 039458 to Rosenbluth et al., Application PCT / US2022 / 074376 (published as PCT Publication No. WO 2023 / 015158) to Schulte et al., the entire contents of each of the above patents are hereby incorporated by reference into this disclosure.

[0158] Controller

[0159] Figure 8C shows a block diagram of an embodiment of a controller 880 that can be implemented with the hardware components described above with respect to Figures 8A - 8B described. The controller 880 can include multiple engines for performing the processes and functions described herein. These engines can include programmed instructions to perform the processes discussed herein for detecting input conditions and controlling output conditions. These engines can be executed by one or more hardware processors of the neuromodulation (e.g., neural stimulation) device 800 alone or in combination with the user interface device 850. The programmed instructions can be stored in the memory 810. The programmed instructions can be implemented in C, C++, JAVA, or any other suitable programming language. In some embodiments, some or all of the portions of these engines included in the controller 880 can be implemented in dedicated circuits such as ASICs and FPGAs. Certain aspects of the functionality of the controller 880 can be remotely executed by a server (not shown) over a network. Although shown as separate engines, the functions of these engines discussed below do not necessarily need to be separate. Thus, the controller 880 can be implemented with the hardware components referenced above with respect to Figures 8A - 8B described.

[0160] The controller 880 can include a signal collection engine 802. The signal collection engine 802 can be implemented to obtain raw data from sensors embedded in the device, including but not limited to obtaining accelerometer or gyroscope data from the IMU 802. In some embodiments, the signal collection engine 802 can also perform signal preprocessing on the raw data. Signal preprocessing can include noise filtering, smoothing, averaging, and other signal preprocessing techniques to clean the raw data. In some embodiments, portions of these signals can be discarded by the signal collection engine 802.

[0161] The controller 880 can also include a feature extraction engine 804. The feature extraction engine 804 can extract relevant features from the signals collected by the signal collection engine 802. These features can be in the time domain and / or the frequency domain. For example, some of these features can include amplitude, bandwidth, area under the curve (e.g., power), energy in frequency bins, peak frequency, ratio between frequency bands, etc. These features can be extracted using signal processing techniques such as Fourier transform, band-pass filtering, low-pass filtering, high-pass filtering, etc.

[0162] The controller can further include a rule generation engine 806. The rule generation engine 806 can use the extracted features from the collected signals and determine rules corresponding to the neuromodulation therapy. The rule generation engine 806 can automatically determine the correlation between specific extracted features and the neuromodulation therapy outcome. In some cases, features are extracted from the biological signals sensed by one or more sensors and / or neuroeffectors (such as one, two, four, or six stimulation electrodes). In some embodiments, the stimulation electrodes themselves are used as sensing elements (e.g., for detecting electrodermal activity; or cardiac activity; or EEG) and can be placed on or near the ear of the subject or placed on or near different parts of the subject's body (such as the wrist, finger, arm section, etc.). The one or more sensors can be selected from the group consisting of or mainly consisting of: a photoplethysmography sensor (PPG), a galvanic skin response sensor (GSR), an inertial measurement unit sensor (IMU), a temperature sensor (e.g., obtaining body / skin temperature or ambient temperature), a respiration sensor (e.g., an acoustic device, a microphone, etc.) and / or an electroencephalography sensor (EEG) (or a combination of two or more thereof). In some embodiments, the features extracted from the biological signals include motion data, an electrocardiogram, or a plethysmograph signal. The rule generation engine 806 can determine a stimulation pattern for improving the treatment outcome.The results can include, for example, identifying patients who will respond to treatment (e.g., during an initial trial fitting or calibration process) based on features of kinematic data (e.g., approximate entropy), predicting the stimulation settings for a given patient that will result in the best treatment outcome (e.g., dose, where the dose or parameters of the treatment include, but are not limited to, the duration of the stimulation, the frequency and / or amplitude of the stimulation waveform, and the time of day the stimulation is applied), predicting the severity of a patient's condition at a given point, predicting a patient's response over time, examining a patient's medication responsiveness in conjunction with the severity of the condition over time, predicting the response to transcutaneous or percutaneous stimulation or other nerve stimulation or neurosurgical procedures based on the characteristics and severity of the condition over time, and predicting the optimal time for a patient to receive transcutaneous or percutaneous stimulation or deep brain stimulation or thalamotomy based on the characteristics and severity of the condition over time, assessing kinematic measurements using condition characteristics obtained from the device to predict patient-reported treatment outcomes or user-reported satisfaction; using condition characteristics evaluated from kinematic measurements and a patient usage log obtained from the device to predict a patient's response to an undesired user experience, where the undesired user experience can include, but is not limited to, device failure and adverse events such as skin irritation or burns; predicting a patient response trend based on condition severity, where the trend can be evaluated across the total number of treatment courses, within a single user, or across user groups; predicting or classifying subtypes based on kinematic analysis of condition characteristics to predict user response; predicting or classifying subtypes to provide guidance for individually optimized treatment parameters; predicting or classifying subtypes to optimize future study designs based on the subtype (e.g., selecting a specific subtype for a clinical study, where the specific design addresses the treatment needs of that subtype); and predicting user or customer satisfaction (e.g., net promoter score) based on user response or other kinematic characteristics from measured movement. In some embodiments, different dosing regimens and / or different stimulation parameters can reduce tolerance or habituation and / or can increase user comfort / compliance.

[0163] These conditions include, but are not limited to, tremors, such as essential tremor. In one embodiment, with respect to tremors, the results can include identifying patients who will respond to treatment (e.g., during an initial trial fitting or calibration process) based on kinematic data of the tremor, predicting the stimulation settings for a given patient (based on their tremor characteristics) that will result in the best treatment outcome (e.g., dose, where the dose or parameters of the treatment include, but are not limited to, the duration of the stimulation, the frequency and / or amplitude of the stimulation waveform, and the time of day the stimulation is applied), predicting the tremor severity at a given point for the patient, predicting the patient's response over time, examining the patient's medication responsiveness in conjunction with tremor severity over time, predicting the response to transdermal or percutaneous stimulation or other nerve stimulation or neurosurgical procedures based on tremor characteristics and severity over time, predicting the optimal time for the patient to receive transdermal or percutaneous stimulation or deep brain stimulation or thalamotomy based on tremor characteristics and severity over time, using tremor characteristics obtained from the device to evaluate kinematic measurements to predict patient-reported treatment outcomes or user-reported satisfaction; using tremor characteristics evaluated from kinematic measurements and the patient usage log obtained from the device to predict the patient's response to an undesired user experience, where the undesired user experience can include, but is not limited to, adverse events such as device failure and skin irritation or burns; predicting the patient response trend based on tremor severity, where the trend can be evaluated across the total number of treatment courses, within a single user, or across user groups; predicting or classifying tremor subtypes based on kinematic analysis of tremor characteristics to predict user response; predicting or classifying tremor subtypes to provide guidance for individually optimized treatment parameters; predicting or classifying tremor subtypes to optimize future study designs based on the subtype (e.g., selecting a specific subtype of essential tremor for a clinical study, where the specific design addresses the treatment needs of that subtype); and predicting user or customer satisfaction (e.g., net promoter score) based on user response or other kinematic characteristics from measuring tremor movement. In some embodiments, different dosing regimens and / or different stimulation parameters can reduce tolerance or habituation and / or can increase user comfort / compliance. In several embodiments, a neuromodulation (e.g., ear, wrist, leg nerve stimulation) device is used to identify patients who may be candidates for other treatments, such as drug therapy, surgical intervention, deep brain stimulation, or thalamotomy. In some embodiments, the response and tolerance to the nerve stimulation described herein are used to provide input to a prediction model that provides an assessment of the likelihood of a patient's response to an implantable deep brain stimulation or other implantable or non-implantable treatment. The algorithms and sensor measurements obtained from the device can help identify patients who may be good or poor candidates for other treatments, such as deep brain stimulation, drug therapy, surgical intervention, thalamotomy.The devices described herein, in some embodiments, can be used to classify subjects who have used the device for 1 week to 1 year or longer as being in the top 50%, 25%, or 10% or bottom 50%, 25%, or 10% of subjects who will respond to other such treatments. This can be particularly helpful in enabling patients who will benefit from most such treatments, such as deep brain stimulation, to receive such treatment. In several embodiments, this type of predictive diagnostic ability should lead to more personalized treatment and better health outcomes.

[0164] In some embodiments, the rule generation engine 886 relies on calibration instructions to determine rules between features and outcomes. The rule generation engine 886 can use machine learning modeling together with signal processing techniques to determine rules, where the machine learning modeling and signal processing techniques include, but are not limited to: supervised and unsupervised algorithms for regression and classification. Specific algorithm categories include, for example, artificial neural networks (perceptron, backpropagation, convolutional neural network, recurrent neural network, long short-term memory network, deep belief network), Bayesian (naive Bayes, multinomial Bayes, and Bayesian network), clustering (k-means, expectation maximization, and hierarchical clustering), ensemble methods (classification and regression tree variants and boosting), instance-based (k-nearest neighbor, self-organizing map, and support vector machine), regularization (elastic net, ridge regression, and least absolute shrinkage and selection operator), and dimensionality reduction (principal component analysis variants, multidimensional scaling, discriminant analysis variants, and factor analysis). In some embodiments, the controller 886 can automatically determine outcomes using the rules. The controller 886 can also use the rules to control or change the settings of the neuromodulation device, including but not limited to stimulation parameters (e.g., stimulation amplitude, frequency, mode (e.g., burst stimulation), interval, time of day, individual session, or cumulative on time, etc.), as described below. In some cases, the rules can be hard-coded and need not be generated.

[0165] Thus, the rules can improve the operation of neuromodulation (e.g., neuromodulation device) and advantageously increase patient comfort. The generated rules can be stored in the memory 810 and / or the memory 854. For example, the rules can be generated after calibration and stored prior to operation of the neuromodulation device 800. Thus, in some embodiments, the rule application engine 888 can apply the stored rules to new data collected by the IMU or the physiological sensor(s) to determine outcomes or control neuromodulation (e.g., neuromodulation device 100). For example, the rule application engine 888 can generate electrical stimulation pattern instructions based on the rules generated by the rule generation engine 886 or stored in the memory.

[0166] Stimulation gating

[0167] In some embodiments, a sudden burst of stimulation is applied in the ear (such as Figure 9A shown). This is helpful for enhancing patient comfort in certain patients, where gated stimulation may be uncomfortable and unexpected for the user. In some embodiments, the sudden burst of stimulation occurs only during a portion of the respiratory cycle. For example, in some embodiments, when the pulse is turned on at full power, there is no ramp period that masks the perceived intensity of the stimulation. Thus, in some embodiments, the regular application engine 886 can be programmed to generate stimulation instructions that are progressive after each burst of stimulation.

[0168] For example, the regular application engine 886 can generate a progressive burst pattern as Figure 9B shown. The burst pattern can start at a lower stimulation intensity and then progressively increase to the selected intensity. For example, if the selected intensity is set to 3 mA, at the start of each pulse, the amplitude can start at an initial intensity (such as 0.4 mA) and vary in 0.1 mA increments to reach the selected amplitude over a 0.5 s time period. In certain cases, the rule generation engine 886 can determine the initial intensity, increment, and time period based on the learning algorithm discussed above.

[0169] In additional examples, the regular application engine 886 can generate a progressive initial burst pattern as Figure 9C shown. The initial pulse at the start of the stimulation can ramp up. For example, if the selected amplitude is 3 mA, at the start of each pulse, the first phase can be extended, where the initial amplitude can start at 0.4 mA and vary in 0.1 mA increments to reach the selected amplitude over a 0.5 s time period. In certain cases, the second phase may require an increase in amplitude and / or duration to maintain charge balance throughout the phase.

[0170] In some embodiments, the stimulation can ramp up over a period of 0.5 - 30 seconds or longer (e.g., 0.5 - 2, 2 - 5, 5 - 10, 10 - 15, 15 - 30 seconds and overlapping ranges therein) from 0.05 - 0.8 mA (e.g., 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 mA and overlapping ranges therein) or the ramp up can be about 10 - 50%, 50 - 100% or double with each increment. The difference between increments can be constant or different. For example, the gradual increase or ramp up can be 0.1 mA to 0.2 mA to 0.3 mA to 0.4 mA to 0.8 mA to 1.0 A to 1.6 A to 3.2 A (higher if desired). Alternatively, the gradual increase or ramp up starts at 0.5 mA and continuously increases by 0.2 mA to reach a set point (such as 2.5 A). The ramp up can occur upon each initial turn - on of the stimulation or when the user increases the stimulation during a treatment session. The user can adjust the ramp up or it can be automated by the system. In some embodiments, a ramp down is included. In some embodiments, the gradual increase or ramp up can also be used for non - burst stimulation (such as tonic stimulation).

[0171] The regular application engine 886 is also capable of generating other gradual stimulation patterns that are variations of the above - described patterns to enhance comfort and reduce the impact of the electrical stimulation on the user.

[0172] The devices, systems, and methods described above and in the claims are used in several embodiments to treat depression (including but not limited to postpartum depression, depression related to neurological disorders, major depression, seasonal affective disorder, depression, etc.). In some embodiments, inflammation is also treated, including but not limited to inflammatory gastrointestinal disorders and skin disorders. In some embodiments, the inflammation includes neuroinflammation. In one embodiment, Lyme disease and chronic fatigue syndrome (including chronic inflammatory states and symptoms) are treated. Neurological disorders (such as Parkinson's disease and Alzheimer's disease) and their related symptoms and manifestations (such as depression, tremors, movement disorders, etc.) are treated in several embodiments. In some embodiments, rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, osteoarthritis, and psoriasis are treated. As described herein in several embodiments, cardiac conditions (such as atrial fibrillation, hypertension, and stroke) can also be treated via neuromodulation. In one embodiment, epilepsy and other seizure disorders are treated. Headache disorders (such as migraines) are treated in other embodiments.

[0173] In some embodiments, instead of or in addition to being placed on the ear, the neuromodulation (e.g., stimulation) devices described herein are placed on the wrist or finger, or elsewhere on the arm. One, two, three, or four neuromodulation devices may be worn. For example, the devices may be worn on or near the ear and on or near the wrist. When two or more devices are used, they may be activated (e.g., synchronized) individually or together. In some embodiments, a system for applying neuromodulation to a subject includes a plurality of neuromodulation devices placed on or near different parts of the subject's body. For example, such a system can include a first neuromodulation device (such as any ear device described herein) that can be placed on or near the subject's ear and a second neuromodulation device that can be placed on or near a different part of the subject's body (such as the wrist, finger, arm portion, etc.).

[0174] In some embodiments, the system can include a plurality of neuromodulation devices that communicate wirelessly with each other and provide synchronized, patterned stimulation. In some embodiments, the plurality of neuromodulation devices can be electrically connected to a plurality of electrode pairs to simultaneously stimulate multiple nerves. In one embodiment, the system can include a neuromodulation device that targets a nerve of the subject (e.g., the median nerve) at the wrist or other location on the arm and a neuromodulation device that targets the vagus nerve in the ear (such as any ear device described herein). In some embodiments, such a neuromodulation device on the wrist or arm includes one or more electrodes that at least partially surround the wrist, a skin interface that ensures good electrical contact with the user, an electronics box or housing that contains the stimulator, one or more physiological sensors, and other associated electronics such as a controller or processor for executing instructions, a memory for storing instructions, a user interface that can include a display and buttons, a communication module, a battery that can be rechargeable and optionally an induction coil for charging the battery, etc., and / or a strap for holding all these components together and securing the device firmly around the user's wrist. In some implementations, each neuromodulation device in the system can communicate with each other via a wired or wireless connection. The plurality of neuromodulation devices can provide synchronized stimulation to multiple nerves. The stimulation can be, for example, burst, offset, or alternating between multiple nerves.

[0175] According to several embodiments, the regulation of the vagus nerve is achieved with the devices described herein. In some embodiments, the devices described herein are used to stimulate the autonomic system. In some embodiments, the devices described herein are used to balance the sympathetic / parasympathetic nervous system.

[0176] In several embodiments, a method of treating a user and / or applying neuromodulation to a user includes receiving electroencephalogram (EEG) data related to the user, and generating parameters of a first electrical stimulation signal (e.g., a first burst electrical stimulation signal) and / or a second burst electrical stimulation signal (e.g., a second burst electrical stimulation signal) at least in part by analyzing the EEG data related to the user. This can be particularly advantageous in allowing customized stimulation based on specific abnormal neuronal oscillations that can cause one or more conditions of the user, such as migraines or other headache pathologies. In some embodiments, the EEG data can be recorded using a single-channel, 2-channel, 4-channel, 8-channel, 16-channel, 32-channel system, or a system having more than 32 channels, where one or more channels are positioned over a predetermined region of interest.

[0177] In some embodiments, methods of treating a neurological condition using neuromodulation are provided. The method can include any number of the following steps: positioning a first nerve effector (e.g., of a first neuromodulation device) on the skin surface near the median nerve of the user's arm or wrist; positioning a second nerve effector (e.g., of a first or second neuromodulation device) on the skin surface near a nerve other than the median nerve of the user's arm or wrist; receiving data related to the user, where the data is optionally EEG data; generating parameters of a first neuromodulation signal and a second neuromodulation signal, where generating the parameters includes analyzing the data related to the user; delivering the first neuromodulation signal to the first nerve effector to modulate the median nerve; and delivering the second neuromodulation signal to the second nerve effector to modulate a nerve other than the median nerve (e.g., the ulnar nerve or the vagus nerve of the user), thereby treating the neurological condition.

[0178] In some embodiments, a method of treating migraines using transcutaneous peripheral nerve stimulation can include any number of the following steps: positioning a first peripheral nerve effector (e.g., of a first neuromodulation device) on the skin surface near the median nerve of the user's arm or wrist; positioning a second peripheral nerve effector (e.g., of a first or second neuromodulation device) on the skin surface near a nerve other than the median nerve of the patient's arm or wrist; transcutaneously delivering a first electrical stimulation signal to the first peripheral nerve effector to stimulate the median nerve; and transcutaneously delivering a second electrical stimulation signal to the second peripheral nerve effector to stimulate a nerve other than the median nerve.

[0179] In some embodiments, a neuromodulation device for treating migraine using transcutaneous peripheral nerve stimulation can include any number of the following devices: a first peripheral nerve effector configured to be placed on the skin surface near the median nerve of the user's arm or wrist; a second peripheral nerve effector configured to be placed on the skin surface near a nerve other than the median nerve of the user's arm or wrist; and a controller configured to: transcutaneously deliver a first electrical stimulation signal to the first peripheral nerve effector to stimulate the median nerve; and transcutaneously deliver a second electrical stimulation signal to the second peripheral nerve effector to stimulate a nerve other than the median nerve (such as the vagus nerve).

[0180] Respiratory-gated ear stimulation has been shown to target brain networks involved in migraine and has shown promise in treatment. In some embodiments, systems and methods for providing nerve stimulation to one, two, or more peripheral nerve targets that modulate vagal tone, parasympathetic efferents, vagal brainstem regions, sympathetic efferents, or sympathetic-mediated brainstem regions, where the stimulation is initiated in phase with a portion of the respiratory cycle by measuring the respiratory cycle. Specifically, these systems and methods can use a detection device to detect changes in the respiratory cycle over time. When a predetermined relationship or correlation or within a predetermined range between the detected activity and a threshold (such as matching, rate of change of activity) is detected, the stimulator is instructed to provide stimulation to at least one or more peripheral nerves. The stimulation can advantageously be related to the detected respiratory phase (such as exhalation), thereby providing a potentially synergistic increase in stimulation and thus improving the therapeutic benefit. Any of the neuromodulation devices discussed (e.g., any ear device discussed herein) can be used for respiratory-gated ear stimulation. In some embodiments, the nerve stimulation devices and methods disclosed herein do not use or rely on any respiratory gating. In some embodiments, the nerve stimulation devices and methods disclosed herein use or rely on respiratory gating.

[0181] In some embodiments, when combined with drug therapy - including but not limited to antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and MAO inhibitors - peripheral nerve stimulation can advantageously have a synergistic effect. These effects can include: enhanced response to treatment; lower doses of tricyclic antidepressants, selective serotonin reuptake inhibitors, and MAO inhibitors required to achieve these effects and thus reduce adverse reactions, etc. The combination therapy can in some embodiments be beneficial in reducing the time taken to achieve a therapeutic effect (e.g., reducing by at least 10%, 25%, 50% or more, or overlapping ranges thereof) or extending the therapeutic effect (e.g., extending by at least 10%, 20%, 40% or more, or overlapping ranges thereof), or improving the overall benefit (e.g., more reduction in the amplitude or frequency of mood disorder symptoms).

[0182] According to several embodiments, the nerve stimulation embodiments described herein work in concert with pharmacological agents. This synergy is particularly beneficial given that the digestive systems of many patients with inflammatory bowel disease and other gastrointestinal conditions are already sensitive and inflamed, because in one embodiment the patient will require a lower overall dose of the pharmacological agent to achieve an equivalent (or better) effect than achieved without nerve stimulation. These pharmacological agents can include, but are not limited to, anti-tumor necrosis factor (anti-TNF) drugs, Janus kinase (JAK) inhibitors, or 5-aminosalicylic acid derivatives (5-ASA). This results in fewer undesirable side effects in several embodiments.

[0183] According to several embodiments, the nerve stimulation embodiments described herein work in concert with pharmacological agents for rheumatoid arthritis. This synergy is particularly beneficial for rheumatoid arthritis because in one embodiment the patient will require a lower overall dose of the pharmacological agent to achieve an equivalent (or better) effect than achieved without nerve stimulation. These pharmacological agents can include, but are not limited to, conventional disease-modifying antirheumatic drugs (DMARDs), biologics and biosimilars, and JAK inhibitors. This results in fewer undesirable side effects in several embodiments.

[0184] In several embodiments, when combined with drug therapies - including those for mental health disorders, cardiac disorders, pain, and other diseases - stimulation regulated by one or more measured biological signals can advantageously have a synergistic effect. These effects can include enhanced response to treatment, lower doses of drug therapy required to achieve these effects and thus reduced adverse reactions, and so on. This is beneficial in some embodiments for reducing the time taken to achieve a therapeutic effect (e.g., reducing by at least 10%, 25%, 50% or more, or overlapping ranges thereof) or extending the therapeutic effect (e.g., extending by at least 10%, 20%, 40% or more, or overlapping ranges thereof), or improving the overall benefit (e.g., greater reduction in pain, blood pressure, heart rate, frequency of arrhythmias, etc.).

[0185] In several embodiments, when combined with drug therapies including triptans, ergots, or CGRP inhibitors, peripheral nerve stimulation can advantageously have a synergistic effect. These effects can include enhanced response to treatment, lower doses of triptans, ergots, or CGRP inhibitors required to achieve these effects and thus reduce adverse reactions, and the like. The combination therapy can, in some embodiments, be beneficial in reducing the time taken to achieve a therapeutic effect (e.g., reducing by at least 10%, 25%, 50% or more, or overlapping ranges thereof) or extending the therapeutic effect (e.g., extending by at least 10%, 20%, 40% or more, or overlapping ranges thereof), or improving the overall benefit (e.g., greater reduction in the magnitude or frequency of migraine symptoms).

[0186] Any of the neuromodulation devices discussed herein (e.g., any of the ear devices discussed herein) can be used to modulate, for example, the vagus nerve of a subject alone (e.g., stimulate) via a separate neuromodulation device or in combination with one or more other nerves of the subject, and such one or more other nerves can include, but are not limited to, the median nerve, radial nerve, ulnar nerve, peroneal nerve, saphenous nerve, tibial nerve, and / or other nerves or meridians that can be accessed on a limb.

[0187] In some embodiments, transcutaneous nerve neuromodulation at the arm and / or wrist (e.g., median nerve and / or radial nerve stimulation) can advantageously inhibit the blood pressure increase associated with sympathetic nerve excitation and the pre-motor sympathetic discharge in the rostral ventrolateral medulla (rVLM). Neuromodulation of the median nerve and / or radial nerve can, for example, provide more convergent input to the cardiovascular pre-motor sympathetic neurons in the rVLM.

[0188] In addition, in some embodiments, vagus nerve stimulation is also capable of modulating the trigeminal nuclei to inhibit inflammation. Thus, in several embodiments, the vagus nerve is stimulated to reduce inflammation via the trigeminal pathway. In other embodiments, instead of or in addition to the vagus nerve, the trigeminal nerve is directly stimulated. In some embodiments, transcutaneous nerve stimulation projects to the nucleus of the solitary tract (NTS) and the spinal trigeminal nucleus (Sp5) regions to modulate trigeminal sensory complex excitability and connections with higher brain structures. During migraine (characterized, for example, by vasodilation), the trigeminal sensory nuclei can participate in neurogenic inflammation. In some embodiments, stimulating the vagus nerve modulates the trigeminal sensory pathway to improve migraine pathophysiology and reduce headache frequency and severity. For example, increased activation of the raphe nuclei and locus coeruleus can inhibit nociceptive processing within the sensory trigeminal nucleus. Human skin is well innervated by the autonomic nervous system, and the neuromodulation (e.g., stimulation) of nerves or acupuncture points disclosed herein can potentially contribute to the treatment of migraine or other headache conditions. For example, transcutaneous nerve stimulation of afferent nerves in the periphery or distal extremities - including but not limited to the median nerve - is connected by neural circuits to the arcuate nucleus of the hypothalamus. In some embodiments, the devices and methods described herein increase, decrease, or otherwise balance vasodilation and vasoconstriction through neuromodulation (such as the vagus nerve, trigeminal nerve, and / or other nerves around the ear). For example, in several embodiments, a reduction in vasodilation is provided to treat or prevent migraine or other conditions exacerbated by vasodilation. In other embodiments, vasoconstriction is reduced in conditions where, for example, dilation is beneficial (such as in hypertension and pain). In some embodiments, the regulation (dilation or constriction) of blood vessels is used to treat tinnitus. In one embodiment, the devices and methods described herein reduce inflammation (including but not limited to inflammation following microbial infection), and the reduction of inflammation treats tinnitus.

[0189] In various embodiments, neuromodulation of one or more nerves of an object is responsive to a physiological parameter or other information associated with the object (e.g., movement of the object, position data). Such physiological parameters or other information can include, but are not limited to, ground reaction force or foot pressure (e.g., force sensors or pressure insoles), muscle activity (e.g., EMG), cardiovascular measurements (e.g., heart rate, heart rate variability (HRV), photoplethysmography (PPG) or measuring ECG and / or arrhythmic ventricular and / or atrial asynchrony using electrodes), skin conductance (e.g., skin conductance response, galvanic skin response), respiratory rate, skin temperature, pupil diameter, and sleep state (e.g., awake, light sleep, deep sleep, REM). Using standard statistical analysis, machine learning, deep learning, or big data techniques (such as logistic regression or naive Bayes classifier), such information can be analyzed to evaluate the activity state of the object (such as sedentary vs. active, stress level, etc.), and thus can serve as a predictor of migraine or headache attacks or other conditions.

[0190] Sympathetic and parasympathetic activities can be measured by several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response. HRV can provide a quick and effective rough approximation of the autonomic activities in the body. HRV can be determined by analyzing the time intervals between heartbeats (also known as RR intervals). Heart rate can be accurately obtained, for example, by a chest strap, finger sensor, or recording device of a nerve effector (such as one, two, four, or six stimulation electrodes). The differences between consecutive RR intervals can provide a portrait of an individual's cardiac health and autonomic activities. Generally speaking, the healthier the heart, the greater the variability between its consecutive RR intervals. This inter-beat data can also be used to represent the levels of sympathetic and parasympathetic activities of the user. Through frequency domain analysis, the heart rate frequency can be divided into different frequency bands. High-frequency signals (about 0.15 - 0.4 Hz) can almost exclusively reflect parasympathetic activities, while low-frequency signals (about 0.04 - 0.15 Hz) can represent the mixture of sympathetic and parasympathetic activities. Therefore, calculating the ratio of high-frequency (HF) to low-frequency (LF) signals can yield an approximation of an individual's sympathetic nerve tone. In some embodiments, in addition to frequency domain methods, HRV can also be analyzed, for example, using time domain and geometric domain methods. In some embodiments, an increase in heart rate variability can indicate an increased parasympathetic response and / or a decreased sympathetic response. A decrease in heart rate variability can indicate a decreased parasympathetic response and / or an increased sympathetic response. In some embodiments, the system can sense an increase or decrease in HRV by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, 100% or more compared to a baseline value (or a target desired HRV value), and institute changes in one, two, or more stimulation modality parameters (such as frequency, width, phase, timing, amplitude, offset, nerve target, etc.). For example, in some embodiments, one, two, or more stimulation modalities can be configured to adjust (such as increase or decrease) the stimulation modality parameters for one or more nerves (such as peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems and / or change or modify which of these one or more nerves is the target, and can confirm the response to treatment by sensing an increase or decrease in parasympathetic or sympathetic nerve tone (including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency content of HRV).In some embodiments, one, two, or more stimulation modalities can be configured to adjust (e.g., increase or decrease) the amplitude of stimulation for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and can confirm a response to treatment by sensing an increase or decrease in parasympathetic or sympathetic tone (including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency content of HRV). In some embodiments, one, two, or more stimulation modalities can be configured to adjust (e.g., increase or decrease) the frequency of stimulation for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and can confirm a response to treatment by sensing an increase or decrease in parasympathetic or sympathetic tone (including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency content of HRV). In some embodiments, one, two, or more stimulation modalities can be configured to adjust (e.g., increase or decrease) the pulse width for one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and can confirm a response to treatment by sensing an increase or decrease in parasympathetic or sympathetic tone (including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency content of HRV). In some embodiments, one, two, or more stimulation modalities can be configured to adjust (e.g., change or modify) which one of one or more nerves associated with the sympathetic and / or parasympathetic nervous systems is the target (e.g., the axonal nerve) based on, for example, sensed biomarkers (e.g., heart rate, heart rate variability, heart rhythm, skin sympathetic nerve activity, skin electrical activity, body temperature measured at the wrist, respiratory cycle, electroencephalogram activity, and / or cytokine levels, etc.), and can confirm a response to treatment by sensing an increase or decrease in parasympathetic or sympathetic tone (including but not limited to an increase or decrease in HRV, a change in the high-frequency content of HRV, and a change in the ratio of high-frequency to low-frequency content of HRV). In some embodiments, the method provides multiple treatment paths that at least partially rely on sensing user biomarkers (e.g., heart rate, heart rate variability, heart rhythm, skin sympathetic nerve activity, skin electrical activity, body temperature measured at the wrist, respiratory cycle, electroencephalogram activity, cytokine levels, physical activity, oxygen level, etc.). In some embodiments, biomarkers can include patient demographics, prior medication use, prior device treatment use, and / or sleep cycle. In some embodiments, additional data affecting stimulation and / or treatment, such as weather information (e.g., air temperature, humidity, air pressure, altitude, etc.) at the patient's local address, can be monitored. In one embodiment, physical activity can be measured with a motion sensor. In one embodiment, oxygen level can be measured with a pulse oximeter (e.g., via pulse oximetry).In some embodiments, one or more biomarkers are sensed immediately before, during, and / or after a therapeutic stimulus. In another embodiment, biomarkers are sensed hours or days before or after the stimulus. For example, body fluids can be used to determine elevated biomarkers such as cytokines or other inflammatory compounds, elevated microorganisms, low / high electrolytes, and the stimulus is applied as a treatment to reduce such biomarkers (or raise them if they are below the desired range). Body fluids used to determine biomarkers include blood, urine, saliva, sweat, tears, nasal secretions, etc. These can be measured using sensors that are separate from (e.g., independent of) or communicate with the neuromodulation components described herein. The sensors can measure a condition (such as microorganism levels) or a symptom indicative of a condition (such as elevated body temperature due to a microorganism infection), and either or both can be treated with the neuromodulation parameters described herein. In some embodiments, sensors are used after treatment to confirm efficacy or alternative therapies (drugs, different or additional non-invasive or implantable nerve stimulation, etc.).

[0191] In some embodiments, the balance of parasympathetic and sympathetic activity can be evaluated by frequency analysis of heart rate variability measured by plethysmography using an LED light source and an optical sensor disposed in the device to measure fluctuations in light levels caused by blood flow, targeting a major blood vessel around the knee or, in other embodiments, in the arm or neck or ear. In some embodiments, heart rate can be measured using an accelerometer-based sensor, a neuroeffector (such as one, two, four, or six stimulating electrodes), or an electrical-based sensor - similar to a single-lead or multi-lead ECG monitor. In some embodiments, the stimulating electrodes themselves are used as sensing elements (e.g., for detecting skin electrical activity; or cardiac activity; or EEG) and can be placed on or near the ear of the subject or on or near different parts of the subject's body (such as the wrist, finger, arm section, etc.).

[0192] In some embodiments, stimulation of one, two, or more nerves in the upper and / or lower limbs can be combined with stimulation of the auricular branch of the vagus nerve (ABVN) - such as through the concha (e.g., the cymba conchae or the cavum conchae) or the tragus - to modulate vagal activity and restore balance in the autonomic nervous system. Some embodiments of the disclosed systems, devices, and methods can stimulate only the ABVN.

[0193] Any neuromodulation device discussed herein (e.g., any ear device discussed herein) can respond to multiple symptom onsets, including in some cases unilateral pulsatile cranial pain, sensitivity to sensations of light, sound, and smell, nausea, and dysfunction of the autonomic, cognitive, emotional, and motor systems. If the number of onsets in a day is relatively high, treatment can be increased, for example, by increasing the stimulation amplitude, stimulation duration, or number of treatment sessions. The number of symptom onsets can be detected in various ways to control the stimulation applied by the system and / or the device(s). In some embodiments, the subject can input symptom-related events on a mobile device configured to communicate directly and / or indirectly with the neuromodulation device, including but not limited to unilateral pulsatile cranial pain, sensitivity to sensations of light, sound, and smell, nausea events.

[0194] In some embodiments, the neuromodulation device is applied to both wrists / arms and / or both ears to bilaterally stimulate nerves in the wrists and / or arms and / or ears. In some embodiments, two bilateral neuromodulation devices (e.g., in both ears and / or on both wrists) can operate simultaneously to stimulate the target nerves simultaneously. The stimulation parameters of each device can be the same or different. The two devices can communicate wirelessly to synchronize or offset the waveforms between the devices. In some embodiments, the two bilateral neuromodulation devices can operate in an alternating manner such that only one device delivers stimulation at a time. The alternating devices can alternate stimulation hourly, daily, weekly, or monthly; and the frequency of alternation can be modified based on sensor measurements.

[0195] Treatment via an acute relief pathway and / or a prophylactic treatment pathway

[0196] In some embodiments, a method framework for treating rheumatoid arthritis, atrial fibrillation, or migraine using peripheral nerve stimulation includes multiple treatment paths (e.g., two or more paths): (a) an acute relief path, and / or (b) a prophylactic treatment path. In one embodiment, the treatment framework and each treatment path can be executed by applying peripheral nerve stimulation via a wrist-worn neuromodulation device, an ear neuromodulation device, or any combination of a wrist-worn device and an ear device.

[0197] In one embodiment, the first treatment path is an acute relief path consisting of two phases: a detection phase and a treatment delivery phase. In one embodiment, the detection phase is the phase of the method for identifying a rheumatoid arthritis episode or an atrial fibrillation or a migraine acute episode. The occurrence of these acute events can be detected by a certain sensor measuring a biomarker indicating the in-vivo condition, or can be self-reported by the user. After detecting an acute attack, the treatment delivery phase is initiated by the neuromodulation device 800. In one embodiment, the treatment delivery phase can be initiated by a prompt on the neuromodulation device for the user to initiate treatment delivery, or it can be automatically initiated by the processor 808 and the controller or the stimulation circuit 804 within the neuromodulation device 800 once a certain sensor threshold is reached. In one embodiment, this can also be determined by a machine learning algorithm, an evolutionary algorithm, or some other form of artificial intelligence. The measured biomarker can include any one or more of the following: heart rate, heart rate variability, heart rhythm, cutaneous sympathetic nerve activity, skin electrical activity, body temperature measured on the wrist or ear, respiratory cycle, electroencephalogram activity, and / or cytokine level.

[0198] In one embodiment, the threshold of the heart rate can be as low as at least 90 beats per minute. In one embodiment, the threshold of the heart rate variability can be as low as 1. However, these thresholds and any thresholds may vary from patient to patient. In one embodiment, the electrical stimulation for treatment delivery can be delivered in the form of pulse bursts. The frequency range of these bursts can be 0 - 150 Hz (e.g., 1, 10, 20, 25, 40, 50, 60, 75, 90, 100, 110, 120, 125, 140, 150 Hz and the values and ranges therein), and the frequency range of the pulses can be 0 - 15 Hz (e.g., 1, 2, 4, 6, 8, 10, 12, 13, 15 Hz and the values and ranges therein).

[0199] In one embodiment, as Figure 10 shown, the framework involves cardiac measurement tasks, acute relief treatment, and preventive treatment. In one embodiment, the cardiac measurement tasks include the user performing a 90 - second heart rate and HRV measurement task via PPG while remaining stationary. The time range of these heart rate or HRV measurement tasks can be 0 - 10 minutes (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 minutes and the values and ranges therein). These tasks are performed when the user is most prone to atrial fibrillation attacks (e.g., after waking up in the morning). No strenuous physical activity should be performed within 10 minutes or more before the measurement. The PPG sensor can optionally be integrated into the stimulator 800, the base station, or the accessory device.

[0200] In one embodiment, if the heart rate is abnormally high (e.g., over 100 bpm), acute relief treatment is initiated to consider whether the user may be in atrial fibrillation. The user is delivered one or more 15-minute stimulation sessions, interspersed with cardiac measurement tasks, until the heart rate returns to normal. The duration of these stimulation sessions ranges from 0 - 120 minutes (e.g., 1.0, 5.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 minutes and values and ranges therein). During initial use, amplitude ramping up to the next session (between the felt amplitude and the maximum tolerable amplitude) is performed starting from one session. In some embodiments, a relatively low stimulation amplitude is employed.

[0201] In one embodiment, if the HRV (LF:HF ratio) is abnormally high (e.g., the ratio is greater than or equal to 2, or is a patient-specific measurement value, the user may be pre-atrial fibrillation), preventive treatment is initiated. The user is delivered one or more stimulation sessions, interspersed with cardiac measurement tasks, until the heart rate (LF:HF) returns to normal. During initial use, amplitude ramping up to the next session (between the felt amplitude and the maximum tolerable amplitude) is performed starting from one session. In some embodiments, a relatively high stimulation amplitude is employed.

[0202] In one embodiment, a method senses biomarkers associated with rheumatoid arthritis, atrial fibrillation, or migraine and provides electrical stimulation based on the sensed biomarker levels. In various embodiments, the method incorporates various types of devices and sensors, including one or more of the following: a wrist-worn device, an ear device, other peripheral nerve stimulation devices, an intra-ear photoplethysmography sensor, an electrocardiogram, a temperature sensor, an acoustic sensor (e.g., a microphone), a thermal camera, an infrared reflection or transmission light monitor, an intra-ear electroencephalogram, or other sensors.

[0203] Respiratory-gated auricular vagus nerve afferent stimulation

[0204] In various embodiments as Figures 11 - 15C shown, the neuromodulation device 800 and system include an ear device 100 that delivers electrical stimulation to the auricular branch of the vagus nerve. The system consists of an electrical stimulation pulse generator (stimulator) that delivers electrical stimulation pulses to the earpiece and electrodes, and thus to the desired nerve. In one embodiment, as Figure 11 and Figure 12As shown, the ear device 100 includes earphones similar to earbuds, having two electrodes extending from the top of the earbud / earphone's protective cover 165. In one embodiment, these electrodes are capable of stimulating the auricular branch of the vagus nerve. In one embodiment, the earphones further include at least one sensor for measuring biomarkers of the user's physiological state and a controller for receiving this information to adjust the stimulation parameters.

[0205] In one embodiment, the system is configured to deliver stimulation continuously or in pulses with a pulse frequency range of 1 - 100 Hz. In one embodiment, the stimulator can have a circular "disc-like" form factor and can be attached to a strap, shirt, or some other garment article by a clip. In one embodiment, the stimulator can also be integrated into the earphones, such that the earphones are similar to hearing aids.

[0206] In one embodiment, as Figure 13 shown, an additional stimulation device can be added to the system. The device can be a watch-like device worn on the wrist, as disclosed in PCT / US2022 / 074376 and the entire content of which is incorporated by reference as part of this disclosure. This watch-like device delivers electrical stimulation to the peripheral nerves of the wrist and includes a band with integrated dry electrodes. The electrodes in the band include two rows of three electrodes, where the central electrode in each row is a charge-balanced electrode and the electrodes on either side of the central electrode are stimulation electrodes. The device will deliver bursts of electrical stimulation from a stimulator integrated into the device. The device can include a user interface that includes an electronic ink display on the surface of the watch-like device. It can also include a base station to charge the device and house the device.

[0207] Figures 14A - 14B A neuromodulation device for delivering electrical stimulation to the auricular branch of the vagus nerve according to various embodiments of the present disclosure is shown. Figures 15A - 15CA neuromodulation device for delivering electrical stimulation to the auricular branch of the vagus nerve in accordance with various embodiments of the present disclosure is shown. In one embodiment, various sensors 812 are incorporated into the system to measure various biomarkers. In one embodiment, one such sensor can be a photoplethysmography sensor and the biomarker measured is heart rate or heart rate variability. Another sensor can be an electrocardiogram and the biomarker heart rhythm. Such an EKG can be integrated into a watch-like device, or into a base station, or into a patch worn on the user's body. Another sensor can be a sensor for detecting biomarkers of skin sympathetic nerve activity. One of the previously mentioned sensors can also potentially detect skin electrical activity or skin temperature. Another potential sensor can be a mechanical sensor integrated into a strap worn around the chest to detect changes in the respiratory cycle. Another sensor can be a microphone worn in the ear to detect changes in the user's respiratory cycle. Another sensor can measure the temperature of the ear. Another sensor can be an infrared reflection light monitor integrated into headphones to detect changes in the user's respiratory cycle. Another potential sensor can be an electroencephalogram integrated into headphones to measure brain activity. Another potential sensor can measure cytokine levels in the body and be integrated into the stimulator device, skin patch, or strap.

[0208] In one embodiment, the electrical stimulator device can communicate wirelessly with the previously described strap respiratory sensor and deliver electrical stimulation to the headphones via a catheter (wire). In this system, the headphones can be a silicone protective cover 165 placed at the entrance of the ear canal, or it can also be a clamp attached to the helix of the ear and including a reflective or transmissive photoplethysmography sensor.

[0209] In one embodiment, the system can be used to provide acute treatment to users suffering from migraines, colitis, irritable bowel disease, rheumatoid arthritis, hypertension, atrial fibrillation episodes or other arrhythmias or pathologies. It can also be used to prevent future atrial fibrillation episodes or other arrhythmia episodes. In one embodiment, the device includes headphones containing electrodes, an electrical pulse generator, and at least one sensor. The pulse generator delivers electrical pulses to the electrodes to stimulate the auricular branch of the vagus nerve. Stimulating this nerve can bring various therapeutic benefits, including the treatment of atrial fibrillation or other arrhythmias, colitis, rheumatoid arthritis, migraines, irritable bowel disease, hypertension. The present invention can be used in series with other neuromodulation devices (e.g., a neuromodulation device worn on the wrist) to enhance the therapeutic benefits.

[0210] Algorithm for detecting inspiratory and expiratory phases of respiration

[0211] In various embodiments, Figures 16 - 17An algorithm for determining a person's current respiratory phase and when the respiratory phase begins or ends is shown. In various embodiments, the algorithm can be used in a variety of applications, including but not limited to: respiratory gating for peripheral nerve stimulation, underwater breathing equipment, aerospace training, sports training, sleep apnea, diagnosis of irregular breathing conditions, meditation, and treatment of anxiety conditions.

[0212] In one embodiment, a method for determining a user's respiratory phase includes using a sensor for detecting and measuring respiration. The sensor produces a certain quantitative measurement related to the user's respiratory state. Then the controller receives this value from the sensor and applies an algorithm that uses various parameters to determine whether the person is inhaling or exhaling.

[0213] In one embodiment, one such parameter that the algorithm utilizes is a respiration threshold. This threshold is the minimum magnitude difference between two sample values obtained from the sensor.

[0214] In one embodiment, a second potential type of parameter can be a sample check count. The sample check count is the minimum number of consecutive samples that need to be checked to consider whether the user has switched from one respiratory phase to another (e.g., from inhalation to exhalation).

[0215] In one embodiment, a third potential type of parameter may be a respiration slope threshold. The respiration slope threshold is the minimum slope value assigned to the change from one respiratory phase to another (e.g., from inhalation to exhalation).

[0216] In one embodiment, a fourth potential parameter can be a lock-in length. The lock-in length is the minimum amount of time that the algorithm pauses. The algorithm may also include a genetic evolution algorithm, a machine learning algorithm, or some other algorithm based on artificial intelligence. In these cases, the algorithm may rely on as few as zero parameters to determine the user's respiratory phase.

[0217] In one embodiment, the respiratory state is determined via the respiration threshold through respiratory data. The amplitude distance between samples is a metric for considering state changes. Optionally, adaptive respiration or sustained respiration is considered.

[0218] In one embodiment, the respiratory state is determined via the sample check count through respiratory data. The number of consecutive samples for triggering a change in respiratory state, incrementing or decrementing according to a response threshold.

[0219] In one embodiment, the respiratory state is determined via the respiration slope threshold through respiratory data. The absolute amplitude change between the first sample and the last sample of the sample check count to trigger a change in respiratory state.

[0220] In one embodiment, the respiratory state is determined via the respiratory data by way of a lock-in length. The number of samples before another respiratory state change can occur after one respiratory state change.

[0221] Figure 17 A flowchart showing an embodiment of the algorithm is presented. In various embodiments, a method for determining a user's respiratory cycle includes: a sensor for detecting and measuring respiration to generate sample values; and a controller that receives the values from the sensor and applies an algorithm that utilizes various parameters to determine whether a person is exhaling or inhaling.

[0222] In one embodiment, one of the parameters utilized by the algorithm is a respiration threshold, where the respiration threshold is the minimum amplitude difference between two sample values. In one embodiment, one of the parameters utilized by the algorithm is a sample inspection count, where the sample inspection count is the minimum number of consecutive samples that need to be inspected to account for whether the user has switched from one respiratory cycle to another. In one embodiment, one of the parameters utilized by the algorithm is a respiration slope threshold, where the respiration slope threshold is the minimum slope value required to assign a change from one respiratory cycle to another. In one embodiment, one of the parameters utilized by the algorithm is a lock-in length, where the lock-in length is the minimum amount of time the algorithm pauses. In one embodiment, a transition from one respiratory cycle to another is from inhalation to exhalation.

[0223] Other considerations and terms

[0224] Conditional terms used herein, such as "can", "could", "might", "may", "for example", etc., unless specifically stated otherwise or otherwise understood in the context in which they are used, are generally intended to convey that certain features, elements, and / or steps are optional. Thus, such conditional terms are generally not intended to imply that the features, elements, and / or steps are necessary in any way, nor are they intended to imply that one or more embodiments necessarily include logic for determining (with or without other input or cues) whether these features, elements, and / or steps are included or are to be performed in total. The terms "comprising", "including", "having", etc. are synonymous and are used inclusively in an open-ended manner without excluding additional elements, features, acts, operations, etc. Further, the term "or" is used in its inclusive sense (and not in its exclusive sense) such that when used in conjunction with a list of elements, for example, the term "or" means one, some, or all of the elements in the list. Additionally, the term "each" used herein, in addition to having its ordinary meaning, can also mean any subset of the group of elements to which the term "each" applies.

[0225] Unless otherwise specifically set forth, a conjunctive term such as the phrase "at least one of X, Y, and Z" shall be understood in the context in which it is used as generally conveying that an item, term, etc. can be any one of X, Y, or Z. Thus, such conjunctive terms are not generally intended to imply that certain embodiments require the presence of at least one of X, at least one of Y, and at least one of Z.

[0226] Degree terms used herein, such as the terms "about", "approximately", "generally", and "substantially" as used herein, indicate that a value, quantity, or property that is close to the stated value, quantity, or property still performs the desired function or achieves the desired result. For example, the terms "about", "approximately", "generally", and "substantially" can refer to a quantity that falls within the following ranges: less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated quantity. As another example, in certain embodiments, the terms "generally parallel" and "substantially parallel" refer to a value, quantity, or property that deviates from exact parallelism by less than or equal to 10 degrees, 5 degrees, 3 degrees, or 1 degree. As another example, in certain embodiments, the terms "generally perpendicular" and "substantially perpendicular" refer to a value, quantity, or property that deviates from exact perpendicularity by less than or equal to 10 degrees, 5 degrees, 3 degrees, or 1 degree. The terms "about", "approximately", "generally", and "substantially" include the number following such terms. For example, "about 10 mm" includes support for the value 10 mm.

[0227] Although certain embodiments and examples have been described herein, those skilled in the art will understand that many aspects of the systems and devices shown and described in this disclosure can be differently combined and / or modified to form further embodiments or acceptable examples. All such modifications and variations are intended to be included within the scope of this disclosure. A variety of designs and methods are possible. None of the features, structures, or steps disclosed herein are essential.

[0228] Any method disclosed herein need not be performed in the order set forth. The methods disclosed herein can include certain acts by a practitioner; however, they can also include any third-party instructions for such acts, whether explicit or implicit.

[0229] The methods and tasks described herein can be performed by a computer system and fully automated. In some cases, the computer system can include multiple different computers or computing devices (e.g., physical servers, workstations, storage arrays, cloud computing resources, etc.) that communicate and interoperate over a network to perform the described functions. Each such computing device generally includes a processor (or processors) that executes program instructions or modules stored in a memory or other non-transitory computer-readable storage medium or device (e.g., solid-state storage device, disk drive, etc.). The various functions disclosed herein can be embodied in such program instructions and / or can be implemented in the dedicated circuitry (e.g., ASIC or FPGA) of the computer system. In cases where the computer system includes multiple computing devices, these devices can, but need not, be located at the same location. The results of the disclosed methods and tasks can be persistently stored by converting physical storage devices such as solid-state memory chips and / or disks into different states. The computer system can be a cloud-based computing system whose processing resources are shared by multiple different commercial entities or other users.

[0230] Depending on the embodiment, certain actions, events, or functions of any process or algorithm described herein can be executed in a different sequence, can be added, combined, or all omitted (e.g., not all described operations or events are necessary for the practice of the algorithm). Additionally, in some embodiments, operations or events can be executed simultaneously, rather than sequentially, for example, by multithreading, interrupt processing, or multiple processors or processor cores, or on other parallel architectures.

[0231] The various illustrative logical blocks, modules, routines, and algorithm steps described in connection with the disclosure herein can be implemented as electronic hardware (e.g., ASIC or FPGA devices), computer software running on general-purpose computer hardware, or a combination of both. The various illustrative components, blocks, and steps can be described generally herein in terms of their functionality. Whether such functionality is implemented as dedicated hardware or as software running on general-purpose hardware depends on the particular application and the design constraints imposed on the overall system. For each particular application, the described functionality can be implemented in different ways, but such implementation decisions should not be construed as causing a departure from the scope of the disclosure.

[0232] In addition, each of the illustrative logical blocks and modules described in connection with the disclosure herein can be implemented or performed by a machine, such as a general-purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor device can be a microprocessor, but in the alternative, the processor device can be a controller, a microcontroller, or a state machine, combinations thereof, or the like. The processor device can include circuitry configured to process computer-executable instructions. The processor device can include an FPGA or other programmable device that performs logic operations without processing computer-executable instructions. The processor device can also be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, multiple microprocessors, the combination of one or more microprocessors and a DSP core, or any other such configuration. Although described primarily in connection with digital technology herein, the processor device can also include primarily analog components. For example, some or all of the rendering techniques described herein can be implemented in analog circuitry or in hybrid analog and digital circuitry. The computing environment can include any type of computer system, including but not limited to a microprocessor-based computer system, a mainframe computer, a digital signal processor, a portable computing device, a device controller, or a computing engine within an appliance, to name a few.

[0233] Elements of any method, process, routine, or algorithm described in connection with the disclosure herein can be embodied directly in hardware, in a software module executed by a processor device, or in a combination of both. The software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, a hard disk, a removable disk, a CD-ROM, or any other form of non-transitory computer-readable storage medium. An example storage medium can be coupled to the processor device such that the processor device can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integrated into the processor device. The processor device and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. In the alternative, the processor device and the storage medium can reside as discrete components in the user terminal.

[0234] Although the foregoing detailed description has shown, described, and pointed out novel features, it will be understood that various omissions, substitutions, and changes in the form and details of the device or algorithm shown can be made without departing from the spirit of the present disclosure. As will be recognized, some portions of the description herein can be embodied in a form that does not provide all of the features and benefits set forth herein, since some features can be used or practiced separately from other features. The scope of some embodiments disclosed herein is indicated by the appended claims rather than the foregoing description. All changes that fall within the meaning and scope of the claims are embraced within their scope.

Claims

1. A neuromodulation system, comprising: a headset and an electrical stimulation pulse generator, wherein the electrical stimulation pulse generator is configured to deliver a plurality of electrical stimulation pulses to the headset, wherein the headset is configured to be placed in a user's ear, and the headset includes: a protective cover configured to be placed on the concha of the ear; a first electrode extending from the protective cover; a second electrode extending from the protective cover; a first pressure applicator including a first spring-loaded actuating surface connected to the first electrode; and a second pressure applicator including a second spring-loaded actuating surface connected to the second electrode; wherein the first electrode and the second electrode are configured to deliver the plurality of electrical stimulation pulses to stimulate the auricular branch of the vagus nerve, wherein the first pressure applicator is configured to bias the first electrode in a first direction toward the ear by increasing a first pressure level at the first electrode against the ear to reduce a first impedance between the first electrode and the ear, and wherein the second pressure applicator is configured to bias the second electrode in a second direction toward the ear by increasing a second pressure level at the second electrode against the ear to reduce a second impedance between the second electrode and the ear.

2. The neuromodulation system according to claim 1, further comprising: one or more sensors that measure biomarkers, wherein the biomarkers indicate the condition of the user, and wherein the first electrode and the second electrode are configured to deliver the plurality of electrical stimulation pulses to treat the condition.

3. The neuromodulation system according to claim 1, wherein the protective cover includes silicone and is configured to be placed at the entrance of the ear canal, and wherein the headset includes a clip configured to be attached to the helix of the ear.

4. The neuromodulation system according to claim 1, wherein the electrical stimulation pulse generator is integrated into the headset.

5. A neuromodulation system, comprising: a headset in communication with an electrical stimulation pulse generator, wherein the headset is configured to be placed in or around the ear, and the headset includes: a protective cover configured to be placed in or around the ear; two electrodes extending from the protective cover; a pressure applicator including an actuating surface connected to at least one of the two electrodes; and wherein at least one of the two electrodes delivers electrical stimulation pulses to stimulate the auricular branch of the vagus nerve, and wherein the pressure applicator is configured to bias at least one of the two electrodes in a direction toward the ear by increasing the pressure at at least one of the two electrodes against the ear to reduce the impedance between at least one of the two electrodes and the ear.

6. The neuromodulation system according to claim 5, further comprising: one or more sensors that measure biomarkers, wherein the biomarkers indicate the condition of the user, and At least one of the two electrodes is configured to deliver the electrical stimulation pulses to treat the condition.

7. The neuromodulation system according to any one of claims 1-6, wherein the plurality of electrical stimulation pulses are configured to provide treatment to a user suffering from migraine, colitis, irritable bowel disease, rheumatoid arthritis, hypertension, or atrial fibrillation.

8. The neuromodulation system according to any one of claims 1-6, wherein the electrical stimulation pulse generator includes a clamp configured to be attached to a clothing article.

9. The neuromodulation system according to any one of claims 1-6, wherein the first pressure applicator is configured to deliver a first pressure in the range of 2-3 N.

10. The neuromodulation system according to any one of claims 1-6, wherein the first pressure applicator is configured to deliver a first pressure in the range of 0.01-1 N.

11. The neuromodulation system according to any one of claims 1-6, wherein the first pressure applicator is configured to deliver a first pressure in the range of 0.01-5 N.

12. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors are integrated into any one of the following: the earphone, the skin patch, and the strip.

13. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors include reflectance or transmittance photoplethysmography sensors.

14. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors include a microphone worn in the ear to detect changes in the breathing cycle of the user.

15. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors measure the temperature in the ear.

16. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors include an infrared reflectance monitor integrated into the earphone to detect changes in the breathing cycle of the user.

17. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors include an electroencephalogram integrated into the earphone to measure brain activity.

18. The neuromodulation system according to any one of claims 2-4 or 6, wherein the one or more sensors measure cytokine levels in the body and are integrated into the earphone, the skin patch, or the strip.

19. The neuromodulation system according to any one of claims 2-4 or 6, wherein the biomarker is at least one of heart rate and heart rate variability.

20. The neuromodulation system according to any one of claims 2-4 or 6, wherein the biomarker is heart rhythm.

21. The neuromodulation system according to any one of claims 2-4 or 6, wherein the biomarker is skin electrical activity.

22. The neuromodulation system according to any one of claims 2-4 or 6, wherein the biomarker is breathing cycle or body activity.

23. The neuromodulation system according to any one of claims 2-4 or 6, wherein the biomarker is a cytokine level.

24. A neuromodulation system, comprising: a headset in communication with an electrical stimulation pulse generator, the headset being configured to be placed in or around an ear, the headset comprising: a protective cover configured to be positioned in or around the ear; two electrodes extending from the protective cover; at least one pressure applicator comprising an actuating surface connected to at least one of the two electrodes; and wherein at least one of the two electrodes delivers an electrical stimulation pulse to stimulate one or more nerves innervating the ear, wherein the at least one pressure applicator is configured to bias at least one of the two electrodes in a direction towards the ear by increasing the pressure level at at least one of the two electrodes against the ear to increase the electrical conductivity between at least one of the two electrodes and the ear.

25. A neuromodulation method for treating rheumatoid arthritis, atrial fibrillation or migraine using a biomarker, comprising: positioning a first electrode against a patient's skin near a first peripheral nerve; positioning a second electrode against the patient's skin near the first peripheral nerve or a second peripheral nerve; sensing the level of a biomarker associated with rheumatoid arthritis, atrial fibrillation or migraine; if the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation or migraine, delivering a first electrical stimulation via the first electrode and the second electrode to provide acute relief treatment; and if the sensed level indicates that the user is in an episode of rheumatoid arthritis, atrial fibrillation or migraine, delivering a second electrical stimulation via the first electrode and the second electrode to provide symptom alleviation treatment, wherein the value of the stimulation modality parameter of the first electrical stimulation is different from the value of the stimulation modality parameter of the second electrical stimulation.

26. The method according to claim 25, wherein the stimulation modality parameter is amplitude, and wherein the value of the stimulation modality parameter of the first electrical stimulation is lower than the value of the stimulation modality parameter of the second electrical stimulation.

27. The method according to claim 25, wherein a machine learning algorithm is used to evaluate when to start the treatment delivery phase at least based on the sensed level of the biomarker.

28. The method according to claim 25, wherein a predetermined threshold of heart rate is greater than 90, 100, 110 or 120 beats per minute, and when the sensed level exceeds the predetermined threshold, the acute relief treatment is applied.

29. The method according to claim 25, wherein a predetermined threshold of heart rate variability is greater than 1, 2, 3, 4 or 5, and wherein when the sensed level exceeds the predetermined threshold, the treatment is applied.

30. The method according to claim 25, wherein the predetermined threshold is determined on a case-by-case basis and varies from patient to patient.

31. The method according to any one of claims 25 - 30, wherein the stimulation modality parameter is frequency.

32. The method according to any one of claims 25 - 30, wherein the stimulation modality parameter is pulse width.

33. The method according to any one of claims 25 - 30, wherein the first electrode and the second electrode are disposed on a neuromodulation device configured as a wrist - worn device.

34. The method according to any one of claims 25 - 30, wherein the first electrode and the second electrode are disposed on a neuromodulation device configured to be worn in or near the ear.

35. The method according to any one of claims 25 - 30, wherein one of the first electrode and the second electrode is configured to be disposed on the user's wrist and the other of the first electrode and the second electrode is configured to be worn in or near the ear.

36. The method according to any one of claims 25 - 30, wherein the sensing of the level of the biomarker occurs during a detection phase, and wherein the acute relief treatment and the treatment occur during a treatment delivery phase and after the detection phase.

37. The method according to claim 36, wherein the sensing of the level of the biomarker is performed by one or more sensors, and wherein the first electrode, the second electrode, and the one or more sensors are integrated into a neuromodulation device.

38. The method according to claim 36, wherein the detection phase is performed by a patient's self - reporting of symptoms.

39. The method according to claim 36, wherein the treatment delivery phase is initiated by instructing the user to initiate delivery of the first electrical stimulation to provide the acute relief treatment or delivery of the second electrical stimulation to provide the treatment.

40. The method according to claim 36, wherein the treatment delivery phase is automatically initiated after the sensed level indicates that the user is experiencing rheumatoid arthritis, atrial fibrillation, or migraine, or that the user is in the onset of experiencing rheumatoid arthritis, atrial fibrillation, or migraine.

41. The method according to any one of claims 25 - 30, wherein at least one of the first electrical stimulation or the second electrical stimulation is delivered in the form of a pulse burst.

42. The method according to claim 41, wherein the burst frequency of the stimulation is any value between 0 Hz and 15 Hz or between 4 Hz and 12 Hz.

43. The method according to claim 41, wherein the pulse frequency of the stimulation is any value between 0 Hz and 200 Hz or between 50 Hz and 150 Hz.

44. A neuromodulation method for treating rheumatoid arthritis, atrial fibrillation, or migraine, comprising: positioning a first electrode against the patient's skin near a first peripheral nerve; positioning a second electrode against the patient's skin near the first peripheral nerve or a second peripheral nerve; Sensing a level of a biomarker associated with rheumatoid arthritis, atrial fibrillation, or migraine, wherein the biomarker is heart rate; and If the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation, or migraine, delivering electrical stimulation via the first electrode and the second electrode to provide acute relief treatment.

45. A neuromodulation method for treating rheumatoid arthritis, atrial fibrillation, or migraine, comprising: Positioning a first electrode against the patient's skin near a first peripheral nerve; Positioning a second electrode against the patient's skin near the first peripheral nerve or a second peripheral nerve; Sensing a level of a biomarker associated with rheumatoid arthritis, atrial fibrillation, or migraine, wherein the biomarker is heart rate variability; and If the sensed level indicates that the user is in an episode of rheumatoid arthritis, atrial fibrillation, or migraine, delivering electrical stimulation via the first electrode and the second electrode to provide symptom relief treatment.

46. The method according to claim 44 or 45, wherein the electrical stimulation is delivered in the form of a burst of pulses.

47. The method according to claim 46, wherein the burst frequency of the stimulation is any value between 0 Hz and 15 Hz or between 4 Hz and 12 Hz.

48. The method according to claim 46, wherein the pulse frequency of the stimulation is any value between 0 Hz and 200 Hz or between 50 Hz and 150 Hz.

49. The method according to claim 46, wherein the burst frequency of the stimulation is any value between 0 Hz and 15 Hz or between 1 Hz and 14 Hz.

50. The method according to claim 46, wherein the pulse frequency of the stimulation is any value between 0 Hz and 150 Hz or between 1 Hz and 149 Hz.

51. A neuromodulation method for treating rheumatoid arthritis, atrial fibrillation, or migraine, comprising: Positioning a first electrode against the patient's skin near a first peripheral nerve; Positioning a second electrode against the patient's skin near the first peripheral nerve or a second peripheral nerve; Sensing a level of a biomarker associated with rheumatoid arthritis, atrial fibrillation, or migraine; If the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation, or migraine, delivering a first electrical stimulation via the first electrode and / or the second electrode to one or more targeted first nerves to provide acute relief treatment; and If the sensed level indicates that the user has rheumatoid arthritis, atrial fibrillation, or migraine, delivering a second electrical stimulation via the first electrode and / or the second electrode to one or more targeted second nerves to provide symptom relief treatment, wherein at least one nerve of the one or more targeted first nerves or at least one nerve of the one or more targeted second nerves is not common to both the one or more targeted first nerves and the one or more targeted second nerves.

52. The method according to claim 51, wherein the value of the stimulation modality parameter of the first electrical stimulation is different from the value of the stimulation modality parameter of the second electrical stimulation.

53. The method according to claim 51, wherein the value of the stimulation modality parameter of the first electrical stimulation is the same as the value of the stimulation modality parameter of the second electrical stimulation.

54. A neuromodulation system, comprising: An electrical stimulation pulse generator that delivers electrical stimulation pulses to a headset placed in the ear, the headset comprising: Two electrodes extending from the top of the protective cover, the two electrodes being disposed on the concha of the ear to stimulate the auricular branch of the vagus nerve; and A pressure applicator configured to bias at least one of the two electrodes in a direction towards the ear; One or more sensors that measure data of one or more biomarkers of the physiological state of the user; and A controller that receives and uses the measured data to adjust one or more stimulation parameters of the electrical stimulation pulses.

55. The neuromodulation system according to claim 54, wherein one of the sensors measures the cytokine level in the body and is integrated into the headset, skin patch or strip.

56. The neuromodulation system according to claim 54, wherein the pressure applicator is configured to increase the pressure level applied by the two electrodes against the ear to reduce the impedance between the two electrodes and the ear.

57. The neuromodulation system according to claim 54, wherein the pressure applicator is a spring-loaded actuating surface.

58. The neuromodulation system according to claim 54, wherein the electrical stimulation pulses are delivered at a pulse frequency of 1 Hz to 100 Hz.

59. The neuromodulation system according to claim 54, wherein the electrical stimulation is delivered continuously.

60. The neuromodulation system according to claim 54, wherein the electrical stimulation pulse generator has a circular form factor and is attached to a certain clothing article via a clamp.

61. The neuromodulation system according to claim 54, wherein the electrical stimulation pulse generator is integrated into the headset to include a device with an appearance similar to a hearing aid.

62. The neuromodulation system according to any one of claims 54-61, further comprising a watch-like wrist-worn stimulation device that delivers electrical stimulation to the peripheral nerve located in the wrist, the watch-like wrist-worn stimulation device comprising: A band that contains two rows of three electrodes, wherein: The central electrode of each row is a stimulation electrode; The electrodes on either side of the central electrode are charge-balancing electrodes; A second electrical stimulation pulse generator that is worn on the wrist and delivers electrical stimulation pulse bursts to the electrodes on the band; A user interface that includes a display on the surface of the watch-like wrist-worn stimulation device; and A base station configured to charge the watch-like wrist-worn stimulation device and accommodate the watch-like wrist-worn stimulation device.

63. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is a photoplethysmography sensor and the measured biomarker is heart rate or heart rate variability.

64. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is an electrocardiogram and the biomarker is heart rhythm.

65. The neuromodulation system according to claim 64, wherein the electrocardiogram is integrated into the stimulator of the wrist - worn stimulation device.

66. The neuromodulation system according to claim 64, wherein the electrocardiogram is integrated into the base station.

67. The neuromodulation system according to claim 64, wherein the electrocardiogram is integrated into a patch to be worn on the user's body.

68. The neuromodulation system according to any one of claims 54 - 61, wherein one of the above - mentioned sensors is a sensor for detecting the biomarker of skin sympathetic nerve activity.

69. The neuromodulation system according to any one of claims 54 - 61, wherein one of the above - mentioned sensors is a sensor for detecting skin electrical activity.

70. The neuromodulation system according to any one of claims 54 - 61, wherein one of the above - mentioned sensors is a sensor for detecting skin temperature.

71. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is a mechanical sensor integrated into a strap worn around the chest, and the mechanical sensor detects changes in the respiratory cycle.

72. The neuromodulation system according to any one of claims 54 - 61, wherein the electrical stimulation pulse generator wirelessly communicates with the strap respiratory sensor and delivers electrical stimulation to the earpiece via a catheter.

73. The neuromodulation system according to claim 72, wherein the earpiece is a silicone protector placed at the entrance of the ear canal.

74. The neuromodulation system according to claim 72, wherein the earpiece is a clamp attached to the helix of the ear and includes a reflectance or transmittance photoplethysmography sensor.

75. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is a microphone worn in the ear to detect changes in the user's respiratory cycle.

76. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors measures the temperature in the ear.

77. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is an infrared reflection light monitor integrated into the earpiece to detect changes in the user's respiratory cycle.

78. The neuromodulation system according to any one of claims 54 - 61, wherein one of the sensors is an electroencephalogram integrated into the earpiece to measure brain activity.

79. The neuromodulation system according to any one of claims 54-61, wherein the system is for providing acute treatment to a user suffering from migraine, colitis, irritable bowel disease, rheumatoid arthritis, hypertension, atrial fibrillation episodes or other arrhythmias or pathologies.

80. The neuromodulation system according to any one of claims 54-61, wherein the system is for alleviating the symptoms of future episodes of atrial fibrillation or episodes of other arrhythmias.

81. A system for determining a user's respiratory phase, comprising: a sensor for detecting and measuring a quantitative value generally related to the user's respiratory phase, wherein the quantitative value is one or more of a respiratory threshold, a sample inspection count, a respiratory slope threshold, and a lock-in length; and a controller configured to: apply an algorithm to the quantitative value; and determine the user's respiratory phase based on the application of the algorithm to the quantitative value.

82. The system according to claim 81, wherein the quantitative value is the respiratory threshold, and wherein the respiratory threshold is the minimum magnitude difference between two sample values.

83. The system according to claim 81, wherein the quantitative value is the sample inspection count, and wherein the sample inspection count is the minimum number of consecutive samples to be inspected to consider whether the user has switched from one respiratory phase to another.

84. The system according to claim 81, wherein the quantitative value is the respiratory slope, and wherein the respiratory slope threshold is the minimum slope value for the assigned change from one respiratory phase to another.

85. The system according to claim 81, wherein the quantitative value is the lock-in length, and wherein the lock-in length is the minimum amount of time during which the algorithm pauses.

86. The system according to any one of claims 81-85, wherein the determined respiratory phase is an inhalation phase or an exhalation phase.

87. A method for reducing the dosage of a drug treatment with neurostimulation and a medicament, comprising: positioning a first electrode adjacent to a first peripheral nerve against the skin in a patient's ear; positioning the second electrode adjacent to the first peripheral nerve or a second peripheral nerve against the patient's skin; delivering electrical stimulation via the first electrode and the second electrode to provide a neurostimulation treatment; wherein the neurostimulation treatment synergistically reduces the dosage of the drug treatment using the medicament and / or reduces the duration of the drug treatment using the medicament; and further comprising one or more of the following: (i) positioning a headset in the ear, wherein the headset includes a first electrode, a second electrode, and a pressure applicator, and wherein the pressure applicator is configured to bias at least one of the first electrode and the second electrode in a direction toward the ear; (ii) a sensor for detecting and measuring a quantitative value generally related to the user's respiratory phase, wherein the quantitative value is one or more of a respiratory threshold, a sample inspection count, a respiratory slope threshold, and a lock-in length, and a controller configured to apply an algorithm to the quantitative value; and determining the respiratory phase of the user based on the application of the algorithm to the quantitative value; and (iii) sensing a level of a biomarker associated with rheumatoid arthritis, colitis, atrial fibrillation, or migraine; and if the sensed level indicates that the user has rheumatoid arthritis, colitis, atrial fibrillation, or migraine, delivering a first electrical stimulation via the first electrode and the second electrode to provide acute relief treatment.

88. A method of predicting a patient's responsiveness to additional treatment, the method comprising: positioning the first electrode adjacent to a first peripheral nerve against the skin in the patient's ear; positioning the second electrode adjacent to the first peripheral nerve or a second peripheral nerve against the patient's skin; delivering electrical stimulation via the first electrode and the second electrode to provide a nerve stimulation treatment; sensing the patient's responsiveness to the delivered nerve stimulation treatment; determining whether the patient would be a suitable candidate for additional treatment based on the sensed responsiveness, wherein the additional treatment is selected from one or more of the following: drug therapy, deep brain stimulation, and thalamotomy; and further comprising one or more of the following: (i) positioning a headset within the ear, wherein the headset includes a first electrode, a second electrode, and a pressure applicator, and wherein the pressure applicator is configured to bias at least one of the first electrode and the second electrode in a direction toward the ear; (ii) a sensor for detecting and measuring a quantitative value generally associated with the respiratory phase of the user, wherein the quantitative value is one or more of a respiratory threshold, a sample inspection count, a respiratory slope threshold, and a lock length, and a controller is configured to apply an algorithm to the quantitative value; and determining the respiratory phase of the user based on the application of the algorithm to the quantitative value; and (iii) sensing a level of a biomarker associated with rheumatoid arthritis, colitis, atrial fibrillation, or migraine; and if the sensed level indicates that the user has rheumatoid arthritis, colitis, atrial fibrillation, or migraine, delivering a first electrical stimulation via the first electrode and the second electrode to provide acute relief treatment.

89. The method according to any one of claims 87 and 88, wherein the nerve stimulation treatment reduces side effects of the drug therapy, wherein the side effects are selected from the group consisting of: addiction, tolerance, dependence, gastrointestinal problems, nausea, confusion, movement disorders, and appetite changes.

90. The method according to any one of claims 87 and 88, wherein the drug therapy is used to treat tremors, epilepsy, depression, anxiety, or headache.

91. The method according to any one of claims 87 and 88, wherein the drug therapy is used to treat multiple sclerosis, colitis, Crohn's disease, or functional dyspepsia.

92. The method according to any one of claims 87 and 88, wherein the drug therapy is used to treat rheumatoid arthritis, psoriatic arthritis, psoriasis, or chronic fatigue syndrome.

93. The method according to any one of claims 87 and 88, wherein the agent is an antidepressant, a selective serotonin reuptake inhibitor or an MAO inhibitor.

94. A method of predicting an object's responsiveness to additional treatment, comprising using the device or method according to any one of claims 1-93, wherein such additional treatment is selected from one or more of the following: drug treatment, deep brain stimulation, and thalamotomy.

95. The system and method according to any one of the preceding claims, wherein 1, 2, 3, 4 or 5 additional electrodes are used.

96. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of depression (such as postpartum depression), inflammation (such as neuroinflammation), Lyme disease, neurological diseases (such as Parkinson's disease and Alzheimer's disease), and gastrointestinal problems (including those in Parkinson's disease).

97. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of inflammatory bowel disease (such as Crohn's disease, colitis, and functional dyspepsia), rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, psoriasis, chronic fatigue syndrome, and other inflammatory diseases (such as neuroinflammation).

98. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of cardiac conditions (such as atrial fibrillation, hypertension, and stroke).

99. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of epilepsy and / or seizures.

100. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of headache such as migraine.

101. Use of any of the devices described herein for the alleviation and / or treatment of symptoms of inflammatory skin conditions and immune dysfunction.

102. The device and method for regulating one or more nerves described in the specification.

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